Electrophysiological investigations of peripheral nerves and muscles: a method for looking at cell dysfunction in the critically ill patients
KeywordsMuscle weakness Polyneuropathy Myopathy Organ dysfunction Mitochondrial dysfunction Energy metabolism
Resting trans-membrane potential difference (Em) of skeletal muscle is correlated to the energy status of the organism: the more severe the illness, the lower the Em. In 1971, Cunningham demonstrated this association with severely debilitating medical conditions, showing an increase in intracellular sodium concentration possibly due to a “generalized cellular abnormality” . The study posed the basis for considering local (muscle) bio-electrical events generated by excitable tissues as indicative of the well-being of the entire organism. In 1995, Leijten showed that patients with electrophysiological signs of polyneuropathy had increased intensive care unit (ICU) mortality, more prolonged rehabilitation, and persistent 1-year motor handicap than those without . In 1996, Latronico demonstrated normal nerve histology, despite electrophysiological findings of axonal neuropathy, in biopsies taken in the early stage of acute disease. In late biopsies, however, axonal nerve degeneration was evident . This generated the hypothesis that functional (electrical) impairment may precede structural (histologic) changes and that electrophysiological study (EPS) might be used to look indirectly but non-invasively at cell functioning. During sepsis, a prototypical low-energy hyper-catabolic state, the nerves were trying to maintain their structure and survive by reducing or abolishing the function, a phenomenon easily documented by EPS. If sepsis persisted, the energy supply and/or use might not be restored and the histologic alterations would eventually ensue. According to this theory of the bioenergetic failure, “stunned but still living peripheral nerves and muscles may serve as a sentinel for the development of multiple organ dysfunction syndrome” . In 1999, Hotchkiss described a similar divergence between in vivo clinical evidence of organ failure and post-mortem histologic absence of extensive organ damage sufficient to explain the morbidity and mortality of sepsis . They also hypothesized that in situations of energy failure the cells may revert to a low energy state, a “hibernation” of the cell, to avoid cell death. The theory received support from two multi-center clinical studies, CRIMYNE  and CRIMYNE-2 , showing that the peroneal nerve, a long lower limb motor nerve, was the most commonly affected nerve. The axons are devoid of the machinery for biosynthetic processes, and all axonal components are synthesized in the cell body. Their anterograde transportation to the nerve terminal requires considerable energy expenditure and may fail if the nerve does not receive adequate nourishment .
Several clinical studies have shown an association of EPS alterations with clinical severity, most notably studies on intensive insulin treatment in surgical and medical ICU patients (reviewed in) , as well as an association with morbidity , and with hospital  and 1-year mortality . Most recently, Kelmenson and colleagues have shown that patients with abnormal EPS had significantly fewer 28-day ICU-free days, a worse discharge disposition and higher mortality in the ICU and in the hospital when compared to patients with normal EPS . So, in the last half century, a considerable amount of evidence has demonstrated that reduced bodily energy production, as it can be inferred from altered EPS, can be associated with disease severity and can be predictive of ominous prognoses. The time has come that we, as a clinical and scientific community devoted to unraveling the complex pathophysiology and timely treatment of multiple organ failure, would consider a wider adoption of EPS into the daily clinical practice.
None for this Editorial.
None for this Editorial.
Availability of data and materials
NL conceived the manuscript and wrote the part dedicated to the general and clinical aspects of the syndrome. OF wrote the part dedicated to the pathophysiological mechanisms of the syndrome and drew the figure. Both authors revised and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
Both authors have reviewed the final version of the manuscript and approve the manuscript for publication.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 1.Cunningham JN, Carter NW, Rector FC, Seldin DW. Resting transmembrane potential difference of skeletal muscle in normal subjects and severely ill patients. J Clin Invest. 1971;50:49–59 Available from: https://www.ncbi.nlm.nih.gov/pubmed/5101298.
- 5.Latronico N, Bertolini G, Guarneri B, Botteri M, Peli E, Andreoletti S, et al. Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multi-centre CRIMYNE study. Crit Care. 2007;11:R11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17254336.CrossRefGoogle Scholar
- 6.Latronico N, Nattino G, Guarneri B, Fagoni N, Amantini A, Bertolini G. Validation of the peroneal nerve test to diagnose critical illness polyneuropathy and myopathy in the intensive care unit: the multicentre Italian CRIMYNE-2 diagnostic accuracy study. F1000Res. 2014;3:127 Available from: http://f1000research.com/articles/3-127/v3.CrossRefGoogle Scholar
- 10.Friedrich O, Reid MB, Van den Berghe G, Vanhorebeek I, Hermans G, Rich MM, et al. The sick and the weak: neuropathies/myopathies in the critically ill. Physiol Rev. 2015;95:1025–109 Available from: http://www.physiology.org/doi/10.1152/physrev.00028.2014.CrossRefGoogle Scholar
- 11.Latronico N, Herridge M, Hopkins RO, Angus D, Hart N, Hermans G, et al. The ICM research agenda on intensive care unit-acquired weakness. Intensive Care Med. 2017;43:1270–81 Available from: http://link.springer.com/10.1007/s00134-017-4757-5.CrossRefGoogle Scholar
- 15.Kelmenson DA, Quan D, Moss M. What is the diagnostic accuracy of single nerve conduction studies and muscle ultrasound to identify critical illness polyneuromyopathy: a prospective cohort study. Crit Care. 2018;22:342 Available from: https://ccforum.biomedcentral.com/articles/10.1186/s13054-018-2281-9.CrossRefGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.