Multimodal analysis of the effects of dexamethasone on high-altitude cerebral oedema: protocol for a pilot study.

BACKGROUND: Acute mountain sickness (AMS) is a cluster of symptoms that commonly occur in those ascending to high altitudes. Symptoms can include headaches, nausea, insomnia and fatigue. Exposure to high altitude can also lead to high-altitude cerebral oedema (HACE), which is a potential cause of death whilst mountaineering. Generally, AMS precedes the development of HACE. Historical studies have demonstrated the effectiveness of regular dexamethasone administration in reducing the symptoms of AMS. However, the mechanism by which dexamethasone works to reduce symptoms AMS remains poorly understood. Further studies, simulating altitude using hypoxic tents, have characterised the effect of prolonged exposure to normobaric hypoxia on cerebral oedema and blood flow using MRI. This randomised trial assesses the effect of dexamethasone on hypoxia-induced cerebral oedema in healthy adult volunteers. METHODS/DESIGN: D4H is a double-blind placebo-controlled randomised trial assessing the effect of dexamethasone on hypoxia-induced cerebral oedema. In total, 20 volunteers were randomised in pairs to receive either 8.25 mg dexamethasone or normal saline placebo intravenously after 8 h of hypoxia with an FiO2 of 12%. Serial MRI images of the brain and spinal cord were obtained at hours 0, 7, 11, 22 and 26 of the study along with serum and urinary markers to correlate with the severity of cerebral oedema and the effect of the intervention. DISCUSSION: MRI has been used to identify changes in cerebral vasculature in the development of AMS and HACE. Dexamethasone is effective at reducing the symptoms of AMS; however, the mechanism of this effect is unknown. If this study demonstrates a clear objective benefit of dexamethasone in this setting, future studies may be able to demonstrate that dexamethasone is an effective therapy for oedema associated with brain and spinal cord ischaemia beyond AMS. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03341676 . Registered on 14 November 2017.

Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema.

INTRODUCTION: The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available. AREAS COVERED: Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018. EXPERT OPINION: Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema.

Pre-operative Functional Cardiovascular Reserve Is Associated with Acute Kidney Injury after Intervention.

BACKGROUND: Acute kidney injury (AKI) is a common complication after endovascular intervention, associated with poor short and long-term outcomes. However, the mechanisms underlying AKI development remain poorly understood. The impact of pre-existing cardiovascular disease and low cardiovascular reserve (CVR) in AKI is unclear; it remains unknown whether AKI is primarily related to pre-existing comorbidity or to procedural parameters. The association between CVR and AKI after EVAR was therefore assessed. METHODS: This is a case control study. From a database of 484 patients, 292 undergoing elective endovascular aneurysm repair (EVAR) of an infrarenal abdominal aortic aneurysm (AAA) in two tertiary centres were included. Of these, 73 patients who had developed AKI after EVAR were case matched, based on pre-operative estimated glomerular filtration rate (eGFR; within 5 mL/min/1.73 m2) and age, with patients who had not developed AKI. Cardiopulmonary exercise testing (CPET) was used to assess CVR using the anaerobic threshold (AT). Development of AKI was defined using the Kidney Disease Improving Outcomes (KDIGO) guidance. Associations between CVR (based on AT levels) and AKI development were then analysed. RESULTS: Pre-operative AT levels were significantly different between those who did and did not develop AKI (12.1±2.9 SD vs. 14.8±3.0 mL/min/kg, p < .001). In multivariate analysis, a higher level of AT (per 1 mL/min/kg) was associated with a lower odds ratio (OR) of 0.72 (95% CI, 0.63-0.82, p < .001), relative to AKI development. A pre-operative AT level of < 11 mL/min/kg was associated with post-operative AKI development in adjusted analysis, with an OR of 7.8 (95% CI, 3.75-16.51, p < .001). The area under the curve (receiver operating characteristic) for AT as a predictor of post-operative AKI was 0.81 (standard error, 0.06, 95% CI, 0.69-0.93, p < .001). CONCLUSIONS: Poor CVR was strongly associated with the development of AKI. This provides pathophysiological insights into the mechanisms underlying AKI.

Prospective validation study of transorbital Doppler ultrasound imaging for the detection of transient cerebral microemboli.

BACKGROUND: Transient cerebral microemboli are independent biomarkers of early risk of ischaemic stroke in acute carotid syndromes. Transcranial Doppler imaging (TCD) through the temporal bone is the standard method for detection of cerebral microemboli, but an acoustic temporal bone window for TCD is not available in around one in seven patients. Transorbital Doppler imaging (TOD) has been used when TCD is not possible. The aim of this study was to validate the use of TOD against TCD for detecting cerebral microemboli. METHODS: The study included patients undergoing elective carotid endarterectomy; all had confirmed temporal and orbital acoustic windows. Subjects gave written informed consent to postoperative TCD and TOD monitoring, which was performed simultaneously for 30 min by two vascular scientists. RESULTS: The study included 100 patients (mean(s.e.m.) age 72(1) years; 65 men). Microemboli were detected by one or both methods in 40·0 per cent of patients: by TOD and TCD in 24 patients, by TOD alone in ten and by TCD alone in six. For detecting microemboli, TOD had a sensitivity of 80·0 per cent, specificity of 86·1 per cent, positive predictive value of 71·6 per cent and negative predictive value of 91·2 per cent. Bland-Altman analysis revealed no significant bias (bias 0·11 (95 per cent c.i. -0·52 to 0·74) microemboli; P = 0·810) with upper and lower limits of agreement of +6 and -6 microemboli. CONCLUSION: TOD appears a valid alternative to TCD for detecting microembolic signals in patients with no suitable temporal acoustic window.

A novel treatment for embolising carotid dissection.

INTRODUCTION: A rare but significant cause for stroke is sub-intimal carotid dissection and this mechanism accounts for approximately 2.5% of all strokes.(1) Dissection of the carotid artery is often caused by trauma to the face or neck.(2) Under 45 years old, it is the second leading cause of stroke.(3) Neurological symptoms can be lacking or subtle, therefore the condition may be overlooked but the pathological processed is believed to be attributed to thromboembolism.(4) Microemboli in the middle cerebral artery, are known as a risk factor for ischaemic stroke following a transient ischaemic attack (TIA) and can be detected by transcranial Doppler examination (TCD).(5) The established treatment regime is antiplatelet therapy, anticoagulation or both along with supportive therapy.(6) Current evidence suggests managing microemboli in both crescendo TIA's and post carotid endarterectomy improves outcome.(7) We have found the use of Tirofiban, a potent intravenous antiplatelet agent currently licensed for use in acute coronary syndrome, effective in the treatment of microemboli in this manner.(7) CASE PRESENTATION: We report a case of symptomatic carotid artery dissection post radical neck dissection, causing TCD detected microemboli and successfully treated with Tirofiban. CONCLUSION: We believe further study into the use of Tirofiban in the treatment of microemboli after carotid dissection is indicated.

A clinical review of the management of frostbite.

Frostbite is a thermal injury that can occur when temperatures drop low enough for tissue to freeze. On rewarming the tissues, an inflammatory process develops which is often associated with tissue loss. The extent of the tissue loss reflects the severity of the cold exposure and includes factors such as temperature, duration, wind chill, altitude, and systemic hypothermia. This review discusses the epidemiology, the pathophysiological processes involved, and the clinical management of frostbite injuries. Practical advice is given on both the field and hospital management and how to seek expert advice from remote situations. The review also discusses newer developments in frostbite treatment such as intra-vascular thrombolysis and adjunctive treatments such as the use of intravenous vasodilators.

Nonfreezing cold-induced injuries.

Non-freezing cold injury (NFCI) is the Cinderella of thermal injuries and is a clinical syndrome that occurs when tissues are exposed to cold temperatures close to freezing point for sustained periods. NFCI is insidious in onset, often difficult to recognize and problematic to treat, and yet the condition accounts for significant morbidity in both military and civilians who work in cold conditions. Consequently recognition of those at risk, limiting their exposure and the appropriate and timely use of suitable protective equipment are essential steps in trying to reduce the impact of the condition. This review addresses the issues surrounding NFCI.

Systemic blood pressure, arterial stiffness and pulse waveform analysis at altitude.

OBJECTIVES: Systemic arterial pressure rises on acute exposure to high altitude and changes in blood pressure (BP) and endothelial function may be important in the pathogenesis of clinical syndromes occurring at high altitude. METHODS: Arterial BP, stiffness (SI) and tone (RI) were studied over 11 days in 17 subjects (three having mild hypertension) ascending to 3,450m and 4,770m using a non-invasive, finger photoplethysmography technique. RESULTS: At 3,450m BP rose from mean 131/75 mmHg (SD 23/12) to 145/86 (23/12) and was maintained at this level (p < 0.001). SI did not change significantly from 8.5 m/sec (2.5) to 9.7 (3.2). RI fell during the first day at 3,450m from 74.4% (7.9) to 70.5% (13.8) (NS p > 0.05) and to 69.9% (12.0) (p < 0.02) at 4,770m but then reverted to baseline. Changes in SI and RI did not relate to changes in blood pressure. Changes in both arterial stiffness and tone were similar in those who developed AMS compared with those who did not. Baseline SI tended to be higher in the three subjects with hypertension 11.1m/sec (SD 2.7)) compared with the normotensives 8.3 m/sec (SD 2.7) (NS) and baseline RI lower 74.7% (7.0) compared with the normotensives 76.5% (8.5) (NS). Changes in SI and RI at altitude in the hypertensive subjects were similar to the non-hypertensive subjects. CONCLUSIONS: We conclude that acute exposure temporarily affected endothelial function as measured by a change in vascular tone but this did not predict the development of AMS. The rise in arterial BP was not related to changes in arterial stiffness or tone.

Changes to colour vision on exposure to high altitude.

OBJECTIVES: Several studies have shown deterioration in colour vision at altitudes above 3,000m. These studies have been conducted in photopic (bright daylight) conditions, whereas many military operations take place in mesopic (dim light) conditions. Data suggests that the tritan colour vision axis (blue cones, TA) are more susceptible to hypoxic insult than protan axis (red cones, PA). The objective of this study was to examine colour vision at high altitude, in mesopic conditions, and using a novel method of assessment to discriminate between the tritan and protan axis. METHODS: We examined 42 eyes (21 subjects, mean age 44, range 22-71), at sea level and within 12-36 hours of exposure to 3300m. This was done in a darkened room, with refractive error correction. Colour vision was studied using ChromaTest, a software programme that analyzes colour contrast threshold (CCT) of both TA and PA. We planned to repeat CCT measurement at 4,392m, but technology failure prevented this. Non-parametric paired data was examined using the Wilcoxon signed rank test. RESULTS: There was found to be no change to either the PA (p = 0.409) or the TA (p = 0.871) upon ascent. Within the PA 16 eyes had a lower CCT at high altitude, whilst 26 were higher. In the TA 20 eyes had a lower CCT and 22 were higher. At sea level, mean CCT for PA was 4.21 (SD 2.29) TA was 7.06 (SD 1.77). At 3,300m mean CCT for PA was 4.36 (SD 2.86) and TA was 6.93 (SD 2.39). CONCLUSIONS: This experiment revealed no changes to colour vision with exposure to 3,300m. This may be below the threshold altitude for cone dysfunction, alternatively colour vision deterioration may be less significant in mesopic conditions.

Transcranial Doppler ultrasonography-directed intravenous glycoprotein IIb/IIIa receptor antagonist therapy to control transient cerebral microemboli before and after carotid endarterectomy.

BACKGROUND: Patients with a transient focal neurological deficit, critical carotid stenosis and/or microemboli detected by transcranial Doppler ultrasonography (TCD) have a significant risk of stroke. The effect of tirofiban, a selective glycoprotein IIb/IIIa inhibitor, was assessed in patients with microembolic signals on TCD after transient ischaemic attacks or carotid endarterectomy (CEA). METHODS: Thirty-three patients with microemboli on TCD (13 symptomatic preoperative, 19 postoperative, one both) were treated with tirofiban between 2002 and 2007. All patients had carotid stenosis greater than 70 per cent. TCD monitoring was used during and after tirofiban therapy. RESULTS: The median (range) rate of microemboli decreased from 22 (4-260) per h before surgery and 81 (44-216) per h after surgery to 0 (0-9) per h in both groups (P < 0.001, Mann-Whitney U test). This occurred rapidly (preoperative median 30 min; postoperative median 45 min) and was well tolerated in all patients, with no serious adverse effects. CONCLUSION: Cerebral microemboli were controlled by tirofiban both before and after CEA. Further study is required to compare the relative efficacy of tirofiban and dextran.

Effect of exercise on cerebral perfusion in humans at high altitude.

The effects of submaximal and maximal exercise on cerebral perfusion were assessed using a portable, recumbent cycle ergometer in nine unacclimatized subjects ascending to 5,260 m. At 150 m, mean (SD) cerebral oxygenation (rSO2%) increased during submaximal exercise from 68.4 (SD 2.1) to 70.9 (SD 3.8) (P < 0.0001) and at maximal oxygen uptake (.VO2(max)) to 69.8 (SD 3.1) (P < 0.02). In contrast, at each of the high altitudes studied, rSO2 was reduced during submaximal exercise from 66.2 (SD 2.5) to 62.6 (SD 2.1) at 3,610 m (P < 0.0001), 63.0 (SD 2.1) to 58.9 (SD 2.1) at 4,750 m (P < 0.0001), and 62.4 (SD 3.6) to 61.2 (SD 3.9) at 5,260 m (P < 0.01), and at .VO2(max) to 61.2 (SD 3.3) at 3,610 m (P < 0.0001), to 59.4 (SD 2.6) at 4,750 m (P < 0.0001), and to 58.0 (SD 3.0) at 5,260 m (P < 0.0001). Cerebrovascular resistance tended to fall during submaximal exercise (P = not significant) and rise at .VO2(max), following the changes in arterial oxygen saturation and end-tidal CO(2). Cerebral oxygen delivery was maintained during submaximal exercise at 150 m with a nonsignificant fall at .VO2(max), but at high altitude peaked at 30% of .VO2(max) and then fell progressively at higher levels of exercise. The fall in rSO2 and oxygen delivery during exercise may limit exercise at altitude and is likely to contribute to the problems of acute mountain sickness and high-altitude cerebral edema.

An audit of vascular surgical intervention for complications of cardiovascular angiography in 2324 patients from a single center.

This study examines the incidence and outcome of complications requiring surgical intervention in a major vascular unit serving interventional radiology and interventional cardiology. Between April 2000 and March 2001, 2324 patients underwent angiographic examinations (male/female = 1579:745, mean age = 68 years, range 45-88). In non-stent patients, a 4-or 5-mm French (4-mm F, 5-mm F) guage nonheparinized arterial catheter was used, and in patients requiring stents a 6- or 7-mm French guage catheter was used. Pressure was applied to the puncture site for up to 6 min. Fifteen complications requiring vascular surgical procedure were recorded during in-hospital follow-up (9 males, 6 females). Our early operative (30-day) mortality rate was 0.086%. Although the number of major complications requiring surgical intervention after interventional or diagnostic cardiovascular radiology is diminishing, vigilance in these cases is still required. Where possible, a small catheter with a J-shaped guidewire should be used and prolonged compression should be brought to bear on the puncture site.

Effects of breathing air containing 3% carbon dioxide, 35% oxygen or a mixture of 3% carbon dioxide/35% oxygen on cerebral and peripheral oxygenation at 150 m and 3459 m.

The effects of gas mixtures comprising supplementary 3% carbon dioxide, 35% oxygen or a combination of 3% CO(2) plus 35% O(2) in ambient air have been compared on arterial blood gases, peripheral and cerebral oxygenation and middle cerebral artery velocity (MCAV) at 150 m and on acute exposure to 3459 m in 12 healthy subjects. Breathing 3% CO(2) or 35% O(2) increased arterial blood oxygen at both altitudes, and the CO(2)/O(2) combination resulted in the most marked rise. MCAV increased on ascent to 3459 m, increasing further with 3% CO(2) and decreasing with 35% O(2) at both altitudes. The CO(2)/O(2) combination resulted in an increase in MCAV at 150 m, but not at 3549 m. Cerebral regional oxygenation fell on ascent to 3459 m. Breathing 3% CO(2) or 35% O(2) increased cerebral oxygenation at both altitudes, and the CO(2)/O(2) combination resulted in the greatest rise at both altitudes. The combination also resulted in significant rises in cutaneous and muscle oxygenation at 3459 m. The key role of carbon dioxide in oxygenation at altitude is confirmed, and the importance of this gas for tissue oxygenation is demonstrated.

Control of emboli in patients with recurrent or crescendo transient ischaemic attacks using preoperative transcranial Doppler-directed Dextran therapy.

BACKGROUND: Transcranial Doppler (TCD)-directed Dextran 40 treatment after carotid endarterectomy reduces the rate of early postoperative thrombosis. This study assessed the efficacy of intravenous Dextran 40 at controlling symptoms and emboli before elective carotid endarterectomy in patients with recurrent or crescendo transient ischaemic attacks (TIAs). METHODS: In a prospective study, patients with more than 70 per cent internal carotid artery stenosis who had two or more symptomatic episodes within 30 days and TCD-detected microemboli were studied. Dextran 40 was commenced at 20 ml/h and TCD was repeated to reassess the rate of embolization. The infusion was increased in 20-ml/h increments until symptoms and emboli were controlled. The patient then had carotid surgery on the next elective list. RESULTS: Nineteen patients with internal carotid stenosis greater than 70 per cent, recurrent symptoms and TCD-detected emboli were studied. All patients had symptoms and emboli controlled with Dextran 40. One patient with both unstable angina (awaiting urgent operation) and crescendo TIAs died from a myocardial infarct before undergoing operation. Of the 18 patients who had an operation, one suffered a non-disabling stroke on the third postoperative day. CONCLUSION: TCD-directed Dextran 40 offers a safe approach to high-risk patients before elective carotid endarterectomy, and warrants further study.