Adjunctive hyperbaric oxygen therapy in the management of severe lower limb soft tissue injuries: a systematic review.

PURPOSE: Traumatic crush injuries of the lower limb often accompany severe complications. The incorporation of hyperbaric oxygen therapy to standard trauma care may have the potential to diminish injury-related complications and improve outcome in such cases. This systematic review aims to evaluate the effectiveness of hyperbaric oxygen therapy in the management of severe lower limb soft tissue injuries. METHODS: The electronic databases Medline, Embase and Cochrane Library were searched to identify studies involving patients with crush-associated sever lower limb soft tissue injuries who received hyperbaric oxygen therapy in conjunction with standard trauma care. Relevant data on type of injury, hyperbaric oxygen therapy protocol and outcome related to wound healing were extracted. RESULTS: In total seven studies met the inclusion criteria, involving 229 patients. The studies included two randomized clinical trials, one retrospective cohort study, three case series and one case report. The randomized placebo-controlled clinical trial showed a significant increase in wound healing and decrease in the need for additional surgical interventions in the patient group receiving hyperbaric oxygen therapy when compared to those undergoing sham therapy. The randomized non-placebo-controlled clinical trial revealed that early hyperbaric oxygen therapy reduces tissue necrosis and the likelihood of long-term complications. The retrospective cohort study indicated that hyperbaric oxygen therapy effectively reduces infection rates and the need for additional surgical interventions. The case series and case report presented beneficial results with regard to wound healing when hyperbaric oxygen therapy was added to the treatment regimen. CONCLUSION: Hyperbaric oxygen therapy is generally considered a safe therapeutic intervention and seems to have a beneficial effect on wound healing in severe lower limb soft tissue injuries when implemented as an addition to standard trauma care.

Computer tomography perfusion patterns in iatrogenic cerebral arterial gas embolism: A retrospective cohort study.

PURPOSE: Cerebral arterial gas embolism (CAGE) occurs when air or medical gas enters the systemic circulation during invasive procedures and lodges in the cerebral vasculature. Non-contrast computer tomography (CT) may not always show intracerebral gas. CT perfusion (CTP) might be a useful adjunct for diagnosing CAGE in these patients. METHODS: This is a retrospective single-center cohort study. We included patients who were diagnosed with iatrogenic CAGE and underwent CTP within 24 h after onset of symptoms between January 2016 and October 2022. All imaging studies were evaluated by two independent radiologists. CTP studies were scored semi-quantitatively for perfusion abnormalities (normal, minimal, moderate, severe) in the following parameters: cerebral blood flow, cerebral blood volume, time-to-drain and time-to-maximum. RESULTS: Among 27 patient admitted with iatrogenic CAGE, 15 patients underwent CTP within the designated timeframe and were included for imaging analysis. CTP showed perfusion deficits in all patients except one. The affected areas on CTP scans were in general located bilaterally and frontoparietally. The typical pattern of CTP abnormalities in these areas was hypoperfusion with an increased time-to-drain and time-to-maximum, and a corresponding minimal decrease in cerebral blood flow. Cerebral blood volume was mostly unaffected. CONCLUSION: CTP may show specific perfusion defects in patients with a clinical diagnosis of CAGE. This suggests that CTP may be supportive in diagnosing CAGE in cases where no intracerebral gas is seen on non-contrast CT.

Benefits and harms of perioperative high fraction inspired oxygen for surgical site infection prevention: a protocol for a systematic review and meta-analysis of individual patient data of randomised controlled trials.

INTRODUCTION: The use of high fraction of inspired oxygen (FiO2) intraoperatively for the prevention of surgical site infection (SSI) remains controversial. Promising results of early randomised controlled trials (RCT) have been replicated with varying success and subsequent meta-analysis are equivocal. Recent advancements in perioperative care, including the increased use of laparoscopic surgery and pneumoperitoneum and shifts in fluid and temperature management, can affect peripheral oxygen delivery and may explain the inconsistency in reproducibility. However, the published data provides insufficient detail on the participant level to test these hypotheses. The purpose of this individual participant data meta-analysis is to assess the described benefits and harms of intraoperative high FiO2compared with regular (0.21-0.40) FiO2 and its potential effect modifiers. METHODS AND ANALYSIS: Two reviewers will search medical databases and online trial registries, including MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and WHO regional databases, for randomised and quasi-RCT comparing the effect of intraoperative high FiO2 (0.60-1.00) to regular FiO2 (0.21-0.40) on SSI within 90 days after surgery in adult patients. Secondary outcome will be all-cause mortality within the longest available follow-up. Investigators of the identified trials will be invited to collaborate. Data will be analysed with the one-step approach using the generalised linear mixed model framework and the statistical model appropriate for the type of outcome being analysed (logistic and cox regression, respectively), with a random treatment effect term to account for the clustering of patients within studies. The bias will be assessed using the Cochrane risk-of-bias tool for randomised trials V.2 and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. Prespecified subgroup analyses include use of mechanical ventilation, nitrous oxide, preoperative antibiotic prophylaxis, temperature (<35°C), fluid supplementation (<15 mL/kg/hour) and procedure duration (>2.5 hour). ETHICS AND DISSEMINATION: Ethics approval is not required. Investigators will deidentify individual participant data before it is shared. The results will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42018090261.

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.

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.

Seizures in Iatrogenic Cerebral Arterial Gas Embolism.

OBJECTIVES: Iatrogenic cerebral arterial gas embolism occurs when gas enters the cerebral arterial circulation during a medical procedure and is considered a severe complication. Seizures have been described in these patients, but information on clinical characteristics, treatment, and outcome is lacking in current literature. The aim of the study was to explore seizures in patients with iatrogenic cerebral arterial gas embolism and to evaluate management strategies. DESIGN: Retrospective single-center observational study. SETTING: The only university hospital in the Netherlands with a hyperbaric oxygen therapy facility. PATIENTS: All patients presenting at or referred to our center with iatrogenic cerebral arterial gas embolism between May 2016 and December 2020. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Fifteen patients with iatrogenic cerebral arterial gas embolism were identified, of whom 11 (73%) developed seizures. Five patients developed their first seizure prior to hyperbaric oxygen therapy, three during hyperbaric oxygen therapy, and three after hyperbaric oxygen therapy. Of the 11 patients with seizures, all but one were treated with anti-epileptic drugs. With a median follow-up time of 5 months (range, 1-54 mo), five patients showed complete neurologic recovery, five had minor neurologic deficit, two had moderate to severe neurologic deficit, and three had died. Four patients still used anti-epileptic drugs at follow-up. No patients had recurrent seizures after hospital discharge. CONCLUSIONS: `Seizures are a common symptom in iatrogenic cerebral arterial gas embolism. They are often treated with anti-epileptic drugs and do not seem to lead to chronic epilepsy.

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.

Second Update for Anaesthetists on Clinical Features of COVID-19 Patients and Relevant Management.

The COVID-19 pandemic poses great challenges for healthcare workers around the world, including perioperative specialists. Previously, we provided a first overview of available literature on SARS-CoV-2 and COVID-19, relevant for anaesthetists and intensivists. In the current review, we provide an update of this topic, after a literature search current through May 2020. We discuss the evidence on perioperative risk for COVID-19 patients presenting for surgery, the risk of transmission of SARS-CoV-2 in the operating room, and the current literature on laboratory diagnostics. Furthermore, cardiovascular and nervous system involvement in COVID-19 are discussed, as well as considerations in diabetic patients. Lastly, the latest evidence on pharmacological treatment is summarised.

Perioperative Hyperoxyphobia: Justified or Not? Benefits and Harms of Hyperoxia during Surgery.

The use of an inspiratory oxygen fraction of 0.80 during surgery is a topic of ongoing debate. Opponents claim that increased oxidative stress, atelectasis, and impaired oxygen delivery due to hyperoxic vasoconstriction are detrimental. Proponents point to the beneficial effects on the incidence of surgical site infections and postoperative nausea and vomiting. Also, hyperoxygenation is thought to extend the safety margin in case of acute intraoperative emergencies. This review provides a comprehensive risk-benefit analysis for the use of perioperative hyperoxia in noncritically ill adults based on clinical evidence and supported by physiological deduction where needed. Data from the field of hyperbaric medicine, as a model of extreme hyperoxygenation, are extrapolated to the perioperative setting. We ultimately conclude that current evidence is in favour of hyperoxia in noncritically ill intubated adult surgical patients.

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.

Characterization and quantification of porcine circulating endothelial cells.

BACKGROUND: Endothelial damage is a critical step in the development of (xeno) transplantation-related and cardiovascular pathology. In humans, the amount of circulating endothelial cells (CEC) correlates to disease intensity and functions as a valuable damage marker. While (xeno) transplantation and cardiovascular research is regularly performed in porcine models, the paucity of antibodies against porcine endothelium epitopes hinders the use of CEC as damage marker. OBJECTIVE: This study aimed to develop a method for porcine CEC detection using anti-human antibodies against porcine endothelium epitopes. METHODS: Human umbilical vein endothelial cells (HUVEC, control) and their swine equivalent (SUVEC) were used to assess the cross-species immunoreactivity of fluorescently labeled anti-human CD31/CD51/CD54/CD62E/CD105/CD106/CD144/CD146/PAL-E/lectin-1/vWF antibodies by isotype-controlled fluorescence-activated cell sorting (FACS) and confocal microscopy. Next, reactivity was ascertained with mature porcine kidney-derived endothelial cells (PKEC), and a FACS-based whole blood CEC quantification method was employed using osmotic erythrolysis and CD105 and CD146 double staining after CD45 exclusion. RESULTS: Of the 21 assayed antibodies, the MEM-229 clone of CD105 and P1H12 clone of CD146 showed immunoreactivity with SUVEC and PKEC. Double staining showed baseline porcine CEC count of 673.1 ± 551.4 CEC/ml, while the first 7.5 ml of drawn blood (representative of vascular damage) contained 1118 ± 661.4 CEC/ml (n = 14, P = 0.04). A second experiment (n = 5) including CD45 exclusion identified only 14.5 ± 10.8% double-positive CD105-146 events per ml blood. CONCLUSION: Porcine endothelium can be specifically labeled using anti-human CD146 and CD105 antibodies. These antibodies can therefore be used for the identification and quantification of CEC in porcine whole blood by FACS after osmotic erythrolysis.

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.

Animal models of cerebral arterial gas embolism.

Cerebral arterial gas embolism is a dreaded complication of diving and invasive medical procedures. Many different animal models have been used in research on cerebral arterial gas embolism. This review provides an overview of the most important characteristics of these animal models. The properties discussed are species, cerebrovascular anatomy, method of air embolization, amount of air, bubble size, outcome parameters, anesthesia, blood glucose, body temperature and blood pressure.

Quantitative electroencephalography in a swine model of cerebral arterial gas embolism.

OBJECTIVE: Cerebral arterial gas embolism (CAGE) is a serious hazard in cardiovascular surgery and other invasive procedures. We used a swine model of CAGE to determine if quantitative electroencephalography (qEEG) is a useful tool in diagnosis and prognostication of CAGE. METHODS: 0.05 ml/kg of air was injected into the ascending pharyngeal artery in 16 pigs. Intracranial pressure, lactate in brain microdialysate and brain oxygen tension were measured during 4h after embolization. The qEEG parameters mean amplitude (MAMP), alpha-delta ratio (ADR), spectral edge frequency (SEF(90)), spatial brain symmetry index (sBSI) and temporal brain symmetry index (tBSI) were calculated. RESULTS: MAMP and tBSI but not ADR, SEF(90) and sBSI correlate with intracranial pressure, brain lactate and brain oxygen tension after 4h. Early levels of MAMP and tBSI can predict intracranial pressure, brain lactate and brain oxygen tension after 4h. CONCLUSIONS: MAMP and tBSI are sensitive for cerebral injury and can predict outcome in a swine model of CAGE. SIGNIFICANCE: This study provides evidence for the utility of qEEG for diagnosis and prognosis in CAGE. Further studies are necessary to investigate the use of this method in patients.

Cerebral arterial gas embolism in swine. Comparison of two sites for air injection.

Cerebral arterial gas embolism is a risk in diving and occurs as a complication in surgery and interventional radiology. Swine models for cerebral arterial gas embolism have been used in the past. However, injection of air into the main artery feeding the pig brain - the ascending pharyngeal artery - might be complicated by the presence of the carotid rete, an arteriolar network at the base of the brain. On the other hand, anastomoses between external and internal carotid territories are present in the pig. In order to determine the most appropriate vessel for air injection, we performed experiments in which air was injected into either the ascending pharyngeal artery or the external carotid artery. We injected 0.25 ml/kg of room air selectively into the ascending pharyngeal artery or the external carotid artery of 35-40 kg Landrace pigs (n=8). We assessed the effect on cerebral metabolism by measuring intracranial pressure, brain oxygen tension and brain glucose and lactate concentrations using cerebral microdialysis. Intracranial pressure and brain oxygen tension changed significantly in both groups, but did not differ between groups. Brain lactate increased significantly more in pigs in which air was injected into the ascending pharyngeal artery. Intracranial pressure, brain oxygen tension and brain lactate correlated after injection of air into the ascending pharyngeal artery, but not after injection into the external carotid artery. Our model is suitable for investigation of cerebral arterial gas embolism. The ascending pharyngeal artery is the most appropriate vessel for air injection.