Target mean arterial pressure in critically ill cirrhotic patients with septic shock: More is not always better!

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shockJournal of HepatologyVol. 79Issue 2PreviewA high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85 mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. Full-Text PDF Reply to: “Target mean arterial pressure in critically ill cirrhotic patients with septic shock: More is not always better!”: High low target mean arterial pressure in septic shock in cirrhosis – A personalized TARGET-C approach may solve the conundrum!Journal of HepatologyPreviewHigh vs. low target mean arterial pressure in septic shock in cirrhosis – A personalized TARGET-C approach may solve the conundrum! Full-Text PDF We read with great interest a recently published prospective open-label randomized-controlled trial by Maiwall et al.[1]Maiwall R. Rao Pasupuleti S.S. Hidam A.K. Kumar A. Tevethia H.V. Vijayaraghavan R. et al.A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock.J hepatol. 2023; 79: 349-361https://doi.org/10.1016/j.jhep.2023.04.006Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar including 150 of 604 critically ill patients with cirrhosis (CIC) with septic shock. Over 31 months, the authors randomized 75 patients each into high (80-85 mmHg) vs. low (60-65 mmHg) mean arterial pressure (MAP) target groups. The baseline MAP of all included patients was around 57 mmHg. All patients initially received norepinephrine, while terlipressin, vasopressin and intravenous low-dose hydrocortisone were used as second-line vasopressors, to maintain the target MAP for a maximum of 5 days or until recovery of shock and or acute kidney injury (AKI). We have a few essential comments to note: First, the basic premise of using a higher MAP strategy in CIC patients to improve organ perfusion needs reconsidering. Inotropically targeting higher MAP in CIC with septic shock shows a J-shaped curve for outcomes. While optimal organ perfusion requires a MAP of 65-70 mmHg, there is a risk of hypo-perfusion with a MAP lower than this. Paradoxically, a high MAP is also associated with hypo-perfusion due to microcirculatory ischemia from prolonged systemic vasoconstriction. Note, in this study, the H-MAP strategy was associated with more ischemic adverse events (30.7% vs. 18.7%) in more patients (25.3% vs. 13.3%) requiring more protocol violations (24% vs. 10.6%). Although the authors suggest that higher MAP may improve endothelial function, based upon better markers of endothelial injury and repair in a subgroup (n = 40) of H-MAP patients, findings on organ protection should be interpreted cautiously. The authors assumed a 28-day survival of 60% vs. 35% in H-MAP and L-MAP groups of CIC with septic shock, respectively. However, 28-day mortality was approximately 60%, similar in both the L-MAP vs. H-MAP groups, on both intention-to-treat (56% vs. 65%) and per-protocol analyses (60% vs. 61%), respectively. The study trial included mostly middle-aged males with alcohol-related liver disease with a mean MELD score of 32 with septic shock. Inherently such patients have a high risk of short-term mortality attributable to multiple factors. So the validity of using short-term mortality (28 days) as the primary study endpoint of this study is not very convincing. The current trial results demonstrate that targeting a higher MAP was associated with improved renal outcomes and a better tolerance of dialysis. However, the baseline creatinine of this entire cohort was around 0.9 mg/dl. Hence it will be interesting to know how many CIC with septic shock had AKI at baseline. Besides, the outcomes of AKI depend on the stage, so it would be good to know the AKI staging of this cohort. The study used the ADQI definition to define AKI recovery in patients on dialysis, as a very small proportion of patients met the definitions of complete renal recovery proposed by the International Club of Ascites. This finding deserves some attention. Factually even then only a numerical trend toward higher AKI reversal at day five was observed in the H-MAP vs. L-MAP group (34 [45%] vs. 23 [31%], p = 0.06). Only 23 patients had AKI recovery (ten were in the high MAP group, and 13 were in the low MAP group). Taken together, we are unconvinced that a higher MAP strategy has improved renal outcomes. Lastly, terlipressin is an effective vasopressor agent and its usage is mainly indicated in patients with cirrhosis, with hepatorenal syndrome and variceal bleeding. In this study, 29% and 36% of patients received terlipressin as the second vasopressor agent. Firm evidence exists that terlipressin is associated with a significantly higher incidence of ischemic and pulmonary complications,[2]Sigal S.H. Sanyal A.J. Frederick R.T. Weinberg E.M. Pappas S.C. Jamil K. Terlipressin treatment is associated with reversal of hepatorenal syndrome in patients with alcoholic hepatitis [published online ahead of print, 2023 Feb 26].Clin Gastroenterol Hepatol. 2023; (;S1542-3565(23)00157-X. https://doi.org/10.1016/j.cgh.2023.02.015)Google Scholar and can increase mortality in patients with high AKI stages. Consequently, the FDA label includes a warning regarding terlipressin use in patients with ACLF grade 3.[3]FDA Cardiovascular and Renal drugs Advisory committee. Mallinckrodt Pharmaceuticals.Google Scholar Also, the reasonable dosage of terlipressin in CIC with septic shock is still unknown. In this context, more evidence is required before the routine use of terlipressin as a vasopressor in CIC without AKI can be justified. To summarize, septic shock in CIC is a major healthcare concern and is associated with high morbidity and mortality. We commend the authors for conducting a very exhaustive and complex trial, studying an important clinical question. We believe a H-MAP strategy comes with high rates of serious adverse effects. The organ protection effect of H-MAP needs to be further investigated. Pending an unmet need for appropriate target MAP pressures in CIC with septic shock, individual patient care should be guided by fluid and vasopressor responsiveness and its effect on microcirculation. The authors received no financial support to produce this manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Kishore Kumar Ariga – Data curation; original draft; review & editing Dhiraj Agrawal - Conceptualization; Data curation; original draft; review & editing and approval of the final version. The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1