Contemporary national outcomes of hyperbaric oxygen therapy in necrotizing soft tissue infections.

BACKGROUND: The role of hyperbaric oxygen therapy (HBOT) in necrotizing soft tissue infections (NSTI) is mainly based on small retrospective studies. A previous study using the 1998-2009 National Inpatient Sample (NIS) found HBOT to be associated with decreased mortality in NSTI. Given the argument of advancements in critical care, we aimed to investigate the continued role of HBOT in NSTI. METHODS: The 2012-2020 National Inpatient Sample (NIS) was queried for NSTI admissions who received surgery. 60,481 patients between 2012-2020 were included, 600 (<1%) underwent HBOT. Primary outcome was in-hospital mortality. Secondary outcomes included amputation, hospital length of stay, and costs. A multivariate model was constructed to account for baseline differences in groups. RESULTS: Age, gender, and comorbidities were similar between the two groups. On bivariate comparison, the HBOT group had lower mortality rate (<2% vs 5.9%, p<0.001) and lower amputation rate (11.8% vs 18.3%, p<0.001) however, longer lengths of stay (16.9 days vs 14.6 days, p<0.001) and higher costs ($54,000 vs $46,000, p<0.001). After multivariate analysis, HBOT was associated with decreased mortality (Adjusted Odds Ratio (AOR) 0.22, 95% CI 0.09-0.53, P<0.001) and lower risk of amputation (AOR 0.73, 95% CI 0.55-0.96, P = 0.03). HBO was associated with longer stays by 1.6 days (95% CI 0.4-2.7 days) and increased costs by $7,800 (95% CI $2,200-$13,300), they also had significantly lower risks of non-home discharges (AOR 0.79, 95%CI 0.65-0.96). CONCLUSIONS: After correction for differences, HBOT was associated with decreased mortality, amputations, and non-home discharges in NSTI with the tradeoff of increase to costs and length of stay.

Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

A novel method for tracking nitrogen kinetics in vivo under hyperbaric conditions using radioactive nitrogen-13 gas and positron emission tomography.

Decompression sickness (DCS) is caused by gaseous nitrogen dissolved in tissues forming bubbles during decompression. To date, no method exists to identify nitrogen within tissues, but with advances in positron-emission tomography (PET) technology, it may be possible to track gaseous radionuclides into tissues. We aimed to develop a method to track nitrogen movement in vivo and under hyperbaric pressure that could then be used to further our understanding of DCS using nitrogen-13 (13N2). A single anesthetized female Sprague-Dawley rat was exposed to 625 kPa, composed of air, isoflurane, and 13N2 for 10 min. The PET scanner recorded 13N2 during the hyperbaric exposure with energy windows of 250-750 keV. The PET showed an increase in 13N2 concentration in the lung, heart, and abdominal regions, which all reached a plateau after ∼4 min. This showed that it is possible to gain noninvasive in vivo measurements of nitrogen kinetics through the body while at hyperbaric pressures. Tissue samples showed radioactivity above background levels in the blood, brain, liver, femur, and thigh muscle when assessed using a γ counter. The method can be used to evaluate an array of challenges to our understanding of decompression physiology by quantifying nitrogen load through γ counts of 13N2, and signal intensity of the PET. Further development of the method will improve the specificity of the measured outcomes, and enable it to be used with larger mammals, including humans.NEW & NOTEWORTHY This article describes a method for the in vivo quantification and tracking of nitrogen through the mammalian body whilst exposed to hyperbaric pressure. The method has the potential to further our understanding of decompression sickness, and quantitatively evaluate the effectiveness of both the treatment and prevention of decompression sickness.

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial.

BACKGROUND: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. METHODS: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. RESULTS: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort. CONCLUSIONS: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial.

INTRODUCTION: Long COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL. METHODS AND ANALYSIS: A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board. ETHICS AND DISSEMINATION: The trial is approved by the Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access. TRIAL REGISTRATION NUMBER: NCT04842448.

Paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty: protocol for the randomised, placebo-controlled, parallel 4-group, blinded, multicentre RECIPE trial.

INTRODUCTION: Multimodal analgesia with paracetamol, non-steroidal anti-inflammatory drug and glucocorticoid is recommended for hip arthroplasty, but with uncertain effects of the different combinations. We aim to investigate benefit and harm of different combinations of paracetamol, ibuprofen and dexamethasone following total hip arthroplasty. METHODS AND ANALYSIS: RECIPE is a randomised, placebo-controlled, parallel 4-group, blinded trial with 90-day and 1-year follow-up performed at nine Danish hospitals. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Eligible participants undergoing total hip arthroplasty are randomised to:group A: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous placebo; group B: oral paracetamol 1000 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group C: oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group D: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg.Primary outcome is cumulative opioid consumption at 0-24 hours. Secondary outcomes are pain at rest, during mobilisation and during a 5 m walk and adverse events. Follow-up includes serious adverse events and patient reported outcome measures at 90 days and 1 year. A total of 1060 participants are needed to demonstrate a difference of 8 mg in 24-hour morphine consumption assuming an SD of 24.5 mg, a risk of type I errors of 0.0083 and a risk of type 2 errors of 0.2. Primary analysis will be a modified intention-to-treat analysis.With this trial we aim to verify recommendations for pain treatment after total hip arthroplasty, and investigate the role of dexamethasone as an analgesic adjuvant to paracetamol and ibuprofen. ETHICS AND DISSEMINATION: This trial is approved by the Region Zealand Committee on Health Research Ethics (SJ-799). Plans for dissemination include publication in peer-reviewed journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT04123873.

The Host-Microbiome Response to Hyperbaric Oxygen Therapy in Ulcerative Colitis Patients.

BACKGROUND & AIMS: Hyperbaric oxygen therapy (HBOT) is a promising treatment for moderate-to-severe ulcerative colitis. However, our current understanding of the host and microbial response to HBOT remains unclear. This study examined the molecular mechanisms underpinning HBOT using a multi-omic strategy. METHODS: Pre- and post-intervention mucosal biopsies, tissue, and fecal samples were collected from HBOT phase 2 clinical trials. Biopsies and fecal samples were subjected to shotgun metaproteomics, metabolomics, 16s rRNA sequencing, and metagenomics. Tissue was subjected to bulk RNA sequencing and digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed. Fecal samples were also used for colonization experiments in IL10-/- germ-free UC mouse models. RESULTS: Proteomics identified negative associations between HBOT response and neutrophil azurophilic granule abundance. DSP identified an HBOT-specific reduction of neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with a proportional increase in Firmicutes and a secondary bile acid lithocholic acid. A major source of the reduction in diversity was the loss of mucus-adherent taxa, resulting in increased MUC2 levels post-HBOT. Targeted database searching revealed strain-level associations between Akkermansia muciniphila and HBOT response status. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared with non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses. CONCLUSIONS: HBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A muciniphila, may contribute to HBOT non-response.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Point-of-care ultrasound in a multiplace hyperbaric chamber.

Historically, electronic devices have been generally prohibited during hyperbaric oxygen (HBO2) therapy due to risk of fire in a pressurized, oxygen-rich environment. Point-of-care ultrasound (POCUS) however has emerged as a useful imaging modality in diverse clinical settings. Hyperbaric chambers treating critically ill patients would benefit from the application of POCUS at pressure to make real-time patient assessments. Thus far, POCUS during HBO2 therapy has been limited due to required equipment modifications to meet safety standards. Here we demonstrate proof of concept, safety, and successful performance of an off-the-shelf handheld POCUS system (SonoSite iViz) in a clinical hyperbaric environment without need for modification.

Randomised, controlled, open label, multicentre clinical trial to explore safety and efficacy of hyperbaric oxygen for preventing ICU admission, morbidity and mortality in adult patients with COVID-19.

INTRODUCTION: COVID-19 may cause severe pneumonitis and trigger a massive inflammatory response that requires ventilatory support. The intensive care unit (ICU)-mortality has been reported to be as high as 62%. Dexamethasone is the only of all anti-inflammatory drugs that have been tested to date that has shown a positive effect on mortality. We aim to explore if treatment with hyperbaric oxygen (HBO) is safe and effective for patients with severe COVID-19. Our hypothesis is that HBO can prevent ICU admission, morbidity and mortality by attenuating the inflammatory response. The primary objective is to evaluate if HBO reduces the number of ICU admissions compared with best practice treatment for COVID-19, main secondary objectives are to evaluate if HBO reduces the load on ICU resources, morbidity and mortality and to evaluate if HBO mitigates the inflammatory reaction in COVID-19. METHODS AND ANALYSIS: A randomised, controlled, phase II, open label, multicentre trial. 200 subjects with severe COVID-19 and at least two risk factors for mortality will be included. Baseline clinical data and blood samples will be collected before randomisation and repeated daily for 7 days, at days 14 and 30. Subjects will be randomised with a computer-based system to HBO, maximum five times during the first 7 days plus best practice treatment or only best practice treatment. The primary endpoint, ICU admission, is defined by criteria for selection for ICU. We will evaluate if HBO mitigates the inflammatory reaction in COVID-19 using molecular analyses. All parameters are recorded in an electronic case report form. An independent Data Safety Monitoring Board will review the safety parameters. ETHICS AND DISSEMINATION: The trial is approved by The National Institutional Review Board in Sweden (2020-01705) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative and any inconclusive results will be published in peer-reviewed scientific journals with open access. TRIAL REGISTRATION: NCT04327505. EudraCT number: 2020-001349-37.

Can hyperbaric oxygen safely serve as an anti-inflammatory treatment for COVID-19?

INTRODUCTION: SARS-CoV-2 affects part of the innate immune response and activates an inflammatory cascade stimulating the release of cytokines and chemokines, particularly within the lung. Indeed, the inflammatory response during COVID-19 is likely the cause for the development of acute respiratory distress syndrome (ARDS). Patients with mild symptoms also show significant changes on pulmonary CT-scan suggestive of severe inflammatory involvement. HYPOTHESIS: The overall hypothesis is that HBO2 is safe and reduces the inflammatory response in COVID-19 pneumonitis by attenuation of the innate immune system, increase hypoxia tolerance and thereby prevent organ failure and reduce mortality. EVALUATION OF THE HYPOTHESIS: HBO2 is used in clinical practice to treat inflammatory conditions but has not been scientifically evaluated for COVID-19. Experimental and empirical data suggests that HBO2 may reduce inflammatory response in COVID-19. However, there are concerns regarding pulmonary safety in patients with pre-existing viral pneumonitis. EMPIRICAL DATA: Anecdotes from "compassionate use" and two published case reports show promising results. CONSEQUENCES OF THE HYPOTHESIS AND DISCUSSION: Small prospective clinical trials are on the way and we are conducting a randomized clinical trial.

Local Anesthetic Wound Infiltration after Osteosynthesis of Extracapsular Hip Fracture Does Not Reduce Pain or Opioid Requirements: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial in 49 Patients.

Background and purpose: Local infiltration analgesia (LIA) supports early mobilization after hip and knee arthroplasty. Inspired by this, we studied the effectiveness of wound infiltration with the long acting local anesthetic ropivacaine in an effort to decrease the need for postoperative opioids after osteosynthesis of extracapsular hip fracture. Methods: Forty-nine patients undergoing osteosynthesis with a sliding hip screw were randomized into two groups in a double-blind study (ClinicalTrials.gov:NCT01119209). The patients received intraoperative infiltration followed by 6 postoperative injections through a wound catheter in eight-hour intervals. 23 patients received ropivacaine and 26 received saline. The intervention period was 2 days, and the observation period was 5 days. In both groups, there were no restrictions on the total daily dose of opioids. Pain was assessed at specific postoperative time points, and the daily opioid usage was registered. Results: Intraoperative infiltration with 200 mg ropivacaine and postoperative repeated infiltration with 100 mg ropivacaine did not result in statistically significant difference between the groups regarding postoperative opioid consumption or pain. Interpretation: Ropivacaine as single component in postoperative treatment of pain after hip fracture is not effective. In our setup, wound infiltration with ropivacaine is not statistically significantly better than placebo.

Acute effects of glossopharyngeal insufflation in people with cervical spinal cord injury.

OBJECTIVES: To evaluate acute effects of glossopharyngeal insufflation (GI) on lung function, airway pressure (Paw), blood pressure and heart rate (HR) in people with cervical spinal cord injury (CSCI). DESIGN: Case-control design. SETTING: Karolinska Institutet, Stockholm, Sweden. PARTICIPANTS: Ten participants with CSCI suffering from lesions between C4 and C8, and ASIA classification of A or B were recruited. Ten healthy particpants familiar with GI were recruited as a reference group. OUTCOME MEASURES: Spirometry, mean arterial blood pressure (MAP), Paw, and HR were measured in a sitting and a supine position before, during, and after GI. RESULTS: GI in the study group in a sitting position increased total lung capacity (TLC) by 712 ml: P < 0.001, vital capacity (VC) by 587 ml: P < 0.0001, Paw by 13 cm H2O: P < 0.01, and HR by 10 beats/min: P < 0.001. MAP decreased by 25 mmHg, P < 0.0001. Significant differences were observed between groups comparing baseline with GI. The reference group had a higher increase in; TLC (P < 0.01), VC (P < 0.001), Paw (P < 0.001) and HR (P < 0.05) and a higher decrease in MAP (P < 0.001). With GI in a sitting compared to a supine position, TLC, MAP, HR, Paw remained unchanged in the study group, while residual volume decreased in the supine position (P < 0.01). CONCLUSION: There was a difference between the groups in the increase in TLC; VC; Paw, HR and in the decrease in MAP with GI, however MAP, HR and Paw responded in similar way in both groups in a sitting as well as a supine position. If performed correctly, the risks of GI resulting in clinically significant hemodynamic changes is low, although syncope may still occur.

Effects of hyperbaric oxygen on nitric oxide generation in humans.

BACKGROUND: Hyperbaric oxygen (HBO2) has been suggested to affect nitric oxide (NO) generation in humans. Specific NO synthases (NOSs) use L-arginine and molecular oxygen to produce NO but this signaling radical may also be formed by serial reduction of the inorganic anions nitrate and nitrite. Interestingly, commensal facultative anaerobic bacteria in the oral cavity are necessary for the first step to reduce nitrate to nitrite. The nitrate-nitrite-NO pathway is greatly potentiated by hypoxia and low pH in contrast to classical NOS-dependent NO generation. We investigated the effects of HBO2 on NO generation in healthy subjects including orally and nasally exhaled NO, plasma and salivary nitrate and nitrite as well as plasma cGMP and plasma citrulline/arginine ratio. In addition, we also conducted in-vitro experiments in order to investigate the effects of hyperoxia on nitrate/nitrite metabolism and NO generation by oral bacteria. METHODS: Two separate HBO2 experiments were performed. In a cross-over experiment (EXP1) subjects breathed air at 130 kPa (control) or oxygen at 250 kPa for 100 minutes and parameters were measured before and after exposure. In experiment 2 (EXP 2) measurements were performed also during HBO2 at 250 kPa for 110 minutes. RESULTS: HBO2 acutely reduced orally and nasally exhaled NO by 30% and 16%, respectively. There was a marked decrease in salivary nitrite/nitrate ratio during and after HBO2, indicating a reduced bacterial conversion of nitrate to nitrite and NO. This was supported by in vitro experiments with oral bacteria showing that hyperoxia inhibited bacterial nitrate and nitrite reduction leading to reduced NO generation. Plasma nitrate was unaffected by HBO2 while plasma nitrite was reduced during HBO2 treatment. In contrast, plasma cGMP increased during HBO2 as did citrulline/arginine ratio after treatment and control. CONCLUSION: HBO2-exposure in humans affects NO generation in the airways and systemically differently. These data suggest that the individual NOSs as well as the nitrate-nitrite-NO pathway do not respond in a similar way to HBO2.

Effects of dietary inorganic nitrate on static and dynamic breath-holding in humans.

Inorganic nitrate has been shown to reduce oxygen cost during exercise. Since the nitrate-nitrite-NO pathway is facilitated during hypoxia, we investigated the effects of dietary nitrate on oxygen consumption and cardiovascular responses during apnea. These variables were measured in two randomized, double-blind, placebo-controlled, crossover protocols at rest and ergometer exercise in competitive breath-hold divers. Subjects held their breath for predetermined times along with maximum effort apneas after two separate 3-day periods with supplementation of potassium nitrate/placebo. In contrast to our hypothesis, nitrate supplementation led to lower arterial oxygen saturation (SaO(2), 77 ± 3%) compared to placebo (80 ± 2%) during static apnea, along with lower end-tidal fraction of oxygen (FETO(2)) after 4 min of apnea (nitrate 6.9 ± 0.4% vs. placebo 7.6 ± 0.4%). Maximum apnea duration was shorter after nitrate (329 ± 13 s) compared to placebo (344 ± 13 s). During cycle ergometry nitrate had no effect on SaO(2), FETO(2) or maximum apnea duration. The negative effects of inorganic nitrate during static apnea may be explained by an attenuated diving response.

Nitrox permits direct exit for attendants during extended hyperbaric oxygen treatment.

BACKGROUND: Intermittent breathing of oxygen-enriched air, nitrox (1:1 air:oxygen, 60.5% O2), for attendants in multiplace hyperbaric chambers should enable treatment protocols (HOPAN - hyperbaric oxygen protocol attendants' nitrox) of up to 200 minutes at 2.8 atmospheres absolute (ATA), while retaining the option of a direct decompression and exit. METHODS: HOPAN with cycles of 15 minutes of nitrox breathing followed by 10 minutes of chamber air for attendants were occasionally used from 2007-2009. HOPAN vs. LTP (local treatment protocols) were evaluated via an anonymous enquiry among attendants; patients' medical records were followed six months post-HBO2 treatment (HBO2T). RESULTS: 88 HOPANs, with 59 chamber attendants assisting 30 patients, were documented. HOPAN duration ranged from 55-167 minutes (median 140 minutes). 31/59 attendants answered the enquiry. Perceived comfort of each protocol (HOPAN vs. LTP) by attendants was reported as equal. Symptoms, both minor (parestesias) and severe (joint pain), were reported in connection with LTP, while only one occurrence (mild joint pain) was reported in connection with HOPAN. No complications were documented among the attendants or the patients. It is suggested that nitrox breathing for chamber attendants provide flexible HBO2T for patients at 2.8 ATA for up to 200 minutes within no-decompression limits, facilitating future studies of HBO2T dosage.

Local anaesthetic wound infiltration after internal fixation of femoral neck fractures: a randomized, double-blind clinical trial in 33 patients.

Pain control may assist early mobilisation after internal fixation of femoral neck fractures. Systemic opioids have significant side effects in elderly patients. We present an evaluation of the effect of local anaesthetic infiltration in such cases , the objective being to decrease the need for postoperative opioids and to improve pain control for patients after surgery. 33 patients undergoing internal fixation with 2 parallel hook pins were randomized into 2 groups in a double blind study (ClinicalTrials.gov: NCT00529425). 33 patients received intraoperative infiltration followed by 6 postoperative injections through an intraarticular catheter in eight-hour intervals. 19 patients received ropivacaine and 14 received saline. The intervention period was 48 hours and the observation period was 5 days. In both groups there were no restrictions on the total daily dose of rescue analgesics. Pain was assessed at specific postoperative time-points and the daily consumption of opioid drugs needed for analgesia was registered. There was no significantly reduced consumption of standardized opioid rescue analgesics or pain in the study group receiving ropivacaine injections. Apart from a reduction in nausea in the study group on the second postoperative day, there were no significant differences in the occurrence of side effects between the groups. On day 2 the placebo group had less pain than the study group. Local anaesthetic infiltration after fixation of femoral neck fractures does not reduce opioid consumption or pain'.

Tissue oxygenation measured with near-infrared spectroscopy during normobaric and hyperbaric oxygen breathing in healthy subjects.

To evaluate the possibility of using near-infrared spectroscopy (NIRS) to measure tissue oxygenation (StO(2)) during hyperbaric oxygen (HBO) therapy. Nine healthy volunteers (1 female) age 25-37 years, breathed air or oxygen. Tissue oxygenation was measured using NIRS on the thumb. Subjects were blinded to breathing gas. A range of partial pressures of oxygen were administered in 10-min intervals: 21, 101, 21 kPa (compression to 280 kPa), 59, 280, 59 (decompression), 21 kPa. Data were averaged over last 5 min at each pressure. When switching from air to normobaric oxygen (NBO 101 kPa) StO(2) increased from 83% (82-85%, median and interquartile range) to 85% (84-87%) (P < 0.01), while when switching from air at pressure (59 kPa O(2)) to HBO (280 kPa), StO(2) increased from 85% (85-86%) to 88% (87-89%) (P < 0.001). There was no difference between baseline StO(2) while air breathing before NBO or after decompression. Values did not reach the maximal value of 100% at any point. The changes in hemoglobin oxygen saturation in tissue registered by the NIRS monitor when switching from air to oxygen followed inspired PO(2) under normobaric and hyperbaric conditions.

Glossopharyngeal pistoning for lung insufflation in children with spinal muscular atrophy type II.

AIM: To evaluate whether children with spinal muscular atrophy (SMA) type II were able to learn glossopharyngeal pistoning for lung insufflation (GI), and to evaluate the effects of GI on pulmonary function and chest expansion. METHODS: Eleven children with SMA type II were recruited. They performed 10 cycles of GI, four times per week, for 8 weeks. Lung function and chest expansion were measured before and after the 8-week period. RESULTS: Five of the 11 children learned the technique. The median GI volume was 0.28 (range 0.15-0.98) L. Four of the children who completed the study showed a mean increase in inspiratory vital capacity (IVC) of 0.13 L (95% confidence interval (CI) 0.03-0.23) and peak expiratory flow (PEF) of 116 L/min (95% CI 60-173). They also had an increased chest expansion with GI at the level of the xiphoid process of 1.50 cm (95% CI 0.16-2.84) and at the level of the fourth costa of 1.79 cm (95% CI 0.85-2.73). The children reported temporary symptoms of dizziness and tension in the chest. CONCLUSION: Five of the 11 children were able to learn the technique of GI and for the four who fulfilled the training, it had positive effects on IVC, PEF and chest expansion. GI did not cause major discomfort.

Effects of glossopharyngeal pistoning for lung insufflation in elite swimmers.

PURPOSE: To investigate whether sessions of glossopharyngeal pistoning (GP) to lung volumes exceeding maximum inspiratory capacity in a group of extremely well-trained elite swimmers would affect maximum lung volumes and buoyancies. METHODS: Ten female and 16 male swimmers performed GP four times a week for 5 wk in addition to their regular swimming training program. Pulmonary function, chest expansion, hydrostatic weights (maximally inhaled and exhaled), and body composition (relative amounts of fat, bone, muscle, and fat-free tissue) were measured. RESULTS: Training compliance was 79% for the males and 82% for the females. Chest expansion increased significantly during the training period, by 1.0 cm and by 0.8 cm at the level of the xiphiod and the fourth costae for the males, and by 0.6 cm and 0.8 cm for the females. The buoyancy lifting force increased significantly by 0.17 and 0.37 kg for the males and the females, respectively. The females also increased their vital capacity significantly by 2%. No significant changes in body composition took place in either group. CONCLUSION: The lung volumes and buoyancies of swimmers can be increased by sessions of GP.