Completed IRB application and Consent Enclosed

Download the PDF Here

By Paul G. Harch M.D.
April 16, 2020

For months, the coronavirus pandemic has continued its worldwide spread, but the development of effective treatments is still lacking. Given the likelihood of second and third waves to the coronavirus pandemic, similar to the Spanish Flu experience, the need for effective treatment is still emergent. While we have seen a number of different drugs progress through the treatment/study (and news) cycle, their effectiveness remains an open question. This lack of consensus agreement on the best treatment course is why in early March I called for more resources to be put toward studying the impact of Hyperbaric Oxygen Therapy (HBOT) in treating COVID-19 patients, especially those who seemed destined to need ventilator care.

Published and unpublished evidence is accumulating on improvement in coronavirus patients treated with HBOT. Doctors in China officially published their 5-patient case-series experience in a Chinese language journal and physicians in Louisiana presented their experience with 5 patients in a webinar, both last week.  Additional positive experience will be announced in the coming days.  The results in China and Louisiana are very similar and mimic the experience of Dr. Orval Cunningham with dying Spanish Flu patients in 1918. Formal studies on HBOT in coronavirus are underway at a number of sites internationally and in the U.S. with additional studies to begin soon.

In the meantime, however, there is nothing to prevent physicians from treating coronavirus patients off-label with HBOT and informed consent in identical fashion to the treatment with hydroxychloroquine and other off-label drugs.

This is known as the practice of medicine and occurs in doctors’ offices and hospitals every day throughout the U.S. When compared to the trial and error method already being conducted with these drugs, the risk profile appears to be less with HBOT and there is a solid scientific argument for HBOT posted here and in Medical Gas Research along with successful precedence in a near-identical viral pulmonary infection, the Spanish Flu Pandemic of 1918.

Doctors in China who used HBOT noted no complications in their 35 HBOT coronavirus patients and there is no report of complications from the Louisiana patients. In addition, equally or more severely ill patients with severe blunt chest trauma and the equivalent acute respiratory distress syndrome (ARDS) seen in dying coronavirus patients were successfully treated with HBOT in Russia in 2003 with 100% survival and no mention of complications. The Chinese, Louisiana, and Russian experience all used oxygen pressures in the 1.6-2.0 ATA range for different times while Dr. Cunningham used 1.68 ATA of air. In consideration of all of the data and experience which includes the effects on anti-inflammatory gene activation at 1.5 ATA , 1.6 ATA maybe the most effective dose.

While I encourage the off-label application of HBOT to coronavirus patients (i.e., treatment of coronavirus patients with HBOT) I have posted below our final Louisiana State University IRB (Institutional Review Board)-reviewed protocol and consent to facilitate, expedite, and assist physicians and researchers at any hospital with their IRB application for an HBOT coronavirus study.  Any “study” and treatment experience contributes helpful information, but the medical profession will likely not be moved to action without randomized controlled designs.  Hopefully, more studies will be conducted in hospital settings so that we can further determine the effectiveness of this treatment in a safe and controlled environment.

I would caution against using hyperbaric pressures over 2.0 ATA because of the distinct possibility of increasing the lung injury. In fact, short (one hour) times and pressures close to 1.6 ATA may afford the best opportunity of modulating the lung injury in coronavirus, tiding the patient over the most critical phase of the illness, preventing intubation, and hastening discharge from the hospital.

IRB Application and Consent:

Louisiana State University Institutional Review Board

Reviewed Study on Hyperbaric Oxygen Therapy in the Treatment of COVID-19 (Novel Coronavirus 2019) Pneumonia with Respiratory Distress:

Approved pending Hospital Research Review Committee Approval

4/16/2020

 

Title:  Hyperbaric Oxygen Therapy in the Treatment of COVID-19 (Novel Coronavirus 2019) Pneumonia with Respiratory Distress.

Type of Research and Disease Process:  This is a randomized prospective controlled clinical trial of 1.6 ATA HBOT plus standard of care versus standard of care in COVID-19 pneumonia subjects.

Protocol Abstract: 

Background: COVID-19 is a highly infectious coronavirus that infects the lungs and causes progressive hypoxemia that leads to respiratory distress, respiratory failure, and death in 4.3% of patients^.1 The progressive hypoxemia is secondary to an cumulative barrier to diffusion of oxygen from the alveoli to the pulmonary blood caused by pulmonary inflammation and inflammatory exudate (pneumonia).

Normally, oxygen passes easily from the alveoli through pulmonary tissue to the pulmonary capillaries. Any barrier to diffusion along this path lowers the amount of oxygen finally reaching hemoglobin. The amount of oxygen that dissolves in the interstitial tissue at the start of this process is proportional to the pressure of oxygen in the alveoli (Henry’s Law).²

As the alveoli fill with inflammatory fluid in COVID-19 patients there is an increasing barrier to oxygen diffusion in the alveoli. Standard treatment with oxygen is limited by atmospheric pressure. This cannot be surpassed even with Extracorporeal Membrane Oxygenation (ECMO). This limit can only be surpassed by further exploitation of Henry’s Law, i.e., increasing oxygen above atmospheric pressure in a hyperbaric chamber. The transient elevation in oxygen through hyperbaric oxygen therapy (HBOT) penetrates the diffusion barrier, reverses oxygen debt and mitochondrial dysfunction, suppresses pulmonary inflammation, and causes permanent effects through hyperbaric pressure and oxygen-induced gene modulation.

Proof of this concept was established in 1918 in a near identical pulmonary viral pandemic, the Spanish Flu Pandemic, where multiple dying patients were salvaged with approximately five daily HBOTs in Kansas City.^3,4 Unwittingly, a group of hyperbaric physicians in Wuhan, China recently applied a similar hyperbaric protocol to deteriorating COVID-19 patients with the same result. 35 patients have been treated with an average of 5 HBOTs each. Reports on two of 6 of their severe and deteriorating patients have been published in China.^5,6  The data on 5 of their 6 severe patients was shared with the P.I. and recently published.⁷ 

This study is a randomized, prospective, controlled study in which consecutive HBOTs (3-8) delivered to coronavirus infected patients who are failing standard respiratory therapy will increase daily blood oxygen saturation and reduce the percent of patients who progress to intubation/ventilator use.  By clinical experience at UMC the advancement to non-rebreather mask oxygen constitutes failure of standard therapy since nearly 100% of these patients progress within 12 hours to intubationa and mechanical ventilation. 

References: 

1. World Health Organization.  Coronavirus disease 2019 (COVID-19) Situation Report-64 https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200324-sitrep-64-covid-19.pdf?sfvrsn=703b2c40_2. Last accessed 3/26/2020.
2. Henry’s Law. https://www.britannica.com/science/Henrys-law.  Last accessed 3/26/2020.
3. Vance Trimble. The Uncertain Miracle: Hyperbaric Oxygenation. Doubleday and Company, Inc. Garden City, NY. 1974.

4. Sellers LM. The Fallibility of the Forrestian Principle. The Laryngoscope. 1964;74(5):613-633.

1. Zhong XL, Tao XL, Tang YC, et al. Effect of hyperbaric oxygen therapy to treat hypoxia in Severe novel coronavirus pneumonia patients: First case report. Chin J Nauti and Hyperb Med. 2020,27 (2020-02-24).http://rs.yiigle.com/yufabiao/ 1182641.htm. DOI: 10.3760/cma.j.issn.1009-6906.2020.0001.
2. Xiaoling Z, Xiangqun N, Xiaolan T, Chen R*, Liang Y,  Yanchao T.  Case Report :The First Case of HBOT in Critically Ill Endotracheal Intubation Patient with COVID-19.  Novel coronavirus pneumonia research network sharing platform of China Association for science and technology. 2020.  [email protected]. # Corresponding author：Yanchao Tang，Email：[email protected].  Under submission to: The Academic Journal of Second Military Medical University, Beijing, China.
3. Harch PG.  Commentary:  Hyperbaric oxygen treatment of novel coronavirus (COVID-19) respiratory failure.  Med. Gas Res. 2020;DOI: 10.4103/2045-9912.282177.

http://www.medgasres.com/temp/MedGasRes000-5574032_152900.pdf

 

Protocol Details: 

Principal Investigator:  Paul G. Harch, M.D.

Protocol Title:  Hyperbaric Oxygen Therapy in the Treatment of COVID-19 (Novel Coronavirus 2019) Pneumonia with Respiratory Distress

Duration of the Study:  7 months.

Products or Devices to be Studied:  Hyperbaric Oxygen Therapy (HBOT). The manufacturer is Perry Sigma Elite monoplace chambers or twelve person dual-lock multiplace chamber. The study drug, HBOT, is FDA approved, but not FDA approved for coronavirus pneumonia and respiratory failure.

Purpose of the Study:  Consecutive HBOTs (3-8) delivered to coronavirus infected patients who are failing standard respiratory therapy will reduce the percent of patients who progress to intubation/ventilator use. Our primary specific aim is to determine whether three to eight 1.6 ATA (atmospheres absolute) HBOT’s can improve hypoxemia and prevent COVID-19 pneumonia patients from requiring intubation.

Rationale:  COVID-19 is currently causing a worldwide pandemic with an average mortality of 4.3%, according to WHO weekly statistics.1  One of the critical determinants of mortality is the deterioration of the patient to require intubation and mechanical ventilation.  There is a worldwide shortage of ventilators and ICUs.  Any treatment that could prevent the progression of disease to require mechanical ventilation would have a significant impact.  Such a treatment is hyperbaric oxygen therapy which has the unique ability to penetrate alveoli inflammatory exudate, reduce oxygen debt, and cause permanent trophic tissue changes.  Recently, Chinese physicians applied hyperbaric oxygen therapy (HBOT) to six COVID-19 patients who failed maximal mask oxygen therapy. One was on a ventilator.  All six experienced symptomatic and blood oxygen saturation improvements with the first and each subsequent HBOT.  After an average of 5 HBOTs the patients proceeded to eventual hospital discharge.  Duplication of this experience in our study would have a tremendous impact on the pandemic, especially in New Orleans, currently one of the highest COVID-19 incidence sites in the U.S.

Background and Principal Investigator’s Experience with this Product/Device:  Dr. Harch is a  clinical Professor in Internal Medicine and immediate past program director of Hyperbaric Medicine with an extensive background in the use of HBO for the treatment of various diseases from decompession illness to cardiopulmonary resuscitation, as well as untilization in emergency settings. Dr. Harch has collaborated with several members of the research team on previous studies.

Study Design:  This is a randomized prospective controlled clinical trial of 1.6 ATA HBOT plus standard of care versus standard of care in COVID-19 pneumonia subjects.  Eighty adult subjects, 18 years of older, with bilateral COVID-19 pneumonia who are in respiratory distress and failing standard therapy on non-rebreather mask oxygen will be enrolled and randomized to either once daily HBOT (expected 3-8 treatments)  plus standard of care or no HBOT plus standard of care.

Study Procedures:

Subjects: 80

Setting: Recruitment will be performed primarily at University Medical Center.  Direct engagement of the Emergency Department and inpatient Internal Medicine staff will occur to announce the study..

Eligibility

Inclusion criteria:

1. Adults aged 18-80 years old
2. Confirmed COVID-19 positive
3. Influenza A and B negative
4. CXR or CT positive for pneumonia with bilateral Ground Glass (GGO)
5. In respiratory distress In respiratory distress (OI <315 using SpO2, according to WHO recommendations): patients who have been advanced to non-rebreather mask 100% oxygen.
6. Moderate Disease Severity category (SpO2 <94% OR GGO/infiltrates on CXR) but do not meet the category of Severe Disease Severity, according to Interim COVID-19 Treatment Protocol established 3/19/2020 by The ID divisions of LSU, Tulane, and Ochsner Health systems.

Exclusion criteria:

1 . Intubated

2. Participation in another active treatment trial
3. Individuals younger than 18 years of age
4. Individuals that cannot read and/or understand English
5. Untreated pneumothorax
6. Pulmonary disease that precludes HBOT (e.g., bronchospasm unresponsive to medication, bullous emphysema)
7. Unstable medical conditions that are contraindicated in HBOT (e.g. severe congestive heart failure or heart failure requiring hospital emergency evaluation or admission in the previous year).
8. Severe confinement anxiety (e.g., patients who require anesthesia conscious sedation for MRI)
9. Participation in another experimental trial with active intervention (is this not the same as #2)
10. Cancer on chemotherapy
11. Tracheostomy
12. Prisoners
13. Patients with active psychiatric condition (psychosis) or patients under PEC.

 

Implementation Summary: See appendix A.

Study Procedures Timeline

1. First week: Recruitment, screening, signing of consent, enrollment, pre-study procedures,

randomization, begin treatment .

2. Second week: repeat outcome instruments.
3. Fourth week: repeat outcome instruments.

Study Instruments pre-randomization: blood tests (HIV, Hepatitis B, Hepatitis C, RPR, Troponin, NT-proBNP, Influenza A and B, Respiratory BioFire, Pregnancy test in women of childbearing age, CBC with differential, CMP, CRP, LDH, Ferritin, D-Dimer, CK, CKMB, Fibrinogen, additional inflammatory markers (IL-6, TNF-alpha, IL-1beta, IL8, INF gamma, GM-CSF), lactic acid, EKG, urinalysis, pulse oximetry, chest X-ray or CT of lungs without contrast, symptom questionnaire.  All instruments will be performed before treatment or Control period.

Outcome Instruments post-treatment and two-week follow-up: pulse oximetry, Troponin, NT-proBNP, Respiratory BioFire, white blood cell count, number of lymphocytes, % lymphocytes, number of neutrophils, % neutrophils, CRP, LDH, Ferritin, D-Dimer, CK, CKMB, Fibrinogen, additional inflammatory markers (IL-6, TNF-alpha, IL-1beta, IL8, INF gamma, GM-CSF), lactic acid, EKG, urinalysis, and symptom questionnaire.  Chest X-ray or CT of lungs will only be repeated on the 8^th day.

Pulse oximetry will be performed daily before each HBOT or each morning for the Control Group for the first 8 days of the study.

Hyperbaric Oxygen Therapy (HBOT and Control Groups)

All subjects will be treated in single person acrylic “see-through” chambers, Perry Sigma 40 Elites or similar monoplace chambers in the Hyperbaric Department of UMC or one large multiplace chamber.  Patients will be instructed pre-treatment on how to equalize the pressure in their middle ears. Before entry to the chamber patient non-rebreather oxygen mask will be switched to the same mask inside the chamber that has continual high-flow oxygen (15L/minute).  Patients will be instructed and practice clearing their ears (popping their ears).  Once inside the chamber, just after closure of the chamber door and immediately before pressurization, the subject will be instructed to perform the first Valsalva maneuver to pressurize the middle ear space before the initial 1.0 pounds per square inch (psi) start-up pressurization of the chamber that attains air-tight “seal” of the chamber. This maneuver expands the middle ear space and brings the ear space to neutral volume after the compression effect of the initial 1.0 psi seal pressurization.

HBOT Group: Pressurization will proceed with 100% oxygen at 1.0 pounds per square inch (psi) per minute, the minimal pressurization rate, to 1.6 ATA (atmospheres absolute) or 8.8 psi and will take approximately 10 minutes.  During the entire pressurization the patient will be continuously instructed to clear their ears using various pressure equalization techniques that they have learned and practiced before chamber entry.  Inability to pressure-equalize the middle ear space will immediately truncate pressurization until the subject can equalize pressure.  Pressurization will then resume until the final depth of 1.6 ATA is achieved.  The patient will remain at depth for 60 minutes and the subject will be informed of the onset of depressurization, which will occur at the same rate as pressurization.  The subject will again be instructed to pressure equalize the middle ear space, however, barotrauma is minimized during decompression since gas expansion in the middle ear space passively vents through the Eustachian Tube to the pharynx.  Total dive time will be approximately 80 minutes.  The subject will be queried regarding pain and untoward symptoms after this and all subsequent treatments. In addition, if the patient has bronchospasm decompress with be longer (15 minutes).

HBOT subjects will receive once/daily HBOT until they maintain their baseline pre-daily HBOT SpO2 at 94% or greater on non-rebreather mask or less oxygen support for two consecutive days upto 8 HBOT maximum. In the Chinese experience this was 3-8 HBOTs.

Control Group:  Subjects will continue their standard care during the equivalent 3-8 day HBOT treatment period.  After the HBOTs or equivalent Control period both control and experimental subjects will be retested and then retested in another two weeks.

Placebo: A placebo chamber arm will not be employed because of the impossibility of blinding subjects to pressure effects without placing tympanic membrane tubes, and the extreme unlikelihood that a placebo could reverse systemic hypoxemia in a deteriorating pulmonary patient.

Primary Outcome Variables:

1.The reduction (%) in number of patients who require intubation/mechanical ventilation during the eight day HBOT or equivalent Control Period.

2. The percent increase in blood oxygen saturation after 2 HBOTs and 48 hours , immediately before the 3rd HBOT or equivalent time for the Control Group.

Data Collection:

Once entered into the study the subject will be assigned by a computer in random fashion to one of two groups, A or B.  This randomization process is similar to flipping a coin with “heads” getting assigned to one group and “tails” to the other group.  There will be 40 subjects in Group A and 40 subjects in Group B.  All subjects will answer questionnaires on their symptoms, such as fever, cough, headache, shortness of breath, have a physical exam by one of the investigators, blood tests, chest X-rays or CT scans of their lungs, EKG (electrical recording of the heart beat), analysis of urine, measurement of blood oxygen levels by a painless device that attaches to a finger or ear, all of which are routine tests that are part of the evaluation and treatment of your pneumonia, then enter the hyperbaric chamber.

Group A will be administered HBOT by having the subject lie on a stretcher that is in a fully enclosed chamber.  The purpose of the hyperbaric oxygen is to see if increased oxygen at pressure can help the subject’s low blood oxygen levels, pneumonia, and shortness of breath.  The pressure in the chamber will be increased to a little over one and one-half times atmospheric pressure, or the equivalent pressure one would obtain if breathing compressed air SCUBA diving 20 feet underwater.  There is no water in the chamber, however.  The breathing gas that is delivered is pure oxygen, the same oxygen that you are getting through your mask for the coronavirus infection..  After about 70 minutes in the chamber the pressure will be slowly decreased to surface pressure and the subject removed from the chamber.  The treatment takes 80 minutes.  The subject will undergo treatment once/day until the subject is able to achieve a blood oxygen level above 93% the day after the last HBOT.  This is usually 3-8 HBOTs.  The maximum number of HBOTs a subject will receive is eight..

Group B subjects will simultaneously receive no HBOT.  They will continue with their usual medication and oxygen by mask for the same 3-8 days that Group A gets HBOT.

On the eighth day and at three weeks after entering the study both groups will undergo repeat testing with the symptom questionnaire, blood tests, EKG, analysis of urine, and measurement of blood oxygen levels.  Chest X-rays or CT scans of the lungs will only be repeated once on the 8th day.

Duration of Study:

Estimated study start date: April 13, 2020

Estimated primary completion date: November 13, 2020

Estimated study completion date: December 31, 2021

Risks:

There is risk of pulmonary barotrauma manifesting as a pneumothorax or air embolism, inner ear barotrauma with rupture of the round or oval window, and oxygen toxicity presenting as a grand mal seizure. Emergency department visits for pulmonary barotrauma and inner ear barotrauma are rarely seen in clinical hyperbaric oxygen therapy.  Pulmonary barotrauma results from an overpressurization of the lungs resulting in emphysema (interstitial, mediastinal, subcutaneous), air embolism (including cerebral air embolism), or pneumothorax.  Occurrence is 1 in 50,000 treatments.⁸  Patients with active clinically appreciated bronchospasm, bullous emphysema, or on ventilators are at greatest risk.  All of these subjects are excluded from the study.  Speed of chamber decompression is causally related to pulmonary barotrauma.  Subjects in this study will be decompressed in a slow fashion.  Inner ear barotrauma is a rare event, unreported in 11,376 treatments at 2.4-2.5 ATA in one series that included patients with inner ear emergent conditions.⁹  Inner ear barotrauma usually results from middle ear barotrauma which is discussed below.  Slow compression and decompression will mitigate risk.   Oxygen toxicity to the central nervous system can occur during hyperbaric oxygen therapy.  Central nervous system oxygen toxicity manifest by a grand mal seizure is a rare occurrence at high pressures.¹⁰ The low pressure featured in this study has not been reported to cause seizures in this population. Also there is a risk of cardiac toxicity,¹¹ however, this is thought to be secondary to increased afterload caused by hyperoxia in patients with heart failure or reduced ejection fraction. Patients with congestive heart failure or a history of congestive heart failure will be excluded from the study.

Both central nervous system and cardiac toxicities are mitigated by the low dose of HBOT used in the study.^8,11  Patients are monitored chamberside during treatment and on a daily basis through questioning about side effects such that toxicity can be identified at the earliest time.

The most likely anticipated adverse events would be middle ear barotrauma and much less frequently sinus barotraumas. The occurrence of both can be minimized by screening during the history and physical exam.  Middle ear barotrauma is most common in the young and elderly; children are excluded from this study. Subjects with Eustachian Tube Dysfunction (ETD) will be identified through childhood history of frequent otitis medias, pressure equalization tube (PET) placement, or history of middle ear barotrauma flying or diving.  If the subject cannot pressure equalize the middle ear at ambient pressure the subject will be offered entry into the study or can opt for PET placement.  Middle ear barotrauma will be minimized during treatment by slow compression and decompression and careful chamberside monitoring by the technician.  This is a standard practice in hyperbaric medicine.  Should a subject develop middle ear barotrauma they will be offered oral pseudoephedrine to facilitate drainage of the middle ear or sinus spaces until the subject can clear his/her ears on the surface.  Alternatively, they can opt for placement of temporary pressure equalization tubes (PETs).  Most patients can resolve mild middle ear barotrauma overnite and resume treatment the following day.

Risk of sinus barotrauma will also be screened during the hyperbaric medicine history and physical exam by identifying subjects with a history of recurrent sinusitis.  Mitigation will be through treatment of existing sinus disease pre-HBOT, trial compression, and slow compression and decompression during treatment.

Fire is a very rare risk of hyperbaric oxygen therapy that has only been reported once in the past 89 years of clinical HBOT in North America.  Strict adherence to fire prevention precautions will minimize fire risk.  These include use of 100% cotton or high percentage cotton blend clothing, no electronics, metal, volatile or inflammable vaporous substances, petroleum products, or paper products.  Risk assessment is done daily at chamberside before each patient enters the chamber.  Mitigation during a chamber fire consists of immediately switching the chamber to air supply and emergently decompressing the chamber.

Confinement anxiety for this study is considered anxiety symptoms directly related to fear of entering the chamber, closing the chamber door, or developing within the first 30 minutes of treatment.  Should a subject experience confinement anxiety, the subject may not be able to continue in the study unless his primary care team feels that a mild anxiolytic would not compromise respiratory status.  That anxiolytic would be Xanax one-half mg p.o. as needed before each treatment.  The subject will continue Xanax as needed through the last hyperbaric treatment and then discontinue the Xanax.

Venupuncture: Minor risk from hematoma (frequent), infection (rare), or clotting of vein at blood draw site (occasional).

EKG:  Minor risk from removal of hair from the chest when electrode tabs are removed (frequent), allergic reaction to the adhesive in the electrode tabs (rare).

Benefits:

There is a potential for reduction in the number of patients that progress to intubation and ventilation, as well as reduced mortality.

Risk to Benefit Ratio:

Risk/benefit strongly favors benefit with minimal risk of significant side effects (described above) and significant potential for gain (as described above).   Mitigation of risk will be through careful screening of subjects for potential side effects and risks for complications.  Compression rates will be slow and subjects will be instructed pre-HBOT and coached during treatment to minimize barotrauma, the most common side effect of HBOT.  Potential benefits to the subject are prevention of intubation, ARDS, and death. 

Therapeutic Alternatives:  the two alternatives will be continued standard of care and/or mechanical ventilation.

Data Safety Monitoring:  This study will utilize an independent Safety Monitor with expertise consonant with the nature of risk(s) identified within the protocol. The research monitor functions include:

– Shall have authority to stop a research protocol in progress, remove individual human subjects from a research protocol, and take whatever steps are necessary to protect the safety and well-being of human subjects until the IRB can assess the monitor’s report;

– Shall have the responsibility to promptly report their observations and findings to the IRB or other designated official and the HRPO.

Data and Safety Monitoring will be performed by the P.I. and the Safety Monitor, XXXXXXX. The PI and Safety Monitor will meet daily or by phone during the study. Each subject’s treatment course will be reviewed with specific attention to significant adverse events. Subjects will be inpatients under close scrutiny by large care teams, including hyperbaric technicians and hyperbaric staff.  Complications are readily apparent from a change in signs and symptoms; subjects will be monitored for significant acute changes in symptomatology or physical appearance on a daily basis. Reporting of adverse symptomatology will be recorded on the standard treatment record for that day and the physician in attendance notified.

Significant adverse events will be defined as those requiring emergency department evaluation or pulmonary barotrauma manifest by pneumothorax or air embolism, inner ear barotrauma with round or oval window rupture, and oxygen toxicity manifest by grand mal seizure. All would be reportable to the IRB.

Statistical Analysis:  All statistical analyses will be carried out using SAS software, Version 9.4. We will calculate descriptive statistics (e.g., means, medians, ranges, standard deviations, or frequencies as appropriate) to estimate distributional properties of the variables. All

tests will be carried out at the 5% level. As a first choice, parametric methods will be

used (Box-Cox transformations will be applied to skewed outcomes); however, we will

also consider nonparametric or robust alternatives depending on the nature of the data

and statistical model assumptions. We will start our statistical analyses with basic

comparisons of the two groups, but we will also utilize more complex models. To

achieve our main aim we will compare the reduction (%) in the number of patients who

require intubation/mechanical ventilation between the HBOT and Control groups using

the z-test. We will compare the daily SpO2 levels of the HBOT and Control group using

two-sample t-tests. To assess the effect of the treatment on SpO2 levels, we will utilizea linear mixed model which will be adjusted for potential confounders such as patients’

underlying diseases, age and gender.40 patients in each group will be enough to achieve 80 % power to be able to detect a 25% reduction of intubation/mechanical ventilation requirement in the treatment group. 

Sample Size Calculation:  Sample size projections were calculated based on a conservative reduction in the Chinese data of 100% reduction in ventilator progression and successful extubation of the single ventilator patient that also accounts for possibly worse patients in our study. The Chinese standard of care at the study hospital used maximal therapy as a tight-

fitting non-rebreather mask in which they estimated and FiO 2 of 50%. Our subjects will

be failing on a non-rebreather mask and our success rate will likely not be as great so

we have used a 25% reduction in the HBOT group. Forty patients in each group will be

enough to achieve 80 % power to be able to detect a 25% reduction of

intubation/mechanical ventilation requirement in the treatment group.

Data Storage and Confidentiality:  The UMC investigators will maintain all paper and electronic records will be maintained either in a locked filing cabinet behind a locked door. Electronic copies of the date will be stored on a password protected computer. Only the PI and the research team will have access to the records. Data will be available according to guidelines to the IRB upon request. No data with patient health information will be allowed to leave the site. All reported data will first be de-identified to protect the identity of individual patients.

Costs to Subjects:  The cost of all hyperbaric oxygen therapy, study visits, and study procedures will be covered by the research study. All non-study related current standard of care related medications, treatment will be covered by the patient or patient’s insurance.

 

References:

8. Gesell, L.B. (2009). Chair and Editor, Hyperbaric Oxygen Therapy Indications, 12th ed. The Hyperbaric Oxygen Therapy Committee Committee Report. Durham, NC: Undersea and Hyperbaric Medical Society, pps. 215-220.

1. Plafki, M.D., Peters, P., Almeling, M., Welslau, W., Busch, R.  (2000).  Complications and Side Effects of Hyperbaric Oxygen Therapy.  Aviat Space Environ Med;71:119-24.
2. Clark, J. (2009). Side effects, in: Hyperbaric Oxygen Therapy Indications, 12th ed. The Hyperbaric Oxygen Therapy Committee Report. L.B. Gesell (ed). Undersea and Hyperbaric Medical Society: Durham, NC, pps. 217–218.
3. Weaver, L.K., Churchill, S.  (2001).  Pulmonary edema associated with hyperbaric oxygen therapy.  Chest;120:1407-9
   

 

Appendix A:

Study Flow Chart:

 

80 COVID-19 subjects:

Baseline screening

↓

Enrollment/Randomization

↓

Pre-treatment instruments/blood draw

↓

Group A (HBOT)        or             Group B (Non-HBOT)

↓                                                      ↓

Daily HBOTs + standard therapy     Continuation of standard therapy

↓                                                      ↓

Repeat testing Day 8                          Repeat testing Day 8

(All measures)                                (All measures)

↓                                                       ↓

Two week Standard Treatment       Two weeks continuance of standard therapy

↓                                                       ↓

Repeat testing Day 22                        Repeat testing Day 22

(All measures)                               (All measures)

 

Consent:

Consent to Participate in a Research Study 

KEY INFORMATION For Hyperbaric Oxygen Therapy in the Treatment of COVID-19 (Novel Coronavirus 2019) Pneumonia with Respiratory Distress

Taking place at: University Medical Center New Orleans 

We are asking you to choose whether or not to participate in a research study about the use of hyperbaric oxygen therapy in the treatment of COVID-19 pneumonia with respiratory distress. This page is to give you key information to help you decide whether to participate. We have included detailed information after this page. Please ask the research team any questions you have as you read this document. If you have questions later, the contact information for the research investigator in charge of the study is listed below.

what is the STUDY ABOUT AND HOW LONG WILL IT LAST? 

The purpose of this study is to see if once daily hyperbaric oxygen therapy treatment (HBOT) will reduce the chance of you requiring a breathing tube and going on a ventilator. You will be randomly be assigned to receive either standard treatment or standard treatment plus HBOT. If you are in the HBOT group you will receive once daily treatment between 3-8 times.  

By doing this study, we hope to determine if HBOT is an effective treatment for COVID19 pneumonia with respiratory distress. Your participation in this research will last about three weeks.

The purpose of this research is to gather information on the safety and effectiveness of hyperbaric oxygen therapy for the treatment of COVID-19 pneumonia with respiratory distress. Hyperbaric oxygen therapy treatment is FDA-approved, but not FDA-approved for coronavirus pneumonia and respiratory failure.

what are key reasons you might choose to PARTICIPATE IN this study?

Possible benefits of participating in this study are an improvement in breathing and prevention of having a breathing tube put down your throat and going on a breathing machine. For a complete description of benefits, refer to the Detailed Consent.

what are key reasons you might choose not to PARTICIPATE IN this study?

You may choose not participate in this study because:

• You do not wish to be placed in a hyperbaric chamber
• You cannot or do not want to share medical information
• You cannot or do not wish to be followed by the research team
• You prefer the standard therapy only

For a complete description of benefits, refer to the Detailed Consent.

The alternative would be to receive standard therapy only which may include having a breathing tube place and going on a breathing machine. For a complete description of alternate treatment/procedures, refer to the Detailed Consent and/or Appendix.

DO YOU HAVE TO TAKE PART IN THE STUDY?

If you decide to take part in the study, it should be because you really want to participate. You will not lose any services, benefits or rights you would normally have if you choose not to participate.

what if you have questions, suggestions or concerns?

The person in charge of the study is Paul G. Harch, M.D. of the Louisiana State University Health Sciences Center of New Orleans, Department of Internal Medicine. If you have questions, suggestions, or concerns regarding this study or you want to withdraw from the study his/her contact information is: 504-309-4948.

If you have questions about your rights as a subject, or want to discuss problems, concerns or questions, or obtain information or offer input, you can contact the Chancellor of the LSU Health Sciences Center of New Orleans at (504) 568-4801. 

LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER IN NEW ORLEANS

Informed Consent Form 

1. Study Title: Hyperbaric Oxygen Therapy in the Treatment of COVID-19 (Novel Coronavirus 2019) Pneumonia with Respiratory Distress
2. Performance Sites: University Medical Center (New Orleans, LA)
3. Investigators:

Principal Investigator:  Paul G. Harch, M.D.

Phone:  504-309-4948

24-hour number: 504-309-4948

Co-Investigators:

In case of a research injury contact:  Paul G. Harch, M.D.

Phone:  504-309-4948

4. Purpose of Study:

This is a research study whose purpose is to see:

1. If once daily hyperbaric oxygen therapy treatments (HBOTs) for 3 to 8 days (3 to 8 HBOTs) delivered to you, a coronavirus infected patient who is failing standard respiratory therapy, will reduce the chance of you requiring a breathing tube and going on a ventilator.

You are asked to participate because this treatment is thought to be effective based on previous application to other patients with coronavirus pneumonia and respiratory failure treated with HBOT in China this year and patients infected with Spanish Flu in 1918 who were treated with HBOT.

The study drug, HBOT, is FDA approved, but not FDA approved for coronavirus pneumonia and respiratory failure.

5. Description of the Study:

There will be a maximum of eighty patients recruited for the study.  All of you will be tested and treated at the LSUHSC-New Orleans sites listed on this consent form.

Summary Schedule of Events and Visits

Timing of Event	Event/Visit/Procedures
Day of or Day(s) before signing the consent for the study	Screening questions by your doctor
First day of study	Sign Consent.  History and physical exam by study doctor
First day of study or days earlier during hospital stay	Fill out symptom questionnaire, have blood samples taken, get chest X-ray or CT scan of lungs, EKG, urine sample, pregnancy test, have blood oxygen level measured from your finger
First day of study	Get randomly assigned to either the HBOT Group (Group A) or standard care group (Group B).
First day of study	Begin once daily HBOT for 3-8 HBOTs if you are in Group A
First day of study	Continue your normal care if you are in Group B
Second through 8th days of study	Have blood oxygen measurement from finger every day for both groups
Eighth day of study	Repeat symptom questionnaire, blood samples, chest X-ray or CT scan of lungs, EKG, urine sample at the hospital.
Twenty-second day of study	Repeat symptom questionnaire, blood samples, EKG, urine sample at the hospital.

Once entered into the study you will be assigned by a computer in random fashion to one of two groups, A or B.  This randomization process is similar to flipping a coin with “heads” getting assigned to one group and “tails” to the other group.  There will be 40 of you in Group A and 40 of you in Group B.  All of you will answer questionnaires on your symptoms, such as fever, cough, headache, shortness of breath, have a physical exam by one of the investigators, blood tests, chest X-rays or CT scans of your lungs, EKG (electrical recording of the heart beat), analysis of urine, measurement of blood oxygen levels by a painless device that attaches to your finger or ear, all of which are routine tests that are part of the evaluation and treatment of your pneumonia, then you will enter the hyperbaric chamber.

Group A will be administered HBOT by having you lie on a stretcher that is in a fully enclosed chamber.  The purpose of the hyperbaric oxygen is to see if increased oxygen at pressure can help your low blood oxygen levels, pneumonia, and shortness of breath.  The pressure in the chamber will be increased to a little over one and one-half times atmospheric pressure, or the equivalent pressure you would obtain if breathing compressed air SCUBA diving 20 feet underwater.  There is no water in the chamber, however.  The breathing gas that is delivered is pure oxygen, the same oxygen that you are getting through your mask for the coronavirus infection.  After about 70 minutes in the chamber the pressure will be slowly decreased to surface pressure and you will be removed from the chamber.  The treatment takes 80 minutes.  You will undergo treatment once/day until you are able to achieve a blood oxygen level above 93% the day after the last HBOT.  This is usually 3-8 HBOTs.  The maximum number of HBOTs you will receive is eight.

If you end up in Group B you will receive no HBOT.  You will continue with your usual medication and oxygen by mask for the same 8 days that Group A gets HBOT.

On the eighth day and at three weeks after entering the study all of you will undergo repeat testing with the symptom questionnaire, blood tests, EKG, analysis of urine, and measurement of blood oxygen levels.  Chest X-rays or CT scans of the lungs will only be repeated once on the 8th day.

If you take part in this study, you will have tests and procedures at the start of the study and at the times stated above.  The tests and procedures are:

1. History and physical examination by one of the physician investigators:

This is a comprehensive review of your medical history and a physical exam to ensure that you can safely undergo HBOT.  It will be performed usually on the first day and will take about 45 minutes. It will be repeated on the eighth day and at the end of the 3-week study period.  The repeat exams will only take 15-20 minutes.

1. Questionnaire that records symptoms caused by your coronavirus infection:

This is a one-page written questionnaire that asks about the symptoms you have from the coronavirus pneumonia such as cough, fever, headache, shortness of breath, etc.  These will be completed at the beginning of the study, on the eighth day, and at the end of the study.  It takes about 3-4 minutes to complete each time.  This will monitor changes that occur in symptoms as you are treated.

1. Blood tests: 

These are blood tests that will be drawn from a vein.  Approximately 5 tubes of blood will be drawn at each of the three test times.  

1. Chest X-ray or CT scan of lungs:

The chest X-ray is a single X-ray of the chest to identify the pneumonia.  The CT scan of the lungs is a more detailed study that takes many pictures of the lungs and allows the doctors to look at the pneumonia in slices of the lungs.  Either one or the other tests will be done twice, at the beginning of the study and on the eighth day.

1. EKG:  This is an electrical recording of your heart beat performed by putting one inch adhesive tabs on your chest.  Electrical wires are attached that carry the electrical signals from your heart to a recording machine.  No electricity is sent to your heart.
2. Analysis of urine:

All of you will be tested for abnormalities in the urine related to your pneumonia.  This will be collected in a cup in which you will urinate.

1. Pregnancy test:

If you are a female of child-bearing potential you will be tested for pregnancy before hyperbaric oxygen therapy.  You will give a urine sample to perform this test.  It will usually be done at the time of the history and physical exam.  If positive you will be excluded from the study.

1. Blood oxygen levels:

This is a painless test that is obtained by applying a sticky tab or plastic clamp to the end of your finger or ear that measures blood oxygen levels by shining a light on your fingernail or earlobe.  It does not puncture the skin.   It takes 15 seconds to measure and will be done daily before each HBOT or each morning for Group B subjects through the 9th day of the study and at the two-week follow-up time.

1. Hyperbaric oxygen therapy:

You will be treated in a clear single person acrylic chamber if you are in Group A.  You will lay on a gurney that slides into a chamber that is a tube over three feet in diameter made of clear acrylic with steel ends.  One end has a door.  You will be slid into the chamber on a rolling stretcher that sits on the gurney.  Once inside the chamber you will lie in comfort and be closely attended by one of the hyperbaric staff members outside the chamber.  You may choose to rest, watch television or a videotaped movie, or sleep.  You will receive one of these treatments every day until you can keep your blood oxygen levels above 93% for two consecutive days.  It is expected that this will be 3-8 HBOTs.

Alternatively, a big chamber may be used that has a door and is eight feet in diameter.  If this chamber is used you will walk, be rolled into the chamber in a wheelchair or on a stretcher, and a clear plastic hood will be placed over your head from which you will breathe pure oxygen once the chamber is compressed..

If you have been discharged from the hospital by the end of the study (3 weeks after the starting point) you will be required to visit the hospital at the 3 week time point to have the repeat testing described above.  The study investigators will call you to make this appointment.

A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by U.S. Law.  This web site will not include information that can identify you. At most, the web site will include a summary of the results. You can search this web site at any time.

The National Clinical Trials number for this study is NCT………….. 

6. Benefits to You:

If you agree to take part in this study, there may or may not be direct medical benefits to you if you receive HBOT.

The possible benefits of taking part in this study are an improvement in breathing and prevention of having to have a breathing tube put down your throat into your lungs and go on a breathing machine.

7. Risks to You:

While in the study, you are at risk for the following side effects.  You should discuss these with the researcher and/or your regular doctor.  There also may be other side effects that cannot be predicted.  Other drugs can be given to make side effects less serious and uncomfortable.  Many side effects go away shortly after the hyperbaric oxygen therapy is stopped, but in some cases side effects can be serious or long lasting or permanent. Investigators will take precautions to minimize risk.

Risks and side effects related to the procedures being studied include:

• Symptom questionnaire:

No known risks from these tests.

• History and physical exam by the Principal Investigator:

No known risks from the exam.

• Blood Draw:

Hematoma (blood clot under the skin; occurs frequently), infection at site of skin

puncture (rare), or clotting of vein at blood draw site (occasional).

• EKG

Removal of hair from the chest when electrode tabs are removed (frequent), allergic reaction to the adhesive in the electrode tabs (rare).

• Hyperbaric Oxygen Therapy:

Changes in pressure:  Anytime the atmospheric pressure is changed, all of the air spaces within the body must remain in balance with these changes.  If not, discomfort (barotraumas) will result.  You may experience this discomfort in your ears, sinus spaces, or teeth.  If you experience discomfort, you must notify the hyperbaric technician on the outside or inside of the chamber immediately so that corrective action can be implemented.

• Middle ear barotraumas: fluid or blood-tinged fluid accumulation behind the eardrum if you cannot equalize pressure in your ears (occurs in 2% of patients).
• Sinus barotrauma: fluid or blood-tinged fluid in the facial sinuses if you have congested sinuses (rare).
• Inner ear barotrauma: damage to the inner ear hearing and balance organs from inability to pressure equalize the middle ear space (rare).
• Dental barotrauma: air trapped under a dental filling (rare).
• Pulmonary barotrauma: If your lungs do not ventilate adequately during pressure changes, you may suffer release of air into tissues outside the lung airspaces. You may experience a leak of air into the chest (pneumothorax) or into the bloodstream (air embolism), causing a stroke, heart attack, or death, or into the soft tissues of the lungs, chest wall, or neck.  All of these are rare risks.  If it is determined by the investigators that you are at high risk for this complication you will be excluded from participation.

Oxygen Toxicity:  Oxygen toxicity to the lungs and the central nervous system can occur

during hyperbaric oxygen therapy.

• Pulmonary oxygen toxicity (without any symptoms) is seen in patients receiving typical doses of hyperbaric oxygen therapy for wound treatment which are higher than the dose used in this study. (rare)
• Central nervous system oxygen toxicity can occur as a grand mal seizure. It is a rare occurrence at doses higher than what is being used in this study. The low pressure featured in this study has not been reported to cause seizures in coronavirus patients.
• Nausea (rare).
• Numbness (rare).

Fire:  Increases in oxygen concentration and pressure increase the risk of fire.  The chamber has been specially designed to minimize this risk.  Also, by using only cotton clothing and bedding, and eliminating all other personal items that may produce a spark, this risk is further minimized. (Extremely rare.  One episode in 60 years in the United States).

Anxiety:  You can experience anxiety from feeling enclosed in the chamber. This is called confinement anxiety or claustrophobia.  It is unusual in the large see-through chambers at University Medical Center.  If you have known severe claustrophobia you will be excluded from the study.  If you experience anxiety in the chamber and the investigator finds it is due to claustrophobia you will be offered a short-acting sedative to use before going in the chamber for each treatment.  (Less than 2% of patients).

           Bronchospasm: tightening of the airways which is felt as shortness of breath.  This is a

rare side effect.

           Mild hypertension (rise in blood pressure): routinely occurs during HBOT but is

temporary.

Treatment would be medication administration or removal from the study.

Other Rare but Possible side effects of HBOT:

• Cardiac toxicity has been reported and is thought to be primarily due to increased resistance in arteries caused by excess oxygen in patients with heart failure or reduced squeezing ability of the heart. It is due to the mild rise in blood pressure described above. If you have congestive heart failure or a history of congestive heart failure you will be excluded from the study.  In addition, the dose of HBOT in this study is less than the dose reported to induce congestive heart failure.

For more information on the research to be performed, or any risks, benefits, or alternative treatments, you should ask your regular doctor or any of the researchers listed on the front page of the consent form.

8. Alternatives to Participation in the Study:

The alternative to participation in this study is to have continued oxygen by mask or not participate in this study.

9. Your Removal:

You will be in the study for approximately 3 weeks.  The researchers may stop you from taking part in this study if at any time it is believed to be in your best interest; if you do not follow the study procedures; if the study is stopped. You could be taken off the study if your health worsens; if another treatment option appears to be appropriate; or for any other cause which prevents your continuing in the study

10. Your Right to Refuse to Participate or Withdraw:

Participation is voluntary. You can stop participating at any time.  Refusal to participate will involve no penalty or loss of benefits to which you are otherwise entitled, and you may discontinue participation at any time without penalty or loss of benefits to which you are otherwise entitled. You may refuse to participate or withdraw from the study at any time without jeopardizing, in any way, your medical treatment at this institution in the present or future. Information already collected about you and sent to the sponsor will still be used. Tell the researcher if you are thinking about withdrawing from the study so that you may do so safely. If you decide not to continue participation in the study you should seek medical advice for alternatives. There are no known serious consequences, to our knowledge, of sudden withdrawal from the study. Should significant new findings take place during the course of the research that may relate to your willingness to continue participation that information will be provided to you.

11. Your Right to Privacy:

The results of the study may be released to the funding agency, the state of Louisiana.  Representatives of the state of Louisiana are authorized to review research records.  If the results of the study are published your privacy will be protected and you will not be identified in any way. Your personal information may be disclosed if required by law.

12. Release of Information:

Organizations that may inspect and/or copy your study-related medical records for quality assurance and data analysis include: the sponsor, the state of Louisiana, the LSUHSC-New Orleans Institutional Review Board, the University Medical Center Research Review Committee, the Food and Drug Administration (FDA), and the doctors listed on page 1 of this consent form and their staff. While every effort will be made to maintain your privacy, absolute confidentiality cannot be guaranteed. Records will be kept private to the extent allowed by law.

13. Financial Information:

The costs of all hyperbaric oxygen therapy, study visits, and study procedures will be covered by the state of Louisiana.  The cost of any study-related and unforeseen complications will be your responsibility. Participation in this study will not result in any extra charges above and beyond those routinely incurred by patients with similar conditions.

The investigators will arrange for medical care for any emergency medical problem that you may experience as a direct result of your participation in this research. This will be provided on a fee-for-service basis. There are no funds available to pay for any study related or unrelated, foreseen or unforeseen disability that results from participation in this study, or occurs while participating in this study, or for damages such as lost wages, etc.

14. Signatures:

The study has been discussed with me and all my questions have been answered. Additional questions regarding the study should be directed to the investigators listed on page 1 of this consent form. If I have questions about subject’s rights, or want to discuss problems, concerns or questions, or obtain information or offer input, I can contact the Chancellor of the LSU Health Sciences Center New Orleans at (504) 568-4801. I agree with the terms above, acknowledge I have been given a copy of the consent form, and agree to participate in this study. I have not waived any of my legal rights by signing this consent form.

15. Conflict of Interest: The principal investigator, Dr. Paul G. Harch, has a consulting company that provides hyperbaric treatment services and renders expert opinions in court.

 

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Signature of Subject                                                                                                   Date

 

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Signature of Legally Authorized Representative                   Date

 

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Consent Administered by                                                                                        Date

 

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You have indicated to me that you are unable to read. I certify that I have read this consent form to you and explained that by completing the signature line above you have agreed to take part.

 

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Signature of Witness                                                                                                  Date

 

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