Early development of critical illness myopathy and neuropathy in patients with severe sepsis

The development of neuromuscular dysfunction (NMD) is a major contributor to prolonged intensive care unit (ICU) course and reduction in quality of life for survivors of severe sepsis.^1,2 Little is known about the time course of development of ICU-acquired NMD in the setting of severe sepsis, as early diagnosis of this problem in critically ill patients is difficult and requires an alert and cooperative patient to adequately perform detailed electromyography (EMG). Therefore, most studies examining NMD in critically ill patients have evaluated patients later in their ICU course, when they are able to cooperate.

Two studies have examined patients prospectively soon after development of sepsis. In one study of 25 patients with septic shock, the majority (76%) developed critical illness polyneuropathy within 72 hours of onset of septic shock.³ In a smaller cohort of nine patients, a similar early onset of NMD following onset of sepsis was demonstrated.⁴ However, in a larger prospective study of 98 patients at later time points, only a small fraction of patients developed evidence of NMD within 15 days of artificial respiration.⁵ None of these studies sought to distinguish between critical illness myopathy and critical illness neuropathy. We conducted a prospective observational cohort study of patients with severe sepsis and sequentially studied patients until we could determine the etiology of their neuromuscular dysfunction.

Methods.

The Institutional Review Board of Emory University approved this study, and each patient or legally authorized representative gave informed written consent. Subjects with a diagnosis of severe sepsis were prospectively enrolled from the medical intensive care units (MICUs) at two participating institutions: Emory University Hospital and Grady Healthcare System. We used criteria for severe sepsis from the Recombinant Human Activated Protein C Trial to identify patients.⁶ Patients were eligible for this trial if they met this definition of severe sepsis within the first 72 hours of admission to the MICU and within the first 10 days of hospital admission. Subjects younger than 18 years and those with known pre-existing neuromuscular disorders were excluded.

We recorded demographic and clinical information regarding patient’s gender, age, race, medical comorbidities (diabetes mellitus, HIV, alcohol use/abuse), source of infection, APACHE II score, duration of mechanical ventilation, duration of ICU stay, treatment with neuromuscular blocking agents, and glucocorticoid usage during the hospitalization. Baseline neurologic examination and nerve conduction studies (NCSs) were performed within 72 hours of the development of severe sepsis. Directed neurologic examination detailed the level of consciousness, motor strength using the Medical Research Council Scale, sensory function, muscle stretch reflexes, and plantar responses. All aspects of patient care, including nutritional support, ventilator management, and general ICU supportive care, were left to the discretion of the primary physician caring for the patient.

Electrophysiologic studies were performed in the ICU by two of the authors using standard techniques according to Kimura’s principles using a Nicolet Viking IV (Madison, WI).⁷ The serial studies for each subject were performed by a single examiner to minimize the interexaminer variability and improve reliability.^8,9 NCSs were performed using surface electrodes to record after surface stimulation. When possible, sural sensory, peroneal motor, tibial motor, median sensory, radial sensory, and median motor studies were obtained. Amplitudes were measured from baseline to negative peak for motor and sensory responses. Both clinical and electrophysiologic examinations were repeated every 7 days during the entire length of ICU stay. Concentric needle EMG and in several cases direct muscle stimulation were subsequently performed if the following conditions occurred: 1) clinical weakness was noted on physical examination or 2) a >30% reduction in amplitude was identified between serial NCSs in two or more nerves. All electrophysiologic studies were independently reviewed by three board-certified neurologists blinded to the clinical history of the patients.

Baseline NCSs were categorized as normal or abnormal based upon standard normal values used at the EMG laboratories at Grady Memorial Hospital and Emory University Hospital. After reviewing the studies and excluding patients with electrophysiologic features of primary demyelination, the amplitudes of the sensory and motor responses were analyzed for abnormalities and compared to identify changes between serial studies for each patient. Concentric needle EMG was performed to assess for the presence of fibrillations, motor unit potential morphology, and motor unit recruitment. Abnormal studies were then categorized as consistent with critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or both. CIM was diagnosed when sensory nerve action potentials were greater than 80% the lower limit of normal and EMG showed short-duration, small-amplitude motor unit potentials with early recruitment. CIP was diagnosed when the sensory nerve action potential amplitudes were less than 80% of the lower limit of normal and EMG revealed normal morphology motor unit potentials with reduced recruitment. If electrophysiologic features of CIM and CIP were present in a single patient, that patient was considered to have both myopathy and neuropathy.

Results.

Abnormalities on initial nerve conductions.

Abnormal NCS response amplitudes were detected in 63% (31/48) of patients at the time of enrollment. Pure sensory conduction abnormalities were present in 10% (3/31) and pure motor nerve conduction abnormalities were present in 19% (6/31) of patients. The majority of patients with abnormal NCS, 71% (22/31), had reductions in both sensory and motor nerve conduction amplitude. Patients with abnormal baseline NCS had a higher admission APACHE II score, were older, and were more likely to be diabetic, though none of these differences reached significance (table). Abnormal baseline NCS within 72 hours of the diagnosis of severe sepsis was associated with an increased mortality vs those patients with normal baseline NCS (55% [17/31] vs 0% [0/17]; p < 0.001; figure 1). When patients with chronic conditions such as diabetes mellitus (n = 9) and HIV (n = 6) that could be responsible for pre-existing abnormalities observed on the initial NCS were excluded, the effect of an abnormal NCS on mortality remained (50% [9/18] vs 0% [0/15]; p < 0.001).

View this table:

• View inline
• View popup
• Download powerpoint

Table Patient characteristics stratified by baseline nerve conduction study results

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Mortality rates based on initial electrophysiologic abnormalities.

Development of NMD in critically ill patients.

Twenty-three of the 48 patients had an ICU length of stay of at least 7 days and therefore underwent two or more sets of electrophysiologic tests. Three patients died before day 14 and as a result the presence of acquired NMD could not be definitively determined. Overall 50% (10/20) of the remaining patients met our criteria for NMD during their ICU stay. We made a definitive diagnosis of CIM, CIP, or both conditions in three patients at day 7, six patients at day 14, and one patient at day 21 (figure 2). Eight of these 10 patients had electrophysiologic features of both CIP and CIM, whereas one patient developed only CIP and one patient developed only CIM (figure 3). The longitudinal design of this study allowed the diagnosis of acquired NMD based upon routine electrophysiologic studies. The ability to diagnose NMD was limited by the clinical setting in only one patient. In that patient, direct muscle stimulation was used to discriminate between neuropathy and myopathy.¹⁰ The patient had a nerve evoked response of less than 1 mV, but a direct muscle response of 8 mV, which was diagnostic of neuropathy.^11,12 In that patient, EMG 1 week later revealed reduced recruitment of normal amplitude motor units, which confirmed an acute neuropathy.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. The cumulative incidence of neuromuscular dysfunction while in the intensive care unit.

• Download figure
• Open in new tab
• Download powerpoint

Figure 3. Classification of neuromuscular dysfunction.

Patients who developed acquired NMD had decreased motor strength on formal neurologic examination. Median proximal muscle strength was 2.5 of 5 (1 to 3.25) in patients with NMD vs 5 of 5 (3 to 5) in patients with normal electrophysiologic test results (p = 0.02). Median distal muscle strength was also reduced in patients with NMD compared with control subjects (3/5 [2.75 to 5] vs 5/5 [3 to 5]; p = 0.18).We obtained creatine kinase values on all 20 subjects at day 7 after enrollment. The median value for those patients who developed NMD was 365 (128 to 1,397) and for those without NMD 262 (106 to 588) (p = 0.54). Two of the 20 patients received a neuromuscular blocking agent, and eight received corticosteroids for relative adrenal insufficiency during their ICU course. Both of the patients who received neuromuscular blocking agents developed NMD (100%) vs 44% in those who did not receive neuromuscular blocking agents (p = 0.136). Fifty percent of the eight patients who received steroids developed NMD, and 50% of the patients who did not receive steroids developed NMD (p = 1.0). In agreement with a recent study, the use of corticosteroid was not associated with the development of NMD, though our numbers are small.¹³

Predictive value of early NCSs.

To determine whether early reductions of nerve conduction response amplitude could predict the development of acquired NMD, the amplitudes of the NCS from the time of enrollment were compared with the amplitudes from studies performed on day 7. A significant reduction in NCS amplitude at day 7 compared with a patient’s enrollment study was defined as a 30% or greater decrease in amplitude in two or more sensory, motor, or both nerve responses. At day 7, 70% (14/20) of the patients had reduction in NCS amplitudes. Sixty-four percent (9/14) of these patients developed acquired NMD vs 17% (1/6) of patients that did not have a change in the amplitudes of the NCS (p = 0.01) (figure 4).

• Download figure
• Open in new tab
• Download powerpoint

Figure 4. Predictive value of a change from baseline nerve conduction response amplitude at 1 week on development of clinical neuromuscular dysfunction (NMD).

Discussion.

Reduced amplitudes of nerve conduction responses were present in patients early in the course of severe sepsis, and these abnormalities were predictive of increased mortality. In addition, reduction of nerve conduction response amplitude during the first week of severe sepsis, when the majority of patients were poorly responsive and not cooperative, predicted the eventual development and diagnosis of acquired NMD. Finally, in most patients with acquired NMD following sepsis, both critical illness myopathy and critical illness neuropathy were present.

We found that a majority of patients had reduced nerve conduction amplitudes within 3 days of hospital admission for sepsis. It has been reported previously that NCS amplitudes fall early in the course of sepsis.^3,4,14 We report here that patients with low NCS amplitudes early in the course of sepsis have an increase in mortality. As neither we nor the previous investigators were able to obtain formal testing of neuromuscular function prior to the development of severe sepsis, it is possible that baseline abnormalities reflect chronic presepsis changes.^3,4 One interpretation would be that patients with underlying medical conditions have low NCS amplitudes at baseline and lower survival rates for sepsis. However, none of the patients enrolled in this study had a known history of myopathy or neuropathy. When patients with chronic medical conditions that could be associated with subclinical NMD were removed from the analysis, the association between the baseline nerve conduction abnormalities and increased hospital mortality remained. Our interpretation is that early reduction in NCS amplitudes reflects the effects of systemic inflammation from sepsis on the electrophysiology of peripheral nerves and muscles. Patients who have a drop in NCS amplitudes are more affected by sepsis and thus have higher mortality.

We found that reductions in nerve conduction response amplitudes of at least 30% in two or more nerves during the first week of sepsis identified patients more likely to acquire NMD. The amplitude changes occurred at a time during the ICU stay when most patients were poorly responsive, and as a result detailed neurophysiologic testing necessary for diagnosis was limited. Our data suggest serial NCSs provide a simple method for early detection of patients with an increased risk of developing myopathy or neuropathy during severe sepsis. Most importantly, this at-risk population can be identified at a time when the clinical examination is dominated by severe encephalopathy and detailed neurophysiologic testing is often not possible. Once identified, these patients can be selected for more detailed testing to confirm the presence and severity of NMD and future studies assessing the effectiveness of neuroprotective agents aimed at reducing or eliminating the impact of neuromuscular dysfunction can be facilitated.

Acquired NMD in the ICU is caused primarily by either CIP or CIM.^2,15,16 It has generally been thought that these two syndromes occur in distinct clinical settings due to distinct sets of risk factors. However, it has been proposed that the two syndromes often coexist.^17,18 Our data suggest that most patients with acquired NMD due to sepsis have both CIP and CIM. One possibility is that our conclusion is based on a failure to distinguish between CIP and CIM. There are a number of factors that make it difficult to distinguish between CIP and CIM in critically ill patients.¹² Detailed electrophysiologic studies, including those done during recovery, are often necessary to distinguish between CIP and CIM. Some of the findings most easily identified in the ICU setting, fibrillation potentials and reduced compound muscle action potential (CMAP) amplitudes, are common to both disorders. Sensory responses can be limited by edema or may be low amplitude due to pre-existing neuropathy. The assessment of motor unit potential morphology and recruitment may be hampered by poor patient effort due to the presence of encephalopathy. The technique of direct muscle stimulation may be helpful, but only in the subset of patients with severe reduction in the motor conduction study amplitude.

We followed patients over time and did multiple studies on each patient before classifying them as having either CIM or CIP. The diagnosis of CIM was made if patients had small motor units and early recruitment on EMG. Because of the longitudinal assessment of patients during their stay in the ICU, we were able to document the presence of small motor units and early recruitment in all (9/9) of the patients diagnosed with CIM. We believe that our EMG findings are not subject to technical limitations that might lead to a false diagnosis of CIM. Although muscle biopsy would have helped to confirm myopathy, we believe there is little possibility that we misdiagnosed the nine patients who we classified as having CIM. In eight of the patients we diagnosed with CIM, we also found reduction in sensory nerve action potential (SNAP) amplitudes and thus diagnosed them with coexisting CIP. As we classified SNAPs as having decreased amplitude only if they changed by 30% over time, the issue of pre-existing neuropathy was not a confounding factor in our diagnosis of CIP. We doubt technical factors related to recording in the ICU could account for the drop in SNAP amplitudes as the initial study (with larger SNAP amplitudes) was also done in the ICU. We are thus left with concluding that either 1) edema accounts for the drop in SNAP amplitudes and most patients with NMD following sepsis have only CIM¹² or 2) CIM and CIP coexist in the majority of patients with acquired NMD following sepsis. We paid careful attention to edema and do not believe that it accounted for the reductions we observed in SNAP amplitudes.

One interpretation of our suggestion that CIM and CIP coexist in most patients with NMD after sepsis is that CIM and CIP are distinct disorders that are independently triggered by sepsis. Alternatively, the two syndromes might represent different manifestations of a single pathologic mechanism. It has been found in patients with CIM that the reduction in CMAP amplitude results from loss of muscle excitability.^10,11 Our finding of CIM in patients with sepsis suggests that sepsis can trigger loss of electrical excitability of skeletal muscle. If sepsis also triggers loss of electrical excitability of nerve, one might find CIM and CIP coexisting in many affected patients. There are two findings in patients with CIP that could be explained by the electrical inexcitability of nerve. The first finding is that the neuropathy in many patients with CIP is reversible over several months.¹⁹ This relatively rapid recovery could represent recovery of electrical excitability rather than regeneration of axons. A second finding that could be accounted for by electrical inexcitability of nerve is that in patients with reduced sensory amplitudes following sepsis, nerve biopsy often reveals normal structure.¹⁷ Future studies in animal models are needed to confirm this hypothesis.

We previously reported that there is a significant decrease in QRS amplitude on EKG in septic patients.²⁰ With recovery from sepsis, QRS amplitude rapidly increases. The recovery of QRS amplitude is similar to the recovery of SNAP and CMAP amplitudes that occur in patients recovering from sepsis. It is possible the reversible reduction of SNAP, CMAP, and QRS amplitudes is due to reduction in electrical excitability of nerve, skeletal muscle, and cardiac muscle. There currently are no data on whether reduction in neuronal excitability might contribute to septic encephalopathy.