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Table of Contents    
Year : 2016  |  Volume : 64  |  Issue : 4  |  Page : 606-607

Weakness in the critically ill: Can we predict and prevent?

Department of Neurology, GB Pant Institute of Postgraduate Medical education and Research, New Delhi, India

Date of Web Publication5-Jul-2016

Correspondence Address:
Vinod Puri
Department of Neurology, GB Pant Institute of Postgraduate Medical education and Research, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.185395

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How to cite this article:
Puri V, Gupta A. Weakness in the critically ill: Can we predict and prevent?. Neurol India 2016;64:606-7

How to cite this URL:
Puri V, Gupta A. Weakness in the critically ill: Can we predict and prevent?. Neurol India [serial online] 2016 [cited 2020 Sep 29];64:606-7. Available from:

Intensive Care Unit–acquired weakness (ICU–AW) is a frequent and debilitating neuromuscular complication of critical illness. It develops de novo during the course of an ICU admission and is associated with an increased short and long term mortality and morbidity. No other cause can be identified besides the acute illness or its treatment. This ICU-AW, evoked by critical illness, can be due to axonal neuropathy (Critical illness polyneuropathy – CIP), primary myopathy (Critical illness myopathy – CIM), or both (Critical illness polyneuromyopathy – CIPM or CIPNM) and can involve both peripheral and respiratory muscles. The incidence of the problem varies with the timing of evaluation. The rate varies from 11%, at 24 hours of ICU stay, to as high as 67%, if the stay is ≥10 days.[1]

Despite various studies looking at the risk factors for ICU-AW, the exact causal factor remains elusive. The most consistently implicated risk factors are those associated with severity of the illness, including shock, sepsis, and degree of multiple organ failure. The contribution of concomitant usage of corticosteroids, neuromuscular blockade, glycemic control, aminoglycoside therapy and immobilization yet remains inconclusive. Underlying pathophysiological mechanisms involve complex cascades of microvascular, metabolic, electrical, and bioenergetic changes culminating in loss of muscle strength and/or muscle atrophy [Figure 1]a and [Figure 1]b.[1]
Figure 1: CIP and CIM represent a continuum of neurogenic and myogenic changes of varying severity and course and are an integral part of the same process that leads to multi-organ dysfunction in critical illness. (a) In CIP, cytokines and endotoxins released during sepsis, along with hypoxemia, damage the blood nerve barrier and increase permeability of the endoneurial microvasculature. This releases toxic substances into the nerve ends. Hyperglycemia and hypoalbuminemia induce oedema, compromising the microcirculation to peripheral nerves and leading to distal nerve ischemia. Interleukins and cytokines also affect mitochondrial use of oxygen, causing adenosine triphosphate (ATP) depletion. This impairs nutrient transport from the cell body, through the axons, to the distal portion of nerves. All these factors culminate in axonal degeneration. (b) In CIM, several factors negatively affect muscle structure and function like: (1) Impaired microcirculation, nutritional deficiency, inflammatory mediators (TNF-α, IL -1,6 and GDF-15), denervation, endocrine stress and immobilisation result in decreased protein synthesis and increased protein breakdown, especially myosin. (2) Deficient autophagy [a cellular housekeeping system that removes damaged large organelles and protein aggregates] may be a mediator. (3) Denervation potentiates steroid receptor upregulation causing thick filament loss. Denervation is potentiated by concomitant NMBA usage. (4) An altered intracellular calcium homeostasis, affects the excitation–contraction coupling. (5) Oxidative stress and mitochondrial dysfunction cause ATP depletion and hence bioenergetic failure. (6) Sodium channel dysfunction induces muscle membrane non-excitability

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Short and long term detrimental effects and non-availability of specific treatment modalities underscore the importance of devising clinical strategies for an early diagnosis of ICU-AW. The study, by Gupta and Mishra, published in this issue, is a welcome addition to the Indian literature. The authors have studied 100 patients admitted to the ICU, with a diagnosis of sepsis, who have undergone nerve conduction studies (NCS). 37% patients were found to have features of neuropathy on NCS, with 81% of these developing it in the first 14 days. On risk factor analysis, a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (≥15) at or within 24 hours of admission (Risk ratio: 11.6, 95% confidence interval: 4.9–27.2) and the use of neuromuscular blocking agents were found to be associated with a significant risk of developing CIP. Previous studies from the Western literature have demonstrated a similar association between a higher severity of illness, as reflected by the APACHE score and the risk of developing ICU-AW.

Intensive care doctors must use this relatively easily obtainable score as it has predictive value. The study has some limitations like lack of concomitant clinical data in the patients, which makes it difficult to discriminate between occult and clinically relevant disease. Also, the study included a large number of relatively mild cases, as those who had severe illness expired and were excluded. The interpretation of electro-physiological data, in particular NCS, has limitations in the presence of edema of the limbs due to the disease and/or due to administration of intravenous infusion/s. More so, needle electromyography provides reliable information regarding the existent axonal changes but with the inherent limitation of time factor for development of these changes. The future studies must look into this aspect and assess the findings across all the limbs for reliable documentation of generalized changes in the peripheral nerves.

With limited available treatment options, future studies need to address the following: Developing prediction models using clinical score or risk factors along with relevant biomarkers for triaging the 'high risk' category, identifying reliable and easily obtainable screening tests in sick/comatose patients, and targeting new therapies for prevention and treatment of this entity.

At present, no validated biomarkers are available. Creatine kinase may be increased in patients with ICU-AW, but is not reliable or specific. Plasma levels of neurofilaments, which are biomarkers of axonal injury, are also elevated but peak late into the illness. Two potential and promising biomarkers include microRNA (miR) - 181a, found in post-operative cardiac surgery patients who develop acute muscle wasting [2] and, Growth and Differentiation Factor (GDF) - 15 (stress induced cytokine), the promoter of muscle atrophy during critical illness.[1]

In the diagnostic arena, handgrip dynamometry and quantitative neuromuscular ultrasound have been found to be promising in the critically ill patients.

Therapeutically, a growing body of literature supports the role of early mobilisation to maintain muscle strength and improve function in ICU patients. Studies of in bed cycling or direct muscle stimulation in comatose patients show encouraging results.[3] There are a number of ongoing trials exploring potential preventive pharmacologic agents like serotonin receptor (5-Hydroxytryptamine (2C)) agonists, hydroxymethylbutyrate and eicosapentaenoic acid, and intravenous immunoglobulin.[3] These are primarily anti-inflammatory or metabolic agents. Studies have also shown that avoiding parenteral nutrition during the first week in the ICU actually reduces the incidence of weakness.[4] This could mean that catabolic pathways like autophagy may be crucial in maintaining muscle quality and function. Additional agents aimed at lessening the severity of ICU-AW are still in the nascent phase.

To conclude, ICU-AW is an increasingly recognized clinical entity. Significant knowledge gap exists in identifying high risk patients for its development. Novel strategies are required to identify patients early and institute an aggressive management protocol to reduce the health care costs and improve the quality of life in critical illness survivors.

  References Top

Hermans G, Van den Berghe G. Clinical review: Intensive care unit acquired weakness. Crit Care 2015;19:274.  Back to cited text no. 1
Lugg ST, Howells PA, Thickett DR. The increasing need for biomarkers in intensive care unit-acquired weakness - Are microRNAs the solution? Crit Care 2015;19:189.  Back to cited text no. 2
Jolley SE, Bunnell A, Hough CL. Intensive care unit acquired weakness. Chest. 2016 Apr 7. Doi: 10.1016/j.chest. 2016.03.045.  Back to cited text no. 3
Hermans G, Casaer MP, Clerckx B, Güiza F, Vanhullebusch T, Derde S, et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: A subanalysis of the EPaNIC trial. Lancet Respir Med. 2013;1:621-9.  Back to cited text no. 4


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