Basic Principles in Hepatic Surgery

**7**

**Chapter 2**

**Abstract**

cold ischemia

**1. Introduction**

Hepatic Regeneration Under

Conditions: Controversies and

*Maria Eugenia Cornide-Petronio, Mónica B. Jiménez-Castro,* 

Ischemia-reperfusion (I/R) associated with hepatic resection and living related liver transplantation is an unsolved problem in clinical practice. Indeed, I/R induces damage and regenerative failure in clinical liver surgery. Signaling pathways regarding the pathophysiology of liver I/R and regeneration making clear distinction between situations of cold and warm ischemia, as well as liver regeneration with or without vascular occlusion, will be addressed. The different experimental models used to date to improve the postoperative outcomes in clinical liver surgery will be also described. Furthermore, the most updated therapeutic strategies, as well as the clinical and scientific controversies in the field, will be discussed. Such information may be useful to guide the design of better experimental models as well as the effective therapeutic strategies in liver surgery that can succeed in achieving its clinical application.

**Keywords:** liver surgery, regeneration, ischemia–reperfusion injury, warm ischemia,

Any surgical situation involving liver hepatectomy requires subsequent regeneration in order to restore the liver/body ratio. The liver's ability to restore tissue after loss depends on the interaction of numerous cells and a complex network of mediators [1]. In most cases, in clinical practice, liver surgery involves both ischemia-reperfusion (I/R) injury and regeneration [1]. Liver I/R injury is a pathophysiological event that occurs during surgical interventions such as liver resection or liver transplantation (LT); it controls bleeding during parenchymal dissection and has a significant effect on liver function prognosis [2–6]. I/R injury is a twostage phenomenon in which cell damage due to hypoxia and the lack of biomechanical stimulus is exacerbated upon the restoration of oxygen delivery and shear stress [7]. However, I/R injury is inevitable in liver surgery and significantly reduces the organ's regeneration after hepatectomy [1]. Mechanisms of liver I/R injury are complex; they include mainly microcirculation failure and the related oxidative stress, a series of cellular and molecular responses, and the interaction between hepatocytes,

*Esther Bujaldon, Jordi Gracia-Sancho and Carmen Peralta*

Warm or Cold Ischemia

New Approaches

#### **Chapter 2**

## Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies and New Approaches

*Maria Eugenia Cornide-Petronio, Mónica B. Jiménez-Castro, Esther Bujaldon, Jordi Gracia-Sancho and Carmen Peralta* 

#### **Abstract**

 Ischemia-reperfusion (I/R) associated with hepatic resection and living related liver transplantation is an unsolved problem in clinical practice. Indeed, I/R induces damage and regenerative failure in clinical liver surgery. Signaling pathways regarding the pathophysiology of liver I/R and regeneration making clear distinction between situations of cold and warm ischemia, as well as liver regeneration with or without vascular occlusion, will be addressed. The different experimental models used to date to improve the postoperative outcomes in clinical liver surgery will be also described. Furthermore, the most updated therapeutic strategies, as well as the clinical and scientific controversies in the field, will be discussed. Such information may be useful to guide the design of better experimental models as well as the effective therapeutic strategies in liver surgery that can succeed in achieving its clinical application.

**Keywords:** liver surgery, regeneration, ischemia–reperfusion injury, warm ischemia, cold ischemia

#### **1. Introduction**

Any surgical situation involving liver hepatectomy requires subsequent regeneration in order to restore the liver/body ratio. The liver's ability to restore tissue after loss depends on the interaction of numerous cells and a complex network of mediators [1]. In most cases, in clinical practice, liver surgery involves both ischemia-reperfusion (I/R) injury and regeneration [1]. Liver I/R injury is a pathophysiological event that occurs during surgical interventions such as liver resection or liver transplantation (LT); it controls bleeding during parenchymal dissection and has a significant effect on liver function prognosis [2–6]. I/R injury is a twostage phenomenon in which cell damage due to hypoxia and the lack of biomechanical stimulus is exacerbated upon the restoration of oxygen delivery and shear stress [7]. However, I/R injury is inevitable in liver surgery and significantly reduces the organ's regeneration after hepatectomy [1]. Mechanisms of liver I/R injury are complex; they include mainly microcirculation failure and the related oxidative stress, a series of cellular and molecular responses, and the interaction between hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells, infiltrating neutrophils, macrophages, and platelets [2, 7–11].

 Liver I/R injury involves great many factors and mediators. The associations between the signaling pathways are extremely complex, and at present, the events occurring between the start of reperfusion and the final outcome (either poor function or a nonfunctional liver graft) are not fully understood [6]. The extent and timing of ischemia, the type of liver undergoing I/R, and the existence of liver regeneration may alter the mechanisms of liver I/R injury and the effects of the treatment strategies assessed to date [12]. This point was exemplified by Ramalho et al. who demonstrated the loss of protection against liver damage of Ang-II receptor antagonists in conditions of partial hepatectomy (PH), while in conditions of I/R without hepatectomy, the Ang-II receptor antagonists decreased liver damage [13]. As is well known, the mechanisms of liver damage differ according to the percentage of the liver mass deprived of blood [14]. Therefore, experimental models that reproduce as closely as possible the clinical conditions in which these strategies are applied are likely to lead to the implementation of strategies in clinical practice in the relatively short term [1].

In this chapter, we aim to show that the mechanisms that govern liver I/R injury and regeneration depend on the experimental model applied. These models are valuable tools for elucidating the physiopathology of liver I/R injury and uncovering new therapeutic targets and drugs. A number of strategies for protecting the liver from I/R injury and for improving liver regeneration have been developed in animal models, some of which may find their way into clinical practice [6]. We stress that the type of ischemia (cold or warm) has an important influence in liver surgery, but most of the currently available reviews on the mechanisms of I/R do not distinguish between them [6]. In our view, this information may help to guide the design of future experimental models and treatment strategies in liver surgery for use in clinical practice.

#### **2. Hepatic regeneration under warm ischemia**

Following PH, hepatocytes that are normally quiescent enter the cell cycle in order to replace the part that has been removed. The original liver mass is restored after some 6–8 weeks (in humans) by tightly synchronized rounds of replication of the remaining hepatocytes [15]. Self-replication of the existing individual cell types is thought to be the key mechanism of regeneration after PH. However, it was recently suggested that hepatic progenitor cells may contribute to liver regeneration following PH [15]. A vast number of growth and metabolic factors and cytokines simultaneously regulate liver regeneration during PH. Under the influence of innate immunity components and gut-derived lipopolysaccharide, on Kupffer cells and stellate cells, tumor necrosis factor alpha, and interleukin 6, provided by those cells, prepares hepatocytes to respond to growth factors like epidermal growth factor and hepatocyte growth factor [15]. Among other auxiliary mitogens are norepinephrine, Notch and jagged proteins, vascular endothelial growth factor, platelet-derived growth factor, bile acids, insulin serotonin, estrogens leptin, triodothronine, and FGF1 and 2 [16]. Joint signals from these factors lead to the progression of the liver cell cycle, which in turn results in DNA synthesis and ultimately the proliferation of liver cells as mentioned above [15].

As is well known, remnant liver following PH can be used as an in vivo liver regeneration model in order to assess possible treatment strategies for improving postoperative outcomes after hepatectomy. Nonetheless, a two-third partial hepatectomy alone does not cause death in these models, and the remnant liver has the capacity to regenerate. In contrast, 30 min of liver ischemia just before PH exacerbates the remnant liver function, causing high mortality and negatively affecting liver weight restoration [1, 17]. It is also well known that vascular occlusion of the

*Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 

 hepatic hilum is often used to avoid hemorrhage in liver resection. However, vascular occlusion has been associated with warm ischemia damage, resulting in significant organ dysfunction and regenerative failure [12]. Hepatocytes are severely affected by I/R, especially in normothermic ischemia. Most of the early changes in anoxic hepatocytes take place in the mitochondria. Briefly, due to the unavailability of O2 as a terminal electron carrier for the mitochondrial respiratory chain, the electron flow is immediately interrupted, thus reducing the respiratory chain. Since the mitochondria no longer accept electrons from substrates, pyridine nucleotides decrease, thus causing a rise in the intracellular NADH/NAD+ ratio. The disruption of oxidative phosphorylation rapidly depletes cellular ATP, accelerates glycolysis, increases lactate formation, and alters H+ , Na+ , and Ca2+ homeostasis and thus induces severe damage to the hepatocyte. Ischemia also causes a substantial rise in cAMP, a key factor in glucose metabolism. Via the action of cAMP-dependent protein kinase, cAMP causes the phosphorylation/deregulation of enzymes, which play a major role in the control of carbohydrate metabolism [18, 19]. Reperfusion injury derives mainly from toxic reactive oxygen species (ROS) generated on the reintroduction of O2 to ischemic tissues. ROS are produced both from intracellular and from extracellular sources; in liver cells, the mitochondria are their major source [7, 20].

#### **3. Preclinical studies in normothermic hepatic ischemia associated with hepatic resection**

#### **3.1 Animal species used**

The results of animal studies can be extrapolated to human beings, even though there are limitations such as the differences in ischemia tolerance, the anatomy of the organ in different species, and differences in the surgical conditions applied in clinical practice and in experimental models [21]. Therefore, the correct choice of animal species and experimental model, and the standardization of the protocol according to the clinical issue under study, is particularly important [14]. Small animals like rats and mice are exceptionally useful because they are easy to handle, present minimal, financial, logistical or ethical problems, and allow genetic alterations such as the creation of transgenic and knock-out animals [14]. Larger animals (pigs, sheep, and dogs) have a more similar anatomy and physiology to humans, but their use is restricted by serious financial and logistical difficulties, ethical concerns, and the limited availability of immunological tools for use in these species [14, 21]. The age and sex of animals are also issues to consider. With regard to age, there are significant differences between younger (35–50 g) and older rats (250–400 g) in terms of their hepatic microcirculation at the different stages of ischemia, and with regard to sex, female rats are more sensitive to reperfusion injury than males after normothermic ischemia [14, 22, 23].

#### **3.2 Experimental models of normothermic hepatic ischemia to evaluate the mechanisms involved**

#### *3.2.1 Global hepatic ischemia with portocaval decompression*

The Pringle maneuver is often applied during liver resection, due to safety concerns. However, it has been associated with delayed liver failure and poor prognosis in patients undergoing major hepatectomy in conditions of prolonged liver ischemia [1, 13]. The global liver ischemia model with portal decompression provides an ideal simulation of the clinical condition of warm ischemia after the Pringle maneuver for liver resection and transplant [6, 14]. The first successful

 shunt operation carried out in humans was by Vidal in 1903 [24]. Blakemore was among the first researchers to report successful portal-systemic anastomosis in rats, working mainly with endothelium-lined tubes [25]. Burnett et al. modified the technique to create a portocaval shunt [26]. In 1959, Bernstein and Cheiker developed the portosystemic shunt, which led portal blood into one of the iliac veins after functional hepatectomy [27]. In small animals, many other shunt techniques have been developed such as the portofemoral shunt or the mesentericocaval shunt via the jugular vein. In 1995, the splenocaval shunt was developed by Spiegel [28]. In large animals, on the other hand, a porto-femoro jugular bypass is frequently used [14, 29]. Results from experimental models of hepatic I/R injury alone are often extrapolated to clinical liver resection with PH and ischemia. However, in conventional experimental I/R models (for example, 70% partial hepatic ischemia), reperfusion ensues in the presence of nonischemic lobes [1]. Experimental models that combine PH and I/R injury rule out any contribution to recovery of the nonaffected liver tissue. Furthermore, in this model, postischemic recovery depends on the liver cell damage caused by the IR-injury and also on the stress caused by the liver resection and posthepatectomy liver regeneration [1, 30].

#### *3.2.2 Global liver ischemia with spleen transposition*

 In 1970, Bengmark et al. developed this model for surgical treatment of portal hypertension [31]. In 1981, Meredith and Wade described a rat model that produced a portosystemic shunt in the anhepatic rat by transposition of the spleen, making a small incision in the left hypochondrium [32]. With the spleen inside a subcutaneous pouch, adequate portosystemic anastomoses emerge after some 2–3 weeks. The transposition induces the reversal of the blood flow in the splenic vein, which stimulates angiogenesis. Two weeks later, in the second step, a median laparotomy and temporary occlusion of the hepatoduodenal ligament are performed. This decompression by spleen transposition is easy to perform, because it does not require microsurgery. Within 2 or 3 weeks of surgery, the spleen is encapsulated without any signs of inflammation or bleeding. One drawback of this model is the long time span (3 weeks) until adequate portosystemic collaterals are large enough to take full control of portal vein flow. Furthermore, the effect of the changes in hepatic inflow on the collaterals remains unclear [6, 14, 33].

#### *3.2.3 Partial hepatic resection under vascular occlusion*

 In 1982, Yamauchi et al. reported a hepatic ischemia model in which ischemia is induced by occlusion of the hepatic artery, the portal vein, and the bile duct of the left and median lobes. No extracorporeal shunt is required because the blood continues to flow through the right and caudal liver lobes. This model of partial ischemia (70%) has been extensively used in experimental studies of hepatic I/R [34–36]. An experimental model of 30% partial liver ischemia has also been used, in which occlusion at the hepatic artery and portal vein interrupts the supply of blood to the right lobe of the liver [19]. In the clinical setting, PH under I/R is normally performed to control bleeding during parenchymal dissection [6]. Therefore, an experimental model incorporating both hepatic regeneration and I/R injury can simulate the clinical situation of selective or hemihepatic vascular occlusion for liver resections. In this model, after left hepatic lobe resection, a microvascular clamp is placed across the portal triad supplying the median lobe (30%). Congestion of the bowel is prevented during the clamping because the portal flow through the right and caudate lobes is preserved. At the end of ischemia, the right lobe and caudate lobes are resected, and the clamp is released to achieve reperfusion of the median lobe. In this hepatic resection

*Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 

model, portal decompression is not required, and certain important criteria are also met, such as reversibility, good reproducibility, and ease of execution [14, 19, 37].

#### **3.3 Strategies applied in experimental models of normothermic ischemia**

Many experimental studies have set out to develop in vivo pharmacological strategies for inhibiting the harmful effects of warm I/R [38–46]. Some of these studies are summarized in **Table 1**. However, none of them have been able to prevent hepatic I/R injury [6, 14]. However, it is important to develop strategies in experimental models that reproduce clinical practice conditions as closely as possible: for example, the use of intermittent clamping, and the combination of PH and I/R injury. Few of the studies carried out to date have complied with these requirements [12]. Some of these studies are summarized in **Table 2**. Recent breakthroughs in molecular biology are providing new opportunities for applying gene therapy to reduce liver I/R injury. The experimental data, however, have highlighted several problems inherent in gene therapy, including vector toxicity, difficulties in increasing transfection efficiency and protein expression at the appropriate site and time, and the difficulty of obtaining adequate mutants.



*Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 


#### **Table 1.**

*Pharmacological strategies used in experimental models of warm ischemia.* 


#### **Table 2.**

*Pharmacological strategies used in experimental models of warm ischemia with partial hepatectomy.* 

*Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 

#### **4. Controversies on hepatic regeneration under warm or cold ischemia**

In an attempt to expand the size of the donor pool, the use of living related liver transplantation (LDLT) has helped increase the number of donor livers, but, nonetheless, concerns persist about graft-size disparity and hepatic regeneration. In 1990, Broelsch et al. reported the first 20 series of LDLT in the USA [47]. In 1997, Lo et al. [48] performed the first successful LDLT using an extended right lobe from a living donor for an adult recipient [6]. In LDLT, liver graft must be successfully regenerated; however, cold I/R, which will take place during liver transplantation surgery, will reduce the regenerative capacity of the liver.

 The clinical application of strategies designed at beachside will depend on the use of experimental models that resemble as much as possible the clinical conditions in which the strategy intends to be applied [12]. However, many investigators have used rodent models of PH under or without vascular occlusion to mimic some of the pathophysiological events that occur during LT [6]. To the best of our knowledge, pharmacological strategies, which were used in experimental models of hepatic regeneration under warm ischemia (**Table 2**), were not applied in experimental models of LDLT. However, only three drugs (sirolimus, Ang II receptor type 2 antagonist, and Omega-3) were applied in patients submitted to LDLT (see **Table 3**). In contrast with the benefits on liver regeneration observed in experimental models of PH under I/R [49], the administration of sirolimus in LDLT decreases liver regeneration in patients [50]. Indeed, sirolimus decreases liver injury in patients only in combination with cyclosporine [51]. Similarly, angiotensin II receptor type 2 antagonist does not reduce hepatic injury as opposed to the benefits obtained in preclinical studies of PH under vascular occlusion [13, 52]. By contrast, pharmacological treatment with omega-3 had benefits on hepatic injury in clinical LDLT and in preclinical studies after PH under vascular occlusion [53, 54]. In our view, these controversial results may be explained at least partially, by the differences in the mechanism responsible of I/R damage and liver regenerative failure dependently on the surgical procedure (LDLT versus PH + I/R). Of note, it would be extremely useful to make a clear distinction between the mechanisms for each surgical situation to design therapies that demonstrate its effectiveness under experimental conditions similar to what happens in clinical practice [12]. This will probably lead to translation of the best strategies to clinical practice in the short term [12].


#### **Table 3.**

*Pharmacological strategies used in living donor liver transplantation.* 

### **5. Conclusions**

 Although our knowledge about the mechanisms involved in the development of liver I/R injury and regenerative failure has significantly improved, and it has consequently been accompanied by a long list of potential therapeutic alternatives, I/R injury and regenerative failure after surgical procedure still represent a serious problem in the clinical practice. It should be considered that the mechanisms involved in hepatic I/R and regenerative failure very much depend on the experimental conditions used: which type of research is done, type of ischemia applied (warm or cold), period of ischemia (ranging from minutes to days), extension of hepatic ischemia (partial or total), graft subclinical situation (healthy, steatotic, aged,…), etc. Thus, new therapeutic strategies from experimental studies should be considered specific to the concrete experimental/surgical conditions used, and most probably, they cannot automatically be validated for all clinical situations requiring both vascular occlusion and liver regeneration [7]. We recognize the complication, but multidisciplinary research groups should devote additional efforts to better understand the cellular alterations and the crosstalk within the liver during the different clinical setting, requiring both vascular occlusion and liver regeneration to ultimately develop effectual therapeutic strategies aimed at reducing I/R damage and improving hepatic regeneration after liver surgery.

#### **Acknowledgements**

 This research was supported by the Ministerio de Economía y Competitividad (project grant SAF-2015-64857-R) Madrid, Spain; the European Union (FondosFeder, "una manera de hacer Europa"); by CERCA Program/Generalitat de Catalunya; and by the Secretaria d'Universitats i Recerca (Grant 2017SGR-551) Barcelona, Spain. ME Cornide-Petronio has a Sara Borrell contract from the Instituto de Salud Carlos III (Grant CD15/00129), Madrid, Spain. MB Jiménez-Castro has a contract from the Programa de Promoción del talento y su empleabilidad from the Ministerio de Economía y Competitividad (Grant EMP-TU-2015-4167), Madrid, Spain. J Gracia-Sancho received continuous funding from the Instituto de Salud Carlos III (currently FIS PI17/00012) & the CIBEREHD, from Ministerio de Ciencia, Innovación y Universidades.

#### **Conflict of interest**

The authors declare that they have no conflict of interest.

*Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 

#### **Author details**

Maria Eugenia Cornide-Petronio1†, Mónica B. Jiménez-Castro2†, Esther Bujaldon1 , Jordi Gracia-Sancho3 and Carmen Peralta1,4,5\*

1 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

2 Transplant Biomedicals, S.L., Barcelona, Spain

3 Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain

 4 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain

5 Facultad de Medicina, Universidad International de Cataluña, Barcelona, Spain

\*Address all correspondence to: cperalta@clinic.ub.es

† Both authors contributed equally to this work.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[41] Casillas-Ramírez A, Ben Mosbah I, Ramalho F, Rosello-Catafau J, Peralta C. Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation. Life Sciences. 2006;**79**:1881-1894. DOI: 10.1016/j. lfs.2006.06.024

[42] Ben Mosbah I, Alfany-Fernández I, Martel C, Zaouali M, Bintanel-Morcillo M, Rimola A, et al. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemiareperfusion. Cell Death & Disease. 2010;**1**:e52. DOI: 10.1038/cddis.2010.29

[43] Bahde R, Spiegel H. Hepatic ischaemia-reperfusion injury from bench to bedside. The British Journal *Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies… DOI: http://dx.doi.org/10.5772/intechopen.80340* 

of Surgery. 2010;**97**:1461-1475. DOI: 10.1002/bjs.7176

[44] Zúñiga J, Cancino M, Medina F, Varela P, Vargas R, Tapia G, et al. N-3 PUFA supplementation triggers PPAR-α activation and PPAR-α/ NF-κB interaction: Anti-inflammatory implications in liver ischemiareperfusion injury. PLoS One. 2011;**6**:e28502. DOI: 10.1371/journal. pone.0028502

[45] Ghonem N, Yoshida J, Stolz D, Humar A, Starzl T, Murase N, Venkataramanan R. Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. American Journal of Transplantation. 2011;**11**:2508-2516. DOI: 10.1111/j.1600-6143.2011.03568.x

[46] Kamo N, Shen X, Ke B, Busuttil R, Kupiec-Weglinski J. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation. American Journal of Transplantation. 2011;**11**:2499-2507. DOI: 10.1111/j.1600-6143.2011.03700.x

[47] Broelsch C, Emond J, Whitington P, Thistlethwaite J, Baker A, Lichtor J. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Annals of Surgery. 1990;**212**:368-375

[48] Lo C, Fan S, Liu C, Lo R, Lau G, Wei W, et al. Extending the limit on the size of adult recipient in living donor liver transplantation using extended right lobe graft. Transplantation. 1997;**63**:1524-1528

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**23**

**Chapter 3**

*Ali I. Yahya*

**1. History of IOUS**

detect gallstones.

obstetrics.

diagnosis of brain tumors.

**Abstract**

Use of Intraoperative Ultrasound

Over the last many years, diagnostic imaging has grown from a state of infancy to a high level of maturity. The various imaging modalities were developed over the last 50 years. Ultrasonography is one of the valuable tools in diagnosis of many diseases for a long time. It replaced X-ray in the diagnosis of many different diseases. It is noninvasive and has no complications if used many times in the day even if it is safe during pregnancy. The use of ultrasonography was spread over the years in all branches of medicine. It is promptly used in emergency medicine. Its use was introduced during operations. It showed excellent results when used for the assessment of liver tumors either primary or secondary liver tumors during open surgery and laparoscopy. The use of high-frequency ultrasound probe intraoperatively will

 

In 1942, Neurologist Karl Dussik used ultrasound first time in the medical

In 1948, George D. Ludwig developed the A-mode ultrasound equipment to

John J. Wild is known as the "father of medical ultrasound" for imaging tissue in 1949. Modern ultrasonic diagnostic medical scans are descendants of the equipment

In 1957–1958, Ian Donald, professor of obstetrics and gynecology from Glasgow, invented the ultrasound machine and developed first time the use of ultrasound in

The use of ultrasound during operations which is called intraoperative ultrasound was started in 1960 [3]; however, it was not widely accepted in use because of limited experience and the quality of ultrasound machine. Bernard Sigel is the surgeon who first performed intraoperative ultrasound in biliary surgery; it was in

In 1980, intraoperative ultrasound became more popular and widely used in the

In 1990, the use of intraoperative ultrasound became widely used, especially in liver surgery. And in the mid-1990s, the use of intraoperative ultrasound became a routine use in hepatic surgery; introduction of probes for open and laparoscopic surgery also added much in addition to the utilization of color Doppler flow ultrasound. IOUS is used for the assessment of pancreatic lesions, blood vessel invasion, lymph node

1979, and later in 1980, he started using IOUS in hepatobiliary surgery.

field of hepatobiliary and pancreatic, vascular, and neurosurgery.

(IOUS) in Liver Surgery

nullify the abdominal wall and bowel gas effects on the result.

**Keywords:** intra-opertive ultrasound, liver surgery

developed by him and his colleagues in the 1950s.

#### **Chapter 3**

## Use of Intraoperative Ultrasound (IOUS) in Liver Surgery

*Ali I. Yahya* 

#### **Abstract**

 Over the last many years, diagnostic imaging has grown from a state of infancy to a high level of maturity. The various imaging modalities were developed over the last 50 years. Ultrasonography is one of the valuable tools in diagnosis of many diseases for a long time. It replaced X-ray in the diagnosis of many different diseases. It is noninvasive and has no complications if used many times in the day even if it is safe during pregnancy. The use of ultrasonography was spread over the years in all branches of medicine. It is promptly used in emergency medicine. Its use was introduced during operations. It showed excellent results when used for the assessment of liver tumors either primary or secondary liver tumors during open surgery and laparoscopy. The use of high-frequency ultrasound probe intraoperatively will nullify the abdominal wall and bowel gas effects on the result.

**Keywords:** intra-opertive ultrasound, liver surgery

#### **1. History of IOUS**

In 1942, Neurologist Karl Dussik used ultrasound first time in the medical diagnosis of brain tumors.

In 1948, George D. Ludwig developed the A-mode ultrasound equipment to detect gallstones.

John J. Wild is known as the "father of medical ultrasound" for imaging tissue in 1949. Modern ultrasonic diagnostic medical scans are descendants of the equipment developed by him and his colleagues in the 1950s.

In 1957–1958, Ian Donald, professor of obstetrics and gynecology from Glasgow, invented the ultrasound machine and developed first time the use of ultrasound in obstetrics.

 The use of ultrasound during operations which is called intraoperative ultrasound was started in 1960 [3]; however, it was not widely accepted in use because of limited experience and the quality of ultrasound machine. Bernard Sigel is the surgeon who first performed intraoperative ultrasound in biliary surgery; it was in 1979, and later in 1980, he started using IOUS in hepatobiliary surgery.

In 1980, intraoperative ultrasound became more popular and widely used in the field of hepatobiliary and pancreatic, vascular, and neurosurgery.

 In 1990, the use of intraoperative ultrasound became widely used, especially in liver surgery. And in the mid-1990s, the use of intraoperative ultrasound became a routine use in hepatic surgery; introduction of probes for open and laparoscopic surgery also added much in addition to the utilization of color Doppler flow ultrasound. IOUS is used for the assessment of pancreatic lesions, blood vessel invasion, lymph node

metastasis, and also biopsy. The use of intraoperative ultrasound adds a lot of information on the anatomy and pathology of the lesion to the surgeon when he is standing at the operation table and can change the decision of the surgical management.

### **2. Use of intraoperative ultrasound for liver diseases**

Ultrasound is used for diagnosis and assessment of liver diseases mainly for tumors, like colonic metastasis since 1990 with the use of a transducer either linear or T-shaped 3.7 MHz.

Intraoperative ultrasound can be used during an open or laparoscopic surgery; each approach has a unique probe. The use of ultrasound where the probe is put directly on the liver with no skin and abdominal wall interferes with the picture of the liver tissue.

*The use of IOUS in different diseases:* 

1. Benign liver diseases

2. Malignant liver tumors

#### **2.1 Benign liver diseases**

The liver is a very important intra-abdominal organ, which is involved in different diseases that either originate in the liver itself or by a lesion in another part of the body and involves the liver like hepatic metastasis of malignancy. There are benign liver diseases, which are diagnosed by imaging like ultrasound, computed tomography, and magnetic resonance imaging.

#### *2.1.1 Use of IOUS added changes in treatment of different benign liver lesions*

#### *2.1.1.1 Hydatid liver disease*

Intraoperative ultrasound is used in surgery for hydatid liver disease. It is used routinely in our hospital.

Once the abdomen is opened, we examined the liver manually for localization of the cysts, and defining the number, we use T-shaped ultrasound probe sterilized by glutaraldehyde and examine the liver with the team of our consultant surgeons who perform IOUS and had good training in ultrasound. We examine the number of the cysts and contents in relation to the blood vessels and bile ducts, and visible bile duct communication will be notified if it is visible. Intraoperative ultrasound is more superior and informative than CT and MRI for hepatic hydatid disease, and it is found of value in the following [6–12]:

1. Localization of the cyst in relation to major blood vessels and bile duct.

2. Helping in planning hepatotomy to reach deep-seated cysts.


*Use of Intraoperative Ultrasound (IOUS) in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.81175* 

 from the mother hydatid cyst which was a deep-seated hepatic hydatid cyst in segment VIII with communication to the bile duct which was cleared by MRCP (**Figures 1** and **2**). The surgery was performed to the patient with the use of IOUS. The common bile duct was opened, and the daughter cysts from the bile duct were removed with the help of IOUS the mother cyst was cleared from daughter cysts by approach through the communication with the bile duct, Endocyst was removed, and the residual cavity collapsed which is clearly seen by IOUS. A T-tube was put inside the common bile duct, and the patient was discharged and after 4 weeks she had a T-tube contrast study. The common bile duct was clear, there was no more cyst in the liver, and the patient was cured from the hepatic hydatid-induced obstructive jaundice (**Figure 3**).

Hydatid cyst liver evacuated through bile duct.

CT scan liver showing residual cyst was done after two months after the surgery

#### **Figure 1.**

*Showing the liver with hydatid cysts in a child, aged 9 years, which had preoperative ultrasound which showed few hepatic hydatid cysts, with the use of intraoperative ultrasound; 22 hydatid cysts were removed in spite of the CT scan reporting few cysts.* 

#### *2.1.1.2 Liver hemangioma*

Liver hemangioma is not a common liver lesion; it can have a small size or may increase in size and rupture and can be detected by percutaneous ultrasound, CT, and MRI. Intraoperative ultrasound is used for delineation and plans the resection of the hemangioma. Hemangioma can be differentiated from other liver lesions by contrast-enhanced intraoperative ultrasound. It can be compressed under ultrasound and seen by Doppler, which is a feature of the space containing blood.

*Use of Intraoperative Ultrasound (IOUS) in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.81175* 

#### **Figure 2.**

*Showing a patient with surgery for huge liver hydatid cyst. IOUS was used to scan the liver for other cysts and used in surgical approach to excise the cyst.* 

**Figure 3.**  *Showing a big hydatid cyst in the liver.* 

#### *2.1.1.3 Intraoperative ultrasound study of the gall bladder and the bile duct*

With the development of transducers for intraoperative ultrasound, intrahepatic and extrahepatic bile ducts can be visualized with 7.5 MHz probes. We use T-shaped probes sterilized with glutaraldehyde solution or by gas sterilization; the probe can be covered with sterile sheet. Intraoperative laparoscopic ultrasound is used during laparoscopic cholecystectomy to visualize common bile lesions including stones, tumors, and gall bladder suspicious lesions either sludge or tumors.

Laparoscopic intraoperative ultrasound can replace intraoperative cholangiogram for the detection of common bile duct stones which costs less and consumes less time [1, 2, 4, 5] (**Figure 4**).

#### *2.1.1.4 Liver cysts*

Benign liver cyst, which can be congenital or acquired with the use of intraoperative ultrasound, we can delineate and study the relation of the cysts to the blood vessels and the bile duct.

#### *2.1.1.5 Liver abscess*

Liver abscess is not common; once happened it can be localized and aspirated with the help of intraoperative ultrasound.

#### **Figure 4.**

*A 60-year-old female patient with carcinoma in the gall bladder; the tumor was resected completely with segment of the liver.* 

#### *2.1.1.6 Liver tumors*

For primary liver tumors and hepatocellular carcinoma, IOUS is very helpful in staging the tumor looking for any small lesions. It is very helpful in case of a cirrhotic liver, l for looking the extent of the lesion, relation of the blood vessel to the lesion. It is more useful if contrast-enhanced ultrasound is used. IOUS is more superior in detecting liver lesion than preoperative MRI and CT scan with sensitivity of 95–100% in comparison to others, 80% for CT, and 70% for percutaneous ultrasound. It is very helpful in liver resection for liver malignant tumors and will improve patient survival by taking safety liver resection; with the use of IOUS, limited liver tumor resection can be done in a non-segmental way and will improve patient survival especially in a patient with hepatocellular carcinoma with a background of cirrhosis [25–27, 29–33]. IOUS may have difficulty in detecting small liver lesion in a fatty liver; however, the use of contrast-enhanced ultrasound will be more beneficial [22–24, 28].

For cholangiocarcinoma of the hilar region and Klatskin tumor, intraoperative ultrasound makes a difference in staging the disease and resection of the tumor.

*Use of IOUS in malignant hepatic tumors:* 


The use of IOUS at primary surgery of colonic tumor is as follows: In our hospital it is done when the operation is performed by senior surgeons, and we found it gives more information on the staging of the tumor. It is found more superior than CT scan and percutaneous ultrasound.

#### *2.1.1.7 Hepatic transplantation*

It is used for harvesting the liver and for following the patency of anastomosis of the blood vessels.

*Use of Intraoperative Ultrasound (IOUS) in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.81175* 

### **3. IOUS**

 IOUS changed the surgical decision when used by hepatobiliary and pancreatic surgeons. The benefit of the use of IOUS in surgical treatment of a liver disease may reach to 41.9% according to documented studies and makes the use of IOUS for liver surgery of a big value.

#### **3.1 IOUS training**


#### **3.2 Methods of the use of IOUS**

	- a.The transducer has to be cleaned after finishing the work and dried with dry tissue paper.
	- b.Use the sterile sheet cover over the transducer, and put sterile gel during the examination inside the cover.
	- c. Use a disinfective solution like CISEx; the time is 12 minutes. Glutaraldehyde and dialdehyde are not used nowadays because they may cause inflammatory contact.
	- d.Hydrogen peroxide.
	- e.Plasma.

Open surgery ultrasound transducer

Laparoscopic ultrasound transducer

Robotic ultrasound transducer

### **4. Conclusion**

 Ultrasound is routinely used for the diagnosis of diseases. The use of ultrasound during surgery is applied for a long time, and it is used for surgical treatment of surgical liver diseases. It made a lot of changes in the management of malignant hepatic metastatic colonic tumors. Using IOUS for liver pathology will change the mode of treatment. It also helps in the ablation of liver tumors. IOUS is also used for surgical treatment of benign hepatic pathology like hydatid liver disease, liver cysts, bile duct stones, and bile duct tumors. It can replace intraoperative cholangiography when needed. The advantages of the use of IOUS in liver surgery are the following: it gives better informations about the liver involvement by the lesion than transcutaneous ultrasound, CT scan, or MRI; it will show small lesions which may not be seen by the other modalities; it helps in outlining the resection line when liver resection is planned; it gives informations about the relation of the blood vessels to the lesion; it gives information about the bile duct anatomy; and it can replace intraoperative cholangiogram if needed. Disadvantages of IOUS in liver surgery are the following: it needs special training for the surgeons, it adds more work for the radiologists if it needs to be done by the radiologist, and it is difficult to be used in emergency surgery like where patients are operated on malignant bowel obstruction to check whether the patient has liver metastasis or not. This is because of availability of the trained surgeon or trained radiologist and the availability of the equipment. The use of IOUS in liver surgery will add more cost, and it may not be possible in hospitals where the resources are restricted.

### **Author details**

Ali I. Yahya Zliten Teaching Hospital, Zliten Medical School, Al-Asmaria University, Zliten, Libya

\*Address all correspondence to: aliyahyaz60@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## Damage Control in Liver Surgery

*Ali I. Yahya* 

#### **Abstract**

 Damage control surgery is an old type of surgery practiced for many years to save the lives of badly injured patients. Damage control was first practiced in the American navy where a damaged vessel would receive minimal repair to keep it afloat. This translates to the field of medicine where minimal surgery is performed to save the life of a patient, and minimal action is taken to avoid major ailments, including hypothermia, acidosis, and coagulation defects during major trauma. Before World War II damage control surgery was popular, but later this type of surgery was abandoned. However, with a better understanding of the physiology of trauma and a revision of the outcome of badly injured patients, surgeons have reverted to damage control surgery, for example the packing of bleeding organs such as the liver and the controlling of sepsis, rather than taking patients to intensive care for further assessment. Damage control surgery has many benefits for badly injured patients and improves their chances of survival.

**Keywords:** liver trauma, perihepatic packing, acidosis, hypothermia, hypercoagulability

#### **1. Definition of damage control**

Damage control is defined as measures that are taken to minimize damage whether physical or non-physical. In emergency surgery it is the immediate action taken to stop bleeding and/or minimize sepsis, rather than taking the patient to intensive care for assessment. Damage control was first practiced in the American navy where a damaged vessel would receive minimal repair to keep it afloat.

#### **2. History of damage control surgery**

 In ancient times, Greek and Roman physicians tried to use different modalities available at the time to save the lives of patients bleeding to death due to traumatic and non-traumatic causes. Millions of patients die around the world from bleeding each year. The liver packing technique, a highly effective technique to control bleeding, has been used in surgery for more than 100 years, where gauze packing is placed inside the liver wound to control the bleeding. Organ packing was used before World War II to control bleeding from liver wounds. Perihepatic packing goes back to 1908 when James Hogarth Pringle was the first surgeon to perform packing to stop massive bleeding from damaged liver at the Royal Glasgow Infirmary [1–3]. In 1913, Halstead used a rubber sheet between the gauze packs and the damaged liver tissue. After World War II, liver packing for a massively bleeding liver fell

into decline. During the war the number of trauma patients with liver injury had intrahepatic packing to stop the bleeding. Trauma surgeons reported complications due to packing such as bleeding and abscesses, and since the war packing has been banned. From 1955 onwards, Madding, Lucas, and Ledgerwood performed liver packing on their patients and achieved good results. In 1981, David Felaciano performed liver packing on his patient [3], which gave potential results. In 1983, Harlan Stone was the first surgeon to follow damage control surgery by minimizing emergency surgery on exsanguinating patients from bleeding trauma due to a coagulation system defect [4], and performed periorgan packing, terminating the surgery on those unwell patients [5–7]. With the development of surgery and a better understanding of the physiology and pathology of trauma with different multicenter studies on the outcome of hepatic trauma, trauma surgeons reverted to the practice of ancient surgeons and used packing for bleeding organs. The decision to undertake damage control surgery should be decided as early as possible before the patient succumbs to the lethal triangle of acidosis, hypercoagulability, and hypothermia. By using damage control, 5 to 65% of patients may be controlled by packing. In 1970, no patients with uncontrolled massive liver injury were being treated with packing. In 1993, Rotondo and Schwab used the term damage control for the packing of bleeding organs [8–10]. Peitzman reported good results with damage control for major liver injury. Packing followed by angioembolization has produced excellent results [11]. Asensio had excellent experience with damage control surgery and produced excellent work in this regard. From 1990 to 2000, damage control was successfully applied in the management of severe abdominal trauma.

#### **3. Stages of damage control surgery**

Damage control surgery for patients with trauma or other non-traumatic surgery goes in danger of life if complete surgery. There are indications for damage control surgery, for example absolute indications and relative indications; however, it is better not to wait for indications.

**Absolute indications** include the following:


These indications should be prevented [12]. **Relative indications** 

1. Major intra-abdominal bleeding, which is very difficult to control.


*Damage Control in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.80817* 

**Stage I** of damage control surgery is where the patient is taken to the operating theater and undergoes minimal and necessary surgical operations [13–15]. The above three usual causes following injury are leading causes of death in patients.

Massive transfusion, acidosis, and hypothermia have been considered as significant contributors to deranged clotting and coagulation manifestations. Hypothermia is caused by keeping the abdomen open for a long time, cold intravenous fluid, and blood. Acidosis happens due to low cardiac output. Tissue hypoxia techniques may include:


**Stage II** of damage control consists of:


**Stage III** of damage control ensures that once the patient is hemodynamically stable, he or she should be taken to the operating theater again within 24–72 h where the following procedures can be performed: removal of abdominal packs, removal of devitalized tissue, anastomosis of bowel, removal of shunts and performing vascular anastomosis, performing feeding jejunostomy, and closure of the abdominal wound.

#### **4. Complications of damage control surgery**

 Intra-abdominal hypertension and abdominal compartment syndrome are the main and most serious complications of abdominal damage control surgery where intra-abdominal pressure rises above the normal level, which is 12 mmHg, and where the intra-abdominal pressure rises above 20 mmHg, which will affect the arterial perfusion pressure and result in organ dysfunction or failure; the condition will be labeled as abdominal compartmental syndrome. The following vital organs will be affected: kidneys, heart, lungs, liver, and gastrointestinal system. Its incidence ranges from 14% in patients with severe abdominal trauma to 50% in patients with severe trauma where the intra-abdominal pressure is above 12 mmHg. Perfusion of the vital organs is affected by intra-abdominal pressure (organ perfusion pressure = mean arterial pressure − intra-abdominal pressure). Once the intra-abdominal pressure is raised, perfusion to the vital organs will be decreased. The increase in intra-abdominal pressure is due to tissue edema; this edema could be bowel wall edema or edema of any intra-abdominal tissue, fluid overload by resuscitation, or capillary leakage because of inflammatory mediators released during trauma/sepsis.

### **5. Physiological effects of abdominal compartment syndrome**


Forms of intra-abdominal pressure can be measured as follows:


*Damage Control in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.80817* 

> Grade III when the pressure is from 21 to 25 mmHg. Grade IV when the pressure is above 25 mmHg. The incidence of abdominal compartment syndrome among severe trauma patients ranges from 1 to 14%.

#### **Clinical presentation**:

1. Pale-looking body color and hypotension.


#### **Investigations:**

No specific investigations, only clinical suspicion, measuring the abdominal pressure, and X-ray of the abdomen will show distension of bowel loops; a CT scan will show bowel wall edema.

### **Treatment of abdominal compartment syndrome:**

It is better prevented than treated.

1. Urgent release of abdominal compartment tension by celiotomy.


When applying damage control surgery in trauma patients, it is advisable to leave the abdomen open.

#### **Management of open abdominal wound in cases of damage control surgery:**

 1. To avoid onset of compartment syndrome the abdominal wall should be left completely open or there should be partial approximation of the wound edges or skin only. If the abdomen is left completely open, the patient should be kept on a ventilator and completely paralyzed to avoid eviceration of the bowel outside the abdomen [16]. A plastic bag can be fixed to the edges of the abdomen wall with continuous stitches or skin clips like a sterile urine bag; towel clips, zipper sheath, and surgical mesh can also be used. This type of dressing allows the clinician to inspect the viscera, does not lead to increased intra-abdominal pressure, will not adhere to the bowel, and will be easier to remove. Once the patient improves and abdominal pressure is back to normal the abdominal wound can be closed. The patient may develop an incisional hernia, which can be dealt with later.


**Figures 1–3** show a patient who had damage control laparotomy for intraabdominal bleeding, where the abdomen was not closed.

**Figure 1.**  *Patient after major abdominal trauma, where the abdomen is left open.* 

*Damage Control in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.80817* 

#### **Figure 2.**

*Patient after major abdominal trauma, where the abdomen is closed with the use of a sterile plastic sheath, where we used sterile urine bag.* 

**Figure 3.**  *The wound is approximated and not closed completely.* 

#### **6. Benefits of damage control surgery**

Damage control surgery is self-explanatory and it shows a big change in emergency surgery management. It has benefits for patient management:


#### **7. Zliten Teaching Hospital's experience with damage control surgery**

 Zliten is a busy teaching hospital and provides medical and surgical treatment and nursing care for general and injured patients. It was heavily workloaded with injured people during the Libyan war in 2011 and is still receiving patients associated with weapon injury, in addition to other traumas such as road traffic accidents. In 1991, an 18 years-old Libyan, the first patient who had received perihepatic packing after severe liver injury grade IV, developed renal impairment, liver impairment, pleural effusion, and intestinal obstruction. He survived with major multiorgan insult and now is a medical doctor. The operative mortality of damage control is approximately 12% in Zliten hospital (**Figures 4–6**).

#### **8. Experience of Zliten Teaching Hospital with damage control surgery**

This experience was gained over a period of 27 years from 1991 to 2018. The number of patients with liver trauma is 324, with a female to male ratio of 26:298.

Most of the patients are between 20 and 40 years of age. Patient statistics are as follows:

Over 27 years, before the war, during the war, and after the war the number of patients with major liver trauma: 324.

Number of patients with perihepatic packing: 96.

Patients who survived after packing: 88.

Patients who died during packing and after packing: 8.

Patients who had the packs removed after 72 h: 76.

Patients who had repacking after 24 h: 4.

Patients who had packing removed at 48 h: 8.

Packing for non-trauma intra-abdominal bleeding: 5 patients.

Packing bleeding after hydatid liver surgery: 1 patient.

Massive bleeding postcholecystectomy with retrohepatic varices: 1 patient.

Massive bleeding after hepatic artery injury during postcholecystectomy: 1 patient.

Intragastric packing for gastropathy: 1 patient.

Intraurinary bladder packing for bleeding from prostatic tumor: 1 patient.

#### *Damage Control in Liver Surgery DOI: http://dx.doi.org/10.5772/intechopen.80817*

**Figure 4.** 

*Diagram showing major liver trauma at Zliten Teaching Hospital over a period of 27 years.* 

**Figure 5.**  *Removal of the packs.* 

**Figure 6.**  *Packing for trauma and non trauma intra-abdominal bleeding.* 

Complications after damage control surgery noticed among patients:


#### **Author details**

Ali I. Yahya Zliten Teaching Hospital, Zliten Medical School, Al Asmaria University, Zliten, Libya

\*Address all correspondence to: aliyahyaz60@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
