Early Mobilization in the Intensive Care Unit: To Rest or to Test?

Abstract

POST-INTENSIVE CARE SYNDROME (PICS) encompasses a wide breadth of mental and physical disturbances found in intensive care unit (ICU) survivors. An increasingly recognized part of this syndrome is ICU-acquired weakness,1Kress JP Hall JB. ICU-acquired weakness and recovery from critical illness.N Engl J Med. 2014; 370: 1626-1635Crossref PubMed Scopus (393) Google Scholar with a prevalence of approximately 43% in ICU survivors.2Devlin JW Skrobik Y Gélinas C et al.Executive summary: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.Crit Care Med. 2018; 46: 1532Crossref PubMed Scopus (156) Google Scholar Much research has been put forth concerning this untoward outcome, with the largest trial to date recently published by the Treatment of Mechanically Ventilated Adults with Early Activity and Mobilization (TEAM), and the Australian and New Zealand Intensive Care Society study investigators.3Hodgson CL Bailey M et al.TEAM Study Investigators and the ANZICS Clinical Trials GroupEarly active mobilization during mechanical ventilation in the ICU.N Engl J Med. 2022; 387: 1747-1758Crossref Scopus (12) Google Scholar The TEAM trial was an international, randomized controlled trial at 49 sites in 6 countries. This trial randomized 750 mechanically ventilated patients to either intensive early mobilization (EM) or usual ICU standard physical therapy. The majority of patients were diagnosed with sepsis (66% in each group), followed by trauma (15%) or COVID-19 (≤10%). The daily assessment of maximum ICU Mobility Scale levels dictated EM as patients were mobilized to “the highest level of activity possible for the longest time.” In other words, patients in the EM arm were mobilized until the point of limitation by patient fatigue and other safety parameters. The provision of the intervention appeared to be successful, as the duration of active mobilization was more than double the time in the usual-care group (21 ± 15 v 9 ± 9 min/d, respectively). The intervention lasted for up to 28 days while in the ICU. Perhaps surprisingly, the authors found no difference in the primary outcome of patient days alive and days out of the hospital at 180 days. For the secondary outcomes, there were also no differences in mortality, ventilator-free days, or ICU-free days. Additionally, among survivors, quality of life, activities of daily living, disability, cognitive function, and psychologic function were not different between the 2 groups. A total of 8 serious adverse events were reported, of which 7 occurred in the EM group (5 arrhythmias, 1 desaturation episode, and 1 cerebrovascular accident). Only 1 event occurred in the usual-care group (1 desaturation episode). Less serious adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and less serious desaturations) were reported in 34 of 371 patients (9.2%) in the EM group and in 15 of 370 patients (4.1%) in the usual-care group (p = 0.005). In other words, nearly all serious adverse events were in the EM group, and more than double the less serious adverse events were in the EM group. These data implied significant risk in exercising ventilated patients to the point of fatigue or cardiopulmonary compromise. Critical care providers routinely cite improved patient outcomes with the use of Enhanced Recovery After Surgery (ERAS) protocols, which commonly include EM. The reason for this belief is based on evidence that patients in the ICU who undergo mechanical ventilation for more than 48 hours have skeletal muscle wasting.4Puthucheary ZA Rawal J McPhail M et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1094) Google Scholar However, many researchers believe that while immobilization may contribute to ICU-acquired weakness, this weakness is likely more associated with the pathophysiology of critical illness than to disuse of muscles. This knowledge is based on evidence that myofilament disruption, damage to the sarcoplasmic reticulum, decreased electrical excitability, and mitochondrial dysfunction occur more rapidly in critically ill patients than from immobility alone.5Lad H Saumur TM Herridge MS et al.Intensive care unit-acquired weakness: Not just another muscle atrophying condition.Int J Mol Sci. 2020; 21: 7840Crossref Scopus (32) Google Scholar Although copious data suggest that EM of patients in the ICU may reduce the length of hospital stay and improve function at the time of hospital discharge,6Fleming IO Garratt C Guha R et al.Aggregation of marginal gains in cardiac surgery: Feasibility of a perioperative care bundle for enhanced recovery in cardiac surgical patients.J Cardiothorac Vasc Anesth. 2016; 30: 665-670Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 7Noss C Prusinkiewicz C Nelson G et al.Enhanced recovery for cardiac surgery.J Cardiothorac Vasc Anesth. 2018; 32: 2760-2770Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 8Zaouter C Damphousse R Moore A et al.Elements not graded in the cardiac enhanced recovery after surgery guidelines might improve postoperative outcome: A comprehensive narrative review.J Cardiothorac Vasc Anesth. 2022; 36: 746-765Abstract Full Text Full Text PDF Scopus (6) Google Scholar many barriers to EM exist. Indeed, if there is a minimal benefit and increased risk to this practice, clinicians must evaluate which ICU patients will benefit from EM and to what extent EM should be performed. Although the cause of increased adverse events with aggressive EM is not completely determined at present, the TEAM trial certainly suggested there is a risk with aggressive implementation of EM. A subsequent meta-analysis evaluating the comparative efficacy and safety of EM included the TEAM trial data.9Paton M Chan S Tipping CJ et al.The effect of mobilization at 6 months after critical illness —meta-analysis.N Enlg J Med Evid. 2022; 2: 2Google Scholar This meta-analysis pooled data from 15 trials and 2,703 participants. The meta-analysis concluded that there was a 66.4% possibility of increased adverse events with the implementation of EM, and a 72.2% chance of increased 180-day mortality. Thus, this meta-analysis expanded the growing evidence that there may not be long-term outcome benefits with EM compared to previous data showing benefits, which focused on short-term functional outcomes. Furthermore, this meta-analysis added to the growing belief that, unfortunately, there are inherent risks to EM in critically ill patients. These data are not only important for future research on EM, but are also helpful when educating patients and families on the intimately related topic of realistic expectations after ICU survivorship. Etiologies of increased adverse events with EM could be caused by increased oxygen demand in oxygen-depleted critically-ill patients. All patients in the TEAM trial suffered from conditions known to cause oxygen supply-demand mismatch (sepsis, trauma, or COVID-19). Oxygen demand increases rapidly with increased heart rate, myocardial contractility, and large muscle group use, and these effects are more pronounced in deconditioned patients.10Sorriento D Di Vaia E Iaccarino G. Physical exercise: A novel tool to protect mitochondrial health.Front Physiol. 2021; 12660068Crossref Scopus (23) Google Scholar With the addition of decreased oxygen supply due to mitochondrial dysfunction from critical illness, sepsis, or acute respiratory distress, conditions are ripe for hemodynamic compromise. Indeed, an oxygen supply-demand mismatch appeared to be the etiology of the adverse events noted in the TEAM study. Thus, the age-old proverb of “in all things, moderation” is not just a good rule of thumb, but seems to directly apply to the extent of mobilization and activity prescribed to patients in the ICU. A common criticism of the TEAM trial is that the usual care group seemed to undergo what many hospitals would consider ‘early mobilization’ by common standards. If this was the case, then the intervention group would be considered ‘highly aggressive’ by most hospitals in terms of early timing, long duration, and high intensity of physical therapy. Anecdotally, very few ICU providers attempt to target the “highest level of mobilization provided for as long as possible before a step-down to lower levels of activity if the patient became fatigued,” as dictated in the TEAM trial protocol. This ‘step-down’ approach contrasts with common ‘step-up’ protocols in which the therapy program consists of graduated effort starting with a passive range of motion and increasing in intensity to functional mobility exercises.11Morris PE Berry MJ Files DC et al.Standardized rehabilitation and hospital length of stay among patients with acute respiratory failure: A randomized clinical trial.JAMA. 2016; 315: 2694-2702Crossref PubMed Scopus (220) Google Scholar, 12Moss M Nordon-Craft A Malone D et al.A randomized trial of an intensive physical therapy program for patients with acute respiratory failure.Am J Respir Crit Care Med. 2016; 193: 1101-1110Crossref PubMed Scopus (202) Google Scholar, 13Schweickert WD Pohlman MC Pohlman AS et al.Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial.Lancet. 2009; 373: 1874-1882Abstract Full Text Full Text PDF PubMed Scopus (2102) Google Scholar Although studies using the ‘step-up’ physical therapy approach were heterogeneous in outcomes, most reported no significant increase in adverse events in the intervention groups, unlike the TEAM trial. It is possible that outcomes between the intervention and usual-care groups were not different in the TEAM study because both groups received what most centers would deem robust physical therapy. Case in point, physical therapists assessed usual care patients at a very high rate of 81% of ICU days, compared with 94% of ICU days in the intervention group. In other studies concerning EM in patients admitted to the ICU, usual care reportedly consisted of just 32% of total ICU days14Jolley SE Moss M Needham DM et al.Point prevalence study of mobilization practices for acute respiratory failure patients in the United States.Crit Care Med. 2017; 45: 205-215Crossref PubMed Scopus (96) Google Scholar or, even worse, only 1 day of therapy during the entire hospitalization.11Morris PE Berry MJ Files DC et al.Standardized rehabilitation and hospital length of stay among patients with acute respiratory failure: A randomized clinical trial.JAMA. 2016; 315: 2694-2702Crossref PubMed Scopus (220) Google Scholar Even though patients in the intervention group of the TEAM trial mobilized for longer periods and on more days, nearly the same percentage of the usual-care group achieved the highest mobility milestone level as in the EM group (41% v 47%, respectively). Thus, it may be safe to surmise from previous data that a complete or near-complete lack of EM is detrimental. But analysis of TEAM data would suggest that high levels of EM may not be beneficial over moderate levels of EM. The reasons for the high performance of the usual-care group in the TEAM study were unclear, but it is possible that all ICUs in the study had especially well-resourced, advanced, and proactive ancillary support teams. As the TEAM authors acknowledged in their discussion, mobilizing critically-ill patients “requires clinical expertise, time, and resources.” The majority of the TEAM study concluded enrollment of patients prior to COVID-19 wreaking havoc on healthcare resources. Today, around the world, headlines dominate discussing the shortage of medical providers, especially nursing and therapy staff. The intensive resource requirements used in the TEAM trial protocol may simply be unattainable for many ICUs today. Patients presenting for cardiac surgery are increasingly older and frailer,15Clark K Leathers T Rotich D et al.Gait speed is not associated with vasogenic shock or cardiogenic shock following cardiac surgery, but is associated with increased hospital length of stay.Crit Care Res Pract. 2018; 20181538587Google Scholar making the need for ERAS protocols, including EM, even greater. However, postcardiac surgical patients have unique issues that may prevent EM, including sensitivity to anesthesia and analgesia, chest tubes, pulmonary artery catheterization and other invasive monitoring lines, and a high incidence of delirium, especially in older patients.16Afonso A Scurlock C Reich D et al.Predictive model for postoperative delirium in cardiac surgical patients.Semin Cardiothorac Vasc Anesth. 2010; 14: 212-217Crossref PubMed Scopus (67) Google Scholar Indeed, the TEAM trial did not include cardiac surgical patients, as the risks of EM may be highest in this population. For this reason, the ERAS Society recently published evidence-based recommendations for perioperative care in cardiac surgery. These recommendations included 22 perioperative interventions, beginning with prehabilitation, and ranging from transfusion thresholds to nutrition and, importantly, physical therapy.17Engelman DT Ben Ali W Williams JB et al.Guidelines for perioperative care in cardiac surgery: Enhanced recovery after surgery society recommendations.JAMA Surgery. 2019; 154: 755-766Crossref PubMed Scopus (385) Google Scholar However, these recommendations placed the most importance on prehabilitation, with preoperative physical therapy as a focus compared with postoperative physical therapy. It is hopeful that future iterations of cardiac ERAS pathways will have a larger breadth of evidence on which to base recommendations on postoperative physical therapy and mobilization strategies in patients undergoing cardiac surgery. The TEAM trial was a well-designed, large trial that provides valuable insight into the efficacy—or lack thereof, depending on interpretation—of EM in mechanically ventilated patients in the ICU. The findings that EM was not associated with improvement in days alive and days out of the hospital at Day 180, but was associated with an increase in adverse events, were surprising to many. However, the TEAM trial may have been better reported as “very early and very aggressive” physical therapy compared to “high-quality” physical therapy. If reported in this manner, the take-home message would have been that overly aggressive EM to the point of fatigue or decompensation in ventilated patients is not beneficial and is likely harmful. Although the TEAM trial did not elucidate the optimal timing, patient selection, and degree of mobilization for ventilated patients in the ICU, it did help to reinforce the sage advice that “in all things, moderation” should be applied in future studies concerning EM in ventilated patients.