We thank Jain et al (1) for their thoughtful comments on our article (2). The authors have commented on the utility of initiating continuous renal replacement therapy (CRRT) in pediatric acute liver failure (PALF). The two main causes of death in PALF are sepsis and raised intracranial pressure. Though a number of toxins are implicated in the pathogenesis of cerebral edema of hepatic encephalopathy (HE), the most important, measurable, and clinically modifiable factor identified as a causal link and treatment point for HE is ammonia. Ammonia is neurotoxic and causes cytotoxic cerebral edema. It can cause additional changes in neurotransmitter synthesis and release, mitochondrial function, and neuronal oxidative stress. Drolz et al (3) and Scott et al (4) have clearly demonstrated that high ammonia concentrations are independently associated with increased mortality in acute liver failure (ALF) and inability to decrease ammonia after starting CRRT is a poor prognostic factor. Therefore, removing ammonia in PALF is important. Ammonia is highly water soluble (100 mL of water can dissolve as much as 31 g of ammonia) and has low molecular weight; both these features make it a highly attractive target for CRRT. We agree with Jain et al (1) that other albumin-bound toxins (bilirubin, bile salts, metabolites of aromatic amino acids, and medium chain fatty acids) might be present and contribute to progression of ALF. However, most of these metabolites cannot be measured in clinical practice and their removal by albumin dialysis devices like Molecular Adsorbents Re-Circulating System (MARS) and Single Pass Albumin Dialysis (SPAD) have not shown any correlation to survival. CRRT is mainly used for detoxification of ammonia, lactate, and manipulating fluid balance in PALF. In addition, MARS and SPAD are technically challenging and costly procedures, which are infrequently performed in PICUs when compared with CRRT, which is a commonly performed intervention in a number of non-liver patients.
We have discussed on pages 2 and 3 of our original article that we used eight broad indications to initiate CRRT in our patient cohort (2). We, however, emphasized on page 3 that “Importantly, not one single indication was considered a sole reason to initiate CRRT; it was a clinical decision and all contributory factors were recorded.” Jain et al (1) have pointed out that only 27% of our patients initiated on CRRT had more than grade 2 HE and the remaining had grade 1 or no HE. We would want to clarify that though these patients might have no HE (which anyways in very difficult to diagnose in children and is not an essential criteria to diagnose PALF), they might have other indications to be initiated on CRRT as discussed on page 2. The main aim of CRRT in PALF is to create a milieu for either spontaneous regeneration of the liver or successful liver transplantation.
It is very difficult to stratify mortality in patients treated with CRRT according to grade of encephalopathy due to very small numbers (in each category). Squires R published outcomes of 769 children with and without HE from the PALF Study Group and demonstrated that mortality 21 days after enrollment was highest in participants enrolled with severe HE (grades III or IV) or demonstrating HE progression (5).
Refractory hyperammonemia is probably related to the severity of liver failure as liver is an important organ for ammonia detoxification into urea. As demonstrated by Slack et al (6), increasing the dose of CRRT to 90 mL/kg/hr from a standard dose of 35 mL/kg/hr significantly increased ammonia clearance in patients with liver failure.