Supplemental oxygen for pulmonary embolism (SO-PE): study protocol for a mechanistic, randomised, blinded, cross-over study
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* Mads Dam Lyhne
* Andrew S Liteplo
* Oana Alina Zeleznik
* David M Dudzinski
* Asger Andersen
* Hamid Shokoohi
* Nour Al Jalbout
* Onyinyechi Franca Eke
* Christina C Morone
* Calvin K Huang
* Thomas F Heyne
* Mannudeep K Kalra
* Christopher Kabrhel

## Abstract

**Background** Acute pulmonary embolism (PE) mortality is linked to abrupt rises in pulmonary artery (PA) pressure due to mechanical obstruction and pulmonary vasoconstriction, leading to right ventricular (RV) dilation, increased RV wall tension and oxygen demand, but compromised right coronary artery oxygen supply. Oxygen is a known pulmonary vasodilator, and in preclinical animal models of PE, supplemental oxygen reduces PA pressures and improves RV function. However, the mechanisms driving these interactions, especially in humans, remain poorly understood. The overall objective of the supplemental oxygen in pulmonary embolism (SO-PE) study is to investigate the mechanisms of supplemental oxygen in patients with acute PE.

**Methods and analysis** This randomised, double-blind, cross-over trial at Massachusetts General Hospital will include adult patients with acute PE and evidence of RV dysfunction but without hypoxaemia (SaO2 ≥90% on room air). We will enrol 80 patients, each serving as their own control, with 40 randomised to start on supplemental oxygen, and 40 randomised to start on room air. Over 180 min, patients will alternate between supplemental oxygen delivered by non-rebreather mask (60% FiO2) and room air (21% FiO2). The primary outcome will be the difference in pulmonary artery systolic pressure with and without oxygen. Secondary outcomes include additional echocardiographic measures, metabolomic profiles, vital signs and dyspnoea scores. Echocardiographic data will be compared by a paired t-test or Wilcoxon signed-rank test. For metabolomic analyses, we will perform multivariable mixed effects logistic regression models and calculate false discovery rate (q-value ≤0.05) to account for multiple comparisons. Data will be collected in compliance with National Institutes of Health and National Heart Lung and Blood Institute (NHLBI) policies for data and safety monitoring.

**Ethics and dissemination** The SO-PE study is funded by the NHLBI and has been approved by the Institutional Review Board of Mass General Brigham (no. 2023P000252). The study will comply with the Helsinki Declaration on medical research involving human subjects. All participants will provide prospective, written informed consent.

**Trial registration number** [NCT05891886](http://bmjopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05891886&atom=%2Fbmjopen%2F14%2F11%2Fe091567.atom).

*   Echocardiography
*   Pulmonary Disease
*   Thromboembolism

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   A randomised, blinded, cross-over study.

*   The study is based on clinically available echocardiographic measurements as well as advanced metabolomic analyses.

*   The study focuses on patients with right ventricular dysfunction but no haemodynamic instability and hypoxaemia.

*   As a mechanistic trial, the study does not intend to evaluate the clinical effectiveness of oxygen in acute pulmonary embolism.

## Background

Pulmonary embolism (PE) mortality is linked to increased pulmonary artery (PA) pressure, right ventricular (RV) dysfunction and hypoxaemia. The RV typically pumps against low resistance in the high-compliance pulmonary circulation.1–3 However, in acute PE, PA pressure can rise abruptly due to mechanical obstruction and pulmonary vasoconstriction.4 5 This increased PA pressure causes RV dilation, raising RV wall tension and oxygen demand, compromising myocardial perfusion, and decreasing RV contractility and output. Consequently, RV dilation impacts the intraventricular septum, compressing the left ventricle (LV), reducing LV filling and output, while simultaneously further diminishing RV coronary perfusion pressure due to elevated RV intracavitary pressure. This chain reaction exacerbates RV ischaemia and dysfunction (figure 1).6–8 

![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/14/11/e091567/F1.medium.gif)

[Figure 1](http://bmjopen.bmj.com/content/14/11/e091567/F1)

Figure 1 
Potential mechanisms of oxygen in acute pulmonary embolism (PE). Pathogenesis of acute PE includes increased right ventricular (RV) afterload from pulmonary vascular obstruction and vasoconstriction combined with V/Q mismatch and hypoxia leading to hypoxaemia. Collectively, an oxygen supply/demand mismatch will occur in RV myocardium causing RV dysfunction, failure and ultimately death. The supplemental oxygen in PE study aims to investigate the mechanisms of supplemental oxygen in acute PE.

Oxygen, a potent pulmonary vasodilator, can reduce PA pressure and reverse hypoxic pulmonary vasoconstriction, even without systemic hypoxaemia.9–11 In chronic pulmonary conditions like pulmonary hypertension and chronic obstructive pulmonary disease, oxygen is an established treatment to reduce PA pressure and RV afterload.12–15 In experiments using a porcine model of acute PE, we demonstrated that supplemental oxygen rapidly reduced PA pressure, RV dilation and mechanical work, and pulmonary shunt fraction while increasing RV ejection fraction.16 However, RV contractility, independent of RV afterload, was not increased, suggesting oxygen primarily reduces PA pressure. This has not been demonstrated in humans with PE.

Ventricular function and afterload can be differentiated through the concept of RV-PA coupling.17 This concept describes how RV function aligns with the afterload it must overcome to eject blood and serves as a sensitive indicator of cardiovascular efficiency.18 19 While the invasive catheters typically used to measure RV-PA coupling are rarely used in humans with PE, the ratio of tricuspid annular plane systolic excursion to PA systolic pressure (TAPSE/PASP) can provide a non-invasive estimate of RV-PA coupling.17 20 With PE, increased PA pressure and RV dysfunction (RVD) lead to RV-PA uncoupling, a critical factor in PE mortality.17 21 22 However, the metabolic mechanisms driving these interactions and potential modifications remain poorly understood. We, therefore, designed a study that will provide insight into whether the same mechanisms are present in humans with PE and whether oxygen modulates those mechanisms.

Pulmonary vasoconstriction in PE is metabolically mediated.4 23 Experimental models show haematogenous emboli increase PA pressure more than non-haematogenous material due to the release of vasoactive metabolites that constrict non-occluded arteries.24 These metabolites include adenosine, ATP, cyclooxygenase metabolism products, nitric oxide (NO) pathways, and various enzymes which can induce bronchoconstriction and worsen alveolar hypoxia.25–27 Our understanding of metabolic changes in PE, especially in response to supplemental oxygen, is limited compared with other cardiovascular conditions.28–30 In previous analyses of high-throughput metabolomic data, we identified 42 metabolites that are differentially regulated in high-risk versus low-risk PE, including nucleotide, energy, fatty acid, purine and tricarboxylic acid (TCA)-cycle metabolites, mirroring findings in preclinical studies.31 The current study will assess how supplemental oxygen affects circulating metabolites in patients with acute PE, thereby providing insight into both pathophysiology and potential therapeutic targets.

### Objectives

The overall objective of the supplemental oxygen in pulmonary embolism (SO-PE) study is to investigate the mechanisms of supplemental oxygen in patients with acute PE (figure 1). First, we will evaluate the mechanisms by which supplemental oxygen affects pulmonary arterial systolic pressure and other echocardiographic measurements. Second, we will evaluate metabolic changes associated with supplemental oxygen use in PE. We hypothesise that oxygen affects RVD primarily by relieving hypoxic pulmonary vasoconstriction and reducing PA pressure, and that this process is metabolically driven.

## Methods

### Ethics and design

The SO-PE study has been approved by the Institutional Review Board of MassGeneralBrigham (MGB) (protocol no. 2023P000252). The study is funded by the U.S. National Heart Lung and Blood Institute (NHLBI, R01HL168040-01). The study will comply with the Helsinki Declaration on medical research involving human subjects. All participants will provide prospective, written, informed consent (see online supplemental file 1). The study is registered at ClinicalTrials.org ([NCT05891886](http://bmjopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05891886&atom=%2Fbmjopen%2F14%2F11%2Fe091567.atom)). The protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines.32 

### Supplementary data

[[bmjopen-2024-091567supp001.pdf]](pending:yes) 

SO-PE is a randomised, double-blinded, cross-over mechanistic trial. Non-hypoxic patients with confirmed PE will receive treatment through a non-rebreather mask with either air or supplemental oxygen in a double-blinded, cross-over fashion. At consecutive timepoints for up to 180 min, patients will undergo repeated evaluations including transthoracic echocardiography, blood sampling and clinical evaluations (figure 2). No specific concomitant care or interventions are permitted or prohibited during the trial.

![Figure 2](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/14/11/e091567/F2.medium.gif)

[Figure 2](http://bmjopen.bmj.com/content/14/11/e091567/F2)

Figure 2 
Study design. Enrolled patients will be randomised to air or supplemental oxygen treatment in a double-blinded fashion and crossover to alternative treatment. At consecutive timepoints, patients will undergo clinical, imaging and biochemical evaluation.

### Study population

The target population is adult patients at Massachusetts General Hospital (MGH), Boston, Massachusetts. Eligible patients will have radiographically confirmed acute PE based on a positive CT pulmonary angiogram (CTPA) performed less than 24 hours prior to enrolment, and evidence of RVD based on bedside echocardiogram, but no hypoxaemia (SaO2≥90% on room air). Inclusion and exclusion criteria are listed in table 1. MGH ED’s diverse patient demographics allow for inclusive recruitment across sex, race and ethnicity. Patients are expected to be enrolled during a 4-year period.

View this table:
[Table 1](http://bmjopen.bmj.com/content/14/11/e091567/T1)

Table 1 
Inclusion and exclusion criteria

### Screening, consent and randomisation

Clinical research coordinators (CRCs) will identify patients with PE and screen for eligibility by interacting with clinical staff and reviewing electronic medical records. Screening will occur from 07:00 to 23:00 daily. CRCs will also review the results of CTPA performed overnight to identify potentially eligible patients.

When an eligible patient is identified, trained study investigators (physician (MD) or physician assistant (PA)) will explain the study and obtain written informed consent as soon as possible after patient identification. Non-English speakers will be included with consent obtained with the assistance of institutionally available trained medical interpreters.

Randomisation will be performed by an online random allocation generator. Double blinding will be performed with alternating interventions (supplemental oxygen and room air) by covering the attachment of the oxygen tubing to the gas supply, and by use of a core lab to interpret echocardiograms without knowledge of the treatment assignment of the patient.

### Study interventions and procedures

At the first evaluation timepoint, all patients will undergo a baseline echocardiogram on room air. We will draw blood for metabolomic analysis and record vital signs including blood pressure, heart rate, respiratory rate and SaO2. The subjective sensation of dyspnoea will also be assessed by the Borg Dyspnoea Scale.33 

After randomisation, the supplemental oxygen group will begin the study receiving supplemental oxygen via a non-rebreather mask (approximately 60% FiO2). The room air group will receive medical air (approximately 21% FiO2) via an identical non-rebreather mask.

At the second (and each subsequent) evaluation timepoint (figure 2), the same measurements described above will be performed. These measurements will occur after the patient has received supplemental oxygen (or room air) for at least 15 min. Study measurements will then be performed over the next 15 min. As an example, this will allow the treatment allocation to be alternated 30 min after the initiation of the study, for the second evaluation timepoint.

Venous blood samples will be collected in a cubital vein into one 3.0 mL K2 EDTA tube per blood draw, inverted eight times and immediately placed on ice. Following the completion of study procedures (after 180 min), we will centrifuge blood tubes at 1200 relative centrifugal force for 10 min at 22°C. Plasma will be aliquoted equally into 1–2 sterile 1.5 mL microcentrifuge tubes, labelled and frozen at −80°C. Processing will be lagged so that all samples are processed and frozen 4 hours after collection. After the enrolment of the last patient, we will perform metabolomic analysis using the Metabolon global metabolomic platform. Metabolon’s ultra-high-performance liquid chromatography–mass spectrometry library contains spectra for >5400 purified standards describing >70 metabolic pathways.34 

Echocardiograms will be performed at each evaluation time point with the operator blinding to treatment. Echocardiograms will be performed by fellowship-trained emergency ultrasonographers. To avoid interoperator variation, the same ultrasonographer will perform all examinations of a given patient. To obtain the best possible views, study patients will generally be positioned in the left-lateral decubitus position. Echocardiographic images will be collected with simultaneous 3-lead ECG monitoring attached to the ultrasound machine. Echocardiograms will be analysed by an echocardiography-fellowship trained cardiologist blinded to the study intervention. Using a cardiac ultrasound probe, we will obtain the standard projections and measurements listed in table 2. Measurements will follow society echocardiographic guidelines.35 36 Recorded images will be stored on local servers and in the electronic medical record. Based on clinical experience, we anticipate image acquisition to take 5 min. RV/LV ratio, RV fractional area change and TAPSE/PASP ratio will be calculated post hoc.

View this table:
[Table 2](http://bmjopen.bmj.com/content/14/11/e091567/T2)

Table 2 
Echocardiographic measures

### Outcomes

The primary outcome of SO-PE is the PASP difference with and without supplemental oxygen. Secondary outcomes include changes in echocardiographic measures, metabolomics, vital signs and the Borg Dyspnoea Score.

### Collection of data

Clinical data will be entered into a Health Insurance Portability and Accountability Act (HIPAA)-compliant electronic data collection instrument (REDCap). The final trial dataset will be accessible to investigators and can be accessed on reasonable request.

### Monitoring

The study will comply with the National Institutes of Health and NHLBI Policies for Data and Safety Monitoring and will be monitored by a data and safety monitoring board (DSMB), described below.

### Adverse events

There are only a few potential risks to the participants including minor discomfort from wearing a face mask, blood sample collection and potential anxiety. While it is unlikely, we will terminate study participation in the following circumstances: (1) oxygen desaturation (SaO2<88%) sustained for 1 min while on facemask supplemental oxygen or air. Because patients with SaO2 as low as 90% are eligible for enrolment, we chose <88% as this would represent a meaningful level of hypoxaemia, while not being overly sensitive to minor fluctuations in SaO2. For similar reasons, we will require the SaO2 to be <88% for at least 1 min before terminating participation, so that we do not terminate for transient events that may only last seconds and might be artifactual. (2) Systolic blood pressure <90 mm Hg sustained for >15 min while on facemask supplemental oxygen or air. In contrast to vasodilators (eg, epoprostenol, NO and sildenafil) used in previous studies of PE, oxygen has never been associated with hypotension.37 38 Therefore, we do not anticipate the study intervention to be associated with hypotension, though we recognise that acute PE may result in haemodynamic compromise. (3) Clinical need for escalation of care: we will terminate study participation if the clinical team determines that the patient requires an emergent clinical escalation of care (eg, thrombolysis, surgery). (4) Severe anxiety associated with wearing a non-rebreather mask. Study subjects will be enrolled in the MGH Emergency Department, with highly trained staff immediately available should an adverse event (AE) arise during a study procedure.

### Mitigation

A DSMB has been convened and will monitor the safety of patients, review AEs and ensure the security of data throughout the study. The DSMB will have the power to recommend pausing or terminating the study in the unlikely occurrence of unacceptable adverse clinical events or data security lapses. However, because this is a mechanistic clinical trial, and not designed to assess efficacy, the DSMB will not have prespecified statistical criteria to end the study for clear benefit or futility.

### Patient and public involvement

Members of the public were not involved in the design of the study, nor will be in conduction or reporting. Dissemination will focus on both the scientific but also public community.

## Statistical plan

### Sample size calculation

In our porcine study,16 supplemental oxygen lowered systolic PA pressure to 20 mm Hg (SD 9 mm Hg) from 45 mm Hg. In our conservative sample size calculations, we assumed lower post-PE pulmonary pressures, reduced effect size and greater variation in patients with PE compared with research pigs. We estimate a pulmonary pressure change of 7 mm Hg (eg, from 35 to 28 mm Hg) with oxygen and no change with room air, SD of 10 mm Hg in each group, alpha=0.05 and beta=0.20. Comparing two means, a sample size of n=68 (34 per group) is needed. Conservatively assuming 15% dropout, we aim to include 80 patients (40 per group).

### Echocardiographic and clinical data

Data will be analysed for normal distribution by Shapiro-Wilks test and QQ plots and presented as mean±SD if normally distributed and median (IQR) if not. Echocardiographic measurements will be compared by a paired t-test or Wilcoxon signed-rank test, with p value <0.05 considered statistically significant, and corrected for multiple testing as appropriate.

We will perform two prespecified subanalyses, restricted to patients with <24 hours of symptoms and patients with initial PASP >30 mm Hg.

### Metabolomics

In the main analysis, we will focus on testing hypotheses based on metabolites identified in our prior work and published research: that diacylglycerols, triacylglycerols, plasmenylcholine plasmalogens, TCA cycle intermediates, long-chain acyl carnitines and breakdown products of branched-chain amino acids are involved in the physiological response to SO-PE.

In exploratory analyses, we will perform agnostic analyses to identify metabolites association with supplemental oxygen, and metabolites associated with specific echocardiographic changes found to be associated with oxygen use.31 39 We will use multivariable mixed effects logistic regression models to identify metabolites associated with supplemental oxygen and specific echocardiographic changes allowing for repeated measurements per study participant. Adjustment for confounding factors is not required as each participant will be their own control. For metabolomic analysis, results will first be transformed using the rank-based inverse normal transformation which results in a standard normal distribution. We will calculate false discovery rate (q-value ≤0.05) to account for multiple comparisons.40 In the main analysis, we will have 94% power to detect an effect size of 0.4 assuming 80 participants, each with five repeated measures, type I error rate of 0.05, standard normally distributed continuous predictors metabolites), no covariates and a random effects intercept variance of 1.5.41 

## Discussion

SO-PE is a randomised, double-blind, cross-over trial that aims to elucidate the mechanisms by which supplemental oxygen affects RV function and PA pressure in patients with acute PE, providing insights into both pathophysiology of PE and potential treatment with supplemental oxygen.

Current guidelines recommend supplemental oxygen in acute PE only when saturation drops below 90%.1 To date, no published study has explored the mechanisms of supplemental oxygen on PA pressure and RVD in humans with acute PE. Three studies have investigated other pulmonary vasodilating agents. Kooter *et al* investigated epoprostenol, randomising 14 patients with PE to treatment or placebo.42 Epoprostenol failed to reduce PA pressure, RV dilatation, RV function or biomarkers of RV strain. However, in this study (and the two studies below), patients in the control group all received supplemental oxygen (2 L/min, or 28% FiO2), which may have biased any effect of epoprostenol towards null. Kline *et al* investigated inhaled NO in 76 patients with acute PE.43 Again, the study was null. Patients were randomised to receive (1) NO+oxygen or (2) nitrogen+oxygen. In our porcine model, we observed similar PA pressure reduction with oxygen and inhaled NO,16 so again, it is possible that the use of oxygen in the control group biased this study towards null. Andersen *et al* randomised 20 patients with PE to sildenafil or placebo. Sildenafil did not affect cardiac index measured by MRI.44 Again, both treatment and control groups received supplemental oxygen (2 L/min, or 28% FiO2), which may have biased any effect of sildenafil towards null. A recent study by Barrios *et al* showed promising effects of oxygen in intermediate–high risk PE but the study was prematurely terminated and did not reach statistical significance.45 However, it did support the hypothesis that mechanisms of oxygen observed in porcine study are translatable to human patients.

The successful completion of this study will advance our understanding of PE pathophysiology by performing the first study showing how supplemental oxygen modifies echocardiographic measures of RVD in patients with acute PE and determining whether these mechanisms act through pulmonary vasodilation, RV function or a combination. Of importance, it will also be the first prospective metabolomic study of patients with acute PE. This study may advance our understanding of a simple, ubiquitous, inexpensive, safe and quick treatment option in patients with acute PE. Supplemental oxygen is administrable in nearly any medical setting and does not require any training or special facility, as opposed to most other advanced therapies available for the treatment of acute PE with RVD.

## Ethics and dissemination

The SO-PE study is funded by the NHLBI and has been approved by the Institutional Review Board of MGB (no. 2023P000252). The study will comply with the Helsinki Declaration on medical research involving human subjects. All participants will provide prospective, written informed consent. Study results will be published in international peer-reviewed journals with the highest possible impact factor, regardless of whether results are positive, neutral or negative.

### Trial status

The study was initiated 1 October 2023. As of 1 July 2024, 18 patients have been enrolled.

## Ethics statements

### Patient consent for publication

Not applicable.

## Footnotes

*   X @MadsDam_MD

*   Contributors MDL, ASL, AA, DMD, OAZ, MKK and CK conceived the study. HS, NAJ, OFE, CCM, CKH, TFH and CK performed data acquisition. MDL and CK drafted the paper, and the remaining authors revised its content. All authors have approved the final version of this manuscript and agree to be accountable for all aspects of the work. Guarantor is CK.

*   Funding This work is supported by the NIH and NHLBI (grant no. R01HL168040-01). Funder has no role in study design, interpretation or publication of the study.

*   Competing interests AA is a consultant of Inari Medical and has received teaching honorarium from Gore Medical, Janssen and Angiodynamics. CK receives grant funding (paid to his institution from Grifols and Diagnostica Stago). CK is a consultant for Siemens Healthineers, Abbot and BMS/Pfizer. CK owns stock in Insera Therapeutics. The remaining authors have no conflicts of interest.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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