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## **Meet the editor**

Dr Forbes' undergraduate, medical school, and residency training was completed at Creighton University/ University of Nebraska Medical Center in Omaha, Nebraska. He continued his Pediatric Cardiology training at Texas Children's Hospital/Baylor University Medical Center in Houston, Tx and completed a year in interventional cardiology training at Children's Memorial

Hospital/Northwestern University in 1997. He joined Children's Hospital of Michigan/Wayne State University in the fall of 1997. His primary interest is in Congenital/Structural Interventional cardiology, authoring over 50 papers and 2 chapters in this area. He assisted in the development of the Genesis XD stent (Cordis, corp, Warren, NJ) and serves as the coordinating center for the Congenital Cardiovascular Interventional Study Consortium (CCISC), which is currently the largest Pediatric Interventional Consortium group in the world.

Contents

**Preface IX** 

Chapter 2 **Cerebral Hyperperfusion** 

Chapter 1 **Percutaneous Angioplasty and** 

**Stenting for Mesenteric Ischaemia 1**  Emily He and Stephen M. Riordan

D. Canovas, J. Estela, J. Perendreu, J. Branera, A. Rovira, M. Martinez and A. Gimenez-Gaibar

Daniel Brandão, Joana Ferreira, Armando Mansilha

**Altered Function of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 63**  Maria Kurthy, Gabor Jancso, Endre Arato, Laszlo Sinay,

Chapter 5 **Antithrombotic Therapy After Peripheral Angioplasty 89**  Beniamino Zalunardo, Diego Tonello, Fabio Busato, Laura Zotta, Sandro Irsara and Adriana Visonà

Chapter 6 **Evidence-Based Invasive Treatments for Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 105** 

Geoffrey Appelboom, Adam Jacoby, Matthew Piazza

Chapter 7 **Angiography for Peripheral Vascular Intervention 121** 

Chapter 8 **Arterial Angioplasty in Congential Heart Disease 169**  Thomas J. Forbes, Srinath Gowda and Daniel R. Turner

Janos Lantos, Zsanett Miklos, Borbala Balatonyi, Szaniszlo Javor, Sandor Ferencz, Eszter Rantzinger, Dora Kovacs, Viktoria Kovacs, Zsofia Verzar, Gyorgy Weber, Balazs Borsiczky and Erzsebet Roth

**Syndrome After Angioplasty 9** 

and António Guedes Vaz

and E. Sander Connolly

Yoshiaki Yokoi

Chapter 4 **Investigation of the Oxidative Stress, the** 

Chapter 3 **Below the Knee Techniques: Now and Then 41** 

### Contents

#### **Preface XI**

Chapter 1 **Percutaneous Angioplasty and Stenting for Mesenteric Ischaemia 1**  Emily He and Stephen M. Riordan

Chapter 2 **Cerebral Hyperperfusion Syndrome After Angioplasty 9**  D. Canovas, J. Estela, J. Perendreu, J. Branera, A. Rovira, M. Martinez and A. Gimenez-Gaibar

Chapter 3 **Below the Knee Techniques: Now and Then 41**  Daniel Brandão, Joana Ferreira, Armando Mansilha and António Guedes Vaz

Chapter 4 **Investigation of the Oxidative Stress, the Altered Function of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 63**  Maria Kurthy, Gabor Jancso, Endre Arato, Laszlo Sinay, Janos Lantos, Zsanett Miklos, Borbala Balatonyi, Szaniszlo Javor, Sandor Ferencz, Eszter Rantzinger, Dora Kovacs, Viktoria Kovacs, Zsofia Verzar, Gyorgy Weber, Balazs Borsiczky and Erzsebet Roth


### Preface

*"To the patients whom we treat, allowing us to slowly convert the "art of medicine" into the "science of medicine".* 

Most interventional physicians believe that Andrea Gruentzig, who performed the first successful coronary angioplasty in 1977 in Zurich, Switzerland, began the era of less invasive intervention performed via the transcatheter route. At that time, in his first case, utilizing a *kitchen-built* catheter, he successfully performed dilation of an 80% lesion of a 3 mm section of the left anterior descending artery. He presented his first four coronary angioplasty cases at the "1977 American Heart Association" meeting and the rest, they say, was history. Fascinatingly, at the 10-year anniversary of the initial patient, the patient underwent elective repeat angiography which noted that the LAD narrowing remained almost perfectly expanded. Sadly, the German cardiologist, along with his wife, tragically died in a plane crash on October 27, 1985 at the young age of 46. If he was alive today, he would be amazed at the progress being made in the angioplasty arena for the treatment of congenital and acquired vessel stenosis. Dr. Gruentzig's initial foray into the coronary world served as the "launch pad" for the development of ideas and technology in the treatment of peripheral vascular lesions. For quite some time the treatment of coronary artery pathology has lead the way towards the development and treatment of other vascular lesions..

The past three decades has seen an explosion in interventional techniques to treat both congenital and acquired lesions in the vascular system. When I was first asked to edit this book on angioplasty, it came to my surprise that a similar book dealing with the techniques and issues of these congenital and acquired lesions had not been previously undertaken. Certainly individual chapters and reports have been written in these areas, though no formal book discussing the technical as well as current ongoing challenges in these areas have compiled in one setting.

In particular, the past decade has seen a significant advancement in balloon, wire, and catheter technology in the treatment of complicated congenital and acquired vascular lesions. This decade has born witness to the development of angioplasty procedures that many interventionalists had never imagined being able to treat via the transcatheter route, especially in the peripheral arena. The improvement of stent technology, especially regarding tracking capabilities of the newer generation stents,

#### X Preface

have played a significant role in the treatment of tortuous vascular lesions that otherwise were exclusively relegated to be treated in the surgical operating theater.

Preface XI

Wayne State University / Children's Hospital of Michigan, Detroit

**Dr. Thomas Forbes** 

USA

book would never come to fruition. I also would like to thank my lovely wife Marie who, without her dedication to raising nine children (myself included), I would never have had the remote possibility for being able to find the time to undertake this

endeavor.

At first look, in reviewing the topics covered in this book, one's initial impression may be that this is a compilation of multiple different types of lesions and the treatment of these lesions. The common thread linking these procedures together relates to both the technology shared between disciplines, and the common techniques used to treat various lesions throughout the vascular system. A perfect example of this relates to chronic total obstructive lesions in the peripheral vascular system and the technique used to overcome technical challenges of a completely occluded coronary vessel.

One should not consider this textbook is a compendium of obscure interventional procedures. I believe that this textbook represents the greatest growth potential area in much of interventional cardiovascular medicine. For example, as techniques continue to improve regarding re-vascularization if distal extremities, especially in patients with peripheral vasculopathy secondary to diabetes, tens of thousands of patients will benefit from not having to undergo amputation procedures, or at least forestalling the amputation procedure until a much later time. The treatments, whether it be related to carotid stenosis, mesenteric ischemia, neural vascular spasm, or congenital vascular lesions, have the potential of reaching millions of patients every year.

This book also bridges issues related to complications or other challenges related to performing aggressive angioplasty procedures. Whether it be hyperperfusion syndrome following aggressive angioplasty or oxygen stress and altered function of platelets in patients with peripheral arterial vascular disease, not only do interventionalists need to be knowledgeable in the technique in performing an intervention, they also must have a strong understanding of what the potential ramifications are both on an anatomic and molecular level.

To end, this first edition on Angioplasty will hopefully inspire interventionalists to "cross-link" their experience with other interventionalists regarding the techniques used to treat complicated lesions. I personally feel that communication is the most important ally to overcoming challenges in both acquired and congenital vascular lesions. Hopefully this book will inspire this to occur between interventional radiologists, cardiologists, neurologists, and neurosurgeons. I would not be surprised, with the continued explosion of a technology in this area, that revision of this book will be required within the next 7-10 years. Finally, one would be remiss in not giving credit to Warner Forsmann for his insight in the catheterization procedure and, as previously mentioned, Andre Gruentzig in launching us into an interventional era for the treatment of vascular stenosis. On the shoulders of these two giants (and many others) we are able to proceed onto an exciting and changing world of interventional cardiology.

I would like to greatly acknowledge the authors of this book for their time in writing the chapters. Without their dedication to sharing their interventional expertise, this book would never come to fruition. I also would like to thank my lovely wife Marie who, without her dedication to raising nine children (myself included), I would never have had the remote possibility for being able to find the time to undertake this endeavor.

X Preface

cardiology.

have played a significant role in the treatment of tortuous vascular lesions that otherwise were exclusively relegated to be treated in the surgical operating theater.

At first look, in reviewing the topics covered in this book, one's initial impression may be that this is a compilation of multiple different types of lesions and the treatment of these lesions. The common thread linking these procedures together relates to both the technology shared between disciplines, and the common techniques used to treat various lesions throughout the vascular system. A perfect example of this relates to chronic total obstructive lesions in the peripheral vascular system and the technique used to overcome technical challenges of a completely occluded coronary vessel.

One should not consider this textbook is a compendium of obscure interventional procedures. I believe that this textbook represents the greatest growth potential area in much of interventional cardiovascular medicine. For example, as techniques continue to improve regarding re-vascularization if distal extremities, especially in patients with peripheral vasculopathy secondary to diabetes, tens of thousands of patients will benefit from not having to undergo amputation procedures, or at least forestalling the amputation procedure until a much later time. The treatments, whether it be related to carotid stenosis, mesenteric ischemia, neural vascular spasm, or congenital vascular

This book also bridges issues related to complications or other challenges related to performing aggressive angioplasty procedures. Whether it be hyperperfusion syndrome following aggressive angioplasty or oxygen stress and altered function of platelets in patients with peripheral arterial vascular disease, not only do interventionalists need to be knowledgeable in the technique in performing an intervention, they also must have a strong understanding of what the potential

To end, this first edition on Angioplasty will hopefully inspire interventionalists to "cross-link" their experience with other interventionalists regarding the techniques used to treat complicated lesions. I personally feel that communication is the most important ally to overcoming challenges in both acquired and congenital vascular lesions. Hopefully this book will inspire this to occur between interventional radiologists, cardiologists, neurologists, and neurosurgeons. I would not be surprised, with the continued explosion of a technology in this area, that revision of this book will be required within the next 7-10 years. Finally, one would be remiss in not giving credit to Warner Forsmann for his insight in the catheterization procedure and, as previously mentioned, Andre Gruentzig in launching us into an interventional era for the treatment of vascular stenosis. On the shoulders of these two giants (and many others) we are able to proceed onto an exciting and changing world of interventional

I would like to greatly acknowledge the authors of this book for their time in writing the chapters. Without their dedication to sharing their interventional expertise, this

lesions, have the potential of reaching millions of patients every year.

ramifications are both on an anatomic and molecular level.

**Dr. Thomas Forbes**  Wayne State University / Children's Hospital of Michigan, Detroit USA

**1** 

 *Australia* 

**Percutaneous Angioplasty and** 

Emily He1 and Stephen M. Riordan2

*University of New South Wales, Sydney* 

*Prince of Wales Hospital, Sydney* 

**Stenting for Mesenteric Ischaemia** 

*1Gastroenterology Registrar, Gastrointestinal and Liver Unit* 

 *Sydney, Australia and Professor of Medicine (Conjoint)* 

*2Senior Staff Specialist, Gastrointestinal and Liver Unit, Prince of Wales Hospital* 

Mesenteric ischaemia due to impaired arterial supply is an important cause of abdominal pain, especially in older patients with risk factors for vascular disease. Until recently, surgical revascularisation procedures such as endarterectomy and aorto-coeliac or aortomesenteric bypass grafting were the only available treatment options for patients with mesenteric ischaemia. However, reported rates of peri-operative major complications and mortality are high, influenced by a high prevalence of significant patient co-morbidities. Percutaneous angioplasty and stenting have been shown to be effective and safe alternatives to surgical revascularisation in high-risk patients with mesenteric ischaemia. Indeed, in high-surgical risk patients and in those with suitable lesions, such endovascular

Here, we review current concepts in the diagnosis, treatment selection and outcomes for percutaneous angioplasty and stenting for patients with either chronic or acute mesenteric

Chronic mesenteric ischaemia (CMI) most commonly arises from atherosclerotic diseases of the mesenteric arteries. Other causes of CMI include aortic dissection, fibromuscular

Atherosclerotic disease of the mesenteric arteries is estimated to occur in 17% of patients over the age 65 years (Hansen et al., 2004). Despite its prevalence, the majority of these patients are asymptomatic as a result of the extensive collateral circulation between the celiac trunk, superior mesenteric artery (SMA) and inferior mesenteric artery (IMA). Whether or not ischaemia ensues depends on the site of the stenosis or occlusion and the development or otherwise of collateral vessels (Loffroy et al., 2009). CMI typically occurs in patients who have SMA lesions in conjunction with lesions in either the celiac trunk or IMA. However, mesenteric ischaemia can also develop in patients with a single vessel lesion. Distal lesions are more likely to be symptomatic compared with more proximal arterial

revascularisation has emerged as the primary treatment modality.

dysplasia, vasculitides and median arcuate ligament syndrome.

pathology due to the absence of an effective collateral circulation.

**2. Chronic mesenteric ischaemia** 

**1. Introduction** 

ischemia.

### **Percutaneous Angioplasty and Stenting for Mesenteric Ischaemia**

Emily He1 and Stephen M. Riordan2

*1Gastroenterology Registrar, Gastrointestinal and Liver Unit Prince of Wales Hospital, Sydney 2Senior Staff Specialist, Gastrointestinal and Liver Unit, Prince of Wales Hospital Sydney, Australia and Professor of Medicine (Conjoint) University of New South Wales, Sydney Australia* 

#### **1. Introduction**

Mesenteric ischaemia due to impaired arterial supply is an important cause of abdominal pain, especially in older patients with risk factors for vascular disease. Until recently, surgical revascularisation procedures such as endarterectomy and aorto-coeliac or aortomesenteric bypass grafting were the only available treatment options for patients with mesenteric ischaemia. However, reported rates of peri-operative major complications and mortality are high, influenced by a high prevalence of significant patient co-morbidities. Percutaneous angioplasty and stenting have been shown to be effective and safe alternatives to surgical revascularisation in high-risk patients with mesenteric ischaemia. Indeed, in high-surgical risk patients and in those with suitable lesions, such endovascular revascularisation has emerged as the primary treatment modality.

Here, we review current concepts in the diagnosis, treatment selection and outcomes for percutaneous angioplasty and stenting for patients with either chronic or acute mesenteric ischemia.

#### **2. Chronic mesenteric ischaemia**

Chronic mesenteric ischaemia (CMI) most commonly arises from atherosclerotic diseases of the mesenteric arteries. Other causes of CMI include aortic dissection, fibromuscular dysplasia, vasculitides and median arcuate ligament syndrome.

Atherosclerotic disease of the mesenteric arteries is estimated to occur in 17% of patients over the age 65 years (Hansen et al., 2004). Despite its prevalence, the majority of these patients are asymptomatic as a result of the extensive collateral circulation between the celiac trunk, superior mesenteric artery (SMA) and inferior mesenteric artery (IMA). Whether or not ischaemia ensues depends on the site of the stenosis or occlusion and the development or otherwise of collateral vessels (Loffroy et al., 2009). CMI typically occurs in patients who have SMA lesions in conjunction with lesions in either the celiac trunk or IMA. However, mesenteric ischaemia can also develop in patients with a single vessel lesion. Distal lesions are more likely to be symptomatic compared with more proximal arterial pathology due to the absence of an effective collateral circulation.

Percutaneous Angioplasty and Stenting for Mesenteric Ischaemia 3

to 2006 (Schermerhorn et al., 2009), the number of endovascular procedures steadily increased, surpassing all surgery for CMI in 2002. Endovascular revascularisation is associated with a lower in-hospital mortality and morbidity rate as well as shorter length of stay. Significantly lower rates of bowel resection, as well as fewer renal, cardiac and respiratory complications have been reported in patients who received endovascular revascularisation compared to surgically-treated counterparts (Table 2). A later analysis of published data concerning procedures performed between 2000 and 2009 similarly demonstrated a significantly reduced peri-operative complication rate in patients managed

Mortality 3.7% 15.4% <0.001 Overall morbidity 20% 38% <0.05 Bowel resection 3% 8% <0.001 Cardiac events 0.7% 5.9% <0.001 Respiratory events 0.3% 5.7% <0.001 Acute renal failure 6.0% 10.5% <0.05

Table 2. Mortality, morbidity, peri-operative complications and length of stay (LOS): endovascular revascularisation vs. surgical revascularisation. (adapted from Schermerhorn

A serious potential complication of endovascular treatment is the precipitation of acute intestinal ischemia by plaque embolization or dissection of the artery. Standard catheter based salvage techniques such as stent deployment, embolectomy or thrombolysis are usually successful in treating these complications. Emergency laparotomy with mesenteric bypass and bowel resection is also used as salvage treatment. We recently reported the occurrence of splenic infarction complicating otherwise successful celiac artery stenting, presumably as a consequence of distal embolization of disrupted calcific plaque, with this complication representing a novel cause of abdominal pain post-procedure (Almeida &

The most common procedural complication of endovascular therapy relates to the puncture site, manifesting as either haemorrhage or thrombosis. Haemorrhage is generally controlled with local pressure and/or injection of thrombin. Insertion of interventional sheaths in small arteries is associated with an increased risk of thrombosis. Rapid heparinization after sheath

Another important issue is the longer-term arterial patency rate in patients treated by endovascular means compared to those managed surgically. In a recent review of 328 patients undergoing endovascular treatment for chronic mesenteric ischaemia, the overall technical success rate was 91% and immediate symptomatic relief was achieved in 82% of patients (Kougias et al., 2007). Despite the initial success rate, approximately one third of patients (84/292) available for follow up developed restenosis over a mean follow up period of 26 months. The 30-day mortality rate was 3-5%. Clinical series comparing endovascular and surgical revascularisation have shown that long term patency rates and freedom from

insertion is usually an adequate preventative measure.

**Surgical** 

5 (0-94) 11 (1-135) <0.001

**revascularisation** 

**pvalue** 

by endovascular therapy compared to surgery (Gupta et al., 2010).

LOS

et al., 2009)

Riordan, 2008).

median (range), days

**Endovascular revascularisation** 

#### **3. Clinical presentation**

CMI commonly affects people over the age of 60 years, with women three times more likely to be affected than men (Hansen et al., 2004). Most patients have multiple cardiovascular risk factors and atherosclerotic complications in other vascular territories.

Classic symptoms of CMI include postprandial abdominal pain, fear of eating and significant weight loss. Patients may also present with persistent nausea and diarrhoea. These symptoms are non-specific and extensive investigations are generally undertaken to exclude other pathologies such as gastrointestinal or pancreatic malignancy.

#### **4. Diagnosis**

Duplex ultrasound is a useful, non-invasive screening test for mesenteric ischaemia (Moneta et al., 1993) (Table 1). Its accuracy is affected by operator experience and patient factors such as fasting status, body habitus and presence of bowel gas. CT-angiography and MRangiography are of value in cases where duplex ultrasound is inconclusive (Cademartiri et al., 2008; Horton et al., 2007; Laissy et al., 2002). CT-angiography also provides excellent 3-D anatomical reconstruction to facilitate planning for endovascular revascularisation. Nevertheless, digital subtraction angiography remains the gold standard in evaluating the degree of stenosis in mesenteric vessels.


PSV: peak systolic velocity

Table 1. Duplex ultrasound criteria for detecting >70% stenosis in mesenteric vessels (from Moneta et al., 1993).

#### **5. Treatment options**

Treatment of symptomatic CMI is aimed at relieving symptoms and preventing progression to acute mesenteric ischaemia (AMI) and intestinal infarction. Prophylactic treatment of asymptomatic patients is controversial. The risk of progressing to AMI is greatest in patients with three-vessel disease with an estimated one third of these patients progressing to intestinal infarction if left untreated (Kolkman et al., 2004). The prognosis is relatively benign in those with single-vessel disease. In participants of the Cardiovascular Health Study who were found to have isolated coeliac trunk or mesenteric artery disease on duplex ultrasound, there was no increased risk of mortality, intestinal infarction or development of symptoms consistent with CMI over a median follow up period of 6.5years (Wilson et al., 2006).

The gold standard of treatment has traditionally been surgical revascularisation in the form of bypass, endarterectomy or embolectomy. Given that patients affected by CMI are generally malnourished, of advanced age and have multiple cardiovascular co-morbidities, there is considerable peri-operative mortality (0-17%) and morbidity (15-33%) associated with surgical revascularisation (Kougias et al., 2009).

Endovascular revascularisation is increasingly being offered to patients affected by CMI. In a large US registry study comprising of 5583 patients treated for CMI during the years 1988 Angioplasty, Various Techniques and Challenges in 2 Treatment of Congenital and Acquired Vascular Stenoses

CMI commonly affects people over the age of 60 years, with women three times more likely to be affected than men (Hansen et al., 2004). Most patients have multiple cardiovascular

Classic symptoms of CMI include postprandial abdominal pain, fear of eating and significant weight loss. Patients may also present with persistent nausea and diarrhoea. These symptoms are non-specific and extensive investigations are generally undertaken to

Duplex ultrasound is a useful, non-invasive screening test for mesenteric ischaemia (Moneta et al., 1993) (Table 1). Its accuracy is affected by operator experience and patient factors such as fasting status, body habitus and presence of bowel gas. CT-angiography and MRangiography are of value in cases where duplex ultrasound is inconclusive (Cademartiri et al., 2008; Horton et al., 2007; Laissy et al., 2002). CT-angiography also provides excellent 3-D anatomical reconstruction to facilitate planning for endovascular revascularisation. Nevertheless, digital subtraction angiography remains the gold standard in evaluating the

> Vessel Duplex criteria Sensitivity Specificity Accuracy SMA PSV > 275cm/s 92% 96% 96% Coeliac trunk PSV > 200cm/s 87% 82% 82%

Table 1. Duplex ultrasound criteria for detecting >70% stenosis in mesenteric vessels (from

Treatment of symptomatic CMI is aimed at relieving symptoms and preventing progression to acute mesenteric ischaemia (AMI) and intestinal infarction. Prophylactic treatment of asymptomatic patients is controversial. The risk of progressing to AMI is greatest in patients with three-vessel disease with an estimated one third of these patients progressing to intestinal infarction if left untreated (Kolkman et al., 2004). The prognosis is relatively benign in those with single-vessel disease. In participants of the Cardiovascular Health Study who were found to have isolated coeliac trunk or mesenteric artery disease on duplex ultrasound, there was no increased risk of mortality, intestinal infarction or development of symptoms consistent with

The gold standard of treatment has traditionally been surgical revascularisation in the form of bypass, endarterectomy or embolectomy. Given that patients affected by CMI are generally malnourished, of advanced age and have multiple cardiovascular co-morbidities, there is considerable peri-operative mortality (0-17%) and morbidity (15-33%) associated

Endovascular revascularisation is increasingly being offered to patients affected by CMI. In a large US registry study comprising of 5583 patients treated for CMI during the years 1988

CMI over a median follow up period of 6.5years (Wilson et al., 2006).

with surgical revascularisation (Kougias et al., 2009).

risk factors and atherosclerotic complications in other vascular territories.

exclude other pathologies such as gastrointestinal or pancreatic malignancy.

**3. Clinical presentation** 

degree of stenosis in mesenteric vessels.

PSV: peak systolic velocity

**5. Treatment options** 

Moneta et al., 1993).

**4. Diagnosis** 

to 2006 (Schermerhorn et al., 2009), the number of endovascular procedures steadily increased, surpassing all surgery for CMI in 2002. Endovascular revascularisation is associated with a lower in-hospital mortality and morbidity rate as well as shorter length of stay. Significantly lower rates of bowel resection, as well as fewer renal, cardiac and respiratory complications have been reported in patients who received endovascular revascularisation compared to surgically-treated counterparts (Table 2). A later analysis of published data concerning procedures performed between 2000 and 2009 similarly demonstrated a significantly reduced peri-operative complication rate in patients managed by endovascular therapy compared to surgery (Gupta et al., 2010).


Table 2. Mortality, morbidity, peri-operative complications and length of stay (LOS): endovascular revascularisation vs. surgical revascularisation. (adapted from Schermerhorn et al., 2009)

A serious potential complication of endovascular treatment is the precipitation of acute intestinal ischemia by plaque embolization or dissection of the artery. Standard catheter based salvage techniques such as stent deployment, embolectomy or thrombolysis are usually successful in treating these complications. Emergency laparotomy with mesenteric bypass and bowel resection is also used as salvage treatment. We recently reported the occurrence of splenic infarction complicating otherwise successful celiac artery stenting, presumably as a consequence of distal embolization of disrupted calcific plaque, with this complication representing a novel cause of abdominal pain post-procedure (Almeida & Riordan, 2008).

The most common procedural complication of endovascular therapy relates to the puncture site, manifesting as either haemorrhage or thrombosis. Haemorrhage is generally controlled with local pressure and/or injection of thrombin. Insertion of interventional sheaths in small arteries is associated with an increased risk of thrombosis. Rapid heparinization after sheath insertion is usually an adequate preventative measure.

Another important issue is the longer-term arterial patency rate in patients treated by endovascular means compared to those managed surgically. In a recent review of 328 patients undergoing endovascular treatment for chronic mesenteric ischaemia, the overall technical success rate was 91% and immediate symptomatic relief was achieved in 82% of patients (Kougias et al., 2007). Despite the initial success rate, approximately one third of patients (84/292) available for follow up developed restenosis over a mean follow up period of 26 months. The 30-day mortality rate was 3-5%. Clinical series comparing endovascular and surgical revascularisation have shown that long term patency rates and freedom from

Percutaneous Angioplasty and Stenting for Mesenteric Ischaemia 5

from endovascular to open surgical revascularisation when an occlusion is found (Kasiragjan et al., 2001). Endovascular passage of guide wires and stents through totally occluded lesions is a technically challenging procedure and not without significant risks of vessel perforation or dissection. Although not statistically validated, the degree of difficulty is likely to increase with the length of occlusion. A theoretical concern also exists for plaque fragmentation and distal embolization, which also increases with the length of occlusion. Although the efficacy of endovascular intervention in treating occluded mesenteric vessels is not well established, evolving endovascular technology with low-profile systems has now made recanalization of occluded vessels feasible. Landis et al. (2005) reported technical success and 1-year patency rates of 100% in 9 patients with mesenteric occlusion. A case series by Peck et al also indicated that patients with occluded SMA who underwent revascularisation had lower 3-year symptom recurrence rates, with three year patency rates of 90% for treated SMA occlusions versus 40% for untreated SMA occlusions (Peck et al., 2010). This difference however was not statistically significant, possibly due to the small

There is a lack of uniformity in the follow up of patients who have received endovascular therapy for CMI. Although recurrence of symptoms is correlated with restenosis, this alone is not a reliable predictor of vessel patency, with sensitivity as low as 33% for detection of restenosis (McMillan et al., 1995). Failure to diagnose progressive disease in asymptomatic patients may result in the subsequent development of acute mesenteric thrombosis. This is a potentially fatal vascular emergency with overall mortality rate ranging from 32% to 65%

Abdominal duplex ultrasonography is the most commonly used method of surveillance due to its non-invasive nature. Although duplex ultrasonography has been validated in the diagnosis of mesenteric arterial stenosis (Zwolak et al., 1998), there is no current consensus on which velocity criteria should be used to define high-grade recurrent disease (Kasirajan et al., 2001; Armstrong et al., 2007; Fenwick et al., 2007). CT-angiography and MRangiography are alternative modalities of imaging, although digital substraction angiography is generally considered the gold standard. There is a potential role for functional studies such as gastrointestinal tonometry to detect mesenteric ischemia and

Acute mesenteric ischemia is associated with a daunting mortality rate of greater than 50% (Schermerhorn et al., 2009). Prompt diagnosis and institution of revascularisation therapy

Endovascular treatment for AMI was traditionally reserved for selected patients who have prohibitive operative risk, no clinical signs of peritoneal inflammation, or those with a contaminated peritoneal cavity and no autogenous vessel available for grafting (Loffroy et al., 2009). With evolving expertise and technological advancements in endovascular therapy, there has been an increase in the use of endovascular revascularisation for treatment of AMI. In the US registry study of 5237 patients treated for AMI, the outcomes of patients who were treated with endovascular intervention were compared to those who were treated with

numbers of patients studied.

(Park et al., 2002).

**8. Surveillance of vessel patency** 

guide treatment (Otte et al., 2008).

**9. Acute mesenteric ischemia** 

are crucial for a successful outcome.

symptoms may be inferior in patients who have had endovascular revascularisation (Kougias et al., 2009; Atkins et al., 2007; Kasiragjan et al., 2001). Indeed, an analysis of all published literature comparing surgical and endovascular treatment options for CMI performed between 2000 and 2009 concluded that 5-year primary patency rates were 3.8 times greater in the surgical group (P<0.001), while freedom from symptoms at 5 years was 4.4 times greater in patients managed surgically compared to those treated with endovascular techniques (p<0.001) (Gupta et al., 2010).

#### **6. Angioplasty vs stenting**

There is general agreement that stenting is indicated for residual stenosis following primary angioplasty (defined as residual stenosis of 30% or more, or pressure gradient higher than 15mmHg), for ostial or eccentric lesions, or as a salvage procedure for acute dissection after angioplasty (Kougias et al., 2007). Balloon-expandable stents are preferred because of their accuracy and ability to generate considerable radial force. More distal or long lesions may be better suited to self-expandable stents given their flexibility (Loffroy et al., 2009).

Kougias et al (2007) reported that technical success was significantly higher with stenting compared with angioplasty alone (95% vs 83%, p=0.007), although the rate of restenosis was also higher in the stented subgroup, a finding that may have been biased by the inclusion of earlier studies where more primitive stents were used and peri-procedural anticoagulant and antiplatelet treatment regimens were not standardized. A recent case series demonstrated that long-term patency rate was higher in patients managed with primary stenting compared to angioplasty alone (Daliri et al., 2010).

#### **7. Which vessel to treat**

Literature from the surgical revascularisation setting has shown that complete revascularisation of the coeliac trunk and SMA is associated with improved long-term outcomes (Mateo et al., 1999; McAfee et al., 1992; Foley et al., 2000). The simultaneous treatment of two vessels prevents symptom recurrence in the event of restenosis in either artery. Improved graft patency and survival with complete reconstruction (McAfee et al., 1992), and a higher incidence of symptoms and graft failure with single vessel therapy (Foley et al., 2000) have each been demonstrated.

There is a tendency to treat fewer vessels when choosing endovascular revascularisation compared with surgical revascularisation (Kougias et al., 2009). The conventional approach to endovascular intervention is to treat SMA lesions in preference to celiac trunk or IMA lesions. There is conflicting evidence as to whether treatment of both SMA and celiac arteries will produce better long-term patency. A recent series by Peck et al indicated that two-vessel treatment resulted in lower symptomatic recurrences, improved patency and fewer re-interventions (Peck et al., 2010). On the other hand, Sarac et al. (2008) did not report any difference in 1 year patency between single-vessel and two-vessel treatment, while Malgor et al. (2010) similarly found in a study of longer follow-up of 3 years that two-vessel celiac artery and SMA stenting did not result in improved outcomes when compared with single-vessel SMA stent placement for CMI.

Traditionally, there has been a preference for treating stenotic rather than occlusive lesions by endovascular means. Although the presence of an occluded vessel is not an absolute contraindication to endovascular intervention, the practice in many centres is to convert Angioplasty, Various Techniques and Challenges in 4 Treatment of Congenital and Acquired Vascular Stenoses

symptoms may be inferior in patients who have had endovascular revascularisation (Kougias et al., 2009; Atkins et al., 2007; Kasiragjan et al., 2001). Indeed, an analysis of all published literature comparing surgical and endovascular treatment options for CMI performed between 2000 and 2009 concluded that 5-year primary patency rates were 3.8 times greater in the surgical group (P<0.001), while freedom from symptoms at 5 years was 4.4 times greater in patients managed surgically compared to those treated with

There is general agreement that stenting is indicated for residual stenosis following primary angioplasty (defined as residual stenosis of 30% or more, or pressure gradient higher than 15mmHg), for ostial or eccentric lesions, or as a salvage procedure for acute dissection after angioplasty (Kougias et al., 2007). Balloon-expandable stents are preferred because of their accuracy and ability to generate considerable radial force. More distal or long lesions may be

Kougias et al (2007) reported that technical success was significantly higher with stenting compared with angioplasty alone (95% vs 83%, p=0.007), although the rate of restenosis was also higher in the stented subgroup, a finding that may have been biased by the inclusion of earlier studies where more primitive stents were used and peri-procedural anticoagulant and antiplatelet treatment regimens were not standardized. A recent case series demonstrated that long-term patency rate was higher in patients managed with primary

Literature from the surgical revascularisation setting has shown that complete revascularisation of the coeliac trunk and SMA is associated with improved long-term outcomes (Mateo et al., 1999; McAfee et al., 1992; Foley et al., 2000). The simultaneous treatment of two vessels prevents symptom recurrence in the event of restenosis in either artery. Improved graft patency and survival with complete reconstruction (McAfee et al., 1992), and a higher incidence of symptoms and graft failure with single vessel therapy

There is a tendency to treat fewer vessels when choosing endovascular revascularisation compared with surgical revascularisation (Kougias et al., 2009). The conventional approach to endovascular intervention is to treat SMA lesions in preference to celiac trunk or IMA lesions. There is conflicting evidence as to whether treatment of both SMA and celiac arteries will produce better long-term patency. A recent series by Peck et al indicated that two-vessel treatment resulted in lower symptomatic recurrences, improved patency and fewer re-interventions (Peck et al., 2010). On the other hand, Sarac et al. (2008) did not report any difference in 1 year patency between single-vessel and two-vessel treatment, while Malgor et al. (2010) similarly found in a study of longer follow-up of 3 years that two-vessel celiac artery and SMA stenting did not result in improved outcomes when compared with

Traditionally, there has been a preference for treating stenotic rather than occlusive lesions by endovascular means. Although the presence of an occluded vessel is not an absolute contraindication to endovascular intervention, the practice in many centres is to convert

better suited to self-expandable stents given their flexibility (Loffroy et al., 2009).

endovascular techniques (p<0.001) (Gupta et al., 2010).

stenting compared to angioplasty alone (Daliri et al., 2010).

(Foley et al., 2000) have each been demonstrated.

single-vessel SMA stent placement for CMI.

**6. Angioplasty vs stenting** 

**7. Which vessel to treat** 

from endovascular to open surgical revascularisation when an occlusion is found (Kasiragjan et al., 2001). Endovascular passage of guide wires and stents through totally occluded lesions is a technically challenging procedure and not without significant risks of vessel perforation or dissection. Although not statistically validated, the degree of difficulty is likely to increase with the length of occlusion. A theoretical concern also exists for plaque fragmentation and distal embolization, which also increases with the length of occlusion. Although the efficacy of endovascular intervention in treating occluded mesenteric vessels is not well established, evolving endovascular technology with low-profile systems has now made recanalization of occluded vessels feasible. Landis et al. (2005) reported technical success and 1-year patency rates of 100% in 9 patients with mesenteric occlusion. A case series by Peck et al also indicated that patients with occluded SMA who underwent revascularisation had lower 3-year symptom recurrence rates, with three year patency rates of 90% for treated SMA occlusions versus 40% for untreated SMA occlusions (Peck et al., 2010). This difference however was not statistically significant, possibly due to the small numbers of patients studied.

#### **8. Surveillance of vessel patency**

There is a lack of uniformity in the follow up of patients who have received endovascular therapy for CMI. Although recurrence of symptoms is correlated with restenosis, this alone is not a reliable predictor of vessel patency, with sensitivity as low as 33% for detection of restenosis (McMillan et al., 1995). Failure to diagnose progressive disease in asymptomatic patients may result in the subsequent development of acute mesenteric thrombosis. This is a potentially fatal vascular emergency with overall mortality rate ranging from 32% to 65% (Park et al., 2002).

Abdominal duplex ultrasonography is the most commonly used method of surveillance due to its non-invasive nature. Although duplex ultrasonography has been validated in the diagnosis of mesenteric arterial stenosis (Zwolak et al., 1998), there is no current consensus on which velocity criteria should be used to define high-grade recurrent disease (Kasirajan et al., 2001; Armstrong et al., 2007; Fenwick et al., 2007). CT-angiography and MRangiography are alternative modalities of imaging, although digital substraction angiography is generally considered the gold standard. There is a potential role for functional studies such as gastrointestinal tonometry to detect mesenteric ischemia and guide treatment (Otte et al., 2008).

#### **9. Acute mesenteric ischemia**

Acute mesenteric ischemia is associated with a daunting mortality rate of greater than 50% (Schermerhorn et al., 2009). Prompt diagnosis and institution of revascularisation therapy are crucial for a successful outcome.

Endovascular treatment for AMI was traditionally reserved for selected patients who have prohibitive operative risk, no clinical signs of peritoneal inflammation, or those with a contaminated peritoneal cavity and no autogenous vessel available for grafting (Loffroy et al., 2009). With evolving expertise and technological advancements in endovascular therapy, there has been an increase in the use of endovascular revascularisation for treatment of AMI. In the US registry study of 5237 patients treated for AMI, the outcomes of patients who were treated with endovascular intervention were compared to those who were treated with

Percutaneous Angioplasty and Stenting for Mesenteric Ischaemia 7

Almeida JA, Riordan SM. Splenic infarction complicating percutaneous transluminal coeliac

Armstrong PA. Visceral duplex scanning: evaluation before and after artery intervention for chronic mesenteric ischemia. *Perspect Vasc Surg Endovasc Ther* 2007; 19: 386-92. Arthurs ZM, Titus J, Bannazadeh M, et al. A comparison of endovascular revascularisation

Atkins MD, Kwolek CJ, LaMuraglia GM. Surgical revascularisation versus endovascular

Block TA, Acosta S, Bjorck M. Endovascular and open surgery for acute occlusion of the superior mesenteric artery. Journal of Vascular Surgery 2010; 52 (4): 959-966. Cademartiri F, Palumbo A, Maffei E, et al. Noninvasive evaluation of the celiac trunk and

Daliri A. Grunwald C. Jobst B, et al. Endovascular treatment for chronic atherosclerotic

Fenwick JL, Wright. Endovascular repair of chronic mesenteric occlusive disease: the role of

Flessas II, Papalois AE, Toutouzas K, Zagouri F, Zografos GC. Effects of lazaroids on

Foley MI, Moneta GL, Abou-Zamzam AM Jr, et al. Revascularisation of the superior

Gupta PK, Horan SM, Turaga KK, Miller WJ, Pipinos II. Chronic mesenteric ischemia:

Hansen KJ, Wilson DB, Craven TE, et al. Mesenteric artery disease in the elderly. *J Vasc Surg*

Horton KM, Fishman EK. Multidetector CT angiography in the diagnosis of mesenteric

Kasirajan K, O'Hara PJ, Gray BH, et al. Chronic mesenteric ischemia: Open surgery versus

Kolkman JJ, Mensink PB, van Petersen AS, et al. Clinical approach to chronic

Kougias P, El Sayed H, Zhou W, et al. Management of chronic mesenteric ischemia. The

Kougias P, Huyng TT, Lin PH. Clinical outcomes of mesenteric artery stenting versus

gastrointestinal ischemia from "intestinal angina" to the spectrum of chronic

surgical revascularisation in chronic mesenteric ischemia. *Int Angio.* 2009; 28(2):132-

percutaneous angioplasty and stenting. *J Vasc Surg* 2001;33:63–71

splanchnic disease. *Scand J Gastroenterol Suppl* 2004; 241: 9-16.

Role of Endovascular Therapy. *J Endovasc Ther* 2007; 14:395-405

artery stenting for chronic mesenteric ischaemia. *Journal of Medical Case Reports*

with traditional therapy for the treatment of acute mesenteric ischemia*. J Vasc Surg*

therapy for chronic mesenteric ischemia: a comparative experience. *J Vasc Surg*

superior mesenteric artery with multislice CT in patients with chronic mesenteric

occlusive mesenteric disease: is stenting superior to balloon angioplasty? *Vasa* 2010;

intestinal ischemia and reperfusion injury in experimental models. Journal of

mesenteric artery alone for treatment of intestinal ischemia. *J Vasc Surg* 2000;32:37-

endovascular versus open revascularisation. Journal of Endovascular Therapy

**11. References** 

2008; 2: 261.

2011; 53:698-704.

2007; 45:1162-1171.

39: 319-24

47

137.

2010; 17 (4): 540-549.

2004;40:45-52

ischemia. *Radiol Med* 2008; 113:1135-1142.

Surgical Research 2011; 166: 265-274.

duplex surveillance*. Aust N Z J Surg* 2007; 77:60-63

ischemia. *Radiol Clin North Am* 2007; 45:275-288

surgery (Schermerhorn et al., 2009). Patients who were treated with endovascular measures tended to have higher rates of cardiovascular comorbidities than those undergoing open surgical repair, including hypertension, peripheral vascular disease, coronary artery disease and chronic renal failure. Despite these unfavourable patient characteristics, mortality was significantly lower in the endovascular group compared with the surgical group (16% vs 39%, p<0.001).

In a recent retrospective, single centre case series of 70 patients with AMI, the largest such case series to date, Arthurs et al. (2011) demonstrated that the use of endovascular therapy as primary treatment for AMI produced lower complication rates and better outcomes (Arthurs et al., 2011). During a 9-year study period, endovascular therapy was initiated in 56 patients while surgical therapy was used in 24 patients. Overall, technical success for endovascular therapy was 87%. Failures in endovascular therapy were treated with embolectomy in 78% and revascularisation in 22%. Successful endovascular treatment resulted in a mortality rate of 36%, which was significantly lower compared with a rate of 50% in those treated surgically (p<0.05). Patients who failed endovascular treatment had a mortality rate of 50%, an outcome which was equivalent to that of traditional surgical therapy. Block et al. (2010) have also recently reported improved 30 day and long-term survival with endovascular revascularisation of the SMA compared to surgery in patients identified through the Swedish Vascular Registry from 1999 to 2006, although the need for prospective randomised data to confirm group differences was highlighted.

The general view that laparotomy is crucial for all patients with AMI to assess intestinal viability and perform resection as required has also recently been questioned. Arthurs et al. (2011) challenged this philosophy by performing laparotomy only on patients who had signs of peritoneal inflammation or deteriorated clinically following initial revascularisation. Over 30% of patients in the endovascular therapy group did not ultimately require laparotomy, thereby avoiding further physiologic insult to patients who are already critically ill.

Another important issue is to what extent ischaemia-reperfusion injury of the intestine, leading to microvascular injury and cellular necrosis and apoptosis, contributes to morbidity and mortality in patients in whom arterial revascularisation is attained and whether various recent advances in preventing or limiting this phenomenon described in the experimental situation can be translated clinically (Santora et al., 2011; Petrat & de Groot, 2011; Flessas et al., 2011).

#### **10. Conclusions**

There has been a recent paradigm shift in the treatment of mesenteric ischaemia. Whereas endovascular therapy was once reserved for the few patients who had prohibitive operative risks, it is now increasingly used for revascularisation of both chronic and acute mesenteric ischemia. Endovascular therapy is less invasive than open surgery, and is associated with lower peri-procedural morbidity and mortality. There is growing evidence that stenting may achieve better technical success and patency rates compared with angioplasty alone. The timing and choice of imaging modality for surveillance of vessel patency remains an important question for clinicians. Effective approaches to improving longer-term vessel patency rates following endovascular therapy are required, along with strategies to prevent ischaemia-reperfusion injury in those patients with acute mesenteric ischaemia in whom revascularisation is achieved.

#### **11. References**

Angioplasty, Various Techniques and Challenges in 6 Treatment of Congenital and Acquired Vascular Stenoses

surgery (Schermerhorn et al., 2009). Patients who were treated with endovascular measures tended to have higher rates of cardiovascular comorbidities than those undergoing open surgical repair, including hypertension, peripheral vascular disease, coronary artery disease and chronic renal failure. Despite these unfavourable patient characteristics, mortality was significantly lower in the endovascular group compared with the surgical group (16% vs

In a recent retrospective, single centre case series of 70 patients with AMI, the largest such case series to date, Arthurs et al. (2011) demonstrated that the use of endovascular therapy as primary treatment for AMI produced lower complication rates and better outcomes (Arthurs et al., 2011). During a 9-year study period, endovascular therapy was initiated in 56 patients while surgical therapy was used in 24 patients. Overall, technical success for endovascular therapy was 87%. Failures in endovascular therapy were treated with embolectomy in 78% and revascularisation in 22%. Successful endovascular treatment resulted in a mortality rate of 36%, which was significantly lower compared with a rate of 50% in those treated surgically (p<0.05). Patients who failed endovascular treatment had a mortality rate of 50%, an outcome which was equivalent to that of traditional surgical therapy. Block et al. (2010) have also recently reported improved 30 day and long-term survival with endovascular revascularisation of the SMA compared to surgery in patients identified through the Swedish Vascular Registry from 1999 to 2006, although the need for

The general view that laparotomy is crucial for all patients with AMI to assess intestinal viability and perform resection as required has also recently been questioned. Arthurs et al. (2011) challenged this philosophy by performing laparotomy only on patients who had signs of peritoneal inflammation or deteriorated clinically following initial revascularisation. Over 30% of patients in the endovascular therapy group did not ultimately require laparotomy, thereby avoiding further physiologic insult to patients who are already

Another important issue is to what extent ischaemia-reperfusion injury of the intestine, leading to microvascular injury and cellular necrosis and apoptosis, contributes to morbidity and mortality in patients in whom arterial revascularisation is attained and whether various recent advances in preventing or limiting this phenomenon described in the experimental situation can be translated clinically (Santora et al., 2011; Petrat & de Groot, 2011; Flessas et

There has been a recent paradigm shift in the treatment of mesenteric ischaemia. Whereas endovascular therapy was once reserved for the few patients who had prohibitive operative risks, it is now increasingly used for revascularisation of both chronic and acute mesenteric ischemia. Endovascular therapy is less invasive than open surgery, and is associated with lower peri-procedural morbidity and mortality. There is growing evidence that stenting may achieve better technical success and patency rates compared with angioplasty alone. The timing and choice of imaging modality for surveillance of vessel patency remains an important question for clinicians. Effective approaches to improving longer-term vessel patency rates following endovascular therapy are required, along with strategies to prevent ischaemia-reperfusion injury in those patients with acute mesenteric ischaemia in whom

prospective randomised data to confirm group differences was highlighted.

39%, p<0.001).

critically ill.

al., 2011).

**10. Conclusions** 

revascularisation is achieved.


**2** 

*Spain* 

**Cerebral Hyperperfusion** 

*2Department of Interventional Radiologist* 

*1Department of Neurology* 

*3Department of Neuroradiology 4Department of Intensive Care 5Department of Vascular Surgery Hospital de Sabadell, Barcelona* 

**Syndrome After Angioplasty** 

D. Canovas1, J. Estela1, J. Perendreu2, J. Branera2, A. Rovira3, M. Martinez4 and A. Gimenez-Gaibar5

Cerebral hyperperfusion syndrome (CHS) was first described by Sundt et al. (1981) as a clinical syndrome following carotid endarterectomy (CEA) characterized by headache,

This chapter deals with this uncommon but not exceptional complication of endovascular treatment of the arteries that supply the brain. We use the term carotid artery stenting (CAS) to refer to stenting of the internal carotid artery (ICA) because most publications are centered on this artery. Moreover, we include angioplasty without stent placement in the term CAS to facilitate reading comprehension because the relation between endovascular treatment and CHS is related to revascularization itself rather than to stent placement per se. Given the high rate of ischemic brain disease in relation to carotid stenosis and the high prevalence of asymptomatic carotid stenosis, numerous publications discuss CHS in relation to CEA: the incidence in these series ranges from 0.3% to 2.2%. However, CAS has continually evolved in recent years to the point where, after more than 40 years' experience, it is considered an alternative to CEA. Furthermore, the development of new materials for stents, filters for distal protection, dual antiplatelet treatment, and the learning curve are

Documented complications of CAS include cerebral embolism, hemodynamic compromise, vessel dissection, and early restenosis and occlusion, as well as the hyperperfusion syndrome we deal with in this chapter. Moreover, the spectacular increase in endovascular treatment has revealed that hyperperfusion syndrome can also occur after revascularization of other arteries, such as the vertebral arteries, the subclavian arteries, or even those located

In this chapter we will begin by discussing the pathophysiology, clinical presentation, and incidence of CHS in the different published series. We will then discuss the risk factors, diagnostic methods, and strategies for prevention and treatment. We will also discuss a

neurological deficit, and epileptic seizures that is not caused by cerebral ischemia.

minimizing the short- and long-term adverse effects of CAS.

within the brain, mainly the middle cerebral artery (MCA).

**1. Introduction** 


### **Cerebral Hyperperfusion Syndrome After Angioplasty**

D. Canovas1, J. Estela1, J. Perendreu2, J. Branera2,

A. Rovira3, M. Martinez4 and A. Gimenez-Gaibar5 *1Department of Neurology 2Department of Interventional Radiologist 3Department of Neuroradiology 4Department of Intensive Care 5Department of Vascular Surgery Hospital de Sabadell, Barcelona Spain* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 8 Treatment of Congenital and Acquired Vascular Stenoses

Laissy JP, Trillaud H, Douek P. MR angiography: noninvasive vascular imaging of the

Landis MS, Rajan DK, Simons ME, et al. Percutaneous management of chronic mesenteric ischemia: outcomes after intervention. *J Vasc Inter Radiol* 2005; 16:1319-1325 Loffroy R, Steinmetz E, Guiu B, et al. Role for endovascular therapy in chronic mesenteric

Malgor RD, Oderich GS, McKusick MA, Misra S, Kalra M, Duncan AA, Bower TC, Glaviczki

Mateo RB, O'Hara PJ, Hertzer NR, et al. Elective surgical treatment of symptomatic chronic

McAfee MK, Cherry KJ Jr, Naessens JM, et al. Influence of complete revascularisation on

McMillan WD, McCarthy WJ, Bresticker MR, et al. Mesenteric artery bypass: objective

Moneta GL, Lee RW, Yeager RA, et al. Mesenteric duplex scanning: a blinded prospective

Otte JA, Huisman AB, Geelkerken Rh, et al. Jejunal tonometry for the diagnosis of

Santora RJ, Lie ML, Grigorev DN, Nasir O, Moore FA, Hassoun HT. Journal of Vascular

Sarac TP, Altinel O, Kashyap V, et al. Endovascular treatment of steno tic and occluded visceral arteries for chronic mesenteric ischemia. *J Vasc Surg* 2008; 47:485-91 Schermerhorn ML, Giles KA, Hamdan AD, et al. Mesenteric revascularisation: management and outcomes in the United States, 1988-2006. *J Vasc Surg* 2009; 50:341-348 Wilson DB, Mostafavi K, Craven TE, et al. Clinical course of mesenteric artery stenosis in

Zwolak RM, Fillinger MF, Walsh DB, et al. Mesenteric and celiac duplex scanning: a

gastrointestinal ischemia. Feasibility, normal values and comparison of jejeunal with gastric tonometry exercise testing. *Eur J Gastroenterol Hepatol* 2008; 20:62-67 Peck MC, Conrad MF, Kwolek CJ, et al. Intermediate-term outcomes of endovascular treatment for symptomatic chronic mesenteric ischemia. *J Vasc Surg* 2010; 51:140-7 Petrat F, Ronn T, de Groot H.Protection by pyruvate infusion in a rat model of severe

intestinal ischemia-reperfusion injury. Journal of Surgical Research 2011; 167 (2):

ischemia. Annals of Vascular Surgery 2010; 24 (8): 1094-1101.

chronic mesenteric ischemia. *Am J Surg* 1992; 164:220-4

elderly Americans. *Arch Intern Med* 2006; 166:2095-100.

validation study. J Vasc Surg 1998; 27:1078-87.

patency determination. *J Vasc Surg* 1995; 21: 729-740

study. *J Vasc Surg* 1993; 17:79-84

Surgery 2010; 52 (4): 1003-1014.

P. Results of single- and two-vessel mesenteric artery stents for chronic mesenteric

mesenteric occlusive disease: early results and late outcomes. *J Vasc Surg* 1999;

abdomen. *Abdom Imaging* 2002; 27:488-506

ischemia. *Can J Gastroenterol* 2009; 23:365-373

29:821-31

e93-e101.

Cerebral hyperperfusion syndrome (CHS) was first described by Sundt et al. (1981) as a clinical syndrome following carotid endarterectomy (CEA) characterized by headache, neurological deficit, and epileptic seizures that is not caused by cerebral ischemia.

This chapter deals with this uncommon but not exceptional complication of endovascular treatment of the arteries that supply the brain. We use the term carotid artery stenting (CAS) to refer to stenting of the internal carotid artery (ICA) because most publications are centered on this artery. Moreover, we include angioplasty without stent placement in the term CAS to facilitate reading comprehension because the relation between endovascular treatment and CHS is related to revascularization itself rather than to stent placement per se. Given the high rate of ischemic brain disease in relation to carotid stenosis and the high prevalence of asymptomatic carotid stenosis, numerous publications discuss CHS in relation to CEA: the incidence in these series ranges from 0.3% to 2.2%. However, CAS has continually evolved in recent years to the point where, after more than 40 years' experience, it is considered an alternative to CEA. Furthermore, the development of new materials for stents, filters for distal protection, dual antiplatelet treatment, and the learning curve are minimizing the short- and long-term adverse effects of CAS.

Documented complications of CAS include cerebral embolism, hemodynamic compromise, vessel dissection, and early restenosis and occlusion, as well as the hyperperfusion syndrome we deal with in this chapter. Moreover, the spectacular increase in endovascular treatment has revealed that hyperperfusion syndrome can also occur after revascularization of other arteries, such as the vertebral arteries, the subclavian arteries, or even those located within the brain, mainly the middle cerebral artery (MCA).

In this chapter we will begin by discussing the pathophysiology, clinical presentation, and incidence of CHS in the different published series. We will then discuss the risk factors, diagnostic methods, and strategies for prevention and treatment. We will also discuss a

Cerebral Hyperperfusion Syndrome After Angioplasty 11

increased the risk of intracranial hemorrhage (ICH) (Jansen et al, 1994; Macfarlane et al, 1991; Ouriel et al, 1999; Sbarigia et al, 1993). Preoperative significant reduction in flow velocity compared with baseline values is indicative of hypoperfusion and is associated with

Sudden revascularization brought about by angioplasty leads to dysfunction of the bloodbrain barrier after the failure of arteriolar vasoconstriction. This results in transudation of fluid into the pericapillary astrocytes and interstitium, giving rise to vasogenic edema. This hydrostatic edema predominantly affects the vertebrobasilar circulation territory in both CHS and hypertensive encephalopathy, possibly as a result of regional variation in cerebral

The most extreme form of this syndrome is bleeding, either ICH, which results in high morbidity and mortality, or subarachnoid hemorrhage (SAH), which has a better prognosis. The pathophysiology of the hemorrhage that results from revascularization might be different from that of CHS described by Sundt, et al (1981). Some authors (Karapanayiotides et al, 2005) prefer to call this entity "reperfusion syndrome" to emphasize the damage to tissues caused by simple reperfusion. Several investigators have analyzed the characteristics of this ICH when it appears in the first few hours and without prodromes, attributing it to the rupture of deep penetrating arteries as a result of the sudden normalization of the pressure of cerebral perfusion after angioplasty, similar to what occurs in hemorrhage due

Many cases of SAH after CAS have been reported (Abou-Chebl et al, 2004; Coutts et al, 2003; Hartmann et al, 2004; Ho et al, 2000; McCabe et al, 1999; Meyers et al, 2000; Morrish et al, 2000; Nikolsky et al, 2002; Pilz et al, 2006; Qureshi et al, 2002); these have a better

It is logical to assume that CBF increases substantially after CAS in a severely stenosed carotid artery. However, studies show that the increase in CBF is actually related to impaired CVR. In a study by Hosoda et al (1998) CBF significantly increased on the first postoperative day in subjects with reduced preoperative CVR but not in those with normal preoperative CVR. Similarly, in a study of 23 patients, Ko et al (2005) were unable to demonstrate a relation between the degree of stenosis and the increase in CBF. In short, the degree of stenosis cannot be considered a key risk factor for CHS, although some series have

Ascher et al (2003) studied 455 patients undergoing CEA and found no relation between CHS and the severity of ipsilateral or contralateral carotid stenosis, arterial hypertension, or perioperative perfusion pressure. However, mean ICA volume flow and peak systolic velocity measured at the onset of symptoms in the 9 CHS cases were higher than in the

In most cases of symptomatic carotid stenoses due to a hemodynamic mechanism CVR is also deficient, so it is logical to think that they will be more susceptible to developing CHS after revascularization (Brantley et al, 2009). However, in a study of 333 patients undergoing CAS, Karkos et al (2010) found no significant differences between symptomatic and

Fukuda et al (2007) carried out an interesting study of CBF and cerebral blood volume (CBV) in 15 patients without contralateral carotid stenosis undergoing CEA. They observed a correlation between increased CBV and increased CBF after CEA on single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), with signs of hyperperfusion in seven patients (47%). Two of these seven patients developed

postoperative hyperperfusion (Keunen et al, 2001).

to hypertension (Buhk et al, 2006; Coutts et al, 2003).

sympathetic innervation.

prognosis than ICH.

taken it into account.

remaining 446 cases.

asymptomatic patients.

condition that shares the same pathophysiology as CHS, contrast-induced encephalopathy, in which contrast agents crossing the blood-brain barrier have a toxic effect on the brain parenchyma, resulting in signs and symptoms similar to those of CHS. Given the larger number of publications about hyperperfusion after CEA and the obvious similarities in aspects like the pathophysiology and risk factors, we refer to CEA on numerous occasions in this chapter.

#### **2. Pathophysiology**

First, we must differentiate between the concept of hyperperfusion and CHS. In general, hyperperfusion is considered to occur when cerebral blood flow (CBF) in the revascularized territory increases by 100% or more with respect to the baseline values. In series by Ogasawara (2007) and Fukuda (2007), 16.7% to 28.6% of the patients with an increase in CBF 100% developed CHS. Moreover, a few cases of CHS in which CBF had increased less than 100% have been reported (Karapanayiotides et al, 2005; Henderson et al, 2001). Thus, other factors must be involved in CHS (Hosoda et al, 2003; Kaku et al, 2004; Ogasawara et al 2003; Suga et al, 2007; Yoshimoto et al, 1997).

All authors agree that it is very likely that there has to be damage to cerebral autoregulation, in other words, impaired cerebral vasoreactivity (CVR), for CHS to occur (Keunen et al, 2001).

Cerebral hemodynamics and CVR are individualized in each patient. This could be explained by the different extent of collateral circulation available and by the autoregulatory mechanisms of the cerebral circulation. The presence of sufficient collateral circulation has a key role in the preservation of CVR, and thus protects against CHS.

Similarly, other risk factors for CHS are low pulsatility index, severe ipsilateral and contralateral carotid disease, and an incomplete circle of Willis (Jansen et al, 1994; Reigel et al, 1987; Sbarigia et al 1993).

CVR makes it possible to keep blood pressure (BP) between acceptable limits (60 mmHg - 160 mmHg) through arteriolar vasodilatation or vasoconstriction in response to changes in carbon dioxide. This response is most pronounced in smaller arteries (diameter 0·5–1·0 mm), whereas arteries with a diameter of 2·5 mm or more like the ICA show no substantial change.

Regulation involves a myogenic and a neurogenic component. In myogenic autoregulation, increased intravascular pressure results in vasoconstriction of small arterioles at high systemic BP, but when BP exceeds the limit of myogenic autoregulation, the remaining autoregulation in small arteries is dependent on sympathetic autonomic innervation. As a result of sparse sympathetic innervation, the vertebrobasilar system is less protected than other regions of the brain, which explains why this system is more affected in entities like hypertensive encephalopathy. Impaired CVR results in failure of the arterial system to respond to a sudden increase in CBF and is usually due to severe vascular stenosis together with insufficient collateral blood flow. When these two factors coexist, cerebral perfusion is maintained by the maximum dilation of the arterioles. This prolonged vasodilation makes the vessels unable to respond with vasoconstriction when blood flow is increased, and especially when it is increased suddenly (Ascher et al, 2003; Jansen et al, 1994; Reigel et al, 1987; Tang et al, 2008 Sbarigia et al, 1993).

At the end of the 1990s, some surgical reports already suggested that patients with preoperative hemodynamic failure were at definite risk for CHS (Baker et al, 1998; Cikrit et al 1997; Yoshimoto et al, 1997) and that the presence of a critical stenosis in the ICA Angioplasty, Various Techniques and Challenges in 10 Treatment of Congenital and Acquired Vascular Stenoses

condition that shares the same pathophysiology as CHS, contrast-induced encephalopathy, in which contrast agents crossing the blood-brain barrier have a toxic effect on the brain parenchyma, resulting in signs and symptoms similar to those of CHS. Given the larger number of publications about hyperperfusion after CEA and the obvious similarities in aspects like the pathophysiology and risk factors, we refer to CEA on numerous occasions in

First, we must differentiate between the concept of hyperperfusion and CHS. In general, hyperperfusion is considered to occur when cerebral blood flow (CBF) in the revascularized territory increases by 100% or more with respect to the baseline values. In series by Ogasawara (2007) and Fukuda (2007), 16.7% to 28.6% of the patients with an increase in CBF 100% developed CHS. Moreover, a few cases of CHS in which CBF had increased less than 100% have been reported (Karapanayiotides et al, 2005; Henderson et al, 2001). Thus, other factors must be involved in CHS (Hosoda et al, 2003; Kaku et al, 2004; Ogasawara et al 2003;

All authors agree that it is very likely that there has to be damage to cerebral autoregulation, in other words, impaired cerebral vasoreactivity (CVR), for CHS to occur (Keunen et al,

Cerebral hemodynamics and CVR are individualized in each patient. This could be explained by the different extent of collateral circulation available and by the autoregulatory mechanisms of the cerebral circulation. The presence of sufficient collateral circulation has a

Similarly, other risk factors for CHS are low pulsatility index, severe ipsilateral and contralateral carotid disease, and an incomplete circle of Willis (Jansen et al, 1994; Reigel et

CVR makes it possible to keep blood pressure (BP) between acceptable limits (60 mmHg - 160 mmHg) through arteriolar vasodilatation or vasoconstriction in response to changes in carbon dioxide. This response is most pronounced in smaller arteries (diameter 0·5–1·0 mm), whereas

Regulation involves a myogenic and a neurogenic component. In myogenic autoregulation, increased intravascular pressure results in vasoconstriction of small arterioles at high systemic BP, but when BP exceeds the limit of myogenic autoregulation, the remaining autoregulation in small arteries is dependent on sympathetic autonomic innervation. As a result of sparse sympathetic innervation, the vertebrobasilar system is less protected than other regions of the brain, which explains why this system is more affected in entities like hypertensive encephalopathy. Impaired CVR results in failure of the arterial system to respond to a sudden increase in CBF and is usually due to severe vascular stenosis together with insufficient collateral blood flow. When these two factors coexist, cerebral perfusion is maintained by the maximum dilation of the arterioles. This prolonged vasodilation makes the vessels unable to respond with vasoconstriction when blood flow is increased, and especially when it is increased suddenly (Ascher et al, 2003; Jansen et al, 1994; Reigel et al,

At the end of the 1990s, some surgical reports already suggested that patients with preoperative hemodynamic failure were at definite risk for CHS (Baker et al, 1998; Cikrit et al 1997; Yoshimoto et al, 1997) and that the presence of a critical stenosis in the ICA

arteries with a diameter of 2·5 mm or more like the ICA show no substantial change.

key role in the preservation of CVR, and thus protects against CHS.

this chapter.

2001).

**2. Pathophysiology** 

Suga et al, 2007; Yoshimoto et al, 1997).

al, 1987; Sbarigia et al 1993).

1987; Tang et al, 2008 Sbarigia et al, 1993).

increased the risk of intracranial hemorrhage (ICH) (Jansen et al, 1994; Macfarlane et al, 1991; Ouriel et al, 1999; Sbarigia et al, 1993). Preoperative significant reduction in flow velocity compared with baseline values is indicative of hypoperfusion and is associated with postoperative hyperperfusion (Keunen et al, 2001).

Sudden revascularization brought about by angioplasty leads to dysfunction of the bloodbrain barrier after the failure of arteriolar vasoconstriction. This results in transudation of fluid into the pericapillary astrocytes and interstitium, giving rise to vasogenic edema. This hydrostatic edema predominantly affects the vertebrobasilar circulation territory in both CHS and hypertensive encephalopathy, possibly as a result of regional variation in cerebral sympathetic innervation.

The most extreme form of this syndrome is bleeding, either ICH, which results in high morbidity and mortality, or subarachnoid hemorrhage (SAH), which has a better prognosis. The pathophysiology of the hemorrhage that results from revascularization might be different from that of CHS described by Sundt, et al (1981). Some authors (Karapanayiotides et al, 2005) prefer to call this entity "reperfusion syndrome" to emphasize the damage to tissues caused by simple reperfusion. Several investigators have analyzed the characteristics of this ICH when it appears in the first few hours and without prodromes, attributing it to the rupture of deep penetrating arteries as a result of the sudden normalization of the pressure of cerebral perfusion after angioplasty, similar to what occurs in hemorrhage due to hypertension (Buhk et al, 2006; Coutts et al, 2003).

Many cases of SAH after CAS have been reported (Abou-Chebl et al, 2004; Coutts et al, 2003; Hartmann et al, 2004; Ho et al, 2000; McCabe et al, 1999; Meyers et al, 2000; Morrish et al, 2000; Nikolsky et al, 2002; Pilz et al, 2006; Qureshi et al, 2002); these have a better prognosis than ICH.

It is logical to assume that CBF increases substantially after CAS in a severely stenosed carotid artery. However, studies show that the increase in CBF is actually related to impaired CVR. In a study by Hosoda et al (1998) CBF significantly increased on the first postoperative day in subjects with reduced preoperative CVR but not in those with normal preoperative CVR. Similarly, in a study of 23 patients, Ko et al (2005) were unable to demonstrate a relation between the degree of stenosis and the increase in CBF. In short, the degree of stenosis cannot be considered a key risk factor for CHS, although some series have taken it into account.

Ascher et al (2003) studied 455 patients undergoing CEA and found no relation between CHS and the severity of ipsilateral or contralateral carotid stenosis, arterial hypertension, or perioperative perfusion pressure. However, mean ICA volume flow and peak systolic velocity measured at the onset of symptoms in the 9 CHS cases were higher than in the remaining 446 cases.

In most cases of symptomatic carotid stenoses due to a hemodynamic mechanism CVR is also deficient, so it is logical to think that they will be more susceptible to developing CHS after revascularization (Brantley et al, 2009). However, in a study of 333 patients undergoing CAS, Karkos et al (2010) found no significant differences between symptomatic and asymptomatic patients.

Fukuda et al (2007) carried out an interesting study of CBF and cerebral blood volume (CBV) in 15 patients without contralateral carotid stenosis undergoing CEA. They observed a correlation between increased CBV and increased CBF after CEA on single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), with signs of hyperperfusion in seven patients (47%). Two of these seven patients developed

Cerebral Hyperperfusion Syndrome After Angioplasty 13

headache, confusion, altered levels of consciousness, and sometimes vomiting. On the other hand, the edema usually manifests as a neurological deficit on the side of the untreated carotid artery, often associated with epileptic activity (seizures, usually starting as partial seizures). Arterial hypertension is the norm in patients that develop symptoms of CHS; however, it is important to remember that bradycardia and hypotension often occur initially

When a patient has symptoms of neurological deficit after angioplasty, the first diagnosis considered is embolic stroke from carotid plaque broken off during the procedure. Thus, CHS can mimic a stroke or transient ischemic attack (TIA), so it is important to take into account symptoms like headache, seizures, and altered mental status that can suggest CHS. Nevertheless, acute neurological deficit accompanied by headache or even seizures is

Neurological deficit due to vasogenic edema is usually transitory, given the absence of ischemic infarction (Bernstein et al, 1984; Piepgras et al 1988; Reigel et al, 1987; Sundt et al, 1981; Solomon et al, 1986). Although the neurological symptoms can vary, the most common are visual or motor deficits and aphasia. Other, rarer, symptoms include psychotic

Seizures are generally partial at first and sometimes become generalized later, although generalized seizures can also occur initially (Ho et al, 2000); in fact, even status epilepticus has been reported up to two weeks after the procedure (Kaku et al, 2004). One third of patients with CHS after CEA have seizures without hemiparesis, another third have

Curiously, the onset of symptoms after CEA and CAS differs. Symptoms usually do not appear until three to six days after CEA. In contrast, symptoms usually appear within a few hours of CAS. Ogasawara et al (2007) report that the incidence of CHS peaks six days after CEA and 12 hours after CAS. After reviewing 36 studies, Bouri et al (2011) concluded CHS

The same is true of ICH, which appears 10.7 ± 9.9 days after CEA and 1.7 ± 2.1 days after CAS, peaking in the first 12 hours. Tan et al (2004) studied the appearance and onset of complications after CAS in 201 patients; they report 10 cases with TIA (4.9%), 5 of which occurred more than 48 hours after the procedure, and 8 strokes (3.9%), 5 of which occurred between 2 and 19 days after the procedure. Curiously, however, these authors found no

The headache in CHS is usually moderate to severe and throbbing, similar to a migraine headache (Coutts et al, 2003), and it usually affects the same side as the artery treated. Headache may be the only manifestation of CHS (Connolly 2000; Ouriel et al, 1999; Sbarigia et al, 1993), so occasionally it has been considered a diagnostic criterion. After CEA, headaches are reported in 20% of patients without CHS, in 59% of those with CHS, and in

Postprocedural hypertension is a critical, though not essential, finding associated with CHS (Solomon et al, 1986; Schroeder et al, 1987; Ouriel et al 1999). Bouri et al review (2011) found that the mean systolic BP of CHS cases was 189 mmHg at presentation, and the proportion of patients with severe hypertension was significantly higher in patients who developed

Hypotension occurs immediately after CAS in 19% to 51% of patients. It is usually transient and rarely symptomatic, although it lasts longer than 24 hours in nearly 5% of patients. Bradycardia is also common, with an incidence of 3% to 37% in patients administered

obviously compatible with ICH, which can be ruled out only by neuroimaging.

hemiparesis without seizures, and another third have both (Bouri et al, 2011).

peaks five days after CEA and the latest case occurred after 28 days.

cases of CHS.

84% of those with ICH (Bouri et al, 2011).

CHS after CEA than in those who did not.

after angioplasty due to stimulation of the baroreceptor reflex.

alterations or mild cognitive deficit (Ogasawara et al, 2005).

The endothelial damage caused mainly by chronic hypertension in the small arteries may also be related to cerebral autoregulation (Skydell et al, 1987). In fact, some authors relate a history of stroke with a greater risk of CHS (Chamorro et al, 2000; McCabe et al, 1999).

Another important but not essential factor associated with CHS is high blood pressure. High blood pressure is the only factor we can treat, so it has become the principal target for prevention and treatment. Indeed, the pathophysiology of CHS is similar to that of hypertensive encephalopathy in which the blood-brain barrier ruptures as a consequence of severe hypertension. Furthermore, histologic changes like fibrinoid necrosis and petechial hemorrhage also occur in both hypertensive encephalopathy and CHS (Bernstein et al, 1984; Mansoor et al, 1996; Schwartz 2002; Vaughan & Delanty, 2000).

The mechanisms by which BP increases after carotid revascularization are poorly understood. The baroreceptor reflex might break down after receptor denervation after CEA or CAS, and hypertension accompanying this feature might increase cerebral perfusion which is more evident after bilateral carotid surgery (Ahn et al, 1989; Bove et al, 1979; Timmers et al, 2004) and is reported in 19% to 64% after CEA.

The stimulation of these baroreceptors in the carotid bifurcation during angioplasty can cause transient bradycardia and hypotension that can be followed by rebound hypertension. Other phenomena proposed to explain the high blood pressure include increased norepinephrine levels probably related to cerebral edema and increased intracranial pressure, the release of vasoactive neuropeptides, the use of anesthetic drugs, and perioperative stress (Bajardi et al, 1989; Benzel & Hoppens, 1991; Macfarlane et al, 1991; Towne JB & Bernhard, 1980; Skydell et al, 1987; Skudlarick & Mooring, 1982;).

Another possible mediator of impaired autoregulation in CHS is nitric oxide, which causes vasodilatation and can increase the permeability of cerebral vessels. Increased nitric oxide levels during clamping of the ICA and increased oxygen-derived free radicals produced during the restoration of cerebral perfusion are involved in endothelial dysfunction and deterioration of autoregulatory mechanisms after CEA (Suga et al, 2007). Several authors (Ogasawara et al, 2004; Saito et al, 2007) have reported that the degree of reactive oxygen species production after ischemia and reperfusion during CEA depends on the intensity of cerebral ischemia during ICA clamping.

Reactive oxygen species can play a role in the pathogenesis of post-CEA hyperperfusion, leading to widespread endothelial damage in the ipsilateral cerebral arteries and thereby increasing the risk of ICH in the early postoperative period. Furthermore, administering a free-radical scavenger can prevent CHS, providing additional support for this mechanism (Ogasawara et al, 2004).

Finally, an axon-like trigeminovascular reflex has been implicated in the pathophysiology of CHS (Macfarlane et al, 1991). The release of vasoactive neuropeptides from perivascular sensory nerves via axon reflex-like mechanisms has a significant bearing upon a number of hyperperfusion syndromes.

#### **3. Clinical presentation**

The typical clinical presentation of CHS combines symptoms due to ICH and those due to brain damage caused by vasogenic edema. The most common symptoms caused by ICH are Angioplasty, Various Techniques and Challenges in 12 Treatment of Congenital and Acquired Vascular Stenoses

CHS, whereas none of the eight patients with normal CBV developed CHS. In this study, elevated preoperative CBV was the only significant independent predictor of post-CEA

The endothelial damage caused mainly by chronic hypertension in the small arteries may also be related to cerebral autoregulation (Skydell et al, 1987). In fact, some authors relate a history of stroke with a greater risk of CHS (Chamorro et al, 2000; McCabe et al, 1999). Another important but not essential factor associated with CHS is high blood pressure. High blood pressure is the only factor we can treat, so it has become the principal target for prevention and treatment. Indeed, the pathophysiology of CHS is similar to that of hypertensive encephalopathy in which the blood-brain barrier ruptures as a consequence of severe hypertension. Furthermore, histologic changes like fibrinoid necrosis and petechial hemorrhage also occur in both hypertensive encephalopathy and CHS (Bernstein et al, 1984;

The mechanisms by which BP increases after carotid revascularization are poorly understood. The baroreceptor reflex might break down after receptor denervation after CEA or CAS, and hypertension accompanying this feature might increase cerebral perfusion which is more evident after bilateral carotid surgery (Ahn et al, 1989; Bove et al, 1979;

The stimulation of these baroreceptors in the carotid bifurcation during angioplasty can cause transient bradycardia and hypotension that can be followed by rebound hypertension. Other phenomena proposed to explain the high blood pressure include increased norepinephrine levels probably related to cerebral edema and increased intracranial pressure, the release of vasoactive neuropeptides, the use of anesthetic drugs, and perioperative stress (Bajardi et al, 1989; Benzel & Hoppens, 1991; Macfarlane et al, 1991;

Another possible mediator of impaired autoregulation in CHS is nitric oxide, which causes vasodilatation and can increase the permeability of cerebral vessels. Increased nitric oxide levels during clamping of the ICA and increased oxygen-derived free radicals produced during the restoration of cerebral perfusion are involved in endothelial dysfunction and deterioration of autoregulatory mechanisms after CEA (Suga et al, 2007). Several authors (Ogasawara et al, 2004; Saito et al, 2007) have reported that the degree of reactive oxygen species production after ischemia and reperfusion during CEA depends on the intensity of

Reactive oxygen species can play a role in the pathogenesis of post-CEA hyperperfusion, leading to widespread endothelial damage in the ipsilateral cerebral arteries and thereby increasing the risk of ICH in the early postoperative period. Furthermore, administering a free-radical scavenger can prevent CHS, providing additional support for this mechanism

Finally, an axon-like trigeminovascular reflex has been implicated in the pathophysiology of CHS (Macfarlane et al, 1991). The release of vasoactive neuropeptides from perivascular sensory nerves via axon reflex-like mechanisms has a significant bearing upon a number of

The typical clinical presentation of CHS combines symptoms due to ICH and those due to brain damage caused by vasogenic edema. The most common symptoms caused by ICH are

Towne JB & Bernhard, 1980; Skydell et al, 1987; Skudlarick & Mooring, 1982;).

Mansoor et al, 1996; Schwartz 2002; Vaughan & Delanty, 2000).

Timmers et al, 2004) and is reported in 19% to 64% after CEA.

cerebral ischemia during ICA clamping.

(Ogasawara et al, 2004).

hyperperfusion syndromes.

**3. Clinical presentation** 

hyperperfusion.

headache, confusion, altered levels of consciousness, and sometimes vomiting. On the other hand, the edema usually manifests as a neurological deficit on the side of the untreated carotid artery, often associated with epileptic activity (seizures, usually starting as partial seizures). Arterial hypertension is the norm in patients that develop symptoms of CHS; however, it is important to remember that bradycardia and hypotension often occur initially after angioplasty due to stimulation of the baroreceptor reflex.

When a patient has symptoms of neurological deficit after angioplasty, the first diagnosis considered is embolic stroke from carotid plaque broken off during the procedure. Thus, CHS can mimic a stroke or transient ischemic attack (TIA), so it is important to take into account symptoms like headache, seizures, and altered mental status that can suggest CHS. Nevertheless, acute neurological deficit accompanied by headache or even seizures is obviously compatible with ICH, which can be ruled out only by neuroimaging.

Neurological deficit due to vasogenic edema is usually transitory, given the absence of ischemic infarction (Bernstein et al, 1984; Piepgras et al 1988; Reigel et al, 1987; Sundt et al, 1981; Solomon et al, 1986). Although the neurological symptoms can vary, the most common are visual or motor deficits and aphasia. Other, rarer, symptoms include psychotic alterations or mild cognitive deficit (Ogasawara et al, 2005).

Seizures are generally partial at first and sometimes become generalized later, although generalized seizures can also occur initially (Ho et al, 2000); in fact, even status epilepticus has been reported up to two weeks after the procedure (Kaku et al, 2004). One third of patients with CHS after CEA have seizures without hemiparesis, another third have hemiparesis without seizures, and another third have both (Bouri et al, 2011).

Curiously, the onset of symptoms after CEA and CAS differs. Symptoms usually do not appear until three to six days after CEA. In contrast, symptoms usually appear within a few hours of CAS. Ogasawara et al (2007) report that the incidence of CHS peaks six days after CEA and 12 hours after CAS. After reviewing 36 studies, Bouri et al (2011) concluded CHS peaks five days after CEA and the latest case occurred after 28 days.

The same is true of ICH, which appears 10.7 ± 9.9 days after CEA and 1.7 ± 2.1 days after CAS, peaking in the first 12 hours. Tan et al (2004) studied the appearance and onset of complications after CAS in 201 patients; they report 10 cases with TIA (4.9%), 5 of which occurred more than 48 hours after the procedure, and 8 strokes (3.9%), 5 of which occurred between 2 and 19 days after the procedure. Curiously, however, these authors found no cases of CHS.

The headache in CHS is usually moderate to severe and throbbing, similar to a migraine headache (Coutts et al, 2003), and it usually affects the same side as the artery treated.

Headache may be the only manifestation of CHS (Connolly 2000; Ouriel et al, 1999; Sbarigia et al, 1993), so occasionally it has been considered a diagnostic criterion. After CEA, headaches are reported in 20% of patients without CHS, in 59% of those with CHS, and in 84% of those with ICH (Bouri et al, 2011).

Postprocedural hypertension is a critical, though not essential, finding associated with CHS (Solomon et al, 1986; Schroeder et al, 1987; Ouriel et al 1999). Bouri et al review (2011) found that the mean systolic BP of CHS cases was 189 mmHg at presentation, and the proportion of patients with severe hypertension was significantly higher in patients who developed CHS after CEA than in those who did not.

Hypotension occurs immediately after CAS in 19% to 51% of patients. It is usually transient and rarely symptomatic, although it lasts longer than 24 hours in nearly 5% of patients. Bradycardia is also common, with an incidence of 3% to 37% in patients administered

Cerebral Hyperperfusion Syndrome After Angioplasty 15

maps can show local hyperemia. Karapanayiotides et al (2005) reported no abnormalities on diffusion-weighted MRI in patients with CHS after CEA, ruling out acute ischemia;

Hypoperfusion before revascularization and especially hyperperfusion (increase in CBF > 100% with respect to baseline values) after revascularization are conditions that are closely related with CHS. TCD is the method most often used to detect these conditions because it enables variations in CBF to be calculated in real time. TCD has many advantages and multiple indications in cerebral vascular disease (Alexandrov et al, 2010). TCD monitoring can provide direct and real-time information on MCA flow indicative of preoperative cerebral hypoperfusion, CVR, postoperative hyperperfusion, and emboli after CEA and CAS. Moreover, TCD is widely available, noninvasive, and reproducible. It is important to do a baseline study to enable flow velocities before and after revascularization to be

Asher et al (2003) studied 455 patients undergoing CEA and reported a significant increase in mean ICA flow volume in all patients with CHS during the symptomatic period; moreover, after flow velocities return to normal, the symptoms of hyperperfusion

Diverse publications about patients undergoing CAS emphasize the role of TCD in detecting hemodynamic changes that make it possible to select patients with greater risk of developing CHS. For example, in one interesting study published recently, Kablak et al (2010) monitored both MCAs before and after CAS, finding a relation between ICH in 3 patients and an increase in peak systolic velocities in both MCAs after CAS. Fujimoto et al (2004) examined the changes in the MCA mean flow velocity measured by TCD before and 4 days after CEA. They reported a significant correlation between changes in mean flow velocity and changes in regional CBF; mean flow velocity increased more than 50% in all

Some studies have used both TCD and SPECT to assess patients before and after revascularization. Recently, Iwata et al (2011) used these two techniques to study 64 patients and found 9 patients who fulfilled the clinical criteria for CHS. These authors relate CHS

Perfusion CT has also contributed to our understanding of CHS. Tseng at al (2009) used CT to study 55 patients with symptomatic stenoses >70% of the ICA, analyzing absolute values of CBV, mean transit time (MTT), and CBF. Three (5%) of 55 patients had CHS after CAS. The only significant factor related to the occurrence of CHS was MTT. An MTT cutoff of 3 seconds distinguished between the occurrence and absence of CHS. MTT prolongation is proportional to the degree of stenosis and decrease in blood flow (Maeda et al, 1999; Lythgoe et al, 2000; Soinne et al, 2003). Findings of decreased CBF together with MTT prolongation and a slight increase in CBV indicate that blood vessels are dilated, thus

Several authors have examined the role of CT and MRI in demonstrating hyperperfusion (Adhiyaman & Alexander 2007; Imai et al 2005; Sundt et al, 1981). Multislice dynamic susceptibility contrast MRI or perfusion-weighted MRI can also be used in the preoperative assessment of CBF (Fukuda et al, 2007; Wiart et al 2000). Perfusion sequences, however, are

PET has also provided valuable information about CHS. Matsubara et al (2009) used PET to study patients before and after angioplasty. They found that the vascular reserve tended to improve gradually after CAS, while CBF, cerebral perfusion pressure, and cerebral

not quantitative and can only help in the absence of contralateral ICA stenosis.

with decreased CVR and changes in MCA flow velocity after angioplasty.

confirming that the autoregulation mechanism is impaired.

however, perfusion sequences revealed differences in CBF between the hemispheres.

compared (Dalman et al, 1999; Jansen et al, 1994).

disappear.

cases of CHS.

prophylactic atropine and of 20% to 60% in series with no use of prophylactic atropine. Increased age, symptomatic lesions, presence of ulceration and calcification, and carotid bulb lesions are significant predictors of bradycardia during CAS (Cayne et al, 2005; Lin et al, 2007; Pappada et al, 2006 & Taha et al, 2008).

Another complication with more dramatic consequences is ICH, which affects less than 1% of patients after CEA and between 0.36% and 4.5% after CAS. Generally, ICH has a poor prognosis, with a 37% to 80% mortality rate and a 20% to 30% risk of poor recovery in survivors after CEA (Piepgras et al,1988; Connolly 2000) and similar consequences after CAS.

#### **4. Diagnosis**

The diagnosis of CHS is based on the initial suspicion arising from the characteristic triad of headache, focal neurological deficit, and seizure after arterial revascularization. The differential diagnosis should include stroke and TIA. Seizures and altered consciousness favor the diagnosis of CHS. After the initial clinical suspicion, neuroimaging plays a crucial role because in addition to ruling out ischemic and hemorrhagic lesions it can reveal characteristic signs of hyperperfusion.

Given the widespread availability of CT, any acute neurological event after revascularization is usually studied with this technique. CT is most useful for ruling out hemorrhagic processes. Given that the initial symptoms of CHS can mimic stroke or TIA, CT can give us clues that argue against an ischemic stroke, because CT findings are usually normal after a TIA and are often normal within hours after a stroke. Diffusion MRI is the technique of choice to rule out acute ischemic stroke; MRI has shown that there are a greater number of embolic lesions up to 48 hours after CAS, although nearly all are asymptomatic (Rapp et al, 2007).

We will comment on two important aspects of neuroimaging studies. First, we will discuss their usefulness in the diagnosis of CHS, as apart from demonstrating typical findings like vasogenic edema (Case 1) they also enable CBF to be quantified (increases in CBF > 100% with respect to baseline values have been related to greater risk of developing CHS). Second, we will discuss the usefulness of these techniques in the evaluation of CVR, the key pathophysiological factor in CHS.

#### **4.1 Diagnosing cerebral hyperperfusion**

The imaging techniques that can demonstrate hyperperfusion are single-photon emission computed tomography (SPECT), positron emission tomography (PET), transcranial Doppler (TCD), CT and MRI. According to Penn et al (1995), xenon-enhanced CT is the best method for demonstrating hyperperfusion. Nevertheless, SPECT and TCD are the most common methods in the literature, followed by CT and MRI.

CT in CHS typically reveals ipsilateral sulcal effacement and cerebral edema immediately following the onset of symptoms; these findings are considered indirect signs of hyperperfusion. CT findings early after the onset of symptoms can be completely normal, even when SPECT shows hyperperfusion.

Without doubt, T2-weighted and FLAIR MRI sequences are more precise in demonstrating areas of cerebral edema, and diffusion-weighted MRI makes it possible to rule out hyperacute ischemic lesions.

However, normal findings on MRI do not exclude the presence of CHS. Both MRI and CT enable angiographic maps to be constructed to rule out arterial occlusions and perfusion Angioplasty, Various Techniques and Challenges in 14 Treatment of Congenital and Acquired Vascular Stenoses

prophylactic atropine and of 20% to 60% in series with no use of prophylactic atropine. Increased age, symptomatic lesions, presence of ulceration and calcification, and carotid bulb lesions are significant predictors of bradycardia during CAS (Cayne et al, 2005; Lin et

Another complication with more dramatic consequences is ICH, which affects less than 1% of patients after CEA and between 0.36% and 4.5% after CAS. Generally, ICH has a poor prognosis, with a 37% to 80% mortality rate and a 20% to 30% risk of poor recovery in survivors after CEA (Piepgras et al,1988; Connolly 2000) and similar consequences after CAS.

The diagnosis of CHS is based on the initial suspicion arising from the characteristic triad of headache, focal neurological deficit, and seizure after arterial revascularization. The differential diagnosis should include stroke and TIA. Seizures and altered consciousness favor the diagnosis of CHS. After the initial clinical suspicion, neuroimaging plays a crucial role because in addition to ruling out ischemic and hemorrhagic lesions it can reveal

Given the widespread availability of CT, any acute neurological event after revascularization is usually studied with this technique. CT is most useful for ruling out hemorrhagic processes. Given that the initial symptoms of CHS can mimic stroke or TIA, CT can give us clues that argue against an ischemic stroke, because CT findings are usually normal after a TIA and are often normal within hours after a stroke. Diffusion MRI is the technique of choice to rule out acute ischemic stroke; MRI has shown that there are a greater number of embolic lesions up to 48 hours after CAS, although nearly all are asymptomatic

We will comment on two important aspects of neuroimaging studies. First, we will discuss their usefulness in the diagnosis of CHS, as apart from demonstrating typical findings like vasogenic edema (Case 1) they also enable CBF to be quantified (increases in CBF > 100% with respect to baseline values have been related to greater risk of developing CHS). Second, we will discuss the usefulness of these techniques in the evaluation of CVR, the key

The imaging techniques that can demonstrate hyperperfusion are single-photon emission computed tomography (SPECT), positron emission tomography (PET), transcranial Doppler (TCD), CT and MRI. According to Penn et al (1995), xenon-enhanced CT is the best method for demonstrating hyperperfusion. Nevertheless, SPECT and TCD are the most common

CT in CHS typically reveals ipsilateral sulcal effacement and cerebral edema immediately following the onset of symptoms; these findings are considered indirect signs of hyperperfusion. CT findings early after the onset of symptoms can be completely normal,

Without doubt, T2-weighted and FLAIR MRI sequences are more precise in demonstrating areas of cerebral edema, and diffusion-weighted MRI makes it possible to rule out

However, normal findings on MRI do not exclude the presence of CHS. Both MRI and CT enable angiographic maps to be constructed to rule out arterial occlusions and perfusion

al, 2007; Pappada et al, 2006 & Taha et al, 2008).

characteristic signs of hyperperfusion.

pathophysiological factor in CHS.

**4.1 Diagnosing cerebral hyperperfusion** 

even when SPECT shows hyperperfusion.

hyperacute ischemic lesions.

methods in the literature, followed by CT and MRI.

**4. Diagnosis** 

(Rapp et al, 2007).

maps can show local hyperemia. Karapanayiotides et al (2005) reported no abnormalities on diffusion-weighted MRI in patients with CHS after CEA, ruling out acute ischemia; however, perfusion sequences revealed differences in CBF between the hemispheres.

Hypoperfusion before revascularization and especially hyperperfusion (increase in CBF > 100% with respect to baseline values) after revascularization are conditions that are closely related with CHS. TCD is the method most often used to detect these conditions because it enables variations in CBF to be calculated in real time. TCD has many advantages and multiple indications in cerebral vascular disease (Alexandrov et al, 2010). TCD monitoring can provide direct and real-time information on MCA flow indicative of preoperative cerebral hypoperfusion, CVR, postoperative hyperperfusion, and emboli after CEA and CAS. Moreover, TCD is widely available, noninvasive, and reproducible. It is important to do a baseline study to enable flow velocities before and after revascularization to be compared (Dalman et al, 1999; Jansen et al, 1994).

Asher et al (2003) studied 455 patients undergoing CEA and reported a significant increase in mean ICA flow volume in all patients with CHS during the symptomatic period; moreover, after flow velocities return to normal, the symptoms of hyperperfusion disappear.

Diverse publications about patients undergoing CAS emphasize the role of TCD in detecting hemodynamic changes that make it possible to select patients with greater risk of developing CHS. For example, in one interesting study published recently, Kablak et al (2010) monitored both MCAs before and after CAS, finding a relation between ICH in 3 patients and an increase in peak systolic velocities in both MCAs after CAS. Fujimoto et al (2004) examined the changes in the MCA mean flow velocity measured by TCD before and 4 days after CEA. They reported a significant correlation between changes in mean flow velocity and changes in regional CBF; mean flow velocity increased more than 50% in all cases of CHS.

Some studies have used both TCD and SPECT to assess patients before and after revascularization. Recently, Iwata et al (2011) used these two techniques to study 64 patients and found 9 patients who fulfilled the clinical criteria for CHS. These authors relate CHS with decreased CVR and changes in MCA flow velocity after angioplasty.

Perfusion CT has also contributed to our understanding of CHS. Tseng at al (2009) used CT to study 55 patients with symptomatic stenoses >70% of the ICA, analyzing absolute values of CBV, mean transit time (MTT), and CBF. Three (5%) of 55 patients had CHS after CAS. The only significant factor related to the occurrence of CHS was MTT. An MTT cutoff of 3 seconds distinguished between the occurrence and absence of CHS. MTT prolongation is proportional to the degree of stenosis and decrease in blood flow (Maeda et al, 1999; Lythgoe et al, 2000; Soinne et al, 2003). Findings of decreased CBF together with MTT prolongation and a slight increase in CBV indicate that blood vessels are dilated, thus confirming that the autoregulation mechanism is impaired.

Several authors have examined the role of CT and MRI in demonstrating hyperperfusion (Adhiyaman & Alexander 2007; Imai et al 2005; Sundt et al, 1981). Multislice dynamic susceptibility contrast MRI or perfusion-weighted MRI can also be used in the preoperative assessment of CBF (Fukuda et al, 2007; Wiart et al 2000). Perfusion sequences, however, are not quantitative and can only help in the absence of contralateral ICA stenosis.

PET has also provided valuable information about CHS. Matsubara et al (2009) used PET to study patients before and after angioplasty. They found that the vascular reserve tended to improve gradually after CAS, while CBF, cerebral perfusion pressure, and cerebral

Cerebral Hyperperfusion Syndrome After Angioplasty 17

A 71-year–old man with symptomatic pseudo-occlusion of the right ICA had a seizure with Todd´s paralysis six days after CEA. Neuroimaging showed vasogenic edema

However, the high cost and limited availability of SPECT preclude its clinical use.

hypocapnia (induced by breath holding or by inhalation of CO2) or acetazolamide.

(1- CT, 2- Axial T2-weighted MRi, 3-Coronal FLAIR MRi, 4- Axial diffusion-weighted MRi,

CBF. These authors determined that pretreatment resting CBF value, degree of carotid stenosis, and interval from the onset of ischemic symptoms were not significant risk factors.

TCD has numerous advantages in diagnosing hemodynamic reserve: it is noninvasive, relatively simple, cheap, and reproducible, and it is risk free when the breath-hold and hyperventilation method is used. TCD enables CVR to be calculated using stimuli like

The response to these stimuli reflects the cerebral autoregulation capacity and thus makes it possible to determine which patients have a high risk of developing CHS (Sfyroeras 2006,

**Case 1** 

5- CT angiography)

metabolic rate of oxygen increased rapidly and peaked soon after CAS. These results suggest that a large discrepancy between rapidly increased CBF, perfusion pressure, and a small increase in vascular reserve in the acute stage after CAS could cause CHS.

Cerebral oxygen saturation can serve as an indirect measure of CBF. Clinically, regional cerebral oxygen saturation can be monitored using transcranial near-infrared spectroscopy, which enables noninvasive continuous real-time detection of changes in the ratio of oxyhemoglobin to deoxyhemoglobin in the frontal cortex, an indirect measure of cerebral oxygenation. Recently, a strong linear correlation was reported between increased transcranial regional cerebral oxygen saturation and increased CBF after CEA (Ogasawara et al, 2003). When compared with SPECT, the sensitivity and specificity of transcranial regional cerebral oxygen saturation for the detection of hyperperfusion were 100%. Transcranial near-infrared spectroscopy can demonstrate decreased cerebral oxygenation resulting from ICA clamping (Beese et al, 1998; Duncan et al, 1995; Kirkpatrick et al, 1995; Samra et al, 1996) and can predict post-CEA CHS. Matsumoto et al (2009) used transcranial near-infrared spectroscopy to study 64 patients undergoing CAS, two of whom developed CHS (diagnosed by increased CBF at SPECT the day after treatment). An increase in regional oxygen saturation > 24% three minutes after revascularization was associated with the development of CHS (with impaired CVR). In contrast, in patients without CHS, the normal upper limit of the change in regional oxygen saturation three minutes after revascularization was 10 %.

Oxygen saturation should be monitored for a prudential time because bradycardia and hypotension often occur with CAS and can occasionally lead to low initial values. As occurs in many studies, the small number of patients with CHS in this study does not allow clear conclusions to be drawn; nevertheless, given that transcranial near-infrared spectroscopy is noninvasive and easy to perform, it should be considered for monitoring patients at risk for CHS.

Alternative methods have been applied to identify risk factors for postoperative hyperperfusion, but their utility is not yet clearly established. Electroencephalography is used for neurological monitoring during CEA, but it is of low predictive value for CHS (Reigel et al, 1987). Nicholas et al (1993) reported that a postoperative increase in ocular blood flow greater than 204% measured by ocular pneumoplethysmography is associated with a high risk for CHS.

#### **4.2 Diagnosing hemodynamic reserve**

One strategy that is key to preventing CHS is the study of CVR, which is usually done by TCD and SPECT.

SPECT is sensitive for recognizing CHS, differentiating between ischemia and hyperperfusion, and identifying patients at risk for hyperperfusion after CEA (Hosoda et al, 2001; Naylor et al, 2003; Sfyroeras et al, 2006). Several studies using SPECT have demonstrated that decreased CVR using acetazolamide is a significant predictor of post-CEA hyperperfusion (Ogasawara et al, 2003; Yoshimoto et al, 1997).

Fewer studies have focused on patients undergoing CAS. Kaku et al (2004) published one of the first studies about predicting CHS with nuclear medicine techniques in patients undergoing CAS.

They measured resting CBF and CVR to acetazolamide to evaluate CVR, using split-dose [123I] iodoamphetamine SPECT before and 7 days after CAS in 30 patients with critical carotid stenosis. The 3 patients with hyperperfusion all had impaired CVR and asymmetrical carotid

#### **Case 1**

Angioplasty, Various Techniques and Challenges in 16 Treatment of Congenital and Acquired Vascular Stenoses

metabolic rate of oxygen increased rapidly and peaked soon after CAS. These results suggest that a large discrepancy between rapidly increased CBF, perfusion pressure, and a

Cerebral oxygen saturation can serve as an indirect measure of CBF. Clinically, regional cerebral oxygen saturation can be monitored using transcranial near-infrared spectroscopy, which enables noninvasive continuous real-time detection of changes in the ratio of oxyhemoglobin to deoxyhemoglobin in the frontal cortex, an indirect measure of cerebral oxygenation. Recently, a strong linear correlation was reported between increased transcranial regional cerebral oxygen saturation and increased CBF after CEA (Ogasawara et al, 2003). When compared with SPECT, the sensitivity and specificity of transcranial regional cerebral oxygen saturation for the detection of hyperperfusion were 100%. Transcranial near-infrared spectroscopy can demonstrate decreased cerebral oxygenation resulting from ICA clamping (Beese et al, 1998; Duncan et al, 1995; Kirkpatrick et al, 1995; Samra et al, 1996) and can predict post-CEA CHS. Matsumoto et al (2009) used transcranial near-infrared spectroscopy to study 64 patients undergoing CAS, two of whom developed CHS (diagnosed by increased CBF at SPECT the day after treatment). An increase in regional oxygen saturation > 24% three minutes after revascularization was associated with the development of CHS (with impaired CVR). In contrast, in patients without CHS, the normal upper limit of the change in regional oxygen saturation three minutes after revascularization

Oxygen saturation should be monitored for a prudential time because bradycardia and hypotension often occur with CAS and can occasionally lead to low initial values. As occurs in many studies, the small number of patients with CHS in this study does not allow clear conclusions to be drawn; nevertheless, given that transcranial near-infrared spectroscopy is noninvasive and easy to perform, it should be considered for monitoring patients at risk

Alternative methods have been applied to identify risk factors for postoperative hyperperfusion, but their utility is not yet clearly established. Electroencephalography is used for neurological monitoring during CEA, but it is of low predictive value for CHS (Reigel et al, 1987). Nicholas et al (1993) reported that a postoperative increase in ocular blood flow greater than 204% measured by ocular pneumoplethysmography is associated

One strategy that is key to preventing CHS is the study of CVR, which is usually done by

SPECT is sensitive for recognizing CHS, differentiating between ischemia and hyperperfusion, and identifying patients at risk for hyperperfusion after CEA (Hosoda et al, 2001; Naylor et al, 2003; Sfyroeras et al, 2006). Several studies using SPECT have demonstrated that decreased CVR using acetazolamide is a significant predictor of post-

Fewer studies have focused on patients undergoing CAS. Kaku et al (2004) published one of the first studies about predicting CHS with nuclear medicine techniques in patients

They measured resting CBF and CVR to acetazolamide to evaluate CVR, using split-dose [123I] iodoamphetamine SPECT before and 7 days after CAS in 30 patients with critical carotid stenosis. The 3 patients with hyperperfusion all had impaired CVR and asymmetrical carotid

CEA hyperperfusion (Ogasawara et al, 2003; Yoshimoto et al, 1997).

small increase in vascular reserve in the acute stage after CAS could cause CHS.

was 10 %.

for CHS.

with a high risk for CHS.

TCD and SPECT.

undergoing CAS.

**4.2 Diagnosing hemodynamic reserve** 

A 71-year–old man with symptomatic pseudo-occlusion of the right ICA had a seizure with Todd´s paralysis six days after CEA. Neuroimaging showed vasogenic edema (1- CT, 2- Axial T2-weighted MRi, 3-Coronal FLAIR MRi, 4- Axial diffusion-weighted MRi, 5- CT angiography)

CBF. These authors determined that pretreatment resting CBF value, degree of carotid stenosis, and interval from the onset of ischemic symptoms were not significant risk factors. However, the high cost and limited availability of SPECT preclude its clinical use.

TCD has numerous advantages in diagnosing hemodynamic reserve: it is noninvasive, relatively simple, cheap, and reproducible, and it is risk free when the breath-hold and hyperventilation method is used. TCD enables CVR to be calculated using stimuli like hypocapnia (induced by breath holding or by inhalation of CO2) or acetazolamide.

The response to these stimuli reflects the cerebral autoregulation capacity and thus makes it possible to determine which patients have a high risk of developing CHS (Sfyroeras 2006,

Cerebral Hyperperfusion Syndrome After Angioplasty 19

explain the greater number of complications, including CHS, in patients treated with CAS. Furthermore, the endovascular procedure is performed with stricter antithrombotic management, with anticoagulation and dual antiplatelet treatment that might lead to a higher rate of hemorrhagic events, although not all authors agree with this hypothesis (Abou-Chebl et al, 2004; Meyers et al, 2000). Table 2 lists risk factors for CHS, broken down

Although procedural and midterm complication rates of CAS in elderly patients are acceptable, high age seems to be a possible risk factor for CHS (Kadkhodayan et al, 2007). Other risk factors often mentioned in the literature are severe (>90%) ipsilateral stenosis, impaired collateral flow secondary to advanced occlusive disease in other extracranial cerebral vessels or an incomplete circle of Willis, perioperative and postoperative hypertension, and the use of antiplatelet agents or other anticoagulants (Chamorro et al,

Abou et al (2004) report a series of 450 patients undergoing CAS where 5 (1.1%) developed CHS, 3 of them developed ICH (0.67%), and 2 of them (0.44%) died. All the patients that developed CHS had stenoses >90%, contralateral stenoses >80%, and longstanding preprocedural hypertension. The authors calculate that in patients with these three conditions, the risk of developing CHS was 16%. Only 5.8% of the patients that did not develop CHS met these three criteria. The low incidence of CHS in this series might be due to the fact that CHS was not diagnosed in cases with headache and vomiting. Two of the cases of ICH appeared a few days after CAS and only one occurred immediately after the

Ogasawara et al (2007) published a series of 4494 patients revascularized with CEA or CAS. Of the 1596 patients treated with CEA, 30 (1.9%) developed CHS and 6 of these developed ICH (0.4% of the total). Of the 2898 patients treated with CAS, 31 (1.1%) developed CHS and 21 (0.7% of the total) of these developed ICH. In the group of patients treated with CEA but not in those treated with CAS, poor BP control after revascularization correlated with CHS. CHS and ICH ocurred significantly earlier after CAS than after CEA. The difference between the two procedures in terms of the timing of CHS onset may be explained as follows. First, the higher incidence of embolisms after CAS (Roh et al, 2005) might explain how a hemorrhagic transformation could occur after the resolution of the embolism in the tissue that was damaged; from a pathophysiological point of view, however, this would represent hemorrhagic infarction due to reperfusion rather than CHS. Second, the higher incidence of bradycardia and hypotension after the stimulation of the carotid baroreceptors during CAS (Mendelsohn et al, 1998; McKevitt et al, 2003; Qureshi et al, 1999) can favor cerebral ischemia and CHS after severe rebound hypertension (Abou-Chebl et al, 2007). In an earlier publication (Ogasawara et al, 2003), these authors suggested that SPECT findings of hyperperfusion continuing at least three days after revascularization predisposes to CHS. In an excellent review of 9 studies of CAS comprising a total of 4446 patients, Moulakakis et al (2009) found the incidences of CHS and ICH were 1.16% (range, 0.44% - 11.7%) and 0.74% (range, 0.36% -4.5%), respectively. Table 3 shows the incidence of CHS and of ICH in the largest series published before 2010, including series of patients undergoing angioplasty of

In order to document the incidence of CHS after CAS and to determine possible predisposing factors, Sfyroeras et al (2009) studied 29 patients with CT, MRI, TCD including assessment of CVR, and SPECT before and after the procedure. A total of 5 patients developed adverse neurological events. Two of them developed CHS (6.9%); both had

into modifiable and non-modifiable factors.

procedure.

intracranial arteries.

2000; Reigel et al, 1987; Sfyroeras et al 2008; Zahn et al, 2007).

2009). However, TCD has some drawbacks. The absence of a cranial window makes TCD impossible in 15% of patients, mainly elderly women. Moreover, TCD is operatordependent and the results also depend on anatomic variants, the degree of collateralization, and contralateral ICA occlusion or stenosis.

Table 1 shows the formulas to calculate the CVR using breath-holding and CO2 inhalation or acetazolamide. In the breath-hold method, patients are asked to hold their breath for at least 30 seconds during continuous MCA flow velocity monitoring; normal values are 1.2 +/- 0.6% / sec. In the hyperventilation/ breath-holding method, patients are asked to hyperventilate for 40 seconds followed by a breath-holding phase of at least 30 seconds. Flow velocity values under maximal hyperventilation and hypoventilation are compared; a relative difference greater than 15% argues against relevant impairment of CVR.

Table 1.

Chang et al (2009) used functional MRI to assess baseline CVR and changes in CBF after CAS. Although this small series of 14 patients had no cases of CHS, this study revealed that after CAS early CBF changes on the lesion side are more prominent in patients with impaired CVR. Therefore, baseline CVR might predict early CBF increase after CAS. New MRI techniques like dynamic susceptibility contrast MRI or perfusion-weighted MRI can determine CVR (Wiart et al, 2000).

#### **5. Incidence and risk factors**

This section reviews the incidence of CHS after CAS in the most relevant series included in PubMed from 2003 to April 2011. We focus on three aspects of CHS: extracranial CAS, angioplasty of intracranial arteries (including the ICA) with or without stenting, and cerebral hemorrhage, the most-feared complication of this treatment.

#### **5.1 Extracranial carotid angioplasty**

Most articles about CHS refer to CAS or CEA of the ICA because occlusive disease is more prevalent in these arteries than elsewhere. Bouri et al (2011) reviewed 36 studies of patients undergoing CEA and found 1% incidence of CHS and a 0.5% incidence of ICH.

In many CAS series, patients referred for endovascular treatment comprise a high-risk cohort of suboptimal candidates for conventional surgical management. This might partially Angioplasty, Various Techniques and Challenges in 18 Treatment of Congenital and Acquired Vascular Stenoses

2009). However, TCD has some drawbacks. The absence of a cranial window makes TCD impossible in 15% of patients, mainly elderly women. Moreover, TCD is operatordependent and the results also depend on anatomic variants, the degree of collateralization,

Table 1 shows the formulas to calculate the CVR using breath-holding and CO2 inhalation or acetazolamide. In the breath-hold method, patients are asked to hold their breath for at least 30 seconds during continuous MCA flow velocity monitoring; normal values are 1.2 +/- 0.6% / sec. In the hyperventilation/ breath-holding method, patients are asked to hyperventilate for 40 seconds followed by a breath-holding phase of at least 30 seconds. Flow velocity values under maximal hyperventilation and hypoventilation are compared; a

> ---------------------------------------------------------------------------- CO2 inhalation test/acetazolamide test

Chang et al (2009) used functional MRI to assess baseline CVR and changes in CBF after CAS. Although this small series of 14 patients had no cases of CHS, this study revealed that after CAS early CBF changes on the lesion side are more prominent in patients with impaired CVR. Therefore, baseline CVR might predict early CBF increase after CAS. New MRI techniques like dynamic susceptibility contrast MRI or perfusion-weighted MRI can

This section reviews the incidence of CHS after CAS in the most relevant series included in PubMed from 2003 to April 2011. We focus on three aspects of CHS: extracranial CAS, angioplasty of intracranial arteries (including the ICA) with or without stenting, and

Most articles about CHS refer to CAS or CEA of the ICA because occlusive disease is more prevalent in these arteries than elsewhere. Bouri et al (2011) reviewed 36 studies of patients

In many CAS series, patients referred for endovascular treatment comprise a high-risk cohort of suboptimal candidates for conventional surgical management. This might partially

undergoing CEA and found 1% incidence of CHS and a 0.5% incidence of ICH.

 CO2/acetazolamide – V baseline CVR = -------------------------------------- x 100%)

relative difference greater than 15% argues against relevant impairment of CVR.

Breath-holding index (BHI)

 V apnea - V baseline BHI = ------------------------- x 100 V baseline x T apnea

Vbaseline

cerebral hemorrhage, the most-feared complication of this treatment.

Table 1.

determine CVR (Wiart et al, 2000).

**5. Incidence and risk factors** 

**5.1 Extracranial carotid angioplasty** 

and contralateral ICA occlusion or stenosis.

explain the greater number of complications, including CHS, in patients treated with CAS. Furthermore, the endovascular procedure is performed with stricter antithrombotic management, with anticoagulation and dual antiplatelet treatment that might lead to a higher rate of hemorrhagic events, although not all authors agree with this hypothesis (Abou-Chebl et al, 2004; Meyers et al, 2000). Table 2 lists risk factors for CHS, broken down into modifiable and non-modifiable factors.

Although procedural and midterm complication rates of CAS in elderly patients are acceptable, high age seems to be a possible risk factor for CHS (Kadkhodayan et al, 2007). Other risk factors often mentioned in the literature are severe (>90%) ipsilateral stenosis, impaired collateral flow secondary to advanced occlusive disease in other extracranial cerebral vessels or an incomplete circle of Willis, perioperative and postoperative hypertension, and the use of antiplatelet agents or other anticoagulants (Chamorro et al, 2000; Reigel et al, 1987; Sfyroeras et al 2008; Zahn et al, 2007).

Abou et al (2004) report a series of 450 patients undergoing CAS where 5 (1.1%) developed CHS, 3 of them developed ICH (0.67%), and 2 of them (0.44%) died. All the patients that developed CHS had stenoses >90%, contralateral stenoses >80%, and longstanding preprocedural hypertension. The authors calculate that in patients with these three conditions, the risk of developing CHS was 16%. Only 5.8% of the patients that did not develop CHS met these three criteria. The low incidence of CHS in this series might be due to the fact that CHS was not diagnosed in cases with headache and vomiting. Two of the cases of ICH appeared a few days after CAS and only one occurred immediately after the procedure.

Ogasawara et al (2007) published a series of 4494 patients revascularized with CEA or CAS. Of the 1596 patients treated with CEA, 30 (1.9%) developed CHS and 6 of these developed ICH (0.4% of the total). Of the 2898 patients treated with CAS, 31 (1.1%) developed CHS and 21 (0.7% of the total) of these developed ICH. In the group of patients treated with CEA but not in those treated with CAS, poor BP control after revascularization correlated with CHS. CHS and ICH ocurred significantly earlier after CAS than after CEA. The difference between the two procedures in terms of the timing of CHS onset may be explained as follows. First, the higher incidence of embolisms after CAS (Roh et al, 2005) might explain how a hemorrhagic transformation could occur after the resolution of the embolism in the tissue that was damaged; from a pathophysiological point of view, however, this would represent hemorrhagic infarction due to reperfusion rather than CHS. Second, the higher incidence of bradycardia and hypotension after the stimulation of the carotid baroreceptors during CAS (Mendelsohn et al, 1998; McKevitt et al, 2003; Qureshi et al, 1999) can favor cerebral ischemia and CHS after severe rebound hypertension (Abou-Chebl et al, 2007). In an earlier publication (Ogasawara et al, 2003), these authors suggested that SPECT findings of hyperperfusion continuing at least three days after revascularization predisposes to CHS.

In an excellent review of 9 studies of CAS comprising a total of 4446 patients, Moulakakis et al (2009) found the incidences of CHS and ICH were 1.16% (range, 0.44% - 11.7%) and 0.74% (range, 0.36% -4.5%), respectively. Table 3 shows the incidence of CHS and of ICH in the largest series published before 2010, including series of patients undergoing angioplasty of intracranial arteries.

In order to document the incidence of CHS after CAS and to determine possible predisposing factors, Sfyroeras et al (2009) studied 29 patients with CT, MRI, TCD including assessment of CVR, and SPECT before and after the procedure. A total of 5 patients developed adverse neurological events. Two of them developed CHS (6.9%); both had

Cerebral Hyperperfusion Syndrome After Angioplasty 21

Tietke et al (2010) analyzed the outcomes of 358 patients treated with CAS using small closed-cell stents without distal protection. The peri-interventional and 30-day mortality/stroke rate was 4.19% (15/358). These events included 3 deaths, 5 CHS (comprising one death by a secondary fatal ICH), one SAH and 7 ischaemic strokes. All but one of the patients with CHS had an initial stenosis of >90%; the remaining patient had an initial stenosis of 50% to 70% and was the only one with CHS without ICH. The patient who died was the only woman with CHS and she also had an occluded contralateral ICA. Most

The risk of CHS related to the type of protection (proximal or distal) has not been thoroughly studied. Pieniazek et al. (2004) compared the complications in 135 patients undergoing CAS, 42 with proximal protection and 93 with distal protection, but only one

Bilateral carotid stenoses are generally treated in two separate stenting procedures to minimize hemodynamic impairment from stimulation of the carotid sinus baroreceptor reflex (severe bradycardia, hypotension) and the risk of CHS. As we explained in section 2 (pathophysiology), the baroreceptor reflex might break down after receptor denervation after CEA or CAS; this is more common after bilateral carotid surgery, and accompanying

**Author / Year Patients CHS (%) ICH (%)**  Meyers / 2000 140 7 (5%) 1 (0.7%) Coutts / 2003 44 3 (6.8%) 2 (4.5%) Abou / 2004 450 2 (0.44%) 3 (0.67%) Kaku / 2004 30 1 (3.33%) 0% Imai / 2005 17 2 (11.7%) 2 (11.7%) du Mesnil de Rochemontn / 2006 50 1 (2%) 0% Kablak-Ziembicka / 2006 92 2 (2.2%) 2 (2.2%) Abou / 2007 836 8 (0.96%) 3 (0.36%) Ogasawara / 2007 2989 31 (1.1%) 21 (0.7%) Sfyroeras / 2008 29 2 (7%) 0% Brantley / 2009 482 7 (1.5%) 0% Grunwald / 2009 417 7 (1.7%) 3 (0.7%) Tietke et al (2010) 358 4 (1.1%) 1 (0.27%) Karkos et al (2010). 316 10 (3%) 0%

Table 3. Incidence of hyperperfusion syndrome, and intracranial hemorrhage after CAS in

complications occurred in initial symptomatic patients (5.36%).

case of CHS developed.

hypertension might increase the risk of CHS.

the reviewed series from 2003 to 2010

exhausted CVR in the preoperative TCD examination. All studies that investigate CVR before treatment have found a relation between impaired CVR and the risk of CHS. Brantley et al (2009) studied 482 patients, 7 (1.45%) of whom developed CHS after CAS. None had an ICH and all recovered within 6 to 24 hours. All had been classified as high risk for CEA, and CHS was more common in those with a previous TIA. The absence of ICH was probably related to the fact that 64% of the patients had asymptomatic stenoses. These authors found no significant relation between CHS and risk factors reported in other series like hypertension, high-grade ICA stenosis, and contralateral disease. The postprocedural BP in the CHS cohort tended to be higher than in the other patients, but this difference did not reach statistical significance.


#### Table 2.

Grunwald et al (2009) report a series of 417 patients treated with CAS in whom BP was meticulously controlled during the first 24 hours; furthermore, MRI was performed before and after the procedure in 269 cases. The mean degree of carotid stenosis was 87%, and 65% of the patients were symptomatic. Of the 10 (2.4%) patients who developed CHS, seven had excessive small vessel disease with old territorial infarcts or freshly demarked lesions. Small vessel disease is considered a risk factor for CHS because it impairs the capacity of these arteries to contract. Curiously, none of these patients had severe hypertension. In three cases, ICH occurred within a few hours of CAS, and all of these had extensive microvascular changes and impaired collateral blood flow due to high-grade stenosis (>80%) of the contralateral ICA. However, 23% of the patients that did not develop CHS also had highgrade stenosis of the contralateral ICA. On MRI, all had increased signal intensity in the subarachnoid space on the same side as the stented ICA, which resolved within 3–5 days.

Curiously, this study was unable to demonstrate a relation between CHS and factors like postprocedural hypertension, advanced age, degree of ipsilateral stenosis, or contralateral disease.

Regarding prior stroke as a risk factor for CHS, many authors have found that diseases like diabetes mellitus or longstanding pre-existing hypertension in which microangiopathy affects the endothelium of small vessels predispose to hyperperfusion and CHS (Chamorro et al, 2000; McCabe et al, 1999; Naylor et al, 2003; van Mook et al, 2005).

Angioplasty, Various Techniques and Challenges in 20 Treatment of Congenital and Acquired Vascular Stenoses

exhausted CVR in the preoperative TCD examination. All studies that investigate CVR

Brantley et al (2009) studied 482 patients, 7 (1.45%) of whom developed CHS after CAS. None had an ICH and all recovered within 6 to 24 hours. All had been classified as high risk for CEA, and CHS was more common in those with a previous TIA. The absence of ICH was probably related to the fact that 64% of the patients had asymptomatic stenoses. These authors found no significant relation between CHS and risk factors reported in other series like hypertension, high-grade ICA stenosis, and contralateral disease. The postprocedural BP in the CHS cohort tended to be higher than in the other patients, but this difference did

Potential risk factors for CHS

Excessive administration of antithrombotic drugs Hypertensive microangiopathy

Recent (<3 months) contralateral CEA High grade carotid artery stenosis

Grunwald et al (2009) report a series of 417 patients treated with CAS in whom BP was meticulously controlled during the first 24 hours; furthermore, MRI was performed before and after the procedure in 269 cases. The mean degree of carotid stenosis was 87%, and 65% of the patients were symptomatic. Of the 10 (2.4%) patients who developed CHS, seven had excessive small vessel disease with old territorial infarcts or freshly demarked lesions. Small vessel disease is considered a risk factor for CHS because it impairs the capacity of these arteries to contract. Curiously, none of these patients had severe hypertension. In three cases, ICH occurred within a few hours of CAS, and all of these had extensive microvascular changes and impaired collateral blood flow due to high-grade stenosis (>80%) of the contralateral ICA. However, 23% of the patients that did not develop CHS also had highgrade stenosis of the contralateral ICA. On MRI, all had increased signal intensity in the subarachnoid space on the same side as the stented ICA, which resolved within 3–5 days. Curiously, this study was unable to demonstrate a relation between CHS and factors like postprocedural hypertension, advanced age, degree of ipsilateral stenosis, or contralateral

Regarding prior stroke as a risk factor for CHS, many authors have found that diseases like diabetes mellitus or longstanding pre-existing hypertension in which microangiopathy affects the endothelium of small vessels predispose to hyperperfusion and CHS (Chamorro

et al, 2000; McCabe et al, 1999; Naylor et al, 2003; van Mook et al, 2005).

Modifiable Not modifiable High blood pressure Diminished CVR

Simultaneous revascularization of multiple vessels Recent minor stroke Use of high doses of volatile halogenated Age >70 years

 Incomplete circle of Willis Contralateral carotid occlusion

 Increase in regional cerebral oxygen saturation >24% Diabetes mellitus, Hypertension Increase in perfusion >100% Preoperative hypoperfusion

Poor collateral flow

before treatment have found a relation between impaired CVR and the risk of CHS.

not reach statistical significance.

hydrocarbon anesthetics

Table 2.

disease.

Tietke et al (2010) analyzed the outcomes of 358 patients treated with CAS using small closed-cell stents without distal protection. The peri-interventional and 30-day mortality/stroke rate was 4.19% (15/358). These events included 3 deaths, 5 CHS (comprising one death by a secondary fatal ICH), one SAH and 7 ischaemic strokes. All but one of the patients with CHS had an initial stenosis of >90%; the remaining patient had an initial stenosis of 50% to 70% and was the only one with CHS without ICH. The patient who died was the only woman with CHS and she also had an occluded contralateral ICA. Most complications occurred in initial symptomatic patients (5.36%).

The risk of CHS related to the type of protection (proximal or distal) has not been thoroughly studied. Pieniazek et al. (2004) compared the complications in 135 patients undergoing CAS, 42 with proximal protection and 93 with distal protection, but only one case of CHS developed.

Bilateral carotid stenoses are generally treated in two separate stenting procedures to minimize hemodynamic impairment from stimulation of the carotid sinus baroreceptor reflex (severe bradycardia, hypotension) and the risk of CHS. As we explained in section 2 (pathophysiology), the baroreceptor reflex might break down after receptor denervation after CEA or CAS; this is more common after bilateral carotid surgery, and accompanying hypertension might increase the risk of CHS.


Table 3. Incidence of hyperperfusion syndrome, and intracranial hemorrhage after CAS in the reviewed series from 2003 to 2010

Cerebral Hyperperfusion Syndrome After Angioplasty 23

It is important to remember that hemorrhage caused by vessel injury is also a possible mechanism of hemorrhagic complications. For instance, in the patient with SAH in Terada et al (2006) studies, wall dissection, perforation of the vessel wall by the guidewire, or rupture of a tiny aneurysm located at the distal part of ICA were not completely ruled out. Rezende et al (2006) reported a case of CHS after stenting for intracranial vertebral stenosis. They point out the significant hemodynamic component due to the absence of the

More recent articles about intracranial angioplasty show more promising results. Guo et al (2010) implanted 53 self-expanding stents with a technical success rate of 98%. Complications included SAH (1.9%) and occlusion (3.8%), but there were no cases of CHS. Zhang et al (2008) reported the first case of ICH after CAS in both vertebral arteries with stenosis >90%. The flow velocity of both vertebral arteries measured by TCD increased more than 100% and high BP coincided with the abrupt onset of ICH three hours after the

In conclusion, the factors involved in the development of CHS after intracranial procedures seem similar to those involved in extracranial procedures, and the results of intracranial

ICH is the severest form of CHS and it has the worst prognosis (Case 2). The low incidence of ICH and the small number of patients in the various series reported precludes clear conclusions about the risk factors involved, although presumably they are the same as those involved in CHS. The first question is whether ICH is an extreme consequence of CHS or whether it has a distinct pathophysiology. Numerous mechanisms are possible: CHS, hemorrhagic diathesis caused by antiplatelet and anticoagulation therapy after stenting, hemorrhage around or in a recent infarction or other associated lesion (including

In an interesting article published in 2003, Coutts et al try to narrow the definition of CHS. After studying 129 patients treated with CEA and 44 treated by CAS, these authors postulate that three different syndromes can occur in relation to hyperperfusion: acute focal edema, acute hemorrhage, and delayed classic presentation described for Sundt et al (1981). One of their patients had ICH three hours after CAS in the absence of high BP or symptoms suggestive of hyperperfusion. Other authors like Buhk et al (2006) argue for the existence of two distinct syndromes: first, classic CHS, in which symptoms of ipsilateral, frontotemporal, or retro-orbital headache, neurological deficit, and sometimes seizures typically begin between the fifth and seventh days after revascularization, and second, a more dramatic clinical presentation with ICH considered as damage due to reperfusion (Imparato et al, 1984; Takolander & Bergqvist 1983). In many of the cases published, ICH occurred within a few hours of the procedure and predominantly affected the basal ganglia; furthermore, all the patients in these cases presented with a high-grade stenosis. Therefore, the pathophysiology of this type of ICH might differ from that of CHS, being closer to that of hypertensive ICH, in this case due to rupture of small perforating arteries in the basal ganglia after acute exposure to suddenly normalized perfusion pressure after angioplasty of

Brantley et al (2009) reported a patient with a nearly occlusive ICA stenosis who developed a fatal ipsilateral ICH immediately after the intervention; ICH was due to hemorrhagic

contralateral vertebral artery and collateral supply from the carotid territory.

procedure.

angioplasty are very promising.

a high grade stenosis.

conversion of a prior stroke.

**5.3 Intracranial hemorrhage after angioplasty** 

hypertensive ICH), or rupture of an intracranial aneurysm.

Few studies have addressed the subject of simultaneous bilateral CAS. Henry et al. (2005) reported a series of 17 patients who underwent simultaneous bilateral CAS and 40 patients who underwent bilateral CAS in a staged manner (among these 40 patients 10 underwent the second procedure 24 hours after the first, while the other 30 underwent the second procedure from 2 days to 2 months after the first). Two cases of CHS occurred, one each group, although the patient in the simultaneous treatment group who developed CHS died. Lee et al. (2006) found no CHS in a series of 27 patients who underwent bilateral CAS. Diehm et al. (2008) studied patients treated with bilateral CAS with at least one month between procedures and reported no significant differences in complications compared to patients treated with unilateral CAS.

An interesting study that deals with pseudo-occlusive carotids was published by Choi et al (2010). These authors analyze the outcome after CAS in 48 patients with nearly occlusive stenosis of the ICA. The procedural success rate was 98% and a good outcome at six months (modified Rankin scale 2) was achieved in 44 patients (92%). Four (8%) patients developed CHS.

Another interesting article was published by Karkos et al (2010). They studied the complications in the first 30 days in 333 angioplasties in 316 patients, 35% of whom had symptomatic carotid disease. Perioperative neurological events included stroke in 6 patients (1.8%), TIA in 15 (4.5%), and CHS in 10 (3.0%). The incidence of CHS did not differ between the group of patients with symptoms and those without. Bradycardia was noted in 48 patients (14%) and hypotension in 45 (13%), and two of these patients (0.6%) required admission to the intensive care unit for hemodynamic instability. Curiously, the only factors related to increased morbimortality were hyperlipidemia and current or previous smoking.

#### **5.2 Angioplasty in intracranial arteries**

As is to be expected, fewer studies have addressed CHS in relation to intracranial angioplasty because this procedure is newer than angioplasty in extracranial arteries. In this section, we will discuss the most interesting series and cases of patients treated with this technique. In 2000, Meyers et al reported the first SAH due to stenosis of the intracranial vertebral artery. In their series of 140 patients treated with CAS (including 10 intracranial carotids, 14 intracranial vertebral arteries, 4 basilar arteries, and 1 MCA), the incidence of CHS was 5% (7 of 140 patients, 5 carotids and 2 vertebral arteries), one with ICH and another with SAH. Importantly, six patients (85%) were symptomatic with crescendo TIAs before treatment, and these symptoms were probably related to impaired CVR. The first case of CHS with ICH after intracranial MCA angioplasty was reported by Liu et al in 2001.

One of the first series of patients undergoing intracranial CAS was published by Terada et al (2006). These authors reported 106 procedures in 99 patients (57 patients had intracranial ICA stenosis, 23 had MCA stenosis, and 19 had vertebrobasilar stenosis). The ICA stenosis involved the petrous or cavernous in 47 cases (24 patients were treated with angioplasty and 23 with stenting). Four hemorrhagic complications occurred in 106 procedures. One patient had SAH and the other 3 cases had the following characteristics: severe stenosis with poor collateral flow, low perfusion with CVR damage on SPECT, appearance of ICH between 30 minutes and 16 hours after the procedure, and patient age greater than 70 years. The rate of ICH directly related to CAS was 3%. In two of three cases, CHS was strongly suspected from the SPECT findings. In the nonhemorrhagic group, hemodynamic compromise was found in 27 of 47 (57%) patients.

Angioplasty, Various Techniques and Challenges in 22 Treatment of Congenital and Acquired Vascular Stenoses

Few studies have addressed the subject of simultaneous bilateral CAS. Henry et al. (2005) reported a series of 17 patients who underwent simultaneous bilateral CAS and 40 patients who underwent bilateral CAS in a staged manner (among these 40 patients 10 underwent the second procedure 24 hours after the first, while the other 30 underwent the second procedure from 2 days to 2 months after the first). Two cases of CHS occurred, one each group, although the patient in the simultaneous treatment group who developed CHS died. Lee et al. (2006) found no CHS in a series of 27 patients who underwent bilateral CAS. Diehm et al. (2008) studied patients treated with bilateral CAS with at least one month between procedures and reported no significant differences in complications compared to

An interesting study that deals with pseudo-occlusive carotids was published by Choi et al (2010). These authors analyze the outcome after CAS in 48 patients with nearly occlusive stenosis of the ICA. The procedural success rate was 98% and a good outcome at six months (modified Rankin scale 2) was achieved in 44 patients (92%). Four (8%)

Another interesting article was published by Karkos et al (2010). They studied the complications in the first 30 days in 333 angioplasties in 316 patients, 35% of whom had symptomatic carotid disease. Perioperative neurological events included stroke in 6 patients (1.8%), TIA in 15 (4.5%), and CHS in 10 (3.0%). The incidence of CHS did not differ between the group of patients with symptoms and those without. Bradycardia was noted in 48 patients (14%) and hypotension in 45 (13%), and two of these patients (0.6%) required admission to the intensive care unit for hemodynamic instability. Curiously, the only factors related to increased morbimortality were hyperlipidemia and current or previous smoking.

As is to be expected, fewer studies have addressed CHS in relation to intracranial angioplasty because this procedure is newer than angioplasty in extracranial arteries. In this section, we will discuss the most interesting series and cases of patients treated with this technique. In 2000, Meyers et al reported the first SAH due to stenosis of the intracranial vertebral artery. In their series of 140 patients treated with CAS (including 10 intracranial carotids, 14 intracranial vertebral arteries, 4 basilar arteries, and 1 MCA), the incidence of CHS was 5% (7 of 140 patients, 5 carotids and 2 vertebral arteries), one with ICH and another with SAH. Importantly, six patients (85%) were symptomatic with crescendo TIAs before treatment, and these symptoms were probably related to impaired CVR. The first case of CHS with ICH after intracranial MCA angioplasty was reported by Liu et al in 2001. One of the first series of patients undergoing intracranial CAS was published by Terada et al (2006). These authors reported 106 procedures in 99 patients (57 patients had intracranial ICA stenosis, 23 had MCA stenosis, and 19 had vertebrobasilar stenosis). The ICA stenosis involved the petrous or cavernous in 47 cases (24 patients were treated with angioplasty and 23 with stenting). Four hemorrhagic complications occurred in 106 procedures. One patient had SAH and the other 3 cases had the following characteristics: severe stenosis with poor collateral flow, low perfusion with CVR damage on SPECT, appearance of ICH between 30 minutes and 16 hours after the procedure, and patient age greater than 70 years. The rate of ICH directly related to CAS was 3%. In two of three cases, CHS was strongly suspected from the SPECT findings. In the nonhemorrhagic group, hemodynamic compromise was found in

patients treated with unilateral CAS.

**5.2 Angioplasty in intracranial arteries** 

patients developed CHS.

27 of 47 (57%) patients.

It is important to remember that hemorrhage caused by vessel injury is also a possible mechanism of hemorrhagic complications. For instance, in the patient with SAH in Terada et al (2006) studies, wall dissection, perforation of the vessel wall by the guidewire, or rupture of a tiny aneurysm located at the distal part of ICA were not completely ruled out.

Rezende et al (2006) reported a case of CHS after stenting for intracranial vertebral stenosis. They point out the significant hemodynamic component due to the absence of the contralateral vertebral artery and collateral supply from the carotid territory.

More recent articles about intracranial angioplasty show more promising results. Guo et al (2010) implanted 53 self-expanding stents with a technical success rate of 98%. Complications included SAH (1.9%) and occlusion (3.8%), but there were no cases of CHS.

Zhang et al (2008) reported the first case of ICH after CAS in both vertebral arteries with stenosis >90%. The flow velocity of both vertebral arteries measured by TCD increased more than 100% and high BP coincided with the abrupt onset of ICH three hours after the procedure.

In conclusion, the factors involved in the development of CHS after intracranial procedures seem similar to those involved in extracranial procedures, and the results of intracranial angioplasty are very promising.

#### **5.3 Intracranial hemorrhage after angioplasty**

ICH is the severest form of CHS and it has the worst prognosis (Case 2). The low incidence of ICH and the small number of patients in the various series reported precludes clear conclusions about the risk factors involved, although presumably they are the same as those involved in CHS. The first question is whether ICH is an extreme consequence of CHS or whether it has a distinct pathophysiology. Numerous mechanisms are possible: CHS, hemorrhagic diathesis caused by antiplatelet and anticoagulation therapy after stenting, hemorrhage around or in a recent infarction or other associated lesion (including hypertensive ICH), or rupture of an intracranial aneurysm.

In an interesting article published in 2003, Coutts et al try to narrow the definition of CHS. After studying 129 patients treated with CEA and 44 treated by CAS, these authors postulate that three different syndromes can occur in relation to hyperperfusion: acute focal edema, acute hemorrhage, and delayed classic presentation described for Sundt et al (1981). One of their patients had ICH three hours after CAS in the absence of high BP or symptoms suggestive of hyperperfusion. Other authors like Buhk et al (2006) argue for the existence of two distinct syndromes: first, classic CHS, in which symptoms of ipsilateral, frontotemporal, or retro-orbital headache, neurological deficit, and sometimes seizures typically begin between the fifth and seventh days after revascularization, and second, a more dramatic clinical presentation with ICH considered as damage due to reperfusion (Imparato et al, 1984; Takolander & Bergqvist 1983). In many of the cases published, ICH occurred within a few hours of the procedure and predominantly affected the basal ganglia; furthermore, all the patients in these cases presented with a high-grade stenosis. Therefore, the pathophysiology of this type of ICH might differ from that of CHS, being closer to that of hypertensive ICH, in this case due to rupture of small perforating arteries in the basal ganglia after acute exposure to suddenly normalized perfusion pressure after angioplasty of a high grade stenosis.

Brantley et al (2009) reported a patient with a nearly occlusive ICA stenosis who developed a fatal ipsilateral ICH immediately after the intervention; ICH was due to hemorrhagic conversion of a prior stroke.

Cerebral Hyperperfusion Syndrome After Angioplasty 25

Matsuo et al (2000) reported two cases of ICH, one of which affected the basal ganglia the day after CAS. The fatal ICH reported by Abou et al (2004) appeared at the level of the basal ganglia one hour after CAS. Finally, the series of 161 patients reported by Koch et al (2002) included a single case of fatal ICH after CAS in a severely stenosed ICA. Kablak et al (2010) reported 3 (1.4%) cases ICH among 210 patients, one of whom had SAH. In their study, increased systolic velocity in both MCAs was a clear risk factor, and one of the three patients

In addition to impaired CVR, the most widely accepted risk factors are insufficient intracranial collateralization and signs of cerebral microangiopathy. We know that hypertensive encephalopathy does not consist only of periventricular demyelination but possibly also includes small areas of perivascular hemorrhage that can be associated with higher risk of developing ICH. It also seems that the severity of the stenosis plays an

Neurotoxicity from contrast agents is a rare but well-known complication of diagnostic and

Leptomeningeal enhancement is often reported after CAS due to the abrupt increase in blood flow even when this does not cause symptoms (Wilkinson et al, 2000). Nevertheless, some authors purport that this phenomenon represents the extravasation of contrast material toward the subarachnoid space; Bretschneider and Strotzer (2000) reported 11 cases, some of which were related to hypoxic brain damage. Ekel et al (1998) reported a case of contrast enhancement mimicking SAH, and Mamourian et al (2000) used an animal model to demonstrate that contrast material can cross into the cerebrospinal spinal fluid in sufficient concentration to alter the appearance of the subarachnoid space on MRI. Dangas et al (2001) reported a case of contrast-induced encephalopathy after CAS in an 82-year-old man with a TIA and 90% stenosis in the right carotid. Immediately after CAS, this patient presented confusion and left hemiparesis in the territory of the right carotid. CT showed marked cortical enhancement and edema of the right cerebral hemisphere. The patient improved rapidly and by day 2 was completely recovered; MRI found no cortical edema

Canovas et al (2007) published a case of extravasation of contrast material immediately after the rupture of the balloon in a woman with a very calcified plaque (Case 3) in whom the pressure of the balloon reached 8 atmospheres. The pressure of the balloon probably magnified the hemodynamic effect, making the extravasation of the contrast material very aggressive and giving rise to a clinical picture identical to an embolic stroke of the MCA. As in other cases reported in the literature, this patient's condition improved and the imaging

Contrast-induced encephalopathy should be differentiated from the classical CHS described Sundt et al (1981), although it probably has a similar pathophysiology. A high dose of contrast agent may result in acute breakdown of the blood-brain barrier, allowing the contrast material to enter the brain and resulting in the acute development of a dramatic clinical presentation. The higher osmolality of ioxaglate compared with blood may in turn produce fluid extravasation and cerebral edema. The prognosis is usually excellent, as is evidenced by other recently published cases occurring after endovascular procedures

had occlusion or severe stenosis of the contralateral carotid.

**6. Contrast-induced encephalopathy** 

and normal sulci.

findings were normal after 48 h.

(Guimaraens et al, 2010, Fang et al, 2009; Paúl et al, 2009).

therapeutic procedures that employ these agents.

important role, as most patients in the literature have severe stenosis.

The incidence of ICH after CEA in the series published ranges between 0.2% and 0.7% (Piepgras et al, 1988; Pomposelli et al, 1988; Solomon et al, 1986; Wilson & Ammar, 2005), whereas the incidence of ICH after CAS is higher (Timaran et al, 2009), reaching 5% in some series.

Schoser et al (1997) reported the first case of ICH after CAS, a 59-year-old woman with severe stenosis of the left ICA who developed putaminal hemorrhage on the third day after the procedure. CT showed an ipsilateral border zone infartion.

McCabe et al (1999) reported the first fatal case of ICH after CAS, a man with severe stenosis who developed ICH within hours of CAS without any prodromes. Mori et al (1999) reported a similar case in which ICH affected the basal zones with ventricular and subarachnoid extension. Both cases had signs of microangiopathy, which is associated with increased risk of ICH (Chamorro et al, 2000; McCabe et al, 1999).

#### **Case 2**

1- Angiogram showing 95% stenosis of the left ICA in a patient with occlusion of the right ICA.

2- Angiogram after left CAS.

3- No lesions were discernible on the pre-treatment CT .

4- CT 24 hours later shows extensive hematoma in the left frontal lobe

(Courtesy of Dr. Carlos Castaño).

Tan and Phatouros (2009) reviewed 170 patients treated with CAS, 4 (2.3%) of whom developed CHS, one of these with cerebral edema, one with petechial hemorrhage, and two with ICH, which was fatal in one case. All developed CHS within six hours of the procedure and all had stenoses of the internal carotid >95%. Both patients who developed ICH had been treated within three weeks after an ischemic event.

Morrish et al (2000) observed a 4.4% incidence of ICH after 104 CAS in 90 patients; the mean ICA stenosis was 95% in those who developed ICH. In two of the patients, who died, ICH involved the basal ganglia. In this series, the incidence of ICH may have been increased due to a high dose of heparin and the absence of distal protection, given that recent ischemia is a risk factor for ICH.

Angioplasty, Various Techniques and Challenges in 24 Treatment of Congenital and Acquired Vascular Stenoses

The incidence of ICH after CEA in the series published ranges between 0.2% and 0.7% (Piepgras et al, 1988; Pomposelli et al, 1988; Solomon et al, 1986; Wilson & Ammar, 2005), whereas the incidence of ICH after CAS is higher (Timaran et al, 2009), reaching 5% in some

Schoser et al (1997) reported the first case of ICH after CAS, a 59-year-old woman with severe stenosis of the left ICA who developed putaminal hemorrhage on the third day after

McCabe et al (1999) reported the first fatal case of ICH after CAS, a man with severe stenosis who developed ICH within hours of CAS without any prodromes. Mori et al (1999) reported a similar case in which ICH affected the basal zones with ventricular and subarachnoid extension. Both cases had signs of microangiopathy, which is associated with increased risk

the procedure. CT showed an ipsilateral border zone infartion.

1- Angiogram showing 95% stenosis of the left ICA in a patient with

4- CT 24 hours later shows extensive hematoma in the left frontal lobe

Tan and Phatouros (2009) reviewed 170 patients treated with CAS, 4 (2.3%) of whom developed CHS, one of these with cerebral edema, one with petechial hemorrhage, and two with ICH, which was fatal in one case. All developed CHS within six hours of the procedure and all had stenoses of the internal carotid >95%. Both patients who developed ICH had

Morrish et al (2000) observed a 4.4% incidence of ICH after 104 CAS in 90 patients; the mean ICA stenosis was 95% in those who developed ICH. In two of the patients, who died, ICH involved the basal ganglia. In this series, the incidence of ICH may have been increased due to a high dose of heparin and the absence of distal protection, given that recent ischemia is a

3- No lesions were discernible on the pre-treatment CT .

been treated within three weeks after an ischemic event.

of ICH (Chamorro et al, 2000; McCabe et al, 1999).

series.

**Case 2** 

 occlusion of the right ICA. 2- Angiogram after left CAS.

risk factor for ICH.

(Courtesy of Dr. Carlos Castaño).

Matsuo et al (2000) reported two cases of ICH, one of which affected the basal ganglia the day after CAS. The fatal ICH reported by Abou et al (2004) appeared at the level of the basal ganglia one hour after CAS. Finally, the series of 161 patients reported by Koch et al (2002) included a single case of fatal ICH after CAS in a severely stenosed ICA. Kablak et al (2010) reported 3 (1.4%) cases ICH among 210 patients, one of whom had SAH. In their study, increased systolic velocity in both MCAs was a clear risk factor, and one of the three patients had occlusion or severe stenosis of the contralateral carotid.

In addition to impaired CVR, the most widely accepted risk factors are insufficient intracranial collateralization and signs of cerebral microangiopathy. We know that hypertensive encephalopathy does not consist only of periventricular demyelination but possibly also includes small areas of perivascular hemorrhage that can be associated with higher risk of developing ICH. It also seems that the severity of the stenosis plays an important role, as most patients in the literature have severe stenosis.

#### **6. Contrast-induced encephalopathy**

Neurotoxicity from contrast agents is a rare but well-known complication of diagnostic and therapeutic procedures that employ these agents.

Leptomeningeal enhancement is often reported after CAS due to the abrupt increase in blood flow even when this does not cause symptoms (Wilkinson et al, 2000). Nevertheless, some authors purport that this phenomenon represents the extravasation of contrast material toward the subarachnoid space; Bretschneider and Strotzer (2000) reported 11 cases, some of which were related to hypoxic brain damage. Ekel et al (1998) reported a case of contrast enhancement mimicking SAH, and Mamourian et al (2000) used an animal model to demonstrate that contrast material can cross into the cerebrospinal spinal fluid in sufficient concentration to alter the appearance of the subarachnoid space on MRI. Dangas et al (2001) reported a case of contrast-induced encephalopathy after CAS in an 82-year-old man with a TIA and 90% stenosis in the right carotid. Immediately after CAS, this patient presented confusion and left hemiparesis in the territory of the right carotid. CT showed marked cortical enhancement and edema of the right cerebral hemisphere. The patient improved rapidly and by day 2 was completely recovered; MRI found no cortical edema and normal sulci.

Canovas et al (2007) published a case of extravasation of contrast material immediately after the rupture of the balloon in a woman with a very calcified plaque (Case 3) in whom the pressure of the balloon reached 8 atmospheres. The pressure of the balloon probably magnified the hemodynamic effect, making the extravasation of the contrast material very aggressive and giving rise to a clinical picture identical to an embolic stroke of the MCA. As in other cases reported in the literature, this patient's condition improved and the imaging findings were normal after 48 h.

Contrast-induced encephalopathy should be differentiated from the classical CHS described Sundt et al (1981), although it probably has a similar pathophysiology. A high dose of contrast agent may result in acute breakdown of the blood-brain barrier, allowing the contrast material to enter the brain and resulting in the acute development of a dramatic clinical presentation. The higher osmolality of ioxaglate compared with blood may in turn produce fluid extravasation and cerebral edema. The prognosis is usually excellent, as is evidenced by other recently published cases occurring after endovascular procedures (Guimaraens et al, 2010, Fang et al, 2009; Paúl et al, 2009).

Cerebral Hyperperfusion Syndrome After Angioplasty 27

hyperperfusion and thus on the importance of strict, prolonged BP control and appropriate

As we discussed in the Diagnosis section, various options are available for assessing CVR. Probably the most widely available option is TCD, which has many advantages and enables us to measure cerebral flow at rest and under certain stimuli (breath-holding, inhalation of CO2, intravenous acetazolamide administration). The simplest and most noninvasive TCD test is breath-holding with or without hyperventilation (see the Diagnosis section). Therefore, the first preventive measure that is recommended before revascularization is

It would also be advisable to do a thorough MRI study of the supra-aortic trunks and of the circle of Willis as well as a study of the cerebral parenchyma using FLAIR, T2-weighted, and diffusion sequences to detect hyperacute lesions and small-vessel disease, which are also related to increased risk of CHS. As mentioned in the Diagnosis section, CVR can also be assessed by SPECT, CT, and MRI, although these approaches are more expensive and less

Again, TCD is very useful for monitoring cerebral flow during revascularization procedures. In patients undergoing CEA, TCD can detect increases in MCA flow velocity greater than 100% during the intervention, thus alerting to a situation of risk. Likewise, TCD monitoring during CAS and probably in the hours after the procedure can help select high risk patients (Dalman et al, 1999; Fujimoto et al, 2004; Kablak et al, 2010; Jansen et al, 1994;

Strict control of hypertension is one of the preventive measures that has received the most attention. Most Investigators recommend strict control of BP in the postoperative period to prevent ICH after CEA (Ahn et al, 1989; Bernstein et al, 1984; Bove et al, 1979; Buhk et al, 2006; Hosoda et al, 2001; Ko et al, 2005; Roh et al, 2005; Safian et al, 2006; Tang et al, 2008)

It has been suggested that even BP in the normal range may be deleterious in patients at high risk for CHS (Piepgras et al, 1988; Ouriel et al, 1999; Jorgensen & Schroeder, 1993). Regarding strict control of BP, Abou-Chebl et al (2007) published an interesting study that analyzed the presence of CHS and ICH in 836 patients treated with CAS. These authors maintained BP < 140/90 mmHg in patients with lower risk and BP < 120/80 mm Hg in patients with a treated stenosis 90%, contralateral stenosis 80%, and hypertension (i.e., risk factors for CHS). They conclude that comprehensive management of arterial hypertension can lower the incidence of ICH and CHS in high-risk patients following CAS, without additional complications or prolonged hospitalization. The strict control of BP must be maintained until CVR is restored, and this interval varies among patients. Thus, the use of TCD to assess the recovery of CVR can probably help guide antihypertensive therapy

Bando et al (2001) reported a stroke patient with a 90% stenosis of the intracranial left vertebral artery treated with CAS. Immediately after the procedure, hyperperfusion was detected by SPECT and TCD. The patient recovered from CHS quickly after a week's

Brus-Ramer et al (2010) published an interesting case of a patient treated with CAS who developed signs of hyperperfusion detected by TCD and depicted on angiography as hyperintense punctate foci potentially representing small dilations in the vascular territory of stented arteries. Lowering BP by 40% probably prevented CHS; thus, in high risk patients, aggressive BP management during and after CAS can prevent potentially serious sequelae.

antithrombotic management.

widely available.

(Buhk 2006).

antihypertensive therapy.

CVR assessment using TCD (Sfyroeras 2006, 2009).

Iwata et al, 2011; Sfyroeras et al, 2009).

and after CAS, as we will see below.

#### **Case 3**


#### **7. Prevention and treatment**

It is crucial to identify patients with risk factors for developing hyperperfusion so that preventive measure can be taken during and after revascularization. In the previous section, we discussed the factors most commonly considered to increase this risk, and in this section we discuss the most interesting preventive strategies.

There is a consensus that the most important risk factors are severely impaired CVR and deficient collaterality (severe ipsilateral stenosis, impaired collateral flow, occlusive disease in other extracranial cerebral vessels, and incomplete circle of Willis). Other proposed factors include advanced age, perioperative and postoperative hypertension, and the use of antiplatelet agents or other anticoagulants. Thus, we should concentrate our efforts on the factors in which we can intervene. Regarding preventive measures before the procedure, we will discuss the assessment of CVR as the primary measure and we will also examine the usefulness of assessing the supra-aortic trunks and the circle of Willis. Regarding preventive measures during and after the procedure, we will focus on detecting cerebral Angioplasty, Various Techniques and Challenges in 26 Treatment of Congenital and Acquired Vascular Stenoses

1- Angiogram before left CAS showing 70% stenosis of the left ICA

3- Axial diffusion-weighted MRi showing ipsilateral silent ischemic lesions

It is crucial to identify patients with risk factors for developing hyperperfusion so that preventive measure can be taken during and after revascularization. In the previous section, we discussed the factors most commonly considered to increase this risk, and in this section

There is a consensus that the most important risk factors are severely impaired CVR and deficient collaterality (severe ipsilateral stenosis, impaired collateral flow, occlusive disease in other extracranial cerebral vessels, and incomplete circle of Willis). Other proposed factors include advanced age, perioperative and postoperative hypertension, and the use of antiplatelet agents or other anticoagulants. Thus, we should concentrate our efforts on the factors in which we can intervene. Regarding preventive measures before the procedure, we will discuss the assessment of CVR as the primary measure and we will also examine the usefulness of assessing the supra-aortic trunks and the circle of Willis. Regarding preventive measures during and after the procedure, we will focus on detecting cerebral

**Case 3** 

2- Angiogram after left CAS

5- Axial FLAIR MRi 6- Axial T1-weighted MRi

4- CT with extravasation of the contrast

we discuss the most interesting preventive strategies.

**7. Prevention and treatment** 

hyperperfusion and thus on the importance of strict, prolonged BP control and appropriate antithrombotic management.

As we discussed in the Diagnosis section, various options are available for assessing CVR. Probably the most widely available option is TCD, which has many advantages and enables us to measure cerebral flow at rest and under certain stimuli (breath-holding, inhalation of CO2, intravenous acetazolamide administration). The simplest and most noninvasive TCD test is breath-holding with or without hyperventilation (see the Diagnosis section). Therefore, the first preventive measure that is recommended before revascularization is CVR assessment using TCD (Sfyroeras 2006, 2009).

It would also be advisable to do a thorough MRI study of the supra-aortic trunks and of the circle of Willis as well as a study of the cerebral parenchyma using FLAIR, T2-weighted, and diffusion sequences to detect hyperacute lesions and small-vessel disease, which are also related to increased risk of CHS. As mentioned in the Diagnosis section, CVR can also be assessed by SPECT, CT, and MRI, although these approaches are more expensive and less widely available.

Again, TCD is very useful for monitoring cerebral flow during revascularization procedures. In patients undergoing CEA, TCD can detect increases in MCA flow velocity greater than 100% during the intervention, thus alerting to a situation of risk. Likewise, TCD monitoring during CAS and probably in the hours after the procedure can help select high risk patients (Dalman et al, 1999; Fujimoto et al, 2004; Kablak et al, 2010; Jansen et al, 1994; Iwata et al, 2011; Sfyroeras et al, 2009).

Strict control of hypertension is one of the preventive measures that has received the most attention. Most Investigators recommend strict control of BP in the postoperative period to prevent ICH after CEA (Ahn et al, 1989; Bernstein et al, 1984; Bove et al, 1979; Buhk et al, 2006; Hosoda et al, 2001; Ko et al, 2005; Roh et al, 2005; Safian et al, 2006; Tang et al, 2008) and after CAS, as we will see below.

It has been suggested that even BP in the normal range may be deleterious in patients at high risk for CHS (Piepgras et al, 1988; Ouriel et al, 1999; Jorgensen & Schroeder, 1993).

Regarding strict control of BP, Abou-Chebl et al (2007) published an interesting study that analyzed the presence of CHS and ICH in 836 patients treated with CAS. These authors maintained BP < 140/90 mmHg in patients with lower risk and BP < 120/80 mm Hg in patients with a treated stenosis 90%, contralateral stenosis 80%, and hypertension (i.e., risk factors for CHS). They conclude that comprehensive management of arterial hypertension can lower the incidence of ICH and CHS in high-risk patients following CAS, without additional complications or prolonged hospitalization. The strict control of BP must be maintained until CVR is restored, and this interval varies among patients. Thus, the use of TCD to assess the recovery of CVR can probably help guide antihypertensive therapy (Buhk 2006).

Bando et al (2001) reported a stroke patient with a 90% stenosis of the intracranial left vertebral artery treated with CAS. Immediately after the procedure, hyperperfusion was detected by SPECT and TCD. The patient recovered from CHS quickly after a week's antihypertensive therapy.

Brus-Ramer et al (2010) published an interesting case of a patient treated with CAS who developed signs of hyperperfusion detected by TCD and depicted on angiography as hyperintense punctate foci potentially representing small dilations in the vascular territory of stented arteries. Lowering BP by 40% probably prevented CHS; thus, in high risk patients, aggressive BP management during and after CAS can prevent potentially serious sequelae.

Cerebral Hyperperfusion Syndrome After Angioplasty 29

of carotid revascularization are greatest in the first two weeks after the event, and the subgroup of patients with less risk for early revascularization are those with small ischemic lesions and mild neurologic impairment (Keldahl et al, 2010). A recent (<3 months) contralateral CEA is an additional potential risk factor for CHS and should also be considered in the timing of surgery (Ascher et al, 2003). Very few studies have addressed the use of CAS in hyperacute strokes, but those that have report good safety outcome

Some authors (Henry et al, 2005; Lee et al, 2006) claim that treatment of both carotid arteries is feasible in carefully selected patients, either in the same procedure or in two procedures separated by an interval of one day; these authors report safety and complication rates comparable to those of large published series in high-risk patients. Nevertheless, careful monitoring of the patient, blood pressure, and heart rate is mandatory to avoid

Owing to the presence of free radicals during reperfusion and their relation to post-ischemic hyperperfusion, substances like edaravone have been investigated. Edaravone inhibits lipid peroxidation and vascular endothelial cell injury, improving edema cerebral and tissue injury. Pretreatment with edaravone decreased the incidence of hyperperfusion after CEA

Once CHS occurs, aggressive measures to lower BP are imperative. As there are no data from randomized trials comparing the optimal perioperative management protocol for patients with CHS due to the rarity of this complication, we must focus on controlling BP, reducing cerebral edema, and, according to some authors, temporarily withdraw antithrombotic therapy. Treatments for cerebral edema include adequate sedation, hyperventilation, and administration of mannitol or hypertonic saline. Evidently, there are no data to support these treatments in CHS. Corticosteroids and barbiturates have also been

There are no available data recommending prophylactic use of anticonvulsant therapy in patients undergoing carotid revascularization; however, in the presence of seizures,

In conclusion, assessing CVR before treatment and monitoring CBF velocities during and after the procedure can help select the patients who need strict control of BP to prevent CHS. The optimal BP remains to be determined, but BP should be lowered to below the baseline after luminal gain with stenting to prevent secondary injury. Despite the lack of a precise BP target, lowering systolic BP to at least 20% to 30% below baseline values seems critical, particularly in patients with critical stenosis and above all in patients with impaired CVR. Labetalol and clonidine seem to be the most appropriate drugs for BP control in this

To determine when discharge is safe after CAS, patients should be divided into two groups. One group includes asymptomatic, hemodynamically stable patients with low comorbidity who could be discharged after 6 h of observation, according to some authors. These patients should be treated using a hemostatic closure device for the arterial puncture. The other group includes older patients with associated comorbidity, mainly those with altered renal function, those that require anticoagulation, and those with altered BP or bradycardia. Finally, it is recommendable to warn the family about symptoms that call for re-evaluation, especially seizures, neurological deficit, and

(Miyamoto et al, 2008; Setacci et al 2010).

as measured by SPECT (Ogasawara et al, 2004).

treatment with anticonvulsants is indicated.

headaches associated with hypertension.

complications related to CHS.

used in CHS.

context.

Another aspect that remains to be determined is the most appropriate type of drugs for these patients. In this context, it seems logical that drugs that have no direct effects on CBF and those that give some degree of cerebral vasoconstriction could be beneficial. Drugs like nitroprusside and calcium antagonists that increase CBF should be avoided. The ß 1 adrenergic antagonists (beta-blockers) reduce BP with little effect on intracranial pressure within the autoregulatory range, although they can exacerbate the bradycardia that can occur after CAS.

The mixed alpha-adrenergic antagonist and ß -adrenergic antagonist labetalol, which has no direct effects on CBF and decreases the cerebral perfusion pressure and mean arterial pressure by about 30% compared with baseline, has successfully been used in CHS after CEA (Halliday et al, 2004). The alpha 2-adrenergic agonist clonidine, which is commonly used after CEA (associated with raised cranial and plasma catecholamine concentrations), has the advantage of decreasing CBF.

General anesthesia is often unnecessary for CAS. However, when general anesthesia is required, it is important to use anesthetics that do not increase CBF. Studies of CBF during surgery have shown that high doses of volatile halogenated hydrocarbon anesthetics may lead to the development of CHS (Skydell et al, 1987). Isoflurane is the volatile anesthetic of choice in neurosurgery because it results in less pronounced vasodilation than other halogenated anesthetics at equipotent doses. The effects of isoflurane on cerebral metabolic rate and autoregulation are dose dependent, with impairment of CVR at high doses. Propofol has been used in patients with CHS, it normalizes CBF, probably because of its effects on cerebral metabolism (Kaisti et al, 2003).

Safety concerns have been raised about the effects of anticoagulants and antiplatelet agents and the risk of ICH following CEA, but no causal link has been found (Ouriel et al, 1999; Penn et al, 1995). Likewise, no association between these drugs and ICH has been found in patients undergoing CAS (Abou et al, 2003), although some studies have reported higher incidences of ICH, probably related to higher than usual doses of anticoagulants (Meyers et al, 2000 ; Morrish et al, 2000).

Levy et al (2002) propose an interesting preventive strategy consisting of performing angioplasty in two phases, with posterior stent collocation. These authors published a series of 8 cases of intracranial vertebral stenosis with good outcomes despite one case of arterial dissection that required stenting. Yoshimura et al (2009) also used two-step endovascular treatment in high risk patients with impaired CVR. These authors first performed angioplasty with a small balloon (3 mm), and once hyperperfusion improved on SPECT about one month later they performed a second, definitive angioplasty with stent placement. None of the 9 patients treated with the two-step approach had problems related with hyperperfusion (one required stenting for a dissected artery), whereas 5 of the 9 patients in the control group had hyperperfusion and one had status epilepticus related to CHS.

Additional efforts to reduce the risk of ICH may include limiting the duration of balloon inflation and employing emboli-prevention devices, as these practices have been related to ischemia with posterior development of ICH (Jansen et al, 1994; Sakaki et al, 1992; Sundt et al 1981).

An important, somewhat controversial factor is the optimal interval between stroke and revascularization. We know that an extensive ischemic lesion represents a greater risk of damage due to reperfusion. Furthermore, classically a six-week interval was recommended to avoid treatment complications. However, studies like the NASCET show that the benefits Angioplasty, Various Techniques and Challenges in 28 Treatment of Congenital and Acquired Vascular Stenoses

Another aspect that remains to be determined is the most appropriate type of drugs for these patients. In this context, it seems logical that drugs that have no direct effects on CBF and those that give some degree of cerebral vasoconstriction could be beneficial. Drugs like nitroprusside and calcium antagonists that increase CBF should be avoided. The ß 1 adrenergic antagonists (beta-blockers) reduce BP with little effect on intracranial pressure within the autoregulatory range, although they can exacerbate the bradycardia that can

The mixed alpha-adrenergic antagonist and ß -adrenergic antagonist labetalol, which has no direct effects on CBF and decreases the cerebral perfusion pressure and mean arterial pressure by about 30% compared with baseline, has successfully been used in CHS after CEA (Halliday et al, 2004). The alpha 2-adrenergic agonist clonidine, which is commonly used after CEA (associated with raised cranial and plasma catecholamine concentrations),

General anesthesia is often unnecessary for CAS. However, when general anesthesia is required, it is important to use anesthetics that do not increase CBF. Studies of CBF during surgery have shown that high doses of volatile halogenated hydrocarbon anesthetics may lead to the development of CHS (Skydell et al, 1987). Isoflurane is the volatile anesthetic of choice in neurosurgery because it results in less pronounced vasodilation than other halogenated anesthetics at equipotent doses. The effects of isoflurane on cerebral metabolic rate and autoregulation are dose dependent, with impairment of CVR at high doses. Propofol has been used in patients with CHS, it normalizes CBF, probably because of its

Safety concerns have been raised about the effects of anticoagulants and antiplatelet agents and the risk of ICH following CEA, but no causal link has been found (Ouriel et al, 1999; Penn et al, 1995). Likewise, no association between these drugs and ICH has been found in patients undergoing CAS (Abou et al, 2003), although some studies have reported higher incidences of ICH, probably related to higher than usual doses of anticoagulants (Meyers et

Levy et al (2002) propose an interesting preventive strategy consisting of performing angioplasty in two phases, with posterior stent collocation. These authors published a series of 8 cases of intracranial vertebral stenosis with good outcomes despite one case of arterial dissection that required stenting. Yoshimura et al (2009) also used two-step endovascular treatment in high risk patients with impaired CVR. These authors first performed angioplasty with a small balloon (3 mm), and once hyperperfusion improved on SPECT about one month later they performed a second, definitive angioplasty with stent placement. None of the 9 patients treated with the two-step approach had problems related with hyperperfusion (one required stenting for a dissected artery), whereas 5 of the 9 patients in the control group had hyperperfusion and one had status epilepticus related

Additional efforts to reduce the risk of ICH may include limiting the duration of balloon inflation and employing emboli-prevention devices, as these practices have been related to ischemia with posterior development of ICH (Jansen et al, 1994; Sakaki et al, 1992; Sundt et

An important, somewhat controversial factor is the optimal interval between stroke and revascularization. We know that an extensive ischemic lesion represents a greater risk of damage due to reperfusion. Furthermore, classically a six-week interval was recommended to avoid treatment complications. However, studies like the NASCET show that the benefits

occur after CAS.

has the advantage of decreasing CBF.

al, 2000 ; Morrish et al, 2000).

to CHS.

al 1981).

effects on cerebral metabolism (Kaisti et al, 2003).

of carotid revascularization are greatest in the first two weeks after the event, and the subgroup of patients with less risk for early revascularization are those with small ischemic lesions and mild neurologic impairment (Keldahl et al, 2010). A recent (<3 months) contralateral CEA is an additional potential risk factor for CHS and should also be considered in the timing of surgery (Ascher et al, 2003). Very few studies have addressed the use of CAS in hyperacute strokes, but those that have report good safety outcome (Miyamoto et al, 2008; Setacci et al 2010).

Some authors (Henry et al, 2005; Lee et al, 2006) claim that treatment of both carotid arteries is feasible in carefully selected patients, either in the same procedure or in two procedures separated by an interval of one day; these authors report safety and complication rates comparable to those of large published series in high-risk patients. Nevertheless, careful monitoring of the patient, blood pressure, and heart rate is mandatory to avoid complications related to CHS.

Owing to the presence of free radicals during reperfusion and their relation to post-ischemic hyperperfusion, substances like edaravone have been investigated. Edaravone inhibits lipid peroxidation and vascular endothelial cell injury, improving edema cerebral and tissue injury. Pretreatment with edaravone decreased the incidence of hyperperfusion after CEA as measured by SPECT (Ogasawara et al, 2004).

Once CHS occurs, aggressive measures to lower BP are imperative. As there are no data from randomized trials comparing the optimal perioperative management protocol for patients with CHS due to the rarity of this complication, we must focus on controlling BP, reducing cerebral edema, and, according to some authors, temporarily withdraw antithrombotic therapy. Treatments for cerebral edema include adequate sedation, hyperventilation, and administration of mannitol or hypertonic saline. Evidently, there are no data to support these treatments in CHS. Corticosteroids and barbiturates have also been used in CHS.

There are no available data recommending prophylactic use of anticonvulsant therapy in patients undergoing carotid revascularization; however, in the presence of seizures, treatment with anticonvulsants is indicated.

In conclusion, assessing CVR before treatment and monitoring CBF velocities during and after the procedure can help select the patients who need strict control of BP to prevent CHS. The optimal BP remains to be determined, but BP should be lowered to below the baseline after luminal gain with stenting to prevent secondary injury. Despite the lack of a precise BP target, lowering systolic BP to at least 20% to 30% below baseline values seems critical, particularly in patients with critical stenosis and above all in patients with impaired CVR. Labetalol and clonidine seem to be the most appropriate drugs for BP control in this context.

To determine when discharge is safe after CAS, patients should be divided into two groups. One group includes asymptomatic, hemodynamically stable patients with low comorbidity who could be discharged after 6 h of observation, according to some authors. These patients should be treated using a hemostatic closure device for the arterial puncture. The other group includes older patients with associated comorbidity, mainly those with altered renal function, those that require anticoagulation, and those with altered BP or bradycardia. Finally, it is recommendable to warn the family about symptoms that call for re-evaluation, especially seizures, neurological deficit, and headaches associated with hypertension.

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#### **8. Abbreviations**

CHS: Cerebral Hyperperfusion Syndrome CBF: Cerebral Blood Flow CBV: Cerebral blood volume CT: Cranial tomography CVR: Cerebral Vasoreactivity HTA: hypertension ICA: Internal Carotid Artery ICH: Intracranial Hemorrhage MMT: mean transit time MCA: Middle Cerebral Artery MRi: magnetic resonance imaging, PET: Positron Emission Tomography TCD: transcranial doppler TIA: Transient Ischemic Attack SAH: Subarachnoid hemorrhage SPECT: Single-photon emission computed tomography

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ischemia.


**3** 

*Portugal* 

**Below the Knee Techniques: Now and Then** 

*2Department of Biochemistry, Faculty of Medicine of the University of Porto* 

*3Angiology and Vascular Surgery Department; São João University Hospital, Porto* 

Critical Limb Ischemia (CLI) is defined as the presence of ischemic rest pain for more than two weeks or ischemic tissue loss associated with an absolute ankle pressure less than 50 mmHg or great toe pressure less than 30 mmHg (Norgren et al., 2007). Patients with CLI experience high amputation rates, significant morbidity and cardiovascular events exceeding those in patients with symptomatic coronary heart disease (Varu et al., 2010). In spite of recent developments in revascularization techniques and wound care centers, amputations continue to be performed, partly because patients with CLI are referred late to vascular surgeons (Varu et al., 2010). However, revascularization when compared with amputation have an overall lower perioperative mortality and enhanced long-term survival (Brosi et al., 2007; Varu et al., 2010). However, CLI is associated with multisegmental complex arterial lesions and consequently with high rates of revascularization failure (Allie et al., 2009). Specific features of the tibial vessels, such as the small caliber, the remote location, the slow flow of the distal bed, and the need of preserving runoff capacity, make this vascular territory particularly challenging for endovascular treatment (Blevins and Schneider, 2010). Meanwhile, continued technical improvements and very encouraging results have changed the paradigm of CLI therapy, until recently based on vein graft bypass. As so, the endovascular approach is, nowadays, the first-line modality for limb-threatening

ischemia for a majority of authors (Allie et al., 2009; DeRubertis et al., 2007).

CLI is a global epidemic, with high clinical, social and economic costs (Adam et al., 2005; Allie et al., 2009; Brosi et al., 2007). Its incidence in the United States (US) is estimated to be 50-100 per 10 000 every year (Adam et al., 2005). It affects 1% of the population aged 50 and older and the incidence roughly doubles in the over 70 age group (Allie et al., 2009). The prevalence of CLI is also higher in diabetic patients and its prognosis is even worst in this population: one of every four diabetics will face CLI within his/her lifetime, and a diabetic is at 7 to 40 times greater risk of an amputation than a non-diabetic (Allie et al., 2009). As so,

**1. Introduction** 

**2. Epidemiology** 

Daniel Brandão1,2, Joana Ferreira1,2,

*1Angiology and Vascular Surgery Department Vila Nova de Gaia / Espinho Hospital Center* 

*4Faculty of Medicine of the University of Porto* 

Armando Mansilha3,4 and António Guedes Vaz1


### **Below the Knee Techniques: Now and Then**

Daniel Brandão1,2, Joana Ferreira1,2,

Armando Mansilha3,4 and António Guedes Vaz1 *1Angiology and Vascular Surgery Department Vila Nova de Gaia / Espinho Hospital Center 2Department of Biochemistry, Faculty of Medicine of the University of Porto 3Angiology and Vascular Surgery Department; São João University Hospital, Porto 4Faculty of Medicine of the University of Porto Portugal* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 40 Treatment of Congenital and Acquired Vascular Stenoses

Yoshimura, S.; Kitajima, H.; Enomoto, Y.; Yamada, K.; Iwama, T. Staged angioplasty for

Zahn, R.; Ischinger, T & Hochadel, M et al. Carotid artery stenting in octogenarians: results

2009 Mar;64(3 Suppl):122-8; discussion 128-9.

carotid artery stenosis to prevent postoperative hyperperfusion. Neurosurgery.

from the ALKK Carotid Artery Stent (CAS) Registry. Eur Heart J 2007. 28:370–375

Critical Limb Ischemia (CLI) is defined as the presence of ischemic rest pain for more than two weeks or ischemic tissue loss associated with an absolute ankle pressure less than 50 mmHg or great toe pressure less than 30 mmHg (Norgren et al., 2007). Patients with CLI experience high amputation rates, significant morbidity and cardiovascular events exceeding those in patients with symptomatic coronary heart disease (Varu et al., 2010). In spite of recent developments in revascularization techniques and wound care centers, amputations continue to be performed, partly because patients with CLI are referred late to vascular surgeons (Varu et al., 2010). However, revascularization when compared with amputation have an overall lower perioperative mortality and enhanced long-term survival (Brosi et al., 2007; Varu et al., 2010). However, CLI is associated with multisegmental complex arterial lesions and consequently with high rates of revascularization failure (Allie et al., 2009). Specific features of the tibial vessels, such as the small caliber, the remote location, the slow flow of the distal bed, and the need of preserving runoff capacity, make this vascular territory particularly challenging for endovascular treatment (Blevins and Schneider, 2010). Meanwhile, continued technical improvements and very encouraging results have changed the paradigm of CLI therapy, until recently based on vein graft bypass. As so, the endovascular approach is, nowadays, the first-line modality for limb-threatening ischemia for a majority of authors (Allie et al., 2009; DeRubertis et al., 2007).

#### **2. Epidemiology**

CLI is a global epidemic, with high clinical, social and economic costs (Adam et al., 2005; Allie et al., 2009; Brosi et al., 2007). Its incidence in the United States (US) is estimated to be 50-100 per 10 000 every year (Adam et al., 2005). It affects 1% of the population aged 50 and older and the incidence roughly doubles in the over 70 age group (Allie et al., 2009). The prevalence of CLI is also higher in diabetic patients and its prognosis is even worst in this population: one of every four diabetics will face CLI within his/her lifetime, and a diabetic is at 7 to 40 times greater risk of an amputation than a non-diabetic (Allie et al., 2009). As so,

Below the Knee Techniques: Now and Then 43

Abou-Zamzam et al. analyzed the functional outcomes after surgery in CLI patients (Abou-Zamzam et al., 1997). This report aimed at identifying the *ideal* post-infrainguinal bypass results from CLI patient's functional perspective (Abou-Zamzam et al., 1997). The patient who survived the intervention, had his wounds healed at 6 months, was living independently and completely mobile, was defined as the *ideal functioning* patient (Abou-Zamzam et al., 1997). Disappointingly, despite excellent graft patency and limb salvage rates, only 14.3% of their infrainguinal bypass patients achieved the *ideal* result at 6 months (Allie et al., 2009). Avoidance of incisional wound creation and subsequent common healing problems have been strongly considered an advantage in favor of endovascular intervention versus infrainguinal bypass in our practice (Allie et al., 2009; Chung et

Meanwhile, in patients expected to live more than two years and who were fit, the apparent improved durability and reduced re-intervention rate of surgery might outweigh the short-

The endoluminal therapy for lower extremity occlusive disease has extraordinary evolved in the last decade and the armamentarium now available for the vascular interventionist is quite considerable (DeRubertis et al., 2007). This has allowed an impressive expansion of the endovascular approach in complex, formerly considered unachievable, infra-inguinal lesions (Allie et al., 2009). As a result, the endoluminal intervention is now considered the

In addition, the understanding of CLI patients had improved considerably (Allie et al., 2009). The so called *limb salvage-graft patency gap* has been consistently identified in all infrainguinal bypass surgery reports regardless of conduits (Allie et al., 2009). Even after an occlusion of an infrainguinal bypass graft following limb salvage, the limb will oftentimes remain viable and not regress back to CLI since the blood flow and metabolic needs to achieve wound healing in CLI are much greater than to keep viability (Allie et al., 2009). This paradigm shift has opened the door to a potential change of the goals in the post procedural follow-up of the CLI patients from vessel patency to limb salvage. This has become the cornerstone in treating CLI patients, allowing an impressive expansion of

In fact, scrutinizing the data of endovascular approach for CLI treatment from the last

Dorros et al. used percutaneous transluminal angioplasty (PTA) as the first treatment in 235 CLI patients with a 91% 5-year limb salvage rate and a small number of complications

Faglia et al. reported tibial PTA as primary treatment in 993 CLI diabetic patients. During a 26±15 months follow-up, only 1.7% underwent major amputation. Limb salvage was achieved in more than 98% of patients and an 88% 5-year primary clinical patency rate was

Kudo et al. also published a 10-year PTA experience in 111 CLI patients. A 0.9% procedural mortality and a 96.4% technical success rate were described. The 5-year limb salvage rate was 89.1% (Kudo et al., 2005). The same authors published their 12-year experience of tibial PTA versus bypass surgery in 192 CLI patients. They further concluded that PTA was safe

and effective, pointing it as the primary treatment for CLI (Kudo et al., 2006).

term considerations of increased morbidity and cost (Adam et al., 2005).

first-line treatment in CLI patients for a majority of authors.

endovascular therapy indications (Allie et al., 2009).

decade shows very encouraging results in regard to limb salvage.

al., 2006).

**4.2 Endovascular approach** 

(Dorros et al., 2001).

described (Faglia et al., 2005).

it is expected that the incidence of CLI would rise significantly with the current aging population and the expected increase in inactivity, obesity and consequently in diabetes (Allie et al., 2009; van Dieren et al., 2010). As a result and despite advances in medical therapies, the number of patients needing lower limb revascularization for severe limb ischemia will probably increase in the near future (Adam et al., 2005). Moreover, the diagnosis of CLI remains a predictor of poor survival and outcomes (Varu et al., 2010): the overall mortality in these patients approaches 50% at 5 years and 70% at 10 years (Varu et al., 2010). Within one year of being diagnosed with CLI, 20% to 25% will die and 40% to 50% of the diabetics will experience an amputation (Allie et al., 2009; Kroger et al., 2006). The economic impact of CLI is considerable. It has been assessed that the total cost of treating CLI in the US is \$10 to \$20 billion per year (Allie et al., 2009). The cost of follow-up, longterm care, and treatment for an amputee who remains at home has been estimated at \$49,000 per year compared to only \$600 to \$800 per year after limb salvage (Allie et al., 2009). It is estimated that just a 25% reduction in amputations could save \$2.9 to \$3.0 billion yearly in US healthcare costs (Allie et al., 2009). Despite the facts noted above, CLI is still poorly understood, infrequently reported and inconsistently treated (Allie et al., 2009).

#### **3. The arterial lesions in patients with critical limb ischemia**

CLI is highly predictive for failure of both primary and secondary patency, as a result of the increased prevalence of advanced lesion severity and treatment complexity (DeRubertis et al., 2007). There is several indicators of lesion severity in these patients: (1) increasing TASC grade (mostly C and D lesions); (2) multilevel intervention; (3) general involvement of tibial arteries in diabetic patients; (4) diffusely diseased tibial arteries (combination of long stenoses and occlusions; (5) reduced outflow bed (DeRubertis et al., 2007; Graziani et al., 2007; Ihnat and Mills, 2010).

#### **4. Revascularization in CLI patients**

#### **4.1 Bypass surgery approach**

Historically, infrainguinal autogenous saphenous vein bypass surgery has been considered the gold-standard therapy for CLI, with long-term anatomical patency, clinical durability and high limb salvage rates (Adam et al., 2005; Allie et al., 2009; Varu et al., 2010). The Pomposelli's classic report of more than 1000 pedal bypasses over a decade documented a 10-year primary patency rate of 37.7% and limb salvage rates of 57.8% (Pomposelli et al., 2003). Regrettably, most of these single center series were reported in optimal surgical candidates with favorable anatomy and adequate autogenous vein conduits (Allie et al., 2009). Furthermore, the durability of the vein graft may rely on routine ultrasonography surveillance, frequently leading to repeated prophylactic re-interventions and relevant resource utilization (Adam et al., 2005; Varu et al., 2010). Unfortunately an adequate vein is often unavailable and the long-term results of bypasses constructed with prosthetic graft are clearly much less satisfactory (Adam et al., 2005). The good results of infrainguinal surgery are not applicable to contemporary CLI patients who seldom have favorable anatomy and recurrently have poor autogenous conduits (Allie et al., 2009). Additionally, the *real world* CLI patients are frequently very elderly and have numerous medical issues, significantly increasing the mortality and morbidity associated with infrainguinal bypass (Allie et al., 2009; Brosi et al., 2007). Consequently the open surgery option could come at the cost of high morbidity and mortality, as well as substantial resource use (Adam et al., 2005).

Angioplasty, Various Techniques and Challenges in 42 Treatment of Congenital and Acquired Vascular Stenoses

it is expected that the incidence of CLI would rise significantly with the current aging population and the expected increase in inactivity, obesity and consequently in diabetes (Allie et al., 2009; van Dieren et al., 2010). As a result and despite advances in medical therapies, the number of patients needing lower limb revascularization for severe limb ischemia will probably increase in the near future (Adam et al., 2005). Moreover, the diagnosis of CLI remains a predictor of poor survival and outcomes (Varu et al., 2010): the overall mortality in these patients approaches 50% at 5 years and 70% at 10 years (Varu et al., 2010). Within one year of being diagnosed with CLI, 20% to 25% will die and 40% to 50% of the diabetics will experience an amputation (Allie et al., 2009; Kroger et al., 2006). The economic impact of CLI is considerable. It has been assessed that the total cost of treating CLI in the US is \$10 to \$20 billion per year (Allie et al., 2009). The cost of follow-up, longterm care, and treatment for an amputee who remains at home has been estimated at \$49,000 per year compared to only \$600 to \$800 per year after limb salvage (Allie et al., 2009). It is estimated that just a 25% reduction in amputations could save \$2.9 to \$3.0 billion yearly in US healthcare costs (Allie et al., 2009). Despite the facts noted above, CLI is still poorly

understood, infrequently reported and inconsistently treated (Allie et al., 2009).

CLI is highly predictive for failure of both primary and secondary patency, as a result of the increased prevalence of advanced lesion severity and treatment complexity (DeRubertis et al., 2007). There is several indicators of lesion severity in these patients: (1) increasing TASC grade (mostly C and D lesions); (2) multilevel intervention; (3) general involvement of tibial arteries in diabetic patients; (4) diffusely diseased tibial arteries (combination of long stenoses and occlusions; (5) reduced outflow bed (DeRubertis et al., 2007; Graziani et al.,

Historically, infrainguinal autogenous saphenous vein bypass surgery has been considered the gold-standard therapy for CLI, with long-term anatomical patency, clinical durability and high limb salvage rates (Adam et al., 2005; Allie et al., 2009; Varu et al., 2010). The Pomposelli's classic report of more than 1000 pedal bypasses over a decade documented a 10-year primary patency rate of 37.7% and limb salvage rates of 57.8% (Pomposelli et al., 2003). Regrettably, most of these single center series were reported in optimal surgical candidates with favorable anatomy and adequate autogenous vein conduits (Allie et al., 2009). Furthermore, the durability of the vein graft may rely on routine ultrasonography surveillance, frequently leading to repeated prophylactic re-interventions and relevant resource utilization (Adam et al., 2005; Varu et al., 2010). Unfortunately an adequate vein is often unavailable and the long-term results of bypasses constructed with prosthetic graft are clearly much less satisfactory (Adam et al., 2005). The good results of infrainguinal surgery are not applicable to contemporary CLI patients who seldom have favorable anatomy and recurrently have poor autogenous conduits (Allie et al., 2009). Additionally, the *real world* CLI patients are frequently very elderly and have numerous medical issues, significantly increasing the mortality and morbidity associated with infrainguinal bypass (Allie et al., 2009; Brosi et al., 2007). Consequently the open surgery option could come at the cost of high

morbidity and mortality, as well as substantial resource use (Adam et al., 2005).

**3. The arterial lesions in patients with critical limb ischemia** 

2007; Ihnat and Mills, 2010).

**4.1 Bypass surgery approach** 

**4. Revascularization in CLI patients** 

Abou-Zamzam et al. analyzed the functional outcomes after surgery in CLI patients (Abou-Zamzam et al., 1997). This report aimed at identifying the *ideal* post-infrainguinal bypass results from CLI patient's functional perspective (Abou-Zamzam et al., 1997). The patient who survived the intervention, had his wounds healed at 6 months, was living independently and completely mobile, was defined as the *ideal functioning* patient (Abou-Zamzam et al., 1997). Disappointingly, despite excellent graft patency and limb salvage rates, only 14.3% of their infrainguinal bypass patients achieved the *ideal* result at 6 months (Allie et al., 2009). Avoidance of incisional wound creation and subsequent common healing problems have been strongly considered an advantage in favor of endovascular intervention versus infrainguinal bypass in our practice (Allie et al., 2009; Chung et al., 2006).

Meanwhile, in patients expected to live more than two years and who were fit, the apparent improved durability and reduced re-intervention rate of surgery might outweigh the shortterm considerations of increased morbidity and cost (Adam et al., 2005).

#### **4.2 Endovascular approach**

The endoluminal therapy for lower extremity occlusive disease has extraordinary evolved in the last decade and the armamentarium now available for the vascular interventionist is quite considerable (DeRubertis et al., 2007). This has allowed an impressive expansion of the endovascular approach in complex, formerly considered unachievable, infra-inguinal lesions (Allie et al., 2009). As a result, the endoluminal intervention is now considered the first-line treatment in CLI patients for a majority of authors.

In addition, the understanding of CLI patients had improved considerably (Allie et al., 2009). The so called *limb salvage-graft patency gap* has been consistently identified in all infrainguinal bypass surgery reports regardless of conduits (Allie et al., 2009). Even after an occlusion of an infrainguinal bypass graft following limb salvage, the limb will oftentimes remain viable and not regress back to CLI since the blood flow and metabolic needs to achieve wound healing in CLI are much greater than to keep viability (Allie et al., 2009). This paradigm shift has opened the door to a potential change of the goals in the post procedural follow-up of the CLI patients from vessel patency to limb salvage. This has become the cornerstone in treating CLI patients, allowing an impressive expansion of endovascular therapy indications (Allie et al., 2009).

In fact, scrutinizing the data of endovascular approach for CLI treatment from the last decade shows very encouraging results in regard to limb salvage.

Dorros et al. used percutaneous transluminal angioplasty (PTA) as the first treatment in 235 CLI patients with a 91% 5-year limb salvage rate and a small number of complications (Dorros et al., 2001).

Faglia et al. reported tibial PTA as primary treatment in 993 CLI diabetic patients. During a 26±15 months follow-up, only 1.7% underwent major amputation. Limb salvage was achieved in more than 98% of patients and an 88% 5-year primary clinical patency rate was described (Faglia et al., 2005).

Kudo et al. also published a 10-year PTA experience in 111 CLI patients. A 0.9% procedural mortality and a 96.4% technical success rate were described. The 5-year limb salvage rate was 89.1% (Kudo et al., 2005). The same authors published their 12-year experience of tibial PTA versus bypass surgery in 192 CLI patients. They further concluded that PTA was safe and effective, pointing it as the primary treatment for CLI (Kudo et al., 2006).

Below the Knee Techniques: Now and Then 45

potentially increasing total costs. Meanwhile, distal lesions are still difficult to reach and

Iliac and proximal SFA lesions -

Safer closure devices utilization -

segment -

Perhaps the most critical decision in revascularizing CLI patients with predominant BTK arteries involvement is to decide which vessel(s) should be approached to achieve successful limb salvage. In spite of arbitrarily recanalize a tibial artery only based on arteriography,

The angiosome concept was initially described in plastic and reconstructive surgery papers and was intended to provide the basis for a logical planning of incisions and flaps (Taylor and Palmer, 1987; Taylor and Pan, 1998). These anatomical studies delineated threedimensional anatomic units of tissue (from skin to bone) fed by a given source artery, defined as angiosomes. In foot it has been described six angiosomes, arising from the posterior tibial artery (n=3), the anterior tibial artery (n=1), and the peroneal artery (n=2) (figure 1). The posterior tibial artery gives rise to a calcaneal branch that supplies the medial ankle and plantar heel, a medial plantar artery that feeds the medial plantar instep and a lateral plantar artery that supplies the lateral forefoot, plantar midfoot and entire plantar forefoot. The anterior tibial artery continues as the *dorsalis pedis* artery feeding the dorsum of the foot. The peroneal artery supplies the lateral ankle and plantar heel via the calcaneal branch and the lateral anterior upper ankle via an anterior perforating branch. Alexandrescu et al. applied more recently this angiosome model to guide endovascular procedures in diabetic CLI patients with remarkable results (Alexandrescu et al., 2008). This rational approach for the revascularization of the foot was followed by several authors who confirmed its relevance for ulcer healing and consequent limb salvage (Alexandrescu et al., 2011; Iida et al., 2010; Neville et al., 2009). In fact, Iida et al. analyzed 203 limbs in 177 patients and separated them into direct and indirect groups depending on whether feeding artery flow to the site of ulceration was successfully acquired or not based on the angiosome concept. They found that limb salvage rate was significantly higher in the direct group (86%) than in the indirect group (69%) for up to 4 years after the procedure (Iida et al., 2010).

**Antegrade access Contralateral access**

unfavorable aortic bifurcations or aortic grafts may preclude its utilization. Table 1 summarizes the advantages and disadvantages of each approach.

More complex and distal lesion -

More technically demanding -

More frequent local complications -

Remote access from treated

Table 1. Antegrade and contralateral retrograde access

**5.2 Tibial vessel selection for intervention – The key step** 

one should consider some basic and prevailing principles.

**5.2.1 Angiosome model** 

A meta-analysis of 30 articles from Romiti et al. looked at immediate technical success, primary and secondary patency, limb salvage, and survival after infrapopliteal PTA in CLI patients. The results were compared with a meta-analysis of popliteal-to-distal vein bypass graft that the authors had previously published (Albers et al., 2006). Even if there was a significant difference in favor of vein bypass concerning durability, the limb salvage rates were equivalent between both techniques (Albers et al., 2006; Romiti et al., 2008).

From the data presented, it results that endovascular approach is currently considered as the first-line treatment for CLI patients with below-the-knee arteries involvement.

#### **5. Below-the-knee intervention – Technical issues**

#### **5.1 Access**

The access for below the knee (BTK) vessels can be granted either by antegrade ipsilateral approach or by retrograde contralateral approach.

#### **5.1.1 Antegrade ipsilateral approach**

As it allows a nearer distance to the tibial arteries, the antegrade technique permits the utilization of shorter devices, which leads to an improvement of the guidewires and catheters' characteristics like pushability, torqueability, crossability or trackability. As a result, it may become easier to treat complex lesions as long occlusions, distal lesions as in foot vessels or use complex techniques like the pedal-plantar loop technique. However, the antegrade puncture implies that the iliac arteries and the proximal superficial femoral artery are free of significant disease. Even if the pattern of arterial involvement in diabetic, CLI patients is mostly at BTK level, the presence of palpable femoral and popliteal pulses should not be considered as synonym of absence of an upstream significant lesion. As so, an arterial ultrasound of the iliac and femoral arteries should be previously performed to insure that an adequate inflow is available. Moreover, the antegrade approach can be difficult in obese patients. In those patients, some tricks can help in turning the puncture easier: (1) wrap the abdominal pannus with tape in cranial and contralateral directions; (2) put a folded sheet under the ipsilateral hip; (3) place the patient in Trendelenburg position; (4) consider longer needles; (5) consider reinforced sheaths (e.g. SuperArrow® Flex). The antegrade technique is also more prone to local complications and should be performed using a single wall needle to avoid a double puncture and its consequent additional potential problems. It should also be completed under fluoroscopy to localize the femoral head and puncture the common femoral artery (Dotter et al., 1978; Grier and Hartnell, 1990). In hostile heavily scarred groins or in very obese patients, ultrasound guided puncture of either the common femoral or the superficial femoral arteries may reduce radiation doses, screen times and complications (Biondi-Zoccai et al., 2006; Marcus et al., 2007; Yeow et al., 2002).

#### **5.1.2 Retrograde contralateral approach**

Contralateral puncture is technically easier to achieve and safer in regard to local complications (Nice et al., 2003). It permits performing a strategic arteriography and the correction of proximal iliac and femoral lesions. It allows a more secure utilization of closure devices and maintains the puncture site remote from the treated segment. The utilization of long sheaths especially designed for BTK intervention (e.g. Cook® Shuttle Tibial) may provide additional external support, allowing intervention in more demanding cases, but Angioplasty, Various Techniques and Challenges in 44 Treatment of Congenital and Acquired Vascular Stenoses

A meta-analysis of 30 articles from Romiti et al. looked at immediate technical success, primary and secondary patency, limb salvage, and survival after infrapopliteal PTA in CLI patients. The results were compared with a meta-analysis of popliteal-to-distal vein bypass graft that the authors had previously published (Albers et al., 2006). Even if there was a significant difference in favor of vein bypass concerning durability, the limb salvage rates

From the data presented, it results that endovascular approach is currently considered as the

The access for below the knee (BTK) vessels can be granted either by antegrade ipsilateral

As it allows a nearer distance to the tibial arteries, the antegrade technique permits the utilization of shorter devices, which leads to an improvement of the guidewires and catheters' characteristics like pushability, torqueability, crossability or trackability. As a result, it may become easier to treat complex lesions as long occlusions, distal lesions as in foot vessels or use complex techniques like the pedal-plantar loop technique. However, the antegrade puncture implies that the iliac arteries and the proximal superficial femoral artery are free of significant disease. Even if the pattern of arterial involvement in diabetic, CLI patients is mostly at BTK level, the presence of palpable femoral and popliteal pulses should not be considered as synonym of absence of an upstream significant lesion. As so, an arterial ultrasound of the iliac and femoral arteries should be previously performed to insure that an adequate inflow is available. Moreover, the antegrade approach can be difficult in obese patients. In those patients, some tricks can help in turning the puncture easier: (1) wrap the abdominal pannus with tape in cranial and contralateral directions; (2) put a folded sheet under the ipsilateral hip; (3) place the patient in Trendelenburg position; (4) consider longer needles; (5) consider reinforced sheaths (e.g. SuperArrow® Flex). The antegrade technique is also more prone to local complications and should be performed using a single wall needle to avoid a double puncture and its consequent additional potential problems. It should also be completed under fluoroscopy to localize the femoral head and puncture the common femoral artery (Dotter et al., 1978; Grier and Hartnell, 1990). In hostile heavily scarred groins or in very obese patients, ultrasound guided puncture of either the common femoral or the superficial femoral arteries may reduce radiation doses, screen times and complications (Biondi-Zoccai et al., 2006; Marcus et al.,

Contralateral puncture is technically easier to achieve and safer in regard to local complications (Nice et al., 2003). It permits performing a strategic arteriography and the correction of proximal iliac and femoral lesions. It allows a more secure utilization of closure devices and maintains the puncture site remote from the treated segment. The utilization of long sheaths especially designed for BTK intervention (e.g. Cook® Shuttle Tibial) may provide additional external support, allowing intervention in more demanding cases, but

were equivalent between both techniques (Albers et al., 2006; Romiti et al., 2008).

first-line treatment for CLI patients with below-the-knee arteries involvement.

**5. Below-the-knee intervention – Technical issues** 

approach or by retrograde contralateral approach.

**5.1.1 Antegrade ipsilateral approach** 

2007; Yeow et al., 2002).

**5.1.2 Retrograde contralateral approach** 

**5.1 Access** 

potentially increasing total costs. Meanwhile, distal lesions are still difficult to reach and unfavorable aortic bifurcations or aortic grafts may preclude its utilization.

Table 1 summarizes the advantages and disadvantages of each approach.


Table 1. Antegrade and contralateral retrograde access

#### **5.2 Tibial vessel selection for intervention – The key step**

Perhaps the most critical decision in revascularizing CLI patients with predominant BTK arteries involvement is to decide which vessel(s) should be approached to achieve successful limb salvage. In spite of arbitrarily recanalize a tibial artery only based on arteriography, one should consider some basic and prevailing principles.

#### **5.2.1 Angiosome model**

The angiosome concept was initially described in plastic and reconstructive surgery papers and was intended to provide the basis for a logical planning of incisions and flaps (Taylor and Palmer, 1987; Taylor and Pan, 1998). These anatomical studies delineated threedimensional anatomic units of tissue (from skin to bone) fed by a given source artery, defined as angiosomes. In foot it has been described six angiosomes, arising from the posterior tibial artery (n=3), the anterior tibial artery (n=1), and the peroneal artery (n=2) (figure 1). The posterior tibial artery gives rise to a calcaneal branch that supplies the medial ankle and plantar heel, a medial plantar artery that feeds the medial plantar instep and a lateral plantar artery that supplies the lateral forefoot, plantar midfoot and entire plantar forefoot. The anterior tibial artery continues as the *dorsalis pedis* artery feeding the dorsum of the foot. The peroneal artery supplies the lateral ankle and plantar heel via the calcaneal branch and the lateral anterior upper ankle via an anterior perforating branch. Alexandrescu et al. applied more recently this angiosome model to guide endovascular procedures in diabetic CLI patients with remarkable results (Alexandrescu et al., 2008). This rational approach for the revascularization of the foot was followed by several authors who confirmed its relevance for ulcer healing and consequent limb salvage (Alexandrescu et al., 2011; Iida et al., 2010; Neville et al., 2009). In fact, Iida et al. analyzed 203 limbs in 177 patients and separated them into direct and indirect groups depending on whether feeding artery flow to the site of ulceration was successfully acquired or not based on the angiosome concept. They found that limb salvage rate was significantly higher in the direct group (86%) than in the indirect group (69%) for up to 4 years after the procedure (Iida et al., 2010).

Below the Knee Techniques: Now and Then 47

according to the angiosome model. In those circumstances, approaching an alternative tibial vessel considering the anastomoses between angiosomes may be the only option available in

In the past, the BTK interventional techniques were performed with large caliber, nonspecific instruments, which resulted in poor results and skepticism upon its applicability in this specific sector. The relative similarity between BTK and coronary vessels led vascular interventionists to employ low profiling coronary devices, which improved outcomes. Additional developments brought specifically designed devices, achieving results that

Fluoroscopy is supposed to have high resolution (less than 0.3 mm), should allow roadmapping and overlay techniques and must permit a high range of angulation. In fact, the last point is highly relevant since some significant lesions can be occulted or underestimated by standard posterior-anterior view. Moreover, oblique incidences allow clear observation of tibial vessels avoiding superposed bone and potentially revealing useful

One may start with a 0.035" regular angled glidewire™ to cross simple stenoses. However,

Vascular specialists began BTK treatment with some scarcity of options in regard to guidewires, but currently there has been an increasing choice in this particular matter

Tip load, tip stiffness, hydrophilic/hydrophobic coating of the tip and body, guidewire flexibility, ability to shape, shaping memory, shaft support, torque transmission, trackability, and pushability are all critical components for a BTK intervention guidewire,

The selection should consider some specificities of the lesion: (1) the localization (some authors prefer 0.018" guidewires for tibial arteries, leaving 0.014" guidewires for pedal arteries); (2) CTO or stenosis (occlusions may require specifically designed tip); (3) length (long lesions, especially CTOs, usually demand additional support to allow the passage of

Non-hydrophilic guidewires allow a better tactile feel and a more controlled torque response when compared with hydrophilic wires. They are less likely to cause dissection of a vessel but have a higher resistance within the lesion, which may decrease the chances of successful crossing, particularly in CTOs. To counterweigh this, some uncoated, spring-coil wires have a specifically designed tapered-tip which confers more penetrating power to the tip. On the other hand, some guidewires may have, rather than increased sharpness, greater

Hydrophilic wires typically advance with minimal resistance, providing good maneuverability in tortuous and long vessels but at a cost of reduced tactile feel. They are

especially for chronic total occlusions (CTOs) (Godino et al., 2009) (see tables 2 & 3).

tip stiffness due to weights addition, which increases their penetration ability.

also more prone in penetrating beneath plaque inducing a dissection of the vessel.

trying to preserve a CLI limb.

changed the paradigm of CLI patients treatment approach.

calcifications that can be used as *natural roadmapping*.

more complex lesions must be addressed with specific guidewires.

**5.3 BTK Recanalization** 

**5.3.1 Imaging** 

**5.3.2 Guidewires** 

other interventional devices).

(Table 2).

Lately, Alexandrescu et al. compared 213 CLI limbs revascularized prior (n=89) and after (n=134) the introduction of the angiosome model. They also concluded that angiosometargeted revascularization was associated with significantly higher limb preservation (89% vs. 79% at 36 months) (Alexandrescu et al., 2011). To simply allow pulsatile flow to the correct portion of the foot is the contemporary paramount for ulcer healing.

Fig. 1. Angiosome model. A – Calcaneal branch of the posterior tibial artery. B - Calcaneal branch of the peroneal artery. C – Anterior perforating branch of the peroneal artery.

#### **5.2.2 Additional concepts**

Adjacent angiosomes are bordered by reduced caliber (choke) or artery-similar caliber (true) anastomoses, which link neighboring angiosomes to one another and demarcate the border of each angiosome (Attinger et al., 2006; Taylor and Pan, 1998). In addition, these vessels are important safety conduits that allow a given angiosome to provide blood flow to an adjacent angiosome if the latter's source artery is damaged.

This concept should be taken into account in CLI limb revascularization. In fact, after having revascularized the key artery according to the angiosome concept, one may consider revascularizing other tibial vessels. The rationale to do so can be based on: (1) limited permeability rates with current angioplasty techniques may compromise the feeding artery before complete lesion healing; (2) trophic lesion may include more than one angiosome. Nevertheless, this attempt should never place the recanalized feeding artery at risk.

Meanwhile, some technical issues, as the lack of visible run-off, the presence of heavy calcification precluding transluminal or subintimal occlusion crossing, an occlusion at an arterial bifurcation (like the anterior tibial artery origin) or the presence of an important collateral at the beginning of an occlusion may restrict or prevent revascularization according to the angiosome model. In those circumstances, approaching an alternative tibial vessel considering the anastomoses between angiosomes may be the only option available in trying to preserve a CLI limb.

#### **5.3 BTK Recanalization**

In the past, the BTK interventional techniques were performed with large caliber, nonspecific instruments, which resulted in poor results and skepticism upon its applicability in this specific sector. The relative similarity between BTK and coronary vessels led vascular interventionists to employ low profiling coronary devices, which improved outcomes. Additional developments brought specifically designed devices, achieving results that changed the paradigm of CLI patients treatment approach.

#### **5.3.1 Imaging**

Angioplasty, Various Techniques and Challenges in 46 Treatment of Congenital and Acquired Vascular Stenoses

Lately, Alexandrescu et al. compared 213 CLI limbs revascularized prior (n=89) and after (n=134) the introduction of the angiosome model. They also concluded that angiosometargeted revascularization was associated with significantly higher limb preservation (89% vs. 79% at 36 months) (Alexandrescu et al., 2011). To simply allow pulsatile flow to the

Fig. 1. Angiosome model. A – Calcaneal branch of the posterior tibial artery. B - Calcaneal branch of the peroneal artery. C – Anterior perforating branch of the peroneal artery.

Adjacent angiosomes are bordered by reduced caliber (choke) or artery-similar caliber (true) anastomoses, which link neighboring angiosomes to one another and demarcate the border of each angiosome (Attinger et al., 2006; Taylor and Pan, 1998). In addition, these vessels are important safety conduits that allow a given angiosome to provide blood flow to an adjacent

This concept should be taken into account in CLI limb revascularization. In fact, after having revascularized the key artery according to the angiosome concept, one may consider revascularizing other tibial vessels. The rationale to do so can be based on: (1) limited permeability rates with current angioplasty techniques may compromise the feeding artery before complete lesion healing; (2) trophic lesion may include more than one angiosome.

Meanwhile, some technical issues, as the lack of visible run-off, the presence of heavy calcification precluding transluminal or subintimal occlusion crossing, an occlusion at an arterial bifurcation (like the anterior tibial artery origin) or the presence of an important collateral at the beginning of an occlusion may restrict or prevent revascularization

Nevertheless, this attempt should never place the recanalized feeding artery at risk.

**5.2.2 Additional concepts** 

angiosome if the latter's source artery is damaged.

correct portion of the foot is the contemporary paramount for ulcer healing.

Fluoroscopy is supposed to have high resolution (less than 0.3 mm), should allow roadmapping and overlay techniques and must permit a high range of angulation. In fact, the last point is highly relevant since some significant lesions can be occulted or underestimated by standard posterior-anterior view. Moreover, oblique incidences allow clear observation of tibial vessels avoiding superposed bone and potentially revealing useful calcifications that can be used as *natural roadmapping*.

#### **5.3.2 Guidewires**

One may start with a 0.035" regular angled glidewire™ to cross simple stenoses. However, more complex lesions must be addressed with specific guidewires.

Vascular specialists began BTK treatment with some scarcity of options in regard to guidewires, but currently there has been an increasing choice in this particular matter (Table 2).

Tip load, tip stiffness, hydrophilic/hydrophobic coating of the tip and body, guidewire flexibility, ability to shape, shaping memory, shaft support, torque transmission, trackability, and pushability are all critical components for a BTK intervention guidewire, especially for chronic total occlusions (CTOs) (Godino et al., 2009) (see tables 2 & 3).

The selection should consider some specificities of the lesion: (1) the localization (some authors prefer 0.018" guidewires for tibial arteries, leaving 0.014" guidewires for pedal arteries); (2) CTO or stenosis (occlusions may require specifically designed tip); (3) length (long lesions, especially CTOs, usually demand additional support to allow the passage of other interventional devices).

Non-hydrophilic guidewires allow a better tactile feel and a more controlled torque response when compared with hydrophilic wires. They are less likely to cause dissection of a vessel but have a higher resistance within the lesion, which may decrease the chances of successful crossing, particularly in CTOs. To counterweigh this, some uncoated, spring-coil wires have a specifically designed tapered-tip which confers more penetrating power to the tip. On the other hand, some guidewires may have, rather than increased sharpness, greater tip stiffness due to weights addition, which increases their penetration ability.

Hydrophilic wires typically advance with minimal resistance, providing good maneuverability in tortuous and long vessels but at a cost of reduced tactile feel. They are also more prone in penetrating beneath plaque inducing a dissection of the vessel.

Below the Knee Techniques: Now and Then 49

2010). This may explain, at least partially, the relative ease in crossing tibial CTOs by retrograde pedal approach. The composition of the core correlates with CTO age. Older CTOs have higher concentrations of fibrocalcific material ("*hard plaque*"), while CTOs present for less than one year have more cholesterol clefts and foam cells among less fibrous material ("*soft* 

Neovascularization starts early, as part of the organization of the CTO, and increases with time. As it has been demonstrated in coronary arteries, many CTOs are not completely occluded when examined under the microscope (Srivatsa et al., 1997). In fact, the new sprouting vessels, in contrast with *vasa vasorum* that run in radial directions, proceed within and parallel to the occluded parent vessel (Strauss et al., 2005). As a result they may originate microchannels throughout the CTO which diameter can vary between 100 and 500 m (Srivatsa et al., 1997; Stone et al., 2005). Those can be used to engage the tip of the guidewire, which can further help in crossing CTOs. In this particular matter, tapered tips increase the ability to insert the guidewire in those microchannels, while hydrophilic tips are

According to the lesion and the guidewire, different techniques to penetrate CTOs fibrous

In the *drilling technique*, the tip is bended in a short extension and clockwise and counterclockwise rotations of the guidewire are performed while the tip is pushed modestly against the CTO lesion (figure 2). The important issue in this technique is that one does not push the guidewire very hard. If the tip of the guidewire does not advance any more with gentle pushing, it is by far better to exchange for a stiffer wire, rather than continue pushing. If one pushes the wire hard, it will easily go into the subintimal space. Yet, when a stiff guidewire is used, it may be difficult to perceive whether the tip has been engaged in the true or in a false lumen inside the CTO. The movement of the tip may help in distinguishing one from the other. Typically, when the guidewire is in the subadventitial space, the tip budges markedly. Additionally, the extension of the tip curve may look exaggerated, especially when using floppy tip guidewires. Tactile feel from the guidewire during pullback can also aid as true lumen usually offers higher resistance. This technique has an increased risk of perforation, especially when using stiff tips guidewires and is not usually recommended for

*plaque*"). This may, in part, explain the greater simplicity in crossing these younger CTOs.

more prone to progress inside them.

complex lesions (Godino et al., 2009; Kim, 2010).

**5.3.3.1 Crossing CTOs** 

caps may be applied.

5.3.3.1.1 Antegrade techniques

Fig. 2. Drilling technique.


Table 2. Possible 0.014" guidewires for BTK purposes. BS – Boston Scientific. LS, MS, ES (light, medium, and extra support). Y/N – Both versions are available. \*1 – Only in the 9, 12 and 15 g tips. GW – Guidewire; HF hydrophobic; NA – Not Available.


Table 3. Possible 0.018" guidewires for BTK purposes. BS – Boston Scientific; NA – Not Available.

#### **5.3.3 Chronic Total Occlusions (CTOs)**

CTOs are generally defined as occluded arteries of three months duration or longer (Stone et al., 2005). CTOs are characterized by proximal and distal fibrous caps, a mix of luminal *soft* and *hard* plaque, thrombin, fibrin, inflammatory cells (in the intima, media, and adventitia), and neovascularization. The plaque is composed of a collagen rich extracellular matrix, intra, and extracellular lipids, smooth muscle cells, and calcium (Katsuragawa et al., 1993; Srivatsa et al., 1997). The proximal and distal caps have higher concentrations of collagen and calcium (fibrocalcific), even if the distal cap is frequently softer than the proximal cap (Fefer et al., Angioplasty, Various Techniques and Challenges in 48 Treatment of Congenital and Acquired Vascular Stenoses

Abbott Pilot™ 50, 150, 200 Y Y N 2,4,6 Coronary GW Abbott Wisper LS, MS, ES Y N N 1 Coronary GW Asahi Confianza™ N N Y (0.009") 9 Coronary GW Asahi Intecc Miracle ™ N N N 3, 4.5, 6, 9, 12 Coronary GW

MS, ES Y N N 0.27 Coronary GW Biotronik Cruiser® MS, ES HF N N 0.27 Coronary GW Biotronik XT-14 Y N N NA BTK GW

Grafix P2™ LS, MS Y Y N 3-4 Coronary GW Cook Approach® Hydro ST Y N N NA BTK GW Cook Approach® CTO N N N 6, 12, 18, 25 BTK GW Cordis Shinobi™ Y N N 2 Coronary GW Medtronic Provia™ N Y/N Y (0.009")\*1 3, 6, 9, 12, 15 BTK GW Table 2. Possible 0.014" guidewires for BTK purposes. BS – Boston Scientific. LS, MS, ES (light, medium, and extra support). Y/N – Both versions are available. \*1 – Only in the 9, 12

and 15 g tips. GW – Guidewire; HF hydrophobic; NA – Not Available.

Abbott SteelCore 18 LT N N N NA

**0.018" Guidewires Hydrophilic Tapered tip Tip stiffness** 

Biotronik Cruiser® 18 Y N N NA Increased

BS V-18™ Control Wire® Y N N 3-4 Increased

Cook Roadrunner® ES N N N NA Increased

CTOs are generally defined as occluded arteries of three months duration or longer (Stone et al., 2005). CTOs are characterized by proximal and distal fibrous caps, a mix of luminal *soft* and *hard* plaque, thrombin, fibrin, inflammatory cells (in the intima, media, and adventitia), and neovascularization. The plaque is composed of a collagen rich extracellular matrix, intra, and extracellular lipids, smooth muscle cells, and calcium (Katsuragawa et al., 1993; Srivatsa et al., 1997). The proximal and distal caps have higher concentrations of collagen and calcium (fibrocalcific), even if the distal cap is frequently softer than the proximal cap (Fefer et al.,

Table 3. Possible 0.018" guidewires for BTK purposes. BS – Boston Scientific; NA – Not

**tip body**

**(g) Remarks** 

**(g) Remarks** 

body stiffness

body stiffness

body stiffness

0.009") 4.8, 9.7, 13 BTK GW

**0.014" Guidewires Hydrophilic Tapered tip Tip stiffness** 

**tip body**

Abbott HT Winn™ 40, 80, 200 Y HF Y (0.012-

Biotronik Cruiser® Hydro

BS PT Graphix™;

Available.

**5.3.3 Chronic Total Occlusions (CTOs)** 

2010). This may explain, at least partially, the relative ease in crossing tibial CTOs by retrograde pedal approach. The composition of the core correlates with CTO age. Older CTOs have higher concentrations of fibrocalcific material ("*hard plaque*"), while CTOs present for less than one year have more cholesterol clefts and foam cells among less fibrous material ("*soft plaque*"). This may, in part, explain the greater simplicity in crossing these younger CTOs.

Neovascularization starts early, as part of the organization of the CTO, and increases with time. As it has been demonstrated in coronary arteries, many CTOs are not completely occluded when examined under the microscope (Srivatsa et al., 1997). In fact, the new sprouting vessels, in contrast with *vasa vasorum* that run in radial directions, proceed within and parallel to the occluded parent vessel (Strauss et al., 2005). As a result they may originate microchannels throughout the CTO which diameter can vary between 100 and 500 m (Srivatsa et al., 1997; Stone et al., 2005). Those can be used to engage the tip of the guidewire, which can further help in crossing CTOs. In this particular matter, tapered tips increase the ability to insert the guidewire in those microchannels, while hydrophilic tips are more prone to progress inside them.

#### **5.3.3.1 Crossing CTOs**

According to the lesion and the guidewire, different techniques to penetrate CTOs fibrous caps may be applied.

#### 5.3.3.1.1 Antegrade techniques

In the *drilling technique*, the tip is bended in a short extension and clockwise and counterclockwise rotations of the guidewire are performed while the tip is pushed modestly against the CTO lesion (figure 2). The important issue in this technique is that one does not push the guidewire very hard. If the tip of the guidewire does not advance any more with gentle pushing, it is by far better to exchange for a stiffer wire, rather than continue pushing. If one pushes the wire hard, it will easily go into the subintimal space. Yet, when a stiff guidewire is used, it may be difficult to perceive whether the tip has been engaged in the true or in a false lumen inside the CTO. The movement of the tip may help in distinguishing one from the other. Typically, when the guidewire is in the subadventitial space, the tip budges markedly. Additionally, the extension of the tip curve may look exaggerated, especially when using floppy tip guidewires. Tactile feel from the guidewire during pullback can also aid as true lumen usually offers higher resistance. This technique has an increased risk of perforation, especially when using stiff tips guidewires and is not usually recommended for complex lesions (Godino et al., 2009; Kim, 2010).

Fig. 2. Drilling technique.

Below the Knee Techniques: Now and Then 51

Highly calcified lesions may add some resistance to the guidewire progression, making predilatation necessary, and can, in addition, make difficult or impede re-entry in true lumen. Recoil is more common and care should be especially taken to avoid damaging collaterals. As subintimal space is larger than true lumen, the balloon should be slightly oversized (0.5 mm). In the *parallel wire technique*, when the initial wire passes into a dissection plane, it is left there using it as a reference point to assist in passing a second wire through the true lumen (figure 5. This technique has two main purposes: re-directing a wire inside the CTO and

5.3.3.1.2 Subintimal Arterial Flossing with Antegrade–Retrograde Intervention (SAFARI) During antegrade recanalization, reentry into the distal true lumen can be difficult or impossible for several reasons. In those circumstances retrograde puncture has to be considered. This technique should also be envisaged when the proximal occlusion stump cannot be determined, which occurs most frequently with the anterior tibial artery (figure 6, case 1). It can be performed in all three leg arteries at the calf, ankle or foot levels. The puncture is performed under fluoroscopic guidance. Vessel calcification can be very useful. At the ankle or foot level, a 21 G, 4 cm long, needle can be used (the same needle used in a radial artery line placement). Crural level puncture implies a longer needle (21 G, 7 cm long, from a micropuncture kit). When the needle is in the artery lumen, a weak back-bleeding of arterial blood is observed. At that point, a 300 cm, 0.014", hydrophilic, intermediate or stiff shaft guidewire is engaged in the true lumen of the target vessel, subsequently assisted by a low profile support catheter or balloon catheter, without sheath placement. Subsequently, retrograde subintimal recanalization is carried out and continued until entry in the proximal true lumen or in the subintimal space from the antegrade approach is achieved. Sometimes, neither are obtained after several attempts. At that moment, the *rendez-vous technique* should be performed to break the membrane that separates the retrograde and antegrade subintimal spaces and, consequently, get continuity between them (figures 6-F and 7). At that time, the guidewire is typically snared or directed into the antegrade catheter or sheath to create a *flossing*-type guidewire which provides reliable access and adequate support (as it is fixed at both ends) for antegrade balloon angioplasty or stent placement (Figure 6) (Spinosa et al., 2003). When adequate flow has been reestablished into the target vessel, a catheter (diagnostic catheter, low profile support catheter or balloon catheter) is advanced distally to the lesion. The guidewire is then retrieved proximally, inverted and re-inserted (if not damaged). Hemostasis of the retrograde puncture site in foot and ankle is achieved by gentle local compression. At the calf level, hemostasis is performed by inflating a short balloon in the artery at the puncture site, usually for two minutes and at low pressure.

puncturing distal CTO fibrous cap.

Fig. 5. Parallel wire technique.

In the *penetration technique*, the tip shape is usually straighter than in the drilling technique and a less rotational tip motion and a more direct forward probing is used (figure 3). Some heavily calcified CTO caps may require the use of very aggressive guidewires to achieve passage using the described technique (tapered stiff tips and increased body support guidewires, like the Abbott HT Winn 200™). Additionally, the target has to be clearly identified and careful monitoring of the progressive guidewire advancement should be done. Only experienced interventionists should make use of this technique in difficult CTOs, due to the particularly augmented risk of complications.

Fig. 3. Penetration technique.

The *sliding technique* utilizes hydrophilic guidewires. Reduced surface friction enhances passage through the CTO core. It is recommended that the tip is initially shaped with a single, long shallow bend and movement consists of simultaneous smooth tip rotation and gentle probing. The guidewire typically advances with minimal resistance and tactile feel, resulting frequently in inadvertent entry to the subintimal space.

This technique is particularly indicated for engaging softer CTOs with microchannels, subtotal occlusions or angulated lesions (Godino et al., 2009).

The *subintimal dissection technique* is usually performed when transluminal crossing has been unsuccessful. A hydrophilic guidewire with a floppy tip and an intermediate or stiff body is generally preferred. The loop is made with the floppy tip of the guidewire and should be relatively small to reduce the risk of perforation (figure 4).

Fig. 4. A – Loop of the guidewire tip for *subintimal dissection* technique (BS V-18™ Control Wire®); B, C – Case of a long anterior tibial artery (ATA) occlusion (arrow pointing to distal ATA); D – Guidewire advanced subintimally all the way through ATA. E, F – Final result.

Angioplasty, Various Techniques and Challenges in 50 Treatment of Congenital and Acquired Vascular Stenoses

In the *penetration technique*, the tip shape is usually straighter than in the drilling technique and a less rotational tip motion and a more direct forward probing is used (figure 3). Some heavily calcified CTO caps may require the use of very aggressive guidewires to achieve passage using the described technique (tapered stiff tips and increased body support guidewires, like the Abbott HT Winn 200™). Additionally, the target has to be clearly identified and careful monitoring of the progressive guidewire advancement should be done. Only experienced interventionists should make use of this technique in difficult

The *sliding technique* utilizes hydrophilic guidewires. Reduced surface friction enhances passage through the CTO core. It is recommended that the tip is initially shaped with a single, long shallow bend and movement consists of simultaneous smooth tip rotation and gentle probing. The guidewire typically advances with minimal resistance and tactile feel,

This technique is particularly indicated for engaging softer CTOs with microchannels,

The *subintimal dissection technique* is usually performed when transluminal crossing has been unsuccessful. A hydrophilic guidewire with a floppy tip and an intermediate or stiff body is generally preferred. The loop is made with the floppy tip of the guidewire and should be

Fig. 4. A – Loop of the guidewire tip for *subintimal dissection* technique (BS V-18™ Control Wire®); B, C – Case of a long anterior tibial artery (ATA) occlusion (arrow pointing to distal ATA); D – Guidewire advanced subintimally all the way through ATA. E, F – Final result.

CTOs, due to the particularly augmented risk of complications.

resulting frequently in inadvertent entry to the subintimal space.

subtotal occlusions or angulated lesions (Godino et al., 2009).

relatively small to reduce the risk of perforation (figure 4).

Fig. 3. Penetration technique.

Highly calcified lesions may add some resistance to the guidewire progression, making predilatation necessary, and can, in addition, make difficult or impede re-entry in true lumen. Recoil is more common and care should be especially taken to avoid damaging collaterals. As subintimal space is larger than true lumen, the balloon should be slightly oversized (0.5 mm). In the *parallel wire technique*, when the initial wire passes into a dissection plane, it is left there using it as a reference point to assist in passing a second wire through the true lumen (figure 5. This technique has two main purposes: re-directing a wire inside the CTO and puncturing distal CTO fibrous cap.

5.3.3.1.2 Subintimal Arterial Flossing with Antegrade–Retrograde Intervention (SAFARI)

During antegrade recanalization, reentry into the distal true lumen can be difficult or impossible for several reasons. In those circumstances retrograde puncture has to be considered. This technique should also be envisaged when the proximal occlusion stump cannot be determined, which occurs most frequently with the anterior tibial artery (figure 6, case 1). It can be performed in all three leg arteries at the calf, ankle or foot levels. The puncture is performed under fluoroscopic guidance. Vessel calcification can be very useful. At the ankle or foot level, a 21 G, 4 cm long, needle can be used (the same needle used in a radial artery line placement). Crural level puncture implies a longer needle (21 G, 7 cm long, from a micropuncture kit). When the needle is in the artery lumen, a weak back-bleeding of arterial blood is observed. At that point, a 300 cm, 0.014", hydrophilic, intermediate or stiff shaft guidewire is engaged in the true lumen of the target vessel, subsequently assisted by a low profile support catheter or balloon catheter, without sheath placement. Subsequently, retrograde subintimal recanalization is carried out and continued until entry in the proximal true lumen or in the subintimal space from the antegrade approach is achieved. Sometimes, neither are obtained after several attempts. At that moment, the *rendez-vous technique* should be performed to break the membrane that separates the retrograde and antegrade subintimal spaces and, consequently, get continuity between them (figures 6-F and 7). At that time, the guidewire is typically snared or directed into the antegrade catheter or sheath to create a *flossing*-type guidewire which provides reliable access and adequate support (as it is fixed at both ends) for antegrade balloon angioplasty or stent placement (Figure 6) (Spinosa et al., 2003). When adequate flow has been reestablished into the target vessel, a catheter (diagnostic catheter, low profile support catheter or balloon catheter) is advanced distally to the lesion. The guidewire is then retrieved proximally, inverted and re-inserted (if not damaged). Hemostasis of the retrograde puncture site in foot and ankle is achieved by gentle local compression. At the calf level, hemostasis is performed by inflating a short balloon in the artery at the puncture site, usually for two minutes and at low pressure.

Below the Knee Techniques: Now and Then 53

Meanwhile, there are several limitations to this technique. As so, an occluded or severely diseased artery may impede the puncture. Additionally, one should be extremely careful when the working artery is the only one patent in the leg, as a dissection, perforation or

This technique consists in creating a loop with the guidewire from the anterior tibial artery to the posterior tibial artery, or the inverse, through the foot vessels (Fusaro et al., 2007; Manzi et al., 2009). The most common pathway is through *dorsalis pedis* artery, deep plantar artery, deep plantar arterial arch, lateral plantar artery and posterior tibial artery. Indications for this technique are similar to the SAFARI technique. However, unlike the SAFARI technique, it can be performed when no distal vessel is available for puncture, being also less invasive. Moreover, this technique can provide a better outflow for tibial

On the other hand, complications related to foot vessels manipulations can precipitate a

Additional information in regard to this technique is provided in the chapter from the

If neither the anterior nor the posterior tibial artery can be treated despite several intraluminal and subintimal crossing attempts, the alternative treatment may consist of providing direct flow along the peroneal artery. The distal peroneal artery has several collateral branches that connect with foot arteries. In particular, the communicating branch connects the peroneal with the posterior tibial artery, whereas the perforating branch goes through the interosseous membrane and links the peroneal to the *dorsalis pedis* artery. This technique aims at creating an effective pathway from the peroneal to tibial vessels by means

The *transcollateral* technique may be of value specifically when a proximal occlusion stump is not evident, when a dissection flap or a perforation in the proximal tract of the target vessel impairs guidewire advancement, or when distal disease makes retrograde

The major limitation of this technique is the absence of collaterals suitable for wiring (Fusaro

In all the above described techniques, a low-profile supportive catheter (Cook CXI™, Spectranetics® Quickcross®, Medtronic/Invatec Diver) or a low-profile balloon catheter can be used to provide additional support to the advancement of the guidewire. They also allow wire exchange without sacrificing the progress made through the lesion. Additionally, their lumen can be used to inject contrast and verify position and distal outflow. In this circumstances, diluted contrast, with diminished viscosity, may be preferable as the very

Specific low-profile balloons (less than 4F) have been recently designed for BTK purposes. They are made to work on a 0.014" or a 0.018" platform. The catheters of those balloons should provide increased shaft strength to allow adequate pushability, particularly in complex CTOs. In those circumstances, the over-the-wire technique should be preferred as it

rupture may preclude a possible rescue surgery bypass.

5.3.3.1.3 Pedal-plantar loop technique

serious worsening of the ischemic condition.

5.3.3.1.4 Revascularization through peroneal artery collaterals

of guidewire tracking through the referred collaterals (figure 8).

low profile of catheter lumen is associated with high flow resistance.

present book written by Manzi et al.

percutaneous puncture impossible.

et al., 2008; Graziani et al., 2008).

**5.3.4 Balloons** 

arteries.

Fig. 6. SAFARI interventions. *Case 1.* A – Initial arteriography; occlusion of popliteal and all three tibial arteries (black arrow: patent *dorsalis pedis* artery). B – Snaring of the retrograde guidewire. C – Final result. / *Case 2*. D – Initial arteriography; patent peroneal artery, but ending in unsatisfactory collaterals (black arrow head: proximal anterior tibial artery). E – X-Ray showing percutaneous retrograde guidewire. F – *Rendez-vous technique*. G – Retrograde guidewire introduced inside 4F Bernstein catheter (the catheter should be turned to the arterial wall; the angled tip of the guidewire have to be engaged inside catheter lumen through simultaneous smooth tip rotation and gentle probing). H – Final result (guidewire can still be seen in the foot in a percutaneous position).

Fig. 7. *Rendez-vous technique*. A – Antegrade and retrograde guidewires in their respective subintimal space. B – A balloon catheter is advanced over each guidewire. C – The tip of the balloons are placed at the same level and guidewires tips are retrieved inside the balloon catheter. D – Balloons are inflated and the separating membrane broken. E – Retrograde guidewire is thoroughly advanced to proximal true lumen.

Angioplasty, Various Techniques and Challenges in 52 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 6. SAFARI interventions. *Case 1.* A – Initial arteriography; occlusion of popliteal and all three tibial arteries (black arrow: patent *dorsalis pedis* artery). B – Snaring of the retrograde guidewire. C – Final result. / *Case 2*. D – Initial arteriography; patent peroneal artery, but ending in unsatisfactory collaterals (black arrow head: proximal anterior tibial artery). E – X-Ray showing percutaneous retrograde guidewire. F – *Rendez-vous technique*. G – Retrograde guidewire introduced inside 4F Bernstein catheter (the catheter should be turned to the arterial wall; the angled tip of the guidewire have to be engaged inside catheter lumen through simultaneous smooth tip rotation and gentle probing). H – Final result (guidewire

Fig. 7. *Rendez-vous technique*. A – Antegrade and retrograde guidewires in their respective subintimal space. B – A balloon catheter is advanced over each guidewire. C – The tip of the balloons are placed at the same level and guidewires tips are retrieved inside the balloon catheter. D – Balloons are inflated and the separating membrane broken. E – Retrograde

A B C D E

can still be seen in the foot in a percutaneous position).

guidewire is thoroughly advanced to proximal true lumen.

Meanwhile, there are several limitations to this technique. As so, an occluded or severely diseased artery may impede the puncture. Additionally, one should be extremely careful when the working artery is the only one patent in the leg, as a dissection, perforation or rupture may preclude a possible rescue surgery bypass.

#### 5.3.3.1.3 Pedal-plantar loop technique

This technique consists in creating a loop with the guidewire from the anterior tibial artery to the posterior tibial artery, or the inverse, through the foot vessels (Fusaro et al., 2007; Manzi et al., 2009). The most common pathway is through *dorsalis pedis* artery, deep plantar artery, deep plantar arterial arch, lateral plantar artery and posterior tibial artery. Indications for this technique are similar to the SAFARI technique. However, unlike the SAFARI technique, it can be performed when no distal vessel is available for puncture, being also less invasive. Moreover, this technique can provide a better outflow for tibial arteries.

On the other hand, complications related to foot vessels manipulations can precipitate a serious worsening of the ischemic condition.

Additional information in regard to this technique is provided in the chapter from the present book written by Manzi et al.

5.3.3.1.4 Revascularization through peroneal artery collaterals

If neither the anterior nor the posterior tibial artery can be treated despite several intraluminal and subintimal crossing attempts, the alternative treatment may consist of providing direct flow along the peroneal artery. The distal peroneal artery has several collateral branches that connect with foot arteries. In particular, the communicating branch connects the peroneal with the posterior tibial artery, whereas the perforating branch goes through the interosseous membrane and links the peroneal to the *dorsalis pedis* artery. This technique aims at creating an effective pathway from the peroneal to tibial vessels by means of guidewire tracking through the referred collaterals (figure 8).

The *transcollateral* technique may be of value specifically when a proximal occlusion stump is not evident, when a dissection flap or a perforation in the proximal tract of the target vessel impairs guidewire advancement, or when distal disease makes retrograde percutaneous puncture impossible.

The major limitation of this technique is the absence of collaterals suitable for wiring (Fusaro et al., 2008; Graziani et al., 2008).

In all the above described techniques, a low-profile supportive catheter (Cook CXI™, Spectranetics® Quickcross®, Medtronic/Invatec Diver) or a low-profile balloon catheter can be used to provide additional support to the advancement of the guidewire. They also allow wire exchange without sacrificing the progress made through the lesion. Additionally, their lumen can be used to inject contrast and verify position and distal outflow. In this circumstances, diluted contrast, with diminished viscosity, may be preferable as the very low profile of catheter lumen is associated with high flow resistance.

#### **5.3.4 Balloons**

Specific low-profile balloons (less than 4F) have been recently designed for BTK purposes. They are made to work on a 0.014" or a 0.018" platform. The catheters of those balloons should provide increased shaft strength to allow adequate pushability, particularly in complex CTOs. In those circumstances, the over-the-wire technique should be preferred as it

Below the Knee Techniques: Now and Then 55

behavior is lacking (Karnabatidis et al., 2009a). Meanwhile, balloon expandable stents in tibial vessels seem to be surprisingly less vulnerable to compressions and fracture than in the

Long, thin-strut, low-profile, self-expanding nitinol stents designed and engineered specifically for the infrapopliteal arteries are now commercially accessible. Yet, data concerning their efficacy is still scarce. More concrete and solid evidence will arise when the results from the Expand-Trial (Astron Pulsar Stent versus PTA in patients with symptomatic critical limb ischemia or Severe intermittent claudication) and the XXS-Trial (Balloon

Though, considering the existing data, bare metal stents should be reserved to bailout situations after balloon angioplasty. As so, they should be inserted in the following situations: flow-limiting dissection resistant to prolonged balloon angioplasty, significant elastic recoil, and relevant residual stenosis (higher than 30%). Still, they have also been advocated to correct challenging lesions in bifurcations using the *crush technique* originally described in coronary arteries (Colombo et al., 2003; Schwarzmaier-D'Assie et al., 2007).

Systemic and access complications are common to all endovascular procedures. Additional

A perforation or an arteriovenous fistula that occurs while attempting to cross a tibial CTO is rarely of any clinical significance as it will almost constantly closes within few minutes when only a guidewire or a low-profile catheter has passed extraluminally (Lyden, 2009) (figure 9). Thus, one should be sure to be inside the vessel before inflating a balloon. Removing the devices to above the proximal extremity of the CTO and reattempting to cross the lesion from the top, may allow successful passage and aid in solving the perforation or the arteriovenous fistula. When those complications do not auto-resolve, external compression guided by angiography or temporary vessel occlusion with a balloon can be

femoro-popliteal sector, except if placed distally (Karnabatidis et al., 2009b).

Angioplasty Versus Xpert Stent in CLI Patients) will become available.

considerations should be made in regard to some direct local complications.

Fig. 9. A – Perforation; extraluminal contrast is easily noticed. B – Peroneal

A B

attempted. In very rare situations, coiling must be envisaged.

**5.4 Complications** 

arteriovenous fistula.

Fig. 8. *Transcollateral* technique. A – Black arrow head: peroneal artery; white arrow head: occlusion of the distal anterior tibial artery; white arrow head: occlusion of the distal anterior tibial artery; white arrow: communicating branch of peroneal artery anastomosing with posterior tibial artery; black arrow: perforating branch anastomosing with *dorsalis pedis*  artery. B – Inflated balloon throughout distal peroneal artery, perforating branch and *dorsalis pedis* artery. Notice the posterior to anterior transition. C - Final result.

promotes better support when compared to the rapid-exchange monorail technique. The transition between the guidewire and the tip of the catheter should be as smooth as possible to avoid the catheter getting stuck in the lesion, optimizing its crossability. Hydrophilic coating of the catheter is particularly relevant in long complex lesions. Long catheters should be considered when the contralateral approach is performed.

In regard to the balloon itself, its compliance should be kept at minimum, as diameter accuracy is crucial for BTK interventions. In this particular matter, even conical balloons have been recently released. Long sizes are now available allowing angioplasty of an almost entire tibial vessel. The shoulders should be reduced to keep precision on the extension of the vessel to be treated. Segmental pre-dilatation with smaller diameter balloons may be required to allow the passage of the definitive balloon.

Although there is no consensus on insufflation time, most of the authors recommend a period longer than 3 minutes.

#### **5.3.5 Bare-metal stents**

The tibial arteries are small diameter vessels and have a limited flow. As so, they are particularly prone to neointimal hyperplasia and re-stenosis after balloon-expandable baremetal stent (BMS) placement (Siablis et al., 2005). In fact, reocclusion occurs in up to 50% of the cases by one year (Scheinert et al., 2006; Siablis et al., 2007; Siablis et al., 2005). Additionally, balloon-expandable stents are available in only small lengths as they are originally coronary stents. There is only one long balloon-expandable stent device (up to 8 cm) dedicated to the infrapopliteal segment (Medtronic Invatec Chromis Deep). However, data regarding its Angioplasty, Various Techniques and Challenges in 54 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 8. *Transcollateral* technique. A – Black arrow head: peroneal artery; white arrow head: occlusion of the distal anterior tibial artery; white arrow head: occlusion of the distal anterior tibial artery; white arrow: communicating branch of peroneal artery anastomosing with posterior tibial artery; black arrow: perforating branch anastomosing with *dorsalis pedis*  artery. B – Inflated balloon throughout distal peroneal artery, perforating branch and *dorsalis* 

promotes better support when compared to the rapid-exchange monorail technique. The transition between the guidewire and the tip of the catheter should be as smooth as possible to avoid the catheter getting stuck in the lesion, optimizing its crossability. Hydrophilic coating of the catheter is particularly relevant in long complex lesions. Long catheters

In regard to the balloon itself, its compliance should be kept at minimum, as diameter accuracy is crucial for BTK interventions. In this particular matter, even conical balloons have been recently released. Long sizes are now available allowing angioplasty of an almost entire tibial vessel. The shoulders should be reduced to keep precision on the extension of the vessel to be treated. Segmental pre-dilatation with smaller diameter balloons may be

Although there is no consensus on insufflation time, most of the authors recommend a

The tibial arteries are small diameter vessels and have a limited flow. As so, they are particularly prone to neointimal hyperplasia and re-stenosis after balloon-expandable baremetal stent (BMS) placement (Siablis et al., 2005). In fact, reocclusion occurs in up to 50% of the cases by one year (Scheinert et al., 2006; Siablis et al., 2007; Siablis et al., 2005). Additionally, balloon-expandable stents are available in only small lengths as they are originally coronary stents. There is only one long balloon-expandable stent device (up to 8 cm) dedicated to the infrapopliteal segment (Medtronic Invatec Chromis Deep). However, data regarding its

*pedis* artery. Notice the posterior to anterior transition. C - Final result.

should be considered when the contralateral approach is performed.

required to allow the passage of the definitive balloon.

period longer than 3 minutes.

**5.3.5 Bare-metal stents** 

behavior is lacking (Karnabatidis et al., 2009a). Meanwhile, balloon expandable stents in tibial vessels seem to be surprisingly less vulnerable to compressions and fracture than in the femoro-popliteal sector, except if placed distally (Karnabatidis et al., 2009b).

Long, thin-strut, low-profile, self-expanding nitinol stents designed and engineered specifically for the infrapopliteal arteries are now commercially accessible. Yet, data concerning their efficacy is still scarce. More concrete and solid evidence will arise when the results from the Expand-Trial (Astron Pulsar Stent versus PTA in patients with symptomatic critical limb ischemia or Severe intermittent claudication) and the XXS-Trial (Balloon Angioplasty Versus Xpert Stent in CLI Patients) will become available.

Though, considering the existing data, bare metal stents should be reserved to bailout situations after balloon angioplasty. As so, they should be inserted in the following situations: flow-limiting dissection resistant to prolonged balloon angioplasty, significant elastic recoil, and relevant residual stenosis (higher than 30%). Still, they have also been advocated to correct challenging lesions in bifurcations using the *crush technique* originally described in coronary arteries (Colombo et al., 2003; Schwarzmaier-D'Assie et al., 2007).

#### **5.4 Complications**

Systemic and access complications are common to all endovascular procedures. Additional considerations should be made in regard to some direct local complications.

A perforation or an arteriovenous fistula that occurs while attempting to cross a tibial CTO is rarely of any clinical significance as it will almost constantly closes within few minutes when only a guidewire or a low-profile catheter has passed extraluminally (Lyden, 2009) (figure 9). Thus, one should be sure to be inside the vessel before inflating a balloon. Removing the devices to above the proximal extremity of the CTO and reattempting to cross the lesion from the top, may allow successful passage and aid in solving the perforation or the arteriovenous fistula. When those complications do not auto-resolve, external compression guided by angiography or temporary vessel occlusion with a balloon can be attempted. In very rare situations, coiling must be envisaged.

Fig. 9. A – Perforation; extraluminal contrast is easily noticed. B – Peroneal arteriovenous fistula.

Below the Knee Techniques: Now and Then 57

tibial vessels. Nevertheless, more consistent data is needed to determinate the precise role of

There are additional devices, some already available, other still in the pipeline of manufacturers, which may become relevant in near future. Bioabsorbable stents (drug-

Endoluminal therapy for BTK arteries is now a key part of the vascular specialist armamentarium. Tibial arteries endovascular approach has demonstrated to lead to high limb salvage rates with low morbidity and mortality. As a result, the paradigm for treatment of CLI patients has changed. One should now consider endovascular intervention as the first line treatment in the majority of CLI patients, especially in those with significant medical comorbidities. To do so, the vascular specialist should have a consistent knowledge of the BTK endovascular techniques and devices. The first step decision in tibial endovascular therapy is the access. In this context, antegrade ipsilateral approach is generally preferred. The next critical decision is the choice of the vessel(s) to be approached in order to reach successful limb salvage. Allowing pulsatile flow to the correct portion of the foot is the contemporary paramount for ulcer healing. As so, an adequate understanding of the current angiosome model should enhance clinical results. However, this concept does not preclude the recanalization of the other tibial vessels as trophic lesion may include more than one angiosome and the limited long-term permeability rate of angioplasty may compromise the feeding artery before complete lesion healing. The selection of the devices should be judicious. The choice of the guidewire is extremely relevant and should be based on the characteristics of the lesion (location, length, and stenosis/occlusion) as well as on the characteristics of the guidewire itself (tip load, stiffness, hydrophilic/hydrophobic coating, flexibility, torque transmission, trackability, and pushability). Going through chronic total occlusions may be quite challenging. Therefore, the vascular interventionist should master the techniques that have been recently described: antegrade techniques, including the drilling technique, the penetrating technique, the subintimal technique and the parallel technique; subintimal arterial flossing with antegrade-retrograde intervention (SAFARI); pedal-plantar loop technique and revascularization through peroneal artery collaterals. The specifically designed, low-profile, increased shaft strength, balloons catheters were conceived for a 0.0.014" or a 0.018" platform. The balloons should have minimal compliance and be available in long sizes. Bare metal stents should be available, even though their use

Meanwhile, the continuous arising of new technologies will possibly convulse the currently accepted BTK endovascular techniques. In fact, drug-eluting stents, drug-coated balloons, atherectomy devices, bioabsorbable stents among others may play a relevant role in BTK

The authors would like to thank the staff of the Angiology and Vascular Surgery Department, the Radiology Technicians, the Radiology Nurses and the Staff of Diabetic Foot

eluting or not), cryoplasty, and laser atherectomy are among them.

these tools in BTK intervention.

**5.6.4 Additional technology** 

is presently reserved for bailout situations.

intervention in the near future.

**7. Acknowledgements** 

**6. Conclusions** 

#### **5.5 Adjunctive medication**

All patients should be placed on intravenous heparin when the sheath is introduced. The dose should be adjusted to keep an activated clotting time between 250 and 300. Other anticoagulants, such as bivalirudin, have been shown to be equally effective (Patel et al., 2010).

All patients should already be on a chronic aspirin regimen. Clopidogrel should be started 5 days before the procedure. Alternatively, a 300 mg load can be administrated periprocedure. Although adequate evidence is lacking, aspirin plus clopidogrel should be kept for six months.

Tibial arteries are particularly prone to vasospasm. As so, arterial vasodilators should be available at all times. There are mostly four that can be used in: nitroglycerin, papaverine, tansolusine and verapamil, although nitroglycerin is most commonly used (Cronenwett et al., 2005). Besides their use in treating catheterization-associated vasospasm, they may be administrated prophylactically before balloon insufflation or guidewire manipulation of tortuous vessels, especially foot vessels.

Thrombolytics should also be accessible, as dissection, spasm or elastic recoil may precipitate an acute thrombosis.

#### **5.6 Emergent techniques and alternatives**

#### **5.6.1 Drug-eluting stents**

Driven by the encouraging results of the trials on drug-eluting stents in coronary arteries, some vascular interventionists have applied them in the infrapopliteal arteries to overcome restenosis and prolong amputation- and reintervention-free survival of CLI patients (Schofer et al., 2003). Several single-center series have demonstrated that drug-eluting stents effectively seem to be associated with a higher primary patency and a reduced need for reintervention in comparison to bare metal stents (Scheinert et al., 2006; Siablis et al., 2009). Meanwhile, considering that bare metal stents have currently restricted indications, most of

CLI patients have long complex infrapopliteal lesions, only short coronary drug-eluting balloon-expandable stents are currently available, and taking into account the so called *limb salvage-graft patency gap*, one could consider that the potential role for drug-eluting stents in BTK vessels is still to be determined.

#### **5.6.2 Drug-coated balloons**

The concept of delivering a local antiproliferative drug to the vessel surface utilizing drugcoated balloons to prevent restenosis without placing a permanent foreign material seems very appealing. Moreover, in opposition to current drug-eluting stents, drug-coated balloons can treat long lesions.

Nevertheless, more solid evidence is required to clarify the utility of drug-coated balloons in infrapopliteal arteries. The PICOLLO and PADI ongoing trials may provide the needed additional data (Hawkins and Hennebry, 2011).

#### **5.6.3 Atherectomy devices**

The OASIS trial proved that orbital atherectomy in infrapopliteal vessels may provide predictable and safe lumen enlargement. Short-term data demonstrated substantial symptomatic improvement and infrequent need for further revascularization or amputation (Korabathina et al., 2010). Specific directional atherectomy devices are also available for tibial vessels. Nevertheless, more consistent data is needed to determinate the precise role of these tools in BTK intervention.

#### **5.6.4 Additional technology**

There are additional devices, some already available, other still in the pipeline of manufacturers, which may become relevant in near future. Bioabsorbable stents (drugeluting or not), cryoplasty, and laser atherectomy are among them.

#### **6. Conclusions**

Angioplasty, Various Techniques and Challenges in 56 Treatment of Congenital and Acquired Vascular Stenoses

All patients should be placed on intravenous heparin when the sheath is introduced. The dose should be adjusted to keep an activated clotting time between 250 and 300. Other anticoagulants, such as bivalirudin, have been shown to be equally effective (Patel et al.,

All patients should already be on a chronic aspirin regimen. Clopidogrel should be started 5 days before the procedure. Alternatively, a 300 mg load can be administrated periprocedure. Although adequate evidence is lacking, aspirin plus clopidogrel should be kept

Tibial arteries are particularly prone to vasospasm. As so, arterial vasodilators should be available at all times. There are mostly four that can be used in: nitroglycerin, papaverine, tansolusine and verapamil, although nitroglycerin is most commonly used (Cronenwett et al., 2005). Besides their use in treating catheterization-associated vasospasm, they may be administrated prophylactically before balloon insufflation or guidewire manipulation of

Thrombolytics should also be accessible, as dissection, spasm or elastic recoil may

Driven by the encouraging results of the trials on drug-eluting stents in coronary arteries, some vascular interventionists have applied them in the infrapopliteal arteries to overcome restenosis and prolong amputation- and reintervention-free survival of CLI patients (Schofer et al., 2003). Several single-center series have demonstrated that drug-eluting stents effectively seem to be associated with a higher primary patency and a reduced need for reintervention in comparison to bare metal stents (Scheinert et al., 2006; Siablis et al., 2009). Meanwhile, considering that bare metal stents have currently restricted indications, most of CLI patients have long complex infrapopliteal lesions, only short coronary drug-eluting balloon-expandable stents are currently available, and taking into account the so called *limb salvage-graft patency gap*, one could consider that the potential role for drug-eluting stents in

The concept of delivering a local antiproliferative drug to the vessel surface utilizing drugcoated balloons to prevent restenosis without placing a permanent foreign material seems very appealing. Moreover, in opposition to current drug-eluting stents, drug-coated

Nevertheless, more solid evidence is required to clarify the utility of drug-coated balloons in infrapopliteal arteries. The PICOLLO and PADI ongoing trials may provide the needed

The OASIS trial proved that orbital atherectomy in infrapopliteal vessels may provide predictable and safe lumen enlargement. Short-term data demonstrated substantial symptomatic improvement and infrequent need for further revascularization or amputation (Korabathina et al., 2010). Specific directional atherectomy devices are also available for

**5.5 Adjunctive medication** 

tortuous vessels, especially foot vessels.

**5.6 Emergent techniques and alternatives** 

precipitate an acute thrombosis.

BTK vessels is still to be determined.

**5.6.2 Drug-coated balloons** 

balloons can treat long lesions.

**5.6.3 Atherectomy devices** 

additional data (Hawkins and Hennebry, 2011).

**5.6.1 Drug-eluting stents** 

2010).

for six months.

Endoluminal therapy for BTK arteries is now a key part of the vascular specialist armamentarium. Tibial arteries endovascular approach has demonstrated to lead to high limb salvage rates with low morbidity and mortality. As a result, the paradigm for treatment of CLI patients has changed. One should now consider endovascular intervention as the first line treatment in the majority of CLI patients, especially in those with significant medical comorbidities. To do so, the vascular specialist should have a consistent knowledge of the BTK endovascular techniques and devices. The first step decision in tibial endovascular therapy is the access. In this context, antegrade ipsilateral approach is generally preferred. The next critical decision is the choice of the vessel(s) to be approached in order to reach successful limb salvage. Allowing pulsatile flow to the correct portion of the foot is the contemporary paramount for ulcer healing. As so, an adequate understanding of the current angiosome model should enhance clinical results. However, this concept does not preclude the recanalization of the other tibial vessels as trophic lesion may include more than one angiosome and the limited long-term permeability rate of angioplasty may compromise the feeding artery before complete lesion healing. The selection of the devices should be judicious. The choice of the guidewire is extremely relevant and should be based on the characteristics of the lesion (location, length, and stenosis/occlusion) as well as on the characteristics of the guidewire itself (tip load, stiffness, hydrophilic/hydrophobic coating, flexibility, torque transmission, trackability, and pushability). Going through chronic total occlusions may be quite challenging. Therefore, the vascular interventionist should master the techniques that have been recently described: antegrade techniques, including the drilling technique, the penetrating technique, the subintimal technique and the parallel technique; subintimal arterial flossing with antegrade-retrograde intervention (SAFARI); pedal-plantar loop technique and revascularization through peroneal artery collaterals. The specifically designed, low-profile, increased shaft strength, balloons catheters were conceived for a 0.0.014" or a 0.018" platform. The balloons should have minimal compliance and be available in long sizes. Bare metal stents should be available, even though their use is presently reserved for bailout situations.

Meanwhile, the continuous arising of new technologies will possibly convulse the currently accepted BTK endovascular techniques. In fact, drug-eluting stents, drug-coated balloons, atherectomy devices, bioabsorbable stents among others may play a relevant role in BTK intervention in the near future.

#### **7. Acknowledgements**

The authors would like to thank the staff of the Angiology and Vascular Surgery Department, the Radiology Technicians, the Radiology Nurses and the Staff of Diabetic Foot

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**4** 

Maria Kurthy et al\*

*Hungary* 

**Investigation of the Oxidative Stress, the** 

**Altered Function of Platelets and Neutrophils,** 

**in the Patients with Peripheral Arterial Disease** 

*Department of Surgical Research and Techniques, Pecs University Medical School, Pecs* 

Ischemia reperfusion injury (I/R) is a relevant problem in case of myocardial infarction (Moens AL, Claeys MJ et al. 2005.), stroke, (Kato H and Kogure K 1999), coronary bypass surgery, (Bakkaloglu C, and Soyagir B, 2006), under thrombolysis, (Krumholz HM and Goldberger 2006), revascularization surgery of lower limb (Arato et al 2006., Laird IR 2003), balloon angioplasty (Weissand A.G. and Zahger AT 1999) and in every cases, when the physiological blood flow in the occluded vessels are restored (Falkensammer J and Oldenburg WA 2006), (Ferencz A et al 2004). Vessel closure and hypoxia can be caused by embolism (thrombus, tumour, fat, foreign body) stenotic arteriopathy, arterial spasm, compression, arterial thrombus, trauma, etc. During the exclusion of a segment of the vessels from the circulation, ischemia and acidosis appeared in the surrounding tissues. In case of the heart, when oxygen supply is inadequate, the respiration shift from aerobic fatty acid consumption and metabolism to anaerobic glycolysis, resulting in a reduced ATP production. The results of hypoxia in the metabolically active tissues (cardiac, skeletal muscle and neuronal tissues) are more profound than in other cell types. The cells are exposed to hypoxia try to adapt to the absence of oxygen, by switching their metabolism from aerobic to anaerobic. Finally this strategy leads to tissue damages and loss of cells too, as it can be seen in acute or chronic occlusive diseases, as well. The measures of the tissue injuries depend on the duration of hypoxia, the mass of tissues are involved, the ATP requirement of the cell types and the blood pressure of the patients. Under hypoxic condition the generations of reactive oxygen species (ROS), such as O2.-, H2O2, are increased. During normoxyc, physiological condition mitochondria generate low level of ROS by the respiratory chain. These are managed by natural antioxidants, such as manganese superoxid dismutase (SOD) in the mitochondria, or copper-zinc SOD in the inter-membrane space in the mitochondria, and in the cytosol, making the dismutation of superoxide anion

Gabor Jancso2, Endre Arato2, Laszlo Sinay2, Janos Lantos1, Zsanett Miklos1, Borbala Balatonyi1, Szaniszlo Javor1, Sandor Ferencz1, Eszter Rantzinger1, Dora Kovacs, Viktoria Kovacs, Zsofia Verzar2,

*1Department of Surgical Research and Techniques, Pecs University Medical School, Pecs 2Department of General and Vascular Surgery of Baranya County Hospital, Pécs, Hungary* 

Gyorgy Weber1, Balazs Borsiczky1 and Erzsebet Roth1

**1. Introduction** 

 \*


### **Investigation of the Oxidative Stress, the Altered Function of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease**

Maria Kurthy et al\*

*Department of Surgical Research and Techniques, Pecs University Medical School, Pecs Hungary* 

#### **1. Introduction**

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*Cardiovasc Prev Rehabil* 17 Suppl 1, S3-8.

21, 1413-1416.

Ischemia reperfusion injury (I/R) is a relevant problem in case of myocardial infarction (Moens AL, Claeys MJ et al. 2005.), stroke, (Kato H and Kogure K 1999), coronary bypass surgery, (Bakkaloglu C, and Soyagir B, 2006), under thrombolysis, (Krumholz HM and Goldberger 2006), revascularization surgery of lower limb (Arato et al 2006., Laird IR 2003), balloon angioplasty (Weissand A.G. and Zahger AT 1999) and in every cases, when the physiological blood flow in the occluded vessels are restored (Falkensammer J and Oldenburg WA 2006), (Ferencz A et al 2004). Vessel closure and hypoxia can be caused by embolism (thrombus, tumour, fat, foreign body) stenotic arteriopathy, arterial spasm, compression, arterial thrombus, trauma, etc. During the exclusion of a segment of the vessels from the circulation, ischemia and acidosis appeared in the surrounding tissues. In case of the heart, when oxygen supply is inadequate, the respiration shift from aerobic fatty acid consumption and metabolism to anaerobic glycolysis, resulting in a reduced ATP production. The results of hypoxia in the metabolically active tissues (cardiac, skeletal muscle and neuronal tissues) are more profound than in other cell types. The cells are exposed to hypoxia try to adapt to the absence of oxygen, by switching their metabolism from aerobic to anaerobic. Finally this strategy leads to tissue damages and loss of cells too, as it can be seen in acute or chronic occlusive diseases, as well. The measures of the tissue injuries depend on the duration of hypoxia, the mass of tissues are involved, the ATP requirement of the cell types and the blood pressure of the patients. Under hypoxic condition the generations of reactive oxygen species (ROS), such as O2.-, H2O2, are increased. During normoxyc, physiological condition mitochondria generate low level of ROS by the respiratory chain. These are managed by natural antioxidants, such as manganese superoxid dismutase (SOD) in the mitochondria, or copper-zinc SOD in the inter-membrane space in the mitochondria, and in the cytosol, making the dismutation of superoxide anion

<sup>\*</sup> Gabor Jancso2, Endre Arato2, Laszlo Sinay2, Janos Lantos1, Zsanett Miklos1, Borbala Balatonyi1, Szaniszlo Javor1, Sandor Ferencz1, Eszter Rantzinger1, Dora Kovacs, Viktoria Kovacs, Zsofia Verzar2, Gyorgy Weber1, Balazs Borsiczky1 and Erzsebet Roth1

*<sup>1</sup>Department of Surgical Research and Techniques, Pecs University Medical School, Pecs 2Department of General and Vascular Surgery of Baranya County Hospital, Pécs, Hungary* 

Investigation of the Oxidative Stress, the Altered Function

were improved in animal studies (Vinten-Johansen J 2007).

(Szabo S. et al 2005).

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 65

(NO), which are absolutely necessary for the endothelium dependent relaxation of the vessels (Moncada et al 1991), for the proper function of cardiomyocytes (Umar S, van der Laarse A. 2010), and for the physiological function of circulating cells, such as thrombocytes (Massberg S 1998) and leukocytes, and red blood cells. It can be stated that free radicals are

It is very difficult to monitor the cellular processes which influence the outcome of the surgical interventions, or serves as a marker of the postoperative events. A huge amount of data emerged for the characterization of ischemia reperfusion injury, but function of platelets and other circulating cells or their interaction with each other or with endothelial cells has been hardly investigated (Buchholz AM, Bruch L 2003.). Limitation of reperfusion injury is inevitably important to prevent tissue damages, manifested in apoptosis, necrosis or both, and frequently occurred after restoration of circulation after stroke, myocardial infarction, organ transplantations, and in all types of revascularization surgeries. There are pharmacologic tools, and protective processes, which can reduce IR injury. Antioxidants, such as N-acetylcysteine, vitamin E, mannitol, thiols, alkaloids and endogenous antioxidants, such as superoxide dismutase, reduced glutathion, glutathione reductase, catalase, or ion chelators functions due to inactivation of free radicals, which are key element in IR induced tissue damages (Arato et al 2010), (Peto K, et al 2007), but leukocyte depletion, anti-cytokine or leukocyte adhesion molecule monoclonal antibody therapies ended with conflicting results (Arato et al 2010) (Loberg AG et al ,2011). Among other effective possibilities, ischemic postconditioning is one of the most effective processes in reducing IR caused damages, which was first introduced by Vinten-Johansen's group in 2003. The main essence of application of short (some seconds) repetitive interruption of early reperfusion by brief ischemic episodes resulting in reduced infarct size in the heart, diminished tissue edema, reduced infiltration of leukocytes into the area of injury, as they

Angioplasty with or without vascular stenting is an effective method, was developed by Dotter and Judkins (Misty M et al 2001) to reconstruct the proper flow within the narrowed or occluded vessels. The procedure is carried out mainly in the coronary arteries, but it is frequently applied in other parts of the circulation. The procedure itself is a typical example of I/R injury was characterized above, with main risks of endothelium dysfunction and reocclusion due to thrombus formation and/or smooth muscle proliferation. The potential role of the circulating cells, such as PLT, WBC, and RBC in the vessel closure is intensively studied, and their interactions with the components of vessel wall, mainly with the smooth muscle cells and the endothelial linage have special attention (Ming Wei Liu et al 1989). Platelet leukocyte interaction is also investigated, because of their unique role in reocclusion

In the present study we aimed to investigate the function of circulating cells in the course of acute (emergency) and elective revascularization surgery in lower limb of patients with Peripheral arterial disease (PAD). In our studies thrombocyte function, antioxidant and prooxidant status were investigated in two groups of patients, who were scheduled to elective revascularization surgery (Elective) and were compared to the patients with acute vessel closure and were undergone revascularization surgery in emergency, 4-6 hours after of vessel closure (Acute). Data obtained in the two patients groups were compared to the same parameters of healthy veterinary blood donors (Control). Patients of the two groups (Acute and Elective) have other chronic diseases too, such as diabetes mellitus. Diabetes is a disease when patients have high blood sugar concentration due to the inadequate production: DM1, or

both our friends and enemy at the same time (Downey JM, and Cohen MV 2008).

generation to H2O2, which transformed further by catalase, glutathion plus glutathion peroxydase. Under hypoxic condition several sources of free radicals activated, e.g. the NADPH oxydase, xanthin oxidase, and others. ROS generated by hypoxia disrupts respiratory chain, causing a vicious cycle, manifested in modification in permeability transmission, loss of membrane potential, altering the function of mitochondrial complex I, III, and generating ubisemiquinon radical, which donates its electron to oxygen resulting in superoxyde anion. In reduced oxygen tension complex II switches its activity from succinate dehydrogenase to fumarate reductase (Henrich M et al, 2004.), Kolamunne RT et al 2011). Chronic sever hypoxia induces ATP depletion, and cell death. In the course of hypoxia, ATP generation decrees, exhausting the ATP sources, which responsible for the overflow of hypoxanthine, an ATP metabolite. Hypoxanthine in normoxyc condition metabolized further by xanthine dehydrogenase to xanthine (by means of nicotinamide adenine dinucleotide (NAD) as cofactor), but during hypoxia xanthin dehydrogenase converted to xanthin oxidase, which is unable to catalyse this conversion, but in the presence of high oxygen level in reoxygenation phase it continuously generates toxic ROS, because it uses oxygen as cofactor. ROS are effective oxidizing and reducing agents that directly damage cellular membranes, leading to impairment of membrane ion channels, disturbing cellular ionic balance resulting in cell swelling. ROS can activate leucocytes as well, and induce chemotaxis, cytokine release, leukocyte infiltration into the injured tissues, and due to endothelium dysfunction, a systemic reperfusion inflammatory response occurs. The most serious consequences of IR are the development of remote organ injuries in non-ischemic organs and can induce systemic inflammatory response injury (SIRS) or multiorgan failure syndrome (MOFS) which are responsible for of 20-40% of death in intensive care units (Levy JH, and Tanaka KA 2003). Tough reconstruction of the flow in the occluded vessels is not without risk, because of the generated volume, pressure and metabolic load, accompanied by further tissue damages resulting in the so-called reperfusion injury.

The main components of the molecular pathophysiological cascades are the activated circulating cells, first of all the white blood cells (WBC), mainly the neutrophils, due to their intensive free radical production, but, thrombocytes (PLT), red blood cells (RBC), and the cells of the vessel wall (endothelial cells and smooth muscle cells) also participate in the free radical production and the tissue damage (Roth and Hejjel 2003). In the early reperfusion the release of inflammatory cytokines, such as tumor necrosis factor alpha (TNF) increase too. These events together with the elevated Ca2+ levels inside the attached cells threat the integrity of the whole organism, destroying the crucial macromolecules, proteins, lipids and nucleic acids (Arato et al. 2005), (Blaisdell FW 1989).

Reactive oxygen species are Janus-faced agents. They have important role in eliminating pathogen microorganisms from the body, and can regulate cell growth and differentiation. ROS can act as important signalling molecules, in the circulation and participate in the maintenance of intra- and extracellular milieu. They can induce redox sensitive transcription factors, regulate redox sensitive signalization cascades and can act as secondary messengers (Kathy K et al 2000), (Dröge W, 2002). Oxygen free radicals can act as second messengers and they are able to influence the function of enzymes, and transcription factors, leading to the induction of genes are sensitive to them (Li W et al 2008). Their intra- and extracellular levels are regulated by SOD and catalase (the enzymes are present in almost all living organisms are exposed to oxygen) and other antioxidant, respectively. On the other hand they can cause endothelial dysfunction due to eliminating vital nitrogenous monoxides Angioplasty, Various Techniques and Challenges in 64 Treatment of Congenital and Acquired Vascular Stenoses

generation to H2O2, which transformed further by catalase, glutathion plus glutathion peroxydase. Under hypoxic condition several sources of free radicals activated, e.g. the NADPH oxydase, xanthin oxidase, and others. ROS generated by hypoxia disrupts respiratory chain, causing a vicious cycle, manifested in modification in permeability transmission, loss of membrane potential, altering the function of mitochondrial complex I, III, and generating ubisemiquinon radical, which donates its electron to oxygen resulting in superoxyde anion. In reduced oxygen tension complex II switches its activity from succinate dehydrogenase to fumarate reductase (Henrich M et al, 2004.), Kolamunne RT et al 2011). Chronic sever hypoxia induces ATP depletion, and cell death. In the course of hypoxia, ATP generation decrees, exhausting the ATP sources, which responsible for the overflow of hypoxanthine, an ATP metabolite. Hypoxanthine in normoxyc condition metabolized further by xanthine dehydrogenase to xanthine (by means of nicotinamide adenine dinucleotide (NAD) as cofactor), but during hypoxia xanthin dehydrogenase converted to xanthin oxidase, which is unable to catalyse this conversion, but in the presence of high oxygen level in reoxygenation phase it continuously generates toxic ROS, because it uses oxygen as cofactor. ROS are effective oxidizing and reducing agents that directly damage cellular membranes, leading to impairment of membrane ion channels, disturbing cellular ionic balance resulting in cell swelling. ROS can activate leucocytes as well, and induce chemotaxis, cytokine release, leukocyte infiltration into the injured tissues, and due to endothelium dysfunction, a systemic reperfusion inflammatory response occurs. The most serious consequences of IR are the development of remote organ injuries in non-ischemic organs and can induce systemic inflammatory response injury (SIRS) or multiorgan failure syndrome (MOFS) which are responsible for of 20-40% of death in intensive care units (Levy JH, and Tanaka KA 2003). Tough reconstruction of the flow in the occluded vessels is not without risk, because of the generated volume, pressure and metabolic load, accompanied

by further tissue damages resulting in the so-called reperfusion injury.

nucleic acids (Arato et al. 2005), (Blaisdell FW 1989).

The main components of the molecular pathophysiological cascades are the activated circulating cells, first of all the white blood cells (WBC), mainly the neutrophils, due to their intensive free radical production, but, thrombocytes (PLT), red blood cells (RBC), and the cells of the vessel wall (endothelial cells and smooth muscle cells) also participate in the free radical production and the tissue damage (Roth and Hejjel 2003). In the early reperfusion the release of inflammatory cytokines, such as tumor necrosis factor alpha (TNF) increase too. These events together with the elevated Ca2+ levels inside the attached cells threat the integrity of the whole organism, destroying the crucial macromolecules, proteins, lipids and

Reactive oxygen species are Janus-faced agents. They have important role in eliminating pathogen microorganisms from the body, and can regulate cell growth and differentiation. ROS can act as important signalling molecules, in the circulation and participate in the maintenance of intra- and extracellular milieu. They can induce redox sensitive transcription factors, regulate redox sensitive signalization cascades and can act as secondary messengers (Kathy K et al 2000), (Dröge W, 2002). Oxygen free radicals can act as second messengers and they are able to influence the function of enzymes, and transcription factors, leading to the induction of genes are sensitive to them (Li W et al 2008). Their intra- and extracellular levels are regulated by SOD and catalase (the enzymes are present in almost all living organisms are exposed to oxygen) and other antioxidant, respectively. On the other hand they can cause endothelial dysfunction due to eliminating vital nitrogenous monoxides (NO), which are absolutely necessary for the endothelium dependent relaxation of the vessels (Moncada et al 1991), for the proper function of cardiomyocytes (Umar S, van der Laarse A. 2010), and for the physiological function of circulating cells, such as thrombocytes (Massberg S 1998) and leukocytes, and red blood cells. It can be stated that free radicals are both our friends and enemy at the same time (Downey JM, and Cohen MV 2008).

It is very difficult to monitor the cellular processes which influence the outcome of the surgical interventions, or serves as a marker of the postoperative events. A huge amount of data emerged for the characterization of ischemia reperfusion injury, but function of platelets and other circulating cells or their interaction with each other or with endothelial cells has been hardly investigated (Buchholz AM, Bruch L 2003.). Limitation of reperfusion injury is inevitably important to prevent tissue damages, manifested in apoptosis, necrosis or both, and frequently occurred after restoration of circulation after stroke, myocardial infarction, organ transplantations, and in all types of revascularization surgeries. There are pharmacologic tools, and protective processes, which can reduce IR injury. Antioxidants, such as N-acetylcysteine, vitamin E, mannitol, thiols, alkaloids and endogenous antioxidants, such as superoxide dismutase, reduced glutathion, glutathione reductase, catalase, or ion chelators functions due to inactivation of free radicals, which are key element in IR induced tissue damages (Arato et al 2010), (Peto K, et al 2007), but leukocyte depletion, anti-cytokine or leukocyte adhesion molecule monoclonal antibody therapies ended with conflicting results (Arato et al 2010) (Loberg AG et al ,2011). Among other effective possibilities, ischemic postconditioning is one of the most effective processes in reducing IR caused damages, which was first introduced by Vinten-Johansen's group in 2003. The main essence of application of short (some seconds) repetitive interruption of early reperfusion by brief ischemic episodes resulting in reduced infarct size in the heart, diminished tissue edema, reduced infiltration of leukocytes into the area of injury, as they were improved in animal studies (Vinten-Johansen J 2007).

Angioplasty with or without vascular stenting is an effective method, was developed by Dotter and Judkins (Misty M et al 2001) to reconstruct the proper flow within the narrowed or occluded vessels. The procedure is carried out mainly in the coronary arteries, but it is frequently applied in other parts of the circulation. The procedure itself is a typical example of I/R injury was characterized above, with main risks of endothelium dysfunction and reocclusion due to thrombus formation and/or smooth muscle proliferation. The potential role of the circulating cells, such as PLT, WBC, and RBC in the vessel closure is intensively studied, and their interactions with the components of vessel wall, mainly with the smooth muscle cells and the endothelial linage have special attention (Ming Wei Liu et al 1989). Platelet leukocyte interaction is also investigated, because of their unique role in reocclusion (Szabo S. et al 2005).

In the present study we aimed to investigate the function of circulating cells in the course of acute (emergency) and elective revascularization surgery in lower limb of patients with Peripheral arterial disease (PAD). In our studies thrombocyte function, antioxidant and prooxidant status were investigated in two groups of patients, who were scheduled to elective revascularization surgery (Elective) and were compared to the patients with acute vessel closure and were undergone revascularization surgery in emergency, 4-6 hours after of vessel closure (Acute). Data obtained in the two patients groups were compared to the same parameters of healthy veterinary blood donors (Control). Patients of the two groups (Acute and Elective) have other chronic diseases too, such as diabetes mellitus. Diabetes is a disease when patients have high blood sugar concentration due to the inadequate production: DM1, or

Investigation of the Oxidative Stress, the Altered Function

PLT aggregation inhibitors

Anticoagulant

**measurements:** 

groups, was measured also.

(Cl-

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 67

**Groups of medicine Acute Elective** 

(perioperative) 12/12 10/12 Antihypertensive 6/12 8/10 Antidiabetic 4/12 5/10 Others 12/12 10/10

**Laboratory measurements**: were carried out in Department of Surgical Research and Techniques of Pecs University Medical School, Hungary. **Hematologic measurement:** red and white blood cell numbers, haemoglobin concentration, platelet numbers were measured by Minitron automatic analysator (Diatron LTD Budapest, Hungary). **Platelet aggregation** 

1. in platelet rich plasma (PRP), according to Born's turbidimetric method (Born 1965a), Born et al 1965b), by means of Carat aggregometer (Carat Diagnostic ltd, Budapest, Hungary), using ADP (5 µM; and 10 µM) and collagen (2 µg/ml) as inductors.

**Measurement of main antioxidants:** *SOD* is an ancient antioxidant enzyme of pro- and eukaryotic organisms, containing metal (Cu, Zn, Fe, Mn Ni, respectively) in its active centre, and it has several isoforms, which can be found intra- and extracellularly, in almost all living creature, as well. Measurement of SOD activity was carried out by the method of Misra and Fridovich (Misra and Fridovich 1972). Reduced glutathione *(GSH)* levels were determined in plasma were obtained after centrifugation of anticoagulated whole blood, using Ellman's reagent (Sedlak and Lindsday 1968). GSH cystein is able to neutralize free radicals by donating one electron and stabilizes them. In the course of this reaction it became reactive, as well, but an other GSH can neutralize it, forming GSSG, which will be regenerated to GSH by glutathione reductase. Plasma proteins (such as albumin) contain sulphydril groups, as well and exert remarkable antioxidant capacity though its –SH

**Measurement of prooxidants:** Reactive oxygen species *(ROS*) was measured in the mixture of whole blood (20 µl) and phosphate buffered saline (1400 µl) by chemiluminometric, kinetic method, by means of Chrono-Log lumino-aggregometer. The main sources of ROS in the blood are leukocytes. ROS production was induced in whole blood by phorbol -12 miristate-13-acetate (PMA) and was made detectable by luminol (Arato et al 2010b).) Malondialdehyde *(MDA),* the main lipid peroxidation marker, which signs the polyunsaturated fatty acid peroxidation of the biological membranes. It was measured in anticoagulated whole blood and in plasma (Ohkawa H (1979). Myeloperoxidase *(MPO)* produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion

) (or the equivalent from a non-chlorine halide) during the neutrophil's respiratory burst.

Aggregation was followed for 8 minutes after its induction and expressed in %. 2. **in whole blood** was measured by the method of Ingerman-Wojenski and Silver by Chrono-log lumino-aggregometer (type 560VS, USA), according to the user's manual of the instrument (Ingerman-Wojenski CM and Silver MJ), using the same inductors as was used in PRP. In whole blood platelet aggregation was measured by impedance, and

expressed in Ohm, and was followed for six minutes from its induction.

(Aspirin protect or Astrix) 12/12 10/10

Table 2. Medication of patients with PAD in the 1st series of the study

inadequate effects on the tissues of otherwise physiological or high level of circulating insulin: DM2. In the second series of experiments, thrombocyte function and prooxidant/antioxidant status of DM1 and DM2 patients with PAD were also investigated. In vitro effects of exogenous insulin (Actrapid Insulin (Novo-Nordisk) In 0, 40, 80, 160 µU/ml) were also investigated on collagen induced platelet aggregation and phorbol – 12 myristate-13 acetate (PMA) induced reactive oxygen species (ROS) production in whole blood.

#### **2. Materials and methods**

Patients selection and investigation in this randomized, open, prospective studies was carried out according to the Helsinki declaration (1996), considering the statute of Hungarian Ministry of Health (32/2005. (VIII:26), with the permission of the local ethical board of the Pecs University, Medical School. (Permission No.: 2498).

#### **2.1 The first series of experiments**

The aim of this study was to investigate the effect of the duration of hypoxia on the thrombocyte function, free radical production and antioxidant/prooxidant statuses of the patients who were undergone revascularization surgery of lower limb.

Patients: Two groups of patients were investigated:


Other chronic diseases accompanied by PAD in our patients are summarized in Table 1. Surgical interventions were carried out in General and Vascular Surgery Department of Baranya County Hospital (Pecs; Hungary), and were performed in spinal anaesthesia, with 43.8±17 min ischemic time. Patients of both groups received similar anticoagulant and antiplatelet therapy (at least 75 mg Aspirin) and low molecular weight heparin was also prescribed in the perioperative period. Medication of the patients is summarized in Table 2.


Table 1. Chronic diseases accompanied with PAD in the first series of the study

**Blood sampling:** Venous blood samples were obtained by venipuncture. Samples of 10 healthy blood donors (Blood Donation Center of Pecs, Hungary) served as Control. Venous blood samples of the two patients groups were obtained before and 2 and 24 hours and one week after the surgery. Blood samples were collected into three Vacutainer tubes containing trisodium citrate (3.8%) or K3-EDTA (7.5 %) (Becton Dickinson, UK). Informed consents were obtained from all patients and volunteers participated in the study.

Angioplasty, Various Techniques and Challenges in 66 Treatment of Congenital and Acquired Vascular Stenoses

inadequate effects on the tissues of otherwise physiological or high level of circulating insulin: DM2. In the second series of experiments, thrombocyte function and prooxidant/antioxidant status of DM1 and DM2 patients with PAD were also investigated. In vitro effects of exogenous insulin (Actrapid Insulin (Novo-Nordisk) In 0, 40, 80, 160 µU/ml) were also investigated on collagen induced platelet aggregation and phorbol – 12 myristate-13 acetate

Patients selection and investigation in this randomized, open, prospective studies was carried out according to the Helsinki declaration (1996), considering the statute of Hungarian Ministry of Health (32/2005. (VIII:26), with the permission of the local ethical

The aim of this study was to investigate the effect of the duration of hypoxia on the thrombocyte function, free radical production and antioxidant/prooxidant statuses of the

1. Acute group: n=12; 9 males and 3 female, age: 58.1±7.3 years, suffered from ischemia 4-6 hours before revascularization surgery of lower limb because of seriously ischemic extremities due to embolism, acute arterial thrombosis or rupture of infrarenal artery before the surgery. They were undergone revascularization surgery in emergency. 2. Elective group n=10, (6 male 4 female) were scheduled to elective revascularization surgery because of chronic obliterative arterial stenosis. Ischemia was diagnosed by

Other chronic diseases accompanied by PAD in our patients are summarized in Table 1. Surgical interventions were carried out in General and Vascular Surgery Department of Baranya County Hospital (Pecs; Hungary), and were performed in spinal anaesthesia, with 43.8±17 min ischemic time. Patients of both groups received similar anticoagulant and antiplatelet therapy (at least 75 mg Aspirin) and low molecular weight heparin was also prescribed in the perioperative period. Medication of the patients is summarized in Table 2.

**Disease Acute group Elective group** 

Hypertension 6/12 8/10 Ischemic heart disease 3/12 4/10 Diabetes mellitus 4/12 5/10 Lung complications 4/12 4/10 Smooking 5/12 4/10

**Blood sampling:** Venous blood samples were obtained by venipuncture. Samples of 10 healthy blood donors (Blood Donation Center of Pecs, Hungary) served as Control. Venous blood samples of the two patients groups were obtained before and 2 and 24 hours and one week after the surgery. Blood samples were collected into three Vacutainer tubes containing trisodium citrate (3.8%) or K3-EDTA (7.5 %) (Becton Dickinson, UK). Informed consents

Table 1. Chronic diseases accompanied with PAD in the first series of the study

were obtained from all patients and volunteers participated in the study.

(PMA) induced reactive oxygen species (ROS) production in whole blood.

board of the Pecs University, Medical School. (Permission No.: 2498).

patients who were undergone revascularization surgery of lower limb.

**2. Materials and methods** 

**2.1 The first series of experiments** 

angiography, and Doppler test.

Patients: Two groups of patients were investigated:


Table 2. Medication of patients with PAD in the 1st series of the study

**Laboratory measurements**: were carried out in Department of Surgical Research and Techniques of Pecs University Medical School, Hungary. **Hematologic measurement:** red and white blood cell numbers, haemoglobin concentration, platelet numbers were measured by Minitron automatic analysator (Diatron LTD Budapest, Hungary). **Platelet aggregation measurements:** 


**Measurement of main antioxidants:** *SOD* is an ancient antioxidant enzyme of pro- and eukaryotic organisms, containing metal (Cu, Zn, Fe, Mn Ni, respectively) in its active centre, and it has several isoforms, which can be found intra- and extracellularly, in almost all living creature, as well. Measurement of SOD activity was carried out by the method of Misra and Fridovich (Misra and Fridovich 1972). Reduced glutathione *(GSH)* levels were determined in plasma were obtained after centrifugation of anticoagulated whole blood, using Ellman's reagent (Sedlak and Lindsday 1968). GSH cystein is able to neutralize free radicals by donating one electron and stabilizes them. In the course of this reaction it became reactive, as well, but an other GSH can neutralize it, forming GSSG, which will be regenerated to GSH by glutathione reductase. Plasma proteins (such as albumin) contain sulphydril groups, as well and exert remarkable antioxidant capacity though its –SH groups, was measured also.

**Measurement of prooxidants:** Reactive oxygen species *(ROS*) was measured in the mixture of whole blood (20 µl) and phosphate buffered saline (1400 µl) by chemiluminometric, kinetic method, by means of Chrono-Log lumino-aggregometer. The main sources of ROS in the blood are leukocytes. ROS production was induced in whole blood by phorbol -12 miristate-13-acetate (PMA) and was made detectable by luminol (Arato et al 2010b).) Malondialdehyde *(MDA),* the main lipid peroxidation marker, which signs the polyunsaturated fatty acid peroxidation of the biological membranes. It was measured in anticoagulated whole blood and in plasma (Ohkawa H (1979). Myeloperoxidase *(MPO)* produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl-) (or the equivalent from a non-chlorine halide) during the neutrophil's respiratory burst.

Investigation of the Oxidative Stress, the Altered Function

**Elective** and **Control** ones, in the course of the study

**3.1.2 Platelet aggregation in platelet-rich plasma** 

**3.1 Results of the first series of experiment 3.1.1 Results of clinical chemistry measurements** 

**3. Results**

**A D P-induced m**

 **ax ag g reg atio n (5 µM ) in %**

> **Before surgery**

**\***

**After Surgery**

PRP.\*= p<0.05 vs. Control, \*\*= p<0.01 vs. control.

**Collagen-induced aggregation** 

**(2 µg/ml) aggregáció %**

**\*\* \*\* \*\***

**24 hours later**

compared to Control. \*= p<0,05, \*\*=p<0.01 compared to controls.

**Before surgery**

**\*\* \*\***

> **After Surgery**

Fig. 2. Maximum values of collagen (2 g /ml) induced platelet aggregation in PRP,

**\*\* \*\***

> **24 hours later**

**\*\* \*\***

> **1 week later**

**\*\***

**\*\***

**Control Elective Acute**

**\*\* \*\***

**1 week later**

Fig. 1. ADP (5 and 10 µM) induced aggregation in platelet rich plasma. Antiplatelet therapy seemed to be effective in both patients groups using 5 and 10 µM ADP, as inductor in

**ADP-induced max aggregation (10 µM) %**

**Before surgery** **After Surgery 24 hours later 1 week later**

**\*\* \*\* \*\* \*\* \*\* \*\* \*\* \***

**Control Elective Acute**

**\*\***

**\***

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 69

Red blood cell numbers were similar in the three groups, but haemoglobin concentration was significantly lower and leukocyte number was higher in Acute group, compared to the

ADP and Collagen were selected as aggregation inductors. These agents were used to control the efficacy of the two most frequently used groups of antiplatelet drugs, the cyclooxygenase (COX) inhibitors and adenosine diphosphate (ADP) receptor antagonists.

> **Control Elective Acute**

It requires hem as a cofactor. Furthermore, it oxidizes tyrosine to tyrosyl radical using hydrogen peroxide as an oxidizing agent. MPO level was measured in plasma, according to the method of (Xia and Zweier 1997).

#### **2.2 The second series of experiments**

#### **The aim of this study**

Insulin resistance and diabetes mellitus are causal or worsening factors in the peripheral arterial diseases (Jude EB 2001). In the second part of the study we intended to investigate thrombocyte function parallel with antioxidant prooxidant status of ambulant diabetic (DM1 and DM2) patients with PAD were under the care of General and Vascular Surgery Department of Baranya County Hospital (Pecs; Hungary). Eleven healthy volunteers of Blood Donation Centre of Pecs served as controls

#### **Methods**

This study involved 24 patients with DM1 (18 male and 6 female; age: 62 ± 2.3 year), and 22 with DM2 (18 male and 4 female; age: 65,7 ±3.7) with PAD. Healthy blood donors served as control (8 male and 2 female; age: 33 ± 6.7 years). Anticoagulated whole blood of ambulant patients and volunteers were used. Informed consents were obtained from all participants. Regular medication of the two patients group is summarized in **Table 3.** 


Table 3. Medication of the DM1 and DM2 patients.

#### **Parameters to be measured**

*Clinical chemistry data:* Glucose triglyceride, cholesterol was measured by commercial kits (Diagnosticum Ltd Budapest) by photometric method. Platelet aggregation was measured in whole blood and in PRP. PMA induced ROS production; endogenous antioxidant and prooxidant status of these patients were measured as it was described above. *Platelet aggregation*: Platelet aggregation was measured in PRP and in whole blood as it was described above. In the latter case area under the aggregation curves were calculated as well, using Origin 6.0 data analyzing and graphing software. Collagen induced platelet aggregation, and PMA induced ROS production were measured in the presence of 0, 40, 80, 160 µU/ml insulin (Actrapid), too. **Statistical analyses:** Student's paired and unpaired t-test and one way analysis of variance were used. Differences were considered significant, when p was less than 0.05. The results were expressed as mean ± SD or in percentage.

#### **3. Results**

Angioplasty, Various Techniques and Challenges in 68 Treatment of Congenital and Acquired Vascular Stenoses

It requires hem as a cofactor. Furthermore, it oxidizes tyrosine to tyrosyl radical using hydrogen peroxide as an oxidizing agent. MPO level was measured in plasma, according to

Insulin resistance and diabetes mellitus are causal or worsening factors in the peripheral arterial diseases (Jude EB 2001). In the second part of the study we intended to investigate thrombocyte function parallel with antioxidant prooxidant status of ambulant diabetic (DM1 and DM2) patients with PAD were under the care of General and Vascular Surgery Department of Baranya County Hospital (Pecs; Hungary). Eleven healthy volunteers of

This study involved 24 patients with DM1 (18 male and 6 female; age: 62 ± 2.3 year), and 22 with DM2 (18 male and 4 female; age: 65,7 ±3.7) with PAD. Healthy blood donors served as control (8 male and 2 female; age: 33 ± 6.7 years). Anticoagulated whole blood of ambulant patients and volunteers were used. Informed consents were obtained from all participants.

Regular medication of the two patients group is summarized in **Table 3.** 

**Medication DM1 DM2** 

**(Aspirinprotect or Astrix)** 24/24 22/22 **Anticoagulant (Syncumar)** 4/24 4/22 **Anticoagulant (LMWH)** 12/24 10/22 **Antihypertensive** 18/24 18/22 **Insulin** 24/24 2/22 **Oral antidiabetic** 0/24 20/22 **Other** 24/24 22/22

*Clinical chemistry data:* Glucose triglyceride, cholesterol was measured by commercial kits (Diagnosticum Ltd Budapest) by photometric method. Platelet aggregation was measured in whole blood and in PRP. PMA induced ROS production; endogenous antioxidant and prooxidant status of these patients were measured as it was described above. *Platelet aggregation*: Platelet aggregation was measured in PRP and in whole blood as it was described above. In the latter case area under the aggregation curves were calculated as well, using Origin 6.0 data analyzing and graphing software. Collagen induced platelet aggregation, and PMA induced ROS production were measured in the presence of 0, 40, 80, 160 µU/ml insulin (Actrapid), too. **Statistical analyses:** Student's paired and unpaired t-test and one way analysis of variance were used. Differences were considered significant, when p was less than 0.05. The results were expressed as mean ±

the method of (Xia and Zweier 1997).

**Platelet aggregation inhibitors** 

**Parameters to be measured** 

SD or in percentage.

**The aim of this study** 

**Methods** 

**2.2 The second series of experiments** 

Blood Donation Centre of Pecs served as controls

Table 3. Medication of the DM1 and DM2 patients.

#### **3.1 Results of the first series of experiment**

#### **3.1.1 Results of clinical chemistry measurements**

Red blood cell numbers were similar in the three groups, but haemoglobin concentration was significantly lower and leukocyte number was higher in Acute group, compared to the **Elective** and **Control** ones, in the course of the study

#### **3.1.2 Platelet aggregation in platelet-rich plasma**

ADP and Collagen were selected as aggregation inductors. These agents were used to control the efficacy of the two most frequently used groups of antiplatelet drugs, the cyclooxygenase (COX) inhibitors and adenosine diphosphate (ADP) receptor antagonists.

Fig. 1. ADP (5 and 10 µM) induced aggregation in platelet rich plasma. Antiplatelet therapy seemed to be effective in both patients groups using 5 and 10 µM ADP, as inductor in PRP.\*= p<0.05 vs. Control, \*\*= p<0.01 vs. control.

Fig. 2. Maximum values of collagen (2 g /ml) induced platelet aggregation in PRP, compared to Control. \*= p<0,05, \*\*=p<0.01 compared to controls.

Investigation of the Oxidative Stress, the Altered Function

**3.1.3.2 Collagen induced aggregation in whole blood** 

**Collagen-induced aggregation in whole** 

**blood (Elective) Impedance (Ohm)**

Fig. 5. Collagen induced platelet aggregation in Elective group.

Fig. 6. Collagen induced aggregation in whole blood in Acute group.

**Collagen-induced aggregation in whole** 

blood.

**3.1.4.1 GSH level** 

level 1 week later.

**3.1.4 Investigation of antioxidants** 

level one week after the surgery. **3.1.4.2 Plasma thiol groups** 

**blood Acute)** 

**Impedance (Ohm)**

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 71

**Before surgery After surgery 24 hours later 1 week later**

**Control**

**Before surgery After surgery 24 hours later 1 week later Control \*\***

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In whole blood of healthy subjects, the collagen induced platelet aggregation started with one minute delay. In the patient groups, collagen induced aggregation started without delay, mainly in Acute group, one week after the surgery. Application of the inductor in this case resulted in an immediate induction of platelet aggregation. The effect of antiplatelet therapy was detected in platelet- rich plasma was missed in whole

Before surgery GSH levels were similar in the three groups. In patients groups a transient reduction occurred 2 hours after and one day after the surgery, but returned to the baseline

Before the surgery the plasma SH-group concentration of the patient groups did not differed from each other or the healthy controls, but a transient, significant reduction was measured 2 hours and 24 hours after surgery in both patients groups, which returned to the normal

**Time (min)**

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In figure 1 and 2 the ADP- and in figure 3 the collagen induced aggregation maximums were summarized, and compared to the values of healthy subjects. According to our data antiplatelet therapy received by both patients groups were effective on the level of isolated thrombocytes in the whole observation time. Platelet aggregation in Control group was within the normal range either ADP or collagen was used as inductors (61-91% of ADP, and 64-92 of collagen), contrarily in both groups of patients a significantly reduced response to ADP and Collagen were measured, signing an effective anti-platelet therapy.

#### **3.1.3 Investigation of platelet aggregation in whole blood**

#### **3.1.3.1 ADP induced platelet aggregation in acute and elective groups**

Fig. 3. ADP induced platelet aggregation in Elective group, compared to Control (red line)

ADP induced platelet aggregation in whole blood was similar in Acute and Elective and Control groups before the surgery. In the Elective group ADP induced platelet aggregation did not changed significantly in the course of the study. In the Acute group a significant gradual increase was observed in the function of time, with a four times increase at the end of the week (Figure 4).

#### **3.1.3.2 Collagen induced aggregation in whole blood**

Angioplasty, Various Techniques and Challenges in 70 Treatment of Congenital and Acquired Vascular Stenoses

In figure 1 and 2 the ADP- and in figure 3 the collagen induced aggregation maximums were summarized, and compared to the values of healthy subjects. According to our data antiplatelet therapy received by both patients groups were effective on the level of isolated thrombocytes in the whole observation time. Platelet aggregation in Control group was within the normal range either ADP or collagen was used as inductors (61-91% of ADP, and 64-92 of collagen), contrarily in both groups of patients a significantly reduced response to

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ADP induced platelet aggregation in whole blood was similar in Acute and Elective and Control groups before the surgery. In the Elective group ADP induced platelet aggregation did not changed significantly in the course of the study. In the Acute group a significant gradual increase was observed in the function of time, with a four times increase at the end

Fig. 3. ADP induced platelet aggregation in Elective group, compared to Control (red line)

**24 hours later 1 week later**

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**Control Before surgery After surgery 24 hours later**

**(Time (minute)**
