Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.

BACKGROUND: Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. METHODS: HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066. FINDINGS: Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related. INTERPRETATION: We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed. FUNDING: Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.

Commentary: Hyperbaric oxygen treatment for wounds - evidence and the Sword of Damocles.

Increased access to any treatment sensibly follows the clinical and cost benefit being established. For many treatments this requires multiple, high-quality clinical trials and supporting cost analysis. Cost analysis may be applied to a single treatment or used to compare two or more treatments. Clinical efficacy and cost benefit are best scrutinised and validated by publication in the peer-reviewed literature. True peer review is most effectively achieved 'after publication' by the wider scientific community, i.e., the journal readers. However, initially an editor, usually advised by referees, is asked to make a judgment on a paper's suitability for publication. It follows that medical journals are in a position of power and responsibility. Researchers and editors know publications are currency; effectively they are the equivalent of academic bitcoins. Regarding the paper in this issue by Santema et al., the same authors, in designing a prospective randomised controlled trial (RCT) of the role of hyperbaric oxygen treatment (HBOT) in diabetic wounds, included the name "Damocles" in that trial's title. Readers will perhaps appreciate from my comments below as a referee for the Santema et al. paper, that behind the scenes "the Sword of Damocles" (an allusion to the imminent and ever-present peril faced by those in positions of power) hangs over researchers, treating physician, journal editors and referees alike. Whilst positive about its content, upon reflection, my concern was the anticipated reception of this paper by the journal readership. This is, of course, a matter for the Editor; however, herewith is my reasoning. Further to the body of published work by Bennett et al., and others that has focused attention on the lack of good quality evidence for the use of HBOT for most indications, I think this regrettable state of affairs is now both known and accepted by mainstream healthcare purchasers and providers. I speculate that all these bodies already acknowledge and accept this manuscript's conclusions. Accordingly, this situation detracts from an opportunity for it to stand out from existing publications. The authors are addressing this known lack of evidence with their planned DAMOCLES multicentre RCT. Others in mainstream medicine in a position to design and implement clinical research (to whom the paper is presumably aimed) will also be acutely aware of the shortcomings in the available evidence. Accepting the sample size required for economic evaluation may be greater than that required to establish only clinical effectiveness, it remains the case it would be all but impossible to secure research funding for a trial in the absence of such analysis. This means the conclusions of the present paper are already widely acknowledged. If one accepts the above, it follows that its impact on the journal readership will be relatively light. The journal's review process asks referees to consider if the manuscript is "within the journal's scope", and about "the importance (clinical or otherwise) of the work". I think this paper is within the scope and is important. However, in the light of the known and accepted need for further research that includes an economic evaluation, I find myself questioning the 'importance' and 'utility' to the journal readership of the information provided.

Management of severe spinal cord injury following hyperbaric exposure.

There is an increasing body of evidence that drainage of lumbar cerebrospinal fluid (CSF) improves functional neurological outcome after reperfusion injury to the spinal cord that occasionally follows aortic reconstructive surgery. This beneficial effect is considered owing to lowering of the CSF pressure thereby normalising spinal cord blood flow and reducing the 'secondary' cord injury caused by vascular congestion and cord swelling in the relatively confined spinal canal. Whilst lacking definitive proof, there are convincing randomised controlled trials (RCTs), cohort data and systematic reviews supporting this intervention. The therapeutic window for lumbar CSF drainage requires further elucidation; however, it appears to be days rather than hours post insult. We contend that the same benefit is likely to be achieved following other primary spinal cord injuries that cause cord swelling and elicit the 'secondary' injury. Traditionally the concept of CSF drainage has been considered more applicable to the brain as contained in a 'closed box' by lowering intracranial pressure (ICP) to improve cerebral perfusion pressure (CPP). The control of CPP is intended to limit 'secondary' brain injury and is a key concept of brain injury management. Using microdialysis in the spinal cords of trauma patients, it has been shown that intraspinal pressure (ISP) needs to be kept below 20 mmHg and spinal cord perfusion pressure (SCPP) above 70 mmHg to avoid biochemical evidence of secondary cord damage. Vasopressor have also been used in spinal cord injury to improve perfusion, however complications are common, typically cardiac in nature, and require very careful monitoring; the evidence supporting this approach is notably less convincing. Decompression illness (DCI) of the spinal cord is treated with recompression, hyperbaric oxygen, various medications designed to reduce the inflammatory response and fluid administration to normalise blood pressure and haematocrit. These management protocols are based largely on anecdote and transferred evidence from conventional cord trauma, as the low numbers and sporadic nature of DCI in divers makes RCTs nigh on impossible. Unfortunately even with best management, some patients are left with significant neurological deficit. The 'iceberg phenomenon', occurs when patients with DCI of the cord make a good neurological recovery but actually have profound cord damage as revealed in one case some four years later at post mortem and another example in a diver who developed late functional deterioration due to loss of neuronal reserve. This clinical evidence, together with animal study data, support the notion that even a modest preservation of spinal cord axons is associated with significant improvement in neurological outcome. In the light of the positive level two evidence in the vascular literature that CSF drainage limits 'secondary' injury thereby improving neurological outcome, we propose that centres with appropriate clinical experience consider using lumbar CSF drainage to normalise SCPP, as an adjunct to the conventional treatment of severe spinal cord DCI. Divers with severe spinal cord DCI are generally in the most productive years of their lives and, given the potentially devastating impact of this condition, should be given the benefit of any possible adjuvant treatment that may serve to improve long-term outcome.

The effect of acute hyperoxia in vivo on NF kappa B expression in human PBMC.

The mechanisms of hyperbaric oxygen (HBO) therapy have not been fully elucidated. It is presumed that breathing 100% oxygen at pressure generates free radicals and the cellular response to these may confer protection. A crucial signalling molecule, nuclear transcription factor kappa B (NFκB), translocates from the cytoplasm to the nucleus and activates a raft of pathways in response to various stimuli, and plays a role in inflammatory processes. This study focussed upon the expression of NFκB in isolated human peripheral blood mononuclear cells (PBMC) following HBO. Ten healthy male volunteers underwent a single HBO treatment, breathing 100% oxygen at a pressure of 2.8 ATA for 1 h. EDTA blood samples were taken pre-, post- and 4-h post-HBO. PBMC were isolated, nuclear extracts prepared and assayed using a NFkBp50 transcription factor ELISA. Mean NFκB expression of 0.27 (0.20-0.34, 95%CI) absorbance units (mg protein)(-1) was observed pre-HBO and this increased to 0.29 (0.20-0.38, 95%CI) immediately post-HBO. A significant increase in NFκB expression within PBMC was observed 4-h post-HBO, in comparison to pre-HBO (mean 0.38, 0.30-0.47, 95%CI, p = 0.027). This study demonstrates that HBO induces NFκB activation in human PBMC, which could be a crucial step in the mechanism of HBO treatment.

The effect of hyperbaric oxygen preconditioning on heat shock protein 72 expression following in vitro stress in human monocytes.

Hyperbaric oxygen (HBO) is thought to confer protection to cells via a cellular response to free radicals. This process may involve increased expression of heat shock proteins, in particular the highly inducible heat shock protein 72 (Hsp72). Healthy male volunteers (n = 16) were subjected to HBO for 1 h at 2.8 ATA. Inducible Hsp72 expression was measured by flow cytometry pre-, post- and 4 h-post HBO. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood via density centrifugation pre-, post- and 4 h post-HBO. PBMC were then subjected to an in vitro heat shock at 40°C or hypoxia at 37°C (5% O(2)) with a control at 37°C. Cells were then analysed for Hsp72 expression by flow cytometry. Monocytes showed no significant changes in Hsp72 expression following HBO. No detectable Hsp72 was seen in lymphocytes or neutrophils. Following in vitro hypoxic exposure, a significant increase in Hsp72 expression was observed in monocytes isolated immediately post- (p = 0.006) and 4 h post-HBO (p = 0.010) in comparison to control values. HBO does not induce Hsp72 expression in PBMC. The reported benefits of HBO in terms of pre-conditioning are not due to inducement of Hsp72 expression in circulating blood cells, but may involve an enhancement of the stress response.

Randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema after radiotherapy for cancer.

BACKGROUND: A non-randomised phase II study suggested a therapeutic effect of hyperbaric oxygen (HBO) therapy on arm lymphoedema following adjuvant radiotherapy for early breast cancer, justifying further investigation in a randomised trial. METHODS: Fifty-eight patients with ≥ 15% increase in arm volume after supraclavicular ± axillary radiotherapy (axillary surgery in 52/58 patients) were randomised in a 2:1 ratio to HBO (n=38) or to best standard care (n=20). The HBO group breathed 100% oxygen at 2.4 atmospheres absolute for 100 min on 30 occasions over 6 weeks. Primary endpoint was ipsilateral limb volume expressed as a percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK SF-36 Health Survey Questionnaire. FINDINGS: Of 53/58 (91.4%) patients with baseline assessments, 46 had 12-month assessments (86.8%). Median volume of ipsilateral limb (relative to contralateral) at baseline was 133.5% (IQR 126.0-152.3%) in the control group, and 135.5% (IQR 126.5-146.0%) in the treatment group. Twelve months after baseline the median (IQR) volume of the ipsilateral limb was 131.2% (IQR 122.7-151.5%) in the control group and 133.5% (IQR 122.3-144.9%) in the treatment group. Results for the secondary endpoints were similar between randomised groups. INTERPRETATION: No evidence has been found of a beneficial effect of HBO in the treatment of arm lymphoedema following primary surgery and adjuvant radiotherapy for early breast cancer.

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

OBJECTIVE: The objective of this study was to determine whether preconditioning coronary artery disease (CAD) patients with HBO(2) prior to first-time elective on-pump cardiopulmonary bypass (CPB) coronary artery bypass graft surgery (CABG) leads to improved myocardial left ventricular stroke work (LVSW) post CABG. The primary end point of this study was to demonstrate that preconditioning CAD patients with HBO(2) prior to on-pump CPB CABG leads to a statistically significant (P<.05) improvement in myocardial LVSW 24 h post CABG. METHODS: This randomised control study consisted of 81 (control group=40; HBO(2) group=41) patients who had CABG using CPB. Only the HBO(2) group received HBO(2) preconditioning for two 30-min intervals separated 5 min apart. HBO(2) treatment consisted of 100% oxygen at 2.4 ATA. Pulmonary artery catheters were used to obtain perioperative hemodynamic measurements. All routine perioperative clinical outcomes were recorded. Venous blood was taken pre HBO(2), post HBO(2) (HBO(2) group only), and during the perioperative period for analysis of troponin T. RESULTS: Prior to CPB, the HBO(2) group had significantly lower pulmonary vascular resistance (P=.03). Post CPB, the HBO(2) group had increased stroke volume (P=.01) and LVSW (P=.005). Following CABG, there was a smaller rise in troponin T in HBO(2) group suggesting that HBO(2) preconditioning prior to CABG leads to less postoperative myocardial injury. Post CABG, patients in the HBO(2) group had an 18% (P=.05) reduction in length of stay in the intensive care unit (ICU). Intraoperatively, the HBO(2) group had a 57% reduction in intraoperative blood loss (P=.02). Postoperatively, the HBO(2) group had a reduction in blood loss (11.6%), blood transfusion (34%), low cardiac output syndrome (10.4%), inotrope use (8%), atrial fibrillation (11%), pulmonary complications (12.7%), and wound infections (7.6%). Patients in the HBO(2) group saved US$116.49 per ICU hour. CONCLUSION: This study met its primary end point and demonstrated that preconditioning CAD patients with HBO(2) prior to on-pump CPB CABG was capable of improving LVSW. Additionally, this study also showed that HBO(2) preconditioning prior to CABG reduced myocardial injury, intraoperative blood loss, ICU length of stay, postoperative complications, and saved on cost, post CABG.

Endothelial function and stress response after simulated dives to 18 msw breathing air or oxygen.

INTRODUCTION: Decompression sickness is caused by gas bubbles released upon decompression. These bubbles have the potential to occlude blood vessels and damage the vascular endothelium. The aim of this study was to quantify damage to the vascular endothelium resulting from decompression by measuring endothelial microparticles (MP) and endothelial function. METHODS: Five healthy male volunteers undertook a simulated (hyperbaric chamber) air dive and 1 wk later a second dive breathing 100% oxygen at 283 kPa (18 msw) for 60 min bottom time, decompressed with 5-min stops at 161 kPa (6 msw) and 131 kPa (3 msw). Endothelial function was tested pre- and postdive by reactive hyperemia peripheral artery tonometry (RH-PAT) and CD105 (Endoglin) positive MP were quantified by flow cytometry. Plasma E- and P-selectin, interleukin-6, and serum cortisol were also quantified. RESULTS: RH-PAT showed a significantly decreased endothelial function post-decompression after breathing air when compared to oxygen (-0.33 +/- 0.27 vs. +0.18 +/- 0.14). CD105 MP pre- and postdive showed no change on the oxygen dive (460 +/- 370 to 360 +/- 163), however, they increased after breathing air (440 +/- 70 to 1306 +/- 359). There was no change in expression of CD105 on MP. Furthermore no changes were observed in plasma E- or P-selectin, IL-6, or serum cortisol. CONCLUSION: From the data, at least in the time frame involved, there appears to be no detectable physiological/stress response to decompression, rather decompression from breathing air probably caused mechanical damage to the endothelium, resulting in both MP release and a reduction in endothelial function.

Acute antioxidant pre-treatment attenuates endothelial microparticle release after decompression.

PURPOSE: The hyperbaric and hyperoxic effects of a dive have been demonstrated to elicit changes in oxidative stress, endothelial function and microparticle (MP) release. Endothelial MP, which are small membrane vesicles shed from the endothelium, have been suggested as a valid in vivo marker of endothelial function. Furthermore, recent research has shown an increase in CD105 MP post-dive to be associated with a decline in endothelial function. The aim of this study was to ascertain whether antioxidant (AOX) pre-treatment can attenuate increased CD105 MP release post-dive. METHODS: Five healthy, male, pressure-naive subjects completed two simulated dives (control and intervention) breathing compressed air to a depth of 18 metres' sea water for 80 min. For the intervention dive, all subjects received a commercially available AOX pill containing vitamins C and E, selenium and beta-carotene 2 h pre-dive. CD105 MP, total antioxidant capacity (TAC) and thiobarbituric reactive substances assay (TBARS) were determined pre-dive, at depth, immediately and 4 h post-dive. RESULTS: In the control dive, there was a significant increase in CD105 MP immediately post-dive when compared with at depth (P < 0.001) and pre-dive (P = 0.039) values. Antioxidant pre-treatment significantly attenuated this release of CD105 MP post-decompression (P = 0.002). There were no significant changes in TBARS or TAC. CONCLUSION: These results may provide evidence of the potential use of AOX pre-treatment as an effective endothelial pre-conditioner for divers.

Gas bubbles may not be the underlying cause of decompression illness - The at-depth endothelial dysfunction hypothesis.

Gas formed in tissues and the circulating blood due to decompression is thought to be a significant factor in the progression of decompression illness (DCI). DCI is a potential problem for a growing population of professional and recreational divers. We hypothesise that these gas bubbles are not the causative agent in progression of DCI, rather an exacerbating factor. Endothelial dysfunction caused by a temporary loss of haemostasis due to increased total oxidant status is postulated to be the cause in this at-depth endothelial dysfunction hypothesis. Breathing oxygen at any pressure increases the oxidant status in the circulation causing vasoconstriction; this increase can be prevented by antioxidants, such as Vitamin C, maintaining haemostasis and preventing activation of endothelium, leukocyte recruitment and subsequent localised inflammation. Bubbles have the potential to exacerbate the situation on decompression by damaging the vascular endothelium either through ischemia/reperfusion, physical contact with the endothelium or by an increase in shear stress. Furthermore, this damage may manifest itself in the release of endothelial membrane fragments (microparticles).

Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects.

An increased risk of death or severe injury due to late-morning thrombotic events is well established. Tissue factor (TF) is the initiator of the coagulation cascade, and endothelial stresses, coupled with production of pro-coagulant microparticles (MP) are also important factors in loss of haemostasis. TF and vascular cell adhesion molecule-1 (VCAM-1) -positive cell microparticles were assessed periodically over a 24-hour (h) period in healthy human subjects to ascertain if they followed a circadian rhythm. Eleven healthy male subjects were assessed in a temperature-controlled environment with dietary intake consistent between subjects. Blood samples were taken every 4 h by venipuncture, and TF and VCAM-1 positive microparticles were quantified by flow cytometry. A significant circadian rhythm was observed in VCAM-1 MP (p=or<0.0001), and a trend was shown, although not statistically significant (p=0.065) in TF microparticles. A peak was observed at 9 a.m. for VCAM-1 positive MP, followed by a decrease and subsequent peak at 9 p.m. and a minimum at 5 a.m. TF-positive MP followed a strikingly similar trend in both variation and absolute numbers with a delay. A circadian rhythm was observed in VCAM-1 and less so TF-positive MP. This has significant implications in terms of the well known increased risk of cardiovascular thrombotic events matching this data. To our knowledge this is the first such report of quantified measurements of these MP over a 24-h period and the only measurement of a 24-h variation of in-vivo blood-borne TF.

The consequences of misinterpreting dive computers: three case studies.

Three cases are presented where there is a direct link between how the divers used their dive computers and the eventual requirement for their therapeutic recompression. The first case involves a diver with a previous history of decompression incidents making adjustments to their dive computer without understanding the outcomes of those alterations. The second case involves two divers running out of air and surfacing having missed significant amounts of decompression, caused by the dive computer not reducing their decompression obligation in actual time. This effect and performance differences between three models of computers were demonstrated in subsequent compression chamber trials reported here. The final case involves a diver who completed their dive within the indicated limits of their dive computer but subsequently developed serious neurological decompression sickness that left severe permanent residua. Compression chamber trials suggested that a combination of poor measurement accuracy and outdated decompression management in the computer used could have contributed to the diver's eventual poor outcome.

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

Ischemic reperfusion injury (IRI) is an inevitable part cardiac surgery such as coronary artery bypass graft (CABG). While ischemic hypoxia and the ensuing normoxic or hyperoxic reperfusion are critical to the initiation and propagation of IRI, conditioning myocardial cells to an oxidative stress prior to IRI may limit the consequences of this injury. Hyperbaric oxygen (HBO2) is a modality of treatment that is known to generate an oxidative stress. Studies have shown that treatment with HBO2 postischemia and reperfusion is useful in ameliorating myocardial IRI. Moreover, preconditioning the myocardium with HBO2 before reperfusion has demonstrated a myocardial protective effect by limiting the infarct size post ischemia and reperfusion. Current evidence suggests that HBO2 preconditioning may partly attenuate IRI by stimulating the endogenous production of nitric oxide (NO). As NO has the capacity to reduce neutrophil sequestration, adhesion and associated injury, and improve vascular flow, HBO2 preconditioning induced NO may play a role in providing myocardial protection during interventions that involve an inevitable episode of IRI. This current opinion review article attempts to suggest that HBO2 may be used to pharmacologically precondition and protect the myocardium from the effects of IRI that is known to occur during cardiac surgery.

Cold injury to a diver's hand after a 90-min dive in 6 degrees C water.

We present here a case of non-freezing cold injury (NFCI) in a sport scuba diver. There are similarities between the presenting symptoms of NFCI and decompression sickness, e.g., pain and/or altered sensation in an extremity, often reported as numbness. In both conditions patients have been known to describe their lower limbs or feet as feeling woolly. Both conditions are the result of environmental exposure. Additionally, there are no good (high sensitivity and specificity) diagnostic tests for either condition. Diagnosis is made based on patient history, clinical presentation, and examination. NFCI is most frequently seen in military personnel, explorers, and the homeless. When affecting the feet of soldiers it is often referred to as "trench foot." Historically, NFCI has been and continues to be of critical importance in infantry warfare in cold and wet environments. A high priority should be given to prevention of NFCI during military operational planning. With the advent of so-called "technical diving" characterized by going deeper for longer (often in cold water) and adventure tourism, this extremely painful condition is likely to increase in prevalence. NFCI is treated symptomatically.

Can hyperbaric oxygen be used as adjunctive heart failure therapy through the induction of endogenous heat shock proteins?

Heart failure (HF) is a chronic condition that is expected to increase in incidence along with increased life expectancy and an aging population. As the incidence of HF increases, the cost to national healthcare budgets is expected to run into the billions. The costs of lost productivity and increased social reliance on state support must also be considered. Recently, acute myocardial infarction (AMI) has come to be seen as the major contributing factor to HF. Although thrombolysis may restore coronary perfusion after an AMI, it may also introduce ischemic reperfusion injury (IRI). In an attempt to ameliorate sustained protein damage caused by IRI, endogenous chaperone proteins known as heat shock proteins (HSPs) are induced as a consequence of the stress of IRI. Recently, hyperbaric oxygen has been shown to induce the production of HSPs in noncardiac tissue, with a resultant protective effect. This current opinion review article suggests a possible role for hyperbaric oxygen, as a technologically modern drug, in augmenting the induction of endogenous HSPs to repair and improve the function of failing hearts that have been damaged by AMI and IRI. In addition, this simple, safe, noninvasive drug may prove useful in easing the economic burden of HF on already overextended health resources.

Hyperbaric oxygen: a novel technology for modulating myocardial schemia-reperfusion via a single drug.

Over the years, the anecdotal medical use of oxygen has demonstrated, in a non-evidence-based manner, that it may have wide-ranging clinical consequences. Although oxygen is a critical substrate in the alleviation of hypoxia, anoxia, and ischemia, paradoxically, it also functions as a deleterious metabolite during the reperfusion of previously ischemic tissues. In adding to this controversy, a spate of new pioneering work has identified hyperoxygenation (hyperoxia) and its metabolites as solely and purposefully demonstrating cellular and clinical benefit,particularly in the field of ischemic reperfusion injury (IRI). Furthermore, the beneficial effects of oxygen have been technologically augmented by administration at doses above atmospheric pressure and at higher concentrations. The novel technology that involves oxygen treatment at supra-atmospheric pressures in high concentrations is known as hyperbaric oxygen (HBO). Although the concept of hyperbaric oxygen has been around since the mid 20th century, it is only during the past decade or so that its therapeutic potential as a new technology-based drug has been exploited for the purposes of cellular tolerance and protection. HBO has recently been shown to be a useful adjunct in several models of IRI, including myocardial infarction. How it does this remains to be elucidated. This article attempts to bring into the spotlight some pertinent developments regarding HBO and myocardial IRI, while simultaneously stimulating intellect, thought, and discussion as to whether this novel technology--HBO--which consists of only a singular drug--oxygen--is a therapy that warrants further laboratory and clinical investigation as a therapeutic modality that may be safe and cost-effective, without producing significant adverse effects.

Hyperbaric oxygen: a new drug in myocardial revascularization and protection?

Ischemia-reperfusion injury (IRI) occurs following coronary artery revascularization. Reactive oxygen species (ROS) were initially thought to play a role in the pathogenesis of this injury. However, the evidence for this is inconclusive. Recent studies involving ischemic preconditioning have identified ROS as potential mediators for the cardioprotective effects observed following this technique. Furthermore, cardiac studies involving IRI and the use of hyperbaric oxygen (HBO) have demonstrated the ability of HBO to induce cardioprotection and to attenuate IRI. This review suggests the possible role for HBO as a new drug in the arena of myocardial revascularization and cellular protection. While there is mounting clinical evidence for this, a methodological understanding of HBO's cellular mechanisms of actions appears to be lacking. As such, this article attempts to draw the similarity between HBO and other protective oxidative stress mechanisms and then to speculate in an evidence-based manner its possible cellular mechanistic role as a drug via the generation of ROS.