The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial*

Abstract

Objective Nosocomial infection / sepsis occurs in up to 40% of children requiring long stay intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein would reduce the occurrence of nosocomial infection / sepsis in this at-risk population. Design Randomized double blinded comparative effectiveness trial. Setting Eight pediatric intensive care units in the NICHD Collaborative Pediatric Critical Care Research Network. Patients Two hundred and ninety three long stay intensive care patients (age 1–17 years) expected to require more than 72 hours of invasive care. Interventions Patients were stratified according to immunocompromised status and center and then randomly assigned to receive daily enteral zinc, selenium, glutamine and IV metoclopramide (n = 149 ZSGM), or daily enteral whey protein (n = 144 WHEY) and IV saline, for up to 28 days of intensive care unit stay. The primary endpoint was time to development of nosocomial sepsis / infection. The analysis was intention to treat. Measurements and Main Results There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection / sepsis (median WHEY 13.2 days vs ZSGM 12.1 days, p=0.29 by log rank test) or the rate of nosocomial infection / sepsis (4.83/100 days WHEY vs. 4.99/100 days ZSGM, p = 0.81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection / sepsis with ZSGM in this immunocompromised group (6.09/100 days WHEY vs 1.57/100 days ZSGM, p value = 0.011). Conclusions Compared with WHEY supplementation, ZSGM conferred no advantage in the immunecompetent population. Further evaluation of ZSGM supplementation is warranted in the immunocompromised long stay PICU patient.

Inherent Risk Factors for Nosocomial Infection in the Long Stay Critically Ill Child Without Known Baseline Immunocompromise

“…In this regard, we completed the Critical Illness Stress induced Immune Suppression (CRISIS) prevention comparative effectiveness trial in which long stay pediatric intensive care patients were stratified according to baseline immune status and randomized to one of two nutriceutical strategies: whey protein with essential amino acids and lactoferrin, or zinc, selenium, glutamine, and the prolactin secretagogue metoclopromide. 3 There were no differences in time to nosocomial infection or rate of nosocomial infection between treatment arms in the population without known immunocompromise at baseline. In order to identify risk factors for the development of nosocomial infection and to inform future interventional trials in long stay pediatric intensive care unit patients without known baseline immunocompromise, we performed a retrospective cohort analysis of this trial's database comparing patients in this group who did and did not develop nosocomial infection.…”

“…Therefore, we included all pediatric intensive care unit patients who were not known to have baseline immunocompromise, and who were followed for more than 3 days after PICU admission in our previously published randomized, double-blinded, comparative effectiveness trial for the prevention of Critical Illness Stress induced Immune Suppression related nosocomial infection. 3 Children were considered to have no known baseline immunocompromise if they were not found to have an admission diagnosis of cancer, Acquired Immune Deficiency Syndrome, solid organ transplantation, stem cell transplantation, autoimmune disease, primary immunodeficiency syndromes, or chronic use of immune suppressant therapies. In this analysis, patient study records were reviewed in detail for these characteristics, and thus numbers differ slightly from the previously reported “as-randomized” immune competent stratum (3).…”

“…1 It is well established that hospital acquired infections are more common in long stay patients who are in the pediatric intensive care unit (PICU) for longer than three days with concomitant invasive measures. 2,3 Up to 40% of these children acquire nosocomial infection and/or sepsis after being in the pediatric intensive care unit for 14 days. Among this population, children with known immunocompromise at baseline are at greatest risk for acquiring nosocomial infection related in part to their inability to fight infection; however, this group of children accounts for at most 10 % of the population in the pediatric intensive care unit.…”

“…Among this population, children with known immunocompromise at baseline are at greatest risk for acquiring nosocomial infection related in part to their inability to fight infection; however, this group of children accounts for at most 10 % of the population in the pediatric intensive care unit. 3 An important knowledge gap exists as to what factors predispose to, or protect against development of nosocomial infection in the other 90% of long stay pediatric intensive care unit patients without known baseline immunocompromise.…”

Increased plasma selenium is associated with better outcomes in children with systemic inflammation

“…A multicenter, double-blinded trial was conducted in which patients were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide or daily enteral whey protein and intravenous saline for up to 28 d of ICU stay. The supplementation of zinc, selenium, glutamine, and metoclopramide conferred no advantage in nosocomial infection and sepsis prevention except in a small subgroup of 13 patients who were immunocompromised [38].…”