interventions for preventing critical illness ... · [intervention review] interventions for...

Interventions for preventing critical illness polyneuropathy

and critical illness myopathy (Review)

Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT), Outcome 1

Occurence of CIP/CIM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Analysis 1.2. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT), Outcome 2 Duration

of mechanical ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Analysis 1.3. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT), Outcome 3 Duration

of ICU stay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Analysis 1.4. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT), Outcome 4 Death. 28

Analysis 1.5. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT), Outcome 5 Severe

adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Analysis 2.1. Comparison 2 Corticosteroids versus placebo, Outcome 1 Occurence of CIP/CIM. . . . . . . . 30

Analysis 2.2. Comparison 2 Corticosteroids versus placebo, Outcome 2 Death. . . . . . . . . . . . . . 31

Analysis 2.3. Comparison 2 Corticosteroids versus placebo, Outcome 3 Severe adverse events (dichotomous data). . 31

Analysis 2.4. Comparison 2 Corticosteroids versus placebo, Outcome 4 Serious adverse events (continuous data). . 32

Analysis 3.1. Comparison 3 Recombinant human growth hormone versus placebo, Outcome 1 Death. . . . . . 33

Analysis 4.1. Comparison 4 Immediate postoperative enteral feeding versus no enteral feeding, Outcome 1 Duration of

ICU stay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Analysis 5.1. Comparison 5 Inspiratory muscle training (IMT) versus no IMT, Outcome 1 Duration of mechanical

ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

34APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iInterventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)


[Intervention Review]

Interventions for preventing critical illness polyneuropathyand critical illness myopathy

Greet Hermans2, Bernard De Jonghe3, Frans Bruyninckx4 , Greet Van den Berghe1

1Department of Intensive Care Medicine, Catholic University of Leuven, University Hospitals, Leuven, Belgium. 2Department of

General Internal Medicine, Medical Intensive Care Unit, Catholic University of Leuven, University Hospitals Leuven, Leuven, Belgium.3Réanimation Médico-Chirurgicale, Centre Hospitalier de Poissy-Saint-Germain, Poissy, France. 4Physical Medicine and Rehabilita-

tion, Catholic University of Leuven, University Hospitals Leuven, Leuven, Belgium

Contact address: Greet Van den Berghe, Department of Intensive Care Medicine, Catholic University of Leuven, University Hospitals,

Herestraat 49,3000, Leuven, Belgium. [email protected].

Editorial group: Cochrane Neuromuscular Disease Group.

Publication status and date: New, published in Issue 1, 2009.

Review content assessed as up-to-date: 30 October 2007.

Citation: Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Interventions for preventing critical illness polyneu-

ropathy and critical illness myopathy. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006832. DOI:

10.1002/14651858.CD006832.pub2.


A B S T R A C T

Background

Critical illness polyneuro-and/or myopathy (CIP/CIM) is an important and frequent complication in the intensive care unit (ICU),

causing delayed weaning from mechanical ventilation. It may increase ICU stay and mortality.

Objectives

To examine the ability of any intervention to prevent the occurrence of CIP/CIM.

Search strategy

We searched the Cochrane Neuromuscular Disease Group Trials Register (October 2007), MEDLINE (January 1950 to April 2008),

EMBASE (January 1980 to October 2007), checked bibliographies and contacted trial authors and experts in the field.

Selection criteria

All randomised controlled trials (RCTs), examining the effect of any intervention on the incidence of CIP/CIM in adult medical

or surgical ICU patients. The primary outcome measure was the incidence of CIP/CIM after at least seven days in ICU, based on

electrophysiological or clinical examination.

Data collection and analysis

Two authors independently extracted the data.

Main results

Three out of nine identified trials, provided data on our primary outcome measure. Two trials examined the effects of intensive insulin

therapy versus conventional insulin therapy. Eight hundred and twenty-five out of 2748 patients randomised, were included in the

analysis. The incidence of CIP/CIM was significantly reduced with intensive insulin therapy in the population screened for CIP/CIM

(relative risk (RR) 0.65, 95% confidence interval (CI) 0.55 to 0.78) and in the total population randomised (RR 0.60, 95% CI 0.49

1Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)


mailto:[email protected]

to 0.74). Duration of mechanical ventilation, duration of ICU stay and 180-day mortality but not 30-day mortality, were significantly

reduced with intensive insulin therapy, in both the total and the screened population. Intensive insulin therapy significantly increased

hypoglycaemic events and recurrent hypoglycaemia. Death within 24 hours of the hypoglycaemic event was not different between

groups. The third trial examined the effects of corticosteroids versus placebo in 180 patients with prolonged acute respiratory distress

syndrome. No significant effect of corticosteroids on CIP/CIM was found (RR 1.09, 95% CI 0.53 to 2.26). No effect on 180-day

mortality, new serious infections and glycaemia at day seven was found. A trend towards fewer episodes of pneumonia and reduction

of new events of shock was shown.

Authors’ conclusions

Substantial evidence shows that intensive insulin therapy reduces the incidence of CIP/CIM, the duration of mechanical ventilation,

duration of ICU stay and 180-day mortality. There was a significant associated increase in hypoglycaemia. Further research needs to

identify the clinical impact of this and strategies need to be developed to reduce the risk of hypoglycaemia. Limited evidence shows

no significant effect of corticosteroids on the incidence of CIP/CIM, or on any of the other secondary outcome measures, except

for a significant reduction of new episodes of shock. Strict diagnostic criteria for the purpose of research should be defined. Other

interventions should be investigated in randomised controlled trials.

P L A I N L A N G U A G E S U M M A R Y

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

Neuromuscular problems are frequent complications in patients with severe disease that require admission to the intensive care unit

(ICU). Weakness of limbs and respiratory muscles is most frequently due to critical illness polyneuro-and/or myopathy (CIP/CIM).

As a consequence, patients face a delay in weaning from ventilatory support and rehabilitation. Recovery of strength often occurs

within weeks to months but can be incomplete or not occur at all. CIP/CIM is associated with increased ICU stay and mortality rates.

Prevention and treatment of CIP/CIM is therefore of great importance.

We searched for and analysed all randomised controlled trials that examined the effects of any treatment intervention on the incidence

of CIP/CIM in adult patients admitted to an ICU. We ultimately found three trials that focused on two different interventions.

Two trials with 825 participants examined the effect of intensive insulin therapy, aiming to maintain blood glucose levels within

the normal range (80 to 110 mg/dl), versus conventional insulin therapy, aiming to avoid hyperglycaemia (high blood sugar > 215

mg/dl), on the incidence of CIP/CIM in patients staying in ICU for at least one week. Pooling the results of both trials showed that

intensive insulin therapy reduces the incidence of CIP/CIM, the duration of mechanical ventilation, the duration of ICU stay and

mortality at 180 days. No significant effect on mortality at 30 days was noted. Intensive insulin therapy was associated with a significant

increase in hypoglycaemia (low blood sugar), and recurrent hypoglycaemic events. Although no increase in mortality within 24 hours

of hypoglycaemia was noted, hypoglycaemia remains an issue of concern when implementing intensive insulin therapy in critically ill

patients, as it may cause neurological complications. In both trials, no clinical measurement of weakness of the limbs was reported, nor

data on physical rehabilitation. Data were derived from subgroup analysis, which may also limit the conclusions.

The third trial compared corticosteroid therapy versus placebo in 180 patients with persisting acute respiratory distress syndrome.

Results showed no evidence of an effect of corticosteroids on the incidence of CIP/CIM, no effect on mortality at 180 days, on new

serious infections, on glucose levels on day 7 and a trend towards less episodes of suspected or probable pneumonia. The number of

new events of shock was reduced. In this trial, only 92 of the 180 patients were prospectively evaluated for CIP/CIM.

B A C K G R O U N D

Critical illness polyneuropathy (CIP) is an acute and primary ax-

onal motor and sensory polyneuropathy. It occurs in critically ill

patients, leading to severe limb weakness and difficulty in weaning

from a ventilator. The term CIP was first used in 1986 (Bolton

1986). Later on it became clear that in some patients the disease

primarily affected the muscles and the term myopathy in critical

illness or critical illness myopathy (CIM), was introduced.

Clinical signs of CIP and CIM are basically the same and include



flaccid weakness of the limbs. Deep tendon reflexes are usually

normal or reduced in pure CIM but may be absent in CIP. In CIP,

distal loss of sensitivity to pain, temperature and vibration may

also occur. Weakness affects legs more often than arms. Although

head, facial, tongue and jaw movement are relatively spared, facial

muscles can be involved and ophthalmoplegia may occur. Involve-

ment of the phrenic nerves and diaphragm may cause ventilator

weaning problems.

Electromyography (EMG) and nerve conduction studies (NCS)

are useful to confirm the diagnosis and to exclude other causes

of weakness. In contrast to Guillain-Barré syndrome in which

demyelination occurs, nerve conduction velocity is normal or

nearnormal. Electrophysiological examination can be used early,

before clinical assessment is feasible, and typically shows reduced

nerve conduction amplitudes and abnormal spontaneous electri-

cal activity. EMG and NCS findings are not specific, however, and

occur in CIP as well as in CIM and in other disorders. There-

fore, differentiating between both disorders on electrophysiologi-

cal data is often only possible when patients are fully cooperative,

and voluntary motor unit potential recruitment can be obtained.

Also, direct muscle stimulation can be helpful, although techni-

cally demanding. Co-existence of CIP and CIM can also make

interpretation difficult. Ultimately, electrophysiological findings

always need to be correlated with clinical findings. Finally, muscle

biopsy can confirm muscle involvement and differentiate between

the three subtypes of CIM: diffuse non-necrotising myopathy or

CIM in the strict sense; thick filament myopathy; and acute necro-

tising myopathy.

Due to the difficulty in differentiating between CIP and CIM, and

the frequent association of both, terminology that has been used

in the literature is often inconsistent and sometimes merely de-

scriptive (for example. ’ICU acquired paresis’ and ’acquired neu-

romuscular disorders’) and both disorders are frequently grouped

together as critical illness polyneuromyopathy or critical illness

polyneuropathy and myopathy (CIP/CIM).

The incidence rates reported in the literature vary according to

patient population, definition and timing of evaluation. For in-

stance, in patients with sepsis or systemic inflammatory response

syndrome the incidence is 70% (Witt 1991) and rises up to 100%

if complicated with multiple organ failure (MOF) (Tennila 2000).

Patients in the intensive care unit (ICU) for at least seven days

will acquire CIP/CIM in 49% to 84% of cases (Coakley 1998;

Hermans 2006; Van den Berghe 2005).

CIP and CIM have important consequences. They cause muscle

weakness, paralysis, and impaired rehabilitation. CIP/CIM itself

may prolong mechanical ventilation and may increase ICU stay,

hospital stay and mortality. Improvement occurs within weeks in

mild cases and within months in severe cases. In the more severe

cases, recovery may be incomplete or even not occur at all.

Hypotheses concerning the pathophysiology of CIP/CIM are out-

lined in Figure 1. Many risk factors have been related to the

incidence of CIP. Both prospective and retrospective trials have

found sepsis, systemic inflammatory response syndrome (SIRS)

and MOF to play a key part in the development of CIP. Many other

factors have been incriminated although results have not always

been consistent. Factors identified as independent risk factors by

prospective studies are: female sex (DeJonghe 2002), severity of ill-

ness (Bednarik 2005; de Letter 2001), duration of organ dysfunc-

tion (De Jonghe 2002), renal failure and renal replacement ther-

apy (Garnacho-Montero 2001), hyperglycaemia (Van den Berghe

2005; Witt 1991), hyperosmolality (Garnacho-Montero 2001),

parenteral nutrition (Garnacho-Montero 2001), serum albumin (

Witt 1991), duration of ICU stay (Van den Berghe 2005; Witt

1991), vasopressor and catecholamine support (Van den Berghe

2005) and central neurological failure (Garnacho-Montero 2001).



Figure 1. Presumed pathophysiological mechanisms and their interactions involved in the development of

CIP/CIM. Dark shaded area indicates events taking place in the nerves, light shaded area indicates events taking

place in the muscle. (Additional abbreviations: ROS, reactive oxygen species; SR, sarcoplasmic reticulum).

Data on the impact of corticosteroids on neuromuscular function

have been controversial. Many reports have found CIM to occur in

patients treated with a combination of corticosteroids and neuro-

muscular blocking agents (NMBAs). However, most prospective

studies could not identify corticosteroids as an independent risk

factor for CIP (Garnacho-Montero 2001) or CIP/CIM (Bednarik

2005; de Letter 2001; Van den Berghe 2005) although two other

prospective trials on weakness (De Jonghe 2002; Herridge 2003)

did. In one study, corticosteroids were even found to be an inde-

pendent protective factor for the incidence of CIP/CIM (Hermans

2006). Most prospective trials also could not identify NMBA use

as an independent risk factor for CIP or CIP/CIM (Bednarik 2005;

De Jonghe 2002;Van den Berghe 2005), although other trials did

(Garnacho-Montero 2001; Hermans 2006).

Until recently, the only possible way to affect the incidence of

CIP and CIM was controlling risk factors. This includes aggressive

treatment of sepsis and avoiding or limiting the use of corticos-

teroids and NMBAs to the lowest dose possible and the shortest

time feasible.

Interventions studied

Nutritional therapy

As conflicting data exist on the effect of nutritional status and

the route of administration of feeding, we examined the effects

of various feeding protocols such as enteral feeding, parenteral

feeding and also therapies such as protein and amino acid sup-

plementation. As glutamine has been suggested to be relatively

deficient and possibly pathogenically linked to CIM, studies ex-

amining glutamine supplementation were evaluated. Arginine is

also an indispensable amino acid for maintaining body protein

homeostasis and nutrition after burn injury or sepsis. Outcomes

in catabolic critical illness have however been variable (Heyland

2003). Parenteral nutrition supplementation with arginine and

glutamate improved nitrogen balance and attenuated protein my-

ofibrillar catabolism (Berard 2000).

Antioxidant therapy



Excess production of free oxygen radicals and diminished endoge-

nous antioxidant mechanisms have been implicated in multiple

organ failure and septic shock. Whole blood glutathione (GSH)

concentration and absolute synthesis rate were diminished in burn

patients (Yu 2002) and muscle biopsies in critically ill patients also

have shown decreased levels of GSH (Hammarqvist 1997). An-

tioxidant therapy may, therefore, improve outcomes due to their

ability to scavenge free oxygen radicals and replete GSH stores.

Supplementing GSH reduced the oxidative stress indices in criti-

cally ill patients. This effect was more pronounced if N-acetylcys-

tein (NAC), a precursor of GSH, was added (Ortolani 2000).

Hormonal therapy

As the balance between catabolic and anabolic hormones changes

in critical illness, hormonal therapy may be beneficial. The use

of testosterone to improve anabolism is theoretically attractive.

The testosterone derivate oxandrolone improves weight but not

muscle strength in patients with AIDS wasting (Berger 1996). In

malnourished patients with alcoholic hepatitis, oxandrolone may

however improve survival (Mendenhall 1993). Nandrolone de-

canoate also had marked positive effects on the nitrogen balance

in postoperative patients (Michelsen 1982) and improved inspi-

ratory muscle strength in chronic obstructive pulmonary disease

(COPD) patients (Schols 1995). Therefore, testosterone derivates

may have some functional benefits in critically ill male patients.

Basal growth hormone (GH) secretion is increased in acute critical

illness. In contrast, circulating levels of insulin-like growth factor

I (IGF-I) and II (IGF-II) are low secondary to resistance to GH.

The increased protein turnover and negative nitrogen balance in

critical illness are partly due to resistance to GH and decreased

production and action of IGF-I. Several studies have shown that

high doses of recombinant human GH improved nitrogen bal-

ance (Gore 1991; Jeevanandam 1995; Pape 1991; Ponting 1988;

Voerman 1992; Voerman 1995; Ziegler 1990) and resulted in

improved peripheral muscle strength (Jiang 1989), may have fa-

cilitated weaning from mechanical ventilation (Knox 1996) and

improved inspiratory muscle force (Pape 1991). However, other

studies did not show these beneficial effects on muscle strength

or ventilator weaning despite improved nitrogen balance (Pichard

1996; Suchner 1990; Takala 1999). Also various side effects such

as hyperglycaemia (Takala 1999) and increased splanchnic oxygen

consumption have been reported (Dahn 1998) and even increased

mortality (Takala 1999). Studies evaluating the effects of exoge-

nous IGF-1 in critical illness have not demonstrated beneficial ef-

fects on the nitrogen balance (Yarwood 1997).

Conflicting evidence exists concerning the role of hyperglycaemia.

Various mechanisms have been proposed to explain its possible

detrimental effects such as impairment of the microcirculation

to the peripheral nerve, caused by hyperglycaemia (Bolton 2005;

Witt 1991) and passive uptake of glucose with increased genera-

tion/deficient scavenging system for reactive oxygen species (Van

den Berghe 2004). It was hypothesised that avoiding hypergly-

caemia might exert a protective effect on the neural mitochon-

drial function (Van den Berghe 2005) and also reduce organ dam-

age by endothelial protection through diminished release of ni-

tric oxide (Langouche 2005). Two randomised controlled trials

showed that maintaining normoglycaemia with intensive insulin

therapy reduced the incidence of CIP/CIM (Hermans 2006; Van

den Berghe 2005). In the first trial glycaemic control was an inde-

pendent protective factor for the development of CIP/CIM (Van

den Berghe 2005), although it was also hypothesised that some of

the beneficial effects of this therapy may be due to insulin itself (

Van den Berghe 2004).

Some rationale also exists for treatment with corticosteroids (CS)

as these drugs may not only improve survival in some ICU sub-

populations (septic shock, acute respiratory distress syndrome

(ARDS), acute asthma) but could also reduce duration and sever-

ity of multiple organ failure, a major determinant of CIP/CIM (

Bollaert 1998; Boyer 2006; Briegel 1999; Chalwa 1999; Meduri

1998; Rowe 2001; Steinberg 2006). Furthermore, CS showed a

preventive effect on CIP/CIM in one prospective trial (Hermans

2006).

Intravenous immunoglobulins

As immune mechanisms may be implicated in the pathogenesis,

immunoglobulins were administered intravenously in three pa-

tients, without beneficial effects (Wijdicks 1994). However, in a

retrospective study early treatment of gram negative sepsis with

immunoglobulins may have prevented CIP (Mohr 1997).

Physiotherapy and rehabilitation programs

Most authors agree that physiotherapy is useful, probably by ob-

viating disuse atrophy that undoubtedly dominates this disorder (

Pandit 2006). Physiotherapy is also considered to be important in

preventing joint contractures and pressure sores (Bolton 1986).

This review is important for several reasons. Two previous sys-

tematic reviews on CIP/CIM have been published (De Jonghe

1998; Stevens 2007). The first review considered prospective co-

hort studies and focused on assessment and outcomes. The second

review aimed to determine prevalence, risk factors and outcome.

In the current systematic review, we aimed to specifically assess

the effect of any intervention, studied in a RCT, on the incidence

of CIP/CIM. In ICU patients, interventions to reduce mortality

are obviously of paramount importance. However, in acute phase

survivors, reduction of morbidity is also imperative. CIP/CIM is

now recognised as a major complication of severe critical illness

and its highly sophisticated management in the ICU. As both

locomotor and respiratory muscles can be involved, CIP/CIM

significantly influences weaning from mechanical ventilation and

recovery of physical autonomy. Therefore, interventions demon-

strated to reduce the incidence of CIP/CIM are expected to have a



beneficial effect on weaning and mechanical ventilation duration,

muscle function and overall locomotor autonomy in the recovery

phase. Although less clearly investigated to date, other potential

adverse consequences of CIP/CIM include negative psychologi-

cal impact, higher residual mortality after the acute phase, and

increased costs. No systematic review of interventions to prevent

CIP/CIM is known to exist.

O B J E C T I V E S

The objective was to systematically review the evidence from ran-

domised controlled trials concerning the ability of any interven-

tion to reduce the incidence of CIP or CIM in critically ill patients.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all RCTs in humans in which the efficacy of any

treatment used to prevent or reduce the incidence of CIP or CIM

was compared to placebo, no treatment or a different treatment.

Types of participants

Adult participants ( >18 years) of either sex, admitted to a medical,

surgical or mixed ICU.

Types of interventions

We included in the review any form of intervention which has

been related to a decreased risk of CIP or CIM or both in the liter-

ature, such as nutritional interventions: enteral versus parenteral

feeding and supplemental therapies such as protein and amino

acid supplementation (glutamine and arginine). Antioxidant ther-

apy (GSH or NAC), hormone therapy (testosterone, oxandrolone,

GH and IGF-1, intensive insulin therapy, glucocorticoids), intra-

venous immunoglobulin and physiotherapy, electrical stimulation

and rehabilitation programs were also included.

Types of outcome measures

Primary outcomes

The primary outcome measure was the incidence of CIP and/or

CIM during ICU stay. We extracted this outcome measure at least

one week after ICU admission. As no international criteria exist

for this diagnosis, we defined CIP/CIM for the purpose of this

review as weakness of the limbs or respiratory muscles, or EMG

documented peripheral polyneuropathy or myopathy for which

other causes than CIP/CIM have been excluded.

Secondary outcomes

Secondary outcome measures included clinically relevant conse-

quences from a possible reduction in the incidence of CIP/CIM

and also any possible side effects of the therapy.

(a) Weaning from mechanical ventilation. This was defined as the

time to actual and final liberation from the ventilator.

(b) Duration of ICU stay

(c) Death at 30 days (after ICU admission)

(d) Death at 180 days (after ICU admission)

(e) Serious adverse events from the treatment regimens, which

were fatal, life-threatening or required prolonged hospital stay (eg

hypoglycaemia, hyperglycaemia, organ failure).

Search methods for identification of studies

Electronic searches

We searched the Cochrane Neuromuscular Disease Group Tri-

als Register (searched October 2007) for randomised trials us-

ing the following search terms: polyneuropathies, muscle weak-

ness, rhabdomyolysis, quadriplegia, paresis, neuromuscular mani-

festations, myopathy, neuromuscular disorder, neuromuscular dis-

ease, neuromyopath, motor syndrome, muscle function, critical

illness, intensive care, therapeutics, enteral nutrition, parenteral

nutrition, glucocorticoids, exercise therapy, diet therapy, preven-

tion and control, rehabilitation, therapies, investigational, amino

acids, arginine, glutamine, antioxidants, acetylcysteine, growth

hormone, androgens, insulin-like growth factor I, immunoglob-

ulins, insulin, amino acids, arginine, glutamine, anti oxidant, N-

acetylcysteine, glutathione, growth hormone, androgen, testos-

terone, oxandrolone, Immunoglobulin, glucocorticoids, physio-

therapy, electrostimulation.

We adapted this strategy to search MEDLINE (January 1950 to

April 2008) and EMBASE (January 1980 to October 2007). We

used a combination of MeSH and keyword searching in these

databases and we used the RCT strategy from the Cochrane Hand-

book Appendix 5b. The search strategies are given in Appendix 1

and Appendix 2.

Searching other resources

We reviewed the bibliographies of the randomised trials identified

and contacted authors and known experts in the field to identify

additional unpublished data.



Data collection and analysis

Selection of studies

Two of the four authors independently checked titles and abstracts

identified from the Trials Register. The full text of all potentially

relevant studies was obtained and the authors decided which trials

fit the inclusion criteria. If the two authors did not agree, consensus

was achieved by discussion.

Data extraction and management

Two authors independently extracted data. We obtained data on

methodological quality criteria, baseline characteristics and rel-

evant data for the primary and secondary outcome measures if

available. In case of missing data we contacted the investigator

whenever possible. Information about randomised but excluded

patients was also sought and, if available, incorporated into the

analysis.

Assessment of methodological quality of included

studies

Assessment of methodological quality took into account secu-

rity of randomisation, allocation concealment, observer and pa-

tient blinding, completeness of follow-up, intention-to-treat anal-

ysis, explicit diagnostic criteria and adherence to the regimen.

Allocation concealment relates to the randomisation procedures,

whereby investigators involved in participant allocation should

not be able to influence how the groups are assembled. It involves

concealment of the next allocation in the randomisation sequence,

such that neither the investigator nor the participants can be aware

of the next group assignment until after the decision about whether

an individual is eligible for the trial has been finalised. We graded

these items A: adequate; B: moderate risk for bias; C: inadequate

or not done. If the information was not available, the item was

graded as inadequate. For some items graded as not done or un-

clear, we attempted to contact the authors to obtain additional

information about the trial design. In the case of disagreement be-

tween the two authors, we reached agreement by consensus. Data

were entered into the Cochrane statistical package, Review Man-

ager, by one review author, and checked by a second author.

Measures of treatment effect

We analysed and presented results according to the statistical

guidelines of The Cochrane Collaboration as described in Chap-

ter 8 of the Cochrane Handbook for Systematic Reviews of In-

terventions (Deeks 2005). The reliability of the various pieces of

evidence obtained form part of the discussion. Trials of each in-

tervention were analysed and presented separately. Dichotomous

outcome data are presented as relative risks (RRs) and risk dif-

ferences (RD) with 95% confidence intervals (CIs). Continuous

outcome data are presented as weighed mean differences (WMDs)

with 95% CIs. The fixed-effect model was used.

Assessment of reporting biases

Sensitivity analysis was not performed and a funnel plot was not

drawn as these were not appropriate.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

The MEDLINE search revealed 18 possibly relevant references,

out of the 2397 that were retrieved. We excluded 11 of these.

One trial was not randomised (Hsieh 2006) and one trial was a

retrospective analysis (Mohr 1997). Seven trials did not provide

any clinical nor electrophysiological outcome data on the neuro-

muscular system (Berard 2000; Bouletreau 1985; Fläring 2003;

Gamrin 2000; Kuhls 2007; Sevette 2005; Tjader 2004). Finally,

another two trials were not performed in the ICU (Nava 1998;

Porta 2005). In the latter, although the patient population is de-

scribed as a “respiratory intensive care unit” population, patients

were randomised to two rehabilitation programs, that only started

to differ from each other as soon as patients were able to walk and,

therefore, can not be considered ’ICU’ patients any longer. Seven

trials remained that fulfilled the selection criteria (Caruso 2005;

Hermans 2007; Johnson 1993; Pichard 1996; Steinberg 2006;

Van den Berghe 2005; Watters 1997). Our search of EMBASE up

to October 2007 revealed another three out of 191 retrieved trials,

which could possibly be included. Two of these, however, were

not randomised trials (Knox 1996; Ziegler 1990) and the third

did not concern ICU patients (Paddon-Jones 2005). Searching the

Cochrane Neuromuscular Disease Group Trials Register resulted

in three references, which had been identified by previous search

strategies. Personal contact with experts in the field revealed two

additional trials that could be included (Takala 1999; Takala 1999

1).

A total of nine trials fulfilling the inclusion criteria remained. Two

of these trials compared treatment with intensive insulin therapy

versus conventional insulin therapy and included a total of 825

participants (see Characteristics of included studies). The first trial

(Van den Berghe 2005) evaluated the incidence of CIP/CIM in

surgical ICU patients, staying in ICU for at least seven days. The

second trial (Hermans 2007) was performed in a medical ICU.

Both trials were subanalyses of large randomised controlled trials,



examining the effects of intensive insulin therapy versus conven-

tional insulin therapy in a surgical (Van den Berghe 2001) and

medical ICU (Van den Berghe 2006 a). The patients screened for

CIP/CIM were those who were still in ICU on day seven. Four

hundred and five long-stay patients of a total of 1548 patients

randomised were included in the analysis in the surgical trial (Van

den Berghe 2005) and 420 out of 1200 patients randomised in

the medical trial (Hermans 2007). CIP/CIM was diagnosed by

weekly electrophysiological examination. Significantly fewer pa-

tients in the intensive insulin therapy group developed CIP/CIM

compared to the conventional insulin therapy group (reduction

surgical trial:109/224 (49%) to 46/181 (25%), P < 0.0001; med-

ical trial: 107/212 (50%) to 81/208 (39%) P = 0.02).The need

for prolonged mechanical ventilation, defined as mechanical ven-

tilation for at least 14 days, was significantly reduced in the inten-

sive insulin therapy group compared to the conventional insulin

therapy group (reduction surgical trial 93/224 (42%) to 57/181

(31%), P = 0.04; medical trial: 99/212 (47%) to 72/208 (35%),

P = 0.01). Both trials were single centre trials.

Three other trials compared treatment with recombinant human

growth hormone (rhGH) versus placebo (Pichard 1996; Takala

1999; Takala 1999 1), and included a total of 552 patients. A mean

dose of 0.3 IU/kg (Takala 1999; Takala 1999 1) and 0.43 IU/kg

(Pichard 1996) rhGH was given for 12 days (Pichard 1996) to

up to 21 days (Takala 1999; Takala 1999 1). None of these trials

provided data on our primary outcome measure. The two large

trials (Takala 1999; Takala 1999 1) reported an excess of in hospital

mortality (Finish trial: 467/119 (39%) versus 25/123 (20%), P <

0.001, multinational trial: 61/139 (44%) versus 26/141 (18%),

P < 0.001) and, therefore, analyses of other outcome parameters

were considered inappropriate.

One trial compared therapy with corticosteroids versus placebo,

in 180 patients with unresolving ARDS (Steinberg 2006). In-

travenous methylprednisolone was given at a starting dose of 2

mg/kg/day then gradually tapered over more than three weeks.

In this trial, the primary outcome data were only prospectively

available in 92 patients and no difference was noted between both

treatment groups (incidence CIP/CIM placebo 11/48 (23%), in-

tervention 11/44 (25%), P = 0.67).

One trial compared inspiratory muscle training, consisting of

twice-daily exercise sessions, in which resistance was adapted ac-

cording to the individual patient’s capacity and gradually in-

creased, with no inspiratory muscle training in 40 patients (Caruso

2005). No data were provided on our primary outcome measure,

no difference was found in the duration of mechanical ventilation.

One trial compared early postoperative enteral feeding, started at

20 ml/h six hours postoperatively, increased to half of the target

dose on day two and full dose at day three, versus no enteral feeding

in the first six days (Watters 1997). No data were provided on our

primary outcome measure, nor on any of our secondary outcome

measures.

Finally, one trial compared administration of magnesium 6 g/16

hours versus placebo in a cross-over design in 20 patients (Johnson

1993). No data were provided on our primary outcome measure,

nor on any of our secondary outcome measures.

Risk of bias in included studies

Table 1 gives the quality scores for each trial. In seven trials ran-

domisation and allocation concealment was adequate. In two tri-

als however, no information is given with regards to the randomi-

sation procedure and these were, therefore, graded ’C’ (Johnson

1993; Pichard 1996). Patients were unaware of the regimen they

were allocated to in all trials with two exceptions, in which this was

not possible due to the nature of the intervention (Caruso 2005;

Watters 1997). In three trials (Hermans 2007; Van den Berghe

2005; Watters 1997) the treating physician could not be blinded,

also due to the nature of the intervention, and therefore observer

blinding was scored ’C’. In one trial, due to inconsistency on this

subject in the paper, both observer blinding and outcome assessor

blinding were graded ’C’ (Pichard 1996) and in one trial physician

and outcome assessor were not blinded, and graded ’C’ for these

items (Caruso 2005). For the other trials, observer blinding was

adequate. In one other trial, due to lack of information, outcome

assessor blinding was graded ’C’ (Johnson 1993). One trial was

an unblinded trial and therefore also outcome assessor blinding

was graded ’C’ (Watters 1997). In the remaining trials this was

adequate. Completeness of follow-up was adequate in all trials,

except for the two (Takala 1999; Takala 1999 1) in which grip

strength was only measured in survivors, and therefore graded ’B’.

In one trial, in which 40 patients were randomised but data only

presented on 25, completion of follow-up was graded ’C’ (Caruso

2005). Intention-to-treat analysis was only adequate in one trial (

Johnson 1993). Two trials (Hermans 2007; Van den Berghe 2005)

reported on electrophysiological examination, only in those pa-

tients staying in ICU for at least seven days. Concerning inten-

tion-to-treat analysis, therefore, no data are available on presence

or absence of CIP/CIM in patients dead or discharged within one

week. We have graded this item as a moderate risk for bias (see

Discussion). In one trial measurements were not available in 2/20

patients, and therefore it was also graded ’B’ (Pichard 1996). In

two trials (Takala 1999; Takala 1999 1) intention-to-treat analysis

was performed on all outcome measures except for strength, which

was only measured in survivors. Again, no data were available for

dead patients and this item was graded ’B’. In one trial (Steinberg

2006), prospective evaluation of muscle force was performed in

only 92/180 patients and intention- to- treat analysis was graded

’C’. In one trial 25 out of 40 patients randomised, were accounted

for, and this was graded ’C’. Finally, in 1one trial 3/31 patients

were not accounted for in the analysis and therefore the trial was

graded ’B’ (Watters 1997). The major problem concerned the

lack of adequate diagnostic criteria in seven trials (Caruso 2005;

Johnson 1993; Pichard 1996; Steinberg 2006; Takala 1999; Takala

1999 1; Watters 1997), of which only one trial provided data on



our primary outcome measure (Steinberg 2006). In this trial how-

ever, even in the prospectively evaluated population no diagnos-

tic criteria were stated. In the other trials various volitional and

non-volitional measurements of peripheral and respiratory muscle

force were performed. However, no cut-off values for these mea-

surements have been described to discriminate between “normal”

and “weak” patients. In the remaining two trials reporting data on

our primary outcome measure (Hermans 2007; Van den Berghe

2005), the diagnostic criteria used were electrophysiological cri-

teria. As no internationally accepted diagnostic criteria exist for

CIP/CIM, we graded this item ’B’ (see Discussion). Adherence to

the protocol was adequate except for four trials graded ’C’. In three

(Johnson 1993; Pichard 1996; Steinberg 2006) no information is

given on this item, in one trial preset aims appear inadequately

reached (Watters 1997). One trial was graded ’B’ for this item as

144 out of 167 training sessions planned, were completed (Caruso

2005). The most common problem was that the primary outcome

criterion was not stated in the methods section in six out of nine

papers.

Unpublished information derived from the authors of five trials (

Caruso 2005; Hermans 2007; Takala 1999; Takala 1999 1; Van

den Berghe 2005) was used to grade certain items.

Table 1. Methodological quality scores

Study ID Secure

randomi-

sation

Alloca-

tion con-

cealment

Patient

blinding

Observer

blinding

Outcome

assessor

blinding

Com-

plete-

ness of fol-

low-up

Intention-

to-treat

analysis

Diagnos-

tic criteria

Adher-

ence

Van

den Berghe

2005

A A A C A A B B A

Hermans

2007

A A A C A A B B A

Pichard

1996

C C A C C A B C C

Johnson

1993

C C A A C A A C C

Takala-

Finish trial

1999

A A A A A B B C A

Takala-

multina-

tional trial

1999

A A A A A B B C A



Table 1. Methodological quality scores (Continued)

Steinberg

2006

A A A A A A C C C

Watters

1997

A A C C C A B C C

Caruso

2005

A A C C C C C C B

Effects of interventions

Primary outcome measure: occurence of CIP/CIM

Data on the electrophysiological incidence of CIP/CIM were only

available in three trials, of which two trials compared intensive in-

sulin therapy versus conventional insulin therapy (Van den Berghe

2005; Hermans 2007), and one compared corticosteroids versus

placebo (Steinberg 2006).

Data on the incidence of CIP/CIM were available for patients in

the ICU for at least seven days in 389 patients treated with inten-

sive insulin therapy, and 436 patients treated with conventional

insulin therapy. The meta-analysis showed a significant benefit of

intensive insulin therapy with a RR 0.65, 95% CI 0.55 to 0.78 (

Analysis 1.1). We chose the fixed-effect model, although statisti-

cal tests indicated possible heterogeneity as only two studies were

available, and therefore a random-effects analysis would provide

poor estimates of the distribution of intervention effects. Based on

the current data however, a difference in the effect size between

medical and surgical patients can not be excluded. As from a clini-

cal point of view patients can not be identified as needing ICU for

at least one week at the time of admission, we also analysed data on

the primary outcome measure as well as on the secondary outcome

measures in the total randomised population, consisting of 1360

intensive insulin therapy and 1388 conventional insulin therapy

patients. As no electrophysiological examination was performed

in patients in ICU for less then one week, we used imputation

of negative results in these patients. This showed that intensive

insulin therapy had a significantly beneficial effect on CIP/CIM

with RR 0.60, 95% CI 0.49 to 0.74 (Analysis 1.1).

Primary outcome data were also available in terms of clinical weak-

ness in 93 patients, of which 48 received placebo and 44 received

corticosteroids. No significant difference was observed between

both treatment groups (RR 1.09, 95% CI 0.53 to 2.26) (Analysis

2.1). We also performed an intention-to-treat analysis, by imput-

ing data for the first 87 patients that were not prospectively eval-

uated. For this purpose we used the retrospective data available

for these patients. Results show no significant effect with a RR of

1.27, 95% CI 0.77 to 2.08.

Secondary outcome measures

a. Duration of mechanical ventilation

Data on this outcome measure were available in the insulin trials

and in the trial of inspiratory muscle training (IMT). For the in-

sulin trials, in the total population randomised, as well as in the

population screened for CIP/CIM, there was a significant benefi-

cial effect of IIT on the duration of mechanical ventilation (WMD

-2.00, 95% CI -2.93 to -1.07 for total population randomised and

WMD -2.55, 95% CI -4.60 to -0.51 for the population screened)

(Analysis 1.2). A fixed-effect model was used. As in the end only

the patients surviving ICU stay will benefit from an intervention

that reduced CIP/CIM, we also analysed data for ICU survivors

only. This showed that the beneficial effect on duration of mechan-

ical ventilation was also present considering only ICU survivors

of the total population randomised, which consisted of 1181 IIT

patients an 1163 CIT patients (WMD -1.00, 95% CI -1.86 to -

0.14) (Analysis 1.2). When considering only the screened patients

that survived ICU stay, the effect was not significant (WMD -

1.59, 95% CI -3.98 to 0.79). In the IMT trial, no effect was found

on the duration of mechanical ventilation (WMD -1.00, 95% CI

-5.90 to 3.90) (Analysis 5.1).

b. Duration of ICU stay

Data on this outcome measure were only available in the insulin

trials. Applying the fixed-effect model, in the total population that

was randomised, as well as in the population that was screened

for CIP/CIM, the duration of ICU stay was significantly reduced

with IIT (WMD -1.48, 95% CI -2.43 to -0.54 for the total popu-

lation randomised and WMD -3.59, 95% CI -5.70 to -1.48 in the



screened population) (Analysis 1.3). Again when only analysing

the ICU survivors, the benefit remained present in the total popu-

lation randomised, but did not reach statistical significance in the

screened population (WMD total population randomised -1.00,

95% CI -1.90 to -0.10, screened population WMD -2.18 95%

CI -4.66 to 0.30)

c and d: death at 30 and 180 days

In the insulin trials, there was no statistical effect on mortality at

30 days in the total population or in the screened population (total

population: RR 0.94, 95% CI 0.80 to 1.10, screened population

0.91, 95% CI 0.72 to 1.14) (Analysis 1.4). A fixed-effect model

was applied. The meta analysis however did show a significant

beneficial effect on 180-day mortality (total population RR 0.87,

95%CI 0.76 to 1.00, screened population 0.78, 95% CI 0.66 to

0.93). Again for 180-day mortality, statistical tests indicate possi-

ble heterogeneity. As mentioned above, we chose the fixed-effect

model and a different effect size for medical and surgical patients

can not be excluded from the current data.

In the steroid trial, no effect on mortality was shown at 180 days

(RR 0.99, 95%CI 0.64- to 1.52)(Analysis 2.2). No data were avail-

able at 30 days, as this trial’s primary outcome measure was death

at 60 days, which also showed no difference between treatment

groups. Subanalyses however revealed increased mortality in the

steroid-treated patients in the subgroup enrolled at least 14 days

after the onset of ARDS at 60 days as well as at 180 days.

Pooling of data from two growth hormone therapy trials showed a

significant increase in mortality at 30 days (RR 2.27, 95% CI 1.64

to 3.15)(Analysis 3.1) as well as at 180 days (RR 1.98, 95% CI 1.54

to 2.54) in patients treated with growth hormone. This analysis

was performed again using the fixed- effect model, despite statistics

suggesting heterogeneity, for the same reasons as mentioned above.

e. Severe adverse events

In the insulin trials, the incidence of hypoglycaemia, defined as

blood glucose below 40 mg/dl and the occurrence of at least two

hypoglycemic events were significantly higher in the intensive in-

sulin therapy group versus conventional insulin therapy. This oc-

curred in the total patient population randomised, as well as in the

screened patients (Analysis 1.5). There was no increase in death

24 hours after the last hypoglycaemic event in the total population

randomised (RR 1.60, 95% CI 0.42 to 6.10), nor in the screened

patients (RR 0.77, 95% CI 0.15 to 3.96).

Treatment with corticosteroids appeared to have a protective effect

on the occurrence of new episodes of shock (RR 0.41, 95% CI

0.17 to 1.01) (Analysis 2.3), no significant effect on new serious

infections (RR 0.68, 95% CI 0.42 to 1.11) and a trend towards

fewer episodes of suspected or probable pneumonia (RR 0.44,

95% CI 0.18 to 1.09). Blood glucose levels reported in this trial

on day seven were not significantly different (WMD 15.00, 95%

CI -3.41 to 33.41) (Analysis 2.4)

D I S C U S S I O N

Nine studies, examining the effects of six interventions were in-

cluded but only three trials on two interventions provided data

for our primary outcome data, although none of these specifically

evaluated the prevention of critical illness polyneuropathy/myopa-

thy as a primary outcome. This is a very small number of trials.

One of the main reasons for this is that no clear accepted diagnos-

tic criteria for CIP/CIM exist. In several trials some measurements

of peripheral or respiratory muscle force were made, such as maxi-

mal inspiratory pressure, hand grip force and thumb muscle force

without the existence of a cut-off value that allows differentiation

between normal and weak patients. To date, concerning clinical

evaluation, an arbitrarily cut-off value is only described for the

MRC sum score. Also, several trials have evaluated N-metabolism

and protein balance of several interventions without clinical or

electrophysiological correlation.

Two included trials evaluated the effect of intensive insulin therapy

on CIP/CIM and studied a total of 825 participants. One trial was

in a surgical ICU and one trial in a medical ICU at a single cen-

tre. Our primary outcome measure, incidence of CIP/CIM after

at least one week in ICU, was significantly reduced by intensive

insulin therapy (RR 0.65 95% CI 0.55 to 0.78). As ICU stay of at

least seven days can not be predicted accurately on admission, we

also evaluated all outcome measures for the total population ran-

domised. As patients discharged or dead within one week were not

screened for CIP/CIM, we used imputation of negative results for

these patients. Meta-analysis then showed a significant beneficial

effect in the total population randomised (RR 0.60 95% CI 0.49

to 0.74). Imputation of data does have limitations. In patients

discharged within one week, it is likely that no clinically relevant

CIP/CIM was present. In patients dead within the first week, some

diagnoses of CIP/CIM may have been missed, as electrophysiolog-

ical signs may occur early. The diagnosis of CIP/CIM was made

using only the presence of abundant spontaneous electrical activity

on electrophysiological examination, which are observed either in

axonopathy or muscle necrosis, two important components of the

neuromuscular involvement in patients with CIP/CIM. On the

other hand, some myopathies with muscle membrane inexcitabil-

ity may therefore have been missed. Concerning the secondary

outcome measures, a beneficial effect on duration of mechanical

ventilation, ICU stay and 180-day mortality was noted, in the total

population randomised, as well as in the population screened for

CIP/CIM, but not for 30-day mortality, which is likely to be too

early to see the benefit of this intervention. Whether the reduction

in duration of mechanical ventilation is due to improved respi-

ratory muscle force or other beneficial effects of intensive insulin

therapy, such as reduced infections, organ failure remains unclear.

Hypoglycaemia and at least two hypoglycaemic events occurred

more frequently in the intensive insulin therapy group than in the

conventional insulin therapy group in the total population ran-

domised as well as in the screened patients. No increase in mor-



tality within 24 hours of the hypoglycaemia was noted. Although

retrospective analysis from these trials did not show any long-last-

ing detrimental effects in patients developing hypoglycaemia (Van

den Berghe 2006 b), this is a major concern when intensive insulin

therapy is implemented in ICU, as hypoglycaemia may not be

easily recognized in critically ill patients, and profound and pro-

longed hypoglycaemia may cause coma, epilepsy and neurological

sequellae.

The third trial, providing primary outcome data concerned treat-

ment with corticosteroids versus placebo in patients with persisting

ARDS. A total of 180 patients were randomised, but only 92 pa-

tients were prospectively evaluated for the incidence of CIP/CIM.

Results showed that no significant difference was present between

the two treatment groups (RR 1.09, 95% CI 0.53 to 2.26). We

performed an intention-to-treat analysis, by imputing results for

the first 87 patients. As these patients were retrospectively anal-

ysed, these retrospective data were used for this purpose. Analysis

showed that no significant effect was present between both treat-

ment groups (RR 1.27, 95% CI 0.77 to 2.08). Concerning sec-

ondary outcome measures, data on 180-day mortality also showed

no significant difference (RR 0.99, 95% CI 0.64 to 1.52). Con-

cerning severe adverse effects, the only significant difference noted

was for new episodes of shock, occurring less frequently in the

steroid group (RR 0.41, 95% CI 0.17 to 1.01). For other severe

adverse effects that are of concern when treating patients with

corticosteroids, such as infection, pneumonia, hyperglycaemia, no

significant differences were noted.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Evidence from two large single-centre trials shows a significant

benefit of intensive insulin therapy on the electrophysiological in-

cidence of CIP/CIM in patients in ICU for at least one week,

and on its most important associated problem of prolonged me-

chanical ventilation. Whether this is the result of improved respi-

ratory muscle force or other beneficial effects of intensive insulin

therapy is unclear. No data are available concerning the effect of

intensive insulin therapy on clinical weakness of peripheral mus-

cles and physical rehabilitation. Prolonged ICU stay and mortality

rate at 180 days were also significantly reduced. Hypoglycaemia

remains a major issue of concern. In both trials, CIP/CIM was not

a primary outcome measure and results are derived from subgroup

analysis, which may limit conclusions. Limited evidence from one

multi-centre trial showed no evidence of an effect of corticosteroid

treatment on CIP/CIM, but the number of new events of shock

is reduced.

Implications for research

Strict clinical and electrophysiological diagnostic criteria for the

purpose of research in CIP/CIM should be defined and correlating

the two should be standard practice in future trials. Several theo-

retically appealing interventions should be studied in randomised

controlled trials. Further research is needed, concerning the impact

of hypoglycaemia in critically ill patients and into strategies that

minimise the risk for hypoglycaemia when implementing strict

glycaemic control.

A C K N O W L E D G E M E N T S

We thank Jens de Groot for his advice concerning search strategies

and Emmanuel Lesaffre for his statistical support. Greet Hermans

is the recipient of a clinical research fellowship from the Flanders

Research Foundation (FWO-Vlaanderen).

R E F E R E N C E S

References to studies included in this review

Caruso 2005 {published and unpublished data}

Caruso P, Denari SD, Ruiz SA, Bernal KG, Manfrin GM, Friedrich

C, et al.Inspiratory muscle training is ineffective in mechanically

ventilated critically ill patients. Clinics 2005;60(6):479–84.

[MEDLINE: 16358138]

Hermans 2007 {published and unpublished data}

Hermans G, Wilmer A, Meersseman W, Milants I, Wouters PJ,

Bobbaers H, et al.Impact of intensive insulin therapy on

neuromuscular complications and ventilator-dependency in

MICU. American Journal of Respiratory Critical Care Medicine

2007;175(5):480–9. [MEDLINE: 17138955]

Johnson 1993 {published data only (unpublished sought but not used)}

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in patients requiring prolonged mechanical ventilation: a

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Steinberg 2006 {published data only (unpublished sought but not

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hormone treatment in critically ill adults. The New England Journal

of Medicine 1999;341(11):785–92. [MEDLINE: 10477776]

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Watters JM, Kirkpatrick SM, Norris SB, Sharmji FM, Wells GA.

Immediate postoperative enteral feeding results in impaired

respiratory mechanics and decreased mobility. Annals of Surgery

1997;226(3):369–77. [MEDLINE: 9339943]

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Berard MP, Zazzo JF, Condat P, Vasson MP, Cynober L. Total

parenteral nutrition enriched with arginine and glutamate generates

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human muscle. Clinical Science 2003;104(3):275–82.

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inflammatory and anticatabolic effects of short-term beta-hydroxy-

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Caruso 2005

Methods Parallel-group randomised controlled trial.

Participants 25 patients from a clinical surgical ICU, expected duration of mechanical ventilation of at least 3 days.

Age in intervention group 67±10, control group 66±17.

Male patients, percentage in intervention group: 67%, control group: 69%.

Interventions Inspiratory muscle training (IMT) versus no IMT. IMT consisted of 2 exercise sessions daily, started 24

hours after starting mechanical ventilation, and based on overly insensitive trigger threshold. Pressure

trigger sensitivity of the ventilator was adjusted to 20% of the first measured maximal inspiratory pressure

(MIP), for 5 minutes if tolerated, increased by 5 minutes every session up to 30 minutes. If this was

tolerated, next session the pressure sensitivity was increased with 10% up to maximal 40% of the first

measured MIP. If not tolerated at 20%, pressure sensitivity could be reduced to 10% of first measured

MIP.

Outcomes Daily measurement of maximal inspiratory pressure, duration of weaning, reintubation rate. No effect

was found on any of these measures.

Notes Additional exclusion criteria were used after randomisation, of 40 patients recruited, only 25 completed

the study.

Adverse events only reported for the intervention group.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Hermans 2007


Participants 420 patients staying in a medical ICU for at least 7 days.

Age in intervention group 61±15, control group 64±16.

Male patients, percentage intervention group: 59%, control group 61%.

Interventions Intensive insulin therapy (insulin infusion titrated to achieve blood glucose levels 80 to 110 mg/dl), versus

conventional insulin therapy (insulin started if blood glucose > 215 mg/dl, tapered if < 180 mg/dl).

Outcomes Incidence of CIP/CIM, based on presence of abundant spontaneous electrical activity on electrophysio-

logical examination and need for prolonged mechanical ventilation (at least 14 days of mechanical venti-

lation).

The intervention group had significantly less CIP/CIM (81/208 (38.9%) versus 107/212 (50%), P =

0.02). Also the need for prolonged mechanical ventilation was significantly reduced from 72/208 (34.6%)



Hermans 2007 (Continued)

to 99/212 (46.7%), P = 0.01.

Notes Single centre.

Risk of bias


Allocation concealment? Yes A - Adequate

Johnson 1993

Methods Randomised trial with cross-over design.

Participants 20 medical - surgical patients requiring mechanical ventilation for more than 3 days.

Mean age 59 years.

Male/female patients: 14/6.

Interventions MgSO4 6 g/500 ml 5% dextrose in water versus placebo (same infusion without Mg) infused over 16

hour period, second day cross over.

Outcomes Maximal inspiratory pressure, maximal expiratory pressure, hand grip force, measured before randomisa-

tion, on day 1 and day 2. No differences were found before and after Mg infusion.


Risk of bias



Pichard 1996


Participants 20 patients requiring mechanical ventilation for more than 7 days because of acute respiratory failure.

Mean age in intervention group 54 years, control group 63.

Male/female patients intervention group: 5/5, control group: 6/4.

Interventions 0.43 IU recombinant human growth hormone/kg bodyweight/day or saline subcutaneously for 12 days.

Outcomes Thumb muscle function measured by electrical stimulation and duration of weaning. No difference in

thumb muscle function nor duration of mechanical ventilation were found.




Pichard 1996 (Continued)

Risk of bias



Steinberg 2006


Participants 180 patients with ARDS of at least 7 days’ duration and maximal 28 days’ duration.

Age in intervention group: 49±19, control group: 49±17.


Interventions Intravenous methylprednisolone sodium succinate diluted in 50 ml of 5% dextrose in water (single dose

of 2 mg/kg, followed by 0.5 mg/kg 4 times a days for 14 days, followed by 0.5 mg/kg twice daily for 7

days, then tapering the dose) versus placebo.

Outcomes Primary endpoint was mortality at 60 days. Secondary endpoints were ventilator-free days at 28 days,

organ failure-free days at 28 days and markers of inflammation and fibroproliferation at 7 days.

No significant difference in mortality at 60 and 180 days was found. The number of ventilator-free

and shock-free days increased with methylprednisolone during the first 28 days. In the first 87 patients

retrospective evaluation of neuromyopathy was ordered by the safety board. The next 93 patients were

prospectively evaluated.

Notes Multi-centre.

An adequate intention-to-treat analysis was performed concerning the primary outcome of the trial. Con-

cerning CIP/CIM however, data were only prospectively available in 93/180 patients. Also inconsistency

concerning this exact number: in the paper mentioning 91 in the text versus 93 in the table.

Risk of bias



Takala 1999


Participants 247 patients, in ICU for at least 5 to 7 days, who were expected to require intensive care for at least 10

days.





Takala 1999 (Continued)

Interventions 5.3 mg (for patients less than 60 kg) or 8.0 mg (for patients weighing at least 60 kg) of recombinant

human growth hormone or placebo subcutaneously, during the entire ICU stay with a maximum of 21

days. Dose was started at 1/4 and increased to full dose over 3 days.

Outcomes Primary outcome measure was duration of ICU stay. Amongst secondary outcome measures were handgrip

strength, exercise tolerance at discharge and duration of mechanical ventilation.

No difference in handgrip strength and exercise tolerability at discharge were noted among survivors.

However, in-hospital death was significantly increased in the intervention group (47/119 versus 25/123,

P < 0.001). Duration of mechanical ventilation, ICU stay and hospital stay were not significantly different

amongst hospital survivors. Sepsis was reported more frequently in the intervention group (13% versus

8%). Blood glucose levels were significantly higher in the intervention group compared with the control

group.

Notes Multi-centre.

3 patients in the intervention group and 2 patients in the control group dropped out before receiving

treatment.

Due to the mortality excess, planned analysis of primary and secondary end points was considered inap-

propriate.

Risk of bias



Takala 1999 1


Participants 285 patients, in ICU for at least 5 to 7 days, who were expected to require intensive care for at least 10

days.



Interventions 5.3 mg (for patients less than 60 kg) or 8.0 mg (for patients weighing at least 60 kg) of recombinant

human growth hormone or placebo, subcutaneously during the entire ICU stay with a maximum of 21

days. Therapy was started at full dose, and could be continued after ICU discharge for a maximum of 21

days

Outcomes Primary outcome measure was duration of ICU stay. Amongst secondary outcome measures were handgrip

strength, exercise tolerance at discharge and duration of mechanical ventilation.

No difference in handgrip strength was noted among survivors, and a trend towards worse exercise

tolerability at discharge (P = 0.008) was noted in the intervention group. In-hospital death was significantly

increased in the intervention group (61/139 versus 26/141 , P < 0.001). Amongst hospital survivors,

duration of mechanical ventilation was significantly higher (intervention 12 days (7 to 21) versus control

8 days (4 to 14), P < 0.001) and ICU stay was also significantly longer in the intervention group (15

days (9 to 28) versus 11 days (6 to 17)), P = 0.001). Hospital stay was not significantly different amongst



Takala 1999 1 (Continued)

hospital survivors. Sepsis was reported more frequently in the intervention group (18% versus 10%).

Blood glucose levels were significantly higher in the intervention group compared with the control group.

Notes Multicentre.

2 patients in the intervention group and 3 patients in the control group dropped out before receiving

treatment.

Due to the mortality excess, planned analysis of primary and secondary end points was considered inap-

propriate.

Risk of bias



Van den Berghe 2005


Participants 405 patients staying in a surgical ICU for at least 7 days.



Interventions Intensive insulin therapy (insulin infusion was titrated to achieve blood glucose levels of 80 to 110 mg/dl)

versus conventional insulin therapy (insulin was started if blood glucose > 215 mg/dl, tapered if < 180

mg/dl).

Outcomes Incidence of CIP/CIM, based on presence of abundant spontaneous electrical activity on electrophys-

iological examination, and need for prolonged mechanical ventilation (at least 14 days of mechanical

ventilation).


The figures reported (Van den Berghe 2005) are slightly different from those reported in the original trial

(NEJM 2001) due to a statistical error in the query in the latter report, where only patients staying more

than 7 days were considered instead of at least 7 days.

Risk of bias





Watters 1997


Participants 28 patients, undergoing esophagectomy or pancreaticoduodenectomy.

Age intervention group: 64+-11 years, control group: 61+-12 years.

Male/female ratio: intervention group: 11/2, control group: 11/4.

Interventions Immediate postoperative enteral feeding versus no feeding during the first 6 postoperative days. Enteral

feeding was performed via jejunostomy tube, started 6 hours after surgery at a rate of 20 ml/h until the first

postoperative morning, than increased to half the target rate, and increased to target rate on the following

morning if tolerated; maximal feeding rate was the lesser of 125% of preoperative caloric expenditure or

2500 ml/d.

Outcomes Handgrip strength, vital capacity (VC), forced expiratory volume in one second (FEV1), maximal inspira-

tory pressure measured (MIP) before surgery, and on day 2, 4, 6. Also fatigue and mobility were assessed.

No difference was found in postoperative grip strength and MIP.

Notes Unblinded trial.

Risk of bias



Characteristics of excluded studies [ordered by study ID]

Berard 2000 No clinical or electrophysiological data on weakness, outcome is plasma amino acid concentration and nitrogen

balance.

Bouletreau 1985 No clinical or electrophysiological data on weakness, outcome is nitrogen balance, excretion of creatinine, 3-

methyl histidine.

Fläring 2003 No ICU patients, no clinical or electrophysiological data on weakness, outcome is muscle glutathione, free

amino acids in skeletal muscle and plasma.

Gamrin 2000 No clinical or electrophysiological data on weakness, outcome is muscle protein synthesis and muscle free

glutamine.

Hsieh 2006 Not a randomised trial.

Knox 1996 Not a randomised trial.

Kuhls 2007 No clinical nor electrophysiological data on weakness, outcome measure is nitrogen balance.

Mohr 1997 Retrospective analysis.



(Continued)

Nava 1998 Although the patient population is derived from a “respiratory intensive care unit”, this trial randomised

patients to two rehabilitation programs, that only started to differ from each other as soon as patients are able

to walk, and therefore can not be considered ’ICU’ patients any longer.

Paddon-Jones 2005 No ICU patients, healthy volunteers.

Porta 2005 No ICU patients, concerns rehabilitation after extubation in intermediate care unit.

Sevette 2005 No ICU patients, no clinical or electrophysiological data on weakness.

Tjader 2004 No clinical or electrophysiological data on weakness, outcome is plasma glutamine levels, free muscle glutamine,

muscle protein synthesis and content.

Ziegler 1990 Not a randomised trial, no clinical or electrophysiological data on weakness.



D A T A A N D A N A L Y S E S

Comparison 1. Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Occurence of CIP/CIM 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 In total population

randomised

2 2748 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.49, 0.74]

1.2 In screened patients 2 825 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.55, 0.77]

2 Duration of mechanical

ventilation

2 Mean Difference (IV, Fixed, 95% CI) Subtotals only


randomised

2 2748 Mean Difference (IV, Fixed, 95% CI) -2.0 [-2.93, -1.07]

2.2 In patients screened 2 825 Mean Difference (IV, Fixed, 95% CI) -2.55 [-4.60, -0.51]

2.3 in ICU survivors, in total

population randomised


2.4 In ICU survivors, in

population screened

2 594 Mean Difference (IV, Fixed, 95% CI) -1.59 [-3.98, 0.79]

3 Duration of ICU stay 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only


randomised


3.2 In population screened 2 825 Mean Difference (IV, Fixed, 95% CI) -3.59 [-5.70, -1.48]

3.3 In ICU survivors, in total



3.4 In ICU survivors of

population screened


4 Death 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

4.1 At 30 days after ICU

admission, in total population

randomised



admission, in population

screened



admission, in total population

randomised


4.4 At 180 days after

ICU admission, in screened

population


5 Severe adverse events 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


randomised - hypoglycaemia



randomised- at least 2

hypoglycaemic events





randomised - death within 24

hours of last hypoglycaemic

event


5.4 In screened population -

hypoglycaemia



at least 2 hypoglycaemic events



death within 24 hours of last

hypoglycaemic event


Comparison 2. Corticosteroids versus placebo


studies

No. of


1 Occurence of CIP/CIM 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


randomised


1.2 In screened patients 1 92 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.53, 2.26]

2 Death 1 180 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.64, 1.52]

2.1 Death at 180 days in total



3 Severe adverse events

(dichotomous data)

1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

3.1 Shock 1 180 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.17, 1.01]

3.2 Serious infection 1 180 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.42, 1.11]

3.3 Suspected or probable

pneumonia


4 Serious adverse events

(continuous data)

1 180 Mean Difference (IV, Fixed, 95% CI) 15.0 [-3.41, 33.41]

4.1 Glucose on day 7 1 180 Mean Difference (IV, Fixed, 95% CI) 15.0 [-3.41, 33.41]

Comparison 3. Recombinant human growth hormone versus placebo


studies

No. of


1 Death 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only









Comparison 4. Immediate postoperative enteral feeding versus no enteral feeding


studies

No. of


1 Duration of ICU stay 1 28 Mean Difference (IV, Fixed, 95% CI) 0.60 [-0.51, 1.71]

Comparison 5. Inspiratory muscle training (IMT) versus no IMT


studies

No. of


1 Duration of mechanical

ventilation


Analysis 1.1. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT),

Outcome 1 Occurence of CIP/CIM.

Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy

Comparison: 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)

Outcome: 1 Occurence of CIP/CIM

Study or subgroup IIT CIT Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 In total population randomised

Hermans 2007 81/595 107/605 49.6 % 0.77 [ 0.59, 1.00 ]

Van den Berghe 2005 46/765 109/783 50.4 % 0.43 [ 0.31, 0.60 ]

Subtotal (95% CI) 1360 1388 100.0 % 0.60 [ 0.49, 0.74 ]

Total events: 127 (IIT), 216 (CIT)

Heterogeneity: Chi2 = 7.20, df = 1 (P = 0.01); I2 =86%

Test for overall effect: Z = 4.88 (P < 0.00001)

2 In screened patients

Hermans 2007 81/208 107/212 52.1 % 0.77 [ 0.62, 0.96 ]

Van den Berghe 2005 46/181 109/224 47.9 % 0.52 [ 0.39, 0.69 ]

Subtotal (95% CI) 389 436 100.0 % 0.65 [ 0.55, 0.77 ]




0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control




Outcome 2 Duration of mechanical ventilation.



Outcome: 2 Duration of mechanical ventilation

Study or subgroup IIT CIT Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI


Hermans 2007 595 9 (10) 605 11 (13) 49.9 % -2.00 [ -3.31, -0.69 ]

Van den Berghe 2005 765 5 (11) 783 7 (15) 50.1 % -2.00 [ -3.31, -0.69 ]

Subtotal (95% CI) 1360 1388 100.0 % -2.00 [ -2.93, -1.07 ]

Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%

Test for overall effect: Z = 4.23 (P = 0.000023)

2 In patients screened

Hermans 2007 208 16 (11) 212 18 (14) 72.4 % -2.00 [ -4.41, 0.41 ]

Van den Berghe 2005 181 16 (18) 224 20 (22) 27.6 % -4.00 [ -7.90, -0.10 ]

Subtotal (95% CI) 389 436 100.0 % -2.55 [ -4.60, -0.51 ]



3 in ICU survivors, in total population randomised

Hermans 2007 451 8 (9) 443 9 (11) 42.4 % -1.00 [ -2.32, 0.32 ]

Van den Berghe 2005 730 5 (11) 720 6 (11) 57.6 % -1.00 [ -2.13, 0.13 ]

Subtotal (95% CI) 1181 1163 100.0 % -1.00 [ -1.86, -0.14 ]



4 In ICU survivors, in population screened

Hermans 2007 133 15 (11) 124 17 (14) 59.5 % -2.00 [ -5.09, 1.09 ]

Van den Berghe 2005 160 16 (18) 177 17 (17) 40.5 % -1.00 [ -4.75, 2.75 ]

Subtotal (95% CI) 293 301 100.0 % -1.59 [ -3.98, 0.79 ]



Test for subgroup differences: Chi2 = 3.40, df = 3 (P = 0.33), I2 =12%

-10 -5 0 5 10





Outcome 3 Duration of ICU stay.



Outcome: 3 Duration of ICU stay

Study or subgroup IIT CIT Mean Difference Weight Mean Difference



Hermans 2007 595 9 (10) 605 10 (13) 51.5 % -1.00 [ -2.31, 0.31 ]

Van den Berghe 2005 765 7 (12) 783 9 (15) 48.5 % -2.00 [ -3.35, -0.65 ]

Subtotal (95% CI) 1360 1388 100.0 % -1.48 [ -2.43, -0.54 ]



2 In population screened

Hermans 2007 208 18 (11) 212 21 (15) 70.6 % -3.00 [ -5.51, -0.49 ]

Van den Berghe 2005 181 19 (18) 224 24 (22) 29.4 % -5.00 [ -8.90, -1.10 ]

Subtotal (95% CI) 389 436 100.0 % -3.59 [ -5.70, -1.48 ]



3 In ICU survivors, in total population randomised

Hermans 2007 451 7 (9) 443 8 (11) 46.7 % -1.00 [ -2.32, 0.32 ]

Van den Berghe 2005 730 6 (12) 720 7 (12) 53.3 % -1.00 [ -2.24, 0.24 ]

Subtotal (95% CI) 1181 1163 100.0 % -1.00 [ -1.90, -0.10 ]



4 In ICU survivors of population screened

Hermans 2007 133 18 (11) 124 21 (15) 58.8 % -3.00 [ -6.24, 0.24 ]

Van den Berghe 2005 160 20 (19) 177 21 (17) 41.2 % -1.00 [ -4.87, 2.87 ]

Subtotal (95% CI) 293 301 100.0 % -2.18 [ -4.66, 0.30 ]



Test for subgroup differences: Chi2 = 5.22, df = 3 (P = 0.16), I2 =43%

-10 -5 0 5 10





Outcome 4 Death.



Outcome: 4 Death



1 At 30 days after ICU admission, in total population randomised

Hermans 2007 179/595 185/605 78.1 % 0.98 [ 0.83, 1.17 ]

Van den Berghe 2005 40/765 52/783 21.9 % 0.79 [ 0.53, 1.17 ]

Subtotal (95% CI) 1360 1388 100.0 % 0.94 [ 0.80, 1.10 ]




2 At 30 days after ICU admission, in population screened

Hermans 2007 73/208 81/212 74.3 % 0.92 [ 0.71, 1.18 ]

Van den Berghe 2005 22/181 31/224 25.7 % 0.88 [ 0.53, 1.46 ]

Subtotal (95% CI) 389 436 100.0 % 0.91 [ 0.72, 1.14 ]




3 At 180 days after ICU admission, in total population randomised

Hermans 2007 220/595 238/605 74.2 % 0.94 [ 0.81, 1.09 ]

Van den Berghe 2005 55/765 83/783 25.8 % 0.68 [ 0.49, 0.94 ]

Subtotal (95% CI) 1360 1388 100.0 % 0.87 [ 0.76, 1.00 ]




4 At 180 days after ICU admission, in screened population

Hermans 2007 95/208 115/212 68.0 % 0.84 [ 0.69, 1.02 ]

Van den Berghe 2005 32/181 60/224 32.0 % 0.66 [ 0.45, 0.97 ]

Subtotal (95% CI) 389 436 100.0 % 0.78 [ 0.66, 0.93 ]




0.1 0.2 0.5 1 2 5 10





Outcome 5 Severe adverse events.



Outcome: 5 Severe adverse events



1 In total population randomised - hypoglycaemia

Hermans 2007 111/595 19/605 76.1 % 5.94 [ 3.70, 9.54 ]

Van den Berghe 2005 43/765 6/783 23.9 % 7.34 [ 3.14, 17.13 ]

Subtotal (95% CI) 1360 1388 100.0 % 6.27 [ 4.15, 9.49 ]




2 In total population randomised- at least 2 hypoglycaemic events

Hermans 2007 23/595 5/605 90.9 % 4.68 [ 1.79, 12.22 ]

Van den Berghe 2005 8/765 0/783 9.1 % 17.40 [ 1.01, 300.93 ]

Subtotal (95% CI) 1360 1388 100.0 % 5.83 [ 2.37, 14.35 ]




3 In total population randomised - death within 24 hours of last hypoglycaemic event

Hermans 2007 5/595 2/605 57.2 % 2.54 [ 0.50, 13.05 ]

Van den Berghe 2005 0/765 1/783 42.8 % 0.34 [ 0.01, 8.36 ]

Subtotal (95% CI) 1360 1388 100.0 % 1.60 [ 0.42, 6.10 ]




4 In screened population - hypoglycaemia

Hermans 2007 68/208 10/212 68.9 % 6.93 [ 3.67, 13.09 ]

Van den Berghe 2005 28/181 5/224 31.1 % 6.93 [ 2.73, 17.59 ]

Subtotal (95% CI) 389 436 100.0 % 6.93 [ 4.10, 11.72 ]




5 In screened population - at least 2 hypoglycaemic events

Hermans 2007 19/208 3/212 86.9 % 6.46 [ 1.94, 21.49 ]

Van den Berghe 2005 7/181 0/224 13.1 % 18.54 [ 1.07, 322.52 ]

0.001 0.01 0.1 1 10 100 1000


(Continued . . . )



(. . . Continued)Study or subgroup IIT CIT Risk Ratio Weight Risk Ratio


Subtotal (95% CI) 389 436 100.0 % 8.04 [ 2.69, 24.03 ]




6 In screened population - death within 24 hours of last hypoglycaemic event

Hermans 2007 2/208 2/212 59.6 % 1.02 [ 0.14, 7.17 ]

Van den Berghe 2005 0/181 1/224 40.4 % 0.41 [ 0.02, 10.06 ]

Subtotal (95% CI) 389 436 100.0 % 0.77 [ 0.15, 3.96 ]




0.001 0.01 0.1 1 10 100 1000


Analysis 2.1. Comparison 2 Corticosteroids versus placebo, Outcome 1 Occurence of CIP/CIM.


Comparison: 2 Corticosteroids versus placebo

Outcome: 1 Occurence of CIP/CIM

Study or subgroup Corticosteroids placebo Risk Ratio Weight Risk Ratio



Steinberg 2006 26/89 21/91 100.0 % 1.27 [ 0.77, 2.08 ]

Subtotal (95% CI) 89 91 100.0 % 1.27 [ 0.77, 2.08 ]

Total events: 26 (Corticosteroids), 21 (placebo)

Heterogeneity: not applicable


2 In screened patients

Steinberg 2006 11/44 11/48 100.0 % 1.09 [ 0.53, 2.26 ]

Subtotal (95% CI) 44 48 100.0 % 1.09 [ 0.53, 2.26 ]

Total events: 11 (Corticosteroids), 11 (placebo)



0.1 0.2 0.5 1 2 5 10




Analysis 2.2. Comparison 2 Corticosteroids versus placebo, Outcome 2 Death.



Outcome: 2 Death

Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio


1 Death at 180 days in total population randomised

Steinberg 2006 28/89 29/91 100.0 % 0.99 [ 0.64, 1.52 ]

Total (95% CI) 89 91 100.0 % 0.99 [ 0.64, 1.52 ]

Total events: 28 (corticosteroids), 29 (placebo)



0.1 0.2 0.5 1 2 5 10


Analysis 2.3. Comparison 2 Corticosteroids versus placebo, Outcome 3 Severe adverse events

(dichotomous data).



Outcome: 3 Severe adverse events (dichotomous data)

Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio


1 Shock

Steinberg 2006 6/89 15/91 100.0 % 0.41 [ 0.17, 1.01 ]

Subtotal (95% CI) 89 91 100.0 % 0.41 [ 0.17, 1.01 ]




2 Serious infection

Steinberg 2006 20/89 30/91 100.0 % 0.68 [ 0.42, 1.11 ]

Subtotal (95% CI) 89 91 100.0 % 0.68 [ 0.42, 1.11 ]




0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio


3 Suspected or probable pneumonia

Steinberg 2006 6/89 14/91 100.0 % 0.44 [ 0.18, 1.09 ]

Subtotal (95% CI) 89 91 100.0 % 0.44 [ 0.18, 1.09 ]




0.1 0.2 0.5 1 2 5 10


Analysis 2.4. Comparison 2 Corticosteroids versus placebo, Outcome 4 Serious adverse events (continuous

data).



Outcome: 4 Serious adverse events (continuous data)

Study or subgroup corticosteroids placebo Mean Difference Weight Mean Difference


1 Glucose on day 7

Steinberg 2006 89 159 (64) 91 144 (62) 100.0 % 15.00 [ -3.41, 33.41 ]

Total (95% CI) 89 91 100.0 % 15.00 [ -3.41, 33.41 ]



-100 -50 0 50 100




Analysis 3.1. Comparison 3 Recombinant human growth hormone versus placebo, Outcome 1 Death.


Comparison: 3 Recombinant human growth hormone versus placebo

Outcome: 1 Death

Study or subgroup rhGH placebo Risk Ratio Weight Risk Ratio



Takala 1999 37/119 23/123 55.9 % 1.66 [ 1.05, 2.62 ]

Takala 1999 1 54/139 18/141 44.1 % 3.04 [ 1.88, 4.91 ]

Subtotal (95% CI) 258 264 100.0 % 2.27 [ 1.64, 3.15 ]

Total events: 91 (rhGH), 41 (placebo)




Takala 1999 51/119 28/123 44.0 % 1.88 [ 1.28, 2.77 ]

Takala 1999 1 72/139 35/139 56.0 % 2.06 [ 1.48, 2.86 ]

Subtotal (95% CI) 258 262 100.0 % 1.98 [ 1.54, 2.54 ]

Total events: 123 (rhGH), 63 (placebo)



0.1 0.2 0.5 1 2 5 10


Analysis 4.1. Comparison 4 Immediate postoperative enteral feeding versus no enteral feeding, Outcome 1

Duration of ICU stay.


Comparison: 4 Immediate postoperative enteral feeding versus no enteral feeding

Outcome: 1 Duration of ICU stay

Study or subgroup Enteral feeding No enteral feeding Mean Difference Weight Mean Difference


Watters 1997 13 2.9 (1.7) 15 2.3 (1.2) 100.0 % 0.60 [ -0.51, 1.71 ]

Total (95% CI) 13 15 100.0 % 0.60 [ -0.51, 1.71 ]



-10 -5 0 5 10




Analysis 5.1. Comparison 5 Inspiratory muscle training (IMT) versus no IMT, Outcome 1 Duration of

mechanical ventilation.


Comparison: 5 Inspiratory muscle training (IMT) versus no IMT

Outcome: 1 Duration of mechanical ventilation

Study or subgroup IMT no IMT Mean Difference Weight Mean Difference


Caruso 2005 12 9 (4) 13 10 (8) 100.0 % -1.00 [ -5.90, 3.90 ]

Total (95% CI) 12 13 100.0 % -1.00 [ -5.90, 3.90 ]



-10 -5 0 5 10


A P P E N D I C E S

Appendix 1. MEDLINE search strategy

((“Polyneuropathies”[MeSH] OR “Muscle Weakness”[MeSH] OR “Rhabdomyolysis”[MeSH] OR “Quadriplegia”[MeSH] OR “Pare-

sis”[MeSH] OR “Neuromuscular Manifestations”[MeSH] OR polyneuropath* OR myopath* OR polyneuromyopath* OR neuromus-

cular disorder* OR neuromuscular disease OR paresis OR quadriplegia OR muscle weakness OR neuromyopath* OR motor syndrome

OR muscle function) AND (critical* ill* OR intensive care OR “Critical Illness”[MeSH] OR “Intensive Care”[MeSH]))

AND

((“Therapeutics”[MeSH:noexp] OR “Enteral Nutrition”[MeSH] OR “Parenteral Nutrition”[MeSH:noexp] OR “Glucocorti-

coids”[MeSH] OR “Exercise Therapy”[MeSH:noexp] OR “Diet Therapy”[MeSH:noexp] OR “prevention and control”[Subheading]

OR “rehabilitation”[Subheading] OR “Therapies, Investigational”[MeSH] OR “Amino Acids”[MeSH:noexp] OR “Argi-

nine”[MeSH:noexp] OR “Glutamine”[MeSH:noexp] OR “Antioxidants”[MeSH] OR “Acetylcysteine”[MeSH] OR “Growth Hor-

mone”[MeSH] OR “Androgens”[MeSH] OR “Insulin-Like Growth Factor I”[MeSH] OR “Immunoglobulins”[MeSH:noexp] OR

“Insulin”[MeSH:noexp]) OR (IIT OR (insulin AND therapy) OR (insulin AND treatment) OR ((nutritional OR supplemental) AND

(therapy OR treatment)) OR enteral feeding OR parenteral feeding OR ((amino acids OR arginine OR arg OR glutamine OR glu)

AND (therapy OR treatment)) OR ((anti oxidant OR N-acetylcysteine OR NAC OR glutathione) AND (therapy OR treatment))

OR ((growth hormone OR GH) AND (therapy OR treatment)) OR ((androgen* OR testosterone* OR oxandrolone) AND (therapy

OR treatment)) OR ((insulin-like growth factor OR IGF-1) AND (therapy OR treatment)) OR (Immunoglobulin* AND (therapy

OR treatment)) OR (glucocorticoids and (therapy or treatment)) OR physiotherapy OR rehabilitation OR electrostimulation))

AND

(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trial [mh] OR random allocation [mh]

OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trial [mh] OR (“clinical trial” [tw])

OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo*

[tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [pt] OR evaluation studies [pt] OR follow-up studies

[mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) AND humans [mh])



Appendix 2. EMBASE search strategy

1. POLYNEUROPATHY/ or polyneuropath$.mp. or polymyoneuropath$.mp. [mp=title, abstract, subject headings, heading word,

drug trade name, original title, device manufacturer, drug manufacturer name]

2. MYOPATHY/ or myopath$.mp. or neuromyopath$.mp. [mp=title, abstract, subject headings, heading word, drug trade name,

original title, device manufacturer, drug manufacturer name]

3. Muscle Weakness/ or muscle weakness.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,

device manufacturer, drug manufacturer name]

4. RHABDOMYOLYSIS/ or RHABDOMYOLYSIS.mp.

5. QUADRIPLEGIA/ or QUADRIPLEGIA.mp.

6. PARESIS/ or paresis.mp.

7. Muscle Disease/ or muscle disease.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device

manufacturer, drug manufacturer name]

8. Neuromuscular Disease/ or neuromuscular disease.mp. or neuromuscular disorder.mp. [mp=title, abstract, subject headings, heading

word, drug trade name, original title, device manufacturer, drug manufacturer name]

9. motor syndrome.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug

manufacturer name]

10. muscle function.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug

manufacturer name]

11. or/1-10

12. Critical Illness/ or critical$ ill$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


13. Intensive Care/ or Intensive care.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


14. 12 or 13

15. Therapy/

16. Enteric Feeding/ or enter$ feed$.mp. or enter$ nutrition.mp. [mp=title, abstract, subject headings, heading word, drug trade name,


17. paranteral nutrition/ or parenter$ feed$.mp. or parenter$ nutrition.mp. [mp=title, abstract, subject headings, heading word, drug

trade name, original title, device manufacturer, drug manufacturer name]

18. Glucocorticoid/ or Glucocorticoid$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


19. Kinesiotherapy/ or kinesiotherapy.mp. or exercise therapy.mp. [mp=title, abstract, subject headings, heading word, drug trade name,


20. Diet Therapy/ or diet therapy.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


21. (“Prevention and Control”/ or prevention.mp.) and control.mp. [mp=title, abstract, subject headings, heading word, drug trade

name, original title, device manufacturer, drug manufacturer name]

22. REHABILITATION/ or rehabilitation.mp. or physiotherapy.mp. or electrostimulation.mp. [mp=title, abstract, subject headings,

heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

23. Experimental Therapy/ or experimental therapy.mp. or investigational therapy.mp. [mp=title, abstract, subject headings, heading


24. Amino Acid/ or amino acid$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


25. ARGININE/ or arganine.mp. or arg.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device


26. GLUTAMINE/ or glutamine.mp. or glu.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,


27. Antioxidant/ or anti oxidant.mp. or antioxidant.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original

title, device manufacturer, drug manufacturer name]

28. ACETYLCYSTEINE/ or N-acetylcysteine.mp. or NAC.mp. or glutathione.mp. [mp=title, abstract, subject headings, heading




29. Growth Hormone/ or growth hormone.mp. or GH.mp. [mp=title, abstract, subject headings, heading word, drug trade name,


30. Androgen/ or androgen.mp. or testosterone.mp. or oxandrolone.mp. [mp=title, abstract, subject headings, heading word, drug

trade name, original title, device manufacturer, drug manufacturer name]

31. Somatomedin/ or insulin-like growth factor.mp. or IGF-1.mp. [mp=title, abstract, subject headings, heading word, drug trade

name, original title, device manufacturer, drug manufacturer name]

32. Immunoglobulin/ or Immunoglobulin.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,


33. INSULIN/ or insulin.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,

drug manufacturer name]

34. Insulin Treatment/ or IIT.mp. or (insulin and (therap$ or treatment)).mp. [mp=title, abstract, subject headings, heading word,

drug trade name, original title, device manufacturer, drug manufacturer name]

35. or/15-34

36. Randomized Controlled Trial/

37. Clinical Trial/

38. Multicenter Study/

39. Controlled Study/

40. Crossover Procedure/

41. Double Blind Procedure/

42. Single Blind Procedure/

43. exp RANDOMIZATION/

44. Major Clinical Study/

45. PLACEBO/

46. Meta Analysis/

47. phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/

48. (clin$ adj25 trial$).tw.

49. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.

50. placebo$.tw.

51. random$.tw.

52. control$.tw.

53. (meta?analys$ or systematic review$).tw.

54. (cross?over or factorial or sham? or dummy).tw.

55. ABAB design$.tw.

56. or/36-55

57. human/

58. nonhuman/

59. 57 or 58

60. 56 not 59

61. 56 and 57

62. 60 or 61

63. 11 and 14 and 35 and 62

W H A T ’ S N E W

Last assessed as up-to-date: 30 October 2007.

28 July 2008 Amended Converted to new review format.



H I S T O R Y

Protocol first published: Issue 4, 2007

Review first published: Issue 1, 2009

C O N T R I B U T I O N S O F A U T H O R S

Greet Van den Berghe initiated and supervised the project. Greet Hermans and Bernard De Jonghe independently extracted the data.

Greet Hermans wrote the first draft. Bernard de Jonghe and Frans Bruyninckx commented on the first draft and made revisions. Greet

Van den Berghe reviewed and commented on the revised draft prior to submission for formal review.

D E C L A R A T I O N S O F I N T E R E S T

None

I N D E X T E R M SMedical Subject Headings (MeSH)

Adrenal Cortex Hormones [therapeutic use]; Human Growth Hormone [therapeutic use]; Hypoglycemia [chemically induced]; Hypo-

glycemic Agents [adverse effects; therapeutic use]; Insulin [adverse effects; therapeutic use]; Length of Stay [statistics & numerical data];

Muscular Diseases [mortality; ∗prevention & control]; Polyneuropathies [mortality; ∗prevention & control]; Randomized Controlled

Trials as Topic; Recombinant Proteins [therapeutic use]; Respiration, Artificial [utilization]

MeSH check words

Humans



interventions for preventing critical illness ... · [intervention review] interventions for...

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