key: cord-0759165-y5jbtj3a
authors: Núñez-Seisdedos, Maria N.; Lázaro-Navas, Irene; López-González, Luís; López-Aguilera, Lorena
title: Intensive Care Unit- Acquired Weakness and Hospital Functional Mobility Outcomes Following Invasive Mechanical Ventilation in Patients with COVID-19: A Single-Centre Prospective Cohort Study
date: 2022-05-16
journal: J Intensive Care Med
DOI: 10.1177/08850666221100498
sha: 1d711506a86acbd4581bd1c1fe99de52597affba
doc_id: 759165
cord_uid: y5jbtj3a

Background: Acute physical function outcomes in ICU survivors of COVID-19 pneumonia has received little attention. Critically ill patients with COVID-19 infection who require invasive mechanical ventilation may undergo greater exposure to some risk factors for ICU-acquired weakness (ICUAW). Purpose: To determine incidence and factors associated with ICUAW at ICU discharge and gait dependence at hospital discharge in mechanically ventilated patients with COVID-19 pneumonia. Methods: Single-centre, prospective cohort study conducted at a tertiary hospital in Madrid, Spain. We evaluated ICUAW with the Medical Research Council Summary Score (MRC-SS). Gait dependence was assessed with the Functional Status Score for the ICU (FSS-ICU) walking subscale. Results: During the pandemic second wave, between 27 July and 15 December, 2020, 70 patients were enrolled. ICUAW incidence was 65.7% and 31.4% at ICU discharge and hospital discharge, respectively. Gait dependence at hospital discharge was observed in 66 (54.3%) patients, including 9 (37.5%) without weakness at ICU discharge. In univariate analysis, ICUAW was associated with the use of neuromuscular blockers (crude odds ratio [OR] 9.059; p = 0.01) and duration of mechanical ventilation (OR 1.201; p = 0.001), but not with the duration of neuromuscular blockade (OR 1.145, p = 0.052). There was no difference in corticosteroid use between patients with and without weakness. Associations with gait dependence were lower MRC-SS at ICU discharge (OR 0.943; p = 0.015), older age (OR 1.126; p = 0.001), greater Charlson Comorbidity Index (OR 1.606; p = 0.011), longer duration of mechanical ventilation (OR 1.128; p = 0.001) and longer duration of neuromuscular blockade (OR 1.150; p = 0.029). Conclusions: In critically ill COVID-19 patients, the incidence of ICUAW and acute gait dependence were high. Our study identifies factors influencing both outcomes. Future studies should investigate optimal COVID-19 ARDS management and impact of dyspnea on acute functional outcomes of COVID-19 ICU survivors.

domains such as mobility and gait,16 may also lead to a need for continuing care following hospital discharge17 and to worse physical HRQOL. 18 Vast numbers of patients have required ICU admission during the COVID-19 pandemic globally. 19 Speculations anticipating the severity of the physical-related outcomes and rehabilitation needs of critically ill COVID-19 patients were made by clinical experts at the onset of the COVID-19 pandemic. 20, 21 However, further data on the specific epidemiology of acute physical outcomes of critically ill patients with COVID-19 based on direct cohort observation is still required. Furthermore, whereas risk factors for non-COVID-19 ARDS and general critically ill populations 22 have been previously reported, it is yet unknown how these factors specifically influence the development of ICUAW in COVID-19 patients. Determinants of hospital functional outcomes have been less widely investigated, however they are equally important as reduced acute physical functioning affects short-term rehabilitation needs, and it is likely to influence longterm functional disability. Therefore, the purpose of this study was to describe the incidence of ICUAW and hospital functional mobility outcomes in a prospective cohort of critically-ill patients with COVID-19. It also aimed to examine the association of ICUAW at ICU discharge and gait dependence at hospital discharge with baseline and clinical variables.

This was a single-centre, prospective cohort study conducted at the tertiary care Ramón y Cajal University Hospital in Madrid, Spain. Ethical approval was obtained from the institutional Clinical Research Ethics Committee. Need for written consent was waived due to the minimal-risk, observational nature of the study. Nevertheless, verbal informed consent from patients was gained and recorded on electronic patient records. The study was conducted and reported in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines 23 and was registered in ClinicalTrials.gov: NCT NCT04400461.

Consecutive adult (≥18 years) subjects admitted to ICU for IMV ≥ 24 h due to laboratory-confirmed SARS-CoV-2 pneumonia between 27 July and 15 December, 2020 were screened for eligibility. Patients were recruited from the two on-site medical and surgical ICUs starting from the date the first patient with confirmed COVID-19 pneumonia was admitted to ICU at the beginning of the pandemic second surge ("second wave") and ending when ICU admission levels started to rise again ("third wave") . 24 Exclusion criteria included: (1) loss of gait independence prior to hospitalisation (patient requiring the assistance of another person to walk or gait aid excluding a walking stick), (2) cognitive deficit that precluded cooperation with assessments (3) pre-existing neuromuscular disorder, (4) communication/language barrier, (5) acute cerebrovascular accident complication (6) pregnancy and (7) injury or surgical procedure requiring medical bed rest or immobilisation.

For each patient, baseline and clinical characteristics were collected from electronic medical medical records. Baseline characteristics were age, sex, Body Mass Index (BMI), co-morbidities, Charlson Comorbidity Index (CCI), 25 APACHE II scores, 26 and PaO 2 /FiO 2 (worst value during the first 24 h of admission to ICU). Clinical characteristics included ICU and hospital characteristics: IMV duration (number of days on IMV, regardless of the duration of IMV for that day), occurrence of failed extubation (need for reintubation within 72 h), need for tracheostomy, need for at least one episode of prone positioning, length of stay (days) in the ICU, post-ICU and in hospital, number of physiotherapy sessions (total, ICU and ward), and discharge destination and continuation of care required (home with no physiotherapy follow-up, home with domiciliary physiotherapy, home with outpatient physiotherapy and in-patient rehabilitation facility). In addition, clinical characteristics regarding exposure to adjuvant drug therapies for ARDS were recorded: duration (days) and total cumulative doses (mg) of neuromuscular blocking agent (NMBA) continuous infusion, total cumulative doses (mg) of intravenous boluses, excluding tracheal intubation doses; and duration (days) and total cumulative doses (mg) of systemic corticosteroids administered in hospital during pre-ICU and ICU stay. Corticosteroid doses were converted to methylprednisolone equivalents using an online corticosteroid equivalence calculator (https://www.mdcalc.com/steroid-conversion-calculator) to obtain a total corticosteroid equivalent cumulative dose.

Detailed information regarding ICU drugs was collected from daily observation charts by an ICU registered nurse. When ICU charts were not available, medication data were collected from the electronic prescription order entry system (PrescriWin) and electronic medical records. Information regarding hospital corticosteroid administration pre-ICU admission was collected from electronic patient records.

Primary outcomes included the incidence of ICUAW at ICU discharge and at hospital discharge clinically evaluated by bedside manual muscle testing with the standardised Medical Research Council Sum Score (MRC-SS) 27 (range 0-60, higher scores indicate greater muscle strength). ICUAW is defined as the MRC-SS < 48 cut-off. 28 MRC-SS scores used to determine ICUAW were reported.

Secondary outcomes comprised patient functional mobility status and gait dependence, both measured upon hospital discharge. Functional mobility status at hospital discharge was assessed with the Spanish version of the Functional Status Score for the ICU (FSS-ICU) 29 (range 0-35, higher scores indicate better functional mobility) which examines the level of dependence/assistance required to perform 5 tasks: rolling, supine to sit transfer, sitting on the edge of the bed, sit to stand transfer and walking. Gait dependence at hospital discharge was determined with the scores obtained within the 7-point FSS-ICU walking subscale, which is based on a combination of the distance the patient is able to walk and the level of physical assistance by another person required. Patients were dichotomised into: gait dependence (FSS-ICU walking score 0-5) and gait independent (FSS-ICU walking score 6-7) groups.

All outcome measurements were administered by two trained physiotherapists. Patient assignment to each researcher was done by alternation at study entry. All patients received routine daily physiotherapy treatment in the ICU (Monday to Sunday) as soon as they were able to cooperate and continued treatment in the ward (Monday to Friday). Physiotherapy sessions focused on early in-bed and progressive out-of-bed mobilisation during the ICU stay and on the ward according to patient clinical status. Physiotherapists delivering treatments were independent of research physiotherapists carrying out assessments, except for some patients receiving treatment in ICU (n = 16, 22.8%).

Descriptive statistics are presented as medians (interquartile range [IQR]) for continuous variables, and absolute frequencies and percentages for categorical data. Patients were divided into two groups according to the occurrence of ICUAW at ICU discharge. Between-group comparisons were conducted using Mann-Whitney and Chi-square test or Fisher-exact test, as appropriate. Similarly, between-group differences of patients with and without gait dependence at hospital discharge were analysed. Univariate analysis to examine associations between baseline and clinical variables with ICUAW at ICU discharge, and with gait dependence at hospital discharge, as dependent variables, was conducted. The magnitude of the associations was expressed as crude odds ratios (OR) and 95% confidence intervals (95% CI). Two-sided p-values ≤0.05 were considered statistically significant for all tests. Analysis was performed in SPSS IBM statistical software for Windows (version 24.0). Data of non-survivors and excluded patients were not analysed.

During the second COVID-19 outbreak, 113 patients with COVID-19 were admitted to ICU for IMV between 27 July, and 15 December, 2020. Twenty-eight (25%) died before ICU discharge and 14 (12%) met exclusion criteria. Reasons for exclusion were inability to cooperate with assessments (8%), cerebrovascular accident during current hospitalisation episode (4%) and injury requiring bed rest (1%) (Figure 1 ). One patient died on the ward due to cardiac arrest and was excluded from analysis. Thus, the final cohort consisted of 70 patients. Complete datasets were available for all included patients.

Cohort characteristics, incidence of ICUAW at ICU discharge and comparison between patients with and without ICUAW at ICU discharge are presented in Table 1 . There was no significant difference in baseline characteristics upon ICU admission between weak and not-weak patients. ICUAW had developed in 46 patients (65.7%) at ICU discharge and persisted in 22 (31.4%) at hospital discharge. Patients with ICUAW at ICU discharge spent significantly longer on mechanical ventilation (17 days (d) [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] vs. 7 [5-10.5] ); had longer length of stay in ICU (23 d vs. 11.5 [9] [10] [11] [12] [13] [14] [15] [16] ), longer post-ICU stay (13 d [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] vs. 7 [6] [7] [8] [9] [10] [11] ) and longer stay in hospital (41 d [30.7-67.2] vs. 23 [20.2-31] ). The number of patients having an episode of failed extubation was not different between groups. However, patients with ICUAW were more likely to undergo tracheostomy (32.6% vs. 0%). Most patients in both groups had at least one episode of prone ventilation, with weak patients having higher number of episodes (2 [1] [2] [3] vs. 1 ). Moreover, patients with ICUAW at ICU discharge were more likely to require referral to an in-patient rehabilitation facility (37% vs. 8.3%).

Cisatracurium besylate was the drug of choice in all patients who received continuous neuromuscular blockade and IV boluses. A larger proportion of weak patients were treated with continuous NMBA (96% vs. 71%) for a longer median duration (6 d [3] [4] [5] [6] [7] [8] [9] vs. 3 [0-6]) and with greater total cumulative doses (941 mg vs. 493 ). A total of 9 patients (2 [4.3%] in the ICUAW group and 7 [29%] in the non-ICUAW group) did not receive any neuromuscular blockers, either by continuous infusion or intravenous bolus doses, except for the initial tracheal intubation dose.

Dexamethasone was the most commonly administered corticosteroid pre-ICU and during ICU admission. Other systemic corticosteroids included methylprednisolone and hydrocortisone sodium phosphate. Treatment duration and total cumulative dosages of dexamethasone and total equivalent corticosteroids doses did not significantly differ between weak and not-weak patients. (29) (30) (31) (32) (33) (34) (35) ). A total of 38 patients (54.3%) were discharged newly gait dependent, out of which, 11 (15.7%) were not able to attempt to walk (FSS walking = 0). Compared to patients without weakness at ICU discharge, weak patients were more likely to be discharged from hospital without the ability to walk independently (63% vs. 37.5%). A total of 9 (37.5%) patients without weakness at ICU discharge also presented with gait dependence at hospital discharge. (Table 4 ).

In this single-center, prospective, observational study of a chronologic cohort of 70 critically ill COVID-19 survivors who underwent mechanical ventilation during the second pandemic outbreak, our main findings were: (1) ICU-acquired weakness was present in nearly two thirds of patients at ICU discharge and persisted in almost a third at hospital discharge; (2) the occurrence of ICUAW at ICU discharge was associated with the use of continuous neuromuscular blockade and with longer duration of mechanical ventilation, while there was no difference in corticosteroid use and doses between patients with and without ICU weakness; (3) about half (54.3%) presented with gait dependence at hospital discharge, including 9 (37.5%) patients without weakness at ICU discharge; (4) factors associated with gait dependence were lower MRC-SS scores at ICU discharge, older age, greater baseline comorbidity, prolonged mechanical ventilation, longer stay in ICU and longer duration of NMBA treatment. These findings further current knowledge concerning the adverse impact of critical illness on important acute physical outcomes in COVID-19 ICU survivors.

In agreement with our results, available studies reported high rates of ICUAW in mechanically ventilated adults with COVID-19. During the pandemic first surge, clinicallyassessed ICUAW rates were 52% (n = 26/50) 30 and 100% (n = 35) 31 at ICU discharge, in 2 retrospective studies; and 100% at awakening (n = 110) 32 and 69% (n = 16/23) at the time of extubation 33 in two further prospective studies. Interestingly, these high rates contrast with lower event rates observed in earlier large historical trials of mechanically Emerging evidence indicates that critically ill patients with COVID-19 could have undergone greater exposure to previously investigated risk factors for neuromuscular dysfunction. Common adjunctive interventions for ARDS, such as neuromuscular blockade and prone positioning, together with deep sedation have been used more frequently and for longer duration in critically-ill patients with COVID-19 ARDS. 3, 4, [36] [37] [38] [39] In our cohort, 87% received continuous neuromuscular blockade. This percentage is higher than those reported in pre-pandemic large multi-centric trials with ARDS patients which observed rates of continuous paralysis between 26-42%. 40, 41 Furthermore, most patients in our cohort (74%) received a course of paralysing agents beyond the 48-hours recommended by some guidelines for ARDS management. 42, 43 The adverse impact of NMBA on neuromuscular function remains controversial. 44, 45 In our study, patients receiving neuromuscular blockade had higher odds of developing ICUAW. The duration of NMBA treatment, however, did not reach statistical significance (p = 0.052). Given that our study was statistically underpowered to evaluate independent associations between NMBA and muscle weakness, these findings need to be carefully interpreted before further larger studies examine this relationship.

Patients in our cohort underwent prolonged mechanical ventilation which, unsurprisingly, was associated with a greater occurrence of ICUAW, as previously reported. 46 ICU length of stay is highly correlated with IMV duration and consequently, showed a significant association too. Furthermore, recent publications indicate that COVID-19 patients may have required substantially higher doses and longer administration of sedatives than other ARDS patients during IMV. 37, 38 We did not gather data to evaluate the possible myotoxic effects of sedatives. 47 However, delayed physiotherapy interventions due to lack of patient cooperation may have adversely contributed to higher ICUAW rates. Consequently, our study emphasises recommendations for optimal cooperative sedation targets, whenever save, to prevent excessive immobiliation. Additionally, all patients in our cohort were exposed to systemic corticosteroids, which role in critical illness neuromuscular dysfunction remains inconclusive . 48 Updated clinical guidelines incorporated corticosteroids into treatment regimes for severe and critically ill patients with COVID-19. 49, 50 Hence, we did not find difference in exposure to corticosteroids between patients with and without weakness. Further studies with alternative study designs are needed to address this issue.

Our study showed that acute reduction in independent functional mobility was common among COVID-19 ICU survivors in line with recent studies with critically ill COVID-19 patients showing short-term impairments in physical functioning. 32, 33, 51, 52 Notably, functional mobility decline in our cohort was primarily attributable to impaired gait independence. Two previous studies found that 83-92% of COVID-19 survivors were discharged from hospital as autonomous walkers 32, 53 in contrast to the 45.7% of independent walkers in our cohort. Differences in effectiveness of local rehabilitation practices, longer length of stay in acute wards and the specific ceiling effects of the varying outcome measures used may have all contributed to this disparity.

Moreover, we have shown that critical illness neuromuscular weakness was associated with worse acute functional outcome. While previous studies have demonstrated that muscle weakness acquired in the ICU influences long-term physical function, 10,54,55 our results confirm findings from earlier work showing also the impact of ICU weakness on gait ability from the early post-ICU phase. 12 Interestingly, more than one third of patients (n = 9, 37.5%) without weakness at ICU discharge did not recover their baseline independent gait status at hospital discharge. This could be partly explained by the barriers to ward rehabilitation imposed by room isolation restrictions which may have prevented optimal functional recovery. It is also possible that patients with subclinical weakness were undetected by bed-side assessments in ICU. A recent report on critically ill patients with COVID-19 indicated that MRC scores above 48 do not always rule out the presence of neuromuscular complications. 56 Incidentally, we suspect gait impairment may be also due to the exertional dyspnea experienced by many patients during the early recovery phase, which influenced the observed walking distance during physical examination. Although our study was not designed to measure dyspnoea, 44% of patients were discharged from hospital with supplementary oxygen possibly reflecting a degree of underlying persistent respiratory failure. In fact, recent work has identified dyspnoea as a prevalent persisting symptom in hospitalised and ICU patients with COVID-19 pneumonia. 57 Future studies investigating acute functional outcomes in COVID-19 ICU survivors may need to consider not only the impact of muscle weakness but also the influence of exertional dyspnea.

Older age, worse baseline comorbidity status together with the correlated variables prolonged IMV and ICU stay, were also identified as explanatory factors potentially influencing decline in gait independence. This is in agreement with recent work showing reduced acute functional status in invasively ventilated COVID-19 patients. 29, 51, 53 Previous studies in ARDS survivors and other critically ill patient populations also found that these are poor prognostic factors for long-term physical decline. 58, 59 Early recognition of patients most at-risk of functional mobility decline, and support with advance care planning and targeted rehabilitation interventions may help improve long-term outcome in COVID-19 survivors. The association between NMBA duration with reduced mobility status has not been reported before and it is probably mediated through muscle weakness acquired during ICU stay. The covariance between duration of NMBA and duration of IMV could also account for this result which should be tested in future multivariable analyses. This study has some strengths. We provide a comprehensive prospective dataset with lack of missing data and detailed medication information. We also admit several limitations. Firstly, our study is subject to common inherent biases of single-centre unmatched observational designs. Generalisability and capacity to infer cause-effect were limited. Secondly, due to a small cohort size, our study was underpowered to perform further multiple regression analysis to identify factors independently associated with outcomes. Additionally, we excluded patients with delirium and other neurocognitive disorders, which may have introduced a selection bias. Finally, the cut-off point to determine gait dependence within the FSS-ICU walking subscale has not been validated before, which may have affected internal consistency of observations.

In our study, COVID-19 ICU survivors experienced high rates of ICUAW and acute decline in functional mobility independence. Factors associated with ICUAW were the use of continuous neuromuscular blockade and duration of mechanical ventilation. Muscle weakness acquired in the ICU had an impact on impaired gait ability at hospital discharge. Other factors associated with gait dependence were older age, worse baseline comorbidity, prolonged IMV and longer duration of NMBA. Larger multicentre cohort studies are needed to confirm these findings which may inform effective ICU management strategies and rehabilitation interventions, and to evaluate the influence of dyspnea on acute functional outcomes COVID-19 ICU survivors. 

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The authors thank the patients for their participation in this study. We are also grateful to Dr Angel Candela-Toha, Consultant Anaesthetist, and Dr Jose A. Márquez-Alonso, Consultant Intensivist, for their disinterested and valuable comments to this work, and for their encouragement. We warmly thank Laura Gutiérrez-García for her useful insights into Statistics.

María N. Núñez-Seisdedos: Conceptualisation, Methodology, Formal analysis, Writing-original draft, Project administration, Supervision.Irene Lázaro-Navas: Formal analysis, review for editing. All authors contributed to data collection and approved the final version of the manuscript.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Not applicable, because this article does not contain any studies with human or animal subjects.

Supplemental material for this article is available online.

Maria N. Núñez-Seisdedos https://orcid.org/0000-0003-3414-6502 Irene Lázaro-Navas https://orcid.org/0000-0003-4634-9200