ICU-acquired weakness

Abstract

Critically ill patients often acquire neuropathy and/or myopathy labeled ICU-acquired weakness. The current insights into incidence, pathophysiology, diagnostic tools, risk factors, short- and long-term consequences and management of ICU-acquired weakness are narratively reviewed. PubMed was searched for combinations of "neuropathy", "myopathy", "neuromyopathy", or "weakness" with "critical illness", "critically ill", "ICU", "PICU", "sepsis" or "burn". ICU-acquired weakness affects limb and respiratory muscles with a widely varying prevalence depending on the study population. Pathophysiology remains incompletely understood but comprises complex structural/functional alterations within myofibers and neurons. Clinical and electrophysiological tools are used for diagnosis, each with advantages and limitations. Risk factors include age, weight, comorbidities, illness severity, organ failure, exposure to drugs negatively affecting myofibers and neurons, immobility and other intensive care-related factors. ICU-acquired weakness increases risk of in-ICU, in-hospital and long-term mortality, duration of mechanical ventilation and of hospitalization and augments healthcare-related costs, increases likelihood of prolonged care in rehabilitation centers and reduces physical function and quality of life in the long term. RCTs have shown preventive impact of avoiding hyperglycemia, of omitting early parenteral nutrition use and of minimizing sedation. Results of studies investigating the impact of early mobilization, neuromuscular electrical stimulation and of pharmacological interventions were inconsistent, with recent systematic reviews/meta-analyses revealing no or only low-quality evidence for benefit. ICU-acquired weakness predisposes to adverse short- and long-term outcomes. Only a few preventive, but no therapeutic, strategies exist. Further mechanistic research is needed to identify new targets for interventions to be tested in adequately powered RCTs.

Keywords: Clinical outcome; Critical illness; Diagnosis; Intervention; Muscle weakness; Risk factors.

Fig. 1

Mechanisms implicated in the development of ICU-acquired weakness. A conceptual framework is shown of the major pathways that are assumed to be involved in the loss of muscle mass and loss of muscle function that contribute to the development of ICU-acquired weakness [, , –17]. ATP adenosine triphosphate, PCr phosphocreatine, ROS/RNS reactive oxygen species/reactive nitrogen species. Mitochondria, proteins, neurons and ion channels indicated in green represent healthy organelles, molecules and cells, whereas grey symbols point to damaged/dysfunctional organelles, protein aggregates, cells and ion channels

Fig. 2

Overview of risk factors of ICU-acquired weakness. Observational and randomized controlled trials have identified a wide range of non-modifiable and modifiable risk factors associated with the risk of developing weakness in the ICU [, –58]. *certain antibiotics, such as aminoglycosides and vancomycin, have been independently associated with ICU-acquired weakness, although not unequivocally [45, 57, 59]. Other antibiotics, such as clindamycin, erythromycin, quinolones, polymyxin, tetracycline and vancomycin may affect the neuromuscular junction, but have so far not been independently associated with ICU-acquired weakness [45, 60, 61]

Fig. 3

Overview of short-term and long-term consequences of ICU-acquired weakness. The development of weakness in the ICU has been associated with a wide range of adverse consequences in the short term as well as the long term [, , –76]. LOS length of stay

Fig. 4

Impact of ICU-acquired weakness on short-term outcome and one-year and five-year survival. a Kaplan–Meier plots show the cumulative proportion of well-matched long-stay patients (ICU stay > 7 days) with (MRC < 48 at first evaluation) and without ICU-acquired weakness (MRC ≥ 48 at first evaluation) over time who were alive and weaned from the ventilator, discharged alive from the ICU, and discharged alive from the hospital. Patients who died were censored after the last patient had been weaned alive, discharged alive from the ICU or discharged alive from the hospital, respectively. Plots were redrawn in JMP®Pro14.0.0 (SAS Institute, Cary, NC) from the data described in [70]. Hazard ratios and 95% confidence intervals below 1, for the effect of weakness versus no weakness, illustrate a lower chance of earlier live weaning, of earlier live ICU discharge and of earlier live hospital discharge for patients with as compared with patients without ICU-acquired weakness. b Medians, interquartile ranges and 10th and 90th percentiles of 6-min walking distance at hospital discharge and total billed costs, as well as the distribution of the discharge destination, are shown for well-matched long-stay patients (ICU stay > 7 days) with (MRC < 48 at first evaluation) and without ICU-acquired weakness (MRC ≥ 48 at first evaluation), illustrating worse acute morbidity and higher healthcare-related costs for weak patients, as reported in [70]. c One-year survival for matched long-stay patients (ICU stay > 7 days) with (MRC < 48 at first evaluation) and without ICU-acquired weakness (MRC ≥ 48 at first evaluation) are shown (left panel), together with Cox regression estimates for one-year survival for all long-stay patients with ICU-acquired weakness according to whether weakness persisted until final examination in the ICU or not (middle and right panel). The survival curves visually display the model predicted survival time for the “average” patient according to the Medical Research Council (MRC) sum score at final examination in the ICU as described in [70]. The middle panel compares patients who recovered from weakness (MRC ≥ 48 at last evaluation) with all patients who did not (MRC < 48 at last evaluation), whereas the right panel further distinguishes persistently weak patients into patients who remained moderately weak (MRC 36–47) or severely weak (MRC < 36). One-year survival was lower for weak patients as compared with not-weak patients. Survival was further lowered when weakness persisted and was more severe as compared with recovery of weakness at ICU discharge. d Five-year survival is shown for patients according to MRC sum score at final examination in the ICU > 55 versus ≤ 55 (left panel), according to normal or abnormal CMAP on day 8 ± 1 (middle panel), or according to the combined information of the MRC sum score at final examination in the ICU > 55 or ≤ 55 and normal or abnormal CMAP on day 8 ± 1 (right panel) (adapted from [77]). Five-year survival was lower for patients with an MRC sum score at final examination in the ICU ≤ 55 versus > 55 and for patients with an abnormal versus normal CMAP on day 8 ± 1. CMAP compound muscle action potential, HR hazard ratio, MRC Medical Research Council sum score