Withholding parenteral nutrition during critical illness increases plasma bilirubin but lowers the incidence of biliary sludge

Abstract

Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in the intensive care unit (ICU) (late PN) accelerated recovery as compared with early initiation of PN (early PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large randomized controlled trial of early PN versus late PN (n 5 4,640). In all patients plasma bilirubin (daily) and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], twice weekly; n 5 3,216) were quantified. In a random predefined subset of patients, plasma bile acids (BAs) were also quantified at baseline and on days 3, 5, and last ICU-day (n 5 280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n 5 776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late PN than in the early PN group (P < 0.001). In the late PN group, as soon as PN was started on day 8 bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP, and ALT were lower in the late PN group (P < 0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (P < 0.01), similarly for the two groups. Fewer patients in the late PN than in the early PN group developed biliary sludge on day 5 (37% versus 45%; P 5 0.04). Conclusion: Tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP, and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early PN. (HEPATOLOGY 2014;60:202-210)

Cholestatic liver (dys)function during sepsis and other critical illnesses

“…Biochemical markers of hepatocytic damage (maximum levels ALT) and of cholestasis (GGT, ALP) were lower in the group that did not get parenteral nutrition during the first week. In contrast, plasma bilirubin was significantly higher in this group throughout the 7-day intervention window, and became equal to the group receiving parenteral nutrition as soon as parenteral nutrition was started also in the fasting group beyond that first week [60].…”

“…Reducing the load of inflammatory signaling molecules to the liver microenvironment, in order to decrease the need for an adaptive response may be desirable. The latter can be achieved by reducing risk factors that provoke CLD, such as prevention of hyperglycemia and avoiding the administration of parenteral nutrition during acute critical illness [9,60]. Opioids have been suggested to attenuate the inflammatory response and sequential liver injury, but this is still being investigated in vitro and in vivo, and thus clinical evidence is currently lacking [80,81].…”

“…Lowering blood glucose levels with insulin reduced biliary sludge and cholestasis in prolonged critical illness. [9,[60][61][62].…”

Timing and Indication for Parenteral Nutrition in the Critically Ill

“…While hyperbilirubinemia was less frequent, other markers of cholestasis and hepatocellular damage (gamma glutamyl transferase, alkaline phosphatase and alanine amino transferase) increased more in early PN patients. Moreover, early PN increased the incidence of biliary sludge in patients with prolonged ICU stay [ 29 ]. Early PN increased hospital expenditures [ 30 ].…”

Shades of yellow: Monitoring nutritional needs and hepatobiliary function in the critically ill

“…In this issue of H epatology, Vanwijngarden et al report the results of a preplanned subanalysis on hepatobiliary outcome parameters of the large (4,640 patients), multicenter, randomized EPaNIC trial that addressed the fundamental uncertainty regarding caloric goals and parenteral supplementation to achieve these goals that is reflected in the discrepancy between American and European guidelines. Delaying PN beyond day 7 (according to the American standards) was associated with faster recovery and fewer complications overall, as compared with early initiation .…”