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• W3185291644 abstract "Acute liver failure (ALF) is a medical emergency with high short-term (2 weeks) mortality.[1] Patients with acute hepatic dysfunction are categorized based on disease severity into acute liver injury (deranged liver function test [LFT], coagulopathy [INR >1.5], and no encephalopathy) and ALF (deranged LFT, coagulopathy [INR >1.5] and encephalopathy).[2] The management of a patient with ALF needs specialized care. ACCESS TO EMERGENCY LIVER TRANSPLANTATION: KEY DIFFERENCE IN THE MANAGEMENT OF ACUTE LIVER FAILURE IN RESOURCE-CONSTRAINED SETTINGS While the general principles of management of ALF are the same world over, a key difference is the access to emergency liver transplantation. In developed countries, emergency cadaveric transplantation may salvage many patients with ALF. Of 90 patients with ALF listed for liver transplantation in 3 European centers, 56 patients (62%) underwent emergency liver transplantation.[3] In a 20-year experience database from the European Liver Transplant Registry, fewer than 10% of liver transplants in Europe had ALF as their indication.[4] Emergency live donor liver transplantation is increasingly done in countries like India, South Korea, and Japan. However, as demonstrated in a recent study conducted across Tamil Nadu in January 2019 to June 2019, most (99.8%) patients with ALF are treated with nontransplant treatment options. In one of the largest series of ALF from AIIMS Delhi of 1223 patients from 1986 to 2009, no patient underwent liver transplantation.[5] More recently (2011–2018), emergency liver transplantation being performed to treat ALF in India has been reported.[6] However, considering the huge number of patients with ALF in India, it is unlikely that all these patients will be treated with emergency liver transplantation. Thus, at present, the lack of access to emergency liver transplantation to treat most of the patients with ALF in India brings in the need to maximize survival with nontransplant treatment options. The immediate cause of death in ALF patients is often cerebral edema and treatment strategies are implemented to reduce cerebral edema.[7] Thus, the development of altered sensorium in a patient with acute hepatic dysfunction is a serious concern. The longer the duration of altered sensorium and the more profound the obtundation, the risks of attendant complications like aspiration pneumonia increases. This article focuses on the need to avoid the use of sedative medicines in ALF patients in resource-constrained settings. We also discuss the specific indications when sedative drugs may be used in these patients, in reduced doses. INSIGHTS FROM THE TAMIL NADU CHAPTER OF THE INDIAN SOCIETY OF GASTROENTEROLOGY ENDORSED STUDY IN 2019 OF TOXIC HEPATITIS IN TAMIL NADU A study conducted under the aegis of the Tamil Nadu chapter of the Indian Society of Gastroenterology (TNISG) analyzed acute toxic hepatitis in Tamil Nadu from January 2019 to June 2019.[8] This retrospective study conducted in 15 hospitals in 6 districts (Chennai, Coimbatore, Madurai, Tirunelveli, Thanjavur, and Vellore) established rodenticide ingestion as the predominant cause of acute hepatotoxicity in Tamil Nadu. Most of the 450 rodenticidal hepatotoxicity patients were young (75% were 15–34 years old). Most patients consumed rodenticidal poison with suicidal intent, often as an impulsive act. When categorized by liver disease severity, the rodenticidal hepatotoxicity patients had ALF (in 244 patients, 54.2%), acute liver injury (78 patients, 17.3%), and uncomplicated hepatotoxicity (86 patients, 19.1%). These patients were treated with standard medical treatment (396 patients), plasma exchange (54), and plasma exchange followed by liver transplant (1). On analyzing survival, 159 patients (35%) had poor outcome. The outcome was poor in 107 ALF patients (43.9%), 5 acute liver injury patients (6.4%), and in 3 uncomplicated hepatotoxicity patients (3.5%). A few points from this important study are worth highlighting. Rodenticidal hepatotoxicity is a serious illness of public health importance in Tamil Nadu affecting the young. Only 1 patient out of 450 patients (0.2%) with rodenticidal hepatotoxicity opted for liver transplantation. Thus, 99.8% of the patients were treated with medical treatment/nontransplant therapies. The proportion of rodenticidal hepatotoxicity patients who had ALF was 54.2% and acute liver injury was 17.3%. In contrast, in an earlier report from our hospital, of 24 consecutive patients with rodenticidal hepatotoxicity, three patients had ALF (12.5%) while 20 patients had acute liver injury (83.3%).[9] The development of hepatic encephalopathy in ALF patients differentiates this from acute liver injury (deranged LFTs, coagulopathy, and no encephalopathy). The proportion of patients with ALF (i.e., with encephalopathy) were higher in the TNISG study[8] (54%) compared to the previous Vellore study[9] (13%). Why is this so? Delayed presentation to hospital after ingestion of rodenticide is one explanation for higher number in the TNISG study. The small number of patients in the Vellore study may lead to a sampling error. It is also possible that altered sensorium in patients with acute hepatic insult may be due to causes other than hepatic encephalopathy. CAUSES OF ALTERED SENSORIUM IN PATIENT WITH ACUTE HEPATIC DYSFUNCTION As mentioned in Table 1, the causes of altered sensorium in a patient with ALF may be related to the acute hepatic dysfunction or not necessarily related to the acute hepatic dysfunction. The latter causes of altered sensorium may also aggravate cerebral edema.Table 1: Causes of altered sensorium in a patient with acute hepatic dysfunctionCauses of altered sensorium directly related to acute hepatic dysfunction Cerebral edema Cerebral edema is a serious complication seen in ALF and can progress to intracranial hypertension. Although the incidence of intracranial hypertension has been declining in the last decade, when it occurs, the mortality is >50%.[10] Raised levels of blood ammonia, alkalosis, acidosis, hyponatremia, hypoglycemia, or hyperglycemia can worsen cerebral edema. Ammonia levels of >100 mmol/L predict the onset of high-grade encephalopathy and levels >200 mmol/L predict the onset of intracranial hypertension and cerebral herniation.[11] Dehydrating agents (osmotherapy) such as hypertonic saline[12] or mannitol infusion[13] are used as treatment to reduce cerebral edema. Head elevation to 15°–20° is done aimed to facilitate venous drainage. Causes of altered sensorium not necessarily related to acute hepatic dysfunction These causes can per se cause altered sensorium (for example, hyponatremia may cause drowsiness). However, these causes may be linked indirectly to ALF (for example, prolonged half-life of sedative drugs, as the clearance of these drugs by the failing liver is impaired). In addition, some of these causes may aggravate cerebral edema (for example, hyponatremia can worsen cerebral edema). These causes of altered sensorium can be inter-linked (for example, seizures in a patient with significant coagulopathy may precipitate intracranial bleed). Metabolic derangements Hyponatremia per se may cause altered sensorium and serum sodium <120 mmol/L may trigger seizures in any patient. Hypoglycemia can cause altered sensorium, For example, in acute fatty liver of pregnancy.[14] Use of sedation Many drugs are metabolized in the liver. Hepatic clearance of sedative drugs may be affected in liver failure; this may prolong the effect of the sedative drugs. Sepsis The patient with ALF is prone for bacterial sepsis, which can present as altered sensorium. Incidence of clinical bacteremia in ALF is 35%, and bacteremia and systemic inflammatory response syndrome influence the degree of encephalopathy.[15] Delirium in the intensive care unit Delirium manifests as acute confusional state (agitation, tremulousness, and hallucinations) or as “hypoactive delirium” (somnolence, decreased arousal), which develops over hours to days and may fluctuate during the course of the day. The patient has altered consciousness with reduced ability to focus, sustain, or shift attention. Typical causes of delirium are a medical condition, substance intoxication, or medication side effect.[16] There are multiple factors, which can precipitate and worsen delirium. Isolation within the confines of the intensive care unit with no natural light, minimal access to relatives, lack of sleep due to noise and nursing and medical care, critical illness, and the associated treatment may be some of the factors. Multipronged interventions are recommended to prevent delirium.[17] These include identifying and modifying triggers of delirium such as disorientation, dehydration, constipation, infection, hypoxia, drugs, pain, poor nutrition, sensory impairment, and disturbed sleep. Intracranial bleed This is an uncommon event in ALF. Invasive intracranial procedures (such as insertion of a direct pressure monitoring device to monitor intracranial pressure) in this setting carries the risk of precipitating intracranial bleed.[18] Subclinical seizures Some of the metabolic derangements such as hyponatremia, hypoglycemia, or hyperammonemia can precipitate seizures. Furthermore, some of the drugs used may reduce seizure threshold. Psychological distress As mentioned earlier, rodenticidal ingestion, often with suicidal intent, is a common cause of acute hepatic dysfunction in Tamil Nadu.[8] It is possible that the psychological turmoil in such a patient may manifest as agitation or withdrawn behavior. Being in unfamiliar surroundings in a hospital and not being in contact with family members may aggravate this situation. It is even more difficult to differentiate psychological distress from cerebral edema in children with acute hepatic dysfunction. Hypercarbia and hypoxia In a critically ill patient, respiratory failure can also present as altered sensorium. In the setting of severe acute liver injury/ALF and hyperammonemia, the primed brain is more prone to clinical worsening with any of the above super-added triggers. In this milieu, use of chemical restraint (sedation) without addressing these triggers may be deleterious and the tipping point of no return. In this situation, when available, use of transcranial Doppler or ultrasound to measure optic disc diameter can identify elevated intracranial pressure. Use of continuous renal replacement therapy to mitigate hyperammonemia can reduce the need for sedation and mechanical ventilation. DELETERIOUS EFFECTS OF SEDATION USE IN ACUTE HEPATIC DYSFUNCTION Use of sedation (midazolam) and opioid analgesics (morphine or fentanyl) to “calm down” agitated patients could worsen the degree of altered sensorium. In some patients, this may lead to the need for endotracheal intubation and mechanical ventilation for airway protection and respiratory depression. Immobility and depressed level of consciousness in a critically ill patient can predispose to complications such as atelectasis, impaired clearance of secretions from the airway, and pneumonia. In ALF patients who are managed with nonliver transplant therapies in resource-constrained settings, the chances of survival are likely to be higher in those who are not mechanically ventilated (aspiration risk) compared to those who were ventilated (sepsis/sedation risks). Hence, worsening in level of consciousness aggravated by use of sedation which leads to respiratory depression and need for mechanical ventilation may reduce the chances of survival in this scenario. However, one should balance the potential risks of respiratory complications in a patient with low sensorium and self-harm and raised intracranial pressure in an agitated patient to the benefit of protection of airway and control of intracranial pressures offered by sedation and mechanical ventilation. WHAT ARE THE INDICATIONS FOR THE USE OF SEDATION IN A PATIENT WITH ACUTE HEPATIC DYSFUNCTION BEING TREATED WITH NONTRANSPLANT THERAPIES? The approach to the use of sedation in a patient with severe acute liver injury or ALF being treated with nontransplant therapies is different compared to a patient listed for or being considered for emergency liver transplantation. In the patient being treated with nontransplant therapies, sedation is best avoided. The risk of sedation is worsening of encephalopathy, which can be precipitated by benzodiazepines. Liver dysfunction will affect metabolism of most of the available sedatives. There may be associated renal dysfunction affecting excretion of active metabolites. If select patients in whom sedation is deemed necessary, it may be used at the smallest possible dose for the least duration. In view of the risks with the use of sedation in a patient with acute hepatic dysfunction on nontransplant therapies, which are the select / restricted situations where sedation is indicated? [Table 2].Table 2: Indications for use of sedation in acute liver failure patient in resource-constrained settingSedation may be needed for endotracheal intubation and for mechanical ventilation. Endotracheal intubation is fraught with risks of elevation in intracranial pressure if the depth of sedation is inadequate or loss of airway leading to hypoxia and hypercarbia. This intervention is best undertaken by the most experienced doctor in the treating team. An agitated patient can be at risk of self-harm or harming others. The use of sedation in this situation is decided by serially assessing the patient. Interventions such as insertion of nasogastric tube, invasive lines, and noninvasive ventilation are very likely to precipitate or aggravate agitation and lead to complications. A femoral route for venous access may be safer than other routes as positioning is relatively easier and application of pressure is easier if there is bleeding. Similarly, if invasive diagnostic procedures such as transjugular liver biopsy are to be performed, the use of sedation is best avoided, if possible. The option of avoiding/postponing such invasive procedures should be considered. The use of sedation to assist in transfer of a patient with acute hepatic dysfunction will also depend on the access to emergency liver transplantation for that patient. The criteria for sedation during transfer of such a patient to a specialized center with liver transplantation facilities are not clear.[2] However, in resource-constrained settings wherein emergency liver transplantation is not feasible, the only hope for survival is nontransplant treatment. Thus, the need to give/to avoid sedation for transfer of such a patient will be distinctly different in a patient being considered for urgent liver transplantation (like in the West) or in a patient in whom emergency liver transplantation is not feasible (like in resource-constrained settings in most of India at present). The rationale for the use of sedation during endotracheal intubation and when on mechanical ventilation is to control surges of intracranial pressure. However, as discussed earlier, the trade-off between risks of sedation and its attendant complications in ALF patient on nontransplant therapy needs to be balanced. WHEN SHOULD A PATIENT WITH ACUTE HEPATIC DYSFUNCTION ON NONTRANSPLANT THERAPIES HAVE ENDOTRACHEAL INTUBATION AND MECHANICAL VENTILATION? The currently accepted indications for invasive ventilation in patient with ALF[19,20] are: Failure to maintain patent airway due to Decreased level of consciousness (Glasgow Coma Score <9/15). Inability to manage secretions and to prevent pulmonary aspiration during or postseizures Concomitant upper airway obstruction (due to trauma, hematoma, edema, or low sensorium). To achieve normocarbia and pH in patients with high grade encephalopathy and cerebral edema aiming to prevent further increase in intracranial pressure Hypoxemic or hypercapnic respiratory failure, dyspnea with increased work of breathing, and severe circulatory shock. In mechanically ventilated patients, sedatives are used as continuous infusions for endotracheal tube tolerance and synchrony with the ventilator. Among sedatives, propofol has good safety profile in liver disease (though predominantly cleared by liver, dose adjustments are not required in liver disease). Propofol would be the drug of choice if hemodynamics permit.[21] Opioid analgesics like fentanyl as continuous infusion improve tube tolerance in intubated patients, have antitussive action, and hence attenuate intracranial pressure surges. Dexmedetomidine is an alternative but used with caution as the metabolism is mainly in the liver. In resource-constrained settings, the key to survival appears to be avoiding mechanical ventilation to the extent possible and if on mechanical ventilation, to get the patient off it at the earliest. This will entail coming off sedation in a graded manner (smallest dose for the minimum duration) and assessing improvement in level of consciousness serially. ROLE OF PROPHYLACTIC ANTIEPILEPTIC DRUGS IN ACUTE LIVER FAILURE Preventing seizures is desirable in a patient with ALF who is coagulopathic and at risk of surges of intracranial pressure. However, the concerns with use of antiepileptic drugs are potential hepatotoxicity. Levetiracetam appears to be the least hepatotoxic.[22] In self-ventilating patients, levetiracetam is the preferred antiepileptic drug for treatment and prophylaxis. In intensive care units, propofol and benzodiazepines can be used to treat and prevent seizures in patients on mechanical ventilation. Lorazepam, oxazepam, and temazepam drugs are the liver safe benzodiazepines. They are metabolized by conjugation in the liver, which is less dependent global liver function and they do not have any pharmacologically active metabolites. INCREASING AWARENESS ABOUT THE NEED TO REDUCE SEDATION USE IN ACUTE LIVER FAILURE PATIENT The dangers of administering sedative drugs to a patient with ALF should be understood by the treating teams who serially manage this patient. The patient with acute liver injury/failure is usually initially seen by a general practitioner, then referred to a hospital for admission. In any hospital, different treating teams in the emergency department, the medicine/pediatric/gastroenterology/hepatology department, and intensivists are likely to be providing care to this patient at different points during the hospital stay. The need to avoid sedation for invasive procedures should be considered at all times. These treating teams also need to be aware of the restricted use of sedative drugs in select indications in these patients. This situation is similar to the recommendation to avoid sedation in patient with snakebite which can cause neurotoxicity (like cobra bite).[23] The concern is precipitating respiratory depression by use of sedation in this patient. Here, again, the snakebite victim may be looked after by multiple teams from peripheral clinic to a larger hospital. The risks in transferring such a patient are also similar. NONTRANSPLANT THERAPIES TO TREAT ACUTE LIVER INJURY/FAILURE Plasma exchange is a form of nontransplant therapy to treat patients with severe acute liver injury or ALF being increasingly used now in different parts of India. We have detailed a management protocol for the use of plasma exchange and low dose steroid (aimed at treating secondary hemophagocytic lymphohistiocytosis) to treat patients with ALF.[24] CONCLUSIONS Emergency liver transplantation is lifesaving in patients with ALF. However, in resource-constrained settings, most patients with ALF are treated with nontransplant therapies. This article highlights the differences in approach to the use of sedation in ALF patients who are treated with nontransplant therapies in contrast to those who are being considered for emergency liver transplantation. In patients who are on nontransplant therapies, sedation is best avoided. In select situations when sedation is deemed necessary, it is important to use liver safe drugs in the smallest dose, for the least duration of time. This approach may improve survival in patients with acute hepatic dysfunction in resource-constrained settings, in whom emergency liver transplantation is not feasible. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest." @default.
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• W3185291644 title "Safe sedation practices in acute liver failure in resource-constrained settings: A viewpoint" @default.
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