**4. Clinical finding and diagnosis**

Although total plasma volume increases, as a result of collection of blood in the splanchnic area, effective blood capacity cannot be achieved, and central hypovolemia develops. After these changes, activation of the sympathetic nervous system and renin‐aldosterone system occurs; vasopressin release from the hypothalamus increases, which results in fluid and salt

The vasoconstrictor and vasodilator substances in the pathogenesis PHT become effective together. The most important vasoconstrictor substances are norepinephrine, angiotensin II, vasopressin, thromboxane (TX), and leukotrienes. The effects of these substances are related with activation of the sympathetic nervous system and renin‐angiotensin‐aldosterone system. Researches have shown that portal venous tension can be decreased using alpha‐adrenergic antagonists (prazosin), beta‐adrenergic antagonists (propranolol), angiotensin‐II antagonists, cyclooxygenase isoenzyme blockers, and TX antagonists. Results of these researches support

Endothelin (ET) can show vasoconstrictor or vasodilator effects according to the type. Endo‐ thelins are classified as ET‐1, ET‐2, and ET‐3 according to their region in the body. ET‐1 is mainly found in endothelial cells, the kidney, and the brain and ET‐2 in the small intestine and kidney, and ET‐3 is found in the blood. ET‐1 and ET‐2 create a vasoconstrictor effect, whereas ET‐3 has a vasodilator effect. These two opposite effects are associated with the induction of nitric oxide and prostacyclin release. The most potent vasoconstrictor substance in the body is ET‐1, and it is reported that this substance is very effective in the development of PHT complications [22,

Nitric oxide (NO) is another very potent substance in the pathogenesis of PHT. NO is synthe‐ sized from arginine by nitric oxide synthetase (NOS) and causes vasodilatation by increasing cyclic guanosine monophosphate. NO initially increases to compensate against the elevated vasoconstrictor agents in the early stage of PHT, but secondary systemic and splanchnic vasodilatation develops because of excessive NO production. This event is a result of stimu‐ lation of NOS by cytokines such as TNF‐alpha, which increases in cirrhosis [22, 30–36].

The other important vasodilator substances in the pathogenesis of PHT are carbon monoxide (CO), hydrogen sulfide (H2S), prostaglandins, glucagon, and endocannabinoids. CO formed through the heme‐oxygenase system is a weaker vasodilator agent than NO, but it is important for regulation of intrahepatic vascular tone. H2S is formed by intestinal microbiota and

Prostaglandins are endogen vasodilators produced in the endothelium and are important for hyperdynamic circulation. Prostacyclin is produced from the vascular endothelium. It leads to vasodilatation, which increases the level of intracellular cyclic adenosine monophosphate (c‐AMP) through the activation of adenylate cyclase. In recent studies, it was shown that indomethacin, a prostacyclin inhibitor, decreased the hyperdynamic circulation and balanced

Glucagon is a hormone released from the pancreas. Glucagon levels increase as a result of low hepatic clearance and stimulation of pancreatic alpha cells in patients with cirrhosis. Glucagon also has the effect of reducing endogenous vasoconstrictor activity in addition to having a

increases the effects of other vasodilator substances and PHT severity [22, 30–36].

retention [30–33].

262 Cardiomyopathies - Types and Treatments

29–34].

the pathogenesis [22, 29–34].

the vasoconstrictor effect [22, 30–36].

Cirrhotic cardiomyopathy (CCMP) represents a condition in which no real cardiac disease is present but a functional cardiac abnormality exists. With time, CCMP progresses to the chronic phase. In a resting state, there is no real disease, but with stress, the cardiac muscle does not contract appropriately and and/or electrophysiologic abnormalities appear [10–12]. There is no exact classification for CCMP and the criteria proposed by Moller et al. are still used (**Table 2**). These data are taken from an adult studies, pediatric data are very limited [41–45]. The most important points from these criteria are (1) at rest, normal, or increased left ventric‐ ular contractibility; (2) abnormal systolic contraction or diastolic relaxation with pharmaco‐ logic, physiologic, or surgical stress; and (3) cardiac electrical abnormalities [10, 11].

Diagnosis of CCMP in children with cirrhosis is difficult, because invasive methods are life‐ threatening and noninvasive tests are unreliable for them. In recent years, a new article was published in which CCMP criteria for children were reviewed [45]. According to this literature, a prolonged QT interval on electrocardiography (ECG) is an important finding after all non‐ liver causes are excluded, and shows latent cardiomyopathy due to cirrhotic changes. If there is the presence of echocardiographic abnormalities, this event is a manifest CCMP [45].

Cirrhotic cardiomyopathy is a latent disease in which there is no abnormality except under stress conditions. In such patients, there is no cardiac disease till end‐stage disease. At end stage, infrequent arrhythmias or cardiac insufficiency may be seen. If these findings exist in an early cirrhotic stage, other causes of cardiomyopathy such as infections, metabolic disor‐ ders, endocrinopathies, ischemic or toxic causes, and genetic and systemic diseases should be investigated [46].

Cirrhotic cardiomyopathy is more likely dilated cardiomyopathy where some stress factors cause cardiac dysfunction. With stress, the clinical status of the patient deteriorates and decompensation may exist. These stress factors are exercise, infection, positional changes, feeding, paracentesis with high volumes, changes in intravascular volume, the use of vaso‐ constrictor drugs, transjugular intrahepatic portosystemic shunts (TIPS), or surgical proce‐ dures such as minor operations or liver transplantation [10–12]. Exercise tolerance in patients with cirrhosis is abnormal due to cardiac function abnormalities, and this correlates with the patient's Child score [47].


BNP, brain natriuretic peptide; E/A ratio, the ratio between the early (E) and late atrial (A) phases of ventricular velocity

**Table 2.** Diagnostic criteria of cirrhotic cardiomyopathy.

There is a relationship between CCMP and hepatorenal syndrome (HRS), which has been reported in many articles published in recent years, so patients with HRS are at more risk [5, 25, 48].

Cardiac functions in patients with liver cirrhosis are determined by physical examination, ECG, and telecardiography besides of echocardiography. Cardiac functions such as systolic, diastolic, and electromechanical functions should be evaluated in suspected CCMP. ECG is sufficient for determining electrophysiologic function. Systolic and diastolic functions are checked using M‐Mod, two‐ and three‐dimensional echocardiocardiography, and spectral and tissue Doppler echocardiocardiography. Cardiac magnetic resonance imaging, radio nuclear angiography, and myocardial perfusion techniques are more advanced methods. Many times, for a diagnosis of CCMP, the findings on ECG and echocardiocardiography are enough.

Firstly, systolic function worsens in the late stage of CCMP. After then, the diastolic functions gradually decay. Diastolic dysfunction is best shown with echocardiographic measurement of the E/A ratio. Deceleration time (DT) and the isovolumetric relaxation time (IVRT) also are used. The E/A ratio results from blood velocity from the left atrium to the left ventricle, the velocity of which during early systole causes the E wave and the same flow causes the A wave during late diastole.

The measurement of E and A waves is expressed as cm/sec and best is done from mitral valve projection. A normal E/A ratio in healthy individuals until the age of 50 years is 1–2 cm/s, but in older people, it decreases below 1 cm/s. An E/A ratio in healthy individuals aged less than 50 years below 1 cm/s shows diastolic dysfunction. However, the restrictive pattern can be observed in advanced stages depending on the severity of the disorder in the patients with CCMP; the E/A ratio may reverse in these cases and may be determined >2 [10, 11, 49] (**Figure 2**).

**Figure 2. Diastolic dysfunction stages** [49]. MAP, mean atrial pressure; NYHA, New York Heart Association; Ddf stage, diastolic dysfunction stage.


DT, deceleration time; E/A, transmitral early diastolic flow (E)/transmitral late diastolic flow (atrial) (A) ratio; IVGT, isovolumetric relaxation time (msn).

**Table 3.** Echocardiographic stages of left ventricular diastolic dysfunction [49].

**Systolic dysfunction criteria Supporting criteria**

**•** Electrophysiologic abnormalities

**•** Abnormal chronotropic response

**•** Prolonged QT intervals

**•** Expended left atrium

**•** Increased myocardial mass

**•** Increased troponin I levels

BNP, brain natriuretic peptide; E/A ratio, the ratio between the early (E) and late atrial (A) phases of ventricular

There is a relationship between CCMP and hepatorenal syndrome (HRS), which has been reported in many articles published in recent years, so patients with HRS are at more risk [5,

Cardiac functions in patients with liver cirrhosis are determined by physical examination, ECG, and telecardiography besides of echocardiography. Cardiac functions such as systolic, diastolic, and electromechanical functions should be evaluated in suspected CCMP. ECG is sufficient for determining electrophysiologic function. Systolic and diastolic functions are checked using M‐Mod, two‐ and three‐dimensional echocardiocardiography, and spectral and tissue Doppler echocardiocardiography. Cardiac magnetic resonance imaging, radio nuclear angiography, and myocardial perfusion techniques are more advanced methods. Many times, for a diagnosis of CCMP, the findings on ECG and echocardiocardiography are enough.

Firstly, systolic function worsens in the late stage of CCMP. After then, the diastolic functions gradually decay. Diastolic dysfunction is best shown with echocardiographic measurement of the E/A ratio. Deceleration time (DT) and the isovolumetric relaxation time (IVRT) also are used. The E/A ratio results from blood velocity from the left atrium to the left ventricle, the velocity of which during early systole causes the E wave and the same flow causes the A wave

The measurement of E and A waves is expressed as cm/sec and best is done from mitral valve projection. A normal E/A ratio in healthy individuals until the age of 50 years is 1–2 cm/s, but in older people, it decreases below 1 cm/s. An E/A ratio in healthy individuals aged less than 50 years below 1 cm/s shows diastolic dysfunction. However, the restrictive pattern can be observed in advanced stages depending on the severity of the disorder in the patients with CCMP; the E/A ratio may reverse in these cases and may be determined >2 [10, 11, 49]

**•** Increased BNP and pro‐BNP levels

**•** Electromechanical uncoupling/dyssynchronism

**•** Inadequate cardiac flow to pharmacologic agents,

exercise, blood volume changes

264 Cardiomyopathies - Types and Treatments

**•** Resting ejection fraction under 55 %

**•** E/A ratio <1,0 (corrected according to age)

**•** Prolonged isovolumetric relaxation time

**Table 2.** Diagnostic criteria of cirrhotic cardiomyopathy.

**Diastolic dysfunction**

(>80 milliseconds)

during late diastole.

(**Figure 2**).

velocity

25, 48].

**•** Prolonged deceleration time (>200 milliseconds)

> There are different stages in CCMP. Clinical findings differ according to stage (**Table 3**). The E/A ratio worsens according to the severity of hepatic disease and it is worse in patients with ascites than in patients with non‐ascites and normal persons. The E/A ratio improves after paracentesis and this event supports that ascites is the negative effect on cardiac functions [50– 53]. There are no publications on these themes in children. There is no definitive normal value for the E/A ratio in children, but in some publications, it is proposed to be between 1.7 and 2.5 cm/s.

> Electrical conduction abnormalities and arrhythmias can be seen in the patients according to severity of cirrhosis [8, 9] [54–58]. There are three types of electrophysiologic abnormalities caused by cirrhosis: (1) prolonged QT on ECG, (2) inadequate response to chronotropic stress, and (3) electromagnetic dyssynchronism [10, 11, 14]. The prolonged QT on ECG means a corrected QT interval (QTc) is longer than 0.440 value [41, 54, 55]. Prolonged QT shows abnormal myocardial repolarization as a sign of CCMP [10–12, 56–58]. QT prolongation

proportionally increases with cirrhotic stage [56]. Prolonged QT on ECG is frequently seen in patients with CCMP. The rate of determination of prolonged QT is 30–60 % in adults with CCMP and in 18–45 % of pediatric patients [5, 41, 44, 56].

Actually, a prolonged QT interval may cause life‐threatening arrhythmias [55], but in many patients with CCMP, despite a prolonged QT interval, no significant clinical problem and arrhythmia are not observed. Cardiac arrhythmias in cirrhotic patients are frequently related to vasopressin use. There is no evidence that a prolonged QT interval in patients with CCMP causes life‐threatening arrhythmias. Probably, some compensatory mechanisms in cirrhotic patients prevent the disturbances and the disease occurs latent until end stage.

### **5. Treatment**

Treatment consists of preventing stress exposure in patients with CCMP; rest and oxygen supplementation are important [10, 59]. There is no need for pharmacotherapy when there is no cardiac insufficiency. Drugs have adverse effects and pharmacotherapy response is weak in patients with CCMP. In recent years, aldosterone antagonists, cannabinoid receptor antagonists, and spironolactone have been used, but only the effectiveness of beta‐blockers has been proved [10, 35, 59]. Beta‐blockers can decrease QT wave duration [10, 32, 33]. Diagnosis of CCMP at an early stage is important. Early diagnosis and proper treatment with cardioprotective agents are important for decreasing complications during and after liver transplantation. There are no exact data on prognosis for liver transplantation in patients with CCMP. Data from the past showed that CCMP worsens in the early period after liver trans‐ plantation, and later cardiac functions and cardiac electromechanical dysfunctions improve gradually by supplying hemodynamic stabilization of the patient [10, 59–64]. Liver transplan‐ tation can be a definitive treatment for CCMP. New pharmacologic agents are needed to help these patients because many patients do not have the chance to receive a transplant.

### **Author details**

Coskun Celtik1\*, Nelgin Gerenli1 , Halil Haldun Emiroglu2 and Nimet Cındık3

\*Address all correspondence to: cceltik2001@yahoo.com

1 Pediatric Gastroenterology, Health Sciences University, Istanbul Umraniye Training and Research Hospital, Istanbul, Turkey

2 Pediatric Gastroenterology, Selcuk University, Faculty of Medicine, Konya, Turkey

3 Pediatric Cardiology, Health Sciences University, Istanbul Umraniye Training and Re‐ search Hospital, Istanbul, Turkey

### **References**

proportionally increases with cirrhotic stage [56]. Prolonged QT on ECG is frequently seen in patients with CCMP. The rate of determination of prolonged QT is 30–60 % in adults with

Actually, a prolonged QT interval may cause life‐threatening arrhythmias [55], but in many patients with CCMP, despite a prolonged QT interval, no significant clinical problem and arrhythmia are not observed. Cardiac arrhythmias in cirrhotic patients are frequently related to vasopressin use. There is no evidence that a prolonged QT interval in patients with CCMP causes life‐threatening arrhythmias. Probably, some compensatory mechanisms in cirrhotic

Treatment consists of preventing stress exposure in patients with CCMP; rest and oxygen supplementation are important [10, 59]. There is no need for pharmacotherapy when there is no cardiac insufficiency. Drugs have adverse effects and pharmacotherapy response is weak in patients with CCMP. In recent years, aldosterone antagonists, cannabinoid receptor antagonists, and spironolactone have been used, but only the effectiveness of beta‐blockers has been proved [10, 35, 59]. Beta‐blockers can decrease QT wave duration [10, 32, 33]. Diagnosis of CCMP at an early stage is important. Early diagnosis and proper treatment with cardioprotective agents are important for decreasing complications during and after liver transplantation. There are no exact data on prognosis for liver transplantation in patients with CCMP. Data from the past showed that CCMP worsens in the early period after liver trans‐ plantation, and later cardiac functions and cardiac electromechanical dysfunctions improve gradually by supplying hemodynamic stabilization of the patient [10, 59–64]. Liver transplan‐ tation can be a definitive treatment for CCMP. New pharmacologic agents are needed to help

these patients because many patients do not have the chance to receive a transplant.

, Halil Haldun Emiroglu2

1 Pediatric Gastroenterology, Health Sciences University, Istanbul Umraniye Training and

3 Pediatric Cardiology, Health Sciences University, Istanbul Umraniye Training and Re‐

2 Pediatric Gastroenterology, Selcuk University, Faculty of Medicine, Konya, Turkey

and Nimet Cındık3

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**5. Treatment**

266 Cardiomyopathies - Types and Treatments

**Author details**

Coskun Celtik1\*, Nelgin Gerenli1

Research Hospital, Istanbul, Turkey

search Hospital, Istanbul, Turkey

\*Address all correspondence to: cceltik2001@yahoo.com


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#### **Takotsubo Cardiomyopathy as a Neurocardiogenic Injury after Subarachnoid Hemorrhage: Hemodynamics and Fluid Management Takotsubo Cardiomyopathy as a Neurocardiogenic Injury after Subarachnoid Hemorrhage: Hemodynamics and Fluid Management**

Tatsushi Mutoh, Tomoko Mutoh, Yasuyuki Taki and Tatsuya Ishikawa Tatsushi Mutoh, Tomoko Mutoh, Yasuyuki Taki and Tatsuya Ishikawa

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65011

#### **Abstract**

Takotsubo cardiomyopathy (TCM) is a life-threatening systemic disorder that may occur early after aneurysmal subarachnoid hemorrhage (SAH), but precise hemodynamics and fluid management remain unclear. Although TCM is often regarded as a reversible or self-limited phenomenon, it contributes significantly to morbidity and mortality of SAH patients, especially when it is complicated with other neurogenic injuries such as severe left ventricular dysfunction, pulmonary edema, and pneumonia. The purpose of this chapter is to introduce the current practice in intensive hemodynamic monitoring and goal-directed fluid management of post-SAH TCM using advanced hemodynamic devices based on our institutional protocol and the relevant literature and to evaluate their effects on clinical outcomes.

**Keywords:** Takotsubo cardiomyopathy, neurogenic stress cardiomyopathy, fluid therapy, pulmonary edema, subarachnoid hemorrhage

### **1. Introduction**

Postoperative management of aneurysmal subarachnoid hemorrhage (SAH) is sometimes complicated by systemic cardiopulmonary complications to affect a significant impact on the morbidity and mortality of the patients [1, 2]. The neuro-cardiac injury of SAH is of particular importance because of theirimpact on the ability to manage blood pressure and volume status, especially in the setting of cerebral vasospasm or delayed cerebral ischemia (DCI). The pattern

© 2017 The Author(s). Licensee InTech. 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. © 2017 The Author(s). Licensee InTech. 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.

of injury produced is commonly referred to as neurogenic stress cardiomyopathy [3]. One distinct morphological variant of stress cardiomyopathy is Takotsubo cardiomyopathy (TCM), which was first described by the Japanese physician in the early 1990s to be a reversible cardiomyopathy, the shape of which named after an octopus trap used by the native fishermen [4]. Although TCM is typically associated with acute emotional stress in postmenopausal women [5], triggers may also include physical stressors such as head trauma, intracranial bleeding, ischemic stroke, medical, and surgical procedures and catecholaminergic drugs [6]. Previous reports suggest the demographics and clinical characteristics of TCM are similar irrespective of their etiologies. However, there are notable differences in post-SAH TCM from other non-neurologic stressors in that the patients tended to be younger and more frequent in females than what is typically reported and had high in-hospital mortality (25%) [7].

**Figure 1.** Subarachnoid hemorrhage-induced neurogenic injuries. Note that apical ballooning suggestive of Takotsubo cardiomyopathy (TCM) and left ventricular dysfunction detected by apical two-chamber view on initial echocardiogram. Acute pulmonary edema was also observed on chest X-ray. 123I-metaiodobenzylguanidine (MIBG) SPECT depicting apical defect in the two-chamber view and the analysis of two-dimensional polar maps (bull's eyes) show decreased myocardial perfusion in apex. In 4-h delayed images, washout is increased, suggesting the presynaptic sympathetic dysfunction caused by TCM.

TCM is originally characterized by transient hypokinesis which results from apical wall motion abnormalities with sparing of the base. Although most of the TCM patients (>65%) can present such typical patterns on echocardiography (**Figure 1**), there are several different variants of regional wall motion abnormalities (RWMA) that spares the cardiac apex, as well as one that affects the right ventricle. The right ventricle involvement is noted in 26% of the patients with TCM and bilateral pleural effusions are commonly seen in these patients [8].

The diagnosis of TCM is made based on a modified version of the Mayo Clinic Criteria [9] as described in **Table 1**.

1. Transient hypokinesis, akinesis or dyskinesis of the LV mid-segments with or without apical involvement; the

RWMA extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present.

2. Absence of obstructive coronary artery disease or angiographic evidence of acute plaque rupture.

3. New ECG abnormalities (either ST elevation and/or T wave inversion) or modest elevation in cardiac troponin.

4. Absence of other precipitants such as pheochromocytoma and myocarditis.

of injury produced is commonly referred to as neurogenic stress cardiomyopathy [3]. One distinct morphological variant of stress cardiomyopathy is Takotsubo cardiomyopathy (TCM), which was first described by the Japanese physician in the early 1990s to be a reversible cardiomyopathy, the shape of which named after an octopus trap used by the native fishermen [4]. Although TCM is typically associated with acute emotional stress in postmenopausal women [5], triggers may also include physical stressors such as head trauma, intracranial bleeding, ischemic stroke, medical, and surgical procedures and catecholaminergic drugs [6]. Previous reports suggest the demographics and clinical characteristics of TCM are similar irrespective of their etiologies. However, there are notable differences in post-SAH TCM from other non-neurologic stressors in that the patients tended to be younger and more frequent in

females than what is typically reported and had high in-hospital mortality (25%) [7].

**Figure 1.** Subarachnoid hemorrhage-induced neurogenic injuries. Note that apical ballooning suggestive of Takotsubo cardiomyopathy (TCM) and left ventricular dysfunction detected by apical two-chamber view on initial echocardiogram. Acute pulmonary edema was also observed on chest X-ray. 123I-metaiodobenzylguanidine (MIBG) SPECT depicting apical defect in the two-chamber view and the analysis of two-dimensional polar maps (bull's eyes) show decreased myocardial perfusion in apex. In 4-h delayed images, washout is increased, suggesting the presynaptic sym-

TCM is originally characterized by transient hypokinesis which results from apical wall motion abnormalities with sparing of the base. Although most of the TCM patients (>65%) can present such typical patterns on echocardiography (**Figure 1**), there are several different variants of regional wall motion abnormalities (RWMA) that spares the cardiac apex, as well as one that

pathetic dysfunction caused by TCM.

274 Cardiomyopathies - Types and Treatments

LV: left ventricular; RWMA: regional wall motion abnormalities; ECG: electrocardiogram.

**Table 1.** The Mayo Clinic published diagnostic criteria for TCM after SAH.

Patients with akinesis or hypokinesis of left ventricular (LV) apical segments with preserved contractility of the basal segments are considered to have the apical variant of TCM (apical ballooning), while those with akinesis of the basal segments with preserved contractility of the apex and mid-ventricular segments are classified as having reverse TCM (non-apical ballooning).

A massive release of catecholamines into the systemic circulation after aneurysmal rupture has been considered responsible for SAH-induced TCM. In view of the literature reviews (**Table 1**), the incidence of TCM in SAH patients ranges from 0.8 to 17% [1, 2, 7, 10–12], which makes it a relatively common postoperative complication. However, the management of TCM becomes cumbersome in the setting of volumetric and hemodynamic therapy for DCI. In this chapter, we will review the current practice in intensive hemodynamic monitoring and goaldirected fluid management of post-SAH TCM using advanced hemodynamic devices based on our institutional protocol and the relevant literature and to evaluate their effects on clinical outcomes (**Table 2** ).


**Table 2.** Incidence and characteristics of TCM in patients after subarachnoid hemorrhage.
