Physiologic responses to exercise in survivors of critical illness: an exploratory pilot study – Intensive Care Medicine Experimental

In this exploratory study of mechanisms underlying low exercise capacity in survivors of critical illness, we used cardiopulmonary exercise testing and novel measures of muscular oxygen metabolism and found the majority had significantly reduced exercise capacity with exercise responses that paralleled those seen in those with mitochondrial myopathies [8, 20]. We also found that measures of impaired muscular oxygen metabolism correlated strongly with both VO_2Peak and 6MWT, suggesting that exercise capacity in ICU survivors may be limited by oxygen utilization. These exploratory data indicate that impaired oxygen utilization due to mitochondrial dysfunction may contribute to persistent impairments in physical function following ICU hospitalization.

Our findings build upon prior studies of CPET in ICU survivors. Benington and colleagues recruited 50 survivors who had been treated with mechanical ventilation for 5 days or more and performed CPET at 6 weeks after hospital discharge [10]. They showed that 56% of these survivors had reductions in VO_2Peak. Because the mean respiratory exchange rate (RER) at peak exercise was less than 1, they attributed these reductions in exercise capacity to participants not reaching anaerobic threshold due to deconditioning [10]. In contrast, we conducted exercise testing at 6 months after hospitalization in a cohort of ICU survivors with a median duration of mechanical ventilation of only 2 days and found that 11 out of 14 had reduced exercise capacity. Our participants, however, achieved a median RER > 1.05, indicating that the reduced VO_2Peak was not due to submaximal effort. In addition, we used an effort independent measure of exercise capacity (OUES) which was below age and sex predicted normal values in a majority of participants, suggesting that exercise limitations in our cohort were not attributable to only deconditioning. Our findings suggest that reduced exercise capacity following critical illness can be severe and persist beyond the initial recovery period, and careful evaluation of survivors with detailed CPET measurements of oxygen utilization may be valuable in characterizing exercise limitations in future studies.

Our findings also complement prior work by Van Aerde and colleagues, who recruited 313 survivors of critical illness and conducted CPET between 1 and 5 years after hospitalization. They found that 38% of survivors had impaired exercise capacity as measured by VO_2Peak [1]. Because cardiac and pulmonary limitations were not present, the authors pragmatically attributed exercise limitation to a muscular etiology. Our findings extend these through our use of specific measures of muscle oxygen utilization, VO₂-work rate slope and VO₂ recovery half-time. We found these measures to be strongly correlated with exercise capacity measured by both CPET and 6MWT, suggesting that impairments in muscle oxygen metabolism may play a role in reduced exercise capacity in ICU survivors.

Our finding that the global pattern of exercise responses, which included impaired oxygen utilization, increased ventilation, and hyperdynamic heart rate, parallels CPET findings seen in those with mitochondrial myopathies [8, 15, 20] also contributes to existing literature regarding physical function after the ICU. Muscle mitochondrial dysfunction occurs early in critical illness and sepsis [21], and it is strongly linked to survival. Few studies, however, have evaluated mitochondrial function in ICU survivors. Dos Santos and colleagues performed muscle biopsies in 11 patients at both 7 days after ICU discharge and 6 months after critical illness [22]. They found that mitochondrial content (i.e., number of mitochondria) was reduced at 7 days after ICU discharge but had normalized by 6–month follow-up. They did not, however, measure mitochondrial function (i.e., oxidative phosphorylation). We used novel CPET measures and found impaired muscle oxygen utilization, suggesting reduced mitochondrial function may be present. Because mitochondrial function may be impaired, even in the setting of a normal number of mitochondria [23], together our findings suggest that further study of mitochondrial function using both in vitro (e.g., muscle biopsies) and in vivo (e.g., 31-phosphorus magnetic resonance spectroscopy) techniques in survivors of critical illness is warranted.

Our preliminary findings that impaired exercise capacity may be related to impaired muscle oxygen utilization has potentially important relevance in improving physical recovery after critical illness. While prior post-ICU rehabilitation studies have predominantly utilized either self-directed exercise or protocolized exercise [7], our data suggest that future exercise rehabilitation studies could investigate novel rehabilitation approaches aimed at optimizing mitochondrial function [24] or be paired with mitochondrially targeted nutritional or pharmaceutical therapies [25, 26]. By further understanding the mechanisms by which exercise capacity remains impaired among ICU survivors, future interventions may be “metabolically tailored” to target the underlying pathophysiology that drives long-term impairments.

Our exploratory study has several strengths. We employed gold standard CPET to investigate potential mechanisms of exercise limitation and utilized novel measures of oxygen utilization not previously investigated in ICU survivors, finding that oxygen utilization is significantly associated with exercise capacity using two complementary assessments (VO_2Peak and 6MWT distance). Unlike prior studies of CPET who enrolled those with a mean duration of mechanical ventilation > 15 days [25], our participants were treated with mechanical ventilation for a median of 2 days, which is more reflective of a general ICU population and acute critical illness [27] rather than a persistent or chronic critical illness cohort [28]. The short duration of mechanical ventilation also suggests that reductions in exercise capacity may occur rapidly during critical illness, a finding in need of further study.

Our pilot study should also be interpreted considering several limitations. The sample size is small, and we did not include an external control group. Nevertheless, we compared CPET and 6MWT data to widely accepted predicted normative values adjusted for age and sex, making our results exploratory. We also cannot completely rule out impairments in cardiac or microcirculatory function without invasive CPET (e.g., Swan-Ganz and/or femoral catheterization during CPET). Nevertheless, we did exclude participants with known cardiac dysfunction and the routine use of invasive CPET does not reflect clinical practice. Finally, we did not measure muscle mitochondrial function directly using muscle biopsies or other techniques, such as 31-phoshporus magnetic resonance spectroscopy. Nevertheless, we applied validated CPET measures of muscular oxygen utilization that correlate with mitochondrial dysfunction in other clinical populations [20].