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Background: Diving in cold water is thought to increase the risk of decompression sickness (DCS), especially if the diver is cold during decompression. In this study, we investigated hemodynamic function and DCS risk in an animal model, where cold decompression was followed by rewarming at the surface.Methods: Nine female Sprague Dawley rats had pressure-volume catheters inserted into their left heart ventricle and femoral artery before they were exposed to dry air dives in which their core temperature was normothermic during the bottom phase, cold (35°C) during decompression, and normothermic after the dive. Data from an earlier study were used as controls. The rats were compressed in air to 600kPa, maintained at pressure for 45min, and decompressed at 50kPa/min. Hemodynamic data were recorded before, during, and 60min after decompression. Venous gas bubbles were recorded in the right heart ventricle and pulmonary artery for 60min after the dive.Results and Conclusion: During decompression, cardiac output (CO), and stroke volume (SV) decreased equally in cold rats and controls. CO and SV were temporarily re-established at the surface, before falling again in the cold rats. There was no difference in post-dive venous bubble grades. However, as the post-dive fall in CO and SV could be a sign of gas emboli obstructing the pulmonary circulation, we cannot conclude whether the DCS risk was increased. More sensitive bubble detection methods are needed to elucidate this point.

Health monitoring during offshore saturation diving is complicated due to restricted access to the divers, the desire to keep invasive procedures to a minimum, and limited opportunity for laboratory work onboard dive support vessels (DSV). In this pilot study, we examined whether measuring salivary biomarkrers in samples collected by the divers themselves might be a feasible approach to environmental stress assessment. Nine saturation divers were trained in the passive drool method for saliva collection and proceeded to collect samples at nine time points before, during, and after an offshore commercial saturation diving campaign. Samples collected within the hyperbaric living chambers were decompressed and stored frozen at −20°C onboard the DSV until they were shipped to land for analysis. Passive drool samples were collected without loss and assayed for a selection of salivary biomarkers: secretory immunoglobulin A (SIgA), C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins IL-6, IL-8, IL-1β, as well as cortisol and alpha-amylase. During the bottom phase of the hyperbaric saturation, SIgA, CRP, TNF-α, IL-8 and IL-1β increased significantly, whereas IL-6, cortisol and alpha-amylase were unchanged. All markers returned to pre-dive levels after the divers were decompressed back to surface pressure. We conclude that salivary biomarker analysis may be a feasible approach to stress assessment in offshore saturation diving. The results of our pilot test are consonant with an activation of the sympathetic nervous system related to systemic inflammation during hyperbaric and hyperoxic saturation.

Decompression sickness (DCS) develops due to inert gas bubble formation in bodily tissues and in the circulation, leading to a wide range of potentially serious clinical manifestations. Its pathophysiology remains incompletely understood. In this study, we aim to explore changes in the human leukocyte transcriptome in divers with DCS compared to closely matched unaffected controls after uneventful diving. Cases (n = 7) were divers developing the typical cutis marmorata rash after diving with a confirmed clinical diagnosis of DCS. Controls (n = 6) were healthy divers who surfaced from a 25 msw dive without decompression violation or evidence of DCS. Blood was sampled at two separate time points—within 8 h of dive completion and 40–44 h later. Transcriptome analysis by RNA-Sequencing followed by bioinformatic analysis was carried out to identify differentially expressed genes and relate their function to biological pathways. In DCS cases, we identified enrichment of transcripts involved in acute inflammation, activation of innate immunity and free radical scavenging pathways, with specific upregulation of transcripts related to neutrophil function and degranulation. DCS-induced transcriptomic events were reversed at the second time point following exposure to hyperbaric oxygen. The observed changes are consistent with findings from animal models of DCS and highlight a continuum between the responses elicited by uneventful diving and diving complicated by DCS. This study sheds light on the inflammatory pathophysiology of DCS and the associated immune response. Such data may potentially be valuable in the search for novel treatments targeting this disease., peer-reviewed

Introduction: The average age of the diving population is rising, and the risk of atherosclerosis and cardiovascular disease in divers are accordingly increasing. It is an open question whether this risk is altered by diving per se. In this study, we examined the effect of 7-weeks simulated diving on endothelial function and mitochondrial respiration in atherosclerosis-prone rats. Methods: Twenty-four male ApoE knockout (KO) rats (9-weeks-old) were fed a Western diet for 8 weeks before 12 rats were exposed to simulated heliox dry-diving in a pressure chamber (600 kPa for 60 min, decompression of 50 kPa/min). The rats were dived twice-weekly for 7 weeks, resulting in a total of 14 dives. The remaining 12 non-diving rats served as controls. Endothelial function of the pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. Mitochondrial respiration in cardiac muscle tissues was measured using high-resolution respirometry. Results and Conclusion: Both ApoE KO diving and non-diving rats showed changes in endothelial function at the end of the intervention, but the extent of these changes was larger in the diving group. Altered nitric oxide signaling was primarily involved in these changes. Mitochondrial respiration was unaltered. In this pro-atherosclerotic rat model of cardiovascular changes, extensive diving appeared to aggravate endothelial dysfunction rather than promote adaptation to oxidative stress. Copyright © 2020 Berenji Ardestani, Matchkov, Hansen, Jespersen, Pedersen and Eftedal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20-24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development. Open Access Tis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © Te Author(s) 2020

Commercial saturation divers must acclimatize to hyperbaric hyperoxia in their work environment, and subsequently readjust to breathing normal air when their period in saturation is over. In this study, we measured hemoglobin (Hb) during and following 4 weeks of heliox saturation diving in order to monitor anemia development and the time for Hb to recover post-saturation. Male commercial saturation divers reported their capillary blood Hb daily, before, and during 28 days of heliox saturation to a working depth of circa 200 m (n = 11), and for 12 days at surface post-saturation (n = 9–7), using HemoCue 201+ Hb devices. Hb remained in normal range during the bottom phase, but fell during the decompression; reaching levels of mild anemia (≤13.6 g/dl) the day after the divers’ return to the surface. Hb was significantly lower than the pre-saturation baseline (14.7 ± 1.1 g/dl) on the fifth day post-saturation (12.8 ± 1.8 g/dl, p = 0.028), before reverting to normal after 6–7 days. At the end of the 12-day post-saturation period, Hb was not statistically different from the pre-saturation baseline. The observed Hb changes, although significant, were modest. While we cannot rule out effect of other factors, the presence of mild anemia may partially explain the transient fatigue that commercial saturation divers experience post-saturation.

Cardiovascular risk is elevated in divers, but detailed information of cardiac function during diving is missing. The aim of this study was to apply an intact rat model with continuous monitoring of cardiac left ventricular (LV) function in a simulated diving experiment. Thirteen rats were inserted with a LV pressure–volume catheter and a pressure transducer in the femoral artery to measure hemodynamic variables, and randomly assigned to diving (n = 9) and control (n = 4) groups. The diving group was compressed to 600 kPa in air, maintained at pressure for 45 min (bottom phase), and decompressed to surface at 50 kPa/min. Data was collected before, during, and up to 60 min after exposure in the diving group, and at similar times in non-diving controls. During the bottom phase, stroke volume (SV) (−29%) and cardiac output (−30%) decreased, whereas LV end-systolic volume (+13%), mean arterial pressure (MAP) (+29%), and total peripheral resistance (TPR) (+72%) increased. There were no changes in LV contractility, stroke work, or diastolic function. All hemodynamic variables returned to baseline values within 60 min after diving. In conclusion, our simulated dive experiment to 600 kPa increased MAP and TPR to levels which caused a substantial reduction in SV and LV volume output. The increase in cardiac afterload demonstrated to take place during a dive is well tolerated by the healthy heart in our model, whereas in a failing heart this abrupt change in afterload may lead to acute cardiac decompensation. Copyright © 2020 Gaustad, Kondratiev, Eftedal and Tveita. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)

Introduction: The number of divers is rising every year, including an increasing number of aging persons with impaired endothelial function and concomitant atherosclerosis. While diving is an independent modulator of endothelial function, little is known about how diving affects already impaired endothelium. In this study, we questioned whether diving exposure leads to further damage of an already impaired endothelium. Methods: A total of 5 male and 5 female ApoE knockout (KO) rats were exposed to simulated diving to an absolute pressure of 600 kPa in heliox gas (80% helium, 20% oxygen) for 1 h in a dry pressure chamber. 10 ApoE KO rats (5 males, 5 females) and 8 male Sprague-Dawley rats served as controls. Endothelial function was examined in vitro by isometric myography of pulmonary and mesenteric arteries. Lipid peroxidation in blood plasma, heart and lung tissue was used as measures of oxidative stress. Expression and phosphorylation of endothelial NO synthase were quantified by Western blot. Results and Conclusion: A single simulated dive was found to induce endothelial dysfunction in the pulmonary arteries of ApoE KO rats, and this was more profound in male than female rats. Endothelial dysfunction in males was associated with changing in production or bioavailability of NO; while in female pulmonary arteries an imbalance in prostanoid signaling was observed. No effect of diving was found on mesenteric arteries from rats of either sex. Our findings suggest that changes in endothelial dysfunction were specific for pulmonary circulation. In future, human translation of these findings may suggest caution for divers who are elderly or have prior reduced endothelial function. Copyright © 2019 Berenji Ardestani, Matchkov, Eftedal and Pedersen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Saturation diving is an established way to conduct subsea operations with human intervention. While working, the divers must acclimatize to the hyperbaric environments. In this study, genome-wide gene expression and selected plasma biomarkers for vascular function were investigated. We also examined whether antioxidant vitamin supplements affected the outcome. The study included 20 male professional divers, 13 of whom took vitamin C and E supplements in doses of 1,000 and 30 mg daily during saturation periods that lasted 7–14 days. The dives were done in a heliox atmosphere with 40 kPa oxygen partial pressure (ppO2) to a depth of 100–115 m of sea-water (msw), from which the divers performed in-water work excursions to a maximum depth of 125 msw with 60 kPa ppO2. Venous blood was collected immediately before and after saturation. Following gene expression profiling, post-saturation gene activity changes were analyzed. Protein biomarkers for inflammation, endothelial function, and fibrinolysis: Il-6, CRP, ICAM-1, fibrinogen, and PAI-1, were measured in plasma. Post-saturation gene expression changes indicated acclimatization to elevated ppO2 by extensive downregulation of factors involved in oxygen transport, including heme, hemoglobin, and erythrocytes. Primary endogenous antioxidants; superoxide dismutase 1, catalase, and glutathione synthetase, were upregulated, and there was increased expression of genes involved in immune activity and inflammatory signaling pathways. The antioxidant vitamin supplements had no effect on post-saturation gene expression profiles or vascular function biomarkers, implying that the divers preserved their homeostasis through endogenous antioxidant defenses. Blood gene expression and vascular function biomarkers in professional saturation diving Copyright © 2018 Kiboub, Møllerløkken, Hjelde, Flatberg, Loennechen and Eftedal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Purpose: Decompression sickness (DCS) is a poorly understood and complex systemic disease caused by inadequate desaturation following a reduction of ambient pressure. A previous proteomic study of ours showed that DCS occurrence but not diving was associated with changes in the plasma proteome in rats, including a dramatic decrease of abundance of the tetrameric form of Transthyretin (TTR). The present study aims to assess the impact on the human blood proteome of a dive inducing significant decompression stress but without inducing DCS symptoms. Experimental design: Twelve healthy male divers were subjected to a single dive at a depth of 18m of sea water (msw) with a 47-min bottom time followed by a direct ascent to the surface at a rate of 9msw/min. Venous blood was collected before the dive as well as 30mn and 2h following the dive. The plasma proteomes from four individuals were then analyzed by using a two-dimensional electrophoresis-based proteomic strategy. Results: No protein spot showed a significantly changed abundance (fdr< 0.1) between the tested times. Conclusion: These results strengthen the hypothesis according to which significant changes of the plasma proteome measurable with two-dimensional electrophoresis may only occur along with DCS symptoms. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the authors' accepted and refereed manuscript to the article. Locked until 12 May 2018 due to copyright restrictions

Objective: The aim of this study was to determine if, after controlling for weight, age is associated with decompression sickness (DCS) in rats. Methods: Following compression-decompression, male rats aged 11 weeks were observed for DCS. After two weeks recovery surviving rats were re-dived using the same compression- decompression profile. Results: In this experiment there was a clear difference between DCS outcome at ages 11 or 13 weeks in matched rats (p=0.002). Discussion: Even with weight included in the model age was significantly associated with DCS (p=0.01), yet after removal of weight the association was much stronger (p=0.002). Conclusion: We believe that age is likely to be found associated with the probability of DCS in a larger dataset with a wider range of parameters, after accounting for the effect of weight. This is an accepted manuscript of an article published by Taylor & Francis in Archives of Physiology and Biochemistry on 12 Mar 2016, available at http://www.tandfonline.com/doi/full/10.3109/13813455.2016.1140787

PURPOSE: Decompression sickness (DCS) caused by vascular bubble formation is a major risk when diving. Prior studies have shown that physical exercise has a significant impact in both reducing and increasing bubble formation. There is limited knowledge about the mechanisms, but there are indications that exercise-induced muscle injury prior to diving may cause increased bubble formation. The purpose of this study was to investigate the role of exercise-induced muscle injury as a possible mechanism of bubble formation during diving. METHODS: Muscle injury was induced by exposing female Sprague-Dawley rats (n = 30) to a single bout of eccentric exercise, 100 min intermittent, downhill (-16°) treadmill running. Forty-eight hours later, the animals were exposed to a 50-min simulated saturation dive (709 kPa) in a pressure chamber, when the degree of muscle injury and inflammation would be the most pronounced. Bubble formation after the dive was observed by ultrasonic imaging for 4 h. RESULTS: No difference in bubble loads was found between the groups at any time despite evident muscle injury. Maximum bubble loads (bubbles cm-2 heart cycle-1) were not different, exercise: 1.6 ± 3.5 SD vs control: 2.2 ± 4.1 SD, P = 0.90, n = 15 in each group. CONCLUSIONS: Eccentric exercise performed 48 h prior to diving causes skeletal muscle injury but does not increase the amount of vascular bubbles in rats. The prevailing recommendation is that physical activity prior to diving is a risk factor of DCS. However, present and previous studies implicate that pre-dive physical activity does not increase the DCS risk. © Springer-Verlag Berlin Heidelberg 2014. This is the authors' accepted and refereed manuscript to the article

Hyperbaric oxygen preconditioning (HBO-PC) can protect the heart from injury during subsequent ischemia. The presence of high loads of venous gas emboli (VGE) induced by a rapid ambient pressure reduction on ascent from diving may cause ischemia and acute heart failure. The aim of this study was to investigate the effect of diving-induced VGE formation on cardiac stress marker levels and the cardioprotective effect of HBO-PC. To induce high loads of VGE, 63 female Sprague-Dawley rats were subjected to a rapid ambient pressure reduction from a simulated saturation dive (50 min at 709 kPa) in a pressure chamber. VGE loads were measured for 60 min in anesthetized animals by the use of ultrasonography. The animals were divided into five groups. Three groups were exposed to either diving or to HBO-PC (100% oxygen, 38 min at 303 kPa) with a 45 or 180 min interval between HBO-PC and diving. Two additional groups were used as baseline controls for the measurements; one group was exposed to equal handling except for HBO-PC and diving, and the other group was completely unexposed. Diving caused high loads of VGE, as well as elevated levels of the cardiac stress markers, cardiac troponin T (cTnT), natriuretic peptide precursor B (Nppb), and αB-crystallin, in blood and cardiac tissue. There were strong positive correlations between VGE loads and stress marker levels after diving, and HBO-PC appeared to have a cardioprotective effect, as indicated by the lower levels of stress marker expression after diving-induced VGE formation. KEYWORDS: Cardioprotection, decompression illness, diving, gas embolism, hyperbaric oxygen preconditioning (c) 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Objective Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotypes “poor metaboliser” (PM), “extensive metaboliser” (EM) and “ultra-rapid metaboliser” (URM) in a cohort of patients with cancer pain. Methods The patients were genotyped for the most common CYP2D6 variants and serum concentrations of oxycodone and metabolites were determined. Pain was assessed using the Brief Pain Inventory (BPI). The EORTC QLQ-C30 was used to assess the symptoms of tiredness and nausea. Cognitive function was assessed by the Mini Mental State (MMS) examination. Associations were examined by analyses of variance (ANOVA) and covariance (ANCOVA), or ordinal logistic regressions with and without covariates. Results The sample consisted of 27 PM, 413 EM (including heterozygotes) and 10 URM. PM had lower oxymorphone and noroxymorphone serum concentrations and oxymorphone to oxycodone ratios than EM and URM. No differences between PM, EM and URM in pain intensity, nausea, tiredness or cognitive function was found. Conclusion CYP2D6 genotypes caused expected differences in pharmacokinetics, but they had no pharmacodynamic consequence. CYP2D6 genotypes did not influence pain control, the adverse symptoms nausea and sedation or the risk for cognitive failure in this study of patients treated with oxycodone for cancer pain.