primary outcome:
Interventions for preventing critical illness polyneuropathy and critical illness myopathy
The primary outcome measure was the incidence of CIP/CIM during ICU stay. We extracted this outcome measure in ICU. As no internationally accepted criteria exist for this diagnosis, we defined CIP/CIM for the purpose of this review as weakness of the limbs or respiratory muscles, or as EMG documented peripheral polyneuropathy or myopathy for which causes other than CIP/CIM have been excluded.Data on the incidence of CIP/CIM were available from both insulin trials for individuals in the ICU for at least seven days (Hermans 2007; Van den Berghe 2005). In the individual studies, significantly fewer participants in the ongoing IIT group developed CIP/CIM compared to the CIT group. In Van den Berghe 2005, the RR was 0.52 (95% CI 0.39 to 0.69) and in Hermans 2007, the RR was 0.77 (95% CI 0.62 to 0.96). Analysis of the whole surgical population who received CIT or IIT was performed as a post hoc intention‐to‐treat analysis (n = 1548) with negative imputation performed for participants who were not screened by EMG because they were no longer in the ICU on day seven. In the whole population IIT reduced the risk of CIP/CIM, as assessed by weekly EMG screenings (RR 0.49, 95% CI 0.37 to 0.66), but this analysis involved imputing data for 74% of the participants. A similar analysis in the medical population revealed an RR of 0.84 (95% CI 0.70 to 1.01), with imputation of 72% of the data.A meta‐analysis of the two insulin trials was possible, which comprised 389 participants treated with IIT and 436 participants treated with CIT. In the surgical trial, but not in the medical trial, significantly fewer IIT participants entered the screened phase. Any bias originated from earlier ICU discharge in the intervention group and would be expected to reduce rather than inflate the effect. Meta‐analysis using a fixed‐effect model showed a significant benefit of IIT in the 'screened' patients, with an RR of 0.65 (95% CI 0.55 to 0.77) (Analysis 1.1, Figure 3). As the statistical heterogeneity here is the result of clinical diversity, the fixed‐effect analysis provides the best estimate of the intervention effect (Deeks 2011). Use of a more conservative random‐effects model, to account for heterogeneity, changes the RR to 0.64 (95% CI 0.44 to 0.94). With only two studies in the meta‐analysis, however, a random‐effects analysis provides poor estimates of the distribution of intervention effects (Deeks 2011). Based on the current data, we cannot exclude a real or artificial difference in the effect size between medical and surgical patients.We have also performed an analysis of practicality, as it is not possible to identify individuals upon admission to ICU as needing ICU for at least one week. We analysed data on the primary outcome measure as well as on the secondary outcome measures in the total randomised population (1360 IIT and 1388 CIT participants). As participants who were in the ICU for less than one week did not undergo an electrophysiological examination, we imputed data for them. For the purpose of the analysis, we categorised those who died as having CIP/CIM, whereas we categorised patients discharged early, and therefore not evaluated, as not having CIP/CIM. This showed that IIT had a significantly beneficial effect on CIP/CIM, with an RR of 0.70 (95% CI 0.60 to 0.82) (Analysis 1.1) but the effect was lost in the random‐effects analysis (RR 0.65, 95% CI 0.38 to 1.11). This conclusion remained when we imputed data only for participants who had been discharged alive and did not make assumptions about the neuromuscular status of those who died early (fixed‐effect model RR 0.60, 95% CI 0.49 to 0.73; random‐effects model RR 0.58, 95% CI 0.33 to 1.02, analysis not shown).The steroid trial (Steinberg 2006) provided primary outcome data on clinical weakness. The trial involved 92 participants, of whom 48 received placebo and 44 received corticosteroids. There was no significant difference between the treatment groups according to the data that the trialists obtained prospectively (incidence of CIP/CIM in the placebo group was 11/48 (23%), and in the intervention group, 11/44 (25%); RR 1.09, 95% CI 0.53 to 2.26) (Analysis 2.1, Figure 4). We also performed an intention‐to‐treat analysis, by imputing data for the first 88 participants, whom the trial authors did not evaluate prospectively. For this purpose we used the retrospective data available for these participants. With imputed data there was also no significant effect (RR 1.27, 95% CI 0.77 to 2.08).The early physical therapy trial reported data on CIP/CIM at hospital discharge and included imputation using an MRC value of zero for non‐survivors (Schweickert 2009). There was no significant difference in the incidence of CIP/CIM in the total randomised population at hospital discharge (15/49 in the intervention group versus 27/55 in the control group with significant weakness, RR 0.62, 95% CI 0.38 to 1.03, analysis not shown). We obtained further data about participants with weakness at ICU discharge through personal communication with the study authors. For the total population randomised to early therapy versus standard care (intention‐to‐treat analysis, imputing worst values for participants who were not evaluable), the RR for the intervention was not significant at ICU discharge (RR 0.81, 95% CI 0.60 to 1.08) (Analysis 3.1, Figure 5). For participants both randomised and actually screened (alive and co‐operative), the RR of CIP/CIM at ICU discharge judged by weakness was 0.62 (95% CI 0.39 to 0.96) (Analysis 3.1, Figure 5).Routsi 2010 reported the incidence of weakness in the 52 evaluable participants from among the 140 participants who were randomised to EMS or control groups. The evaluable treatment and control groups were not completely comparable. There were considerable differences in the baseline characteristics and severity of illness between the EMS and control groups (see Description of studies). In this evaluable subset of participants, EMS had no effect on reducing the incidence of CIP/CIM (EMS 3/24, control 11/28; RR 0.32, 95% CI 0.10 to 1.01). After imputing worst values for the non‐evaluated 88 participants, as in Schweickert 2009, the effect of EMS on CIP/CIM was even less significant (RR 0.94, 95% CI 0.78 to 1.15) (Figure 6).