Abstract
Context
Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations ...are not evidence-based.
Objective
To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress.
Design and Participants
Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma N = 83, sepsis N = 100, and combat stress N = 105). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration).
Main Outcome Measure
We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress.
Results
Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50–100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range.
Conclusions
Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.
Stress fractures are common amongst healthy military recruits and athletes. Reduced vitamin D availability, measured by serum 25-hydroxyvitamin D (25OHD) status, has been associated with stress ...fracture risk during the 32-week Royal Marines (RM) training programme. A gene-environment interaction study was undertaken to explore this relationship to inform specific injury risk mitigation strategies. Fifty-one males who developed a stress fracture during RM training (n = 9 in weeks 1-15; n = 42 in weeks 16-32) and 141 uninjured controls were genotyped for the vitamin D receptor (VDR) FokI polymorphism. Serum 25OHD was measured at the start, middle and end (weeks 1, 15 and 32) of training. Serum 25OHD concentration increased in controls between weeks 1-15 (61.8±29.1 to 72.6±28.8 nmol/L, p = 0.01). Recruits who fractured did not show this rise and had lower week-15 25OHD concentration (p = 0.01). Higher week-15 25OHD concentration was associated with reduced stress fracture risk (adjusted OR 0.550.32-0.96 per 1SD increase, p = 0.04): the greater the increase in 25OHD, the greater the protective effect (p = 0.01). The f-allele was over-represented in fracture cases compared with controls (p<0.05). Baseline 25OHD status interacted with VDR genotype: a higher level was associated with reduced fracture risk in f-allele carriers (adjusted OR 0.390.17-0.91, p = 0.01). Improved 25OHD status between weeks 1-15 had a greater protective effect in FF genotype individuals (adjusted OR 0.310.12-0.81 vs. 1.780.90-3.49, p<0.01). Stress fracture risk in RM recruits is impacted by the interaction of VDR genotype with vitamin D status. This further supports the role of low serum vitamin D concentrations in causing stress fractures, and hence prophylactic vitamin D supplementation as an injury risk mitigation strategy.
Exertional heat stroke (EHS) is a life-threatening medical condition involving thermoregulatory failure and is the most severe condition along a continuum of heat-related illnesses. Current EHS ...policy guidance principally advocates a thermoregulatory management approach, despite growing recognition that gastrointestinal (GI) microbial translocation contributes to disease pathophysiology. Contemporary research has focused to understand the relevance of GI barrier integrity and strategies to maintain it during periods of exertional-heat stress. GI barrier integrity can be assessed non-invasively using a variety of in vivo techniques, including active inert mixed-weight molecular probe recovery tests and passive biomarkers indicative of GI structural integrity loss or microbial translocation. Strenuous exercise is strongly characterised to disrupt GI barrier integrity, and aspects of this response correlate with the corresponding magnitude of thermal strain. The aetiology of GI barrier integrity loss following exertional-heat stress is poorly understood, though may directly relate to localised hyperthermia, splanchnic hypoperfusion-mediated ischemic injury, and neuroendocrine-immune alterations. Nutritional countermeasures to maintain GI barrier integrity following exertional-heat stress provide a promising approach to mitigate EHS. The focus of this review is to evaluate: (1) the GI paradigm of exertional heat stroke; (2) techniques to assess GI barrier integrity; (3) typical GI barrier integrity responses to exertional-heat stress; (4) the aetiology of GI barrier integrity loss following exertional-heat stress; and (5) nutritional countermeasures to maintain GI barrier integrity in response to exertional-heat stress.
In light of the current COVID-19 pandemic, and given the importance of diet to overall health and well-being, nutrients (macro and micro) deserve special attention.10 As a key micronutrient, vitamin ...D should be given particular focus—not as a ‘magic bullet’ to beat COVID-19, as the scientific evidence base is severely lacking at this time—but rather as part of a healthy lifestyle strategy to ensure that populations are nutritionally in the best possible place.11 Vitamin D is unique: it is a prohormone which is produced in the skin during exposure to sunlight (UVB radiation at 290–315 nm) with, usually, smaller amounts obtained from food. ...in Manchester, UK (53.5N) the nadir of seasonal vitamin D status occurs in February, with sunlight exposure once again becoming effective for vitamin D synthesis in the skin only from March onwards.13 Relatively high prevalence of low vitamin D status globally has been reported over recent decades in a wide range of population groups,14 including those in low latitude areas (despite the abundance of sunlight) and not necessarily confined to winter.15 This may be due to environmental factors, such as air pollution, as well as cultural factors that lead to skin being covered and not subject to sunlight exposure.16 Older, housebound individuals are at particularly high risk of vitamin D deficiency.17 Vitamin D status is reflected by the level of the circulating metabolite 25-hydroxyvitamin D (25OHD), which is produced by hepatic hydroxylation of vitamin D coming from either skin or the gut from oral intake.18 If the 25OHD concentration is low (as defined in the UK by a 25OHD concentration of <25 nmol/L7 and in the USA and some other countries by a 25OHD concentration of <30 nmol/L),8 9 such as observed commonly during and towards the end of the winter, this indicates that stores are depleted and vitamin D-requiring functions may be impaired. ...vitamin D, via its active metabolites, regulates more than 200 genes including those genes that are responsible for cellular proliferation, differentiation and apoptosis.19 The discovery of the expression of nuclear vitamin D receptors and vitamin D metabolic enzymes in immune cells provides a scientific rationale for the potential role of vitamin D in maintaining immune homoeostasis and in preventing the development of autoimmune processes.20 The field of vitamin D research has grown exponentially in recent years with a much improved understanding of its biological importance. Epidemiological studies in children have found a strong association between URTI and rickets.28 A large cross-sectional study of the US population reported that URTI infections were higher in those with lower vitamin D status, with the association being stronger in those with respiratory diseases such as asthma and chronic obstructive pulmonary disease.29 There is evidence that lower vitamin D status is associated with acute respiratory tract infections (ARTIs).30 In a recent systematic review and meta-analysis of individual participant data from vitamin D supplementation RCTs, vitamin D supplementation reduced the risk of ARTI, with the greatest benefit in those with vitamin D deficiency at baseline.31 However, it is important to note the limitations to this systematic review/meta-analysis;32 33 there was a high level of heterogeneity in the findings and concomitantly, the overall significant results in the meta-analysis of the 24 included trials was dependent on the inclusion of the two studies undertaken in developing countries:
New Findings
What is the topic of this review?
Exertional heat illness (EHI) remains a persistent problem for athletes and individuals. This threat remains despite numerous athletic position ...statements and occupational guidance policies. This review explores primary evidence that demonstrates a direct association between ‘known’ risk factors and EHI.
What advances does it highlight?
Primary evidence to support ‘known’ risk factors associated with EHI is not comprehensive. Furthermore, it is not evident that single individual factors predispose individuals to greater risk. In fact, the evidence indicates that EHI can manifest in non‐hostile compensable environments when a combination of risk factors is prevalent.
Despite the widespread knowledge of exertional heat illness (EHI) and clear guidance for its prevention, the incidence of EHI remains high. We carried out a systematic review of available literature evaluating the scientific evidence underpinning the risk factors associated with EHI. Medline, PsycINFO, SportDiscus and Embase were searched from inception to January 2019 with no date limitation, with supplementary searches also being performed. Search terms included permutations of risk and heat illness, with only studies in English included. Study selection, data extraction and quality assessment, using the QUALSYST tool, were performed by two independent reviewers. Of 8898 articles identified by the searches, 42 were included in the systematic review as primary evidence demonstrating a link between a risk factor and EHI. The quality scores ranged from 57.50 to 100%, and studies were generally considered to be of strong quality. The majority of risks attributable to EHI were categorized as those associated with lifestyle factors. The findings from the systematic review suggest complex manifestation of EHI through multiple risk factors rather than any one factor in isolation. Further research is needed to explore the accumulation of risk factors to help in development of effective preventative measures.
Abstract
Context
Survival rates after severe injury are improving, but complication rates and outcomes are variable.
Objective
This cohort study addressed the lack of longitudinal data on the steroid ...response to major trauma and during recovery.
Design
We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15).
Main outcome measures
We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models.
Findings
We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 interquartile range 24–31 years; median NISS 34 29–44). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis.
Conclusion
The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.
Improving Clinical Prediction Model Methods Bullock, Garrett S; Collins, Gary S; Arden, Nigel ...
Medicine and science in sports and exercise,
04/2022, Letnik:
54, Številka:
4
Journal Article
Purpose
Exertional-heat stress adversely disrupts gastrointestinal (GI) barrier integrity, whereby subsequent microbial translocation (MT) can result in potentially serious health consequences. To ...date, the influence of aerobic fitness on GI barrier integrity and MT following exertional-heat stress is poorly characterised.
Method
Ten untrained (UT;
V
O
2max
= 45 ± 3 ml·kg
−1
·min
−1
) and ten highly trained (HT;
V
O
2max
= 64 ± 4 ml·kg
−1
·min
−1
) males completed an ecologically valid (military) 80-min fixed-intensity exertional-heat stress test (EHST). Venous blood was drawn immediately pre- and post-EHST. GI barrier integrity was assessed using the serum dual-sugar absorption test (DSAT) and plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using plasma
Bacteroides
/total 16S DNA.
Results
UT experienced greater thermoregulatory, cardiovascular and perceptual strain (
p
< 0.05) than HT during the EHST. Serum DSAT responses were similar between the two groups (
p
= 0.59), although Δ I-FABP was greater (
p
= 0.04) in the UT (1.14 ± 1.36 ng·ml
−1
) versus HT (0.20 ± 0.29 ng·ml
−1
) group.
Bacteroides
/Total 16S DNA ratio was unchanged (Δ; -0.04 ± 0.18) following the EHST in the HT group, but increased (Δ; 0.19 ± 0.25) in the UT group (
p
= 0.05). Weekly aerobic training hours had a weak, negative correlation with Δ I-FABP and
Bacteroides
/total 16S DNA responses.
Conclusion
When exercising at the same absolute workload, UT individuals are more susceptible to small intestinal epithelial injury and MT than HT individuals. These responses appear partially attributable to greater thermoregulatory, cardiovascular, and perceptual strain.
•S. argenteus strains (t5078, ST2250) had no mec, tsst or LukPV genes present.•SNPs analysis support S. argenteus transmission between recruits training together.•Potential of high number of ...mutations present in carriage S. argenteus isolates.
Objectives During a prospective study of S. aureus carriage in Royal Marines recruits, six S. argenteus strains were identified in four recruits. As S. argenteus sepsis leads to mortality similar to S. aureus, we determined the potential for within same troop transmission, to evaluate future outbreak risk.
Methods We used whole-genome sequencing to characterise S. argenteus and investigate phylogenetic relationships between isolates.
Results S. argenteus strains (t5078, ST2250) were detected in 4/40 recruits in the same troop (training cohort) in weeks 1, 6 or 15 of training. No mec, tsst or LukPV genes were detected. We identified differences of 1–17 core SNPs between S. argenteus from different recruits. In two recruits, two S. argenteus strains were isolated; these could be distinguished by 2 and 15 core SNPs.
Conclusions The identification of S. argenteus within a single troop from the total recruit population suggests a common source for transmission, though high number of SNPs were identified, both within-host and within-cluster. The high number of SNPs between some isolates may indicate a common source of diverse isolates or a high level of S. argenteus mutation in carriage. S. argenteus is newly recognized species; and understanding of the frequency of genetic changes during transmission and transition from asymptomatic carriage to disease is required.
l-Glutamine (GLN) is a conditionally essential amino acid which supports gastrointestinal (GI) and immune function prior to catabolic stress (e.g., strenuous exercise). Despite potential ...dose-dependent benefits, GI tolerance of acute high dose oral GLN supplementation is poorly characterised. Fourteen healthy males (25 ± 5 years; 1.79 ± 0.07 cm; 77.7 ± 9.8 kg; 14.8 ± 4.6% body fat) ingested 0.3 (LOW), 0.6 (MED) or 0.9 (HIGH) g·kg·FFM
GLN beverages, in a randomised, double-blind, counter-balanced, cross-over trial. Individual and accumulated GI symptoms were recorded using a visual analogue scale at regular intervals up to 24-h post ingestion. GLN beverages were characterised by tonicity measurement and microscopic observations. 24-h accumulated upper- and lower- and total-GI symptoms were all greater in the HIGH, compared to LOW and MED trials (
< 0.05). Specific GI symptoms (discomfort, nausea, belching, upper GI pain) were all more pronounced on the HIGH versus LOW GLN trial (
< 0.05). Nevertheless, most symptoms were still rated as mild. In comparison, the remaining GI symptoms were either comparable (flatulence, urge to regurgitate, bloating, lower GI pain) or absent (heart burn, vomiting, urge to defecate, abnormal stools, stitch, dizziness) between trials (
> 0.05). All beverages were isotonic and contained a dose-dependent number of GLN crystals. Acute oral GLN ingestion in dosages up to 0.9 g·kg·FFM
are generally well-tolerated. However, the severity of mild GI symptoms appeared dose-dependent during the first two hours post prandial and may be due to high-concentrations of GLN crystals.
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