Reply
Authors: Nadim Mahmud, Sumeet K. Asrani
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. We appreciate the interest in our article which details the derivation and external validation of the Model for End‐Stage Liver Disease‐Lactate (MELD‐LA) score (bswh.md/meldla).(1) Among patients with cirrhosis admitted to the hospital for liver‐related indications, we found MELD‐LA to significantly improve in‐hospital mortality predictions versus MELD and MELD‐Na. Singh and colleagues note that in the development cohort (n = 14,733), only 38% of patients had admission lactate levels measured, which could indicate selection bias. This is an important consideration as patients who have lactate measured on clinical grounds are intuitively more likely to have hypoperfusion or critical illness compared to those who do not. However, this may not represent selection bias per se but rather speaks to an issue of external validity. MELD‐LA performs well among hospital admissions where lactate levels would typically be measured, a justifiable conclusion from our study because MELD‐LA was compared to MELD and MELD‐Na only among those hospitalizations. Prospective studies where lactate is uniformly measured at hospitalization are necessary to evaluate and potentially expand the role of MELD‐LA to other admissions. Also, the authors point out that incorporating age and hepatic encephalopathy (HE) into the final model could have improved prediction model performance, as well as consideration of preadmission medications. Indeed, we did find age to improve model discrimination (c‐statistic 0.816 for MELD‐LA–age versus 0.805 for MELD‐LA) and overall performance (Brier score 0.119 versus 0.120). However, for a clinical prediction tool to be readily adopted, parsimony must be considered. In this case, we did not feel the incremental improvement attributable to age was sufficient to justify the addition of another model input. HE similarly was not associated with significant improvement in model performance. As an illustration, the net reclassification index for MELD‐LA–age–HE versus MELD‐LA was 2%, indicating that risk classification improved in only 2% of patients when age and HE were incorporated. Furthermore, HE is assessed subjectively, which may be difficult to harmonize in clinical practice. Regarding consideration of prehospital medications, this is an interesting point and warrants future study. The impact of nonselective beta‐blockers in particular would be of interest as they may predispose some patients to worsened hypoperfusion in the setting of critical illness. Finally, the authors point out that patients with acute on chronic liver failure (ACLF) represent a unique group where MELD‐LA should be independently assessed for risk stratification. We agree with this sentiment as ACLF confers extremely high short‐term mortality and represents a significant health care burden. Improved risk‐stratification tools are critical for this condition, and we hope to see dedicated external validation studies of MELD‐LA in patients with ACLF. Efforts to identify patient subsets where MELD‐LA performs well (or not well) are currently underway.