Interventions to reduce neuromuscular complications acquired during the acute phase of critical illness

Review question

We reviewed the evidence about the effect of treatments to prevent or reduce complications affecting the nerves or muscles during the severe, early phase of critical illness. These complications are called critical illness polyneuropathy or myopathy (CIP/CIM) and can affect nerves, muscles or both.

Background

CIP/CIM is a frequent complication of critical care. CIP/CIM causes weakness of limbs and of muscles used for breathing. These difficulties can make it difficult for the person to come off a ventilator and start rehabilitation. CIP/CIM can also mean a longer stay in the intensive care unit (ICU) and increases the risk of death. Recovery takes weeks or months and in severe cases it may be incomplete or absent. Prevention and treatment of CIP/CIM is therefore very important.

Study characteristics

We searched for all randomised controlled trials (RCTs) that looked at the effects of any treatment to prevent CIP/CIM in adults admitted to an ICU. We identified and analysed five trials that were suitable for inclusion in our review. These trials studied four treatments: intensive insulin therapy (IIT), corticosteroid therapy, early rehabilitation, and electrical muscle stimulation.

Key results and quality of the evidence

Two trials, with a total of 825 adults staying in ICU for one week or more, studied the effect of IIT versus conventional insulin therapy (CIT) on the incidence of CIP/CIM. IIT aimed to produce normal blood sugar levels (80 to 110 mg/dL) and CIT aimed to avoid high blood sugar (blood sugar over 215 mg/dL). Combining the results of both trials showed moderate quality evidence that IIT reduces CIP/CIM. There was high quality evidence that it reduced time spent on a ventilator, ICU stay and 180-day mortality but not 30-day mortality. There were more episodes of low blood sugar with IIT. Although there was not an increase in deaths within 24 hours of episodes of low blood sugar, low blood sugar remains a concern as it can damage the brain. Neither trial reported the degree of limb weakness or on physical rehabilitation. The results came from a subgroup of people who were in the ICU for a long time, which may also limit the conclusions.

The third trial compared corticosteroid therapy with a placebo in 180 people with acute respiratory distress syndrome (ARDS). Moderate quality evidence suggested no effect of corticosteroids on CIP/CIM (in 92 participants evaluated). High quality evidence showed no effect on 180-day mortality, new serious infections, blood glucose levels on day seven or episodes of suspected or probable pneumonia. There were fewer episodes of shock (a life-threatening condition where there is a lack of blood flow to vital organs).

The fourth trial was of on early rehabilitation in 104 participants in a medical ICU. There was moderate quality evidence of a reduction in CIP/CIM in the 82 participants who could be evaluated in the ICU. This effect was not significant when imputation to intention-to-treat analysis was performed. Early rehabilitation reduced the duration of mechanical ventilation but did not affect ICU stay or deaths. The trial reported no serious adverse events.

Finally, a trial compared the effect of EMS of the lower limbs to no stimulation. The trial included 140 participants but provided results for only 52 of them. It supplied very low quality evidence that EMS was without effect in preventing CIP/CIM. There was no effect on duration of mechanical ventilation or deaths. Because the EMS and control groups differed in type and severity of disease,   these findings may not be reliable. Results were even less significant when imputation to intention-to-treat analysis was performed. The study found no effect of EMS on duration of mechanical ventilation or deaths.

The evidence is up to date as of October 2011. We re-ran the search for studies in December 2013 and identified nine additional potentially eligible studies that we will assess in the next update of the review.

Authors' conclusions: 

There is moderate quality evidence from two large trials that intensive insulin therapy reduces CIP/CIM, and high quality evidence that it reduces duration of mechanical ventilation, ICU stay and 180-day mortality, at the expense of hypoglycaemia. Consequences and prevention of hypoglycaemia need further study. There is moderate quality evidence which suggests no effect of corticosteroids on CIP/CIM and high quality evidence that steroids do not affect secondary outcomes, except for fewer new shock episodes. Moderate quality evidence suggests a potential benefit of early rehabilitation on CIP/CIM which is accompanied by a shorter duration of mechanical ventilation but without an effect on ICU stay. Very low quality evidence suggests no effect of EMS, although data are prone to bias. Strict diagnostic criteria for CIP/CIM are urgently needed for research purposes. Large RCTs need to be conducted to further explore the role of early rehabilitation and EMS and to develop new preventive strategies.

Read the full abstract...
Background: 

Critical illness polyneuropathy or myopathy (CIP/CIM) is a frequent complication in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, longer ICU stay and increased mortality. This is an interim update of a review first published in 2009 (Hermans 2009). It has been updated to October 2011, with further potentially eligible studies from a December 2013 search characterised as awaiting assessment.

Objectives: 

To systematically review the evidence from RCTs concerning the ability of any intervention to reduce the incidence of CIP or CIM in critically ill individuals.

Search strategy: 

On 4 October 2011, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We checked the bibliographies of identified trials and contacted trial authors and experts in the field. We carried out an additional search of these databases on 6 December 2013 to identify recent studies.

Selection criteria: 

All randomised controlled trials (RCTs), examining the effect of any intervention on the incidence of CIP/CIM in people admitted to adult medical or surgical ICUs. The primary outcome was the incidence of CIP/CIM in ICU, based on electrophysiological or clinical examination. Secondary outcomes included duration of mechanical ventilation, duration of ICU stay, death at 30 and 180 days after ICU admission and serious adverse events from the treatment regimens.

Data collection and analysis: 

Two authors independently extracted the data and assessed the risk of bias in included studies.

Main results: 

We identified five trials that met our inclusion criteria. Two trials compared intensive insulin therapy (IIT) to conventional insulin therapy (CIT). IIT significantly reduced CIP/CIM in the screened (n = 825; risk ratio (RR) 0.65, 95% confidence interval (CI) 0.55 to 0.77) and total (n = 2748; RR 0.70, 95% CI 0.60 to 0.82) population randomised. IIT reduced duration of mechanical ventilation, ICU stay and 180-day mortality, but not 30-day mortality compared with CIT. Hypoglycaemia increased with IIT but did not cause early deaths.

One trial compared corticosteroids with placebo (n = 180). The trial found no effect of treatment on CIP/CIM (RR 1.27, 95% CI 0.77 to 2.08), 180-day mortality, new infections, glycaemia at day seven, or episodes of pneumonia, but did show a reduction of new shock events.

In the fourth trial, early physical therapy reduced CIP/CIM in 82/104 evaluable participants in ICU (RR 0.62. 95% CI 0.39 to 0.96). Statistical significance was lost when we performed a full intention-to-treat analysis (RR 0.81, 95% CI 0.60 to 1.08). Duration of mechanical ventilation but not ICU stay was significantly shorter in the intervention group. Hospital mortality was not affected but 30- and 180-day mortality results were not available. No adverse effects were noticed.

The last trial found a reduced incidence of CIP/CIM in 52 evaluable participants out of a total of 140 who were randomised to electrical muscle stimulation (EMS) versus no stimulation (RR 0.32, 95% CI 0.10 to 1.01). These data were prone to bias due to imbalances between treatment groups in this subgroup of participants. After we imputed missing data and performed an intention-to-treat analysis, there was still no significant effect (RR 0.94, 95% CI 0.78 to 1.15). The investigators found no effect on duration of mechanical ventilation and noted no difference in ICU mortality, but did not report 30- and 180-day mortality.

We updated the searches in December 2013 and identified nine potentially eligible studies that will be assessed for inclusion in the next update of the review.

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