Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective, randomized, placebo-controlled, double-blinded trial

Abstract

Introduction: Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting.

Methods: In this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).

Results: A total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint.

Conclusions: Early treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis.

Trial registration: Clinicaltrials.gov: NCT01867645.

Figure 1

Study timeline. Patients with multiple (≥2) organ failure and a diagnosis of SIRS/sepsis were randomized to be treated either with intravenous immunoglobulins (IVIG) or human albumin (placebo) for three consecutive days. Critical illness polyneuropathy and/or myopathy (CIPNM) was assessed at baseline (Day 0) and on Day 14 by electrophysiological stimulation and histological assessment of a muscle biopsy. Primary endpoint was a CIPNM severity sum score on Day 14.

Figure 2

Screening and randomization scheme. Patients were screened for multiple (≥2) organ failure and a SIRS/sepsis diagnosis. Patients meeting these criteria were assessed by a neurologist for clinical signs of critical illness polyneuropathy and/or myopathy (CIPNM). Patients with clinical signs of CIPNM were randomized to receive either intravenous immunoglobulins (IVIG) or placebo.

Figure 3

Critical illness polyneuropathy, myopathy and critical illness polyneuropathy and/or myopathy scores. Critical illness polyneuropathy and/or myopathy (CIPNM) severity sum score was not different on Day 14 between the intravenous immunoglobulin (IVIG) and placebo treatment group based on electrophysiological stimulation and muscle histology. CIPNM severity sum score deteriorated from baseline (Day 0) to Day 14 in both groups (a). Critical illness polyneuropathy (CIP) was similar in the IVIG and placebo treatment group at all times based on electrophysiological stimulation (b). Critical illness myopathy (CIM) scores were similar in the two groups based on muscle histology (c). A two-sided P-value ≤0.05 was considered statistically significant (*).