Hyperbaric oxygen therapy is well tolerated and effective for ulcerative colitis patients hospitalized for moderate-severe flares: a phase 2A pilot multi-center, randomized, double-blind, sham-controlled trial.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) markedly increases tissue oxygen delivery. Case series suggest it may have a potential therapeutic benefit in ulcerative colitis (UC). We investigated the therapeutic potential of HBOT as an adjunct to steroids for UC flares requiring hospitalization. METHODS: The study was terminated early due to poor recruitment with 18 of the planned 70 patients enrolled. UC patients hospitalized for moderate-severe flares (Mayo score ≥6, endoscopic sub-score ≥2) were block randomized to steroids + daily HBOT (n = 10) or steroids + daily sham hyperbaric air (n = 8). Patients were blinded to study assignment, and assessments were performed by a blinded gastroenterologist. Primary outcome was the clinical remission rate at study day 5 (partial Mayo score ≤2 with no sub-score >1). Key secondary outcomes were: clinical response (reduction in partial Mayo score ≥2, rectal bleeding sub-score of 0-1) and progression to second-line therapy (colectomy or biologic therapy) during the hospitalization. RESULTS: A significantly higher proportion of HBOT-treated patients achieved clinical remission at study day 5 and 10 (50 vs. 0%, p = 0.04). HBOT-treated patients less often required progression to second-line therapy during the hospitalization (10 vs. 63%, p = 0.04). The proportion requiring in-hospital colectomy specifically as second-line therapy for medically refractory UC was lower in the HBOT group compared to sham (0 vs. 38%, p = 0.07). There were no serious adverse events. CONCLUSION: In this small, proof-of-concept, phase 2A trial, the use of HBOT as an adjunctive therapy to steroids for UC patients hospitalized for moderate-severe flares resulted in higher rates of clinical remission, and a reduction in rates of progression to second-line therapy during the hospitalization. Larger well-powered trials are needed, however, to provided definitive evidence of therapeutic benefit.

A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers.

BACKGROUND: Multiple adjunctive therapies have been proposed to accelerate wound healing in patients with diabetes and foot ulcers. The aim of this systematic review is to summarize the best available evidence supporting the use of hyperbaric oxygen therapy (HBOT), arterial pump devices, and pharmacologic agents (pentoxifylline, cilostazol, and iloprost) in this setting. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest were complete wound healing and amputation. RESULTS: We identified 18 interventional studies; of which 9 were randomized, enrolling 1526 patients. The risk of bias in the included studies was moderate. In multiple randomized trials, the addition of HBOT to conventional therapy (wound care and offloading) was associated with increased healing rate (Peto odds ratio, 14.25; 95% confidence interval, 7.08-28.68) and reduced major amputation rate (odds ratio, 0.30; 95% confidence interval, 0.10-0.89), compared with conventional therapy alone. In one small trial, arterial pump devices had a favorable effect on complete healing compared with HBOT and in another small trial compared with placebo devices. Neither iloprost nor pentoxifylline had a significant effect on amputation rate compared with conventional therapy. No comparative studies were identified for cilostazol in diabetic foot ulcers. CONCLUSIONS: There is low- to moderate-quality evidence supporting the use of HBOT as an adjunctive therapy to enhance diabetic foot ulcer healing and potentially prevent amputation. However, there are only sparse data regarding the efficacy of arterial pump devices and pharmacologic interventions.

Applying quality improvement methods in a hyperbaric oxygen program: reducing unnecessary glucose testing.

OBJECTIVE: To describe the implementation of a quality improvement (QI) project that aimed at improving and standardizing glucose checks on patients with diabetes undergoing hyperbaric oxygen (HBO2) therapy. METHODS: This is a prospective cohort study. Following the Model for Improvement, nurses and physicians ran several Plan-Do-Study-Act (PDSA) cycles over a four-month period, with multiple iteration and testing changes. They developed and implemented a nurse-led protocol that was tested prospectively. RESULTS: Compared to the pre-protocol baseline (N = 332), glucose checks per session guided by the protocol decreased by 37.7% (2.84 vs. 1.77 per session, P⟨0.001). Compliance with the new protocol was higher than compliance with the existing protocol (97.3% to 84.2%, P⟨0.001). There were no cases of a symptomatic hypoglycemic event after the implementation of the protocol. CONCLUSIONS: A quality improvement project implemented by a multidisciplinary team in a hyperbaric practice was feasible and has improved the management of diabetic patients undergoing HBO2 therapy. Considering how the hyperbaric community values the culture of safety and considering the feasibility of this project, more QI training and projects in hyperbaric programs should be performed.

The incidence of hypoglycemia during HBO2 therapy: A retrospective review.

BACKGROUND: Hypoglycemia is concerning in patients with diabetes undergoing hyperbaric oxygen (HBO2) therapy. We aimed to estimate the incidence, risk factors and a pretreatment glucose threshold of HBO2-associated hypoglycemia. METHODS: We retrospectively evaluated a patient cohort undergoing HBO2 therapy. We calculated the area under the curve (AUC) and odds ratio (OR) with 95% confidence interval (CI) adjusting for patients' age, gender, diabetes type, insulin use, body mass index, hemoglobin A1c and HBO2 treatment time. RESULTS: During 77 months, 3,136 HBO2 sessions were performed on patients with diabetes. In-chamber glucose was higher than pre-HBO2 glucose in 1,708/3,136 sessions (54%). The incidence of hypoglycemia (defined as ≤ 70 mg/dL) during or immediately after HBO2 treatment was 1.5% (0.8-2.1%). Hypoglycemia that was symptomatic or severe was rare. A glucose value pre-HBO2 of 150 mg/dL best predicted the risk of subsequent hypoglycemia (AUC 0.80; 95% CI, 0.75-0.86). Type 1 diabetes was independently associated with increased risk of hypoglycemia (OR 3.69; 95% CI, 1.67, 8.19) whereas insulin use was not. CONCLUSIONS: In patients with diabetes undergoing HBO2, severe hypoglycemia is rare and occurs more frequently in Type 1 diabetes. Pre-HBO2 glucose values may be used to predict subsequent hypoglycemia and reduce the need for routine glucose monitoring during and after HBO2.

Hyperbaric hyperoxia reduces exercising forearm blood flow in humans.

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O(2) at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min(-1)·100 mmHg(-1)) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O(2), 1 ATA; inspired Po(2) (Pi(O(2))) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O(2), 2.82 ATA, Pi(O(2)) ≈ 150 mmHg) and hyperoxic (100% O(2), 2.82 ATA, Pi(O(2)) ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia (P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min(-1)·100 mmHg(-1), respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min(-1)·100 mmHg(-1), respectively) did not differ (P = 0.66-0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min(-1)·100 mmHg(-1)) during hyperbaric hyperoxia were substantially attenuated compared with other conditions (P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.

Air embolism: diagnosis and management.

Air embolism is an uncommon, but potentially life-threatening event for which prompt diagnosis and management can result in significantly improved patient outcomes. Most air emboli are iatrogenic. Arterial air emboli may occur as a complication from lung biopsy, arterial catheterization or cardiopulmonary bypass. Immediate management includes placing the patient on high-flow oxygen and in the right lateral decubitus position. Venous air emboli may occur during pressurized venous infusions, or catheter manipulation. Immediate management includes placement of the patient on high-flow oxygen and in the left lateral decubitus and/or Trendelenburg position. Hyperbaric oxygen therapy is the definitive treatment which may decrease the size of air emboli by facilitating gas reabsorption, while also improving tissue oxygenation and reducing ischemic reperfusion injury.

Hyperbaric Oxygen as Radiation Sensitizer for Locally Advanced Squamous Cell Carcinoma of the Oropharynx: A Phase 1 Dose-Escalation Study.

PURPOSE: To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO-100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes-twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale-Head and Neck Cancer and the Functional Assessment of Cancer Therapy-Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. RESULTS: Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy-Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. CONCLUSIONS: While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.

Survival, Risk Factors, and Effect of Treatment in 101 Patients With Calciphylaxis.

OBJECTIVE: To report on the survival and the associations of treatments upon survival of patients with calciphylaxis seen at a single center. PATIENTS AND METHODS: Using the International Classification of Diseases, Ninth Revision diagnosis code of 275.49 and the keyword "calciphylaxis" in the dismissal narrative, we retrospectively identified 101 patients with calciphylaxis seen at our institution between January 1, 1999, through September 20, 2014, using a predefined, consensus-developed classification scheme. RESULTS: The average age of patients was 60 years: 81 (80.2%) were women; 68 (68.0%) were obese; 19 (18.8%) had stage 0 to 2 chronic kidney disease (CKD), 19 (18.9%) had stage 3 or 4 CKD; 63 (62.4%) had stage 5 or 5D (dialysis) CKD. Seventy-five patients died during follow-up. Six-month survival was 57%. Lack of surgical debridement was associated with insignificantly lower 6-month survival (hazard ratio [HR]=1.99; 95% CI, 0.96-4.15; P=.07) and significantly poorer survival for the entire duration of follow-up (HR=1.98; 95% CI, 1.15-3.41; P=.01), which was most pronounced in stage 5 or 5D CKD (HR=1.91; 95% CI, 1.03-3.56; P=.04). Among patients with stage 5/5D CKD, subtotal parathyroidectomy (performed only in patients with hyperparathyroidism) was associated with better 6-month (HR=0.12; 95% CI, 0.02-0.90; P=.04) and overall survival (HR= 0.37; 95% CI, 0.15-0.87; P=.02). CONCLUSION: Calciphylaxis is associated with a high mortality rate. Significantly effective treatments included surgical debridement and subtotal parathyroidectomy in patients with stage 5/5D CKD with hyperparathyroidism. Treatments with tissue-plasminogen activator, sodium thiosulfate, and hyperbaric oxygen therapy were not associated with higher mortality.

Calciphylaxis: A Disease of Pannicular Thrombosis.

OBJECTIVE: To identify coagulation risk factors in patients with calciphylaxis and the relationship between anticoagulation use and overall survival. PATIENTS AND METHODS: Study subjects were 101 patients with calciphylaxis seen at Mayo Clinic from 1999 to September 2014. Data including thrombophilia profiles were extracted from the medical records of each patient. Survival status was determined using patient registration data and the Social Security Death Index. Survival was estimated using the Kaplan-Meier method, and associations were evaluated using Cox proportional hazards models. RESULTS: Sixty-four of the 101 patients underwent thrombophilia testing. Of these, a complete test panel was performed in 55 and a partial panel in 9. Severe thrombophilias observed in 60% (33 of 55) of the patients included antiphospholipid antibody syndrome protein C, protein S, or antithrombin deficiencies or combined thrombophilias. Of the 55 patients, severe thrombophilia (85%, 23 of 27) was noted in patients who were not on warfarin at the time of testing (27). Nonsevere thrombophilias included heterozygous factor V Leiden (n=2) and plasminogen deficiency (n=1). For the comparison of survival, patients were divided into 3 treatment categories: Warfarin (n=63), other anticoagulants (n=20), and no anticoagulants (n=18). There was no statistically significant survival difference between treatment groups. CONCLUSION: Laboratory testing reveals a strikingly high prevalence of severe thrombophilias in patients with calciphylaxis, underscoring the importance of congenital and acquired thrombotic propensity potentially contributing to the pathogenesis of this disease. These findings may have therapeutic implications; however, to date, survival differences did not vary by therapeutic choice.

Using GRADE for evaluating the quality of evidence in hyperbaric oxygen therapy clarifies evidence limitations.

OBJECTIVES: The current evidence rating for hyperbaric oxygen therapy indications uses the American Heart Association system, which mainly depends on the study design. STUDY DESIGN AND SETTING: We systematically reviewed the literature and applied the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach to the main patient-important outcomes in each indication. RESULTS: We included 17 systematic reviews that synthesized 44 randomized trials and 131 observational studies enrolling 8,145 participants. The quality of evidence for seven indications with category A was high (1), moderate (2), low (2), and very low (2); for 10 indications with category B, it was moderate (1), low (5), and very low (4); and for 1 indication with category C, it was high. The quality of evidence was rated down for the risk of bias and imprecision for most indications and rated up because of large effect size for some indications. Most discrepant ratings were in the indications of decompression illness (C, high), carbon monoxide poisoning (A, very low), and later presentations of idiopathic sudden hearing loss (A, very low). CONCLUSION: The GRADE approach uncovered factors affecting the quality of evidence that were otherwise implicit. Knowing these factors can influence clinicians' confidence in applying hyperbaric oxygen therapy and orient the research agenda.

Vasoconstrictor responsiveness during hyperbaric hyperoxia in contracting human muscle.

Large increases in systemic oxygen content cause substantial reductions in exercising forearm blood flow (FBF) due to increased vascular resistance. We hypothesized that 1) functional sympatholysis (blunting of sympathetic α-adrenergic vasoconstriction) would be attenuated during hyperoxic exercise and 2) α-adrenergic blockade would limit vasoconstriction during hyperoxia and increase FBF to levels observed under normoxic conditions. Nine male subjects (age 28 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Studies were performed in a hyperbaric chamber at 1 atmosphere absolute (ATA; sea level) while breathing 21% O(2) and at 2.82 ATA while breathing 100% O(2) (estimated change in arterial O(2) content ∼6 ml O(2)/100 ml). FBF (ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC) was calculated from FBF and blood pressure (arterial catheter). Vasoconstrictor responsiveness was determined using intra-arterial tyramine. FBF and FVC were substantially lower during hyperoxic exercise than normoxic exercise (∼20-25%; P < 0.01). At rest, vasoconstriction to tyramine (% decrease from pretyramine values) did not differ between normoxia and hyperoxia (P > 0.05). During exercise, vasoconstrictor responsiveness was slightly greater during hyperoxia than normoxia (-22 ± 3 vs. -17 ± 2%; P < 0.05). However, during α-adrenergic blockade, hyperoxic exercise FBF and FVC remained lower than during normoxia (P < 0.01). Therefore, our data suggest that although the vasoconstrictor responsiveness during hyperoxic exercise was slightly greater, it likely does not explain the majority of the large reductions in FBF and FVC (∼20-25%) during hyperbaric hyperoxic exercise.

Hyperbaric oxygen therapy for chronic refractory osteomyelitis of the sternum.

This report describes a 32-year-old woman with chronic refractory osteomyelitis of the sternum after multiple surgical procedures including a sternotomy with underlying colonic interposition that was successfully managed with hyperbaric oxygen therapy. The clinical course is reviewed, and the complexities of this diagnosis are then discussed, including a brief review of the mechanisms of management with hyperbaric oxygen therapy.