Clinical review: Critical illness polyneuropathy and myopathy

Critical illness polyneuropathy (CIP) and myopathy (CIM) are major complications of severe critical illness and its management. CIP/CIM prolongs weaning from mechanical ventilation and physical rehabilitation since both limb and respiratory muscles can be affected. Among many risk factors implicated, sepsis, systemic inflammatory response syndrome, and multiple organ failure appear to play a crucial role in CIP/CIM. This review focuses on epidemiology, diagnostic challenges, the current understanding of pathophysiology, risk factors, important clinical consequences, and potential interventions to reduce the incidence of CIP/CIM. CIP/CIM is associated with increased hospital and intensive care unit (ICU) stays and increased mortality rates. Recently, it was shown in a single centre that intensive insulin therapy significantly reduced the electrophysiological incidence of CIP/CIM and the need for prolonged mechanical ventilation in patients in a medical or surgical ICU for at least 1 week. The electrophysiological diagnosis was limited by the fact that muscle membrane inexcitability was not detected. These results have yet to be confirmed in a larger patient population. One of the main risks of this therapy is hypoglycemia. Also, conflicting evidence concerning the neuromuscular effects of corticosteroids exists. A systematic review of the available literature on the optimal approach for preventing CIP/CIM seems warranted.


Introduction
Critical illness polyneuropathy (CIP), first described by Bolton and colleagues in 1986 [1], is a frequent complication of critical illness, acutely and primarily affecting the motor and sensory axons. This disorder can cause severe limb weakness and prolonged weaning. Several reports of severely ill patients with muscle wasting and polyneuropathy already existed by the end of the 19th century. Improvement of diagnostics later on revealed that muscle may be primarily involved, which is called myopathy in critical illness or critical illness myopathy (CIM) [2][3][4][5]. The condition has also been described in children [6].
care unit (ICU), satisfactory patient comprehension and cooperation should be evaluated and confirmed. Otherwise, overestimation of muscle weakness may occur [14].
Technical investigations can provide further evidence for CIP/CIM. These include serum measurements of muscle necrosis parameters (serum creatine kinase, CK), electromyography (EMG) and nerve conduction studies, and muscle biopsy. Serum CK levels are not very helpful since they are normal if muscle necrosis is absent or scattered, which commonly is the case. Even in patients with overt muscle necrosis, an increase in CK is often transient and can be missed. EMG and nerve conduction studies provide a bedside method to confirm the diagnosis and to exclude other neuromuscular causes of weakness, although routine electrophysiological examination oftentimes cannot discriminate between CIP and CIM in critically ill, sedated, uncooperative, or extremely weak patients [15]. In contrast to the MRC sum score mentioned above, it can be used before patients have recovered satisfactory consciousness and cooperation and therefore offers the advantage of identifying affected patients in an earlier stage. The first electrophysiological sign that can occur very early, even within 2 to 5 days after the onset of critical illness, is a reduction in amplitude of the nerve conduction potentials (compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) or both) with preserved conduction velocity. Recent data showed that the majority of patients admitted for sepsis showed reduced nerve conduction amplitudes within 3 days of admission and that change of baseline nerve conduction response amplitude at 1 week was predictive for the development of acquired neuromuscular dysfunction [16]. The reduction in amplitudes often precedes the clinical findings as well as the accompanying fibrillation potentials and positive sharp waves that may not occur until the second or third week [17][18][19]. A multicentre prospective trial showed that electrophysiological screening using peroneal CMAP reduction below two standard deviations of the normal value accurately identifies patients with CIP/CIM [20]. Abnormal SNAPs are characteristic for CIP, although local oedema can interfere with optimal sensory nerve stimulation and recording. In addition, CIP and CIM often coexist. Electrophysiological differentiation between CIP and CIM is possible in the adequately awake and cooperative patient in whom voluntary motor unit potential recruitment can be obtained, in the rare case when the polyneuropathy is purely sensory [21], or using direct muscle stimulation. This shows reduced or absent action potentials in the case of CIM, reflecting loss of muscle electrical excitability, in contrast with normal values in CIP [22][23][24]. However, this technique requires an experienced examiner in order to obtain reliable results. As routine electrophysiological examination in critically ill patients frequently cannot differentiate between neuropathy and myopathy [15,25], muscle biopsy can be performed and is considered a gold standard for the involvement of muscles in the disease process. Percutaneous muscle biopsy is relatively easy and can be performed at the bedside. Determination of the myosin/actin ratio has been suggested for rapid diagnosis of myopathy [26]. The clinical relevance of differentiating between neuropathy and myopathy is still under debate. A small case series of ICU survivors suggested a better outcome for patients with CIM in contrast with CIP [27]. A previous larger retrospective trial did not show any difference in outcome between CIP and CIM [28], and a recent systematic review (though not including the data of Guarneri and colleagues [27]) found insufficient data to confirm this [29].
Different changes in muscle histomorphology can be recognised. Three subtypes of acute myopathy of intensive care have been described [30] and are often grouped together as so-called 'acute quadriplegic myopathy': (a) diffuse non-necrotising 'cachectic' myopathy, (b) thickfilament myopathy or myopathy with selective loss of thick (myosin) filaments, and (c) acute necrotising myopathy. Nonnecrotising myopathy is accompanied by abnormal variation of muscle fibre size, fibre atrophy, predominantly type II fibres, angulated fibres, internalised nuclei, rimmed vacuoles, fatty degeneration of muscle fibres, and fibrosis. Type II fibre atrophy, however, is also reported in neuropathy and disuse atrophy. In thick-filament myopathy, a selective loss of myosin filaments is the predominant finding. This diagnosis requires the use of electron microscopy. Acute necrotising myopathy of critical illness is characterised by prominent myonecrosis, with vacuolisation and phagocytosis of muscle fibres, visible on optical microscopy as sparse, diffuse, or massive lesions. In a minority of the patients, this disease can progress to frank rhabdomyolysis [14,31,32]. Although muscle biopsy remains the diagnostic method of choice for detection of structural abnormalities, it remains invasive and therefore is not a practical screening tool. However, using biopsy and direct muscle stimulation, it has been recognised that the incidence of CIM is much higher than previously thought and many patients might even have a combination of CIP and CIM [15,16,33,34].
Apart from the difficulties in differentiating CIP and CIM, they frequently co-occur. Electrophysiological and histological examination of patients indeed showed a significant overlap of CIP and CIM [15,17]. This has led to an often descriptive terminology in the literature, including terms such as 'ICUacquired paresis' and 'acquired neuromuscular disorders'. From a clinical point of view, CIP and CIM are often treated as a group and therefore are designated as critical illness polyneuromyopathy, critical illness neuromyopathy, or critical illness polyneuropathy and myopathy (CIP/CIM) [14,33,35,36].

Incidence
The incidence rates reported depend on the specific ICU subpopulation that is studied, the risk factors to which this population was exposed, the diagnostic criteria used, and the timing of diagnosis during the acute illness [37]. In sepsis or systemic inflammatory response syndrome (SIRS), 70% of patients develop CIP [10]. When further complicated by multiple organ failure (MOF), the incidence increases to up to 100% [18]. Importantly, critically ill comatose patients may become completely paralysed due to CIP/CIM [15]. Similarly, about 60% of patients with acute respiratory distress syndrome (ARDS) suffer from this disease [38]. In unselected patients receiving mechanical ventilation for at least 4 to 7 days, the occurrence of CIP/CIM was noticed to be 25% to 33% on clinical evaluation [12,36,39] and up to 58% on electrophysiological evaluation [40][41][42]. Of patients in the ICU for at least 7 days, 49% to 77% [21,43,44] will acquire CIP/CIM. A neuromuscular disorder with a predominant muscle component (CIM) develops in at least one third of ICU patients treated for status asthmaticus [45], 7% of patients after orthotopic liver transplantation [46], 38% of critically ill patients [33], and 68% of patients in the ICU for at least 7 days [21].

Short-term and long-term implications
CIP and CIM have an important impact on the outcome of patients in the ICU. They typically cause muscle weakness and paralysis and impair rehabilitation [42] in up to 100% of patients staying in the ICU for at least 4 weeks [47]. CIP/CIM itself may prolong the need for ventilatory support [39,41,43,44,48] as the phrenic nerve and diaphragmatic muscle can be involved [10]. Not surprisingly, the duration of weaning in these patients is increased 2 to 7 times [10,33,39,41,49]. CIP/CIM is associated with increased ICU and hospital stays [41,49] and elevated mortality rates [41,42,49,50], although other data suggest that patient selection may partially explain this [20]. Improvement occurs within weeks in mild cases and within months in severe cases. This recovery is characterised by progressive reinnervation of muscle and, in CIP, restoration of sensory function. Full recovery has been reported in over 50% of patients [10,29,51]. However, in the more severe cases, recovery may be incomplete or may not even occur at all [1,10,47]. A systematic review [29] reported severe disability impeding independent walking or spontaneous ventilation in 28% of patients, although this figure may be high due to the limited follow-up period in several case series. A small case series suggests that undetectable CMAPs could be a predictor of prolonged functional disability [52]. In patients recovering from ARDS, persistent functional limitation due to muscle wasting and weakness 1 year after discharge was noted in all patients [53]. Clinical and neurophysiological signs may remain present for up to 5 years after ICU discharge [47]. In the most severe cases, up to 32% are reported to remain severely disabled with tetraparesis, tetraplegia, or paraplegia [51]. Persistent milder disabilities are common even in patients with complete functional recovery, and in a small case series impaired quality of life after 1 year was frequently present in survivors [54].

Risk factors
A large number of studies have been performed to identify patients at risk for CIP/CIM. Among these, both prospective and retrospective trials have repeatedly identified sepsis, SIRS, and MOF as crucial risk factors. Also, the central role of MOF in the pathophysiology has been confirmed in a recent systematic review [37] and in a prospective cohort study [20]. Data reported on a number of other factors, such as hypoxia [55], hypotension [56], hyperpyrexia [57], and age [38], are not always consistent. Aminoglycosides have received particular attention as two studies associated their use with CIP [40,42]. However, other authors could not confirm these findings [10,12,38,43,44,49,58], and therefore it seems that any association is not likely to be causal. The following factors have been identified as independent risk factors in prospective studies: female gender [12], severity of illness [33,36], duration of organ dysfunction [12], renal failure and renal replacement therapy [49], hyperosmolality [49], parenteral nutrition [49], low serum albumin [10], duration of ICU stay [10,43], vasopressor and catecholamine support [43], and central neurologic failure [49]. Hyperglycemia also has been identified as an independent risk factor [10,43], with an important potential impact in terms of prevention (see 'Prevention and therapy' section).
The impact of corticosteroids (CSs) on neuromuscular function in the ICU has been the subject of controversy. Many reports have found CIM to occur in patients treated with a combination of CSs and neuromuscular blocking agents (NMBAs). The myopathy that occurs in these patients mostly treated for severe asthma, chronic obstructive pulmonary disease, solid organ transplantation, leukemia, or lymphoma is most commonly a thick-filament myopathy. However, four prospective studies in unselected ICU populations could not identify CSs as an independent risk factor for CIP [49] or CIP/CIM [33,36,43], although three other prospective trials on weakness did [12,46,53]. In one study, CSs were even found to be an independent protective factor for the occurrence of CIP/CIM [44]. Similarly, four prospective trials did not identify NMBAs as an independent risk factor for CIP or CIP/CIM [12,33,36,43], but two other trials did [44,49]. As CIM has been reported in patients receiving only one of these agents or receiving neither, it is clear that these drugs are not critical or essential in order to develop CIP/CIM.

Pathophysiology
The pathophysiology of CIP and CIM is complex and still unclear. A schematic overview is shown in Figure 1 [59]. The association between CIP/CIM and other organ failures has raised the question as to whether neuromuscular involvement is not simply a part of a systemic critical illness, representing just another organ failure. Bolton and colleagues [10,60] hypothesised that sepsis-related disturbance of the microcirculation in peripheral nerves and muscles is a crucial event in the pathogenesis. In CIP, this may be mediated by the enhanced expression of E-selectin in the vascular endothelium of the peripheral nerves, induced by pro-inflammatory cytokines [61]. Hyperglycemia also may impair the microcirculation to the peripheral nerve. Moreover, cytokines secreted in sepsis have histamine-like properties that may increase microvascular permeability [60]. The resulting endoneural oedema could induce hypoxemia and energy depletion by increasing intercapillary distance and other mechanisms. Severe energy deficits would result, inducing primary axonal degeneration. Passive uptake of glucose with increased generation and deficient scavenging of reactive oxygen species could contribute to bioenergetic failure. Increased permeability may also enhance the passage of neurotoxic factors in the endoneurium and promote endothelial cell-leucocyte adhesion and extravasation of activated leucocytes within the endoneurial space, where they can induce tissue injury with local cytokine production [61]. Also, some cytokines may have direct toxic effects on peripheral nerves. A possible role for a neurotoxic factor in the pathogenesis of CIP has been suggested [62].
The pathophysiology of CIM is also complex, involving metabolic, inflammatory, and bioenergetic alterations. Protein catabolism and muscle wasting are observed in CIM. Proteolytic pathways involving calpain [63] and the ubiquitin-proteasome pathway [64,65] are upregulated due to pro-inflammatory cytokines in conjunction with increased apoptosis [66]. As calpain is a calcium-activated protease, altered cellular calcium homeostasis due to endotoxemia and inflammation might play a role [60,67]. Also, acute stimulation of the TGFβ/MAPK (transforming growth factor-beta/mitogen-activated protein kinase) pathway following stress stimuli has been suggested to explain the muscle loss, coupled with the activation of the ubiquitin-proteasome pathway [68]. Muscle biopsies in these patients demonstrate a decrease in total amino acid concentration and, most strikingly, the glutamine levels [69]. Glutamine is known to stimulate protein synthesis and inhibit protein breakdown. There appears to be a relative deficiency of glutamine to increased demands in critical illness. Decreased levels of anabolic hormones and increased levels of catabolic hormones may contribute to myofilament loss and apoptosis in CIM [31]. Channelopathy is another mechanism that has been suggested in the pathophysiology. Electrodiagnostic studies often show evidence of muscle Presumed pathophysiological mechanisms and their interactions involved in the development of critical illness polyneuropathy/critical illness myopathy (CIP/CIM). CS, corticosteroids; NMBA, neuromuscular blocking agent; ROS, reactive oxygen species; SR, sarcoplasmatic reticulum. membrane inexcitability. This may be related to the inactivation of sodium channels at the resting potential and a shift in the voltage dependence of channel inactivation [70][71][72][73]. Interaction of lipopolysaccharide with voltage-gated sodium channels may contribute to muscle membrane inexcitability in sepsis [74]. Also, altered expression of nitric oxide synthetases has been suggested to possibly affect muscle membrane excitability in CIM as nitric oxide takes part in the maintenance of muscle fibre resting potential [75]. CIM may include alterations in the excitation-contraction coupling as blood sera from patients with CIM were found to affect not only the excitability of muscle fibre membranes but also the release of calcium from the sarcoplasmatic reticulum (SR) [76]. Evidence for these mechanisms and a possible 'myotoxic' factor responsible for this comes from animal data in which sera of patients with CIM had differential effects on resting and action potentials, sodium channels, and the excitation-contraction coupling process at the level of the SR-Ca 2+ release [76]. Nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, muscle ATP depletion, and bioenergetic failure due to damage or inhibition of complex I of the respiratory chain may also be important [77]. The exact role of CSs and NMBAs in CIM is not clearly understood. Interestingly, in experimental models, muscle changes are prevented by concomitant administration of RU38486, a muscle CS receptor antagonist [78], suggesting that sepsis-induced muscle changes are mediated, at least partly, by endogenous CSs. Bolton [60] hypothesised that increased capillary permeability due to sepsis-induced release of cytokines allows NMBAs to cross the membrane and have direct toxic effects on the nerve or cause functional denervation of muscle, thereby possibly facilitating toxic effects of CSs or inflammatory mediators.
Functional denervation resulting from nerve injury in CIP may provide the link between CIP and CIM. Experimental CSinduced muscle alterations are significantly enhanced by limb denervation prior to exposure to CSs, suggesting that, in ICU patients, the axonal component of CIP/CIM or a chemical denervation such as induced by neuromuscular blockers could increase muscle susceptibility to CSs [79]. Another hypothesis is that both CIP and CIM represent different manifestations of a single pathologic mechanism in which sepsis triggers electrical inexcitability of the nerve, the muscle [80], and even the heart and central nervous system [81]. Also, evidence for a role of immune mechanisms in patients with CIP/CIM exists. Indeed, small numbers of activated leucocytes producing pro-and anti-inflammatory cytokines infiltrate the skeletal muscle of patients with CIP/CIM [34].
Whereas most studies have focused on limb muscles, new data have shed light on some of the mechanisms of the diaphramatic muscle involvement. Diaphragm immobilisation in animal models under mechanical ventilation for only 18 hours induces a significant decrease in diaphragmatic force coupled with muscle atrophy and an increase in muscle markers of oxidative stress and calpain and ubiquitin-proteasome proteolytic activity [82], enhanced by NMBAs [83], and prevented by intermittent spontaneous breathing [84] and antiproteases [85]. Similar functional and histochemical diaphragmatic changes have been reported in animals submitted to experimental sepsis [86]. Preliminary human data suggest that the combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibres. These findings are consistent with increased diaphragmatic proteolysis during inactivity [87].

Prevention and therapy
As CIP/CIM not only has immediate detrimental effects in causing weaning difficulties but also causes long-term problems due to prolonged rehabilitation, it is a major cause of morbidity in patients surviving the acute phase of their critical illness. Until recently, only preventive measures consisting of reducing exposition to known risk factors and supportive measures were recommended in critically ill patients. Most authors agree on aggressive treatment of sepsis as the most important measure to reduce the incidence of CIP/CIM. CSs and NMBAs, if indicated, should be used at a minimal dose for as short a period as possible. Managing difficulty in weaning from mechanical ventilation [88] as well as rehabilitation programs [89] and avoiding additional pressure neuropathies by careful positioning are also considered to be major issues.
Several specific therapies have been mentioned as theoretically interesting and therefore potentially beneficial to prevent CIP/CIM. These include nutrition schemes and nutritional interventions [1], supplement therapies [90], antioxidant therapy [91], and the use of testosterone derivates [92], growth hormone [93], and immunoglobulins [58]. None of these, however, has actually been shown to have beneficial effects on muscle function in ICU patients.
Recently, the effect of intensive insulin therapy on CIP/CIM and the need for prolonged mechanical ventilation have been studied in surgical (SICU) and medical (MICU) ICU populations. Interest in this therapy was generated by the fact that hyperglycemia was associated with CIP/CIM by Witt and colleagues in 1991 [10], a finding that was confirmed by other investigators [12]. Avoiding hyperglycemia using insulin therapy to maintain strict glycemic control therefore may be beneficial to prevent CIP/CIM. Insulin itself has some potential beneficial effects, including anti-inflammatory effects [94], endothelial protection [95], improvement of dyslipemia, and neuroprotective effects in animals [96], and is also an anabolic hormone. Two prospectively planned subanalyses [43,44] of two large randomised controlled trials [97,98] were performed. The trials evaluated the effect of intensive insulin therapy on a SICU and a MICU (aiming at glycemia of 80 to 110 mg/dL) versus conventional insulin therapy in which insulin was started when glycemia rose above 220 mg/dL and tempered or stopped at values below 180 mg/dL. In the subanalyses, intensive insulin therapy significantly reduced the incidence of CIP/CIM detected on systematic electrophysiological investigation in patients in the ICU for at least 1 week, from 49% to 25% in the SICU (P <0.0001) and from 51% to 39% in the MICU (P = 0.02). Also, the need for prolonged mechanical ventilation, defined as mechanical ventilation for at least 2 weeks, was reduced from 42% to 32% in the SICU (P = 0.04) and from 47% to 35% in the MICU (P = 0.01). Multivariate analysis attributed the beneficial effect on CIP/CIM to glycemic control [43], whereas the beneficial effect on prolonged mechanical ventilation was due to the insulin dose and was not completely explained by the benefit on CIP/CIM [44]. Although a beneficial effect of intensive insulin therapy is present in patients in whom tight glucose control did not totally succeed in lowering glycemic levels to the preset goal (but rather to between 110 and 150 mg/dL), the benefit on CIP/CIM as well as on mortality is most pronounced in the patients with the tightest control (80 to 110 mg/dL) [99]. These results are derived from post hoc analysis and need to be confirmed. As the beneficial effects of intensive insulin therapy on ICU patients are currently derived from a single centre, these results await confirmation in a larger population. The methodology of electrophysiological diagnosis was limited by the fact that muscle membrane inexcitability was not detected. Further investigations are needed to evaluate the extent to which the significant benefits in terms of electrophysiological abnormalities in the form of spontaneous electrical activity translate into clinical benefits in terms of muscle strength and recovery of neuromuscular function at and after discharge from the ICU [100].
Finally, although the use of CSs is currently discouraged, they theoretically could be interesting as, first of all, survival benefit is present in some subgroups of ICU patients treated with CSs such as those with septic shock, ARDS, and acute asthma. Moreover, CSs in specific ICU settings may reduce the duration and severity of MOF, which is the crucial risk factor for CIP/CIM [101]. CSs indeed showed a preventive effect on CIP/CIM in one prospective trial [44], and in a second prospective trial a trend toward beneficial effect was noticed [43]. The three prospective trials that identified CSs as independent risk factors for acquired weakness in the ICU either did not report glycemia [51] or did not treat hyperglycemia [12,46]. Therefore, these detrimental effects possibly could be related to hyperglycemia rather than CSs. However, even in the trial identifying CSs as a protective factor for CIP/CIM, the use of CSs was identified as an independent risk factor for prolonged mechanical ventilation [44]. Explanations for this remain speculative. As the diagnosis of CIP/CIM was made (on average) on day 8 whereas prolonged mechanical ventilation was defined from day 14 onward, CSs may have a time-dependent effect on the neuromuscular system in critically ill patients characterised by a short-term protective effect and a long-term deleterious effect. Another explanation could be that precise identification of the muscular effect of CSs requires the use of more sophisticated electrophysiological techniques such as direct muscle stimulation. Further study is needed to unravel the probable complex effects and their underlying pathogenetic mechanisms.

Conclusions
Critically ill patients frequently develop CIP/CIM, which delays weaning, compromises rehabilitation, and is associated with increased hospital and ICU stays and increased mortality rates. Until recently, no therapeutic measures had been proven to affect its incidence, and apart from supportive treatment, the only preventive measure was aimed at controlling the most important risk factor, MOF, as best as possible. Recently, two trials in a single centre reported that intensive insulin therapy significantly reduced the electrophysiological incidence of CIP/CIM and the need for prolonged mechanical ventilation in patients in the ICU for at least 1 week. This beneficial effect was present in a surgical as well as a medical population. However, concerns about safety and risk for hypoglycemia and limitations of diagnostic methods used in these trials have been raised, and these results have not yet been confirmed in a larger population. Concerning the neuromuscular effects of CSs, the evidence remains conflicting. Further research should address these questions and investigate the pathophysiological mechanisms underlying this important clinical problem.

Competing interests
The authors declare that they have no competing interests.