Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are conditions frequently encountered in the ICU and are associated with high mortality. The purpose of these guidelines was to develop evidence-based recommendations addressing common clinical questions surrounding the unique manifestations of liver failure in the critically ill patient.
Often, clinical care must be adapted to individual clinical circumstances and patient/family preferences. These guidelines are meant to supplement and not replace an individual clinician’s cognitive decision-making. The primary goal of these guidelines is to aid best practice and not represent standard of care.
Co-chair and vice-chairs were appointed by the Society of Critical Care Medicine (SCCM). Twenty-five other panel members were chosen in accordance with their clinical and/or methodological expertise. Corresponding with individual expertise, the panel was then divided into nine subgroups; the recommendations of five of those subgroups (cardiovascular, hematology, pulmonary, renal, and endocrine) are presented in this document. Each panel member followed all conflict of interest procedures as documented in the American College of Critical Care Medicine/SCCM Standard Operating Procedures Manual. The panel proposed, discussed, and finally developed 30 Population Intervention Comparator Outcome questions which they deemed most important to the patient and the end-users of this guideline. We used Grading Recommendations, Assessment, Development, and Evaluation (GRADE) approach to prioritize outcomes, assess quality of evidence, and determine the strength of outcomes (1). We then used the Evidence-to-Decision framework to facilitate transition from evidence to final recommendations. We classified each recommendation as strong or conditional as per GRADE methodology. We accepted a recommendation if 80% consensus was achieved among at least 75% of panel members. We developed best practice statements as ungraded strong recommendations in adherence with strict conditions.
We report 29 recommendations on the management acute or ACLF in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best practice statements, and in two instances, a recommendation was not issued because due to insufficient evidence. A summary of recommendations is presented in Table 1, and we discuss the abbreviated rationale for the six strong recommendations. The full recommendations and complete rationales can be found in the main article published in critical care medicine.
In critically ill patients with ALF or ACLF, should we recommend using hydroxyethyl starch or gelatin for initial resuscitation versus crystalloid solutions?
We recommend against using hydroxyethyl starch for initial fluid resuscitation of patients with ALF or ACLF (strong recommendation, moderate-quality evidence).
Although the available evidence is limited by indirectness because few patients with liver failure were included, meta-analyses of available trials in critically ill patients suggest no benefit of hydroxyethyl starch over crystalloids. Starches may exacerbate coagulopathy in liver failure and a there is not a compelling physiologic rationale for their use in patients with liver failure (2,3).
In critically ill patients with ALF or ACLF who remain hypotensive despite fluid resuscitation, should norepinephrine be used as a first-line vasopressor agent?
We recommend using norepinephrine as a first-line vasopressor in patients with ALF or ACLF who remain hypotensive despite fluid resuscitation, or those with profound hypotension and tissue hypoperfusion even if fluid resuscitation is ongoing (strong recommendation, moderate-quality evidence).
Patients with liver failure exhibit hyperdynamic circulation and shock states in these patients is typically characterized by distributive physiology. Despite the paucity of studies directly related to liver failure, indirect evidence from trials in other distributive states such as septic shock suggest norepinephrine is superior compared with dopamine is reversing hypotension as well as associated with lower mortality and risk of arrhythmias (4). Epinephrine may cause splanchnic vasoconstriction and increase the risk of mesenteric and hepatic ischemia in the setting of liver failure. Studies comparing vasopressin as a first-line agent to other vasoactive agents are not available.
In critically ill patients with ALF or ACLF undergoing invasive or surgical procedures should we use INR, platelet count, or fibrinogen level versus viscoelastic testing (thromboelastography/rotational thromboelastometry [TEG/ROTEM]) to assess bleeding risk?
We recommend viscoelastic testing (TEG/ROTEM), over measuring international normalized ratio (INR), platelet, fibrinogen, in critically ill patients with ALF or ACLF undergoing procedures (strong recommendation, moderate-quality evidence).
Quantification of INR, platelet count, and fibrinogen fails to consistently provide an assessment of overall hemostatic function and risk of bleeding. Routine use of viscoelastic testing is a well-established way to determine global coagulation status in circumstances such as liver transplant surgery. It allows for real time global and functional evaluation of altered activity of the pro- and anti-coagulant pathways, identifying platelet function, hyper-fibrinolysis, and premature clot dissolution. In one open label randomized controlled trial blood product transfusion guided by viscoelastic testing compared with that guided by quantification of INR or platelet count resulted in significantly fewer patients being transfused with no increase in bleeding complications (5).
In critically ill patients with ALF or ACLF should we use novel coagulation agents (prothrombin complexes, thrombopoietin receptor agonists, antifibrinolytics) to achieve pre-procedure or pre-surgery hematologic targets to reduce bleeding complications/transfusions?
We recommend against using Eltrombopag in ACLF patients with thrombocytopenia prior to surgery/invasive procedures (strong recommendation, moderate-quality evidence).
Thrombocytopenia is common in ACLF. Although Eltrombopag raised platelet counts and avoided platelet transfusions in significantly more patients as compared with placebo in patients with chronic liver disease undergoing elective invasive procedures, it was also associated with thrombotic events of the portal venous system resulting in early termination of the trial (6). Although data on other novel coagulation agents such as prothrombin complex concentrate are not available for ALF/ACLF patients, their use should be tempered by the inability to determine derangements in hemostasis by traditional indices such as INR, fibrinogen and platelet count.
In critically ill patients with ACLF who develop hepatorenal syndrome (HRS) should we use vasopressors?
We recommend using vasopressors, over not using vasopressors, in critically ill patients with ACLF who develop HRS (strong recommendation, moderate-quality evidence).
HRS is a distinct form of kidney injury in patients with cirrhosis and ascites. It occurs in approximately 20% of hospitalized patients with cirrhosis and AKI and portends a very poor prognosis. In the absence of liver transplantation, vasoconstrictor agents combined with albumin remain a common intervention. Patients receiving terlipressin are more likely to survive than those receiving placebo, however, there the available evidence is insufficient to recommend it over other vasoconstrictors (norepinephrine or the combination of midodrine and octreotide) (7,8).
In critically ill patients with ALF or ACLF and hyperglycemia, should we target very tight (80–109 mg/dL) or conventional (110–180 mg/dL) glycemic control?
We recommend targeting a serum blood glucose of 110–180 mg/dL in patients with ALF or ACLF (strong recommendation, moderate-quality evidence).
Evidence does not suggest the benefit of very tight glucose control as compared with conventional glucose control. Very tight glucose control is associated with increased risk of hypoglycemia (9). Further, patients with ALF/ACLF are at risk for hypoglycemia and the risks of hypoglycemia in this population may be underestimated (10). Glycemic management in these patients should incorporate the prevention of hypoglycemia to optimize outcomes.
1. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. 2015. Available at: gradepro.org
. Accessed September 23, 2019
2. Haase N, Perner A, Hennings LI, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis. BMJ 2013; 346:f839
3. Moeller C, Fleischmann C, Thomas-Rueddel D, et al. How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. J Crit Care 2016; 35:75–83
4. Avni T, Lador A, Lev S, et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One 2015; 10:e0129305
5. De Pietri L, Bianchini M, Montalti R, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial. Hepatology 2016; 63:566–573
6. Afdhal NH, Giannini EG, Tayyab G, et al.; ELEVATE Study Group: Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012; 367:716–724
7. Allegretti AS, Israelsen M, Krag A, et al. Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome. Cochrane Database Syst Rev 2017; 6:CD005162
8. Israelsen M, Krag A, Allegretti AS, et al. Terlipressin versus other vasoactive drugs for hepatorenal syndrome. Cochrane Database Syst Rev 2017; 9:CD011532
9. Yamada T, Shojima N, Noma H, et al. Glycemic control, mortality, and hypoglycemia in critically ill patients: A systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 2017; 43:1–15
10. Pfortmueller CA, Wiemann C, Funk GC, et al. Hypoglycemia is associated with increased mortality in patients with acute decompensated liver cirrhosis. J Crit Care 2014; 29:316.e7–e12