Introduction

Welcome to another post on plausible, off-label uses for hyperbaric oxygen therapy (HBOT). We have previously discussed the rationale for using hyperbaric oxygen therapy (HBOT) in an “off-label” indication (see "Investigational HBOT Indications"). We suggested that there must be a scientific rationale, physiology that made sense for use of HBOT, and some sort of verified outcome (case report, case series, controlled clinical trial, etc.). 

Today, we are going to discuss the use of HBOT for patients who have an ischemia/reperfusion injury (IRI) to the myocardium. While HBOT has been studied after acute myocardial infarction (AMI) in conjunction with stenting/angioplasty and/or alteplase (tPA) administration, our primary focus will primarily be on patients who have a planned instrumentation of the coronary arteries or coronary artery bypass grafting (CABG) surgery. 

Unfortunately for you, the reader, this discussion needs to spend some time in the world of cellular and molecular biology. We will briefly discuss the effects of HBOT at the cellular and gene level within the body (primarily vascular endothelial cells). Of necessity, the brevity of this discussion will leave a number of gaps for you to fill in. However, I will provide you with a list of reference papers to read. 

Some of you took a course in cellular/molecular biology in college. I certainly did, because that was a required upper-level course for biology majors. I kept the textbook for a number of years. Whenever I would read from that textbook, I would fall soundly asleep. Now, I'm looking at a stack of cellular/molecular biology articles dealing with the heart and HBOT. After all these years, and many gray hairs ... <wait for it> ... <wait for it> ... I still fall soundly asleep.

So, I'm going to cut to the chase and give you my opinion first!

If I were scheduled to have an angioplasty/stenting or a CABG procedure, I would DEFINITELY approach the hyperbaric physician and cardiologist about having a standard wound healing HBOT table (2.4 ATA for 90 minutes of O2 breathing with standard air breaks) one time immediately (within 4 hours) before the procedure.

There are several randomized controlled studies and multiple animal models that suggest this simple, one-time, treatment reduces risk of death, preserves more myocardial tissue, reduces intensive care unit (ICU) stay, reduces overall blood loss, preserves ejection fraction, and reduces restenosis rates. While we will not discuss it, there are also hints that this one-time treatment reduces the post-cardiopulmonary bypass confusion ("pump brain") that is thought to be caused by lipid peroxidation.

Now for the details. Hold onto your hats, because we are going to move through several areas of research. I will hit only the high points and try not to overwhelm you with minutiae or too many acronyms. Fortunately, or unfortunately, you are going to see how my mind works in devious ways in order to make sense of this literature.

What does scientific literature say regarding HBOT for cardiac surgery preconditioning? 

The Paper Trail

I performed a PUBMED search using the terms "hyperbaric oxygen" cardiac preconditioning. The results netted 17 papers, of which 11 were pertinent to this topic. As a result of searching the references within these papers, two more papers were found of pertinent interest: the HOT-PI and the HOT MI trials. The Rubicon Foundation repository of hyperbaric oxygen studies was also queried. There were 2 papers that were duplicated in the PUBMED search and one abstract presented at the UHMS Annual Scientific Meeting in 2007. Of interest, this abstract was written by the same research group who published several studies found in the PUBMED collection and provides more detail. 

How does HBOT work in the endothelial cells? Why should we even consider this? What is the HBOT mechanism of action here? 

Great questions!  We will discuss the papers in chronological order. Some of the early HBOT work in this area began in 1997...

1. Hyperbaric oxygen and thrombolysis in myocardial infarction: the "HOT MI" pilot study (1997)

The first pilot study (HOT MI) was a randomized clinical trial composed of 82 patients and 16 were excluded for hemodynamic instability. Sixty-six were analyzed with 34 in the tissue plasminogen activator (rTPA) only group and 32 in the HBOT plus rTPA group. These patients had an acute myocardial infarction (AMI) and all were recipients of rTPA. There was no sham treatment with HBOT in this trial. The end result of the study was that the HBOT group had lower creatine kinase (CK) levels at 12 and 24 hours. There were 2 deaths in the control group and none in the HBOT group (not significantly different). There was a trend to higher ejection fraction in the HBOT group (not significant).[1]  It would take nearly 5 years for other research groups to see this trial and begin to look at mechanisms that support HBOT in the presence of IRI of the heart. But, they did. 

2. Inhibition of restenosis by hyperbaric oxygen: a novel indication for an old modality (2002)

A 2002 randomized controlled clinical trial of patients with either unstable angina or AMI undergoing percutaneous coronary intervention (PCI) would be the next stepping stone for HBOT and cardiac preconditioning.[2] The primary endpoints of this study were death, repeat MI, emergent CABG, and target lesion restenosis at 8 months. To qualify for this study, the patients must either have unstable angina or an AMI. Fifty-one patients were enrolled with 24 in the HBOT arm and 27 in the control arm. There was no sham treatment to the control arm. The HBOT arm patients received 2 HBOT treatments consisting of 2.0 ATA for 90 minutes of oxygen breathing and no recorded air breaks. The first treatment was either 2 hours before or immediately after PCI with a second treatment within 18 hours after the first treatment. 

Results were positive for HBOT preconditioning. In follow-up, 8 months from the cardiac incident and intervention, there was 1 repeat MI in the HBOT group and 4 in the control group (not statistically significant). There were 5 restenosis lesions in the control group and none in the HBOT group (p= 0.026). No emergent CABG in either group. Two deaths in the control group during the 8 month followup period (not statistically significant). Finally, recurrence of chronic angina developed in 6 control patients and no HBOT patients (p=0.014). While there could be some bias caused by no sham HBOT control, this is unlikely to be a problem because the final review was 8 months following the intervention.

These authors did not measure any biochemical or other cellular markers. However, they do theorize that heat shock protein (HSP) may ameliorate oxidative stress and that lipid peroxidation was decreased. Much of the bench science of HBOT and IRI has yet to be discovered and fully tested, but this RCT again shows the positive effect of preconditioning the heart for interventional procedures. Another positive clinical study. 

3. Hyperbaric oxygen: a new drug in myocardial revascularization and protection? (2006)

New technologies for mapping gene responses at cellular levels, cellular chaperones, and biochemical markers have emerged by 2006. These could only be imagined and hinted at previously. Yogaratnam (an important researcher in this sub-specialty interest) and colleagues first attempt to explain the biochemical and cellular response mechanisms for HBOT and myocardial function.[3] In addition, they hint that there are protective oxidative functions for HBOT, reactive oxygen species (ROS), and other oxidative mechanisms.[3]

The core mechanism for HBOT function is amelioration of the IRI. The primary fact is that an ischemic injury with resultant reperfusion sets off an inflammatory cascade at which white blood cells are called to the area of injury (the function of cellular chaperones), clog the arterioles/capillaries, degranulate, and set off a self-propagating inflammatory reaction, thus resulting in significant programmed cell death (apoptosis). HBOT can reduce the injury and preserve tissue through reducing the ability of the WBC to attach and degranulate in the vascular endothelium. (I'm going to leave this reference to the reader, but perform a PUBMED search on the terms "Thom S" and white blood cell binding nylon columns.) Hint: Think about Velcro. The vascular walls are the "loops" and the WBCs are the "hooks" in Velcro. When the hooks attach to the loops, then degranulation and injury occurs. Obviously, HBOT applied before or at the exact time of injury would give the best outcome (by reducing/preventing the loops to become active). But, there is a small time window (an hour or so) after injury whereby HBOT reduces the amount of myocardial injury. 

Still awake? Read on ... 

There are also hints that myocardial ischemia and stress activate several heat shock proteins (HSP). These are thought to have protective roles for myocardial tissues. The research question (as of 2006) is, "Does HBOT induce HSP activation?" And, the answer is a distinct "Maybe." Technology in 2006 still limits finding a definitive answer. But, technology will catch up ... you'll see. 

Still with the Yogaratnam (2006) paper, we find that a number of tissues (skeletal muscle, heart muscle, small bowel, and liver) also respond positively to HBOT prior to occlusion and reperfusion injury.[3] The tissue exposed to HBOT prior to the insult maintained homeostasis and ATP levels vs. control. In addition, this paper discusses HBOT and ROS. While we have thought about ROS after HBOT as a negative, this is not shown in the literature. In fact, the opposite has been noted.

HBOT-generated ROS are thought to decrease neutrophil adhesion by one (or more) of the following mechanisms:    

1. HBOT inhibits some of the internal pathways, such as inhibiting cGMP that leads to altering CD11a/18 neutrophils and then inhibits intercellular adhesion molecule-1 (ICAM-1)
2. A specific ROS, superoxide, may inhibit neutrophil adhesion through a Nitric Oxide (NO) pathway
3. ROS, superoxide, and hydrogen peroxide may directly act on ICAM-1and modulate endothelial Nitrix Oxide Synthase (eNOS)

The Yogaratnam (2006) paper demonstrates multiple pathways of activity for HBOT and preservation of myocardial function through a thorough evaluation of the extant literature of the day. Their conclusion is that there are many examples of research that support HBOT in revascularization use, however those theories could not be demonstrated in the laboratory. I suspect that was simply due to lack of advanced techniques in exposing small proteins and pathways that measure in the kilo-Dalton range (very, very small proteins). The authors conclude that the use of HBOT in organ preconditioning is a fascinating theory in its infancy and bears exploring fully.

4. Pharmacological preconditioning with hyperbaric oxygen: can this therapy attenuate myocardial ischemic reperfusion injury and induce myocardial protection via nitric oxide? (2008)

The second study by this group posits that IRI is inevitable during CABG. In this paper, they focus heavily on the research that shows HBOT to stimulate NO.[4] This NO production may be responsible for a measurable myocardial protective effect. This paper again provides significant background material that prepares the team for human clinical research.

5. Hyperbaric oxygen preconditioning improves myocardial function, reduces length of intensive care stay, and limits complications post coronary artery bypass graft surgery (2010)

In 2010, the same team detailed results from a randomized, controlled, blinded clinical trial of using HBOT exposure prior to CABG.[5] From January 2005 to July 2006, there were 774 consecutive patients presenting for first-time elective CABG. Of those patients, 81 matched the study criteria and were randomized to control (no HBOT prior) or the HBOT group (2.4 ATA for 60 minutes of O2 breathing with one 5-minute air break). This treatment was completed approximately 4 hours prior to CABG. All other treating physicians were blinded as to study patients vs. control. The control group (unfortunately) were not treated in a sham manner, hence a small tick-off to interpretation bias potential since the researchers did know which patients received preconditioning. Note that the researchers had no input in any part of the patient surgery, postoperative care, or overall management. This is a small detriment to an otherwise excellent study!

The purpose of the RCT was to demonstrate that the effect of HBOT preconditioning was capable of improving left ventricular stroke work (LVSW). There was a clear increase in stroke volume (SV) and LVSW in the HBOT preconditioned patients. And, as icing on the cake, the HBOT preconditioned group had a number of secondary endpoints significantly different from the control group. The HBOT group had a smaller rise in Troponin T (evidence of lesser myocardial stunning), an 18% drop in ICU length of stay (LOS), nearly 12% less blood loss, lower blood transfusion requirements, lower need for inotrope support, lower pulmonary complications (less intubated time), and lower incidence of wound infections.  

From a fiscal standpoint, this group presented an abstract at the 2007 UHMS Annual Scientific Meeting. At that time, the study discussed above had been closed approximately one year and their data analysis was still ongoing. However, they showed a $570/patient savings in ICU costs to the hospital. Over the timeframe of this study (for 40 patients), the savings was nearly $20,000 (2007 USD). 

At this point, I'm taking a slight jog in the course of literature review. It's about this time (2010) where laboratory science catches up and can demonstrate the effects of HBOT on tiny subcellular and biochemical markers. In particular, there are two studies by Godman, et. al. that deserve some attention.

6. Hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cells (2010)

The first study is a genome-wide microarray analysis of gene expression on human microvascular endothelial cells exposed to HBOT under the same conditions as human patients.[6] The controls received 100% O2 and 1 ATA for the same time that the other cell culture received HBOT (2.4 ATA for 60 minutes O2 exposure). 

Just for your information, this paper still puts me to sleep when I read it ... however, it is full of undeniable gene stimulation or inhibition, up-regulating 6 cellular chaperones, and other mind-boggling details. As a result of one HBOT exposure, there were 8,101 genes that were significantly regulated (up or down) in the HBOT group. Nearly 4,000 of these genes were still up/down regulated at measurements 24 hours after HBOT exposure. The authors were particularly interested in the usefulness of HBOT as a preconditioning stress in order to protect cells and gene expression. Note to reader ... the following should sound familiar ... The chaperone genes are related to HSP. A number of these genes were still active 24 hours after HBOT exposure. A secondary endpoint of this research was that the microvascular cell culture  exposed to HBOT immediately started to form vascular tubules vs. no differentiating growth in the control group.

Interesting, huh? Aren't you glad to be reading the condensed version?

7. Hyperbaric oxygen treatment induces antioxidant gene expression (2010)

Godman et al published a second paper in 2010 looking at effects of HBOT and antioxidant gene expression.[7] They found an up-regulation of antioxidant and cytoprotective effects that resisted otherwise lethal oxidative stress. While I disagree with their conclusion that HBOT may become an anti-aging wonder, the basic science in the paper makes it worthwhile reading. 

8. Research report: the effects of hyperbaric oxygen preconditioning on myocardial biomarkers of cardioprotection in patients having coronary artery bypass graft surgery (2011)

Yogaratnam returns (2011) with a secondary review of their earlier data, specifically myocardial biomarkers suggesting that HBOT preconditioning induced cardioprotection following IRI.[8] Good stuff. By now, you know this research group's methods and general results. I will simply report that they analyzed results of eNOS and HSP72 between the HBOT and control populations. In the HBOT group, both eNOS and HSP72 were increased. 

Well, where are we in the grand scheme of explaining the research?

I think I've covered the bench research down to the gene level in adequate detail. All of the bench research focuses on components that show HBOT to be cytoprotective. I've discussed three randomized controlled trials with significant statistical power. These studies demonstrate HBOT effectiveness in myocardial survival and lowering serum markers showing myocardial injury patterns. What more do we need before we have enough evidence to say that this indication is plausible, even if it is off-label? 

Hang on tight. More papers and more trials yet to report.

Oh, have I said it? Nope, not one negative trial up to this point. Let's see how that holds up.

9. Anti-apoptotic effect of hyperbaric oxygen preconditioning on a rat model of myocardial infarction (2011)

A 2011 paper shows a research protocol using rat myocardium and permanent ischemia.[9] They demonstrated that myocardial infarct size was significantly smaller in the HBOT preconditioned rats. They also showed apoptotic pathways were suppressed, resulting in preserved myocardium. They discussed a biphasic tolerance pathway against subsequent insults. The first lasted 2 - 3 hours after HBOT exposure, then a second, delayed, phase from 24 - 72 hours. 

10. Preconditioning with repeated hyperbaric oxygen induces myocardial and cerebral protection in patients undergoing coronary artery bypass graft surgery: a prospective, randomized, controlled clinical trial (2011)

Another RCT was published in 2011 looking at cerebral and myocardial protection in patients undergoing CABG.[10] This is a randomized, controlled, single-blinded study involving 25 control and 24 HBOT candidates. The preconditioning period was over 5 days prior to CABG. HBOT treatments were at 2.0 ATA with 70 minutes of oxygen breathing in two periods separated by a 5 minute air break. The results of the study mirror those of the Yogaratnam study with similar reduction in ICU stay, reduced ventilatory ICU support, and reduced blood loss. The studies differed in hemodynamic values, and this study found no difference with PVR, SW, and LVSW after surgery. The authors do admit that sample size in this study is small and they may not have the statistical power to notice small differences between groups. They demonstrated a reduced biomarker burden in the HBOT group for neurologic and cardiac injury. They theorize that the HBOT effects had to do with endogenous antioxidant activity being more beneficial for patients in the active HBOT group.

An entire Undersea and Hyperbaric Medicine journal (2015, Volume 2) issue is devoted to preconditioning and HBOT. The editorial for this issue laments the fact that HBOT is not routinely used prior to cardiac insult in the USA. The treatment is simple, with few negative side effects, and relatively inexpensive. 

11. Preconditioning with hyperbaric oxygen and calcium and potassium channel modulators in the rat heart (2019)

We conclude with a Serbian study just published in 2019.[11] This is a bench laboratory study of rat myocardium. There were 4 study groups and all study groups received HBOT. 1) HBOT only, 2) HBOT + Verapamil, 3) HBOT + amlodipine, and 4) HBOT + nicorandil. The study involved a 20 minute global ischemia of the heart and a 30 minute reperfusion period before the animal was sacrificed. After reporting results, this study shows that all four groups were benefited from preconditioning with HBOT. In addition, the amlodipine group better preserved functional and structural properties of the heart after ischemia. 

Summarizing selected clinical articles

Table 1. Summary of articles selected for this review. Only clinical articles are shown, experimental and review articles are not included in the table.

So, what is the conclusion on HBOT for cardiac surgery preconditioning? 

I told you at the beginning of the blog where my sympathies lie for this intervention. Nothing has changed. Every study (animal and human) demonstrated the cardioprotective effect of HBOT preconditioning prior to PCI or to CABG surgery when cardiopulmonary bypass was used. To be fair, there was one paper with several patients in the CABG group who had off-bypass surgical procedures. Cardioprotection from HBOT was less evident in that subset. 

I think that there are enough studies with enough positive evidence of effect that cardioprotection with HBOT should be a UHMS-approved indication. That decision has not happened yet, although it will likely be visited in the near future. 

Related topics

In case you missed, see the introduction to this blog series in "Investigational HBOT Indications".

This blog series focuses on 3 conditions that are off-label and have plausible literature evidence for improvement after HBOT:

• Selected causes of infertility (see "Investigational HBOT Indications - Infertility")
• Preconditioning for cardiac surgery (this article)
• Drug-resistant or non-responsive inflammatory bowel disease (IBD) (see "Investigational HBOT Indications - Inflammatory Bowel Disease")

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