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Publication

Long-term legacy of critical illness: mechanisms and clinical impact

Book - Dissertation

Patients who experience life-threatening illnesses - including major trauma, surgery, medical illness, and severe burns - are cared for at intensive care units (ICUs). Advances in critical care have decreased acute mortality, but in parallel, the proportion of patients requiring prolonged intensive care to overcome vital organ dysfunction has increased. Patients surviving critical illness unfortunately continue to face increased mortality relative to healthy peers, and suffer from a range of new or worsened neurocognitive, psychiatric and physical impairments that extend well beyond the hospitalisation phase up to years following ICU-admission. This so-called 'legacy' of critical illness interferes with activities of daily life, and is associated with reduced quality of life and return to participation in the society. It is unclear to what extent this excess mortality and morbidity burden results from a patient's premorbid health, or is attributable to the duration of the ICU stay, and to the exposures and complications occurring in the ICU. Indeed, during their ICU-stay, patients frequently develop complications related to the severity of their illness, their premorbid health, and to the supportive treatments required to avert death. Neuromuscular complications involving both respiratory and limb muscle function are frequent. They can be diagnosed in cooperative ICU patients by bed-side assessment of limb strength or respiratory muscle strength, or through electrophysiological testing if patients are unconscious. In the short-term, weakness of the limbs - labelled "intensive care unit-acquired weakness3 (ICUAW) - as well as electrophysiological abnormalities are associated with delayed liberation from mechanical ventilation, increased ICU- and hospital- length-of-stay, and increased ICU-mortality. Respiratory muscle weakness in particular associates with delayed weaning from mechanical ventilation and with ICU mortality. The impact of these complications on long-term outcomes however remains unclear. In this PhD-project, we aimed to assess whether the long-term limitations in ICU survivors are actually related to the duration of ICU stay, and to ICU exposures and complications. This was addressed through several studies in 2 patient cohorts. In a large cohort of former ICU patients, we investigated the relationship between the ICU-trajectory of critically ill patients and their long-term health outcomes. These outcomes included 5-year mortality and 5-year morbidity, assessed with handgrip strength, distance walked in 6 minutes and physical function related quality-of-life assessment. In a first study, we demonstrated that both 5-year mortality and morbidity were higher among patients with an ICU stay of at least 8 days ('long-stayers') as compared to those with an ICU stay less than 8 days ('short-stayers'). This difference was supplementary to any baseline pre-morbid vulnerability for ICU admission, and to the type and severity of illness necessitating critical care. We further identified a number of ICU-related risk factors, of which some may be amendable to intervention. Hence, part of the so-called 'legacy' of critical illness may be preventable. In a second study, we showed that also neuromuscular complications of critical illness further mortgage long-term outcome, independently from ICU-length of stay. Lower muscle strength at discharge from the ICU independently related with worse 5-year mortality and morbidity. Strikingly, this was the case even if strength was only mildly reduced. On the other hand, we demonstrated that abnormal motor nerve conduction studies after 1 week of intensive care also independently associated with worse 5-year mortality but not morbidity. These data underline that evaluation of muscle strength and electrophysiological alterations carry complementary information, and support a role of neuromuscular complications in the long-term outcomes of critically ill patients. This information may assist in prognostication and selecting of patients who may benefit from post-ICU follow-up services. In a third study, we additionally demonstrated that respiratory muscle weakness at discharge from the ICU, assessed by maximal pressure generated during a forced inspiratory manoeuver associates with 5-year morbidity but not mortality, independent from duration of ICU stay and limb muscle strength. These findings support the theory that peripheral and respiratory muscle weakness are separate, though overlapping entities and suggest that inspiratory muscle training may have potential to improve outcomes in ICU survivors. In a fourth study, we addressed the subset of ICU survivors from the same cohort in whom strenuous exercise could be safely performed. These patients were additionally evaluated with cardiopulmonary exercise testing - the gold standard to assess cardiorespiratory fitness - at the 5-year follow-up time point, as well as at intermediate (annual) time points starting from year 1 post-ICU. We demonstrated that ICU survivors performed worse than healthy controls. Exercise capacity appeared frequently limited by muscular factors, and the severity of organ failure in the ICU independently associated with exercise limitations. This suggests that, similar to other diseases, cardiopulmonary exercise testing may be useful to individualise rehabilitation programs in ICU survivors. As no change in aerobic exercise capacity in the studied post-1 year follow-up period was observed, the first year post-ICU may represent the window of opportunity for intervention. We performed a fifth study in a cohort of critically ill COVID-19 patients. As this new disease caused by SARS-CoV-2 virus overwhelmed ICUs worldwide, with particular patient profiles and disease characteristics, we studied the incidence, risk factors and short-term outcomes of ICU-acquired weakness in this population. We demonstrated high survival but also a very high incidence of weakness upon awakening in these patients. Potential factors related to this high incidence of weakness include high requirements for sedation and paralysing agents to suppress the respiratory drive, frequent administration of corticosteroids, and mechanical ventilation for particularly long duration. Although strength improved throughout the hospitalisation, functional impact at discharge remained substantial. Given our previous findings, these patients may be at high risk for long-term sequellae. In a final study, we performed a targeted analysis of abnormalities in muscle morphology and a number of pathways potentially involved in reduced strength 5 years after critical illness as compared to healthy controls. Several morphological abnormalities were observed in muscle of ICU-survivors 5 years after critical illness relative to controls, including abnormal myofibre shape, endomysial fibrosis and inflammatory infiltration, and a shift towards smaller type II myofibres. However, these changes did not significantly associate with strength. Investigated molecular markers of myofibrillary protein synthesis and breakdown, of neural signaling/denervation, and of myogenesis/muscle regeneration were comparable for patients at 5-year follow-up and controls, with longitudinal within-patient evaluation suggesting recovery of acute in-ICU changes in these markers. Except for a higher myogenin gene expression, none of the investigated markers were significantly different for patients with or without reduced strength at follow-up. This suggests that other mechanisms may be involved, although selection bias and insufficient power cannot be excluded. To explain reduced strength at 5 years, further research thus remains necessary. In conclusion, our findings suggest that a prolonged ICU stay, ICU-acquired peripheral and respiratory neuromuscular complications of critical illness and the severity of organ failure associate with 5-year mortality and morbidity. Consequently, COVID-19 ICU-survivors, in whom we demonstrated a high incidence of weakness, may be at high risk for such long-term impairments. Unfortunately, molecular and histological analyses of muscle tissue left many questions with respect to the mechanisms explaining persisting weakness unanswered. Nonetheless, our data provide insights into potentially modifiable ICU factors with regard to long-term outcomes, and delineate the population which should be targeted in future studies attempting to reduce the long-term burden of critical illness. Organized follow-up of post-ICU COVID-19 patients to offer tailored rehabilitation seems warranted.
Publication year:2021
Accessibility:Embargoed