In the case of Acute-Chronic Liver Failure (ACLF), liver transplant (OLT) is the only potentially curative option. However, the survival benefit of transplantation varies widely, ranging from 43% to 75% in Europe, with over 90% in the Asia-Pacific regions. In addition to the urgent need for organ transplantation, approximately 67% of those on the waiting list for ACLF patients die before they can be transplanted. This high mortality rate is mainly due to sepsis, respiratory failure with mechanical ventilation, high vasopressor requirement and the need for renal replacement therapy (RRT).
On the other hand, transplantation should be avoided even though there is not much need. Indeed, if often characterized by severe prognosis, many patients do not improve post-transplant course. Many authors agree that organ transplantation should not be recommended when cardiac or pulmonary support is needed or when there is rapidly progressive organ failure, as in these cases, organ transplantation may shorten a person’s lifespan as opposed to offering survival benefits.
It revealed that patients with degradation in the ACLF grade 3 score, when listed in a lower class of transplant, had significantly lower post-transplant mortality than patients without this disorder (12% versus 18%). Improvement in circulatory failure, brain failure, or removal from mechanical ventilation has the strongest impact on post-transplant survival.
These data further reinforce the paradigm that early selection of good candidates for OLT (realistically within the first week after admission) is imperative to avoid futility. To maximize the survival advantage through the correct selection of an OLT candidate, some algorithms have been proposed, but these still await external validation.
Besides OLT, other treatments for liver failure have become attractive in the past few years, with discordant results. This is, at least in part, due to the different criteria used to describe the ACLF from different geographic areas, with difficult conclusions. ACLF can act as a bridging therapy with high levels of circulating pro- and anti-inflammatory agents, extracorporeal depurating devices, the molecular adsorbent recirculation system (MARS) and PROMETHEUS OLT. Unfortunately, data on the effectiveness of these tools is disappointing.
In a meta-analysis and systematic review by Kiaergard et al., No benefit of MARS therapy in reducing mortality compared to standard medical therapy was noted. These results show no benefit on short-term transplant-free survival with these modalities, two recently published European randomized multicenter controlled trials, namely the HELIOS (for Prometheus) and the RELIEF study (for MARS).
Therefore, their use is not currently recommended by international guidelines. Bio-artificial liver (BAL) assist devices such as AMC-BAL Bioreactor, HepatAssist device (using pig hepatocytes attached to collagen-coated microcarriers and charcoal columns) and extracorporeal liver assist device (ELAD) -C3A using human hepatoblastoma cells, inconsistent results on survival provided.
Therefore, the treatment of liver failure as well as OLT is still largely disappointing. An interesting issue is the use of nonselective beta blockers in patients with ACLF. Mookerjee et al. In a retrospective study by. When performed in a subset of patients enrolled in the CANONIC study, patients on carvedilol therapy (47%) had a lower 28-day mortality (24% versus 34%, p = 0.048), a less severe ACLF, and a slower progression. ACLF over the duration of the study relative to non-NSBB.
Moreover, patients who discontinued NSBBs after ACLF developed (n = 78) had a higher mortality (37% versus 13%). These data, Kumar et al. administration of carvedilol to patients with ACLF without esophageal varices and moderately high HVPG. The authors reported that carvedilol improved survival and reduced the risk of developing AKI and SBP for up to 28 days. However, these preliminary data need further validation before carvedilol enters the hepatologists’ medical weapon to improve ACLF.
Treatment of Renal Failure
Acute kidney injury (AKI) is the most common organ failure in patients with ACLF, type 1 hepatorenal syndrome (HRS1) and more severe prototype. AKI complicating ACLF has been shown to be more severe and less responsive to treatment than AKI complicating cirrhosis. The correct approach to AKI in cirrhosis has been specifically addressed in the last few years. Early diagnosis of AKI is crucial to adopting the right treatment. A multidisciplinary panel of experts recently proposed a useful diagnostic algorithm based on serum creatinine (Scr) monitoring.
It should be noted that serum creatinine tends to exaggerate renal function in cirrhotic patients. The International Ascites Club recommends referencing the Scr determined in the last 3 months for monitoring and staging AKI, while GFR assessment is not recommended for hospitalized patients. Oliguria is a useful tool for diagnostic purposes and even a useful clinical parameter in determining the severity of renal dysfunction. Regardless of the increase in Scr, the development of worsening oliguria or anuria should be considered AKI until proven otherwise.
Volume expansion is the fundamental step of AKI management. Albumin should be preferred to crystalloids due to its oncotic and non-oncotic properties and should be the first choice plasma expander in case of bacterial infection, suspected type-1 HRS or when the cause of AKI is uncertain. The recommended regimen is an infusion of 25% albumin 1 g / kg on day 1 followed by 20-40 g / day until renal function is restored.
The purpose of albumin infusion is to counteract dramatic renal hypoperfusion and intrarenal vasoconstriction. Albumin plus vasoconstrictor infusion as terlipressin is the recommended combined therapy for HRS1 and should be initiated as soon as possible. The sooner we start vasoconstrictor therapy, the better the chances of survival.
Renal replacement is the only reasonable approach in the event of renal damage. RRT is recommended if AKI worsens, fluid overload worsens despite diuretic therapy, or acid-base status worsens. However, the role of dialysis is still under evaluation and in clinical practice; mostly reserved for OLT candidates.
Treatment of Circulatory and Cardiac Dysfunction
As stated earlier, circulatory dysfunction due to vascular vasodilation and associated hypotension is a serious complication of ACLF. Cirrhotic patients with a hyperdynamic and hypodynamic circulatory state have a higher risk of fatal ACLF. Arterial hypotension has been shown to be an independent risk factor for the development of ACLF. In particular, cirrhotic patients with a hyperdynamic state expressed by an increased cardiac index (> CI4.2 L / min / m2) have increased circulating levels of IL-6/8 and PCR and are at great risk of developing fatal ACLF. Pharmacological support including amine infusion, inotropic agents and fluid administration is the recommended approach. In critically ill patients, a mean arterial pressure of 60 mmHg or more should be the target.
Repeated serum lactate determination is the best way to monitor circulatory disturbance, and repeated lactate determination is more informative than absolute value due to impaired lactate clearance in patients with cirrhosis. Since aggressive fluid administration in cirrhosis may cause tissue edema and increase in total body water retention, which may adversely affect the result, it is imperative to pay attention to fluid support. It is well known that as a result of very aggressive fluid administration, cirrhotic patients are particularly prone to develop extracellular edema, ascites and pulmonary edema.
In volume depleted patients, normal 0.9% saline solution or balanced salt solutions such as PlasmaLyte are recommended at an initial dose of 10-20 ml / kg. Albumin infusion is highly recommended as a plasma extender. The benefits of albumin infusion in patients with cirrhosis go beyond simple volume expansion and are based on numerous biological properties. Albumin infusion is highly recommended in three specific cases: SBP, large volume paracentesis, and type-1 HRS. Additionally, albumin infusion prevents AKI in patients with infections other than SBP. Regarding amine selection, norepinephrine should be the first-line agent associated with fewer adverse events.
Vasopressin and terlipressin can be used as second-line agents that can provide hemodynamic improvement. In critically ill patients, corticosteroids may be useful in reducing vasopressor doses and increasing the rate of shock recovery. The rationale for corticosteroid administration is based on relative adrenal insufficiency (RAI), which is commonly associated with circulatory dysfunction in critically ill cirrhosis patients. Corticosteroids have shown a survival benefit in some studies, but not in all studies. Hydrocortisone should be administered in divided doses of 200-300 mg / day to patients who are partially responsive to vasopressor agents.
Neurological Dysfunction Treatment
Brain dysfunction is part of the multi-organ failure that complicates ACLF, and HE grade 3 or 4 is required for the diagnosis of ACLF according to the EASL-CLIF definition. Correct interpretation and differential diagnosis of brain dysfunction is difficult as several conditions may be the cause. Although EEG can help rule out other causes of altered mental state, EEG changes are of limited value in the diagnosis of HE. Brain imaging can be useful to exclude other causes of the mental state and exclude intra-cerebral hemorrhage, especially in critically ill cirrhosis patients with coagulative disorders.
Fasting ammonia measurement is routinely done in clinical practice to distinguish HE from other conditions. However, high ammonia levels alone are not recommended for the diagnosis of HE, as false positive results are common. The West Haven criteria (WHC) are useful for HE staging and management and indicate patients in need of advanced airway protection. The Glasgow coma scale (GCS) is another simple clinical tool commonly used in HE patients, and a threshold of <8 is a useful parameter for deciding on airway protection. Lactulose is the recommended initial therapy for HE. Other options such as rifaximin, LOLA, intravenous albumin, or other laxatives are currently not recommended for HE therapy.
Author: Ozlem Guvenc Agaoglu