Palliative Care in Cirrhosis

Poor performance status (palliative performance scale and Karnofsky scale)

Advanced age

Malnutrition

Comorbid illness

Increasing organ dysfunction

Hospitalization for acute decompensation

Principles of Palliative Care

Palliative care is rooted in the interdisciplinary hospice model of care, which focuses on holistic and team-based care [14]. The interdisciplinary palliative care team creates a care plan congruent with the wishes and values of patients and families treating symptoms appropriately, addressing bio-psychological, social, cultural, and spiritual issues to maximize the QOL of patients and their family members along the entire trajectory of the illness including bereavement. The trained interdisciplinary team has the required skills, access, and expertise to provide patient-centered and family-focused care to reach their goals which often includes transition to hospice care. Key tenets of palliative care as put forth by the World Health Organization (WHO) are summarized in Table 35.2 [7].

Table 35.2

Key tenets of palliative care (modified from the World Health Organization) [7]

Relief from pain and other distressing symptoms

Affirmation of life, regarding dying as a normal process

Neither hasten or postpone death

Integration of the psychological and spiritual aspects of patient care

A support system to help patients live as actively as possible until death

A support system to help the family cope during the patient’s illness

A team approach to address the needs of patients and their families, including bereavement counseling

Enhance the quality of life and positively influence the course of illness

Offer palliative care early in the course of illness, along with other therapies and investigations that are intended to manage distressing complications and prolong life

Hospice is a system, a philosophy, and place of care designed to provide a comprehensive multidisciplinary care, mostly at home, for dying patients with an identifiable short prognosis [6]. In the USA, hospice services are delivered in a model established by statue in federal law. The Medicare Hospice Benefit is largely restricted to patients with conditions that have a prognosis of 6 months or less, if the disease follows its natural course. These patients agree to forgo therapies with curative intent, focusing on maximizing comfort and QOL; however, treatment including radiation therapy, chemotherapy, and surgery may be provided, when the intent is truly palliative. The distinction between palliative care and hospice is unique to the USA, while these two terms are often used interchangeably in other countries.

The National Consensus Project for Quality Palliative Care advocates the incorporation of the palliative care philosophy and delivery throughout the illness trajectory across all settings in patients with progressive chronic conditions [14]. While the concurrent care model is now accepted as the ideal palliative care model, there are insufficient palliative care specialists to be the exclusive providers of such services [11]. Basic palliative care expectations and behaviors have been identified that could be provided by all health-care providers, including hepatologists and gastroenterologists [15]. Table 35.3 outlines the skill sets for “primary” and “specialty” palliative care proposed by Quill and Abernethy, which could form the basis for the improvement in the scope of palliative care provided to patients with ESLD. Further research will be required to define the requirements or conditions that are required to engage palliative care specialist involvement [11].

Table 35.3

Primary palliative care	Basic management of pain and other symptoms
	Basic management of anxiety and depression
	Basic discussion about
	Prognosis
	Goals of treatment
	Suffering
	Code status
Specialty palliative care	Management of refractory pain and other symptoms
	Management of more complex depression, anxiety, grief, existential distress
	Assistance with conflict resolution regarding goals or methods of treatment
	Within families
	Between staff and families
	Among treatment teams
	Assistance in addressing cases of near futility

Barriers to the provision of palliative care may be physicians themselves [16]. Practice patterns may delay referral [17]. Some have cited the lack of established metrics to guide physician referral to hospice for patients with ESLD, although the concurrent care model of palliative care deemphasizes the requirement to define a precise prognosis [13]. Therefore, concern about premature palliative care referral is likely misplaced [18]. During the initial encounters when treating patients with ESLD, especially those being considered for LT, a significant amount of information is imparted which can be overwhelming for patients and their families, generating significant stress and uncertainty [19]. Given the high prevalence of hepatic encephalopathy (HE), which compromises a patient’s cognitive status, early identification of a health-care proxy or surrogate is very important in order to address the needs and perceptions about the care plan [20]. A collaborative approach involving primary providers and palliative care specialists can effectively manage concerns across the spectrum of the decompensated state [19]. As the disease progresses, an in-patient palliative care consultation may facilitate integration and transition of care [13]. Advance care planning and clarification of code status, as well as discussions about the futility of additional interventions may be less difficult if effective communication has been established among patient, family and providers.

The literature regarding the value of palliative care in ESLD is scant. Early referral may reduce the burden on health-care system and providers and improve patient and family satisfaction. In the context of ESLD, this could result in care rendered in a more appropriate outpatient setting [10]. Whether early palliative care in ESLD will result in an improvement in QOL and longer median survival, as was noted in patients with non-small-cell lung cancer, remains to be determined [21].

Management of Specific Complications of End-Stage Liver Disease

The following is a review of treatments for specific and common complications associated with patients who are terminally ill with cirrhosis. All treatments must be congruent with the patient’s goals as determined by a thorough discussion of his or her understanding of the diagnosis and prognosis. Furthermore, the priorities of the patient drive the plan, i.e., if he or she wishes to extend life at all costs, strict adherence to practice guidelines may be appropriate. Alternatively, if QOL is the principle concern, then the treatment should reflect the patients’ and families’ goals of care.

Ascites

Ascites , the most common complication of cirrhosis, develops in up to 50 % of patients within 10 years of the diagnosis of cirrhosis [22]. Patients with newly diagnosed ascites have a 1-and 5-year survival of 85 and 56 %, respectively [23]. Ascites can cause dyspnea, orthopnea, limited mobility, abdominal discomfort, anorexia, nausea, and vomiting.

Initial management includes a sodium-restricted diet while avoiding drugs that cause sodium retention, such as nonsteroidal anti-inflammatory agents [22]. For oral diuretic therapy, an aldosterone antagonist (spironolactone or amiloride) may be used alone [24]. However, patients with recurrent ascites usually require a combination of a loop diuretic (such as furosemide) with an aldosterone antagonist [25]. In the terminal phase of liver disease, the use of diuretics to manage ascites is often limited by hypotension, hyponatremia, and renal insufficiency. Midodrine can be added to treat hypotension, which may allow the continuation of diuretics [25]. Vasopressin antagonists such as tolvaptan have been prescribed to treat hypervolemic hyponatremia but are expensive and have shown no clinical benefit in the long-term management of ascites while mortality could be increased in patients with cirrhosis [26]. As a consequence, they have not gained widespread use in any setting. Beta-blockers should be prescribed very cautiously in patients with refractory ascites, given their adverse impact on systemic hemodynamics while causing fatigue and lethargy [27, 28]. Large-volume paracentesis can be performed as required to provide symptomatic relief. Intravenous albumin replacement with 6–8 g/l of fluid removed is recommended when more than 5 liters (l) are removed, to decrease the risk of renal impairment and adverse circulatory changes [22, 25]. The continued administration of albumin to a patient in a hospice setting is debatable since albumin has not been demonstrated to improve long-term patient survival [24]. The placement of a transjugular intrahepatic portosystemic stent shunt (TIPS) is a very effective intervention to control ascites [29]. The most common complication of TIPS is new onset or worsening HE, which is usually controlled with medical treatment and rarely requires occlusion of the shunt to control symptoms. Contraindications to TIPS placement include pulmonary hypertension, heart failure, and advanced decompensated cirrhosis. Therefore, proceeding to TIPS placement in an individual with a prognosis of less than 3 months should only be done after careful consideration given its risks. The insertion of a peritoneovenous shunt, such as the Denver or Le Veen shunt, has declined significantly over the last two decades due to their high incidence of complications including shunt occlusion and sepsis [30]. Such shunts are rarely acceptable options now.

Implanted peritoneal drainage catheters have been used for the treatment of malignant and nonmalignant refractory ascites; they allow convenient drainage of ascitic fluid for symptom relief on an as needed basis. The drainage can be done at home; if small volumes (less than 5 l) are removed, albumin replacement is not required which can minimize the need to travel to a hospital while reducing the cost associated with repeated large-volume paracentesis [31]. Complications include catheter malfunction, leakage of ascites at the incisional site, cellulitis, and peritonitis. Lungren et al. recently reported that the complication event rate for tunneled peritoneal drainage catheters in patients with malignant and nonmalignant ascites was 0.43 events per year [32]. Other studies have shown that peritoneal catheters were safe, practical, and offered symptomatic improvement for most patients with refractory ascites [33, 34]. Prophylactic oral antibiotics may be an appropriate adjunctive therapy to minimize the risk of sepsis associated with an indwelling catheter.

Recently, a multicenter nonrandomized trial evaluated the safety and efficacy of an implanted automated pump from the peritoneal cavity into the bladder for the removal of ascites in patients with cirrhosis. The ascitic fluid was then eliminated through normal urination. The pump was able to remove 90 % of the ascites and reduce the number of large-volume paracentesis. The rate of complications was moderate and included infection, HE, and renal dysfunction [35]. Further evaluation is required before recommending this procedure as a means to control ascites in patients with advanced liver disease.

Hepatic Hydrothorax

Pleural effusions occur in 5–12 % of patients with ESLD; they are most often right-sided (65–85 % of cases) and are commonly seen in conjunction with ascites, although may be present alone [36]. The most likely mechanism for the development of a pleural effusion is the movement of ascitic fluid transdiaphragmatically through minute diaphragmatic defects because of a pressure gradient between the peritoneal space and pleural cavity [37]. Due to the limited compliance of the pleural space, even small to moderate amounts of pleural fluid can cause significant respiratory symptoms including dyspnea, chest pain, and hypoxia.

Similar to the management of ascites, the initial treatment of hepatic hydrothorax is dietary sodium restriction and diuretic therapy. Thoracentesis may be necessary for the rapid relief of dyspnea. This procedure is relatively safe and can be repeated as needed, but there is a small risk of complications including pneumothorax and hemothorax [38]. Evacuation of more than 2 l of pleural fluid is usually not recommended, because of the risk of pulmonary edema and hypotension, although patients with cirrhosis may be able to tolerate the removal of larger volumes of fluid [38]. Albumin replacement is not necessary after a thoracentesis due to the relatively small volume of fluid removed [38].

When frequent thoracenteses are required, alternative treatments must be considered. TIPS placement effectively manages refractory hydrothorax [39, 40]. However, as in the case of patients with refractory ascites , TIPS is often not a viable option in patients with advanced liver dysfunction. Pleurodesis is not an effective therapy for hepatic hydrothorax, probably due to the rapid re-accumulation of pleural fluid, while being associated with significant morbidity and mortality [41]. In addition, incomplete pleurodesis can create loculated pleural effusions, complicating potential subsequent thoracenteses. Chest tube placement has not been recommended for the management of recurrent pleural effusions because of a high rate of complications including bacterial empyema, pneumothorax, hemothorax, electrolyte imbalance, and renal insufficiency [42]. However, in the palliative setting, tunneled pleural catheters have a role in managing respiratory distress associated with malignant and nonmalignant pleural effusions. Several studies have reported complete or partial symptom improvement with low-complication rates [43, 44]. While only a small number of patients with ESLD were included in these studies, given the limited options, we believe that these catheters are an appropriate treatment option for patients with refractory hepatic hydrothorax [36, 45].

Hepatic Encephalopathy

Hepatic encephalopathy is characterized by reversible neuropsychiatric disorders ranging from subtle disturbances and cognitive deficiency to obvious confusion, ataxia, and somnolence progressing to stupor and coma [46]. This entity can cause significantly disability and a negative effect on patients’ QOL. Avoiding precipitating or aggravating factors, such as narcotics and sedatives, can be particularly challenging in the terminally ill patient. A nonabsorbable disaccharide, such as lactulose, is the first line of treatment and can be administered orally or per rectum. The goal of lactulose therapy is to achieve three to five soft bowel movements per day. Excessive administration of lactulose may result in diarrhea, dehydration, and electrolyte imbalance that can precipitate or worsen HE. In patients who cannot tolerate or are refractory to the treatment with lactulose, nonabsorbable antibiotic therapy should be considered. In the past, neomycin was used for the treatment of HE but nephrotoxicity and ototoxicity limited its use [47]. In 2010, rifaximin received approval in the USA for the secondary prevention of HE. This medication can effectively reverse HE and is generally well tolerated, but is expensive [48]. Advance care planning must occur prior to the onset of symptoms for obvious reasons.

Hepatocellular Carcinoma

The 5-year cumulative risk for the development of hepatocellular carcinoma (HCC) in patients with cirrhosis ranges between 5 and 30 %; the 5-year survival rate for HCC is dismal at less than 12 % [49]. Surgical resection is the first-line treatment option for patients with a solitary tumor without clinically significant portal hypertension and who have preserved liver function [50, 51]. LT is the preferred and most effective treatment for selected individuals. For patients who are not eligible for resection or LT, nonoperative treatment modalities are available that provide effective short-term palliation, including ablation with radiofrequency (RFA) and percutaneous ethanol injection (PEI) [52–54]. Arterial chemoembolization has been shown to improve survival among patients with unresectable HCC [55]. The most common adverse events associated with chemoembolization are fever, abdominal pain, nausea, and anorexia. Contraindications include main portal vein thrombosis, decompensated liver disease, macroscopic tumor invasion, and the presence of extra-hepatic metastasis. Systemic chemotherapy, tamoxifen, immunotherapy, anti-androgen, and herbal drugs are not recommended for the clinical management of HCC due to their side effects, dose-limiting hepatotoxicity, and poor efficacy [51]. Sorafenib, an oral multi-tyrosine kinase inhibitor, was shown to have a modest survival benefit in patients with advanced HCC; it is approved for use in the USA for patients with well-compensated liver function who have advanced tumors or tumors that progress after failing locoregional therapies [51, 56]. The most frequent adverse events include diarrhea, hand–foot–skin reaction, fatigue, and weight loss. Its use in terminally ill patients is tempered by its cost and limited benefit. Radiotherapy can be considered to alleviate pain in patients with bone metastasis [51].

Pruritus

Pruritus is a common symptom in patients with liver disease. Generalized pruritus can cause significant distress, leading to sleep deprivation and depression. The initial management includes adequate treatment of the underlying cause of cholestasis, including the drainage of biliary obstruction when possible. An oral antihistamine may be particularly helpful, especially if administered at bedtime exploiting its sedative effect [57]. Current evidence-based guidelines recommend a stepwise approach to the treatment using cholestyramine, rifampin, naltrexone, and sertraline [58].

Cholestyramine, an oral nonabsorbable bile acid exchange resin, prevents the uptake of bile acids in the terminal ileum. Other oral medications must be taken at least 4 hours (h) apart because cholestyramine can interfere with their absorption [58]. Rifampin is a second-line therapy for pruritus; it may improve symptoms by decreasing hepatocyte uptake of bile acids. Significant hepatotoxicity has been reported within 3 months of initiating rifampin in up to 12 % of patients who have cholestatic liver disease [59]. Naltrexone, an oral opioid antagonist, and a third-line treatment for pruritus should only be considered when cholestyramine or other resins and rifampin lack efficacy or when intolerance and adverse effects manifest [58]. Possible withdrawal-like symptoms have been reported in some patients who take naltrexone; logically, it is not recommended in those taking opioid analgesics for pain [57]. While rifampin has not been recommended for use in patients with advanced liver dysfunction, we believe that it has a role in treating pruritus in the palliative setting [58]. Recent studies support the use of sertraline, a serotonin reuptake inhibitor, for cholestatic pruritus [60]. Experimental treatments such as ultraviolet phototherapy, extracorporeal albumin dialysis and nasobiliary drainage can be considered when standard treatments have failed to alleviate severe pruritus . However, debilitated patients may not have access to or be able to undergo such interventions.

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