Our patients with septic shock and mechanically ventilated for more than 72 hours were moderately to deeply sedated for more than half of their time in the ICU and the average ICU stay length was 14.9 ± 9.1 days. We explored screening for CIP and CIM in this acute phase of sepsis before apparition of muscle weakness. Indeed, using the simplified screening test proposed by Latronico et al, 7 this is the first study to evaluate septic patients systematically with PENT, around 72 hours after intubation. Our results revealed early abnormal changes in PENT in short-term critical care patients, which is unprecedented as previous studies only made precise symptomatic diagnosis of CIP and CIM at days to weeks after ICU admission.
The results of this study confirm the likelihood of developing CIP and CIM in patients with MOF, sepsis, and mechanical ventilation 31–32 and add new information on early nerve conduction disorder in critically ill patients.
The incidence of CIP and CIM varies in the literature, depending on the studied population. A study considering a population of patients similar to ours, showed an incidence of up to 70% in septic patients with long-term intubation. 4 The main difference in this study was the time-to-first electrophysiological investigation; Garnacho-Montero evaluated patients at days 10 and 21 after intubation. Using such a late interval, only eight (44.4%) of our patients would have been enrolled in this recruitment method because the others would have been deceased or discharged from the ICU before the MRC could be assessed. A systematic review found an association of about 50% between CIP/CIM and sepsis.5 Recruitment was once again different; most of the studies treated in the review concerned patients tested for polyneuropathy after appearance of muscle weakness and absent deep-tendon reflexes. Testing patients in the early phase of ICU stay allowed us to include a more diversified population of septic patients, including those with early sepsis recovery and therefore shorter ICU stay. Of note, even a fast recovery from sepsis does not protect against eventually contracting critical care illness from ICU stay as seen in the three patients hospitalized for less than 10 days, with critical care illness revealing itself after ICU discharge. Indeed, early testing provided evidence that this patient population is at risk of developing CIP or CIM later as seen in the case of one patient who was dismissed from the ICU on day 9 without benefiting from out-of-bed mobilization, and later re-admitted to the ICU for CIP-induced respiratory failure. This patient only recovered muscle strength and fine motility at 3 months after the first ICU discharge and experienced a very stressful hospitalization.
Systematic acute phase nerve conduction studies on short stay patients offers new diagnostic horizons but is also an organizational challenge, which represents the major limitation of our study. As the study design foresaw a first screening session with PENT and a second for further testing, the second session was not possible for some patients who had either died, left the ICU before further investigation was possible, received muscle relaxants or who were in a state of stress and refused investigation. In addition, the unavailability of nerve conduction studies on some occasions prevented further investigation. Consequently, six patients were only tested with PENT and defined as possible CIP or CIM, without a SNAP analysis allowing differentiating between the CIP and CIM subgroups of ICU acquired weakness patients. This inconvenience hindered the assessment of possible associations between sedation times and CIP and CIM subgroups. Essentially, positive PENT screening should be followed by further electrophysiological testing to allow a more accurate diagnosis of CIP from CIM. Systematic early testing in the ICU is already challenging, and full neurophysiological diagnosis on acute septic patients is remarkably complex in the first acute hospitalization phase. However, as prognosis of CIM is better than CIP, 26 systematic positive PENT coupled to SNAPs, muscle conduction time and at least one CMAP on another limb can already be considered an appropriate systematic testing regime. 33
MRC testing of our patients was difficult as most patients were transferred quickly to the intermediate care unit after awakening and extubation and were either sedated or unable to follow orders before ICU discharge. Advantages of PENT for early screening again crystallize; this method is independent of patient awareness. Six patients presenting loss of amplitude on motor stimulation with PENT also had muscle contraction impairment in the MRC test, corroborating the PENT results. One, however, had an important loss of amplitude in PENT but no contraction deficit on the MRC test, raising the question of a possible focal neuropathy of the peroneal nerve. This patient had the shortest stay of the whole cohort and remission. MRC testing also allowed confirming the presence of muscle weakness in one patient who had not been examined by other electrophysiological investigation than PENT. Even though MRC muscle strength testing was not systematic and was only performed on eight (44.4%) of the 18 patients, it confirmed the presence of muscle weakness.
Exploring polyneuropathy at an early stage also gave a new perspective on risk factors of developing CIP and CIM. Association between the two conditions and COPD, cancer, diabetes and acute kidney injury (AKI) is possible but should be explored further in studies with higher numbers of patients. As COPD impairs ventilation weaning, it would be interesting to compare weaning failure in COPD patients with and without ICU acquired weakness. 31–32, 34 Regarding diabetes, a case report showed a 27-year-old female diabetic patient who developed acute polyneuropathy at day 2 of ICU admission. 35 Our patient population had 5 diabetic patients out of 18 (27.8%), not significantly higher than the 20% expected in a population of similar average age of 63.6 ± 11.6 years according to worldwide diabetes prevalence in 2019 from the International Diabetes Federation.36–37 Furthermore, diabetes does not seem to impair prognosis of septic patients but rather increases the incidence of acute kidney injury (AKI). 38 Concerning the latter risk factor, renal failure is associated with higher mortality and the population we studied showed a particularly high incidence of AKI.35–36AKI shows approximately 50% association with septic shock, 39 which is inferior to the overall incidence of 13 out of 14 patients (92.9%) with AKI in our study. In addition, 8 out of 9 with renal replacement therapy (88.9%) had peripheral nerve conduction impairment, so association between AKI and sepsis severity, as well as ICU acquired weakness warrants further investigation to allow better prediction of its occurrence in early-stage septic shock patients. Furthermore, investigating peripheral nerve conduction impairment in AKI patients could furnish new information on the well-known association between CIP/CIM and MOF. Cancer is also known to worsen prognosis of septic patients. 40–41 All five patients of our cohort with an ongoing malignancy showed nerve conduction impairment, of whom four were clearly diagnosed with CIP and three died. Exploring an association between this risk factor and CIP/CIM would offset the lack of data in the current literature.
Early mobilization techniques have been proven beneficial in shortening ICU stay and improving rehabilitation. 42 Specific treatment of CIP and CIM include limb and respiratory muscle stimulation, but these techniques are still lacking in current practice. 6 A recent review stated that acute pharmacological treatment of inflammation has been explored but that mobilization was poorly investigated41. Beginning mobilization in the first days after onset of critical illness and intubation was reported to be safe and offer a real improvement in rehabilitation and in shortening the length of hospital stay in critically ill patients42− 44. Coupled with efficient sepsis treatment, 45 early mobilization offers better chances of recovery from many complications associated with critical illness. Indeed, early mobilization, especially verticalization associated with cyclic movement, maintains the neuro-vegetative system by stimulating the endogenous adrenergic system and preventing complications from immobilization such as CIP and CIM.46 This passive mobilization method has been proven not to increase the need of using catecholamine for intensive and intermediate care patients with severe brain injuries. As we have shown that CIP and CIM may be detected in the early phase of ICU stay 12 and prompt mobilization improves prognosis, 47 we can expect benefit from new mobilization techniques such as cyclical movement by MOTOmed-letto®. Early mobilization, however, should always be coupled with diaphragm stimulation as the incidence of diaphragm muscle weakness may be twice that of skeletal muscle weakness 32.
Passive robotized verticalization and mobilization techniques are still unexplored, but their use with comatose patients offers a potential treatment of CIP and CIM as they improve passive physiotherapy.
Our study emphasizes the need for early screening of CIP/CIM for three reasons. First, although severe sepsis with MOF and lengthened hospitalization are risk factors, it seems impossible to predict whether a patient is more likely to develop these conditions as we found one patient with severe sepsis and the longest stay, who did not show evidence of polyneuropathy. Second, the average state of consciousness of these patients and average time to awakening makes it impossible to diagnose the CIP/CIM by following symptoms. Early neurophysiological screening is therefore necessary to allow early recognition of the disease and to avoid misdiagnosis of a disorder of consciousness and absence of motor response48. Third, benefit can be expected from early specific passive muscle stimulation since active mobilization techniques are impossible on sedated patients. Early diagnosis would enable a tailored therapy for these at-risk patients. However, specific benefits need to be evaluated in a larger study with the same inclusion criteria and a protocol focusing on the mobilization procedure.