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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.
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)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[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.
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
2Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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).
3Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
4Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
5Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
6Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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,
7Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
8Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
9Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
10Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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-
11Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)}
Johnson D, Gallagher C, Cavanaugh M, Yip R, Mayers I. The lack
of effect of routine magnesium administration on respiratory
function in mechanically ventilated patients. Chest 1993;104(2):
536–41. [MEDLINE: 8339645]
Pichard 1996 {published data only (unpublished sought but not used)}
Pichard C, Kyle U, Chevrolet JC, Jolliet P, Slosman D, Mensi N.
Lack of effects of recombinant growth hormone on muscle function
in patients requiring prolonged mechanical ventilation: a
prospective, randomized, controlled study. Critical Care Medicine
1996;24(3):403–13. [MEDLINE: 8625627]
Steinberg 2006 {published data only (unpublished sought but not
used)}
Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN,
Hyzy R, et al.Efficacy and safety of corticosteroids for persistent
acute respiratory distress syndrome. The New England Journal of
Medicine 2006;354(16):1671–84. [MEDLINE: 16625008]
12Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Takala 1999 {published and unpublished data}
Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF,
Vundelinckx G, et al.Increased mortality associated with growth
hormone treatment in critically ill adults. The New England Journal
of Medicine 1999;341(11):785–92. [MEDLINE: 10477776]
Takala 1999 1 {published and unpublished data}
Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF,
Vundelinckx G, et al.Increased mortality associated with growth
hormone treatment in critically ill adults. The New England Journal
of Medicine 1999;341(11):785–92. [MEDLINE: 10477776]
Van den Berghe 2005 {published and unpublished data}
Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters
PJ. Insulin therapy protects the central and peripheral nervous
system of intensive care patients. Neurology 2005;64(8):1348–53.
[MEDLINE: 15851721]
Watters 1997 {published data only}
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]
References to studies excluded from this review
Berard 2000 {published data only}
Berard MP, Zazzo JF, Condat P, Vasson MP, Cynober L. Total
parenteral nutrition enriched with arginine and glutamate generates
glutamine and limits protein catabolism in surgical patients
hospitalized in intensive care units. Critical Care Medicine 2000;28
(11):3637–44. [MEDLINE: 11098966]
Bouletreau 1985 {published data only}
Bouletreau P, Patricot MC, Saudin F, Guiraud M, Mathian B.
Effects of intermittent electrical stimulations on muscle catabolism
intensive care patients. Journal of Parenteral and Enteral Nutrition
1987;11(6):552–5. [MEDLINE: 3501482]
Fläring 2003 {published data only}
Fläring UB, Rooyackers OE, Wernerman J, Hammarqvist F.
Glutamine attenuates post-traumatic glutathione depletion in
human muscle. Clinical Science 2003;104(3):275–82.
[MEDLINE: 12605586]
Gamrin 2000 {published data only}
Gamrin L, Essen P, Hultman E, McNurlan MA, Garlick PJ,
Wernerman J. Protein-sparing effect in skeletal muscle of growth
hormone treatment in critically ill patients. Annals of Surgery 2000;
231(4):577–86. [MEDLINE: 10749620]
Hsieh 2006 {published data only}
Hsieh LC, CHien SL, Huang MS, Tseng HF, Chang CK. Anti-
inflammatory and anticatabolic effects of short-term beta-hydroxy-
beta-methylbutyrate supplementation on chronic obstructive
pulmonary disease patients in intensive care unit. Asian and Pacific
Journal of Clinical Nutrition 2006;15(4):544–50. [MEDLINE:
17077073]
Knox 1996 {published data only}
Knox JB, Wilmore DW, Demling RH, Sarraf P, Santos AA. Use of
growth hormone for postoperative respiratory failure. American
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[MEDLINE: 11788355]∗ Indicates the major publication for the study
15Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Methods Parallel-group randomised controlled trial.
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%)
16Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hermans 2007 (Continued)
to 99/212 (46.7%), P = 0.01.
Notes Single centre.
Risk of bias
Item Authors’ judgement Description
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.
Notes Single centre.
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Pichard 1996
Methods Parallel-group randomised controlled trial.
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.
Notes Single centre.
17Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pichard 1996 (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Steinberg 2006
Methods Parallel-group randomised controlled trial.
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.
Male patients, percentage intervention group: 40%, control group 58%.
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
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Takala 1999
Methods Parallel-group randomised controlled trial.
Participants 247 patients, in ICU for at least 5 to 7 days, who were expected to require intensive care for at least 10
days.
Age in intervention group: 60±13, control group: 57±15.
Male patients, percentage intervention group: 76%, control group 73%.
18Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Takala 1999 1
Methods Parallel-group randomised controlled trial.
Participants 285 patients, in ICU for at least 5 to 7 days, who were expected to require intensive care for at least 10
days.
Age in intervention group: 61±15, control group: 61±15.
Male patients, percentage intervention group: 68%, control group 64%.
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
19Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Van den Berghe 2005
Methods Parallel-group randomised controlled trial.
Participants 405 patients staying in a surgical ICU for at least 7 days.
Age in intervention group: 61±15, control group: 61±16.
Male patients, percentage intervention group: 67%, control group 69%.
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).
Notes Single centre.
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
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
20Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Watters 1997
Methods Parallel-group randomised controlled trial.
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
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
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.
21Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(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.
22Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
2.1 In total population
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 2344 Mean Difference (IV, Fixed, 95% CI) -1.0 [-1.86, -0.14]
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
3.1 In total population
randomised
2 2748 Mean Difference (IV, Fixed, 95% CI) -1.48 [-2.43, -0.54]
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
population randomised
2 2344 Mean Difference (IV, Fixed, 95% CI) -1.0 [-1.90, -0.10]
3.4 In ICU survivors of
population screened
2 594 Mean Difference (IV, Fixed, 95% CI) -2.18 [-4.66, 0.30]
4 Death 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
4.1 At 30 days after ICU
admission, in total population
randomised
2 2748 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.80, 1.10]
4.2 At 30 days after ICU
admission, in population
screened
2 825 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.72, 1.14]
4.3 At 180 days after ICU
admission, in total population
randomised
2 2748 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.76, 1.00]
4.4 At 180 days after
ICU admission, in screened
population
2 825 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.66, 0.93]
5 Severe adverse events 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
5.1 In total population
randomised - hypoglycaemia
2 2748 Risk Ratio (M-H, Fixed, 95% CI) 6.27 [4.15, 9.49]
5.2 In total population
randomised- at least 2
hypoglycaemic events
2 2748 Risk Ratio (M-H, Fixed, 95% CI) 5.83 [2.37, 14.35]
23Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5.3 In total population
randomised - death within 24
hours of last hypoglycaemic
event
2 2748 Risk Ratio (M-H, Fixed, 95% CI) 1.60 [0.42, 6.10]
5.4 In screened population -
hypoglycaemia
2 825 Risk Ratio (M-H, Fixed, 95% CI) 6.93 [4.10, 11.72]
5.5 In screened population -
at least 2 hypoglycaemic events
2 825 Risk Ratio (M-H, Fixed, 95% CI) 8.04 [2.69, 24.03]
5.6 In screened population -
death within 24 hours of last
hypoglycaemic event
2 825 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.15, 3.96]
Comparison 2. Corticosteroids versus placebo
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Occurence of CIP/CIM 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 In total population
randomised
1 180 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.77, 2.08]
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
population randomised
1 180 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.64, 1.52]
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
1 180 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.18, 1.09]
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
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Death 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Death at 30 days in total
population randomised
2 522 Risk Ratio (M-H, Fixed, 95% CI) 2.27 [1.64, 3.15]
1.2 Death at 180 days in total
population randomised
2 520 Risk Ratio (M-H, Fixed, 95% CI) 1.98 [1.54, 2.54]
24Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Comparison 4. Immediate postoperative enteral feeding versus no enteral feeding
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
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
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Duration of mechanical
ventilation
1 25 Mean Difference (IV, Fixed, 95% CI) -1.0 [-5.90, 3.90]
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 ]
Total events: 127 (IIT), 216 (CIT)
Heterogeneity: Chi2 = 4.68, df = 1 (P = 0.03); I2 =79%
Test for overall effect: Z = 4.86 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
25Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 1.2. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT),
Outcome 2 Duration of mechanical ventilation.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)
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
1 In total population randomised
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 ]
Heterogeneity: Chi2 = 0.73, df = 1 (P = 0.39); I2 =0.0%
Test for overall effect: Z = 2.44 (P = 0.015)
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 ]
Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 2.28 (P = 0.023)
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 ]
Heterogeneity: Chi2 = 0.16, df = 1 (P = 0.69); I2 =0.0%
Test for overall effect: Z = 1.31 (P = 0.19)
Test for subgroup differences: Chi2 = 3.40, df = 3 (P = 0.33), I2 =12%
-10 -5 0 5 10
Favours treatment Favours control
26Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 1.3. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT),
Outcome 3 Duration of ICU stay.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)
Outcome: 3 Duration of ICU stay
Study or subgroup IIT CIT Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 In total population randomised
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 ]
Heterogeneity: Chi2 = 1.08, df = 1 (P = 0.30); I2 =8%
Test for overall effect: Z = 3.09 (P = 0.0020)
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 ]
Heterogeneity: Chi2 = 0.72, df = 1 (P = 0.40); I2 =0.0%
Test for overall effect: Z = 3.33 (P = 0.00087)
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 ]
Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 2.17 (P = 0.030)
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 ]
Heterogeneity: Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0%
Test for overall effect: Z = 1.72 (P = 0.086)
Test for subgroup differences: Chi2 = 5.22, df = 3 (P = 0.16), I2 =43%
-10 -5 0 5 10
Favours treatment Favours control
27Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 1.4. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT),
Outcome 4 Death.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)
Outcome: 4 Death
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 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 ]
Total events: 219 (IIT), 237 (CIT)
Heterogeneity: Chi2 = 1.02, df = 1 (P = 0.31); I2 =2%
Test for overall effect: Z = 0.75 (P = 0.45)
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 ]
Total events: 95 (IIT), 112 (CIT)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 0.83 (P = 0.41)
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 ]
Total events: 275 (IIT), 321 (CIT)
Heterogeneity: Chi2 = 3.32, df = 1 (P = 0.07); I2 =70%
Test for overall effect: Z = 2.00 (P = 0.045)
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 ]
Total events: 127 (IIT), 175 (CIT)
Heterogeneity: Chi2 = 1.31, df = 1 (P = 0.25); I2 =24%
Test for overall effect: Z = 2.71 (P = 0.0067)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
28Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 1.5. Comparison 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT),
Outcome 5 Severe adverse events.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 1 Intensive insulin therapy (IIT) versus conventional insulin therapy (CIT)
Outcome: 5 Severe adverse events
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 - 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 ]
Total events: 154 (IIT), 25 (CIT)
Heterogeneity: Chi2 = 0.18, df = 1 (P = 0.67); I2 =0.0%
Test for overall effect: Z = 8.71 (P < 0.00001)
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 ]
Total events: 31 (IIT), 5 (CIT)
Heterogeneity: Chi2 = 0.77, df = 1 (P = 0.38); I2 =0.0%
Test for overall effect: Z = 3.84 (P = 0.00012)
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 ]
Total events: 5 (IIT), 3 (CIT)
Heterogeneity: Chi2 = 1.20, df = 1 (P = 0.27); I2 =17%
Test for overall effect: Z = 0.69 (P = 0.49)
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 ]
Total events: 96 (IIT), 15 (CIT)
Heterogeneity: Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 7.23 (P < 0.00001)
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
Favours treatment Favours control
(Continued . . . )
29Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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(. . . Continued)Study or subgroup IIT CIT Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Subtotal (95% CI) 389 436 100.0 % 8.04 [ 2.69, 24.03 ]
Total events: 26 (IIT), 3 (CIT)
Heterogeneity: Chi2 = 0.46, df = 1 (P = 0.50); I2 =0.0%
Test for overall effect: Z = 3.73 (P = 0.00019)
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 ]
Total events: 2 (IIT), 3 (CIT)
Heterogeneity: Chi2 = 0.23, df = 1 (P = 0.63); I2 =0.0%
Test for overall effect: Z = 0.31 (P = 0.76)
0.001 0.01 0.1 1 10 100 1000
Favours treatment Favours control
Analysis 2.1. Comparison 2 Corticosteroids versus placebo, Outcome 1 Occurence of CIP/CIM.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 2 Corticosteroids versus placebo
Outcome: 1 Occurence of CIP/CIM
Study or subgroup Corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 In total population randomised
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
Test for overall effect: Z = 0.93 (P = 0.35)
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)
Heterogeneity: not applicable
Test for overall effect: Z = 0.23 (P = 0.81)
0.1 0.2 0.5 1 2 5 10
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30Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.2. Comparison 2 Corticosteroids versus placebo, Outcome 2 Death.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 2 Corticosteroids versus placebo
Outcome: 2 Death
Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
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)
Heterogeneity: not applicable
Test for overall effect: Z = 0.06 (P = 0.95)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Analysis 2.3. Comparison 2 Corticosteroids versus placebo, Outcome 3 Severe adverse events
(dichotomous data).
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 2 Corticosteroids versus placebo
Outcome: 3 Severe adverse events (dichotomous data)
Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
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 ]
Total events: 6 (corticosteroids), 15 (placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 1.95 (P = 0.052)
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 ]
Total events: 20 (corticosteroids), 30 (placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 1.55 (P = 0.12)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
31Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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(. . . Continued)Study or subgroup corticosteroids placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
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 ]
Total events: 6 (corticosteroids), 14 (placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 1.78 (P = 0.076)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Analysis 2.4. Comparison 2 Corticosteroids versus placebo, Outcome 4 Serious adverse events (continuous
data).
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 2 Corticosteroids versus placebo
Outcome: 4 Serious adverse events (continuous data)
Study or subgroup corticosteroids placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
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 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.60 (P = 0.11)
-100 -50 0 50 100
Favours treatment Favours control
32Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 3.1. Comparison 3 Recombinant human growth hormone versus placebo, Outcome 1 Death.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
Comparison: 3 Recombinant human growth hormone versus placebo
Outcome: 1 Death
Study or subgroup rhGH placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Death at 30 days in total population randomised
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)
Heterogeneity: Chi2 = 3.23, df = 1 (P = 0.07); I2 =69%
Test for overall effect: Z = 4.91 (P < 0.00001)
2 Death at 180 days in total population randomised
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)
Heterogeneity: Chi2 = 0.12, df = 1 (P = 0.73); I2 =0.0%
Test for overall effect: Z = 5.35 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Analysis 4.1. Comparison 4 Immediate postoperative enteral feeding versus no enteral feeding, Outcome 1
Duration of ICU stay.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
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
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
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 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.06 (P = 0.29)
-10 -5 0 5 10
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33Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
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Analysis 5.1. Comparison 5 Inspiratory muscle training (IMT) versus no IMT, Outcome 1 Duration of
mechanical ventilation.
Review: Interventions for preventing critical illness polyneuropathy and critical illness myopathy
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
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
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 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.40 (P = 0.69)
-10 -5 0 5 10
Favours treatment Favours control
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])
34Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
13. Intensive Care/ or Intensive care.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
14. 12 or 13
15. Therapy/
16. Enteric Feeding/ or enter$ feed$.mp. or enter$ nutrition.mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer 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$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
19. Kinesiotherapy/ or kinesiotherapy.mp. or exercise therapy.mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer name]
20. Diet Therapy/ or diet therapy.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
21. (“Prevention and Control”/ or prevention.mp.) and control.mp. [mp=title, abstract, subject headings, heading word, drug trade
name, original title, device manufacturer, drug manufacturer name]
22. REHABILITATION/ or rehabilitation.mp. or physiotherapy.mp. or electrostimulation.mp. [mp=title, abstract, subject headings,
heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
23. Experimental Therapy/ or experimental therapy.mp. or investigational therapy.mp. [mp=title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]
24. Amino Acid/ or amino acid$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
25. ARGININE/ or arganine.mp. or arg.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
26. GLUTAMINE/ or glutamine.mp. or glu.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,
device manufacturer, drug manufacturer name]
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
word, drug trade name, original title, device manufacturer, drug manufacturer name]
35Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29. Growth Hormone/ or growth hormone.mp. or GH.mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer 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,
device manufacturer, drug manufacturer name]
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.
36Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
37Interventions for preventing critical illness polyneuropathy and critical illness myopathy (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.