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  Portal hypertension, resulting from increased intrahepatic resistance to portal flow and increased portal inflow, marks the transition from compensated to decompensated cirrhosis.

  
  
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  The sequelae of portal hypertension affect each organ system, requiring multi-disciplinary management.

  
  
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  Grades III and IV hepatic encephalopathy require immediate ICU transfer and elective intubation for airway protection.

  
  
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  Pulmonary derangements resulting from portal hypertension may be severe and include hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax.

  
  
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  Hepatorenal syndrome is a diagnosis of exclusion and is characterized by renal impairment in the setting of advanced liver disease, circulatory dysfunction, and increased activity of the renin-angiotensin system.

  
  
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  SBP is a known precipitant of HRS, which is a cause of increased mortality in cirrhotic patients; therefore empiric antibiotic treatment is warranted in patients in whom the suspicion for SBP is high.

  
  
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  Aggressive intravenous resuscitation, airway protection, and early endoscopic management of cirrhotic patients presenting with suspected variceal bleed is critical.

Hepatic decompensation in the critical care setting can present in two distinct contexts, which include acute liver failure and acute on chronic liver failure. In this chapter, we discuss the critical care approach to acute on chronic liver failure. In the intensive care setting, severe cases of acute on chronic liver failure require a systematic multiorgan system approach to management in order to address hepatic and extrahepatic organ dysfunction. An optimization of hepatic and extrahepatic derangements, including cardiopulmonary, neurologic and renal dysfunction, is essential for the successful management of the critically ill cirrhotic patient.

ACUTE ON CHRONIC LIVER FAILURE

The pathophysiology and sequelae of chronic liver disease warrant a unique approach to ICU management and treatment of disease. Namely, portal hypertension marks the transition from compensated to decompensated cirrhosis, resulting in life-threatening conditions including gastrointestinal variceal bleeding, hepatorenal syndrome, pulmonary complications, and hepatic encephalopathy.¹

Portal hypertension in cirrhosis is a result of the combined effect of intrahepatic resistance to portal flow and increased portal inflow. The resistance to portal flow consists of both fixed and functional components. The fixed component occurs from sinusoidal fibrosis and compression by regenerative nodules. The functional component is secondary to vasoconstriction, resulting from both decreased intrahepatic nitric oxide and enhanced intrahepatic vasoconstrictor activity. The paradoxical decreased intrahepatic nitric oxide and overproduction of extrahepatic nitric oxide produces splanchnic vasodilation and increased portal inflow. Combined, the effects of the intrahepatic resistance to flow and increased portal inflow result in a portal hypertensive state.² In addition, the pathologic splanchnic vasodilation results in a shunting of the cardiac output to the splanchnic circulation, and an associated decrease in effective systemic arterial blood volume perfusing other organ systems. These hemodynamic derangements in the splanchnic and systemic circulation form the basis for current management strategies in decompensated cirrhosis. An organ-system-based review of the management of specific disease manifestations in acute on chronic liver failure follows.

Hepatic encephalopathy is a serious complication of portal hypertension occurring both in the acute and acute on chronic liver failure setting. Its neuropsychiatric clinical presentation ranges widely from mild cognitive impairment to frank coma. The pathophysiology is accepted to be a result of a failed hepatic clearance of toxic products from the gastrointestinal tract in the setting of impaired liver function.³

While the debate continues over which toxins mediate the development of hepatic encephalopathy, elevated ammonia levels have long been implicated in its pathogenesis. Specifically, ammonia’s effect on brain astrocytes is suspected in the development of hepatic encephalopathy. The astrocytes in chronic liver disease take on an Alzheimer-type morphology known as Alzheimer type II astrocytosis. In chronic liver disease, excess serum ammonia levels alter neuronal proteins on the surface of astrocytes leading to abnormal glutamate trafficking. This alteration in glutamate is thought to be partially responsible for abnormal neurotransmission seen in hepatic encephalopathy.⁴ Other studies have suggested the involvement of serotonergic and GABA receptors, manganese, as well as catecholamine pathways in the pathogenesis of hepatic encephalopathy.¹

The diagnosis of hepatic encephalopathy requires a high level of suspicion in patients with chronic liver disease and careful attention to neuropsychiatric abnormalities. Patients may present with symptoms ranging from subtle changes in sleep-wake cycle, to lethargy, to worsened levels of consciousness including somnolence and coma. The West Haven criteria grade hepatic encephalopathy from grade I to grade IV based on varying levels of consciousness, intellectual function, and behavior (Table 107-1)⁵ and are used widely. Neurologic abnormalities on physical exam may be seen in more advanced presentations and include asterixis, hyperactive deep tendon reflexes, and hemiplegia.⁶

Initial management of hepatic encephalopathy involves determining the grade of encephalopathy with prompt ICU transfer and elective intubation for airway protection in grades III and IV. If sedation is needed in the ICU setting, given that patients with cirrhosis are sensitive to sedating agents, a shorter acting agent such as propofol is preferred.⁷ Imaging of the brain should also be considered to rule out other etiologies of altered mental status including CVA, intracranial bleed, or masses. The precipitating factor(s) of hepatic encephalopathy must be identified and treated. These include gastrointestinal bleeding, infection, alkalosis or acidosis, electrolyte disturbances, overdiuresis, dehydration, placement of recent TIPS, constipation, medication or dietary noncompliance, sedatives, tranquilizers, narcotics, or progressive hepatic dysfunction. Supportive care with IV fluid hydration, correction of electrolyte disturbances, and aspiration and fall precautions should be instituted.

Nonabsorbable disaccharides such as lactulose are the main pharmacological agent to aid in the clearance of ammonia in treatment of hepatic encephalopathy. These drugs work by decreasing ammonia production in the gastrointestinal tract and increasing fecal nitrogen excretion. Specifically, when oral lactulose reaches the cecum, it is metabolized by enteric bacteria, causing a drop in the pH. This leads to a shift in bacteria favoring uptake of ammonia, leaving less for mucosal absorption.¹ If the patient is unable to take oral lactulose, then an NG tube must be placed for luminal administration, or lactulose enemas should be administered. The dosage should be titrated to approximately three bowel movements per day. Antibiotics including flagyl, rifaximin, and vancomycin have also been studied and shown to be effective in the treatment of hepatic encephalopathy. These work primarily by eliminating urease-producing bacteria flora.⁸ While these agents can reduce blood ammonia levels and improve mentation, the degree of encephalopathy has not been shown to correlate with specific ammonia levels. Other treatment methods including zinc administration and protein restriction are also used but lack strong clinical supporting evidence.¹ The phenomenon of cerebral edema and intracranial hypertension noted in acute liver failure (ALF) due to hyperammonemia-induced astrocyte swelling⁴ does not occur in chronic liver disease, and is therefore not a concern in the management of hepatic encephalopathy in the cirrhotic patient.

The hemodynamic state associated with cirrhosis is distinctive with a low systemic vascular resistance, an increased cardiac output, and a low mean arterial pressure, thereby mimicking septic physiology. During decompensation or sepsis, hemodynamic abnormalities worsen with increased portal pressures and further exacerbation of systemic hypotension. Vasopressor support is often needed in these patients to maintain adequate end-organ perfusion. Despite this hyperdynamic state, patients with decompensated cirrhosis may also show signs of primary cardiac depression with reduced ejection fraction under conditions of stress and a decreased response to inotropic support, suggesting the possibility of a cirrhotic cardiomyopathy.⁹ Based on current evidence, the initial vasoactive agent of choice for distributive shock is norepinephrine. Its α- and β-adrenergic properties increase systemic vascular tone while preserving cardiac output.¹⁰ Low-dose vasopressin may be used as a second-line agent but can increase afterload. Dopamine should be used with caution as it may cause vasodilation in the splanchnic circulation, thereby worsening portal hypertension.¹⁰ Fluid resuscitation should be guided by dynamic fluid-responsiveness predictors so as to avoid unnecessarily raising central venous pressures and exacerbating portal hypertension. Increased ascites can lead to abdominal compartment syndrome, compress the vena cava, reduce preload, and cause hypovolemic hypotension.

MECHANICAL VENTILATION

In the event that a cirrhotic patient requires mechanical ventilatory support for respiratory failure, there are no current guidelines or evidence-based data on the optimal ventilator modes or settings. There are data suggesting the predilection of cirrhotic patients for developing ALI/ARDS.¹¹ In addition, the sequelae of chronic liver disease including ascites, pleural effusions, and chest wall edema all alter respiratory mechanics. Given these factors, it is important to consider that mechanical ventilation with traditional tidal volumes can increase pulmonary pressures resulting in ventilator induced lung injury.¹⁰ Mechanical damage of lung tissue may further activate cytokines resulting in biotrauma, that may trigger or further worsen a systemic inflammatory response or septic shock.¹² Extrapolation from the acute respiratory distress syndrome network study in 2000 would support the use of low tidal volumes at 6 mL/kg ideal body weight to minimize barotrauma as well as biotrauma in patients with cirrhosis,¹³ especially in the setting of ALI or ARDS.

HEPATOPULMONARY SYNDROME

While there are multiple etiologies for hypoxemia in the cirrhotic patient including atelectasis, pneumonia, and effusions, hepatopulmonary syndrome (HPS) is a distinct pathophysiologic process specifically related to portal hypertension that causes hypoxemia due to a diffusion-limited transfer of oxygen across the alveolar-capillary interface. HPS is characterized by the triad of an increased arterial to alveolar oxygen gradient, pulmonary vascular vasodilation, and underlying liver disease.¹⁴

The pathogenesis of hepatopulmonary syndrome lies in increased circulating vasodilators such as nitric oxide that lead to vasodilation in the capillary and precapillary beds of the lung,¹⁵ as well as arteriovenous malformations. Although these can coexist, when capillary vasodilatations predominate, the syndrome is referred to as type I hepatopulmonary syndrome. When arteriovenous malformations predominate, it is referred to as type II hepatopulmonary syndrome. The distinction between type I and type II hepatopulmonary syndromes is useful, since therapeutic interventions may differ. The hypoxemia that develops in HPS is a result of pulmonary vasodilation causing intrapulmonary shunts that result in excess lung perfusion. Rapid blood flow through a dilated pulmonary arterial circulation prohibits deoxygenated red blood cells (RBC) from being adequately oxygenated due to diffusion-limited oxygen transfer from the alveolus to the RBC that resides in a dilated capillary.¹⁶

Classic clinical manifestations of hepatopulmonary syndrome include platypnea, orthodeoxia, cyanosis, digital clubbing, shortness of breath, and hypoxemia. Diagnostic criteria include a [Math Processing Error] <70 mm Hg on room air with an increased A-a gradient without CO₂ retention.¹⁶ Further work-up includes an arterial blood gas on 100% O₂ and a double bubble echo or 99 mTC macro-aggregated albumin lung perfusion scan to establish the presence of intrapulmonary vascular vasodilatation. A delayed appearance of bubbles in the left heart 3 to 6 beats after visualization in the right heart and a shunt fraction greater than 6% indicates the presence of intrapulmonary vascular dilation and confirms the diagnosis of hepatopulmonary syndrome.¹

While the pharmacologic treatment for hepatopulmonary syndrome remains disappointing, supplemental oxygen does temporarily improve hypoxemia in type I hepatopulmonary syndrome. Given that type II hepatopulmonary syndrome involves shunting of blood supplemental oxygenation will not improve hypoxemia in this subset; embolization therapy may improve oxygenation in these patients.¹⁶ Ultimately, a more promising option for patients with hepatopulmonary syndrome is orthotopic liver transplantation.

PORTOPULMONARY HYPERTENSION

The pathophysiology of portopulmonary hypertension (PPH) is not completely understood. Some theorize that increased intrapulmonary vascular flow causes shear stress that may trigger remodeling of the vascular endothelium. Other theories support the notion that portosystemic shunting and decreased phagocytic capacity of the cirrhotic liver allows circulating bacteria and toxins to enter the pulmonary circulation causing cytokine release and triggering vascular inflammatory changes.¹⁶ Histopathology reveals intimal fibrosis, smooth muscle hypertrophy, and characteristic plexiform lesions seen in small arteries and arterioles.¹⁷ While dyspnea on exertion is the most common presenting symptom, patients may also present with chest pain, fatigue, hemoptysis, or orthopnea. In late stages of the disease, they may demonstrate lower extremity edema, elevated jugular venous pressure, and signs of volume overload, all of which are difficult to interpret in the setting of chronic liver disease. Physical examination may reveal a loud P2 with murmurs of tricuspid and pulmonic regurgitation and a right ventricular heave. Cirrhotic patients who have an estimated pulmonary artery systolic pressure >50 mm Hg on echocardiogram should undergo right heart catheterization to evaluate for PPH.¹

Diagnostic criteria for PPH include a mean pulmonary artery pressure >25 mm Hg, normal pulmonary wedge pressure, and an elevated pulmonary vascular resistance >125 dynes.sec/cm⁵.¹ PPH can further be divided into mild (mPAP 25-34 mm Hg), moderate (mPAP 35-44 mm Hg), and severe (mPAP >45 mm Hg).¹⁶ The importance of subcategorization rests in the increased mortality in patients who undergo liver transplantation with moderate to severe portopulmonary hypertension.¹⁸