key: cord-0892012-35is4h4x
authors: Bohman, J. Kyle; Nei, Scott D.; Mellon, Laurie N.; Ashmun, R. Spencer; Guru, Pramod K.
title: Title: Physical Therapy and Sedation while on Extracorporeal Membrane Oxygenation for COVID-19 associated Acute Respiratory Distress Syndrome
date: 2021-06-29
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2021.06.030
sha: b2228043dd28510e0b52b7d9272ed959b5338389
doc_id: 892012
cord_uid: 35is4h4x

OBJECTIVES: This study aimed to determine if patients on ECMO with COVID-19 achieved lower rates of physical therapy participation and required more sedation than those on ECMO without COVID-19. DESIGN: Retrospective observational matched cohort study. SETTING: Bicenter academic quaternary medical centers. PARTICIPANTS: All adults who underwent ECMO for severe COVID-19 associated ARDS during 2020 and matched (matched 1:1 based on age +/- 15 years and medical center) adults who underwent ECMO for non-COVID-19 ARDS. INTERVENTIONS: Observational only. MEASUREMENTS AND MAIN RESULTS: Measurements collected retrospectively during the first 20 days of ECMO support and included daily levels of physical therapy activity, number of daily sedation infusions and doses, and level of sedation and agitation (Richmond agitation and sedation score). During the first 20 day of ECMO support, the 22 patients who were on ECMO for COVID-19 associated ARDS achieved a similar proportion of days with active physical therapy participation while on ECMO compared to matched patients on ECMO for non-COVID-19 ARDS (22.5% vs 7.5%, respectively; p-value 0.43), a similar proportion of days with RASS ≥-2 while on ECMO (47.5% vs 27.5%, respectively; p-value 0.065), and a similar proportion of days with chemical paralysis while on ECMO (8.4% vs 18.0%, respectively; p-value 0.35). CONCLUSIONS: The results of this matched cohort study support that sedation requirements were not dramatically greater and did not significantly limit early physical therapy for VV-ECMO patients with COVID-19 associated ARDS compared to non-COVID-19 ARDS VV-ECMO patients.

Setting: Bicenter academic quaternary medical centers.

Participants: All adults who underwent ECMO for severe COVID-19 associated ARDS during 2020 and matched (matched 1:1 based on age +/-15 years and medical center) adults who underwent ECMO for non-COVID-19 ARDS.

Interventions: Observational only. Conclusions: The results of this matched cohort study support that sedation requirements were not dramatically greater and did not significantly limit early physical therapy for VV-ECMO patients with COVID-19 associated ARDS compared to non-COVID-19 ARDS VV-ECMO patients.

Keywords: extracorporeal membrane oxygenation, ECMO, adult, COVID-19, sedation, physical therapy Introduction:

Since the appearance of patients with severe COVID-19 in intensive care units across the world in 2020, clinicians and researchers have been reporting their experiences caring for these unique patients. An area of particular interest has been the sedation requirements of this cohort of patients.

Prior to COVID-19, sedation and mobilization of adults on extracorporeal membrane oxygenation (ECMO) was described and noted generally high sedation requirements. [1] [2] [3] In a study by deBacker et al of patients on ECMO for respiratory failure between 2012 and 2015, the majority of patients were deeply sedated for the first 6 days of ECMO, after which 71% of patients were eventually awake enough to participate in physical therapy. [4] Early mobility and physical therapy in ECMO patients has been shown to be safe and potentially associated with decreased ICU mortality. [5, 6] Early reports from Hanidziar et al noted that many COVID-19 patients had "unusually high sedation requirements," and attributed this to younger average age, high respiratory drive and intense inflammation associated with COVID-19. [7] A subsequent case series of 24 patients requiring mechanical ventilation with COVID-19 demonstrated that this cohort required substantially more sedation than historical controls without COVID-19. [8] As the cumulative experience with COVID-19 has expanded, some have suggested that a new approach to multimodal sedation for COVID-19 patients may be required. [9] Based on published reports and anecdotes, the sedation requirements of COVID-19 patients on ECMO remains an area of active interest. A related knowledge gap which persists is whether a difference in degree of sedation may also impact patients' ability to participate in physical therapy. In this study we sought to compare the sedation requirements and ability to actively participate in physical therapy in adult patients on ECMO for respiratory failure with COVID-19 versus those without COVID-19. We hypothesized that patients with COVID-19 on ECMO would require more sedation and achieve active physical therapy less frequently than patients with non-COVID-19 respiratory failure on ECMO.

After receiving institutional IRB approval from both study sites (IRB 20-013094), the existing ECMO database was queried to compile a complete list of all adult patients who had undergone veno-venous ECMO (VV-ECMO) for ARDS between Jan 1, 2019 and Dec 31, 2020.

From this list, each patient who had undergone VV-ECMO for COVID-associated ARDS was matched 1:1 to a non-COVID-associated ARDS VV-ECMO patient; matching was based on study site and age (+/-15 years). A detailed retrospective chart review was completed to record demographic variables and then the complete set of study variables of interest, which had all been determined a-priori.

From a clinical perspective, the study institutions did not use a strict sedation algorithm.

Choice of sedatives and sedation goals were at the discretion of the consultant physician. Light levels of sedation (RASS -1 to 0) were targeted whenever possible. In very general terms, clinicians aimed to titrate sedatives to achieve a safe balance of patient comfort, lack of agitation, ability to participate in physical therapy, and facilitation of lung protective ventilation. This practice is similar to that recommended in the Society of Critical Care Medicine's pain, agitation, delirium, immobility and sleep (PADIS) guideline. [10] The intensive care units in the study institutions also have imbedded physical therapist teams, which help facilitate early physical therapy consultation.

The primary study variables pertaining to sedation medications, Richmond Analgesia and Sedation Score (RASS), physical therapy activity was recorded for each day that each patient was on ECMO. RASS was routinely documented by the trained nursing staff while in the intensive care unit and the RASS recorded at 12:00pm each day was collected and recorded for this study. [11] The "number of sedation infusions" was determined at 12:00pm each day; sedation infusions included any of the following: propofol, midazolam, lorazepam, dexmedetomidine, ketamine, fentanyl, and hydromorphone. The use of any other sedation infusions was extremely rare at the study institutions. The predominant sedative infusions used in the study population were propofol, ketamine and dexmedetomidine; total daily doses (including infusions and boluses) of propofol, ketamine and dexmedetomidine were recorded.

Opioid oral morphine equivalents (OME) were calculated based on standard opioid conversion and included all intravenous and enteral opioids administered. [12, 13] Chemical paralysis use was defined by use of a chemical paralytic infusion at any point during the 24-hour period; paralytic boluses were not recorded in this study as boluses were typically only used to facilitate procedures. Daily physical therapy was documented by either the ICU nurse or Physical Therapist. Passive physical therapy was defined as range of motion exercises performed by the care team without volitional effort exerted by the patient. Active physical therapy was movement or exercise during which the patient participated and exerted effort. The documentation reviewed in a retrospective manner did not have sufficient detail to accurately assign levels of activity described in the well-established ICU mobility score, therefore our study used a simple ordinal score from 0-3 points. [14] For the purposes of this study, physical therapy (PT) was recorded on a scale of 0-3; 0 = none, 1 = passive physical therapy only, 2 = active physical therapy, and 3 = ambulation. Documentation differentiating levels 0 and 1 were often unclear, so these two levels (0 and 1) were combined for practical purposes and recorded as "0-1." For each ECMO day the maximum physical therapy level was recorded in the study database.

The primary outcome, which was determined a priori, was the proportion of days on ECMO with PT level ≥2 (active PT or ambulation). The statistical power analysis for this primary outcome determined that a difference in proportions of 33% with a study power of 80% and α<0.05 would require fewer than 40 subjects in each study group. Unfortunately, from a statistical standpoint, but fortunate from a clinical standpoint, over the entire study period we had less than 40 subjects requiring ECMO for COVID-19.

Secondary endpoints investigated in this study were: proportion of ECMO days with any paralytic infusion (excluding any paralytic boluses), total sedation dosing per ECMO day (propofol, ketamine, dexmedetomidine, and opioids; including infusions and boluses), and daily level of sedation while on ECMO (reported as RASS). Primary and secondary endpoint comparisons excluded data from ECMO day 0 (day of ECMO initiation), because this period could be biased by interventions (including sedative and paralytic dosing) which were required during maximal ventilator support immediately prior to and during ECMO cannulation.

The data were analyzed in a standard approach. Descriptive statistics of categorical data was reported as number and percentages. Statistical comparisons of categorical data were performed using Fisher's exact test. Descriptive statistics of non-normally distributed continuous data was reported as median and interquartile range (IQR). Statistical comparisons of non-normally distributed continuous data were performed using the Mann Whitney U test. For all analyses, a p-value <0.05 was considered statistically significant. All statistical tests were performed using JMP Pro version 14.1.0 (SAS Institute Inc., Cary, NC).

During the study period between January 1, 2019 and December 31, 2020 at the participating study institutions, a total of 22 subjects required VV-ECMO for COVID-19 associated ARDS and 22 site and age-matched controls required VV-ECMO for non-COVID-19 associated ARDS. Demographics for these two groups are summarized in Table 1 .

For the study's primary outcome, the proportion of ECMO days with PT level ≥2 (active PT and/or ambulation) was compared and outlined in Table 2 . During the first 20 days of VV-ECMO, COVID+ ECMO subjects achieved a PT level ≥2 on a median proportion of 58% of ECMO days while non-COVID related respiratory failure ECMO subjects achieved a PT level ≥2 on a median proportion of 31% of ECMO days; p-value 0.43.

For the secondary endpoints, the results of these comparisons are outlined in Table 2 . Table 2 .

Additional analyses of associations with successful achievement of active physical therapy (PT level ≥2) are presented in the Appendix. These analyses were not intended to specifically identify differences between COVID+ and non-COVID related respiratory failure ECMO patients. These comparisons revealed that there was no clear association between the proportion of ECMO days with PT≥2 and survival to hospital discharge. Among subjects who survived to hospital discharge, there was a non-statistically significant association between discharge destination and proportion of ECMO days with PT≥2.

Further analysis of population data (combined data of subjects in the COVID+ ECMO cohort versus subjects in the non-COVID related respiratory failure ECMO cohort) are presented in the Appendix. The population level data revealed that during the first 30 days of ECMO support, patients in the COVID+ group received a similar number of sedative infusions and a similar number of total OME per day compared to those in the non-COVID group. Additionally, the proportion of ECMO days with an endotracheal tube in place was not statistically significantly different between the COVID+ ECMO subjects and the non-COVID respiratory failure ECMO subjects (0.59 vs 0.56, respectively; p-value 0.48), and is reported in the Appendix.

Despite our hypothesis that patients on VV-ECMO for COVID-19 associated ARDS would require more sedation and therefore would be less participatory in PT, the data from our study do not support that hypothesis. In our study, we found that during the first 20 days of VV-ECMO, patients with COVID-19 achieved active PT participation on a similar proportion of ECMO days, required chemical paralysis on a similar proportion of days, and did not have a statistically significantly different level of sedation (proportion of days with RASS ≥-2) compared to non-COVID patients. COVID+ VV-ECMO patients also did not have a significantly different median number of sedation infusions per day, total propofol dosing, total ketamine dosing, or total dexmedetomidine dosing while on VV-ECMO.

Although COVID+ VV-ECMO patients did not appear to have any significant differences in sedation requirements when comparing individual sedatives, does that mean they also did not have any significant difference in cumulative sedation requirements? There is no standardized "sedation equivalent" conversion available for intravenous sedatives (other than OME for opioids). A potential solution for this problem which could be considered would be processed encephalography (such as bispectral index or "BIS" monitoring). However, a BIS Another key limitation of the study presented here is the lack of protocolized sedation algorithms (or at least rigidly documented rationale for sedation dosing changes). This limitation is inherent to the retrospective observational design, but it introduces variability into the data and confounds the interpretation of the data. Due to this limitation, it is certainly possible that an unrecognized confounding factor may have influenced the choice of sedation medications and sedation level targets. An important data point which is absent from the patient records in this study is the rationale for changing sedation regimens and dosing. For example, was sedation increased due to agitation, delirium, subjective air hunger, excessive respiratory efforts, or something else? A significant proportion of patients with ARDS (approximately 50%) do not tolerate spontaneous breathing trials even while fully supported on ECMO, so in our study perhaps a large number of our patients also did not tolerate spontaneous breathing trials and therefore required more sedation to ensure lung protective ventilation. [15] In regards to the risk of chance influencing the findings of this study, the use of primary and secondary endpoints chosen a priori substantially protects against this risk, but the limited statistical power (owing to a relatively small number of COVID-19 subjects) increases this risk.

The results of our study differ somewhat compared to the data reported by Hanidziar et al and Kapp et al. [7, 8] Both groups reported a substantially higher sedation requirement for COVID-19+ patients. The reason for these differences may be due to any number of factors, but one factor which deserves mention is the timing and context of the data. The data reported by Hanidziar et al and Kapp et al came earlier during the pandemic when our COVID-19 experience was more limited and ICU censuses were surging. Perhaps, with crisis mode staffing during early COVID-19 surges there was a tendency to more deeply sedate patients to avoid any unplanned complications from agitation, such as self-extubation. Similarly, it is plausible that observer bias or a few notable outliers may have colored our impressions, suggested an increased sedation requirement in COVID+ patients, and prompted us formulate the hypothesis for the current study. At least based on the range of total daily propofol, ketamine and dexmedetomidine, there is no objective evidence of even a few outliers requiring significantly higher sedative doses in the COVID+ group. One additional potential confounder worth mentioning, is the fact that most of the included patients had at least 1 femoral ECMO cannula, which could potentially interfere with PT efforts. However, there was no significant difference in cannulation configurations between the COVID+ and non-COVID VV-ECMO groups.

All in all, the results of our matched cohort study of ECMO patients suggest that the sedation requirements for patients with COVID-19 associated ARDS did not limit early physical therapy compared to those on ECMO for non-COVID-19 ARDS. The results of this study do not support the hypothesis (nor do they definitely rule out the hypothesis) that COVID-19+ ARDS patients on VV-ECMO require increased sedatives to achieve an equivalent level of sedation. In order to bring more clarity to this question, a more standardized clinical approach to sedation regimens could help control some potential confounders. 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The study team would like to thank our clinical ECMO teams for their care of the patients included in this study. We would also like to thank the generous Mayo Clinic benefactor donations which enabled the investigator-initiated funding for this study provided by the Mayo Clinic Transplant Research Committee. ECMO day 0 (day of ECMO initiation) excluded from these analyses. IQR = interquartile range PT level ≥2 equal active PT and/or ambulation.

Sedation Requirements in Patients on Venovenous or Venoarterial Extracorporeal Membrane Oxygenation

Evaluation of sedatives, analgesics, and neuromuscular blocking agents in adults receiving extracorporeal membrane oxygenation

A retrospective study of sedation and analgesic requirements of pediatric patients on extracorporeal membrane oxygenation (ECMO) from a single-center experience

Sedation Practice in Extracorporeal Membrane Oxygenation-Treated Patients with Acute Respiratory Distress Syndrome: A Retrospective Study

Safety and Feasibility of Early Physical Therapy for Patients on Extracorporeal Membrane Oxygenator: University of Maryland Medical Center Experience

Intensive Care Physiotherapy during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome

Sedation of Mechanically Ventilated COVID-19 Patients: Challenges and Special Considerations

The Use of Analgesia and Sedation in Mechanically Ventilated Patients With COVID-19 Acute Respiratory Distress Syndrome

Rethinking Sedation During Prolonged Mechanical Ventilation for COVID-19 Respiratory Failure

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients

Opioid conversions in acute care

Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing

Feasibility and inter-rater reliability of the ICU Mobility Scale

Spontaneous Breathing during Extracorporeal Membrane Oxygenation in Acute Respiratory Failure