I’ve been a bit remiss lately in posting, due to some exams and deadlines that have kept me unusually busy, but I wanted to briefly promote a new tool in the effort to develop novel, evidence-based therapies for cancer. The National Veterinary Cancer Registry (NVCR) is an effort to build a database of information about veterinary cancer patients. This will allow both epidemiologic studies using the data to better understand the patterns in naturally occurring cancer and also to connect patients with clinical studies of new therapies for their specific disease. This serves the veterinary patient population as a whole as well as the individual patient.

The NVCR is a joint effort between the CARE Foundation, Baylor University Medical Center (BUMC) at Dallas and the Texas Veterinary Oncology Group. This type of database has been of great value in improving the understanding and treatment of cancer in humans, and it is exciting to see such an effort beginning in the veterinary field. I encourage owners of pets with cancer to register your pets as a way to contribute to the growth of our ability to help others going through what you are going through.

A reader recently asked me about the evidence supporting recommended therapy for dental disease in dogs. This is has become a common question given the increasing awareness among pet owners that dental disease is a real and important health problem, and the availability of high quality prophylaxis and treatment.

The American College of Veterinary Dentistry, the organization of board-certified veterinary dental specialists, has a great site with information for pet owners about dental disease. I also find a lot of clear and pretty evidence-based information on the site of Dr. Frasier Hale.

Dental disease is unquestionably common, with some research suggesting it is the most common disease in pet cats and dogs, vying with obesity for the top spot. It primarily takes the form of periodontal disease, and unfortunately it is very difficult to detect or evaluate the severity of this problem in an awake dog. Dogs and cats show few overt symptoms of dental disease. Probing of the tooth sockets and x-rays are necessary, just as they are for humans, to accurately characterize the type and severity of dental disease and determine the appropriate treatment.

Unfortunately, our pets almost never get twice daily brushing and flossing or semi-annual dental cleanings, and they often have very abnormal occlusion (the arrangement and interaction of the teeth in the mouth) as a result of breeding. Toy breed dogs and those with foreshortened faces are at especially high risk of severe dental disease due, in large part, to the same anatomy that makes them appear cute to humans. So proper diagnosis and treatment of dental disease requires general anesthesia, and it is very often necessary to remove infected teeth because the disease is advanced or because the level of care needed to preserve them cannot be accomplished.

Naturally, owners are often anxious or reluctant to pursue care that involves general anesthesia and likely extraction of teeth, due to worries about the safety and comfort of the pet and also due to the high cost of appropriate care. The fact that our pets rarely show recognizable symptoms, even with a level of disease that we know would cause tremendous discomfort in people, also makes it more difficult to convince people that dental care is necessary and beneficial for their pets. While the most obvious reason to pursue this care is that the disease is almost certainly painful, it is sometimes helpful to consider the secondary health risks associated with untreated periodontal disease. I recently took a quick look at the evidence concerning these.

There is pretty strong evidence in humans that untreated periodontal disease is associated with other health problems, notably cardiovascular disease, diabetes, respiratory disease (including infections) and pre-term low-birthweight deliveries. Treatment of periodontal disease leads to clinical improvements in several diseases as well. It is plausible that a similar relationship between dental disease and general health would hold true for cats and dogs, but there is little direct evidence.

At least two studies have identified pathological lesions in specific organs, including the liver, kidneys, and heart (1,2). This demonstrates that periodontal disease is associated with detectable abnormalities in the tissues of these organs. It seems likely that this could also affect the function of these organs and the well-being of the individuals with such lesions, but this was not evaluated  by these studies.

At least one study has taken the next step and evaluated the association between periodontitis and actual disease in another organ system (3). A strong, linear association was identified between dental disease and chronic kidney disease, and while this does not prove dental disease causes kidney disease, it suggests that untreated periodontitis may be an important risk factor for kidney disease in dogs.

A similar study also suggested that periodontal disease may be associated with cardiac disease as well as pathologic lesions in the heart (4). However, there were significant methodological problems with this study, and other investigations have not found a link between dental disease and heart disease in dogs, so there is still controversy about this potential association (5,6).

Finally, one study has looked at common bloodwork variables and measures on inflammation in association with periodontal disease and its treatment (7). A few significant associations were identified, but there was no clear pattern suggesting a causal relationship between periodontitis and any particular disease.

Bottom Line
Dental disease, especially periodontal disease, is very common in dogs and cats. Though affected pets rarely show obvious or severe symptoms, periodontal disease is undoubtedly a source of significant discomfort. The only accurate way to diagnose, characterize, and treat periodontal disease is with a thorough oral examination, dental x-rays, and appropriate cleaning and often extraction or endodontic treatment of infected teeth. This can only be accomplished under general anesthesia.

There is good reason to believe proper prevention and treatment of periodontal disease makes dogs and cats more comfortable. In humans, it is also clear that such prevention and treatment improves health and reduces the risk and severity of other specific diseases. It is likely this is also true in dogs and cats, but the current research evidence regarding this claim is extremely limited.

References

1. DeBowes LJ, Mosier D, Logan E, Harvey CE, Lowry S, Richardson DC. Association of periodontal disease and histologic lesions in multiple organs from 45 dogs. J Vet Dent 1996; 13:57-60.
2. Pavlica Z, Petelin M, Juntes P, Eržen D, et al. Periodontal disease burden and pathological changes in organs of dogs. J Vet Dent 2008; 25: 97-105.
3. Glickman LT, Glickman NW, Moore GE, Lund EM, Lantz GC, Pressler BM. Association between chronic azotemic kidney disease and the severity of periodontal disease in dogs. Prev Vet Med 2011; 99: 193-200.
4. Glickman LT, Glickman NW, Moore GE, Goldstein GS, Lewis HB. Evaluation of the risk of endocarditis and other cardiovascular events on the basis of the severity of periodontal disease in dogs. J Am Vet Med Assoc 2009; 234: 486-494.
5. Pavlica Z, Petelin M, Juntes P, Erzen D, Crossley DA, Skaleric U. Periodontal disease burden and pathological changes in organs of dogs. J Vet Dent. 2008 Jun;25(2):97-105.
   
   
6. Peddle GD, Drobatz KJ, Harvey CE, Adams A, Sleeper MM. Association of periodontal disease, oral procedures, and other clinical findings with bacterial endocarditis in dogs. J Am Vet Med Assoc. 2009 Jan 1;234(1):100-7.
    
7. Rawlinson JE, Goldstein RE, Reiter AM, Attwater DZ, Harvey CE. Association of periodontal disease with systemic health indices in dogs and the systemic response to treatment of periodontal disease. J Am Vet Med Assoc 2011; 238: 601-609.

I recently participated in a couple of discussions on a veterinary web forum about hyperbaric oxygen therapy (HBOT) and evidence-based medicine. This technique is being heavily promoted with confident claims of scientifically proven benefits.  I thought, then, that I would take a look at the evidence.

What Is It?
Hyperbaric oxygen therapy involves placing patients in an airtight chamber and raising the atmospheric pressure and oxygen level so that oxygen is dissolved in the blood and delivered to tissues at higher levels than possible in normal atmospheric conditions. It is the treatment of choice for decompression sickness (The Bends) associated with SCUBA diving, but it is also recommended for numerous other medical indications. The Undersea and Hyperbaric Medical Society list 14 indications for which they consider the evidence sufficient to recommend HBOT.

What’s the Evidence?
When pressed, advocates acknowledged that there is virtually no clinical trial data in companion animal or food animal species to support HBOT for specific indications. This should automatically make any recommendations of HBOT tentative at best, and the therapy should essentially be considered experimental.

There is a large amount of in vitro and animal model research suggesting potential benefits of HBOT for a wide range of conditions, and proponents cite this as justification for putting HBOT chambers in veterinary practices and treating patients. Certainly, this evidence suggests HBOT is plausible and worth investigating. I have heard wacky theories for why HBOT should work (one vet once told me it was so successful because it recreated the state of the Earth’s atmosphere before the Biblical flood, when people lived hundreds of years). However, there are sound physiological rationales for the concept supported by good preclinical evidence.

Unfortunately, such pre-clinical research also has significant limitations and is often not consistent with the results of subsequent clinical trials for many therapies. It is necessary but not sufficient for making clinical decisions, and it is primarily intended to suggest that a new therapy is plausible and might work, not to prove that it does work in the real world. We often have to make the best of a bad business and rely on such evidence when there is nothing better, but any recommendations based purely on pre-clinical research must be made cautiously and with appropriate caveats, something HBOT advocates rarely do.

Most of the animal model studies are in rats, mice, and, to a lesser extent, guinea pigs and rabbits. There are a few experimental studies in dogs, cats, and horses (see Veterinary Studies  below). Most of these involve wounds or skin flaps and grafts, and they are by no means universally positive.

Another source evidence frequently used in veterinary medicine when there are no good veterinary studies is clinical trial data from humans. There is significant risk in extrapolation across species lines, but it is an inevitable and important part of veterinary medicine given the reality of limited resources to support target-species clinical trial research. One advocate of HBOT claims that we can have confidence in the value of HBOT because there are many controlled studies in the human literature showing the benefits of hyperbaric oxygen therapy for many conditions.

One outstanding review of the evidence for wound care, tissue trauma, and neurological disease, commissioned for the Washington State Health Care Authority, has recently been published.

It identifies moderate quality evidence to support the use of HBOT for aiding the healing of chronic wounds in diabetics, late radiation tissue injury, multiple sclerosis symptoms, and possibly in affecting mortality (though not long-term function) in traumatic brain injury. The evidence is of poor quality and inconclusive or not supportive for most other indications evaluated.

I have also taken a quick look at other systematic reviews of HBOT (primarily produced by the Cochrane Collaboration, though there are several from other sources) for the last 5 years. This is the most reliable assessment of the balance of the human clinical trial evidence, and it establishes what degree of confidence we should or should not have in the use of HBOT for specific problems (in humans, of course; again direct extrapolation to veterinary patients often changes the picture significantly)

These reviews are listed below. Again, they provide pretty good (though not always strong or consistent) support for adjunctive use of HBOT in treating wounds (in humans, of course). The evidence is fair to poor for other indications.

Is It Safe?
There is little data on the safety of HBOT in companion animals. One protocol was studied in 3 dogs in Japan and appeared to achieve oxygenation targets without obvious side effects.

(Hiroki YANAGISAWA, Eiichi KANAI, Hideki KAYANUMA, Takuo SHIDA, Tsunenori SUGANUMA. Hyperbaric Air Therapy in Dogs for Clinical Veterinary Medicine: A Basic Study. J. Vet. Med. Sci. 73(10): 1351–1354, 2011). However, there is really very little controlled data on possible risks in most companion animal species.

The Washington State review provides a nice evaluation of safety data (again in humans) for HBOT, which suggests that it is generally pretty safe but that there are common minor side effects and less common serious side effects.

The overall evidence suggests that harms associated with HBOT are generally mild and self-limiting. The majority of reported harms include barotrauma, temporary visual disturbances, and, more rarely, oxygen toxicity. Occasional reports of seizures represent the most serious side effects. The Medical Services Advisory Committee (MSAC) of Australia reported an overall harms incidence rate of 6.3%; 17% incidence of general pain or discomfort during decompression; 4.8% incidence of ear pain; 1.5% incidence of tympanostomy tube placements; 0.9% incidence of persistent ocular changes; 0.6% incidence of ear barotrauma; 0.34% incidence of abdominal pain; and 0.1% incidence of claustrophobia.

Notable indication-specific harms found in the literature include the following:

 ·         Among patients with LRTI, there were reports of ear pain (16% in a trial of 150 patients), transient myopia (3% in one study 8% in another), and confinement anxiety (1.7%).

 ·         Pooled data from 2 trials reported severe pulmonary complications (defined as either, rising oxygen requirements and infiltrates in chest x-ray or cyanosis and hyperpnoea so severe as to imply “impending hyperoxic pneumonia”) among 13% of TBI patients receiving HBOT compared with none in the control groups (RR, 15.57; 95% CI, 2.11-114.72).

 ·         One study reported ear problems among 47% of children with cerebral palsy receiving HBOT versus 22% among controls (P significant but value not reported). Another study reported a 12% seizure rate and found that 35% of patients reported ear problems.

 ·         Another reported that 8% of 50 children stopped treatment due to adverse events, including seizures, and one other study reported 1 seizure in an observational study of 230 patients. 

·         Among patients with MS, a 2011 Cochrane Collaboration review reported 77 patients (55%), across 4 trials, suffered temporary deterioration in visual acuity in the HBOT group versus 3 patients (2.3%) in the sham group (OR, 24.87; 95% CI, 1.44-428.5; NNT, 1; 95% CI, 1-2).

Of course, the most dramatic risk seen in veterinary use of HBOT is the catastrophic explosion of the oxygen chamber. This happened in Florida last year, and both the patient and one of the veterinary staff were killed. While this is clearly a problem with the administration of HBOT, not the technique itself, it is a risk that has to be factored in to any assessment of the pros and cons of the practice.

Bottom Line
HBOT is a biologically plausible therapy with substantial in vitro and animal model research to support possible benefits in a variety of conditions. There is, however, almost no clinical trial evidence to support its use in companion animal species. Justification of veterinary use of HBOT comes only from extrapolation from basic principles, pre-clinical research, anecdote, and extrapolation from research in humans, so this should be viewed as an unproven, experimental veterinary therapy.

There are a few indications for which the human clinical trial research provides at least a moderate degree of confidence that HBOT is effective. There are many others for which there is only limited and low-quality evidence and no clear conclusion can be drawn. Not all uses validated in humans are relevant to veterinary use, and most veterinary applications have not been directly studied in people. Overall, the evidence is strongest for adjunctive use of HBOT to facilitate healing of chronic wounds not resolving with standard therapies.

HBOT is generally quite safe, but there are both minor and serious potential adverse effects, and there is some risk associated with the use of the equipment.

Everyone will interpret this evidence differently in light of their own understanding of how research evidence should be integrated into clinical decision making. For my part, it suggests to me that HBOT is a promising therapy for a variety of indications but not clearly demonstrated effective for very many even in humans, and the veterinary evidence is too weak to be very useful in making recommendations. I would certainly like to see more and better research evidence before there is widespread use of this technique.

Companion Animal Studies

1.      Baumwart, C. A.Doherty, T. J.Schumacher, J.Willis, R. S.Adair, H. S., IIIRohrbach, B. W. Effects of hyperbaric oxygen treatment on horses with experimentally induced endotoxemia. American Journal of Veterinary Research. 2011 72 9 1266-1275

Objective – To determine the effectiveness of preinduction hyperbaric oxygen treatment (HBOT) in ameliorating signs of experimentally induced endotoxemia in horses. Animals – 18 healthy adult horses. Procedures – Horses were randomly assigned to 1 of 3 equal-sized treatment groups to receive normobaric ambient air and lipopolysaccharide (LPS), HBOT and LPS, or HBOT and physiologic saline (0.9% NaCl) solution. Horses were physically examined, and blood was obtained for a CBC and to determine concentration or activity of plasma tissue necrosis factor-?, blood lactate, and blood glucose before the horses were treated with HBOT and then intermittently for 6 hours after administration of LPS or physiologic saline solution. Results – All LPS-treated horses developed signs and biochemical and hematologic changes consistent with endotoxemia. Treatment with HBOT significantly ameliorated the effect of LPS on clinical endotoxemia score but did not significantly improve other abnormalities associated with endotoxemia. Conclusions and Clinical Relevance – The protective effect of HBOT was minimal, and results did not support its use as a treatment for horses prior to development of endotoxemia.

2.      Holder, T. E. C.Schumacher, J.Donnell, R. L.Rohrbach, B. W.Adair, H. S. A. Effects of hyperbaric oxygen on full-thickness meshed sheet skin grafts applied to fresh and granulating wounds in horses. American Journal of Veterinary Research. 2008 69 1 144-147

Objective – To determine the effects of hyperbaric oxygen therapy (HBOT) on full-thickness skin grafts applied to fresh and granulating wounds of horses. Animals – 6 horses. Procedures – On day 0, two 4-cm-diameter circular sections of full-thickness skin were removed from each of 2 randomly selected limbs of each horse, and two 4-cm-diameter circular skin grafts were harvested from the pectoral region. A skin graft was applied to 1 randomly selected wound on each limb, leaving the 2 nongrafted wounds to heal by second intention. On day 7, 2 grafts were harvested from the pectoral region and applied to the granulating wounds, and wounds grafted on day 0 were biopsied. On day 14, 1 wound was created on each of the 2 unwounded limbs, and the wounds that were grafted on day 7 were biopsied. All 4 ungrafted wounds (ie, 2 fresh wounds and 2 wounds with 1-week-old granulation beds) were grafted. The horses then received HBOT for 1 hour daily at 23 PSI for 7 days. On day 21, the grafts applied on day 14 were biopsied. Results – Histologic examination of biopsy specimens revealed that grafts treated with HBOT developed less granulation tissue, edema, and neovascularization, but more inflammation. The superficial portion of the graft was also less viable than the superficial portion of those not treated with HBOT. Conclusions and Clinical Relevance – The use of HBOT after full-thickness skin grafting of uncompromised fresh and granulating wounds of horses is not indicated.

3.      Kerwin, S. C.Lewis, D. D.Elkins, A. D.Oliver, J. L.Hosgood, G.Pechman, R. D., Jr.Dial, S. L.Strain, G. M. Effect of hyperbaric oxygen treatment on incorporation of an autogenous cancellous bone graft in a nonunion diaphyseal ulnar defect in cats. American Journal of Veterinary Research. 2000 61 6 691-698

12 mature cats were used to determine whether hyperbaric oxygen treatment (HBOT) would affect incorporation of an autogenous cancellous bone graft in diaphyseal ulnar defects. Bilateral non-union diaphyseal ulnar defects were created in each cat. An autogenous cancellous bone graft was implanted in 1 ulnar defect in each cat, with the contralateral ulnar defect serving as a non-grafted specimen. Six cats were treated by use of hyperbaric oxygen at 2 atmospheres absolute for 90 min once daily for 14 days, and 6 cats were not treated (control group). Bone labelling was performed, using fluorochrome markers. Cats were killed 5 weeks after implanting, and barium sulfate was infused to evaluate vascularization of grafts. Ulnas were evaluated by use of radiography, microangiography, histological examination, and histomorphometric examination. Radiographic scores did not differ between treatment groups. Microangiographic appearance of grafted defects was similar between groups, with all having adequate vascularization. Differences were not observed between treated and non-treated groups in the overall histological appearance of decalcified samples of tissue in grafted defects. Mean distance between fluorescent labels was significantly greater in cats given HBOT than in non-treated cats. Median percentage of bone formation in grafted defects was significantly greater in cats given HBOT. Hyperbaric oxygen treatment increased the distance between fluorescent labels and percentage of bone formation when incorporating autogenous cancellous bone grafts in induced non-union diaphyseal ulnar defects in cats, but HBOT did not affect revascularization, radiographic appearance or qualitative histological appearance of the grafts.

4.      Hosgood, G.Hodgin, E. C.Strain, G. M.Lopez, M. K.Lewis, D. D. Effect of deferoxamine and hyperbaric oxygen on free, autogenous, full-thickness skin grafts in dogs. American Journal of Veterinary Research. 1995 56 2 241-247

Free, autogenous, full thickness skin grafts were applied to 10 dogs; 5 dogs were given an iron chelator, deferoxamine 10% hydroxyethyl pentafraction starch (DEF-HES; 50 mg/kg of body weight,i.v.), and 5 dogs were given an equal volume of 10% hydroxyethyl pentafraction starch (HES) in 0.9% saline solution (5 ml/kg, i.v.). All dogs (DEF-HES/HBO and HES/HBO treated) were exposed to 60 minutes of hyperbaric oxygen (HBO) at 2 atmospheres absolute pressure twice daily for 10 days, beginning the day of surgery. The percentage of viable graft on day 10 was lower in HES/HBO treated dogs (mean + SD; 13.3 + 21.3%; median, 3.0%) than in DEF-HES/HBO treated dogs (64.7 + 39.2%; 88.3%). There was a positive correlation between percentage of viable graft (on day 10) and percentage of haired skin on the graft site (on day 28) for all dogs. Perivascular aggregates of foamy cells were observed in the superficial and reticular portions of the dermis and in the subcutaneous tissue on both surfaces of the panniculus muscle in the graft sites of DEF-HES/HBO treated dogs. These cells were also observed in the dermis, and in some viscera of DEF-HES/HBO treated dogs. Deferoxamine appeared to attenuate the detrimental effect of HBO and HES on survival of free skin grafts. It is concluded that the clinical use of HBO and DEF-HES is not recommended because it failed to improve the survival of free skin grafts.

5.      Kerwin, S. C.Hosgood, G.Strain, G. M.Vice, C. C.White, C. E.Hill, R. K. The effect of hyperbarbic oxygen treatment on a compromised axial pattern flap in the cat. Veterinary Surgery. 1993 22 1 31-36

A pedicile skin flap based on the caudal superficial epigastric artery was created in 12 cats. The artery was ligated and the vein left intact. Six cats were treated with hyperbaric oxygen at 2 atm absolute for 90 minutes daily for 14 days, starting the day after surgery. Skin flap colour was significantly better in the treated cats on days 1, 2, and 3. The amount of exudate was significantly less in the treated cats on day 3. There was no difference in the amount of swelling between treated and nontreated control cats. Although 5 of 6 of the treated cats had 100% skin flap survival, there was no significant difference in total flap survival between treated and nontreated control cats.

Systematic Reviews of HBOT for Wounds in Humans

1.      Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers.

Liu R, Li L, Yang M, Boden G, Yang G. Mayo Clin Proc. 2013 Feb;88(2):166-75. doi: 10.1016/j.mayocp.2012.10.021.
Thirteen trials (a total of 624 patients), including 7 prospective randomized trials, performed between January 1, 1966, and April 20, 2012, were identified as eligible for inclusion in the study. Pooling analysis revealed that, compared with treatment without HBO, adjunctive treatment with HBO resulted in a significantly higher proportion of healed diabetic ulcers (relative risk, 2.33; 95% CI, 1.51-3.60). The analysis also revealed that treatment with HBO was associated with a significant reduction in the risk of major amputations (relative risk, 0.29; 95% CI, 0.19-0.44); however, the rate of minor amputations was not affected (P=.30). Adverse events associated with HBO treatment were rare and reversible and not more frequent than those occurring without HBO treatment (P=.37).

This meta-analysis reveals that treatment with HBO improved the rate of healing and reduced the risk of major amputations in patients with diabetic foot ulcers. On the basis of these effects, we believe that quality of life could be improved in selected patients treated with HBO.

2.      Hyperbaric oxygen therapy for treating chronic wounds

Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE
April 18, 2012
This review update of randomised trials found that HBOT seems to improve the chance of healing diabetes-related foot ulcers and may reduce the number of major amputations in people with diabetes who have chronic foot ulcers. In addition this therapy may reduce the size of wounds caused by disease to the veins of the leg, but the review found no evidence to confirm or refute any effect on other wounds caused by lack of blood supply through the arteries or pressure ulcers.

3.      A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot.

Peters EJ, Lipsky BA, Berendt AR, Embil JM, Lavery LA, Senneville E, Urban?i?-Rovan V, Bakker K, Jeffcoate WJ. Diabetes Metab Res Rev. 2012 Feb;28 Suppl 1:142-62. doi: 10.1002/dmrr.2247.
There was no improvement in infection outcomes associated with hyperbaricoxygen therapy.

4.      Hyperbaricoxygen therapy: solution for difficult to heal acute wounds? Systematic review.
Eskes AM, Ubbink DT, Lubbers MJ, Lucas C, Vermeulen H. World J Surg. 2011 Mar;35(3):535-42. doi: 10.1007/s00268-010-0923-4.
We included five trials, totaling 360 patients. These trials, with some methodologic flaws, included different kinds of wound and focused on different outcome parameters, which prohibited meta-analysis. A French trial (n = 36 patients) reported that significantly more crush wounds healed with HBOT than with sham HBOT [relative risk (RR) 1.70, 95% confidence interval (CI) 1.11-2.61]. Moreover, there were significantly fewer additional surgical procedures required with HBOT (RR 1.60, 95% CI 1.03-2.50), and there was significantly less tissue necrosis (RR 1.70, 95% CI 1.11-2.61). In one of two American trials (n = 141) burn wounds healed significantly quicker with HBOT (P < 0.005) than with routine burn care. A British trial (n = 48) compared HBOT with usual care. HBOT resulted in a significantly higher percentage of healthy graft area in split skin grafts (RR 3.50, 95% CI 1.35-9.11). In a Chinese trial (n = 145) HBOT did not significantly improve flap survival in patients with limb skin defects. HBOT, if readily available, appears effective for the management of acute, difficult to heal wounds. 

5.      Hyperbaric oxygen therapy for acute surgical and traumatic wounds
Eskes A, Ubbink DT, Lubbers M, Lucas C, Vermeulen H
February 16, 2011
This review did not find any high quality research evidence showing that HBOT is beneficial for wound healing. Two poor quality studies suggested benefits associated with HBOT. The first in patients with crush injuries, showed improved wound healing and fewer adverse outcomes. The second reported improved survival of split skin grafts. A third trial reported no benefits associated with HBOT for skin grafts.

Further, better quality research is needed to determine the effects of HBOT on wound healing.

6.      Hyperbaricoxygen therapy for wound healing and limb salvage: a systematic review.

Goldman RJ. PM R. 2009 May;1(5):471-89. doi: 10.1016/j.pmrj.2009.03.012.

This article is a systematic review evaluating published clinical evidence of the efficacy of hyperbaricoxygen therapy (HBOT) for wound healing and limb salvage… The author evaluated 620 citations, of which 64 reported original observational studies and randomized controlled trials (RCTs) on HBOT and healing outcomes. All citations with 5 subjects were selected for full text review (44 articles) and evaluated according to GRADE criteria for high, medium, low, or very low level of evidence. A Cochrane review identified 1 additional study with a low level of evidence….For patients with diabetic foot ulcers (DFU) complicated by surgical infection, HBOT reduces chance of amputation (odds ratio [OR] 0.242, 95% CI: 0.137-0.428) (7 studies) and improves chance of healing (OR 9.992, 95% CI: 3.972-25.132) (6 studies)…HBOT is associated with remission of about 85% of cases of refractory lower extremity osteomyelitis, but an RCT is lacking to clarify extent of effect. There is a high level of evidence that HBOT reduces risk of amputation in the DFU population by promoting partial and full healing of problem wounds. There is a moderate level of evidence that HBOT promotes healing of arterial ulcers, calciphylactic and refractory vasculitic ulcers, as well as refractory osteomyelitis. There is a low to moderate level of evidence that HBOT promotes successful “take” of compromised flaps and grafts.

Systematic Reviews for Other Indications in Humans

Systematic review of agents for the management of gastrointestinal mucositis in cancer patients.
Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Support Care Cancer. 2013 Jan;21(1):313-26. doi: 10.1007/s00520-012-1644-z. Epub 2012 Nov 10.
…the panel suggests the use of hyperbaricoxygen as an effective means in treating radiation-induced proctitis.

Does hyperbaric oxygen therapy improve the survival and quality of life in patients with traumatic brain injury?
Bennett MH, Trytko B, Jonker B
December 12, 2012
The effectiveness of HBOT on the recovery of brain-injured patients is uncertain. There is also concern regarding potential adverse effects of the therapy, including damage to the ears, sinuses and lungs from the effects of pressure, temporary worsening of short-sightedness, claustrophobia and oxygen poisoning.

In an attempt to address the uncertainty surrounding the use of HBOT, the authors of this review identified all studies which were randomized controlled trials investigating the effects of HBOT in traumatically brain-injured people of all ages.

The authors found seven eligible studies involving 571 people. The combined results suggest that HBOT reduces the risk of death and improves the level of coma; however, there is no evidence that these survivors have an improved outcome in terms of quality of life. It is possible, therefore, that the overall effect of hyperbaric oxygen is to make it more likely that people will survive with severe disability after such injuries. The authors conclude that the routine use of HBOT in brain-injured patients cannot be justified by the findings of this review.

Due to the small number of trials with a limited number of people, it is not possible to be confident in the findings. Further large, high quality trials are required to define the true extent of benefit from HBOT.

Using oxygen at high pressure (in a compression chamber) for the treatment of broken bones
Bennett MH, Stanford RE, Turner R
November 14, 2012
This review found no evidence from randomised trials to support or refute the use of hyperbaric oxygen therapy to avoid or treat poorly healing broken bones. However, in this update, we found three ongoing randomised trials that are likely to provide some evidence to inform on the use of hyperbaric oxygen therapy in the future.

Hyperbaric oxygen therapy for vascular dementia
Xiao Y, Wang J, Jiang S, Luo H
July 11, 2012
This review included one randomised controlled trial of poor methodological quality involving 64 patients with VaD who were also taking donepezil. Safety assessment was not mentioned at all. Although the authors reported cognitive benefit, this trial alone cannot be taken as evidence of efficacy. Further well-designed randomised controlled trials are needed.

Ghanizadeh A.  Hyperbaricoxygen therapy for treatment of children with autism: a systematic review of randomized trials.
Med Gas Res. 2012 May 11;2:13. doi: 10.1186/2045-9912-2-13.
The electronically search resulted in 18 title of publications. Two studies were randomized, double-blind, controlled-clinical trials. While some uncontrolled and controlled studies suggested that HBO therapy is effective for the treatment of autism, these promising effects are not replicated. Therefore, sham-controlled studies with rigorous methodology are required to be conducted in order to provide scientific evidence-based HBO therapy for autism treatment.

Hyperbaric oxygen therapy (HBOT) for the treatment of the late effects of radiotherapy
Bennett MH, Feldmeier J, Hampson N, Smee R, Milross C
May 16, 2012
We found some evidence that LRTI affecting the head, neck and lower end of the bowel can be improved with HBOT. There is little evidence for or against benefit in other tissues affected by LRTI. Our conclusions are based on 11 randomised trials with a limited number of patients. Further research is needed.

High pressure oxygen breathing during radiotherapy for cancer treatment
Bennett MH, Feldmeier J, Smee R, Milross C
April 18, 2012
Breathing oxygen while at raised pressure in a closed chamber (hyperbaric oxygen or HBO) may increase the effectiveness of radiotherapy and thus improve mortality and reduce tumour regrowth. We found some evidence that people with head and neck cancer are less likely to die within five years if they are treated this way, and evidence that regrowth of tumour at the original site is less likely for head and neck, and cervical cancer. However, Hyperbaric oxygen therapy (HBOT) may only be effective when radiotherapy is given in an unusually small number of sessions, each with a relatively high dose. HBOT does not appear to work for other cancers studied. Our conclusions are based on 19 randomised trials with over 2000 patients.

Hyperbaricoxygen treatment for inflammatory bowel disease: a systematic review and analysis.
Rossignol DA. Med Gas Res. 2012 Mar 15;2(1):6. doi: 10.1186/2045-9912-2-6.
Thirteen studies of HBOT in Crohn’s disease and 6 studies in ulcerative colitis were identified….Twelve publications reported using HBOT in animal models of experimentally-induced IBD… Although most publications reported improvements with HBOT, some studies suffered from limitations, including possible publication and referral biases, the lack of a control group, the retrospective nature and a small number of participants.

HBOT lowered markers of inflammation and oxidative stress and ameliorated IBD in both human and animal studies. Most treated patients were refractory to standard medical treatments. Additional studies are warranted to investigate the effects of HBOT on biomarkers of oxidative stress and inflammation as well as clinical outcomes in individuals with IBD.

A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, Löndahl M, Price PE, Jeffcoate WJ. Diabetes Metab Res Rev. 2012 Feb;28 Suppl 1:119-41. doi: 10.1002/dmrr.2246.
The present report is an update of the earlier IWGDF systematic review, but the conclusion is similar: that with the exception of HBOT and, possibly, negative pressure wound therapy, there is little published evidence to justify the use of newer therapies. This echoes the conclusion of a recent Cochrane review and the systematic review undertaken by the National Institute for Health and Clinical Excellence Guidelines Committee in the UK. Analysis of evidence presents considerable difficulties in this field particularly as controlled studies are few and the majority are of poor methodological quality.

High pressure (hyperbaric) oxygen therapy for Bell’s palsy
Holland NJ, Bernstein JM, Hamilton JW
February 15, 2012
Our searches revealed no trials that met the inclusion criteria for the review. We found very low quality evidence from one trial to suggest that hyperbaric oxygen therapy might be beneficial for moderate to severe Bell’s palsy. The quality of evidence from this trial was very low because the assessors of facial function were aware of which treatment each participant had been given, which introduces a high risk of bias. There is therefore no high quality evidence on which to base conclusions about the efficacy of hyperbaric oxygen therapy in Bell’s palsy.

Hyperbaric oxygen therapy, which involves people breathing pure oxygen in a specially designed chamber, for the treatment of multiple sclerosis
Bennett MH, Heard R
August 10, 2011
The review of nine trials found no consistent evidence that HOBT can improve disability or modify the progression of MS. There is little need for further research.

Hyperbaric oxygen may reduce the risk of dying, the time to pain relief and the chance of adverse heart events in people with heart attack and unstable angina
Bennett MH, Lehm JP, Jepson N
August 10, 2011
We first searched the literature in 2004 and most recently in June 2010, finding one further study. Overall,we found some evidence that people with ACS are less likely to die or to have major adverse cardiac events, and to have more rapid relief from their pain, if they receive hyperbaric oxygen therapy as part of their treatment. However, our conclusions are based on six relatively small randomised trials (five of which included only patients with confirmed heart muscle death). While HBOT may therefore reduce the risk of dying, time to pain relief and the chance of adverse heart events in people with heart attack and unstable angina, more work is still needed to be sure that HBOT should be recommended.

There is insufficient evidence to support the use of hyperbaric oxygen for treatment of patients with carbon monoxide poisoning
Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ
April 13, 2011
the review of published trials found conflicting, potentially biased, and generally weak evidence regarding the usefulness of hyperbaric oxygen for the prevention of neurological injury.

Hyperbaric oxygen as an additional treatment for malignant otitis externa
Phillips JS, Jones SEM
February 16, 2011
The review found no trials to demonstrate that the addition of hyperbaric oxygen therapy offers a better outcome than the treatments alone. Further research is required.

Efficacy of pre- and postirradiation hyperbaricoxygen therapy in the prevention of postextraction osteoradionecrosis: a systematic review.
Fritz GW, Gunsolley JC, Abubaker O, Laskin DM. J Oral Maxillofac Surg. 2010 Nov;68(11):2653-60. doi: 10.1016/j.joms.2010.04.015. Epub 2010 Aug 19.
Most of the studies had a small sample size, lacked specific inclusion and exclusion criteria, did not report the interval between radiation and extraction, and provided limited information on the method of extraction. There was also variation in HBO protocols, radiation dosage, the use of antibiotics, and the use of adjunctive cancer therapy.

On the basis of the best available evidence, there is currently insufficient information to show that the use of HBO reduces the incidence of osteoradionecrosis in irradiated patients requiring tooth extraction.

Hyperbaric oxygen therapy for delayed onset muscle soreness and closed soft tissue injury
Bennett MH, Best TM, Babul-Wellar S, Taunton JE
June 16, 2010
Our review included nine small trials, involving a total of 219 participants. Two trials compared HBOT versus sham therapy on ankle sprain and knee sprain respectively. Neither trial provided sufficient evidence to determine if HBOT helped people with these injuries. The other seven trials examined the effect of HBOT on muscle injury following unaccustomed exercise. There was no evidence that HBOT helped people with muscle injury following unaccustomed exercise, but some evidence that people given HBOT had slightly more pain. Further research on HBOT is not a high priority given the variety of other treatment interventions available.

Normal pressure oxygen therapy and hyperbaric oxygen therapy for migraine and cluster headaches
Bennett MH, French C, Schnabel A, Wasiak J, Kranke P
October 7, 2009
In our review, we found some weak evidence to suggest that HBOT helps people with acute migraine headaches and possibly cluster headaches, and that NBOT may help people with cluster headache. We found no evidence that either can prevent future attacks. Because many migraines can be treated simply with appropriate drug therapy, further research is needed to help choose the most appropriate patients (if any) to receive HBOT.

Little evidence that burns patients benefit from hyperbaric oxygen therapy
Villanueva E, Bennett MH, Wasiak J, Lehm JP
October 7, 2009
The review found only two randomised trials, with only a limited number of patients. There was no consistent benefit from HBOT, but one trial did suggest an improvement in healing time. Overall, there is little evidence to support or refute the use of HBOT for burns patients. More research is needed.

Hyperbaric oxygen therapy for acute ischaemic stroke
Bennett MH, Wasiak J, Schnabel A, Kranke P, French C
October 7, 2009
There is little evidence that stroke patients benefit from hyperbaric oxygen therapy….Our review found only six randomised trials involving 283 participants. Too few patients have been studied to say whether or not HBOT decreases the chance of dying and only three trials suggested any improvement in the ability to do everyday tasks. Overall, there is currently little evidence to support the use of HBOT for stroke patients.

Interventions for replacing missing teeth: hyperbaric oxygen therapy for irradiated patients who require dental implants
Esposito M, Grusovin MG, Patel S, Worthington HV, Coulthard P
October 8, 2008
We could only identify one study including a limited number of patients. This study suggested that the use of hyperbaric oxygen (HBO) therapy for patients who require dental implants after radiotherapy is of no apparent clinical benefit….More reliable studies are needed to provide the final answer to this question.

A couple of years ago, I wrote about the question of whether or not surgery was better than medical management for dogs with cranial cruciate ligament (CCL) disease. Here was my conclusion at that time:

As is almost always the case, the evidence is not of the highest possible quality or unequivocal, but this does not exempt us from having to draw conclusions and make recommendations to our clients. My interpretation of the available evidence is that overall, cruciate ligament disease causes significant arthritis and loss of function when untreated. For most dogs under 15kg, conservative management (primarily restricted activity for 3-6 weeks, achieving and maintaining and appropriate body weight, and possibly physical therapy and pain medication) can achieve acceptable comfort and function. In larger dogs, significant arthritis is inevitable and dysfunction is extremely likely without surgical treatment. No single surgical technique is clearly superior, so the choice of specific surgery should be determined by the judgment of the individual surgeon and the needs of the owner.

A recent research article has added an important piece of evidence concerning this subject, and while supporting the value of surgery it does weaken somewhat the case against medical treatment for large dogs.

Wucherer, KL. Conzemius, MG. Evans, R. Wilke, VL. Short-term and long-term outcomes for overweight dogs with cranial cruciate ligament rupture treated surgically or nonsurgically. Journal of the American Veterinary Medical Association 2013;242(10):1364-72.

The authors interpretation of the results supports the argument that both surgical and nonsurgical treatment can be successful, even in overweight large-breed or giant-breed dogs, but that surgery appears to provide a better outcome.

Overweight dogs with CCLR treated via surgical and nonsurgical methods had better outcomes than dogs treated via nonsurgical methods alone. However, almost two-thirds of the dogs in the nonsurgical treatment group had a successful outcome…

Overall, I agree with their conclusion, though I would probably place less confidence in it than the authors do.

The Study
Forty overweight large-breed or giant-breed dogs with unilateral rupture of a CCL were recruited and randomized to either medical therapy alone (a weight loss program, individualized physical therapy, and daily use of a nonsteroidal anti-inflammatory medication) or medical therapy plus surgical therapy (TPLO). Outcomes were assessed at 6 weeks, 12 weeks, 24 weeks, and 52 weeks after the beginning of the study.

There was a high rate of drop out (5 digs by 6 weeks, 11 dogs by 24 weeks, and 17 dogs by 52 weeks). The majority of these dogs (11/17) dropped out due to CCL rupture in the opposite leg, and there was no overall difference in dropouts between the two groups (9 in surgical group and 8 in non-surgical group).

Both subjective outcome measures (surveys of owner perception of their dogs’ pain and lameness and pain scores generated by the investigators) and objective outcome measures (body weight, body fat, body condition scores, and several measures generated by force-plate analysis) were evaluated at the beginning of the study and in the dogs still participating at each follow-up point.

The Results
No adverse effects were reported for the weight loss diet, the NSAID therapy, or the physical therapy. A few minor complications associated with TPLO surgery were reported at rates consistent with those reported in other studies.

The weight loss program did result in decreases in body condition score and percent body fat for both groups, and there were no significant differences between the two groups. Interestingly, while total body weight did decline slightly for both groups, the decrease was not statistically significant for either, and there was no difference between the groups.

Subjective measures, both owner and investigator assessed, improved significantly for both groups. There were no differences between the groups in the subjective outcomes assessed by the investigators. The surgery group had significantly lower scores for pain severity and interference than the non-surgical group only at the 52-week evaluation. Some differences between the groups in visual analog pain scale assessment by owners were reported, but how many measures were assessed and which ones differed were not reported, and no statistical analysis of these differences was reported, so it is difficult to assess this outcome measure.

Of the several force-plate measures assessed (5 or 6 measures; it isn’t clear from the paper), only one differed between the groups, and this difference was significant only at two of the four assessment points (24 weeks and 52 weeks).

The investigators also created a composite measure of “successful outcome,” defined as achieving both a specific force-plate measure that was >85% that of a normal dog and a subjective, owner-assessed improvement in lameness and quality of life >/= 10%. The dogs in the surgical group had higher “successful outcome” scores at all assessment points, but this only reached statistical significance at 24-week evaluation.

Strengths of the Study
Overall, this was a well-designed study. The use of both subjective and objective outcome measures, random assignment of treatment, an aggressive and consistent medical therapy program, and partial standardization of surgical treatment all reduce the risk of bias, confounding, and other error in the study. The consistency of several reported variables (such as surgical complication rate) with those reported in other studies increases the confidence one can have in the results. And the attempt to verify compliance with the weight loss aspect of medical therapy is an important part of any study employing this therapeutic approach.

Limitations and Caveats
A significant limitation is the lack of blinding of owners or investigators to treatment group. While blinding would be difficult, and possibly unethical due to the need for a sham surgery component, the lack of blinding introduces significant risk of information bias, particularly in the subjective outcome measures.

There was some individualization of surgical procedure and physical therapy treatments employed, which means not all subjects had the same treatment. If some techniques used work better than others, or if the selection of technique to be used is associated with the likelihood of a good or bad outcome, this could generate an erroneous impression of the differences between the surgical and non-surgical treatment groups.

The biggest limitation of the study was probably the high dropout rate. In general, dropout rates greater than about 20% are considered to severely compromise the data, and the overall dropout rate was 42.5% in this study. Though the number of dropouts were evenly distributed between the two groups, this does not mean the dropouts did not introduce bias into the results. If those patients who dropped out, most because they developed a second CCL rupture in their other leg, differed in terms of their underlying disease or response to treatment from the subjects who stayed in the study, this could have significantly altered the findings.

Also, as the authors themselves point out, the dropouts caused a significant loss of power in the study (though no power analysis is presented in the report), and this could lead to a failure to detect a difference between the groups. Overall, the dropouts significantly weaken the confidence we can place in these results.

Bottom Line
This study does provide some support for the contention that overweight, large-breed or giant-breed dogs have better long-term outcomes when treated with both surgery and non-surgical therapy rather than with non-surgical therapy alone. However, the limitations in these data are great enough that the case for preferring surgical intervention is not strong. The non-surgically treated patients had overall very good outcomes that, at most time points and by most measures, did not differ significantly from the patients who received surgical treatment. Additional evidence would be required to make a strong statement that overall surgery is superior to aggressive medical therapy.

While it is reasonable to tell dog owners that there is some evidence their pets will benefit more from having surgery than not having it, we must also inform them that most dogs will have a good long-term outcome even without surgery. And it is important to emphasize that even with surgery, aggressive management of weight and physical therapy are important elements of  comprehensive and successful treatment. For those owners who cannot afford surgery, or those patients who are not good candidates, there are still effective therapies that can be offered.