LITHUANIAN UNIVERSITY OF HEALTH SCIENCES FACULTY OF MEDICINE
DEPARTMENT OF INTENSIVE CARE
INTENSIVE CARE UNIT-ACUTE LIVER FAILURE MANAGEMENT AND
LIVER TRANSPLANTATION: A LITERATURE REVIEW
A thesis submitted in partial fulfilment for the degree of Master of Medicine
Author: Berat Zolufi, MF
Supervisor: Vidas Pilvinis, MD, PhD
KAUNAS 2020
TABLE OF CONTENTS
SUMMARY………... 3
ACKNOWLEDGMENT………... 4
CONFLICT OF INTEREST………. 4
SOURCES OF FUNDING………... 4
ETHICS COMMITTEE CLEARANCE……….. 4
ABBREVIATION LIST………... 5,6 INTRODUCTION……….... 7 AIMS……… 8 OBJECTIVES……….. 8 LITERATURE REVIEW………. 9 RESEARCH METHODOLOGY………... 21 RESULTS………... 23 DISCUSSION……….... 32 CONCLUSION……….. 36 REFERENCES………... 37
SUMMARY
The aim is to review the line of management of Acute Liver Failure from organ specific management to liver transplantation.
The objectives of this thesis are to be met by analysing the available literature concerning ALF. The objectives are as follows:
➔ To analyze the methods of organ specific management for patients suffering from ALF in the ICU
➔ To analyze the use of liver transplantation in the management of ALF
Results: Regarding fluid management of patients with ALF there is no evidence suggesting superiority of one type of fluid over the other. Evidence shows better hemodynamic profile for norepinephrine over dopamine as vasopressor. In terms of respiratory management there is seen a reduction in
mortality using low versus non volume limited tidal volume strategies. Concerning nutritional support, lowering caloric intake may lead to progression of HE. Having major bleeding is very uncommon for the patients. Tight glycemic control didn’t show reduction in risk for short-term mortality. To ensure patient safety accurate monitoring of electrolytes is obligatory. As far as when it comes to brain management, ICP monitoring supports the golden standard for measurement and monitoring of ICP thus affecting the risk of morbidity and mortality.
Transplant remains the single most effective treatment method for ALF although it is only performed in small number of patients.
Conclusion: The evolution of acute liver failure (ALF) is very unpredictable therefore transferring the patient to ICU in liver transplant centre or tertiary hospital for further organ specific management is essential for the outcome. Organ supportive management is the best strategy according to the evidence in the literature. Liver transplant in patients with ALF remains the most effective treatment.
ACKNOWLEDGMENT
I would like to thank the department of Intensive Care Unit and specifically Prof. Dr. Vidas Pilvinis for all his help and contributions that made it possible for this research to be done.
CONFLICT OF INTEREST
There wasn’t any conflict of interest.
SOURCES OF FUNDING
None.
ETHICS COMMITTEE CLEARANCE
ABBREVIATION LIST
ICU
Intensive care unit
ALF
Acute liver failure
PT
Prothrombin time
HE
Hepatic encephalopathy
ALI
Acute liver injury
IH
Intracranial hypertension
INR
International normalized ratio
PHES
Psychometric Hepatic
Encephalopathy Score
DILI
Drug-induced liver injury
LTx
Liver transplant
HH
Hypoxic hepatitis
AST
Aspartate transaminase
ALT
Alanine aminotransferase
HLH
Hemophagocytic
lymphohistiocytosis
POD
Paracetamol overdose
AKI
Acute kidney injury
SOFA
Sequential Organ failure
assessment
MELD
Model for end-stage liver
disease
NAC
N-acetylcysteine
RRT
Renal replacement therapy
HBV
Hepatitis B virus
HAV
Hepatitis A virus
HEV
Hepatitis E virus
BCS
Budd-chiari syndrome
WD
Wilsons disease
PAALD
Pregnancy-associated liver
disease
AFLP
Acute fatty liver of pregnancy
POLF
Postoperative liver failure
ECG
Echocardiogram
CNS
Central nervous system
MAP
Mean arterial pressure
ARDS
Acute respiratory distress
syndrome
PEEP
Positive end-expiratory pressure
PN
Parenteral nutrition
PC
Protein C
HF
Hemofiltration
CVVH
Continuous venovenous
hemodialysis
ICH
Intracranial hypertension
GCS
Glasgow coma scale
KCC
King’s college criteria
GI
Gastrointestinal
INTRODUCTION
Acute liver failure being a rare disease with only 10 cases per million persons per year occuring in the developed world is still one of the most difficult diseases to manage in the intensive care unit. First definition of acute liver failure was made in 1970, almost 50 years ago. The term used was fulminant liver failure, a disease that had the potential to recover. There are three main types of acute liver failure, acute, subacute and hyperacute. Presence of hepatic encephalopathy plays a key role in the prognosis of ALF.
Since the disease was defined and until today the mortality remains high. But with advancement in the intensive care management and emergency transplantation the overalt mortality has improved. A high indication of suspicion by the physician, early referral to a specialist liver transplant center and adequate supportive management remains the cornerstone for the management of ALF. With better understanding of the pathophysiology liver injury together with better management of
multiorgan-failure will help improve the outcome of this devastating disease. The etiology of ALF varies where Hepatitis A, B and E being the major cause in the developing world whereas
drug-induced liver injury being in the developed world. Over the past 50 years reveals ALF occurring secondary to Hepatitis A and B have decreased while that of paracetamol(acetaminophen)-induced have increased mainly in the USA and Western Europe. Pathophysiology depends on the etiology of ALF. Certain etiologies of ALF warrant specific treatments, but with all etiologies of ALF, organ supportive care, as well as prevention and management of possible complications are essential. Liver transplantation is reserved as an end stage treatment when organ specific management fails to insure patient’s survivability.
AIMS
To review the line of management of Acute Liver Failure from organ specific management to liver transplantation.
OBJECTIVES
➔ To analyze the methods of organ specific management for patients suffering from ALF in the ICU
LITERATURE REVIEW
Acute liver failure (ALF) is an uncommon disease with reported less than 10 cases per million persons per year occurring in the developed world. The disease is identified by dysfunction of the liver which deteriorates quickly, in correlation with a drop in prothrombin time (PT) ratio levels. Seen in patients presenting without any preexisting liver disease, with ALF occurring in shorter than 26 weeks [1]
.
Definition of severe ALF describes a syndrome marked by a PT ratio less than 50%
[1]. Serious ALF describes a syndrome marked by a PT ratio less than 50% combined with encephalopathy [1]. Other definitions exists established on defining the time passed between the appearance of jaundice and the development of encephalopathy [1]. Prognosis of ALF over the past years has seen gradualimprovement. 90% of the patients with transplantation have shown a survival rate of 2-year, this rate has also been observed in patients with severe ALF due to paracetamol without transplantation [1]. After undergoing extensive liver resection, patients having or not having any underlying chronic liver disease, may progress clinical syndrome of jaundice, coagulopathy and hepatic encephalopathy (HE). This syndrome is not under the definition of ALF even though it appears in some ALF databases [2]. The term Acute liver injury (ALI) describes patients' condition where they develop coagulopathy, but no alteration in level of consciousness [2]. ALF as a clinical course initiates with severe ALI [2]. Elevation of transaminases by a fold of two- to three times is noticed together with decreased liver function and development of jaundice and coagulopathy, in patients without chronic liver disease [2]. The approach of treatment and measurements of support is used routinely targeting the specific
etiology, despite this in patients who don’t undergo spontaneous recovery the only chance for survival remains liver transplantation [3]. Being a devastating syndrome, ALF can lead to multiple organ failure and even death. Healthy normal liver can within days to weeks deteriorate in function, and despite advancement in critical care in intensive care unit (ICU) including organ support, the death rate of ALF remains high [4]. After developing high grade of encephalopathy, survival is less than 20% [4].
Definition & classification
1970 Trey and Davidson made the first definition of Acute Liver Failure (ALF). Fulminant liver failure was the term used to explain a condition which had the potential to reverse. A liver injury which was severe in its nature with complication of encephalopathy appearing within 8 weeks. Pre-existing liver disease had to be absent [2]. In 1993 O’Grady et al. redefined the condition hyperacute liver failure where they saw in their patientens at King’s College Hospital between the years 1972 to 1985, encephalopathy occurring within 7 days after the onset of jaundice [5]. When a patient develops hepatic encephalopathy (HE) between 8 and 28 days after appearance of jaundice it is considered acute liver failure. If HE develops within 5-12 weeks after appearance of jaundice its then considered subacute liver failure. In cases where HE develops after week 28 the condition is
categorised as chronic liver disease [2]. A patient having previously normal liver, experiencing rapid function deterioration combined with developing HE, coagulopathy and jaundice with potential of developing multi-organ failure is defined Acute liver failure (ALF) [6]. Severe coagulopathy, clear raise of serum transaminases, and in beginning with moderate increase in bilirubin defines hyperacute state. In the subacute state there will be mild increase in serum transaminases, patients will have deep jaundice and the coagulopathy will be mild to moderate [2]. Subacute ALF with development of HE gives the patient a low chance of spontaneous recovery. On the other hand having hyperacute ALF gives a much higher chance of spontaneous recovery [7]. Coagulation disruptions needed for defining ALF are determined by increase of International Normalised Ratio (INR), generally > 1.5, or increase of prothrombin time (PT) [8]. No standard on the use of INR has been set, with the background of its design for warfarin therapy monitoring [9]. Use of PT prolongation with attention to its specific laboratory, is now recommended by clinicians considering it as a more accurate marker [2]. Other features of ALF such as jaundice and HE are necessitated to present clinically [2].
In a study by Duarte-Rojo A et al. where 743 volunteers participated, efforts were made to develop measures more sensitive in the establishing of early grades of HE. The method of psychometric hepatic
encephalopathy score (PHES) which is a neuropsychological test used for identifying patients with minimal hepatic encephalopathy, is not available in district hospitals where most patients seek medical attention first [10]. The ability of characterising minimal HE may be useful in patients with subacute presentation so that proper management plan can be assembled. In patients with hyperacute and acute ALF course, the ability of characterising minimal HE is less relevant [2]. When a patient with subacute course develops HE, the possibility of obtaining liver transplant is exceedingly reduced, if any [2]. Preceding severe fibrotic or cirrhotic chronic liver disease are conditions important to be absent when determining ALF [11]. There are some exceptions regarding conditions with pre-existing liver disease, thus showing normal blood profile, that will be considered as having ALF in case they show signs of hepatic encephalopathy. The exceptions mentioned are chronic autoimmune hepatitis, Wilsons disease and Budd-Chiari syndrome [2].
Incidence and mortality
According to the European association for the study of liver (EASL) clinical practical guidelines the incidence of ALF within the European Union remains unclear. Regarding incidence and prevalence no collection of data is performed [2].
In a study by Tharapirom et al.including 20,589 patients between the years 2009 and 2013 the incidence rate of ALF were 62,9 per million population per year. Standing out in the study was that 69,4% of the cases were indeterminate.
Out of these patients, 5502 (26,7%) died within 30 days after admission. Factors having the most effect on prediction of 30 days mortality were ARF (P < 0.001), malignant infiltration of liver (P < 0.001) and septicemia (P < 0.001). According to the study a conclusion was made that patients with ALF had a poor outcome with a 30-day mortality of 26,7% also having high economic burden [12].
In a meta-analysis by McPhail et al. identifying 23 studies and comprising 2153 patients determining the accuracy of King’s college criteria (KCC) compared with model for end-stage liver disease (MELD) it was concluded that KCC is more accurate in estimating hospital mortality among patients with acetaminophen-associated ALF (AALF). In patients with nonassociated acetaminophen ALF (NAALF) the use of MELD was more accurate in estimating hospital mortality [13].
Etiology
In case of rapid-onset deterioration of liver function leading to pathological systemic involvement presenting symptoms such as altered mental status, vasodilatation, renal and pulmonary failure, repeated infection and poor outcome without transplantation we can establish appearance of ALF. Trying to identify the right cause among the many differences is the primary step in comprehension of prognosis and finding the right method of treatment [14]. Considering emergency liver transplant (LTx) there is particular necessity in finding etiology of ALF. Different causes of ALF may present with typical clinical features making it more difficult to find the correct reason [15]. Regarding etiology there will be two main groups under which majority of the causes will fall into. Etiologies with no indication for emergency LTx and Etiologies which form a possible indication for emergency LTx [2]. Establishing the correct origin of ALF can be troublesome and sometimes impossible [14].
Etiology with no indication for emergency LTx
Malignant infiltration of the liver: In case of patient with breast cancer or lymphoma, metastasis to the liver is a complication which might occur. When the metastasis is large it can in turn cause ALI or ALF. In this review by Nicole E Rich et al. they found 27 (1,4%) cases out of 1910 patients with ALF related to malignancy. Of these 27 cases, 24 (89%) of them died within 3 weeks with ALF [16]. Jaundice, hepatic encephalopathy and hepatomegaly were common symptoms seen in patients [16].
Acute ischemic injury: In elderly patients its particular common with this condition. In case of
cardiovascular disorders and severe congestive heart disease there will be raised risk [17]. Right heart dysfunction is associated with an episode of liver hypoxia of hypotension (called hypoxic hepatitis). Respiratory failure and toxic-septic shock are other conditions that together with cardiac dysfunction accounts for 90% of the cases. Hypoxic hepatitis (HH) can also occur due to other uncommon reasons. Prognosis of the condition is poor leading to death of 50% of the patients [17].
In a study by Fuhrmann V et al. where 1066 admissions to the ICU were studied. Of the admitted patients, 118 (11%) of them were found to have HH during their stay in the ICU. HH present in those patients is a high risk factor for mortality [18]. A secondary form of ALF is found to be hypoxic hepatitis. It is therefore needed to find the primary organ failure presentation so that management can be initiated to ease liver recovery [2]. When liver blood test is done, there will be a similar pattern observed as in patients with N-nitrosodimethylamine (NDMA) and paracetamol overdose. Aspartate transaminase (AST) level of >10.000 IU/L and alanine aminotransferase (ALT) twice increased value. At presentation levels of bilirubin will be normal [2].
Other systemic diseases: Hemophagocytic lymphohistiocytosis (HLH) may be caused by viral or fungal infections. HLH is a condition where cytokines are overproduced as a result of defective cytotoxic T lymphocytes and NK cells.
The condition results in cytopenia and multiorgan infiltration and dysfunction which is life-threatening to the patient [19]. Infectious diseases such as malaria, dengue and rickettsiosis can mimic ALF [20].
Etiologies which form a possible indication for emergency LTx
Drug-induced hepatotoxicity: Paracetamol overdose (POD). Paracetamol (acetaminophen) liver toxicity is main reason for ALF in the UK. In a study by Darren G N Craig et al. between the years 1992 and 2008, at the Scottish liver transplant unit were admitted 663 patients with
paracetamol-induced acute severe liver injury. Of these 663 patients it stood out that 500 (75,4%) patients were admitted for POD. Only 110 (16,6%) of the patients had taken an unintended overdose of paracetamol [21]. Unintentional overdose was more common among the elderly patients whose
alcohol abuse was more prominent. Compared to the patients with intended overdose, unintended patients had lower paracetamol and ALT concentrations. According to the study, patients with
unintended overdose had greater organ dysfunction at admission and increased mortality compared to the patients with intended overdose [21].
Patients with accidental hepatotoxicity had taken a big amount of paracetamol to decrease their pain over several days, correlation can be seen with alcohol dependence [2]. A study performed by Larsson et al. in the United States over a period of 6 years, from 1998 to 2003, showed that of the 662 patients admitted 302 (46%) had paracetamol induced hepatotoxicity. During the study they could see a raise from 28% in 1998 to 51% in 2003 of the ALF attributed to paracetamol (acetaminophen) [22]. Screening of every patient admitted with ALF is needed for toxicology and paracetamol levels. With liver failure there will be decreased metabolism of paracetamol, despite this when patient is presented to the hospital, levels of paracetamol will be too low to detect, therefore it's crucial to base etiology on clinical presentation, proper history from relatives of the patient or the person who accompanied the patient and typical laboratory results [2]. Hepatotoxicity induced by paracetamol overdose is seen in the blood lab test with ALT and AST rise (>10,000 IU/L). The level of bilirubin will remain normal. Other symptoms which can present at an early stage are metabolic acidosis, elevated serum lactate, hypoglycemia and acute kidney injury (AKI). [2] In patients with unintended paracetamol overdose the use of INR and PT for prognosis is not informative due to low elevation [23].
Comparing the sequential organ failure assessment (SOFA) with the model for end-stage liver disease (MELD), it showed superiority of SOFA over MELD in the prediction of spontaneous survival in patients with paracetamol-induced acute liver injury [24]. The proper treatment for these patients is proper fluid resuscitation, N-acetylcysteine (NAC). Renal replacement therapy (RRT) may be needed in treating the acidosis. In case the patient doesn’t meet the criteria for emergency LTx the prognosis will be better. For the patients who do meet the criteria might still survive with a percentage rate of 20-40% when receiving modern intensive care management. Patients presenting with POD have shown better outcomes when NAC is used [2].
Non-paracetamol drug induced liver injury: A small percentage, 10%, of patients presenting with DILI caused by other drugs than paracetamol would progress to ALF. Of these up to 80% either require emergency LTx or die [25]. There are some classes of drugs who are more commonly related to ALF. These include antituberculosis drugs (isoniazid), antibiotics ( nitrofurantoin and ketoconazole),
anti-epileptics (phenytoin and valproate), NSAIDS and a large group of other medications [2]. A group of patients will not admit that they have ingested drugs, especially illegal drugs but also herbal
medicine products or nutritional supplements. The admission might come in a later stage when the patient's condition deteriorates or after persistent questioning of the relatives from the physician [2]. There are rare cases when drugs such as cocaine can be the cause of liver ischemia by inducing
hypoperfusion. This injury will be seen by increase of both ALT/AST and lactic dehydrogenase, quick prolongation of PT and raise in serum creatinine. After achieving hemodynamic stabilization of the patient in the intensive care unit there will be a reverse of the abnormal blood values [26].
Viral hepatitis: Acute liver failure (ALF) is caused by hepatic viruses such as hepatitis B virus (HBV), hepatitis A virus (HAV) and hepatitis E virus (HEV) [2].
Hepatitis B virus (HBV): The main cause of ALF in Eastern countries is HBV. ALF due to HBV may take place after acute HBV infection or as a result of acute exacerbation of chronic HBV infection. Acute exacerbation of chronic HBV infection might occur as a result of immunosuppression as a result of chemotherapy or use of immunosuppressive agents [27]. In a study by Xiong et al. they found that only a small percentage of persons with Hepatitis B virus infection would develop ALF. Out of the 293 patients participating in the study, only 13 (4,43%) ended up with ALF. Out of these 13 patients, 3 died due to ALF as a complication of HBV infection [28]. Regardless of the type of the HBV infection (acute or chronic) it is highly recommended to use antiviral treatment such as entecavir or tenofovir [29].
Hepatitis A virus (HAV): Acute liver failure related to HAV infection is very rare, less than 1% will develop ALF. The infection will result in poor prognosis for the patient. Prevalence of HAV infection in developed countries is very low [2,30].
Hepatitis E virus (HEV): In developing countries like India and Bangladesh the most common cause of ALF due to viral etiology is HEV infection. In a study by Fontana et al. in North America over the years 1998 and 2011 it was found that only 3 out of 681 (0,4%) ALF cases where related to HEV infection. [31] In Germany where a single study was done on 80 patients, they found that 10% of the patients had HEV RNA. Conclusion was made that HEV is the probable cause of ALF in these patients [32]. Pregnant womens at risk of getting infected with HEV and developing complications of ALF are particularly seen in the Indian subcontinent and in Africa. Both the life of the mother and the fetus are in danger in case of infection. Therefore preventing infection is of utmost importance where
availability of clean fresh water plays an important role [33].
Autoimmune hepatitis: ALF in patients with autoimmune disorders has high probability of having autoimmune hepatitis as causative factor. For establishment of diagnosis liver biopsy may be needed.
In case of early diagnosis, treating the patient with steroids may have effect. If patient develops ALF then treating with steroids is contraindicated due to its potential of increasing susceptibility of septic complications. If no improvement is seen after treating for one week, the patient needs to be listed for emergency LTx, without any delayment [2].
Budd-Chiari syndrome: BCS is a rare disease. It happens when the hepatic venous outflow tract is obstructed. Patient will complain of abdominal pain and present with jaundice and ascites without direct liver failure. BCS can have a quick course leading to ALF. This will demand rapid diagnosis and initiating treatment with anticoagulants. Use of Transjugular intrahepatic portosystemic shunt (TIPS) and LTx may have led to improvement of mortality [34].
Wilson disease: Patients with Wilsons disease are usually young having an autosomal recessive inherited disorder of copper metabolism. A small number of the patients presenting with fulminant Wilsons disease (FWD) without any known previous liver disease will fall into the diagnostic criteria of ALF. When diagnosing WD patient needs to be examined for Kayser-Fleischer rings, which are only detectable in 50% of the cases.. Liver biopsy for evaluating levels of hepatic copper is another method which can be performed for the establishing of diagnosis, but needs precautions due to its high risk of bleeding. ALF due to WD has shown 100% mortality without emergency LTx [35,36].
Mushroom poisoning: In majority of the cases with mushroom poisoning the main reason is amateur mushroom hunters. Being a rare cause of ALF, the mushroom Amanita phalloides is the main reason for mushroom poisoning with high possibility of having fatal outcome.
Patients ingesting the mushroom wont show any symptoms in the early period. When a patient progresses to having gastrointestinal and hepatic symptoms it might lead to multiorgan failure and death [37]. Poisoning with Amanita phalloides will lead to RNA-polymerase inhibition in the liver causing protein synthesis inhibition and necrosis of the hepatic cells. The management of the poisoning is by supportive measures, therapies of detoxification and orthotopic liver transplantation [38].
Pregnancy related ALF: In case a pregnant woman will develop acute liver failure (ALF) during the pregnancy, the prognosis will be poor. If the patient in her status has developed jaundice together with her ALF, the mortality risk will be higher. A pregnant woman will during her pregnancy undergo many physiological changes, any exacerbation of the condition can cause pregnancy-associated acute liver disease (PAALD). Reason for developing PAALD can be preeclampsia, acute fatty liver of pregnancy or due to HElLP syndrome. PAALD may be the reason for termination of pregnancy [2]. In a study by Sahai et al. they saw that out of 68 pregnant women, 27 (39,70%) of them developed ALF. In case of admission the pregnant women had developed encephalopathy there were seen close
correlation with mortality [39]. Pregnant women who developed acute fatty liver of pregnancy (AFLP) there was risk of developing organ failure, pancreatitis included. Management of the condition is immediate delivery of the baby. Emergency LTx is seldom needed [2].
Acute liver failure induced by hemi-hepatectomy: Patients with malignant liver tumors who are in good physical condition may benefit from hepatic resection surgery for improvement of survival. The surgery comes with increased risk and one of the most serious complications is postoperative liver failure (POLF). Development of POLF is associated with high mortality risk that might exceed 70%. The condition is rarely accepted as a reason for the patient to receive emergency LTx [40].
Clinical presentation and laboratory investigation
Acute liver failure (ALF) is a complex condition when it comes to its management.
Therefore it is very important to follow certain steps for achieving the best possible outcome for the patient in case there is a need for advanced medical care in the ICU or emergency LTx [41].
Medical history: First step is when patient arrives, the physician need to take a proper medical history from the patient and/or patients family. Need to ask about the patient's medicines used last 6 months, this include any type of medication whether it be prescribed medications, herbal supplements or wild mushrooms. Next step is to ask about the patient's mental status. Here it’s important to ask about any psychiatric illnesses. To ask about any recent travels is important in case of traveling to areas where certain viruses are more commonly attained [41].
Physical examination: Second step is to carry out full physical examination. It’s important to assess mental status, to perform neurological examination and also to perform fundoscopic examination in patients who have developed hepatic encephalopathy (HE) grade 2 or more [41].
Laboratory testing: The third step is to perform and order a number of tests for the aim of determining etiology and prognosis for ALF where hepatic panel, prothrombin time/INR, metabolic panel and viral hepatitis serology testing are most important. [41].
There are other specific tests which can be performed in case of suspicion. In case of Wilsons disease evaluation for presence of Kayser Fleischer rings should be done. For all unknown cases transjugular liver biopsy should be obtained. Use of histology is not useful in predicting outcome, but is useful in patients with autoimmune hepatitis. Ultrasound with doppler can also be used to evaluate portal and hepatic vein flow. In case the patient is a candidate for liver transplant, the physician need to order both an echocardiogram and ECG to be performed by cardiologist. ALF patients demand work from a group of specialists to be able to offer the patient best possible treatment for achieving best possible outcome [41].
Management:
Management of patients with Acute liver failure should be done in the ICU. ALF displays an exclusive set of complications and management strategies where liver transplantation is the commonest
treatment outcome [42]. Crucial action in management of ALF is the input of a multidisciplinary team of doctors including hepatologist, intensivist and transplant surgeon. This due to the high probability advancement of multiorgan failure [4]. Management is organ specific including cardiovascular, respiratory, gastrointestinal, metabolic, acute renal injury and renal therapy, coagulation, CNS, and surgical treatment with liver transplantation being the endpoint in most cases [2].
RESEARCH METHODOLOGY
To achieve the objectives defined in this investigation, the research was carried mainly through four online databases: The National Library of Medicine (Pub-Med), European society journal and Uptodate.
Initially research was built by making 3 basic entities: by first gathering the terms referring to mortality rates of Acute liver failure ( “Acute liver failure” OR “ALF”) cross matched with another gathering terms referring to the Intensive care unit (“Intensive care unit” OR “ICU”) and also cross matched with terms referring to Management (“Management”).
The research was limited by adding filters. Mainly studies within the last decade (2010-2020) were utilised, done on humans and preference was give to articles written in English language. After searching in all three electronic databases the number was reduced to 695 relevant papers.
Assessment of Eligibility
The articles were deemed suitable based on objectively reviewing: titel, abstract and full text, meeting the eligibility criteria. Main part of the articles were excluded. It was done due to following reasons: not performed in ICU, inaccessible due to exorbitant fees and an inappropriate research method.
Inclusion criteria
Inclusion criteria were employed in order to further eliminate irrelevant studies and these included: published before between 2010 and 2020, english language, performed in ICU, done on human, topic relevance and had both quantitative and qualitative data.
Exclusion criteria
Articles that were excluded met the following criteria: published before 2010, articles did not discuss treatment strategies, articles that were not free accessible and articles with not enough quantitative and qualitative information.
Included articles
Finally a total of 31 articles were included according to eligibility criteria and they were considered to be the most relevant ones from the initial pool of the obtained results.
RESULTS
Indication
To predict how acute liver failure (ALF) will develop is difficult. In cases with hyperacute presentation prediction becomes even more complicated. Therefore it’s important to consider moving the patient with sufficiently great acute liver injury (ALI) to a liver transplant center or tertiary hospital [2].
ORGAN SPECIFIC MANAGEMENT IN INTENSIVE CARE UNIT (ICU) Cardiovascular management
Majority of patients managed in the ICU with ALF or ALI will develop systemic vasodilation with decreased central blood volume. When examining the patient and the patient don’t have any raise of jugular venous pressure, it will indicate that the patient don’t have any cardiovascular disease. Together with hyperlactatemia as a result of liver failure as well as end organ dysfunction, the probability is very high that the patient is volume depleted and appropriate fluid management will be needed [2]. There is no evidence suggesting the superiority of one type of fluid over the other. Use of crystalloid fluid over colloid is based on critical care litterature [2]. In a systematic review and meta analysis by Avni et al. including 3544 patients to study the use of vasopressors, the evidence suggests a better hemodynamic profile for norepinephrine over dopamine and therefore should be considered as first line vasopressor [43]. In a study by Etogo-Asse et al. including 164 patients it was seen that low levels of HDL in patients with ALF correlated with the severity of condition suggesting a link with adrenal insufficiency seen in 50% of the patients (P < 0.01) [44]. In a retrospective study by Harry et al. including only 40 patients, upon the use of cortisone it was reported that use of hydrocortisone (300 mg per day) might decrease the need for vasopressors [1]. A retrospective study by Mitchell et al. including 247 patients described the effect of volume overload suggesting that 35% of the patients had volume overload upon discharge from intensive care units (ICU). Volume overload after discharge
from ICU was linked with more severe illnesses followed by poor outcome and increased mortality (P = 0.01) [45]. Regarding the maintenance of appropriate blood pressure to target is very
controversial and lacks evidence. Leone et al. suggests that a mean arterial pressure (MAP) of 65 mmHg is sufficient in patients without pre-existing hypertension. Patients with chronic hypertension at risk of developing acute kidney injury their MAP should be around 75 to 85 mmHg [46]. A study in the US by Parekh et al. including 187 patients regarding elevated troponin I level in ALF, concluding elevation of troponin I levels related with increased morbidity and mortality [47]. Audimooolam et al. studying 218 patients states instead that troponin I levels is a poor predictor of outcome (P = 0.221) [48].
The Brain in ALF
Neurological manifestations:
Hepatic encephalopathy (HE) is an crucial expression of ALF. It is described by a lowering in the level of consciousness and altered neurotransmission. HE has a tendency to shift and may advance from a minor lack of awareness to deep coma. Other symptoms may incorporate headache, vomiting,
asterixis, agitation, hyperreflexia and clonus [49]. The diagnosis of HE is done clinically by excluding other causative factors of neurological turmoils such as hypoglycemia, stroke and hypercapnia among many others. Other typical expression of ALF is establishing clinically significant brain edema and intracranial hypertension (ICH). Progression HE is influenced by the result and configuration of liver failure [2].
Management of the patient with altered Glasgow Coma Scale (GCS):
If the patient develops grad 3 HE, ICU practice is to intubate the patient for mechanical ventilation. It’s performed to protect the airway, avoid aspiration and to give more secure respiratory care [7]. Grade 3 coma is defined by increased agitation and frequent aggression in combination with a
lowering in GCS. Progression to grade 4 coma is related to definitive lowering in GSC [11].
Mechanical ventilation is used to protect the brain and to minimise the risk or pulmonary barotraumas. This is done by desiering a partial pressure of carbon dioxide (PaCO2) between 4,5-5,5 kPa (34-42 mmHg) and by using propofol as sedative agent. This can protect from ICH and lower the risk of seizures [50]. An opiate that is not long-acting should be given to assure proper analgesia. For monitoring of appearance of seizures, use of EEG should be applied together with antiepileptic drugs [2].
Intracranial hypertension:
A complication of HE in ALF describes simply brain edema that cause ICH. Despite the lowering of occurence of ICH, it can still have an impact on 1/3 of the cases advancing to grade 3 or 4 HE [6]. ICP monitoring supports the golden standard for measurement and monitoring of ICP. Nevertheless it won't affect patient outcome but is linked with bleeding risk affecting morbidity and mortality [2].
Respiratory management:
Patients with ALF in the ICU may progress quickly to higher grades of HE, therefore a respiratory protective strategy needs to be inplace from the very early moment. This will include invasive methods such as ventilatory support to avoid hypoxia and respiratory failure. Non-invasive methods should be avoided. Particularly in patients with risk of HE and severe metabolic disorder. They will without invasive ventilator support risk further neurological deterioration, aspiration and poor compliance [2].
According to Guidelines for the management of adult acute and acute-on-chronic liver failure by Nanchal et al. they recommend the use of low tidal volume strategy over high tidal volume strategy to be used in patients with ALF or ACLF and acute respiratory distress syndrome (ARDS) [51]. It is stated that use of positive pressure ventilation for respiratory support in the ICU, is for the patients developing ARDS, a life-saving intervention [51].
In a meta-analysis by Walkey et al. where they analysed nine studies including 1629 patients regarding the use of low versus non volume limited tidal volume strategies saw a reduction in mortality when using low tidal volume strategy ( P = 0.0022) [52]. In another study by Walkey et al. performing a meta-analysis of high versus low positive end-expiratory pressure (PEEP) in ICU patients. In the study they didn’t saw any benefits regarding use of high PEEP in mortality. Use of high PEEP had the risk of increasing intracranial pressure (ICP) as well as reducing venous return (P = 0.02) [51,53].
A study by Audimooolam et al. where 148 of the patients were included in the study. The patients were categorised into different stage type, 31 (21%) of the patients had ARDS out of whom 17 had mild ARDS, 9 had moderate ARDS and 5 had acute ARDS. The study showed that prevalence lung damage is very low, were only 21% met the criteria of ARDS. Patients having ARDS didn’t have any or very limited effect on the overall outcome (P = 0.877) [54].
Gastrointestinal management:
In a study by Stravitz et al. including 1770 patients with ALF, bleeding complications was seen only in 187 patients (11%) [55]. Majority (84%) of the casual bleeding events came from upper
gastrointestinal origin and seldomly emanated in transfusion of red blood cells [55].
In another study by Lo et al. studying 97 patients regarding management of upper gastrointestinal bleeding it was seen that performing GI endoscopy facilitated the investigation and further the
treatment of biggest portion of GI bleeding. By consolidating banding ligation and vasoactive therapy for a period of two days it showed a superiority over the use of infusion of vasoactive therapy in a period of five days alone and thereby achieving a lowering of re-bleeding events (P = 0.002) [56].
It was concluded by Stravitz et al. in their study that it is very uncommon for patients with ALF to have major bleeding and thus the bleeding was a sign of severe systemic inflammation rather than of coagulopathy indicating poor prognosis [55].
Coagulation management:
When diagnosing ALF, abnormal values of coagulation plays essential role. Quickly changing ranges of PT and INR are important prognostic parameters. Despite the abnormal coagulation values, it does not correlate with an increased risk of bleeding [2].
In a study by Habib et al. including 32 patients with ALF/ALI and 40 controls, showed that patients with ALF/ALI had normal endogenous thrombin potential (ETP) in the presence of thrombomodulin (TM). This shows that the patients coagulation profile was rebalanced. It came as a result of acquired protein C (PC) resistance as a result of reduced PC, Factor V and accompanying increase in Factor VIII (P < 0.001) [57].
Metabolic management:
Acute liver is commonly linked with electrolyte and metabolic disturbances. It’s more usual in patients with hyperacute stage of ALF, particularly when it’s related with acute kidney injury (AKI) [2].
Hypoglycemia is a well established complication of ALF and has many etiological factors for its pathogenesis. There is reports of many different pathological ways of establishing hypoglycemia in ALF, these include increased hepatic extraction of glucose, increased hepatic glycolysis and impaired gluconeogenesis, as well as failure of compensatory renal gluconeogenesis [11]. In a meta-analysis by Yamada et.al of 36 trials including 17,996 critically ill patients, showed no reduced risk of short-term mortality in the group of very tight (80-109 mmol/dL) glycemic control when compared with tight (110-139 mmol/dl), moderate (140-180 mmol/dL) or liberal (>180 mmol/dL) glycemic control. Contrarily, tight glycemic control was associated with a fivefold bigger risk of mortality when compared to mild or very mild control (P = 0.18) [58].
Hyponatremia is fairly regular in patients with ALF, particularly acute cases [2]. In a randomized controlled clinical trial by Murphy et al. including 30 patients they concluded that initiation and continuation of hypernatremia (145-155 mmol/L) might reduce the occurrence and severity of intracranial hypertension (IH) in the patients presenting with ALF (P <.01) [59].
Acidosis together with elevated circulating lactate and decreased bicarbonate are regular features in patients with hyperacute and acute ALF. This comes as a result of raised systemic production and decreased hepatic clearance [2]. A study by Bernal et al. including 103 retrospective patient samples together with 107 prospective patient samples interprets that arterial blood lactate fastly and correctly identifies patients who will die as result of paracetamol-induced ALF. It may also be used to enhance speed and correctness when selecting suitable candidates for transplantation (P=0.01) [60].
Acute kidney injury and renal replacement therapy:
Acute kidney injury (AKI) is regular in ALF. Around 40% to 80% of the patients with ALF who are referred to tertiary liver units are classified as having AKI. This is linked with increased mortality and the duration of time in hospital. There are several risk factors of AKI such as higher age and
paracetamol-induced ALF among many others [2].
In a prospective study by Slack et al. were 24 patients were studied showed that use of hemofiltration (HF) marked a 22% decrease in median arterial ammonia concentration during 24 hours thereby concluding correlation between HF and drop in arterial ammonia concentration. The clearance of ammonia was tightly correlated with ultrafiltration rate of HF (P < 0.001) [61].
Another prospective observational study by Schultheiss et al. including 28 patients with liver failure who were at risk for citrate accumulation during continuous venovenous hemodialysis (CVVD) with regional citrate anticoagulation.
They concluded that regardless of considerable accumulation of citrate in serum, CVVD with regional citrate anticoagulation looks reasonable in patients with seriously impaired liver function. Accurate monitoring of electrolytes and acid-base status is obligatory to guarantee patient safety [62]. In a prospective study by O’Riordan et al. including 302 patients concludes that in patients with paracetamol-induced hepatotoxicity admitted to ICU developing AKI was very common. The patients outcome will seem worse with AKI than with normal kidney function. Despite this, those patient will manage much better than patients admitted to ICU for other causes. Steady rehabilitation of kidney function was seen in all patients [63].
Nutritional management:
Every patient with ALI should be motivated for oral feeding. In case the patient will lower their caloric intake, it may lead to progression of HE. Sometimes it’s needed to insert a nasogastric tube to ease enteral feeding. Attention must be given to the risks and benefits. Advice concerning nutritional demands in patients with ALF is mostly experimental [2].
A study by Schutz et al. done to evaluate nutritional habit among 33 hepatology units in 11 European countries. Every unit used specified nutritional support regimes in patients with liver failure. 8 units used tube feeding with standard diets, 25 units used parenteral nutrition (PN). 50% of all patients received enteral nutrition [64]. Immoderate infusion of amino acids can worsen the hyperammonemia that is typical of ALF and lead to increased cerebral edema and intracranial hypertension. Therefore routine monitoring of plasma ammonium during both feeding types (enteral and parenteral) is important to avoid any raise [2].
LIVER TRANSPLANTATION
In the last 40 years the single most effective treatment method for ALF has been liver transplantation (LTx) which has transformed the survival outcome of this disease [6]. When comparing emergency LTx with routine transplant regarding one year survival it's marginally worse for emergency LTx. Despite this, one year survival for emergency LTx stands at an impressive 80%. When selecting for liver transplant it is not only dependent on correct prediction regarding patients survival without receiving the transplantation. It also demands consideration of the possibility of survival after the LTx and also if the patient is too sick to undergo the transplantation [2]. Transplantation performed due to ALF as the primary cause is only 8%. Of these 8% we can see as the leading cause, cases related to viral infection 19%. Second largest cause seen is drug-induced liver injury with 18%, 4% having toxic insults and 3% from events occurring postoperative or due to trauma. Biggest portion, 56%, are either classified as unknown or having other causes [65].
Mostly used criteria for emergency liver transplant is King’s College Criteria. The criterion is made up of two parts, ALF due to paracetamol and ALF not due to paracetamol [2].
ALF due to paracetamol includes upcoming criterias: arterial pH > 7,3 after resuscitation and >24h since ingestion, lactate >3 mmol/L or presence of 3 of following criteria: hepatic encephalopathy > grade 3, serum creatinine >300 umol/L and INR >6,5 [2].
ALF not due to paracetamol include instead these criterias: INR >6,5 or presence of 3 of following criteria: etiology (indeterminate etiology hepatitis, drug induced hepatitis), age <10 years or >40 years, interval jaundice-encephalopathy >7 days, bilirubin > 300 umol/L or INR >3,5 [2].
In a study by Brashes et al. containing 1457 patients that were divided into two subgroups consisting of roughly 66% (972 patients) and 33% (486 patients) of the total group. First group was named as the modeling group while the second group was named the cross validation group. Almost 50% of all cases had either misceoullus or unknown origin. The rest, one quarter had drug-caused origin and the other quarter had viral origin. In each group 97% percent of the patients received a cadaveric
complete-organ liver graft (P=0.16). The survival rate for the patients in the first group (modeling group) for the years 1, 5 and 10 post orthotopic liver transplant was 77,1%, 67,2% and 60,0%. For the second group (cross validation group) the survival rate for the same year period 1, 5 and 10 post orthotopic liver transplant was 78,3%, 67,4% and 58,8%. There was no important difference in the survival rate for the patients in both groups (P=0.88) [66].
Major factors affecting morbidity and mortality after liver transplant are sepsis, advanced organ failure with underlying vasoplegic shock, and liver graft dysfunction or failure. Retransplantation occurs mainly due to graft rejection and critical dysfunction as well as hepatic artery thrombosis [2].
Use of living donors is not common in Europe and USA as a result of quick availability of liver grafts from dead persons. Using a living donor can raise emotional pressure on the donors family. Organizing and performing the donation using a living donor comes with risk for the donor during the surgery. In Asia this habit differs because of low availability of cadaveric donors, therefore living donors are used on a routine basis. When comparing the results of living donor LTx with ALF in Asia the results are good and comparable with cadaveric liver donor in Europe and USA [67].
DISCUSSION
Evolvement of acute liver failure (ALF) is very hard to predict. In cases where the patient presents with hyperacute condition it becomes ever more complicated to predict its outcome. Therefore important considering moving the patient with great acute liver injury (ALI) to a transplant center or tertiary hospital where best management is possible [2].
To determine if the patient has mental alteration is not always so easy but it's very important. Even if the patient has mild hepatic encephalopathy (HE) it can in a very short time and the condition can become life-threatening [2].
If conditions of altered mental status, increased INR >1,5 and if labs show hypoglycemia or metabolic acidosis the patient should be transferred to the intensive care unit (ICU) for further management [2].
The management of the patient when arriving at the ICU is done in consultation with a multidisciplinary team including hepatologist, intensivists and transplant surgeons [4].
Treatment in the ICU will be organ supportive and organ specific so that stabilization of the patient can be achieved giving time to the liver to regenerate or while preparing the patient for upcoming liver transplantation. In an emergency liver transplant situation the possibility for preparing the patient psychologically is in most cases not possible due to patients altered mental status or the rapid course of deteriorating condition.
Most of the patients managed in the ICU will develop systemic vasodilation with decreased central blood volume. Therefore proper fluid management will be needed. The use preferences of colloid solution over the crystalloid solution lacks evidence but is based upon critical care litterature [2].
The use of fluids should be done with caution to avoid volume overload in the patients. In study by Mitchell et al. it was seen that 35% of the patients had volume overload when being discharged from the ICU and this in turn was linked with poor outcome and increased mortality.
Regarding the use of vasopressors a study by Avni et al. suggests a better hemodynamic profile of norepinephrine over dopamine. Therefore norepinephrine should be considered as first line
medication. In another study by Harry et al. suggests that use of corticosteroids (300 mg per day) might decrease the need for vasopressors.
Because of high risk of developing hepatic encephalopathy (HE) a respiratory protective strategy should be in place from the early moment. Focus should be on invasive methods such as ventilatory support so that hypoxia and respiratory failure is avoided. Non-invasive methods should be avoided. Nanchal et al. recommends the use of low tidal volume over high. This will, according to Walkey et al. have an impact in lowering mortality. Positive pressure ventilation should be used in patients
developing acute respiratory distress syndrome(ARDS) as a life-saving intervention. A study done by Adimoolam et al. showed that the effect of ARDS in the overall outcome is limited. Proper respiratory management is very important from the moment a patient is brought to the ICU.
Patients in the state of ALI should be encouraged for oral feeding. Lowering the intake of calories can worsen the progression of HE. In a study by Schultze et al. it was seen that every hepatology unit in the 11 European countries that participated, used specified nutritional support. The different units used different methods of giving nutrition, where parenteral nutrition was the most common [64].
Use of INR and PT are important parameters of prognosis. Abnormal values do not necessarily correlate with increased bleeding risk. A study by Stravitz et al. saw bleeding complications in only 11% of the cases. Therefore risk of bleeding is very rare in patients with ALF.
Metabolic disturbances was more common in patients with hyperacute stage of ALF with acute kidney injury (AKI). Hypoglycemia is a complication commonly occurring as a result of deteriorating liver function. Tight glycemic control over moderate or liberal didn’t show to have any impact in the reduced mortality risk according to Yamada et al.
Regarding hyponatremia it was seen in a study by Murphy et al. that keeping the patient on hypernatremia (145-155 mmol/L) might reduce the occurrence and severity of intracranial hypertension (IH).
A study by Bernal et al. saw that arterial blood lactate could quickly and correctly patients who will die due to paracetamol-induced ALF. It was also used for transplant selection.
Acute kidney injury (AKI) occurs commonly in ALF. Around 40% to 80% of the patients with ALF are reported having AKI. It’s linked with increased mortality. Slack et al. studied the correlation of hemofiltration (HF) and decreased ammonia and saw a drop by 23%. Venovenous hemodialysis (VVHD) well motivated in use for patient with severely impaired liver function despite its risk for citrate accumulation according to Schultheiss et al. Monitoring of electrolytes and acid-base status is very important.
Hepatic encephalopathy (HE) is an crucial expression of ALF. Progression of liver failure will have impact on the progression of HE. When patient develops grade 3 on the Glasgow coma scale (GCS), intubation will be needed to protect the airway and avoid aspiration. Mechanical ventilation is also used to protect the brain from further damage. This is done by decreasing partial pressure of carbon dioxide and using propofol as sedative agent. To monitor the intracranial pressure (ICP), use of ICP monitoring is the golden standard. It is very important to avoid raised ICP because of the risk of developing coma which will have further negative impact on the outcome.
Liver transplant is the last and most effective treatment option in ALF. One year survival rate for emergency LTx stands at an impressive 80%. Selecting the patients appropriate for liver transplant is complex and includes meeting the criterias. The best used criterion is Kings College criteria.
Certain etiological causes of ALF like ALF due to paracetamol-overdose (POD) is best managed by proper fluid resuscitation and N-acetylcysteine. Renal replacement therapy may be needed in the treatment of acidosis. In case patient won’t meet criterium of emergency Ltx the prognosis will be better. In case emergency Ltx is needed the survival percentage rate will be 20-40%.
CONCLUSION
The evolution of acute liver failure (ALF) is very unpredictable therefore transferring the patient to ICU in liver transplant centre or tertiary hospital for further organ specific management is essential for the outcome. Organ supportive management is the best strategy according to the evidence in the literature. Liver transplant in patients with ALF remains the most effective treatment.
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