Early physical rehabilitation dosage in the IntensiveCare Unit predicts hospital outcomes after criticalCOVID-19

Objective: to examine the relationship between physical rehabilitation parameters including a novel approach to quantifying dosage with hospital outcomes for patients with critical COVID-19. Design: Retrospective practice analysis from March 5, 2020, to April 15, 2021. Setting: Intensive care units (ICU) at four medical institutions Patients: n = 3,780 adults with ICU admission and diagnosis of COVID-19 Interventions: We measured the physical rehabilitation treatment delivered in ICU and patient outcomes: 1) mortality; 2) discharge disposition; and 3) physical function at hospital discharge measured by the Activity Measure-Post Acute Care (AM-PAC) “6-Clicks” (6–24, 24=greater functional independence). Physical rehabilitation dosage was defined as the average mobility level scores in the first three sessions (a surrogate measure of intensity) multiplied by the rehabilitation frequency (PT + OT frequency in hospital). Measurements and Main Results: The cohort was a mean 64 ± 16 years old, 41% female, mean BMI of 32 ± 9 kg/m2 and 46% (n=1739) required mechanical ventilation. For 2191 patients with complete data, rehabilitation dosage and AM-PAC at discharge were moderately, positively associated (Spearman’s rho [r] = 0.484, p < 0.001). Multivariate linear regression (model adjusted R2= 0.68, p <0.001) demonstrates mechanical ventilation (β = −0.86, p = 0.001), average mobility score in first three sessions (β = 2.6, p <0.001) and physical rehabilitation dosage (β = 0.22, p = 0.001) were predictive of AM-PAC scores at discharge when controlling for age, sex, BMI, and ICU LOS. Conclusions: Greater physical rehabilitation exposure early in the ICU is associated with physical function at hospital discharge.


Objectives
3][4] A potential explanation for the lack of bene ts is a non-speci c exercise dose.
Patients are routinely randomized to "one-size-ts-all" protocols leading to heterogeneity in the response to treatment.Dosage that accounts for the frequency and intensity of exercise is frequently overlooked or not addressed in critical care practice and research.The rehabilitation dosage delivered in large randomized controlled trials (RCTs) is rarely implemented in clinical practice 5,6 , and patients in the ICU seldomly receive a targeted or individualized dose of exercise.Patients with critical COVID-19 have not been studied to determine if dosage of exercise is related to outcomes.The COVID-19 pandemic may have unintentionally altered patterns in rehabilitation practice due to periods of isolation. 7Thus, the primary objective of this study was to examine the relationship between physical rehabilitation parameters including a novel approach to quantifying dosage with hospital outcomes for patients with critical COVID-19.

Design
Retrospective practice analysis for patients hospitalized from March 5, 2020, to April 15, 2021.Inpatient Mobility Short Form (6-24, 24=greater functional independence). 8Physical rehabilitation parameters included time to rst rehabilitation (physical [PT] or occupational [OT]) session in days, number of PT and OT sessions completed during hospital length of stay (LOS), frequency of PT and OT (# of session / hospital LOS), mobility status during rst three and the last recorded (if more than 3 sessions) rehabilitation sessions.Mobility levels were quanti ed by the John Hopkins-Highest Level of Mobility (JH-HLM, 1-8, 1=lying in bed; 8=ambulating >250 feet).The physical rehabilitation dose was quanti ed in a novel method: the average JH-HLM score over the rst three sessions (a surrogate measure of early intensity) was multiplied by rehabilitation frequency (PT + OT frequency).The novel dose provides information on delivery of ICU rehabilitation such that patients who achieve high mobility with daily frequency of rehabilitation receive the highest dosage, whereas patients with lower mobility levels and infrequent rehabilitation receive the lowest dose.Our method is based on our previous published studies demonstrating that the mobility levels obtained in the rst 3 rehabilitation sessions predict, or at minimum, associate with patient-centered outcomes. 9,10

Measurements and Main Results
Descriptive statistics were reported as mean ± SD, median [IQR], or n (%) as appropriate.A total of 3780 patients with COVID critical illness were included.Patients were strati ed into groups according to discharge disposition (in-hospital death, subacute or long-term care facility, acute rehabilitation facility, home with services, or home independent).The change in mobility level during rehabilitation as measured by JH-HLM among discharge groups was compared using a two-way ANOVA.Dose of rehabilitation between discharge disposition groups was compared using Tukey's multiple comparison test.Univariate analyses (Spearman's correlation) were performed to assess associations between rehabilitation parameters and functional outcomes.Multivariate linear regression was performed to analyze the association between rehabilitation dose and discharge AM-PAC scores, which de ned physical function among survivors, adjusting for pre-speci ed covariates including age, sex, body mass index (BMI), ICU length of stay, and receipt of mechanical ventilation.
Patients demographics are described in Table 1.The cohort was a mean 64 ± 16 years old, 41% female and mean BMI of 32 ± 9 kg/m 2 .Mechanical ventilation was required in 46% (n=1739), and the median hospital LOS was 12 days (IQR 7-21).A total of 2200 (58%) and 1698 (45%) patients received at least one PT and OT session, respectively.The rst rehabilitation session occurred 7.5 ± 8.0 days after ICU admission.Patients received PT at a frequency of 0.22 ± 0.14 days a week and OT at a frequency of 0.18 ± 0.11 days a week, equivalent to 2.8 rehabilitation sessions per week.Mobility levels on the JH-HLM scale generally increased from the rst to last session (+0.93 ± 2.1).The mean JH-HLM score for all sessions was 4.6 ± 1.7; this suggests a likely ability to transfer from a bed to a chair but not stand for up to one minute.The mean dose of physical rehabilitation was 1.8 ± 1.3 units.
Patients who died in the hospital (n = 994, 26%) were older, more likely to require mechanical ventilation, had longer durations of mechanical ventilation, and longer ICU LOS (Table 1) compared to patients who survived to hospital discharge.Compared to survivors, those who died in the hospital had an earlier start of rehabilitation, but had lower frequencies of rehabilitation, achieved lower levels of mobility, and received a lower dose of physical rehabilitation (Table 1).Strati ed by discharge disposition, patients discharged to home had the highest dose of rehabilitation (F = 69, p <0.0001; Figure 1).
For 2191 patients with complete data, mean AM-PAC scores at discharge were 15.6 ± 5.9; similar to the JH-HLM mean score, this suggests requiring a lot of help for bed-to-chair transfers. 11Rehabilitation dose and AM-PAC at discharge were moderately, positively associated (Spearman's rho [r] = 0.484, p < 0.001).Physical function at discharge as measured by AM-PAC was signi cantly associated with average mobility achieved in rst 3 sessions (r = 0.799, p < 0.001), change in mobility from rst to last session (r = 0.445, p < 0.001), and PT and OT frequency with physical function (r = 0.130, p < 0.001).Multivariate linear regression (model adjusted R 2 = 0.68, p <0.001) demonstrates mechanical ventilation (β = -0.86,p = 0.001), average mobility score in rst three sessions (β = 2.6, p <0.001) and physical rehabilitation dosage (β = 0.22, p = 0.001) were predictive of AM-PAC scores at discharge when controlling for age, sex, BMI, and ICU LOS.

Conclusions
Our expansive study, involving over 3700 critically ill patients with COVID-19 at four medical insitutions, underscores the pivotal role of physical rehabilitation exposure in the ICU, demonstrating a signi cant correlation with favorable hospital outcomes.This ndings aligns with previous research highlighting the positive association between rehabilitation frequency and outcomes in COVID-19 patients, albeit not speci cally focusing on those with critical illness. 12Introducing a novel methodology, we measure rehabilitation dose by assessing both session frequency and a surrogate marker of intensity derived from achieved mobility levels during sessions.Although our approach lacks physiologic dosage markers such as vital signs, and duration of intensity, it introduces a groundbreaking method for quantifying ICU rehabilitation dose with a single unit.Adopting this approach may enable ICU rehabilitation programs to speci cally delineate the intervention provided and anticipate patient bene t.In future, strati cation and phenotypic analysis accounting for dose hold promise to guide interventions in clinical research settings.this approach may be useful for prescribing interventions in clinical research.
4][15] The intraindividual variations have also been recognized in critical care with ventilatory and pharmaceutical interventions. 16,17To improve the ICU rehabilitation eld, it is imperative that clinicians and researchers examine the dose-response.As clinicians, we must modify and adjust treatments based on patient-and clinical-related factors to enhance outcomes.Our work as well as other research demonstrates that older individuals and patients with chronic disease respond differently to exercise. 10,18Thus, we strongly suggest that researchers and clinicians must begin to examine the response to targeted or individualized rehabilitation dose.
Our study has several strengths including a large sample size from multiple academic medical centers with high functioning ICU rehabilitation programs.We also used real world data directly from each rehabilitation session provided to create our method.The study also has limitations.The retrospective study design limits our ability to draw de nitive conclusions with regard to causation and is at risk of residual confounding, so our ndings should be considered hypothesis-generating.Additionally, while we adjusted for receipt of MV and ICU length of stay, patients who survived may have had lower severity of illness and thus participated at higher levels of mobility with rehabilitation, regardless of the dose.Lastly, we could not account for duration of exercise intensity in our models; longer physiologic demands may produce additional bene ts.In conclusion, we found that greater dose of rehabilitation during critical illness due to COVID-19 was associated with improved outcomes.Future studies should utilize personalized rehabilitation doses and identify the most optimal personalized dosage of rehabilitation in critically ill patients, including those with COVID-19.

Declarations
Ethics approval and consent to participate: Medical IRB with expedited review was approved at University of Kentucky (#47751, 9/27/2022).Informed consent was waived due to the study design and deidentifed nature of data.Data User and Transfer Agreements were approved for sharing of data between sites using REDCap platform with data integrity checks.
ICUs at four academic medical institutions (University of Kentucky, Cleveland Clinic, University of Michigan, and University of Southern California) Patients 3,780 adults (≥ 18 years of age) admitted to ICU with primary diagnosis of COVID-19 Interventions We examined the relationship between ICU-based physical rehabilitation interventions and hospitalbased outcomes.Outcomes included: 1) mortality; 2) discharge disposition; and 3) physical function at or near hospital discharge measured by the Activity Measure-Post Acute Care (AM-PAC) "6-Clicks"

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