Relationship between combat-related traumatic injury and ultrashort term heart rate variability in a UK military cohort: findings from the ADVANCE study.

INTRODUCTION: Combat-related traumatic injury (CRTI) has been linked to an increased cardiovascular disease (CVD) risk. The long-term impact of CRTI on heart rate variability (HRV)-a robust CVD risk marker-has not been explored. This study investigated the relationship between CRTI, the mechanism of injury and injury severity on HRV. METHODS: This was an analysis of baseline data from the ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE) prospective cohort study. The sample consisted of UK servicemen with CRTI sustained during deployment (Afghanistan, 2003-2014) and an uninjured comparison group who were frequency matched to the injured group based on age, rank, deployment period and role in theatre. Root mean square of successive differences (RMSSD) was measured as a measure of ultrashort term HRV via <16 s continuous recording of the femoral arterial pulse waveform signal (Vicorder). Other measures included injury severity (New Injury Severity Scores (NISS)) and injury mechanism. RESULTS: Overall, 862 participants aged 33.9±5.4 years were included, of whom 428 (49.6%) were injured and 434 (50.3%) were uninjured. The mean time from injury/deployment to assessment was 7.91±2.05 years. The median (IQR) NISS for those injured was 12 (6-27) with blast being the predominant injury mechanism (76.8%). The median (IQR) RMSSD was significantly lower in the injured versus the uninjured (39.47 ms (27.77-59.77) vs 46.22 ms (31.14-67.84), p<0.001). Using multiple linear regression (adjusting for age, rank, ethnicity and time from injury), geometric mean ratio (GMR) was reported. CRTI was associated with a 13% lower RMSSD versus the uninjured group (GMR 0.87, 95% CI 0.80-0.94, p<0.001). A higher injury severity (NISS ≥25) (GMR 0.78, 95% CI 0.69-0.89, p<0.001) and blast injury (GMR 0.86, 95% CI 0.79-0.93, p<0.001) were also independently associated with lower RMSSD. CONCLUSION: These results suggest an inverse association between CRTI, higher severity and blast injury with HRV. Longitudinal studies and examination of potential mediating factors in this CRTI-HRV relationship are needed.

The effects of acute hypoxia on tissue oxygenation and circulating alarmins in healthy adults.

The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50 % women; 26.6+/-3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 min) over three hours of continuous normobaric hypoxia (NH, 4,450 m equivalent) and again 60 min after return to normoxia (T240). A 5-min exercise step test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO(2)) and near-infrared spectroscopy (StO(2)), respectively. NH led to a significant reduction in SpO(2), StO(2), sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO(2) or StO(2). In conclusion, short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.

Heart rate variability and plasma nephrines in the evaluation of heat acclimatisation status.

PURPOSE: Heat adaptation (HA) is critical to performance and health in a hot environment. Transition from short-term heat acclimatisation (STHA) to long-term heat acclimatisation (LTHA) is characterised by decreased autonomic disturbance and increased protection from thermal injury. A standard heat tolerance test (HTT) is recommended for validating exercise performance status, but any role in distinguishing STHA from LTHA is unreported. The aims of this study were to (1) define performance status by serial HTT during structured natural HA, (2) evaluate surrogate markers of autonomic activation, including heart rate variability (HRV), in relation to HA status. METHODS: Participants (n = 13) were assessed by HTT (60-min block-stepping, 50% VO2peak) during STHA (Day 2, 6 and 9) and LTHA (Day 23). Core temperature (Tc) and heart rate (HR) were measured every 5 min. Sampling for HRV indices (RMSSD, LF:HF) and sympathoadrenal blood measures (cortisol, nephrines) was undertaken before and after (POST) each HTT. RESULTS: Significant (P < 0.05) interactions existed for Tc, logLF:HF, cortisol and nephrines (two-way ANOVA; HTT by Day). Relative to LTHA, POST results differed significantly for Tc (Day 2, 6 and 9), HR (Day 2), logRMSSD (Day 2 and Day 6), logLF:HF (Day 2 and Day 6), cortisol (Day 2) and nephrines (Day 2 and Day 9). POST differences in HRV (Day 6 vs. 23) were + 9.9% (logRMSSD) and - 18.6% (logLF:HF). CONCLUSIONS: Early reductions in HR and cortisol characterised STHA, whereas LTHA showed diminished excitability by Tc, HRV and nephrine measures. Measurement of HRV may have potential to aid real-time assessment of readiness for activity in the heat.

The effect of high altitude on central blood pressure and arterial stiffness.

Central arterial systolic blood pressure (SBP) and arterial stiffness are known to be better predictors of adverse cardiovascular outcomes than brachial SBP. The effect of progressive high altitude (HA) on these parameters has not been examined. Ninety healthy adults were included. Central BP and the augmentation index (AI) were measured at the level of the brachial artery (Uscom BP+ device) at <200 m and at 3619, 4600 and 5140 m. The average age of the subjects (70% men) were 32.2±8.7 years. Compared with central arterial pressures, brachial SBP (+8.1±6.4 mm Hg; P<0.0001) and pulse pressure (+10.9±6.6 mm Hg; P<0.0001) were significantly higher and brachial diastolic BP was lower (-2.8±1.6 mm Hg; P<0.0001). Compared with <200 m, HA led to a significant increase in brachial and central SBP. Central SBP correlated with AI (r=0.50; 95% confidence interval (CI): 0.41-0.58; P<0.0001) and age (r=0.32; 95% CI: 21-0.41; P<0.001). AI positively correlated with age (r=0.39; P<0.001) and inversely with subject height (r=-0.22; P<0.0001), weight (r=-0.19; P=0.006) and heart rate (r=-0.49; P<0.0001). There was no relationship between acute mountain sickness scores (Lake Louis Scoring System (LLS)) and AI or central BP. The independent predictors of central SBP were male sex (coefficient, t=4.7; P<0.0001), age (t=3.6; P=0.004) and AI (t=7.5; P<0.0001; overall r2=0.40; P<0.0001). Subject height (t=2.4; P=0.02), age (7.4; P<0.0001) and heart rate (t=11.4; P<0.0001) were the only independent predictors of AI (overall r2=0.43; P<0.0001). Central BP and AI significantly increase at HA. This rise was influenced by subject-related factors and heart rate but not independently by altitude, LLS or SpO2.

The Hearts of Heroes: the epidemiology of cardiac disease in the UK Armed Forces.

When the general public look from the outside at the armed services, their impression is often one of earnest young men and women who are the pinnacle of physical fitness and health, and put their lives on the line for their country. There is usually sadness and respect for those killed on active operations, having put themselves in harm's way. Therefore, when the public discover that more than 1 in 10 deaths in the UK Armed Forces are due to cardiovascular disease, the air of sadness is invariably replaced with surprise and disbelief. These figures, while lower than those due to deaths in accidents, are approaching the numbers of those due to suicide in the armed services; yet deaths from cardiac disease are barely recognised by society, in spite of many of them being avoidable. This article reviews the epidemiology of cardiac disease in the UK Armed Forces, both in terms of morbidity and mortality. It outlines current understanding and gaps in the knowledge regarding the burden of cardiovascular disease in the military population. The particular demographics of the Armed Forces and its influence on cardiac disease burden are discussed. The role of inherited and congenital diseases in younger servicemen and women is highlighted, as is the trend that with increasing age, the burden of disease shifts to ischaemic heart disease, which becomes the dominant cause of both death and disability.

Pericarditis and pericardial effusions in the military patient.

The pericardium is the thin double-walled sac encapsulating the heart which has a number of important physiological roles including fixing the heart in the mediastinum, protecting it from cross-organ infection (eg, lung) and lubricating cardiac contraction. The pericardium is associated with several disease syndromes that occasionally affect the military population. These include acute and recurrent pericarditis, pericardial effusion and tamponade, which may result from a large number of different aetiological agents. Pericardial diseases have a wide range of clinical manifestations and the diagnosis of pericardial diseases can be a challenge. This article reviews the anatomy and pathophysiology of pericarditis and pericardial effusions before outlining their clinical features, recommended investigations and management options. Particular emphasis is placed on the impact of these diseases for patients in a military occupational environment.

Managing the military patient with syncope.

Syncope is a relatively common occurrence in military populations. It is defined as a transient loss of consciousness due to global cerebral hypoperfusion, characterised by a rapid onset, short duration and a spontaneous and complete recovery. While the symptom of syncope is easily elicited, discovering the mechanism can be more problematic and may require a plethora of diagnostic tests. The aim of this paper is to review current evidence pertaining to the classification, investigation and management of syncope, from a military perspective. Emphasis is placed on assisting primary healthcare professionals in the assessment and management of syncope, in the UK and on operations, while providing explicit guidance on risk. The occupational limitations required in safely managing patients with syncope are stressed along with the potential long-term limitations.

Copeptin and arginine vasopressin at high altitude: relationship to plasma osmolality and perceived exertion.

PURPOSE: A diuresis is a key part of acclimatisation to high altitude (HA). Arginine vasopressin (AVP) is a hormone involved in salt and water balance and may potentially have a role in the development of altitude illness. ProAVP (copeptin) is more stable than AVP and is assayed by a straightforward, automated method. We investigated the relationship of AVP to copeptin and the copeptin response to exercise and altitude illness in a large cohort during a field study at HA. METHODS: 48 subjects took part in a 10-day trek at HA. Venous blood samples were taken at 3,833, 4,450 and 5,129 m post-trek (exercise) and the following day at rest. Daily recordings of symptoms of altitude illness, oxygen saturations and perceived exertion were carried out. RESULTS: AVP and copeptin levels increased with exercise and correlated closely (ρ 0.621 p < 0.001), this was strongest in the stressed state when AVP secretion was highest, at 5,129 m post-exercise (ρ 0.834 p < 0.001). On two-way ANOVA, both altitude (F = 3.5; p = 0.015) and exercise (F = 10.2; p = 0.002) influenced copeptin levels (interaction F = 2.2; p = 0.08). AVP levels were influenced by exercise (F = 14.4; p = 0.0002) but not altitude (F = 2.0; p = 0.12) with no overall group interactions (F = 1.92.6; p = 0.06). There was no association between copeptin or arginine vasopressin and altitude illness. Copeptin correlated with the Borg RPE score and was significantly higher in the group with a Borg score ≥15 (7.9 vs. 3.7 p < 0.001). CONCLUSION: We have shown that arginine vasopressin and copeptin levels correlate and are suppressed below 5,129 m. Furthermore, we have demonstrated that exertion, rather than altitude illness or increasing osmolality, is the stimulus for increases in copeptin.

Comparison of two methods of assessing total body water at sea level and increasing high altitude.

Fluid retention is a recognized feature of acute mountain sickness. However, accurate assessment of hydration, including the quantification of body water, has traditionally relied on expensive and non-portable equipment limiting its utility in the field setting. We compared the assessment of total body water (TBW) and their relationship to total body weight using two non-invasive methods using the NICas single-frequency bioimpedance analysis (SF-BIA) system and the BodyStat QuadScan 4000 multifrequency BIA system (MF-BIA). TBW measurements were performed at rest at sea level and at high altitude (HA) at 3833 m postexercise and at rest and thereafter at rest at 4450 m and 5129 m on 47 subjects. The average age was 34.5 ± 9.3 years with an age range of 21-54 years (70.2% male). There were strong correlations between TBW assessment with both methods at sea level (r = 0.90; 95% CI 0.78-0.95: P<0.0001) and at HA (r = 0.92; 0.89-0.94: P<0.0001), however, TBW readings were 0.2 l and 1.91 l lower, respectively, with the NICaS. There was a stronger correlation between TBW and body weight with the QuadScan (r = 0.91; P<0.0001) than with the NICaS (r = 0.83; P<0.0001). The overall agreement between the two TBW methods was good, but the 95% confidence intervals around these agreements were relatively wide. We conclude that there was reasonable agreement between the two methods of BIA for TBW, but this agreement was lower at HA.

The effects of acute hypobaric hypoxia on arterial stiffness and endothelial function and its relationship to changes in pulmonary artery pressure and left ventricular diastolic function.

This study investigated, for the first time, the effects of simulated high altitude, following acute hypobaric hypoxia (HH), on simultaneous assessment of large artery stiffness and endothelial function and its inter-relationship to left ventricular (LV) diastolic function, pulmonary artery systolic pressure (PASP), and estimated PA vascular resistance (PVR). Ten healthy subjects were studied at baseline pre and following acute HH to 4800 m for a total of 180 minutes. Assessments of LV diastolic function, mitral inflow, estimated LV filling pressure (E/e'), PVR, and PASP were undertaken using transthoracic echocardiography. Simultaneous assessments of arterial stiffness index (SI), systemic vascular resistance (SVR), vascular tone, and endothelial function (reflective index [RI]) were performed using pulse contour analysis of the digital arterial waveform. Acute hypoxia led to a fall in SpO2 (98.1±0.7 vs. 71.8±7.1%; p=0.0002), SVR (1589.1±191.2 vs. 1187.8±248.7; p=0.004), and RI (50.8±10.3 vs. 33.0±6.5%; p=0.0008) with an increase in PASP (24.3±2.2 to 35.0±5.3 mmHg; p=0.0001) and estimated PVR (116.40±19.0 vs. 144.6±21.5; p<0.001). There was no rise in either SI (p=0.13), mitral early annular early e' filling velocity or E/e'. There was a significant inverse correlation between SpO2 and PASP (r=-0.77; p<0.0001), PVR (r=-0.57; p=0.008) and between the fall in SpO2 and change (Δ) in RI (baseline vs. 150 min, r=-0.52; p<0.001). There was a modest inverse correlation between ΔRI (lower ΔRI=worsening endothelial function) and ΔPAP (r=-0.55; p=0.10) and a strong inverse correlation between ΔRI and ΔPVR (r=-0.89; p=0.0007). Acute hypobaric hypoxia does not significantly alter large artery stiffness or cause overt LV diastolic function. However, the degree of hypoxia influences both the systemic endothelial and pulmonary vascular responses. This noted association is intriguing and requires further investigation.

Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans.

AIM: To examine the response of brain natriuretic peptide (BNP) and NT-proBNP to high altitude (HA) both at rest and following exercise. METHODS: We measured NT-proBNP and BNP and Lake Louise (LL) acute mountain sickness (AMS) scores in 20 subjects at rest in Kathmandu (Kat; 1300 m), following exercise and at rest at 4270 and 5150 m. RESULTS: BNP and NT-proBNP (pg ml(-1) , mean ± SEM) rose significantly from Kat (9.2 ± 2 and 36.9 ± 6.6, respectively) to arrival at 4270 m after exercise (16.6 ± 4 and 152 ± 56.1, P=0.008 and P<0.001, respectively) and remained elevated the next morning at rest (28.9 ± 9 and 207.4 ± 65.1, P = 0.004 and P<0.001 respectively). At 5150, immediately following ascent/descent to 5643 m, BNP and NT-proBNP were 32.3 ± 8.8 and 301.1 ± 96.3 (P=0.003 and P<0.001 vs. Kat, respectively) and at rest the following morning were 33.3 ± 9.7 and 258.9 ± 89.5 (P=0.008 and P=0.001 vs. Kat respectively). NT-proBNP and BNP correlated strongly at 5150 m (ρ 0.905, P<0.001 and ρ 0.914, P<0.001 for resting and post-exercise samples respectively). At 5150 m, BNP levels were significantly higher among the four subjects with severe (LL score>6) AMS (58.4 ± 18.7) compared with those without (BNP 22.7 ± 8.6, P=0.048). There were significant correlations between change in body water from baseline to 5150 m with both BNP and NT-proBNP (ρ 0.77, P=0.001, ρ 0.745, P=0.002 respectively). CONCLUSION: In conclusion, these data suggest that BNP and NT-proBNP increase with ascent to HA both after exercise and at rest. We also report the novel finding that BNP is significantly greater in those with severe AMS at 5150 m.

The use of exercise and dietary supplements among British soldiers in Afghanistan.

BACKGROUND AND OBJECTIVES: Recently published case reports, coupled with a large observational study of 1017 deployed servicemen to Iraq (January 2009), has highlighted the issue and potential concerns regarding the unregulated use of dietary and exercise supplements within the British military. Consequently, an exploratory pilot study was undertaken to assess whether the findings of the previous Iraq study were applicable to current deployed British servicemen in Afghanistan. METHODS: This was a voluntary questionnaire-based study targeted at individuals attending a health promotion fair in Camp Bastion, Afghanistan in June 2010. RESULTS: From 150 questionnaires handed out there were 87 completed questionnaires (58% return). The mean age was 28.0 (SD 7.1; range of 18-50 years) with 89.7% being male. From the total of 87 persons 46.0% were self-declared current smokers with 37.9% admitting to drinking >6 caffeinated drinks per day. Forty nine persons (56.3%) admitted to a history of supplement use with 35 (40.2% compared with 32.0% in 2009 in Iraq) declaring current use. The average duration of supplement use among current users was 3.0 (2.0-9.0) months. The main sources of supplement supply were via local NAAFI purchase (57.1%), internet purchase (40.0%) and via their local chemist (2.9%). The main types of supplement used were proteins/amino acids (85.7%), creatine (34.3%), chromium (31.4%), stimulants (17.1%), hydroxycut (5.7%), and testosterone boosters (1.2%) with no persons admitting to the use of ephedra or anabolic steroids. CONCLUSIONS: A significant proportion of the British servicemen employed on operations in Afghanistan who were sampled, admitted to current dietary and exercise supplement use whilst on deployment. The results of this small study suggest that their use on operations may be increasing. Smoking rates and caffeine consumption, on deployment, remain high in the British military. A larger detailed study with greater representation among soldiers deployed to forward operating bases would be helpful to fully appreciate the scale of supplement use.

Cardiology.

Cardiac disease remains a significant threat to both local and deployed military populations. In this article we present several cardiac case reports which may be of educational use to the military clinician.

Self-administration of exercise and dietary supplements in deployed British military personnel during Operation TELIC 13.

OBJECTIVES: Recent operational experience has led to the identification of several potentially serious adverse events related to the use of dietary and exercise supplements among British Army personnel. This study aimed to establish the point prevalence of dietary and exercise supplement usage in British soldiers on Op TELIC during January 2009. METHODS: A cross-sectional questionnaire-based study of British military personnel located at the Contingency Operating Base (COB), in Basra, was performed during the sixth week of Op TELIC 13. RESULTS: From 1544 questionnaires (target population) issued, a total of 1017 (65.9%) completed questionnaires were evaluated. The mean population age was 29.5 years (range 18-58) of which 87.4% were male. 417/1017 persons (41.0%) admitted to a history of supplement use of which 32.0% were current users and 9.4% were previous users. Of these current users, 66.0% started taking them on their current deployment. The most commonly taken supplements were whey protein (18.8%), amino acids (17.9%), and creatine (13.2%). There were 14 persons (1.4%) who admitted to current use of anabolic steroids. The most-frequently given reasons for taking supplements were either to 'increase muscle bulk' (40.4%) or to aid training and recovery (20.8%). CONCLUSIONS: This is the first study to investigate the use of exogenous nutritional supplements within the British Military and has identified their widespread use during operational deployment. The use of anabolic steroids is particularly worrying, given both their illegality and their well-recognised and deleterious health effects. There is a need for greater awareness and education regarding potential benefits and dangers of supplement use in order to maximise any potential benefits and minimise clinical risk.

Dietary supplements and military operations: caution is advised.

We describe the case of a 32-year-old soldier who presented with acute organic psychosis during an operational tour to Iraq. This was precipitated by excessive consumption of caffeine coupled with additional use of oral nutritional stimulants. Her biochemical profile was compounded by the additional use of exogenous creatine. We present a brief overview of the issue of exercise supplementation and highlight some of the potential problems and clinical issues surrounding their use. This has important implications for both serving soldiers and the wider medical community.

Back pain in a Bangladeshi worker in Iraq.

Pyogenic Spinal Infection (PSI) is an uncommon disorder encompassing a broad spectrum of diseases including septic spondylodiscitis, osteomyelitis, epidural and paravertebral abscess formation. Presentation can be vague and highly variable but usually includes back pain and fever. Whilst predisposing factors, such as trauma and diabetes can often be identified a pathogenic organism may not be identified in up to a half of all cases leading to significant delay in both accurate diagnosis and effective treatment. Precise spinal imaging is essential and includes plain X-ray, CT and preferably MRI. The treatment of PSI can be conservative (including antibiotics); however, spinal surgery may be required for the complications in up to 50% of cases, with varying degrees of success. We present a challenging case of PSI encountered in a locally-employed 42-year-old Bangladeshi civilian working in Iraq. Despite obvious resource limitations available within a Role 2 Field Hospital, clinical suspicion coupled with repeat spinal CT was pivotal in obtaining the diagnosis. The patient was repatriated to Bangladesh for MRI and definitive surgical treatment.

The relationship of circulating endothelial cells to plasma indices of endothelial damage/dysfunction and apoptosis in acute coronary syndromes: implications for prognosis.

BACKGROUND: While coronary artery disease has been linked to both endothelial damage and cellular apoptosis, their inter-relationships and impact on cardiovascular (CV) outcomes has been barely explored. AIMS: First, we investigated the inter-relationships between circulating endothelial cells (CECs, and index of endothelial damage) and circulating plasma markers of endothelial damage/dysfunction [von Willebrand factor (VWF), soluble E selectin (sEsel)] and apoptosis [soluble Fas (sFas), Fas ligand (sFasL) and their ratio, sFas/sFasL] in patients presenting with acute coronary syndrome (ACS). Second, we assessed their prognostic values for major adverse CV events (MACE) in ACS. METHODS: We studied 211 patients with ACS, who were compared with 60 healthy controls (HC) and 45 'disease controls' (patients with stable coronary artery disease, CAD). Simultaneous blood samples for CECs (immunobead method), VWF, sESel, sFas and sFasL (ELISA) were taken within 24 h of presentation of ACS and at 48 h post admission. RESULTS: CEC, sEsel and VWF levels were significantly higher among the ACS groups compared with the CAD and HC (P < 0.05) groups. sFas was higher (P = 0.016) and sFasL lower (P = 0.021) in ACS compared with controls (HC and CAD). There was a significant increase in sFas/sFasL ratio with increasing disease severity (P = 0.0004). There were significant correlations between CECs and both VWF and sEsel (both P < 0.01) but no correlations between CECs and either sFas or sFas ligand. On univariate survival analysis, CECs were associated with an increased risk of both MACE [hazard ratio (HR) 2.4 (95% CI 1.2-4.1); P = 0.009] and cardiovascular death [HR 2.95 (95% CI 1.01-8.81); P = 0.047]. On multivariate Cox regression analysis, only VWF (and not CECs) remained as an independent predictor of MACE [HR 1.02 (95% CI 1.005-1.040); P = 0.009]. CONCLUSION: CECs were associated with abnormal plasma indices of endothelial damage/dysfunction and not apoptosis, despite abnormalities of all these markers being associated with ACS. VWF remained as an independent predictor of MACE, on multivariate analysis.

Antithrombotic treatment in atrial fibrillation.

Atrial fibrillation (AF) can significantly increase morbidity and mortality. It is gaining in clinical and economic importance, being the most commonly encountered tachyarrhythmia in clinical practice. Stroke is the most serious complication. Evidence from AF antithrombotic treatment trials is reviewed, risk stratification of patients with AF is discussed, and recommendations for anticoagulation are presented.