Early hyperbaric oxygen therapy is associated with favorable outcome in patients with iatrogenic cerebral arterial gas embolism: systematic review and individual patient data meta-analysis of observational studies.

BACKGROUND: Iatrogenic cerebral arterial gas embolism (CAGE) caused by invasive medical procedures may be treated with hyperbaric oxygen therapy (HBOT). Previous studies suggested that initiation of HBOT within 6-8 h is associated with higher probability of favorable outcome, when compared to time-to-HBOT beyond 8 h. We performed a group level and individual patient level meta-analysis of observational studies, to evaluate the relationship between time-to-HBOT and outcome after iatrogenic CAGE. METHODS: We systematically searched for studies reporting on time-to-HBOT and outcome in patients with iatrogenic CAGE. On group level, we meta-analyzed the differences between median time-to-HBOT in patients with favorable versus unfavorable outcome. On individual patient level, we analyzed the relationship between time-to-HBOT and probability of favorable outcome in a generalized linear mixed effects model. RESULTS: Group level meta-analysis (ten studies, 263 patients) shows that patients with favorable outcome were treated with HBOT 2.4 h (95% CI 0.6-9.7) earlier than patients with unfavorable outcome. The generalized linear mixed effects model (eight studies, 126 patients) shows a significant relationship between time-to-HBOT and probability of favorable outcome (p = 0.013) that remains significant after correcting for severity of manifestations (p = 0.041). Probability of favorable outcome decreases from approximately 65% when HBOT is started immediately, to 30% when HBOT is delayed for 15 h. CONCLUSIONS: Increased time-to-HBOT is associated with decreased probability of favorable outcome in iatrogenic CAGE. This suggests that early initiation of HBOT in iatrogenic CAGE is of vital importance.

Effect of hyperbaric oxygen treatment on skin elasticity in irradiated patients.

BACKGROUND: Hyperbaric oxygen treatment (HBOT) is often used in an attempt to reverse/treat late radiation-induced tissue fibrosis (LRITF). This study aimed to quantify the effects on skin elasticity. METHODS: Skin retraction time was used as a marker of skin elasticity in 13 irradiated breast cancer patients. The measurements were carried out on the affected side as well as the unaffected/healthy side at a mirrored location. Readings were taken at the start and end of HBOT (mean 43 sessions, 80 min at 243 kPa). RESULTS: Patient age ranged from 39-70 years. All patients underwent surgical lumpectomy and radiotherapy prior to undergoing HBOT. The mean time between radiotherapy and HBOT was 70 months. Seven of the 13 patients underwent chemotherapy. Mean irradiated skin retraction time improved from 417 (SD 158) pre-HBOT to 171 (24) msec post-HBOT (P < 0.001). Mean pre-HBOT retraction time in the non-irradiated skin was 143 (20) msec and did not change. CONCLUSIONS: This promising pilot study that suggests that HBOT may improve skin elasticity in patients with LRITF.

The impact of hyperbaric oxygen therapy on late irradiation injury in oral microcirculation.

BACKGROUND: Late side effects of radiotherapy in patients with head and neck cancer (HNCPs) result in decreased tissue vascularity, a compromised healing capacity and spontaneous breakdown of tissue. The aim of this study was to examine the in vivo effect of hyperbaric oxygen therapy (HBOT) on the microcirculation in irradiated oral tissue. METHODS: Using a handheld microscope, the effect of HBOT on oral mucosal microcirculation parameters was measured in 34 previously irradiated HNCPs prior to HBOT and at 4 weeks and 6 months posttreatment. RESULTS: A significant increase in mean buccal vessel density and decrease in buccal vessel diameter was found 6 months after HBOT compared to baseline, 22 ± 11 versus 25 ± 7 cpll/mm2 (p < 0.05) and 20 ± 4 versus 16 ± 5 µm (p < 0.05), respectively. CONCLUSION: Our results indicate that oral microcirculation histopathology associated with irradiation is able to respond to HBOT by redirecting oral microcirculation parameters towards values consistent with healthy tissue.

The Effect of Hyperbaric Oxygen Therapy on Markers of Oxidative Stress and the Immune Response in Healthy Volunteers.

Hyperbaric oxygen therapy (HBOT) consists of breathing 100% oxygen under increased ambient pressure. There are indications that HBOT induces oxidative stress and activates immune pathways. However, previous research on immunological effects of HBOT has mainly been established in in vitro experiments and selected patient populations, limiting generalizability and increasing the chances of confounding by comorbidities and specific patient-related factors. More insight into the immunological effects of HBOT would aid investigation and comprehension of potentially novel treatment applications. Therefore, in this study, we investigated the effects of three 110-min HBOT-sessions with 24-h intervals on immunological parameters in healthy, young, male volunteers. Blood samples were obtained before and after the first and third HBOT sessions. We assessed neutrophilic reactive oxygen species (ROS) production, systemic oxidative stress [plasma malondialdehyde (MDA) concentrations] as well as neutrophil phagocytic activity, plasma concentrations of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and IL-10, and production of TNF, IL-6, and IL-10 by leukocytes ex vivo stimulated with the Toll-like receptor (TLR) ligands lipopolysaccharide (TLR4) and Pam3Cys (TLR2). We observed decreased neutrophilic ROS production and phagocytosis following the second HBOT session, which persisted after the third session, but no alterations in MDA concentrations. Furthermore, plasma concentrations of the investigated cytokines were unaltered at all-time points, and ex vivo cytokine production was largely unaltered over time as well. These results indicate no induction of systemic oxidative stress or a systemic inflammatory response after repeated HBOT in healthy volunteers but may suggest exhaustion of ROS generation capacity and phagocytosis.

The Effects of Hyperbaric Oxygenation on Oxidative Stress, Inflammation and Angiogenesis.

Hyperbaric oxygen therapy (HBOT) is commonly used as treatment in several diseases, such as non-healing chronic wounds, late radiation injuries and carbon monoxide poisoning. Ongoing research into HBOT has shown that preconditioning for surgery is a potential new treatment application, which may reduce complication rates and hospital stay. In this review, the effect of HBOT on oxidative stress, inflammation and angiogenesis is investigated to better understand the potential mechanisms underlying preconditioning for surgery using HBOT. A systematic search was conducted to retrieve studies measuring markers of oxidative stress, inflammation, or angiogenesis in humans. Analysis of the included studies showed that HBOT-induced oxidative stress reduces the concentrations of pro-inflammatory acute phase proteins, interleukins and cytokines and increases growth factors and other pro-angiogenesis cytokines. Several articles only noted this surge after the first HBOT session or for a short duration after each session. The anti-inflammatory status following HBOT may be mediated by hyperoxia interfering with NF-κB and IκBα. Further research into the effect of HBOT on inflammation and angiogenesis is needed to determine the implications of these findings for clinical practice.

A modified device for continuous non-invasive blood pressure measurements in humans under hyperbaric and/or oxygen-enriched conditions.

BACKGROUND: It would be desirable to safely and continuously measure blood pressure noninvasively under hyperbaric and/or hyperoxic conditions, in order to explore haemodynamic responses in humans under these conditions. METHODS: A systematic analysis according to 'failure mode and effects analysis' principles of a commercially available beat-by-beat non-invasive blood pressure monitoring device was performed using specifications provided by the manufacturer. Possible failure modes related to pressure resistance and fire hazard in hyperbaric and oxygen-enriched environments were identified and the device modified accordingly to mitigate these risks. The modified device was compared to an unaltered device in five healthy volunteers under normobaric conditions. Measurements were then performed under hyperbaric conditions (243 kPa) in five healthy subjects. RESULTS: Modifications required included: 1) replacement of the carbon brush motorized pump by pressurized air connected through a balanced pressure valve; 2) modification of the 12V power supply connection in the multiplace hyperbaric chamber, and 3) replacement of gas-filled electrolytic capacitors by solid equivalents. There was concurrence between measurements under normobaric conditions, with no significant differences in blood pressure. Measurements under pressure were achieved without problems and matched intermittent measurement of brachial arterial pressure. CONCLUSION: The modified system provides safe, stable, continuous non-invasive blood pressure trends under both normobaric and hyperbaric conditions.

Sublingual microvascular perfusion is altered during normobaric and hyperbaric hyperoxia.

Hyperoxia and hyperbaric oxygen therapy can restore oxygen tensions in tissues distressed by ischemic injury and poor vascularization and is believed to also yield angiogenesis and regulate tissue perfusion. The aim of this study was to develop a model in which hyperoxia-driven microvascular changes could be quantified and to test the hypothesis that microcirculatory responses to both normobaric (NB) and hyperbaric (HB) hyperoxic maneuvers are reversible. Sublingual mucosa microcirculation vessel density, proportion of perfused vessels, vessel diameters, microvascular flow index, macrohemodynamic, and blood gas parameters were examined in male rabbits breathing sequential O2/air mixtures of 21%, 55%, 100%, and return to 21% during NB (1.0 bar) and HB (2.5 bar) conditions. The results indicate that NB hyperoxia (55% and 100%) produced significant decreases in microvascular density and vascular diameters (p<0.01 and p<0.05, respectively) accompanied by significant increases in systolic and mean arterial blood pressure (p<0.05, respectively) with no changes in blood flow indices when compared to NB normoxia. HB normoxia/hyperoxia resulted in significant decreases in microvascular density (p<0.05), a transient rise in systolic blood pressure at 55% (p<0.01), and no changes in blood vessel diameter and blood flow indices when compared to NB hyperoxia. All microcirculation parameters reverted back to normal values upon return to NB normoxia. We conclude that NB/HB hyperoxia-driven changes elicit reversible physiological control of sublingual mucosa blood perfusion in the presence of steady cardiovascular function and that the absence of microvascular vasoconstriction during HB conditions suggests a beneficial mechanism associated with maintaining peak tissue perfusion states.

A retrospective cohort study of lidocaine in divers with neurological decompression illness.

Lidocaine is the most extensively studied substance for adjuvant therapy in neurological decompression illness (DCI), but results have been conflicting. In this retrospective cohort study, we compared 14 patients who received adjuvant intravenous lidocaine for neurological decompression sickness and cerebral arterial gas embolism between 2001 and 2011 against 21 patients who were treated between 1996 and 2001 and did not receive lidocaine. All patients were treated with hyperbaric oxygen (HBO2) therapy according to accepted guidelines. Groups were comparable for all investigated confounding factors, except that significantly more control patients had made an unsafe dive (62% vs. 14%, p = 0.007). Groups had comparable injury severity as measured by Dick and Massey score (lidocaine 2.7 +/- 1.7, control 2.0 +/- 1.6), an adapted version of the Dick and Massey score, and the Blatteau score. Number of HBO2 sessions given was comparable in both groups (lidocaine 2.7 +/- 2.3, control 2.0 +/- 1.0). There was neither a positive nor a negative effect of lidocaine on outcome (relative risk for objective neurological signs at follow-up in the lidocaine group was 1.8, 95% CI 0.2-16). This is the first retrospective cohort study of lidocaine in neurological DCI. Since our study is under-powered to draw definitive conclusions, a prospective multicenter study remains the only way to reliably determine the effect of lidocaine in neurological decompression illness.

Frostbite of both first digits of the foot treated with delayed hyperbaric oxygen:a case report and review of literature.

BACKGROUND: Frostbite is an uncommon event that can occur from exposure to temperatures below -4 degrees C and can lead to potential serious tissue damage and necrosis. This in turn can result in debilitating amputations in otherwise healthy people. The pathophysiological mechanisms of frostbite have marked similarities to those seen in thermal burns, ischemia/reperfusion injuries and crush injuries--i.e., non-healing wounds and inflammatory processes. These injuries are commonly treated with hyperbaric oxygen therapy. OBJECTIVES: Evidence for treating frostbite with hyperbaric oxygen (HBO2) is scarce, and to date HBO2 is not a standard addition in the multidisciplinary care of freezing injuries. We aim to contribute to the available evidence with a case report and review the literature to reassess the multidisciplinary treatment of frostbite injuries. CASE REPORT AND REVIEW OF LITERATURE: We present a case report of a woman with deep frostbite of the toes treated with hyperbaric oxygen therapy, after a delay of 21 days, with good results. No surgical intervention was needed. A literature search revealed 17 human case reports on frostbite and four animal studies in which hyperbaric oxygen was applied. All case reports showed positive effects, and in none of the cases was amputation necessary. In the animal studies, two showed significant positive results regarding tissue loss and reduction of inflammatory markers, whereas two did not. CONCLUSIONS: Based on our case report as well as the literature and the mechanisms of hyperbaric oxygen, we make the recommendation that this therapy be considered as an addition to the multidisciplinary treatment of frostbite, even after significant delay of treatment.

Hyperbaric oxygen therapy accelerates vascularization in keratinized oral mucosal surgical flaps.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) is thought to promote vascular regeneration in wounds. The purpose of this study was to investigate the role of HBOT in advancing vascular regeneration in healing oral mucosal surgical flaps. METHODS: A palatine partial-thickness mucosal flap was raised in 10 male-specific pathogen-free New Zealand White rabbits. Randomized into 2 groups of 5 animals each (control and HBOT), functional capillary density was measured preoperatively (baseline), and immediately postoperatively until day 21 using sidestream dark-field video microscopy. Ten HBOT sessions were administered over the course of 2 weeks at 2.5 atmospheres (2.5 bar O2 /90 minutes). RESULTS: Repeated measures analysis of variance was used to compare the HBOT and control group on the sequential functional capillary density measurements. A significant interaction effect was present between time and group (F [8, 64] = 9.60; p < .0001) resulting from a significant increase in microcirculation in the HBOT group relative to the control group on days 7, 9, and 11. CONCLUSION: Our results suggest that HBOT is capable of advancing wound vascular regeneration in healing keratinized oral mucosal flaps.

Hyperbaric oxygen does not improve cerebral function when started 2 or 4 hours after cerebral arterial gas embolism in swine.

OBJECTIVE: Hyperbaric oxygenation is the accepted treatment for cerebral arterial gas embolism. Although earlier start of hyperbaric oxygenation is associated with better outcome, it is unknown how much delay can be tolerated before start of hyperbaric oxygenation. This study investigates the effect of hyperbaric oxygenation on cerebral function in swine when initiated 2 or 4 hours after cerebral arterial gas embolism. DESIGN: Prospective interventional animal study. SETTING: Surgical laboratory and hyperbaric chamber. SUBJECTS: Twenty-two Landrace pigs. INTERVENTIONS: Under general anesthesia, probes to measure intracranial pressure, brain oxygen tension (PbtO2), and brain microdialysis, and electrodes for electroencephalography were placed. The electroencephalogram (quantified using temporal brain symmetry index) was suppressed during 1 hour by repeated injection of air boluses through a catheter placed in the right ascending pharyngeal artery. Hyperbaric oxygenation was administered using U.S. Navy Treatment Table 6 after 2- or 4-hour delay. Control animals were maintained on an inspiratory oxygen fraction of 0.4. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure increased to a mean maximum of 19 mm Hg (SD, 4.5 mm Hg) due to the embolization procedure. Hyperbaric oxygenation significantly increased PbtO2 in both groups treated with hyperbaric oxygenation (mean maximum PbtO2, 390 torr; SD, 177 torr). There were no significant differences between groups with regard to temporal brain symmetry index (control vs 2-hr delay, p = 0.078; control vs 4-hr delay, p = 0.150), intracranial pressure, and microdialysis values. CONCLUSIONS: We did not observe an effect of hyperbaric oxygenation on cerebral function after a delay of 2 or 4 hours. The injury caused in our model could be too severe for a single session of hyperbaric oxygenation to be effective. Our study should not change current hyperbaric oxygenation strategies for cerebral arterial gas embolism, but further research is necessary to elucidate our results. Whether less severe injury benefits from hyperbaric oxygenation should be investigated in models using smaller amounts of air and clinical outcome measures.

Acute neurological symptoms during hypobaric exposure: consider cerebral air embolism.

Cerebral arterial gas embolism (CAGE) is well known as a complication of invasive medical procedures and as a risk in diving and submarine escape. In the underwater environment, CAGE is caused by trapped air, which expands and leads to lung vessel rupture when ambient pressure decreases during ascent. Pressure decrease also occurs during hypobaric activities such as flying and, therefore, CAGE may theoretically be a risk in hypobaric exposure. We reviewed the available literature on this subject. Identified were 12 cases of CAGE due to hypobaric exposure. Based on these cases, we discuss pathophysiology, diagnosis, and treatment of CAGE due to hypobaric exposure. The low and slow pressure decrease during most hypobaric activities (as opposed to diving) account for the low incidence of CAGE during these exposures and suggest that severe air trapping must be present to cause barotrauma. This is also suggested by the large prevalence of air filled cysts in the case reports reviewed. We recommend considering CAGE in all patients presenting with acute central neurological injury during or shortly after pressure decrease such as flying. A CT scan of head and chest should be performed in these patients. Treatment with hyperbaric oxygen therapy should be initiated as soon as possible in cases of proven or probable CAGE.

Effects of hyperbaric treatment in cerebral air embolism on intracranial pressure, brain oxygenation, and brain glucose metabolism in the pig.

OBJECTIVE: To evaluate the effects of hyperbaric oxygen treatment after cerebral air embolism on intracranial pressure, brain oxygenation, brain glucose/lactate metabolism, and electroencephalograph. DESIGN: Prospective animal study. SETTING: Hyperbaric chamber. SUBJECTS: Eleven Landrace/Yorkshire pigs. INTERVENTIONS: In 11 anesthetized pigs, intracranial pressure and brain oxygenation were measured with microsensor technology, brain glucose/lactate by microdialysis, and electroencephalograph by conventional methods. After injection of air into the internal carotid artery, animals were treated immediately (at 3 mins; t = 3) or at 60 mins (t = 60) with U.S. Navy Treatment Table 6 for 4.48 hrs. RESULTS: At the end of hyperbaric oxygen treatment, intracranial pressure in the t = 60 group (39 +/- 8 mm Hg) was significantly higher than in the t = 3 group (27 +/- 6 mm Hg), brain oxygenation values for group t = 3 and t = 60 were 66 +/- 14 and 52 +/- 15 mm Hg, respectively (no significant difference from baseline), and there were no pathologic scores in the visually assessed electroencephalograph. However, there was a significant decrease in brain glucose and a significant increase in brain lactate in both groups at the end of the 5-hr study period. CONCLUSIONS: Hyperbaric oxygen treatment initiated at both 3 and 60 mins after embolization decreased the deleterious effects of cerebral air embolism on intracranial pressure and brain metabolism. Therefore, this model appears suitable to test the application of hyperbaric oxygen treatment with a delay >60 mins after embolization, as is often the case in the clinical situation.

Hyperventilation impairs brain function in acute cerebral air embolism in pigs.

OBJECTIVE: To evaluate, in a model of cerebral air embolism (CAE), the effects of ventilation-induced hypocapnia and hyperoxemia on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain oxygen (PbrO(2)), brain carbon dioxide (PbrCO(2)), brain pH (brpH) and levels of brain glucose and lactate. DESIGN AND SETTING: Prospective animal study in a university medical center. SUBJECTS: Fifteen Landrace/Yorkshire pigs. INTERVENTIONS: In 15 anesthetized pigs ICP, PbrO(2), PbrCO(2) and brpH were measured with multi-parameter sensors, and brain glucose and lactate by microdialysis. All these parameters were recorded for 2 h after injection of air into the internal carotid artery. Nine animals were hyperventilated (PaCO(2 )+/-25 mmHg) and hyperoxygenated (FiO(2) 1.0) and six animals were normoventilated (PaCO(2)()+/-40 mmHg with an FiO(2) 0.4) and served as controls. RESULTS. In the treatment group the ICP rose from 8+/-1 to 52+/-6 mmHg, which was similar to that in the control group (12+/-1 to 57+/-8 mmHg). At the end of the 2-h study period, there were no significant differences in PbrO(2), PbrCO(2) and brpH between the two groups. The decreased brain glucose and increased brain lactate reached severe pathological values in both groups by the end of the 2-h study period. CONCLUSIONS: Hypocapnia and hyperoxemia in acute CAE did not improve pathological functional brain parameters compared with normoventilated controls. Similarly, the pathological changes in brain glucose/lactate could also not be improved by hypocapnia and hyperoxemia.

Quantitative EEG monitoring during cerebral air embolism and hyperbaric oxygen treatment in a pig model.

The purpose of this study was to evaluate the contribution of quantitative EEG (qEEG) to an animal model of cerebral air embolism (CAE). In 12 anesthetized pigs, air was injected into the internal carotid artery, and hyperbaric oxygen (HBO) treatment was started either after 3 minutes or after 60 minutes (United States Navy Treatment Table 6). Off-line spectral analysis was used to determine the frequency content of the EEG signal, and factor analysis was performed to determine the frequency ranges that optimally showed the changes in the power spectrum. Factor analysis revealed two factors that represented different and independent spectral changes during embolization: 0.5 to 7.3 Hz (band 1) and 26.4 to 30.3 Hz (band 2). Shortly after embolization, the power in both bands decreased to a minimum, representing an isoelectric EEG in 11 out of the 12 animals. EEG differences between animals were considerable, despite standardized doses of injected air, and qEEG can objectively assess and quantify these differences in immediate impact of air embolism on brain function. Also, qEEG enabled monitoring of the recovery from the initial embolic event and of the response on treatment. The initial recovery was much more protracted in band 2 than in band 1, but even after completing HBO treatment, qEEG values did not return to baseline values in all animals. In addition, two animals did not survive until the end of the HBO treatment, and qEEG proved to be superior to the other measured hemodynamic variables to detect and ensure a deterioration of brain function. This study showed that qEEG monitoring has significant additional value to monitoring HBO treatment.

Gas embolism: pathophysiology and treatment.

Based on a literature search, an overview is presented of the pathophysiology of venous and arterial gas embolism in the experimental and clinical environment, as well as the relevance and aims of diagnostics and treatment of gas embolism. The review starts with a few historical observations and then addresses venous air embolism by discussing pulmonary vascular filtration, entrapment, and the clinical occurrence of venous air emboli. The section on arterial gas embolism deals with the main mechanisms involved, coronary and cerebral air embolism (CAE), and the effects of bubbles on the blood-brain barrier. The diagnosis of CAE uses various techniques including ultrasound, perioperative monitoring, computed tomography, brain magnetic resonance imaging and other modalities. The section on therapy starts by addressing the primary treatment goals and the roles of adequate oxygenation and ventilation. Then the rationale for hyperbaric oxygen as a therapy for CAE based on its physiological mode of action is discussed, as well as some aspects of adjuvant drug therapy. A few animal studies are presented, which emphasize the importance of the timing of therapy, and the outcome of patients with air embolism (including clinical patients, divers and submariners) is described.

Oxygen tension under hyperbaric conditions in healthy pig brain.

OBJECTIVE: To investigate the effect of hyperbaric conditions on brain oxygenation, intracranial pressure and brain glucose/lactate levels in healthy non-brain-traumatized animals. DESIGN AND SETTING: Prospective animal study in a hyperbaric chamber. SUBJECTS: Twelve adult Landrace/Yorkshire pigs. INTERVENTIONS: The animals were normoventilated in a pressure-controlled mode according to the open lung concept first at normobaric pressures (FiO2 of 0.4 and 1.0) and subsequently in the hyperbaric chamber at 1.9 and 2.8 bar (both at an FiO2 of 1.0). Under these conditions brain oxygen tension and intracranial pressure were recorded and brain glucose/lactate levels were measured by microdialysis. RESULTS: At normobaric conditions, increasing the FiO2 from 0.4 (baseline) to 1.0 resulted in a significant increase in brain oxygen tension from 33 +/- 14 to 63 +/- 28 mmHg (P<0.05). Compared with baseline, both hyperbaric conditions (at an FiO2 of 1.0) led to a significant increase in brain oxygen tension to 151 +/- 65 mmHg (P<0.001) at 1.9 bar and to 294 +/- 134 mmHg (P<0.001) at 2.8 bar. CONCLUSIONS: If there is a need for increased oxygenation in the brain, then one way to achieve this is to apply hyperbaric conditions at 100% oxygen. Compared with an atmospheric pressure with a FiO2 of 0.4, a nine-fold increase (900%) in PbrO2 values can be reached by increasing the FiO2 to 1.0 and the pressure to 2.8 bar. In this study, hyperbaric oxygen pressure in the brain did not lead to changes in intracranial pressure or in brain glucose/lactate levels.