table

Original Research

Prone Positioning in Moderate to Severe Acute Respiratory Distress Syndrome Due to COVID-19: A Cohort Study and Analysis of Physiology

Mehdi C. Shelhamer, DO 1

, Paul D. Wesson, PhD 2 , Ian L. Solari, MD

1 ,

Deanna L. Jensen, CRNA 1 , William Alex Steele, PA

1 , Vihren G. Dimitrov, MD

3 ,

John Daniel Kelly, MD, MPH, PhD(c) 2,4,5

, Shazia Aziz, MD 3 ,

Victor Perez Gutierrez, MD3, Eric Vittinghoff, PhD2, Kevin K. Chung, MD6, Vidya P. Menon, MD3, Herman A. Ambris, MD7, and Sanjiv M. Baxi, MD, PhD, MPH1,2

Abstract Background: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome (ARDS) but it is unknown whether prone positioning improves outcomes in mechanically ventilated patients with moderate to severe ARDS due to COVID-19. Methods: A cohort study at a New York City hospital at the peak of the early pandemic in the United States, under crisis conditions. The aim was to determine the benefit of prone positioning in mechanically ventilated patients with ARDS due to COVID-19. The primary outcome was in-hospital death. Secondary outcomes included changes in physiologic parameters. Fine-Gray competing risks models with stabilized inverse probability treatment weighting (sIPTW) were used to determine the effect of prone positioning on outcomes. In addition, linear mixed effects models (LMM) were used to assess changes in physiology with prone positioning. Results: Out of 335 participants who were intubated and mechanically ventilated, 62 underwent prone positioning, 199 met prone positioning criteria and served as controls and 74 were excluded. The intervention and control groups were similar at baseline. In multivariate-adjusted competing risks models with sIPTW, prone positioning was significantly associated with reduced mortality (SHR 0.61, 95% CI 0.46-0.80, P < 0.005). Using LMM to evaluate the impact of positioning maneuvers on physiological parameters, the oxygenation-saturation index was significantly improved during days 1-3 (P < 0.01) whereas oxygenation-saturation index (OSI), oxygenation-index (OI) and arterial oxygen partial pressure to fractional inspired oxygen (PaO2: FiO2) were significantly improved during days 4-7 (P < 0.05 for all). Conclusions: Prone positioning in patients with moderate to severe ARDS due to COVID-19 is associated with reduced mortality and improved physiologic parameters. One in-hospital death could be averted for every 8 patients treated. Replicating results and scaling the intervention are important, but prone positioning may represent an additional therapeutic option in patients with ARDS due to COVID-19.

Keywords coronavirus disease 2019, acute respiratory distress syndrome, prone position, severe acute respiratory syndrome coronavirus 2, respiratory failure

1 Medical Corps and Nursing Corps, United States Air Force, USA 2 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA 3 Department of Medicine, Lincoln Medical Center, New York City Health and Hospitals, The Bronx, New York City, New York, USA

4 Institute of Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA 5 F.I. Proctor Foundation, University of California, San Francisco, San Francisco, CA, USA 6 Uniformed Services University of the Health Sciences, Bethesda, MD, USA

7 Division of Physical Medicine and Rehabilitation, Lincoln Medical Center, New York City Health and Hospitals, The Bronx, New York City, New York, USA

Received August 14, 2020. Received revised November 03, 2020. Accepted November 23, 2020.

Corresponding Author:

Mehdi C. Shelhamer, DO, NYC Health and Hospitals / Lincoln Medical Center, 234 East 14th Street, Suite 8-20, Bronx, New York, NY 10451, USA.

Email: [email protected]

Journal of Intensive Care Medicine 2021, Vol. 36(2) 241-252 ª The Author(s) 2020

Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0885066620980399 journals.sagepub.com/home/jic

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-

CoV-2), the cause of coronavirus disease 2019 (COVID-19),

has had a profound impact on global public health. The

ongoing COVID-19 pandemic has presented numerous clinical

management challenges further compounded by overwhelmed

health systems. The initial critical care experience in Hubei

province, and more broadly in China, inadequately informed

preparations for what has been seen in Europe and North

America. 1

Healthcare providers have therefore continued to

incorporate and evaluate interventions in real-time. In the setting

of critical COVID-19 illness, SARS-CoV-2 infection often

results in severe pneumonia and hypoxemia with many patients

developing acute respiratory distress syndrome (ARDS). 2

Hypoxemic respiratory failure with ARDS has poor outcomes

overall and COVID-19 associated ARDS is no exception. 3,4

Several interventions for ARDS have been evaluated over the

last 2 decades. In particular, prone positioning is one of few

therapeutic interventions for patients with severe ARDS that

has demonstrated improved oxygenation and a survival benefit. 5

Awake prone positioning outside of the intensive care unit (ICU) is

safe and may decrease respiratory rate and improve oxygenation

with early application potentially delaying need for intubation in

patients with COVID-19. 6-8

In the ICU setting, prone positioning

of patients receiving non-invasive ventilation or high-flow nasal

canula, with or without sedation, may also be beneficial. 8

Physio-

logically, prone positioning may improve matching of ventilation

and perfusion, but studies have not linked physiologic changes to

clinical outcomes, especially in COVID-19. 9,10

The South Bronx is a socioeconomically disadvantaged bor-

ough in New York City (NYC) that had the highest per capita

COVID-19 case count in the United States at 2941 per 100,000

residents with very high hospitalization and death rates. 11,12

The pressing challenge that COVID-19 brought to NYC neces-

sitated external support through the United States Departments

of Defense and Homeland Security, re-distribution and

up-training of local hospital staff, support from clinical volun-

teers, and augmentation through healthcare worker staffing

agencies. Given the high volume of critically-ill patients admit-

ted to the hospital, a multidisciplinary team was assembled to

provide prone positioning given the support for the practice in

other populations with ARDS.

We sought to determine if patients on mechanical ventila-

tion with moderate to severe ARDS who underwent standar-

dized prone positioning had lower mortality and improved

within-person physiologic changes. As we rapidly evaluate

drugs and interventions for COVID-19, it is crucial to under-

stand if serial prone positioning could be a complementary

therapeutic intervention for the most critically ill.

Methods

Study Design

A cohort design with participants from the peak of hospitaliza-

tions for COVID-19 in exposed (prone positioning) and

non-exposed (non-prone-positioning) groups. During the

COVID-19 pandemic, much of the hospital was converted into

make-shift intensive care units and virtually all inpatients had

confirmed COVID-19. During this time, a multidisciplinary

prone team including personnel from the United States Air

Force Medical and Nursing Corps, the United States Army,

civilian contractors, and hospital occupational and physical

therapy was assembled to offer positioning maneuvers which

were otherwise rarely done due to crisis operations. Details of

the prone positioning process, including peri-maneuver check-

lists, team size and roles, supplies and team schedule are

included in Figure 1. In brief, patients were ideally put in the

prone position in the afternoon allowing at least 16 hours in

position before returning to supine position the following

morning. The prone team included a physician, respiratory

therapist, registered nurse, runner, and at least 2 members to

safely support patient movements. The respiratory therapist

served as the default airway expert except when a physician

or advanced practice provider was trained in advanced airway

management and, in that case, these providers served as airway

expert. The prone positioning team did not assume responsi-

bility to provide medical care for any patients during the study

period.

Setting and Participants

Participants were identified from a single level 1 trauma

hospital in the South Bronx, New York City, and were

included across all hospital services (medicine, surgery,

intensive care). All sequential adult patients (>17 years of

age) were included if they were intubated, had not undergone

prone positioning by others, met criteria for prone position-

ing, and had confirmed SARS-CoV-2 infection by real-time

reverse transcription-polymerase chain nasal swab

(Bio-Reference Laboratories, Inc., Elmwood Park, NJ, USA)

from March 25 through May 2, 2020. The prone team offered

positional services for mechanically ventilated patients who

met the following criteria (established a priori): arterial oxy-

gen partial pressure to fractional inspired oxygen (PaO2:

FiO2) < 150 mm Hg, positive end-expiratory pressure (PEEP)

�10 cm of water and FiO2 � 0.6. Patients with a do not resuscitate order were not explicitly excluded from the study.

In addition, continuous venovenous hemodialysis (CVVHD),

nitric oxide or extracorporeal membrane oxygen (ECMO)

were not available in the facility and intermittent hemodia-

lysis or paralytics were rarely used. The ultimate decision for

initiating and discontinuing positional movements was made

by the primary team overseeing and coordinating care for

each patient. Prone positioning was not mandatory, but was

routinely available, 24 hours a day, 7 days a week. The study

received institutional review board approval (IRB # 20-007).

The prone positioning service was advertised through critical

care (surgical and medical), hospital medicine, and physical

medicine and rehabilitation leadership. These services had

knowledge of and direct access to every patient who was

242 Journal of Intensive Care Medicine 36(2)

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243

mechanically ventilated in the hospital, even when they were

not the primary team.

Measures and Outcomes

The primary exposure was positional maneuvers, defined as

regular alternation between prone and supine positioning. The

primary outcomes of interest were in-hospital mortality and,

among exposed patients, differences in physiological para-

meters in prone vs supine position. In the mortality analysis,

every patient had at least 30 days elapse following initiation of,

or meeting criteria for, prone positioning. Follow-up of unex-

posed controls began when the participant first met prone posi-

tioning criteria during the 2 weeks after intubation. In the

analysis of positioning effects on physiologic parameters

among exposed patients, repeated measures of the oxygenation

index (OI), oxygenation saturation index (OSI), PaO2: FiO2 and SpO2: FiO2 were compared during periods of prone and

supine positioning. Episodes of positioning separated by more

than 48 hours were considered separately. The last physiologic

measurement collected in the intervals between each positional

change were used in the analysis. After the final positioning

change, the last measurement collected within 24 hours was

used. Confounders for both analyses were identified based on

literature review and directed acyclic graphs. In particular, age,

sex, race, body mass index (BMI), acute physiology and

chronic health evaluation (APACHE-II) score and vasopressor

use were the primary confounders by indication. In the mortal-

ity analysis, the APACHE-II score was evaluated at the time of

intubation. 13

BMI and age were categorized for ease of

interpretation and clinical utility. The study team obtained the

study data through manual electronic medical record chart

abstraction (Epic Systems, Verona, WI, USA).

Statistical Analysis

Characteristics of the cohort were summarized using descrip-

tive statistics as appropriate. Fine-Gray models were used to

assess the association between prone positioning and death,

accounting for hospital discharge as a competing risk. 14

Parti-

cipants remaining in the hospital at the end of follow-up were

censored. The proportional sub-distribution hazards assump-

tion was assessed visually through cumulative incidence

curves. To minimize confounding by indication, we used stan-

dard regression adjustment as well as a doubly robust approach

adding stabilized inverse probability treatment weights

(IPTWs) to the fully adjusted model. 15-17

A sensitivity analysis

was done to identify changes in results by excluding controls

that died within 48 hours of intubation. In addition, number

needed to treat was calculated by the inverse of the averaged

absolute risk differences at 30 days, for all participants at their

actual and counterfactual values of prone positioning, and in

combination with their observed covariate values. 18

Linear mixed models (LMMs) were used to assess the asso-

ciation of prone vs supine positioning with physiologic para-

meter levels among the exposed. Outcomes were natural log

transformed to meet normality assumptions. The LMMs

included nested random effects for participant and positioning

episode, and allowed for autocorrelation of the residuals. In

addition to estimating overall positional effects, we also

Figure 2. Determination of prone positioning groups during intervention period.

244 Journal of Intensive Care Medicine 36(2)

estimated these effects in days 1-3 and 4-7 of each episode.

Pearson correlation coefficients were also used to characterize

degree of agreement for OI, OSI, PaO2: FiO2 and SpO2: FiO2,

to support clinical utility in practice. Analyses were performed

in Stata (Version 16, StataCorp, College Station, TX, USA).

Results

During the study period, 335 individuals were intubated and

placed on mechanical ventilation. Sixty-two underwent prone

positioning while 199 who did not undergo positioning

changes, but met criteria to do so, were selected as contempo-

rary controls. Seventy-four individuals were excluded for fail-

ing to meet prone positioning criteria or for having undergone

prone positioning by providers outside of the standard protocol.

A study flow diagram depicts the inclusion and exclusion of

participants across groups in Figure 2. Overall, study partici-

pants were older, male and mostly self-reported Hispanic or

Black. The majority of participants were obese. Diabetes and

obstructive lung disease were the most common comorbidities.

Most patients were critically ill and septic on admission with a

median APACHE-II score at intubation of 17. Most partici-

pants required mechanical ventilation at hospital admission

(i.e., intubated in the emergency room) and almost all patients

(85%) received at least some amount of hydroxychloroquine as was consistent with hospital policy during the time. Most

patients ultimately expired within 2 weeks. Compared to the

control group, the participants who underwent prone position-

ing were younger (60 versus 66 years old) and were more

frequently classified as severe rather than critical on admission

to the hospital. Proportions of sepsis on admission and median

APACHE-II scores at the time of intubation were similar across

groups, but the prone positioning intervention group had less

ARDS on admission. Full baseline, demographic and outcome

data is summarized in Table 1.

Prone Positioning and Mortality

Compared to contemporary controls, the prone positioning

group had fewer deaths and a longer time to death in those

who expired, in spite of similar length of stay and

ventilator-free days. Estimates of the association between

prone positioning and mortality are summarized in Table 2.

Unadjusted and adjusted competing risks analysis showed

that exposed patients were at reduced risk of death (SHR

0.51, 95% CI 0.39-0.66, p < 0.005 and SHR 0.57, 95% CI 0.42-0.76, p < 0.005, respectively) compared to unexposed

controls. In the doubly-robust analysis adding stabilized

IPTWs, inferences were similar (SHR 0.61, 95% CI 0.46-0.80, p < 0.005) and for every 8 patients that underwent

prone positioning, one in-hospital death was averted. We found

no evidence for violation of the proportional hazards assump-

tion through visual inspection of cumulative incidence curves

(Figure 3). Covariate effect estimates are available in Table 3.

A sensitivity analysis with removal of controls who died within

48 hours of intubation (N ¼ 18) showed similar results. Regarding adverse events, one dislodged endotracheal tube

was noted in a re-positioned patient, but it was thought to have

been dislodged prior to the maneuver. One peripheral intrave-

nous line and one peripheral arterial line were inadvertently

removed during positioning. Pressure wounds due to position-

ing were not independently tracked.

Prone Positioning and Physiologic Parameters

Figure 4 shows the mean trajectories of physiologic parameters

over time. Improvements were seen for days 1-3 in the OSI,

PaO2: FiO2, SpO2: FiO2 and PaO2. For days 4-7 of prone posi-

tioning, improvement was seen in the PaO2: FiO2, SpO2: FiO2 and PaO2. Only the OI failed to show improvement at any time

and OSI did not show improvement for days 4-7. During crisis

operations with enhanced infection control and use of transport

ventilators for routine ventilation, it may be difficult to obtain

PaO2 and mean airway pressure values and so proxy variables

may be helpful. We therefore looked at Pearson correlation

coefficients among ratios and indices. Overall, PaO2: FiO2 and

SpO2: FiO2 are moderately correlated (p ¼ �0.51), and OSI and OI, and OSI and SpO2: FiO2, are closely correlated

(p ¼ 0.84 and p ¼ �0.80, respectively). The correlations did not differ when split into days 1-3 and 4-7. Results are

summarized in Figure 5.

In analyses using LMMs to estimate the association of posi-

tioning with physiological indices, 19 of 62 exposed partici-

pants contributed more than 1 episode. In these analyses, prone

vs supine positioning was significantly associated with overall

improvement in PaO2: FiO2 (Table 4). In models allowing

positioning effects to differ in days 1-3 and 4-7, prone position-

ing was associated with improved OSI during days 1-3

(p < 0.01) as well as improved OSI, OI and PaO2: FiO2 during days 4-7 (p < 0.05, p < 0.01 and p < 0.001, respectively).

No clear evidence for interaction between positioning and time

was found.

Discussion

We report results from a comprehensive cohort study assessing

the potential benefits of prone positioning in COVID-19

patients with moderate to severe ARDS. We found a nearly

40% reduction in mortality with prone positioning, an effect that appears sustained on cumulative incidence curves. With

respect to physiologic parameters, there were meaningful

changes across all ratios and indices to suggest that prone posi-

tioning is associated with improvements in within-person phy-

siology and that the benefit may persist beyond 3 days. Our

findings across both analyses were robust to various adjust-

ments, modifications, sensitivity analyses and nested compara-

tive testing.

Fundamentally, this study has 3 key findings. First, we

demonstrated a mortality benefit with prone positioning with

a number needed to treat of 8. The durability of the finding is

important, including for a longer time period, and ensuring that

Shelhamer et al 245

Table 1. Baseline Characteristics, Including Demographic and Clinical Presentation and Outcomes, for All Participants in the Prone Positioning Intervention and Non-Prone Positioning Groups.

Overall Underwent prone

positioning Did not undergo prone

positioning

n ¼ 261 n ¼ 62 n ¼ 199 Age, years (median, IQR) 64.0 (55.0-73.0) 60.0 (54.3-66.5) 66.0 (55.0-74.5) Age (years), No. (%)

<41 years 13 (5.0%) 3 (4.8%) 10 (5.0%) 41-60 years 85 (32.6%) 27 (43.5%) 58 (29.1%) 61-80 years 131 (50.2%) 31 (50.0%) 100 (50.3%) >80 years 32 (12.3%) 1 (1.6%) 31 (15.6%)

Sex, female, No. (%) 99 (37.9%) 20 (32.3%) 79 (39.7%) Race, No. (%)

Hispanic 170 (65.1%) 38 (61.3%) 132 (66.3%) Black 63 (24.1%) 12 (19.4%) 51 (25.6%) Asian 2 (0.8%) 0 2 (1.0%) White 6 (2.3%) 0 6 (3.0%) Other 20 (7.7%) 12 (19.4%) 8 (4.0%)

Body mass index, kg/m 2

(median, IQR) 31.0 (27.1-36.8) 30.9 (28.3-35.9) 31.0 (26.7-37.2) Body mass index, No. (%)

< 18.5 kg/m 2

3 (1.1%) 0 3 (1.5%) 18.5-24.9 kg/m2 33 (12.6%) 5 (8.1%) 28 (14.1%) 25-29.9 kg/m

2 78 (29.9%) 19 (30.6%) 59 (29.6%)

� 30 kg/m2 147 (56.3%) 38 (61.3%) 109 (54.8%) Clinical symptoms on presentation, No. (%)

Fever 159 (60.9%) 41 (66.1%) 118 (59.3%) Cough 190 (72.8%) 54 (87.1%) 136 (68.3%) Shortness of breath 220 (84.3%) 54 (87.1%) 166 (83.4%) GI symptoms (diarrhea or vomiting) 36 (13.8%) 12 (19.4%) 24 (12.1%) Neurological symptoms (altered mental status or

seizures) 55 (21.1%) 5 (8.1%) 50 (25.1%)

Comorbidities, No. (%) Current smoking 14 (5.4%) 1 (1.6%) 13 (6.5%) Diabetes 127 (48.7%) 27 (43.5%) 100 (50.3%) Obstructive lung disease (asthma or COPD) 54 (20.7%) 10 (16.1%) 44 (22.1%) Congestive heart failure 19 (7.3%) 1 (1.6%) 18 (9.0%) Autoimmune disease (RA or SLE) 15 (5.7%) 3 (4.8%) 12 (6.0%) Chronic kidney disease (Stage �3) 29 (11.1%) 4 (6.5%) 25 (12.6%) Iatrogenic immunosuppression 6 (2.3%) 1 (1.6%) 5 (2.5%) Cancer 17 (6.5%) 2 (3.2%) 15 (7.5%) Human immunodeficiency virus infection 5 (1.9%) 2 (3.2%) 3 (1.5%) Renal Transplantation 3 (1.1%) 1 (1.6%) 2 (1.0%) Charlson Comorbidity Index (median, IQR) 3.0 (2.0-4.0) 3.0 (1.0-4.0) 3.0 (2.0-5.0)

Severity of COVID-19 on admission, No. (%) (13,23)

Moderate 11 (4.2%) 6 (9.7%) 5 (2.5%) Severe 86 (33.0%) 27 (43.5%) 59 (29.6%) Critical 163 (62.5%) 29 (46.8%) 135 (67.8%) APACHE-II score (median, IQR) at intubation 17.0 (12.0-27.0) 17.5 (12.3-24.0) 17.0 (12.0-28.0) ARDS on admission 146 (55.9%) 27 (43.5%) 119 (59.8%) Sepsis on admission by Quick SOFA 160 (61.3%) 38 (61.3%) 122 (61.3%)

Radiological characteristics, No. (%) Bilateral reticulonodular opacities 173 (66.3%) 41 (66.1%) 132 (66.3%) Ground-glass opacities 96 (36.8%) 28 (45.2%) 68 (34.2%) Focal consolidation 31 (11.9%) 5 (8.1%) 26 (13.1%)

Treatment and clinical course, No. (%) BiPAP prior to mechanical ventilation 37 (14.2%) 17 (27.4%) 20 (10.1%) Mechanical ventilation on admission 186 (71.3%) 31 (50.0%) 155 (77.9%) Vasopressor use during hospital course 221 (84.7%) 53 (85.5%) 168 (84.4%) Acute kidney injury during hospital course 142 (54.4%) 29 (46.8%) 113 (56.8%) Hemodialysis required during hospital course 35 (13.4%) 16 (25.8%) 19 (9.5%)

(continued)

246 Journal of Intensive Care Medicine 36(2)

it can be replicated in other settings will be essential to justify a

recommendation, but we have no evidence to attribute the sur-

vival benefit in the intervention arm to bias. Second, it appears

that there is a benefit to additional days of prone positioning

beyond 3 days. The effect seen with 4-7 days of prone position-

ing may be heavily influenced by a smaller group that realized

a differential benefit, but 34 of 89 positioning sequences

resulted in at least 4 days of intervention, representing a rela-

tively large proportion of individuals. Third, prone positioning

resulted in significant changes in physiologic parameters which

may support the underlying hypothesis that prone positioning

improves ventilation-perfusion matching. 9,10

Additionally, we

demonstrated the utility of relatively accessible clinical infor-

mation in the ICU as reasonable surrogates to monitor changes

in physiology.

Our results are consistent with recent multi-center data sug-

gesting a mortality benefit of prone positioning in patients with

ARDS whether intubated or not. 6-8,19,20

There are recommen-

dations for prolonged prone positioning of 12-16 hours daily

for mechanically ventilated adult patients with COVID-19 and

Table 1. (continued)

Overall Underwent prone

positioning Did not undergo prone

positioning

Hydroxychloroquine administered 219 (83.9%) 52 (83.9%) 167 (83.9%) Bed location

Traditional ICU bed 86 (33.0%) 26 (41.9%) 60 (30.2%) Converted floor ICU bed 175 (67.0%) 36 (58.1%) 139 (69.8%)

Maneuvers and adjustments Total maneuvers – 832 – Prone positioning – 199 – Supine positioning – 190 – Head, neck and shoulder adjustments – 443 – Maneuvers per participant (median, IQR) – 4 (2-8) –

Outcomes (followed minimum of 30 days), no (%) Expired 215 (82.4%) 48 (77.4%) 167 (83.9%) Discharged 43 (16.4%) 13 (21.0%) 30 (15.1%) Ongoing hospitalization 3 (1.1%) 1 (1.6%) 2 (2.0%) Time to death (median, IQR) from admission 8.2 (5.4-13.5) 15.3 (12.2-21.7) 7.2 (4.2-10.9) Length of stay, days (median, IQR) 9.0 (5.4-14.3) 18.1 (13.1-26.9) 8.0 (5.0-14.0) Ventilator-free days (median, IQR) 18.0 (13.0-22.0) 19.0 (16.0-20.0) 18.0 (12.0-22.0) Total extubations 29 (11.1%) 7 (11.3%) 22 (11.1%) Total re-intubations 8 (3.1%) 1 (1.6%) 7 (3.5%) Palliative extubations 10 (3.8%) 2 (3.2%) 8 (4.0%) Tracheostomy 26 (10.0%) 13 (21.0%) 13 (6.5%)

Laboratory values on admission, [reference range and units] reported as median (IQR), N reported if different from total White blood cell count [4.8-10.8 x 10 3 microliter] 9.5 (6.9-12.9) 9.5 (7.1-12.6) 9.6 (6.8-13.1) Platelet count [150 to 450 per microliter] 235 (182-301) 211.5 (186-283) 237.0 (181-303) Highest d-dimer during hospital course

[�230 ng/milliliter] 3543 (1163-11838), n ¼ 218 3988 (2049.5-13049.8) 3185 (1064-11739), n ¼ 156

C-reactive protein [0-0.40 mg/deciliter] 28.0 (14.8-100.0), n ¼ 244 24.1 (14.3-35.9), n ¼ 61 30.8 (15.7-122.2), n ¼ 183 Highest creatinine during hospital course

[0.7-1.20 mg/deciliter] 3.7 (1.5-6.9), n ¼ 260 3.8 (1.1-6.6) 3.7 (1.7-7.1), n ¼ 198

Lactate [0.5-2.2 mmol/liter] 2.1 (1.4-3.2), n ¼ 223 2.0 (1.5-3.2), n ¼ 56 2.1 (1.4-3.2), n ¼ 167 Procalcitonin [�0.08 ng/milliliter] 0.5 (0.2-1.3), n ¼ 230 0.5 (0.3-1.3), n ¼ 55 0.5 (0.2-1.3), n ¼ 174 Interleukin-6 (0-5.5pg/milliliter) 19.8 (15.2-251.3), n ¼ 220 16.1 (15.0-150.7), n ¼ 57 32.3 (15.2-273.5), n ¼ 162 Ferritin [20-250 ng/milliliter] 928.5 (515-1625), n ¼ 225 871.0 (487-1466), n ¼ 59 949 (531-1670), n ¼ 166 International normalized ratio [0.8 to 1.1] 1.3 (1.1-1.4), n ¼ 240 1.3 (1.2-1.4), n ¼ 59 1.3 (1.1-1.4), n ¼ 181

ARDS, acute respiratory distress syndrome; BiPAP, bilevel positive airway pressure; COPD, chronic obstructive pulmonary disease; Pro-BNP-N-terminal pro b-type natriuretic peptide; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Table 2. Association of a Prone Positioning Intervention and Time to Death by Fine-Gray Competing Risks Analysis.

Model SHR 95% CI P-value

Unadjusted 0.51 0.39-0.66 <0.005 Multivariate adjusted 0.57 0.42-0.76 <0.005 Stabilized doubly robust IPTW 0.61 0.46-0.80 <0.005

Adjusted models control for age, sex, race, body-mass index, Apache II score and vasopressor use.

Shelhamer et al 247

refractory hypoxemic respiratory failure, 21

but the optimal

duration of the intervention, its impact on physiologic para-

meters and details regarding how to organize and structure an

intervention team during a crisis have not been completely

evaluated. We acknowledge that prone positioning in mechani-

cally ventilated patients is a resource-intensive intervention,

particularly in overwhelmed healthcare systems during pan-

demic conditions. Before adopting prone positioning tech-

niques, staff education and commitment is paramount. If

justified by hospitalized patient volume, we recommend iden-

tifying personnel and assigning them to a dedicated prone team

and tailoring readily available checklists to institutional needs

and constraints (Figure 1). 22

Some limitations of this study should be noted. First, this is a

single center retrospective cohort study in a resource con-

strained environment under crisis operations. As a result,

although patients had critical care needs, they were frequently

cared for in ad-hoc intensive care units by non-critical care

personnel. The decision to initiate or discontinue the interven-

tion under study was left to the treating primary team without

defining endpoints. We attempted to address any residual con-

founding through IPTW and no differences in the results were

noted. If the prone team was consulted and the patient had

moderate to severe ARDS and met criteria for prone position-

ing, it was felt that they could benefit from the intervention in

addition to lung protective ventilation. Although this was prag-

matic for this setting, if prone positioning is implemented else-

where, the prone teams could consider establishing an opt-out

approach with tailored entry and exit criteria, normal cadence

of evaluation for candidacy for prone positioning and a

mechanism for real-time data capture and quality control

assessments. The results of this study may not be readily gen-

eralizable to all populations, in particular those with milder

disease and those that don’t reflect the ethnic diversity seen

in the Bronx. The institutional mortality proportion was high

(>75%) and therefore the impact of the intervention may be attenuated in the setting of advanced interventions (e.g., extra-

corporeal membrane oxygenation) or the added attention and

care of a multidisciplinary team could in and of itself change

patient’s outcome trajectories, even though they were not

involved in care decisions and did not intervene beyond prone

Figure 3. Cumulative incidence curves for participants undergoing prone positioning versus not.

Table 3. Complete Modeling Output for Cox Regression, With Inverse-Probability Treatment Weighting, Adjustments, Stabilized Weights and Accounting for Competing Risks.

Variable SHR 95% CI P-value

Prone positioning intervention (yes vs no) No Reference – – Yes 0.61 0.46-0.80 <0.001

Age <41 years Reference – – 41-60 years 2.68 0.83-8.59 0.10 61-80 years 4.45 1.39-14.20 0.01 >80 years 7.11 2.13-23.76 0.001

Sex Female Reference – – Male 1.06 0.78-1.44 0.69

Race White Reference – – Hispanic 0.33 0.18-0.60 <0.001 Black 0.38 0.20-0.73 0.003 Asian * * * Other 0.34 0.12-0.96 0.04

Body mass index, No. (%) < 18.5 kg/m2 * * * 18.5-24.9 kg/m2 Reference – – 25-29.9 kg/m2 0.85 0.53-1.36 0.49 � 30 kg/m2 0.87 0.57-1.33 0.52

APACHE-II score 1.01 0.99-1.03 0.26 Vasopressor use

No Reference – – Yes 1.18 0.76-1.85 0.46

* Observations were dropped from model due to small N and no variability in treatment (e.g. all within category were treated or all within category were not treated).

248 Journal of Intensive Care Medicine 36(2)

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249

positioning. Finally, there may be channeling bias due to dis-

ease severity or survivor bias, resulting in lower or higher

probability of exposure, respectively. The net result of this

could be a bias toward or away from the null. We attempted

to address this by ensuring that the populations were compara-

ble at baseline and by systematically including all possible

patients. At intubation, there was little difference in the quick

SOFA, Charlson Comorbidity index and the APACHE-II

scores suggesting that the groups were similar, at least with

respect to severity of illness.

There are also some notable strengths of this work. We were

able to collect detailed physiologic data in a structured manner

to systematically evaluate the impact of the intervention. Also,

our population has been gravely understudied in the COVID-19

pandemic and we’ve been able to contribute significantly to

both describing their clinical course as well as critical care

interventions for socioeconomically marginalized minority

populations. Regarding outcome, we were able to include all

patients who would have been eligible for prone positioning as

controls creating a sound counterfactual for a contemporaneous

comparison of both exposed and unexposed. Finally, compared

to existing literature for patients with COVID-19, this study

provides results for a large intervention group.

Conclusions

In summary, we present data supporting prone positioning as

an intervention to prolong survival and improve physiologic

Figure 5. Pearson correlation of physiologic parameters across prone patients split by duration of maneuvers.

Table 4. Adjusted Associations of Prone vs Supine Positioning With Physiological Parameters by Linear Mixed Effects Models.

Oxygenation index Oxygenation saturation index PaO2: FiO2 SpO2: FiO2

Number (maneuvers) N ¼ 59 (85) N ¼ 60 () N ¼ 59 () N ¼ 54 (76) Coefficient (95% CI) Coefficient (95% CI) Coefficient (95% CI) Coefficient (95% CI)

Prone, overall 0.07 (-0.01, 0.2) 0.04 (-0.01, 0.08) 0.10 (0.04, 0.17) -0.28 (-0.63, 0.08) % improvement 8% 4% 11% 24%

Prone days 1-3 0.1 (-0.1, 0.1) 0.08 (0.0, 0.1)** 0.05 (-0.0, 0.1) -0.32 (-0.7, 0.01) % improvement 1% 8% 5% 27% Prone days 4-7 0.30 (0.1, 0.5)** -0.10 (-0.2, 0.0) 0.31 (0.2, 0.5)*** -0.03 (-1.0, 0.9) % improvement 38% (9% worsening) 36%*** 3% Days 4-7 vs 1-3 -0.08 (-0.2, 0.1) 0.09 (-0.0, 0.2) -0.8 (-0.2, 0.1) 0.06 (-0.7, 0.8)

Adjusted for age, sex, race, BMI, Apache II score, and vasopressor use. * P < 0.05, ** P < 0.01, *** P < 0.001.

250 Journal of Intensive Care Medicine 36(2)

parameters in patients on mechanical ventilation with moderate

to severe ARDS due to COVID-19. The findings should be

replicated across institutions, but prone positioning may be

an important consideration for health systems, particularly in

the setting of an evolving suite of complementary interventions

in the care of such vulnerable patients.

Abbreviations

ARDS ¼ Acute Respiratory Distress Syndrome; APACHE-II ¼ Acute Physiology And Chronic Health Evaluation; BMI ¼ Body Mass Index; COVID-19 ¼ Coronavirus Disease 2019; FiO2 ¼ Fraction of Inspired Oxygen; ICU ¼ Intensive Care Unit; IPTWs ¼ Inverse Probability Treatment Weights; LMM¼Linear Mixed Models; NYC¼New York City; OI ¼ Oxygenation Index; OSI ¼ Oxygenation-Saturation Index; PaO2 ¼ Partial Pressure of Arterial Oxygen; PEEP ¼ Positive End-Expiratory Pressure; SARS-Cov-2 ¼ Severe Acute Respiratory Syndrome Coronavirus 2; sIPTW ¼ Inverse Probability of Treatment Weight; SPO2 ¼ Oxygen Saturation.

Acknowledgments

We would like to acknowledge the Lincoln Hospital COVID-19

research consortium for supporting various components of data

collection (includes Masood Shariff, MD, John Zhang, PhD, Moham-

mad Aldiabat, MD, Alex Carlos Jr., MD, Sara Tavarez Rodriguez,

MD, Bo Yu, MD, Astrid Mendez Batres, MD, Marcia Gossai, MD

and Elisenda Valdez, MD). We would also like to thank the NYC

hospital system staff, first responders, and healthcare volunteers who

came from across the world, and who all made sacrifices to help our

patients during a time of great need.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest

with respect to the research, authorship, and/or publication of this

article: The opinions or assertions contained herein are the private

views of the authors and are not to be construed as official or as

reflecting the views of the Department of the United States Air Force

or the Department of Defense.

Funding

The author(s) disclosed receipt of the following financial support for

the research, authorship, and/or publication of this article: This work

was supported by National Institute of Allergy and Infectious Disease

(K23AI135037 to JDK and K01AI145572 to PW) and National Insti-

tute of General Medical Sciences (R01 grant number GM130900 to

JDK) of the United States National Institutes of Health.

ORCID iDs

Mehdi C. Shelhamer, DO https://orcid.org/0000-0003-4374-7377

Vihren G. Dimitrov, MD https://orcid.org/0000-0002-9322-8500

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