Oral antioxidant supplementation does not prevent acute mountain sickness: double blind, randomized placebo-controlled trial.

BACKGROUND: Acute mountain sickness may be caused by cerebrovascular fluid leakage due to oxidative damage to the endothelium. This may be reduced by oral antioxidant supplementation. AIM: To assess the effectiveness of antioxidant supplementation for the prevention of acute mountain sickness (AMS). DESIGN: A parallel-group double blind, randomized placebo-controlled trial. METHODS: The study was conducted in a university clinical research facility and a high altitude research laboratory. Eighty-three healthy lowland volunteers ascended to 5200 m on the Apex 2 high altitude research expedition. The treatment group received a daily dose of 1 g l-ascorbic acid, 400 IU of alpha-tocopherol acetate and 600 mg of alpha-lipoic acid (Cultech Ltd., Wales, UK) in four divided doses. Prevalence of AMS was measured using the Lake Louise Consensus score sheet (LLS). Secondary outcomes were AMS severity measured using a novel visual analogue scale, arterial oxygen saturation and pulmonary artery systolic pressure (PASP). RESULTS: Forty-one subjects were allocated to the antioxidant group, and 42 to the placebo group. There was no difference in AMS incidence or severity between the antioxidant and placebo groups using the LLS at any time at high altitude. At the pre-determined comparison point at Day 2 at 5200 m, 69% of the antioxidant group (25/36) and 66% of the placebo group (23/35) had AMS using the LLS criteria (P = 0.74). No differences were observed between the groups for PASP, oxygen saturation, presence of a pericardial effusion or AMS assessed by VAS. CONCLUSION: This trial found no evidence of benefit from antioxidant supplementation at high altitude. TRIAL REGISTRATION NUMBER: NCT00664001.

Lowering serum urate does not improve endothelial function in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group. METHODS: Intravenous urate oxidase (1.5 mg) was administered to ten patients with type 2 diabetes and ten healthy participants in a two-way, randomised, placebo-controlled, crossover study. Forearm blood flow responses to intra-brachial acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine (L-NMMA) were measured using venous occlusion plethysmography. The augmentation index (AIx) was determined by pulse wave analysis as a measure of large arterial stiffness. RESULTS: Acetylcholine and L-NMMA evoked lesser responses in patients with type 2 diabetes than in healthy participants. Baseline AIx was higher in patients with type 2 diabetes (mean +/- SD: 13.1 +/- 6.9%) than in healthy participants (2.0 +/- 5.1%; p = 0.006). Urate oxidase lowered serum uric acid concentrations by 64 +/- 11% (p < 0.001), but this had no effect on forearm blood flow responses or AIx in either group. CONCLUSIONS/INTERPRETATION: Substantial short-term lowering of uric acid did not have a direct vascular effect, suggesting that, on its own, this might not be an effective strategy for restoring endothelial function in patients with type 2 diabetes.

Similarity between the suprasystolic wideband external pulse wave and the first derivative of the intra-arterial pulse wave.

BACKGROUND: Wideband external pulse (WEP) monitoring, using a broad bandwidth piezoelectric sensor located over the brachial artery under the distal edge of a sphygmomanometer cuff, can be used for evaluating the contour of the arterial pressure pulse wave. The pulse contour contains valuable information relating to cardiovascular function which may be of clinical use in addition to blood pressure measurements. The aim of this study was to compare the shape of the WEP signal during inflation of the cuff to suprasystolic pressure, with intra-arterial pressure waves, after the administration of vasoactive drugs. METHODS: Radial intra-arterial and suprasystolic WEP waveforms were recorded in 11 healthy men (mean 23 yr) before and at the end of infusion of glyceryl trinitrate, angiotensin II, norepinephrine, and salbutamol. Waveform similarity was assessed by comparing the timing and pressure of incident and reflected waves and by root mean square error (RMSE). RESULTS: The WEP signal was found to closely resemble the first derivative of intra-arterial pressure. The WEP signal could be used to derive an arterial pressure wave with minimal bias in the timing of incident [- 8 (18) ms, mean (SD)] and reflected [- 1 (24) ms] waves. Augmentation index was underestimated by WEP [- 7 (18)%]. WEP also provided a measure of compliance which correlated with pulse wave velocity (r = - 0.44). RMSE values after the administration of each of the four drugs mentioned earlier were 12.4 (3.8), 17.7 (5.0), 22.1 (11.7), and 28.9 (22.4) mm Hg, respectively. Changes in derived WEP signals were similar to those measured by arterial line with all drugs. CONCLUSIONS: The suprasystolic WEP signals can be used to derive arterial pressure waves which, although not identical, track changes in the intra-arterial pulse wave induced by vasoactive drugs.

Hemodynamic effects of methadone and dihydrocodeine in overdose.

BACKGROUND: Opioid overdose is an increasing health problem worldwide. The cardiovascular toxicity of opioids contributes to morbidity and mortality in overdose but the hemodynamic effects of opioids reported in animal and human studies are contradictory. METHODS: We performed a prospective observational study of patients admitted to hospital following an overdose of methadone, dihydrocodeine, or low dose paracetamol (10 each). Basic cardiovascular indices including peripheral blood pressure, pulse rate, radial augmentation index and derived measures of aortic systolic, diastolic, pulse, and mean and end systolic pressures were measured every six hours for up to 18-23 hours after exposure or until hospital discharge. RESULTS: Dihydrocodeine and methadone significantly reduced peripheral and aortic systolic, mean and end systolic pressures. Both opioids significantly decreased peripheral pulse pressure, but only methadone decreased aortic blood pressure. Dihydrocodeine reduced systemic and aortic diastolic blood pressure, an effect not induced by methadone. Methadone significantly reduced peripheral pulse pressure. Augmentation index and heart rate, however, did not change. Both opioids decreased arterial oxygen saturation. CONCLUSION: These results suggest that dihydrocodeine and methadone in overdose both have a significant effect on central and peripheral hemodynamics. These effects might be expected to reduce cardiac afterload, providing a pharmacological explanation for the apparent benefit of opioids in cardiovascular diseases.

Are medical students adequately trained to prescribe at the point of graduation? Views of first year foundation doctors.

BACKGROUND: Drugs are the major therapeutic intervention provided by most doctors throughout their careers. The General Medical Council expects all medical students to be competent to prescribe at the point of graduation. AIMS: The aim of this study was to assess the views of Foundation Year 1 (FY1) doctors who had recently graduated from the University of Edinburgh about their training and competence in relation to the use of drugs based on their early clinical experience. METHOD: A questionnaire was constructed based on Tomorrow's Doctors 2002 and distributed to FY1 doctors who graduated in August 2005. RESULTS: Responses were received from 100 (39.8%) of the doctors who graduated in 2005. Only 32% respondents considered themselves 'competent to prescribe' at the point of graduation. Less than 50% of respondents felt comfortable in providing information about possible treatments to allow patients to make informed decisions about their care. The majority of respondents complained about a lack of formal teaching and practice at basic clinical skills relating to drug therapy. CONCLUSION: Many graduates feel under-prepared to take on prescribing responsibilities after graduation. These findings emphasise the need to ensure that all medical curricula are able to provide sufficient learning opportunities and robust assessment in this important area of clinical practice.

Selectivity of NSAIDs for COX-2 and cardiovascular outcome.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) with increased selectivity for the cyclooxygenase-2 (COX-2) isoform reduce gastrotoxicity but may increase adverse cardiovascular events. METHODS: We searched the literature for studies that reported the odds ratio (OR) for such events following exposure to NSAIDs. RESULTS: For studies comparing NSAID use with no use, increased COX-2 selectivity was significantly related to cardiovascular risk (log OR) amongst observational studies (R = -0.34, P < 0.001) and randomized controlled trials (RCTs) (R = -0.56, P < 0.001). For studies comparing NSAIDs, difference in selectivity was related to risk for observational studies (R = -0.28, P = 0.005) but not for RCTs (R = -0.23, P = 0.15). CONCLUSIONS: Although increased COX-2 selectivity may reduce gastrotoxicity, this may be at the cost of increasing cardiovascular risk.

Failure to implement hospital antimicrobial prescribing guidelines: a comparison of two UK academic centres.

BACKGROUND: Rational antimicrobial therapy should provide maximum benefit to patients while minimizing the development of resistant microorganisms. OBJECTIVES: The aim of this study was to investigate (i) which antimicrobial drugs were chosen by hospital doctors faced with two common infections [community-acquired pneumonia (CAP) and urinary tract infection (UTI)], (ii) whether these choices were compliant with local guidance and (iii) the factors that influenced antimicrobial choice. METHODS: A questionnaire based on two hypothetical clinical scenarios was distributed to 316 hospital doctors across four UK NHS hospitals in two cities (Newcastle and Edinburgh). RESULTS: Doctors in Newcastle were significantly more aggressive in their management: more patients were admitted (CAP: 78.9% versus 48.4%, P < 0.05) and given antimicrobials intravenously (CAP: 53.4% versus 21.2%, P < 0.05). Adherence to the local hospital guideline for CAP was significantly higher in Newcastle (83.3% versus 38.0%; P < 0.05). Fewer than half of the doctors surveyed used the local hospital guideline when choosing an antimicrobial, and the British National Formulary was the most frequently used resource (>90%). Junior doctors also identified medical school teaching and opinions of senior doctors as important influences. CONCLUSIONS: This study highlights inadequacies in the implementation and promotion of local guidelines, and demonstrates the potential for widely varying antimicrobial practices in two comparable UK cities.

Pulse transit time measured from the ECG: an unreliable marker of beat-to-beat blood pressure.

The arterial pulse-wave transit time can be measured between the ECG R-wave and the finger pulse (rPTT), and has been shown previously to have a linear correlation with blood pressure (BP). We hypothesized that the relationship between rPTT, preejection period (PEP; the R-wave/mechanical cardiac delay), and BP would vary with different vasoactive drugs. Twelve healthy men (mean age 22 yr) were studied. Beat-to-beat measurements were made of rPTT (using ECG and photoplethysmograph finger probe), intra-arterial radial pressure, PEP (using cardiac bioimpedance), and transit time minus PEP (pPTT). Four drugs (glyceryl trinitrate, angiotensin II, norepinephrine, salbutamol) were administered intravenously over 15 min, with stepped dosage increase every 5 min and a 25-min saline washout between agents. All subjects in all conditions had a negative linear correlation (R2 = 0.39) between rPTT and systolic BP (SBP), generally constant between different drugs, apart from four subjects who had a positive rPTT/SBP correlation with salbutamol. The 95% limits of agreement between measured and rPTT-predicted SBP were +/-17.0 mmHg. Beat-to-beat variability of rPTT showed better coherence with SBP variability than it did with heart rate variability (P < 0.001). PEP accounted for a substantial and variable proportion of rPTT (12-35%). Diastolic (DBP) and mean arterial BP (MAP) correlated poorly with rPTT (R2 = 0.02 and 0.08, respectively) but better with pPTT (rPTT corrected for PEP, R2 = 0.41 and 0.45, respectively). The 95% limits of agreement between measured and pPTT-predicted DBP were +/- 17.3 mmHg. In conclusion, the negative correlation between rPTT and SBP is generally constant, even with marked hemodynamic perturbations. However, the relationship is not reliable enough for rPTT to be used as a surrogate marker of SBP, although it may be useful in assessing BP variability. DBP and MAP cannot be predicted from rPTT without correction for PEP. The significant contribution of PEP to rPTT means that rPTT should not be used as a marker of purely vascular function.

Co-proxamol overdose is associated with a 10-fold excess mortality compared with other paracetamol combination analgesics.

AIMS: To assess the relative toxicity of co-proxamol in overdose in comparison to the 2 other paracetamol-opioid combination products, co-codamol and co-dydramol. METHODS: Data collected over a 2-year period (July 2000-June 2002) was used to estimate the frequency of overdose and death for the three most popular paracetamol-opioid compound analgesics. Prescription data for Scotland and Edinburgh, the number of overdoses (derived from overdose admissions in Edinburgh) or Poisons Information Service contacts in Scotland, and national death records were used to calculate a series of indicators relating morbidity (admissions), surrogates of morbidity (poisons enquiries by telephone or internet) and mortality to prescriptions. RESULTS: When related to prescription volume overdoses involving co-proxamol in Scotland were 10 times more likely to be fatal (24.6 (19.7, 30.4)) when compared with co-codamol (2.0 (0.88, 4.0)) or co-dydramol (2.4 (0.5, 7.2)). In contrast there was no difference in the presentation rate or enquiry rates for these analgesics when corrected for prescriptions. CONCLUSIONS: The excess hazard from co-proxamol is due to inherent toxicity rather than increased use in overdose. We estimate from this study that withdrawal of co-proxamol would prevent 39 excess deaths per annum in Scotland alone.

Does a hospital formulary influence prescribing practice in an acute medical admissions unit?

AIM: To assess the extent to which prescribing of cardiovascular medications in a busy medical unit deviates from the local joint primary and secondary care drug formulary guidelines. METHOD: A retrospective audit of the case notes, prescription charts and discharge summaries of 150 randomly selected emergency medical admissions over a 4 month period. RESULTS: No patient receiving a non-formulary cardiovascular drug on admission had the choice reviewed in line with formulary recommendations. One third of new cardiovascular medications commenced in hospital were not compliant with formulary recommendations. Decisions about drug therapy were rarely justfied in the written hospital record. CONCLUSIONS: Our results demonstrate that in a busy acute medical admissions' unit there is a clear failure to amend or query non-formulary prescribing at the time of admission and a tendency to exacerbate it during the inpatient period. This potentially undermines the purpose of a joint drug formulary as a guideline for safe, evidence-based and cost-effective prescribing.

Hyperuricaemia does not impair cardiovascular function in healthy adults.

OBJECTIVE: To investigate the possibility that uric acid (UA) can impair endothelial function, an important surrogate for atherosclerosis. DESIGN: UA was administered locally or systemically to healthy adult men and women in a series of randomised placebo controlled studies. This temporarily raised serum UA concentrations, so that the potential effects of hyperuricaemia on mechanisms of cardiovascular disease could be studied. MAIN OUTCOME MEASURES: The effects of UA administration on basal blood flow and responses to locally administered acetylcholine, sodium nitroprusside, and L-N(G)-monomethylarginine were studied in the forearm vascular bed with venous occlusion plethysmography. The effects of hyperuricaemia on systemic vascular resistance, large artery compliance, and baroreflex sensitivity were examined by validated non-invasive techniques. RESULTS: UA administration caused a twofold increase in serum concentrations. However, there were no acute effects on haemodynamic variables, basal forearm blood flow, or nitric oxide dependent endothelial function. CONCLUSION: Unlike other risk factors associated with endothelial dysfunction, acute exposure to high concentrations of UA does not impair cardiovascular function in healthy men. These findings do not support a causal link between hyperuricaemia and atherosclerosis.

Uric acid reduces exercise-induced oxidative stress in healthy adults.

Uric acid (UA) possesses free-radical-scavenging properties, and systemic administration is known to increase serum antioxidant capacity. However, it is not known whether this protects against oxidative stress. The effects of raising UA concentration were studied during acute aerobic physical exercise in healthy subjects, as a model of oxidative stress characterized by increased circulating 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) concentrations. Twenty healthy subjects were recruited to a randomized double-blind placebo-controlled crossover study, and underwent systemic administration of 0.5 g of UA in 250 ml of 0.1% lithium carbonate/4% dextrose vehicle or vehicle alone as control. Subjects performed high-intensity aerobic exercise for 20 min to induce oxidative stress. Plasma 8-iso-PGF2alpha concentrations were determined at baseline, after exercise and after recovery for 20 min. A single bout of high-intensity exercise caused a significant increase in plasma 8-iso-PGF2alpha concentrations from 35.0 +/- 4.7 pg/ml to 45.6 +/- 6.7 pg/ml (P<0.01). UA administration raised serum urate concentration from 293 +/- 16 to 487 +/- 16 micromol/l (P<0.001), accompanied by increased serum antioxidant capacity from 1786+/-39 to 1899 +/- 45 micromol/l (P<0.01). UA administration abolished the exercise-induced elevation of plasma 8-iso-PGF2alpha concentrations. High UA concentrations are associated with increased serum antioxidant capacity and reduced oxidative stress during acute physical exercise in healthy subjects. These findings indicate that the antioxidant properties of UA are of biological importance in vivo.

Lipoprotein oxidation and its significance for atherosclerosis: a mathematical approach.

Atherosclerosis is a chronic disease which involves the build up of cholesterol and fatty deposits within the arterial wall. This results in the narrowing of the vessel lumen, which eventually restricts blood flow to vital organs such as the heart and lungs. These events may culminate in a heart attack or stroke, the commonest causes of death in the U.K. population. In this paper we study the early stages of atherosclerosis which include the build up of cholesterol within subendothelial cells to form what is known as a fatty streak, the earliest identifiable evidence of atherosclerosis. The deposition of cholesterol is believed to be a consequence of oxidation of circulating cholesterol-rich lipoproteins, in particular low density lipoproteins (LDLs). Via a mathematical model we investigate this process of oxidation within the context of an in vitro framework. We first recreate existing experimental results and then extend the model to investigate phenomenon not studied by current experimental protocols. We find that the model displays hysteresis which reveals some interesting insights into possible in vivo events. Mathematical analysis of this behaviour predicts that vitamin E supplementation is not as beneficial as high density lipoproteins (HDLs) and vitamin C. Furthermore, the scavenging of oxidants by HDL can provide an important first line of defence against LDL oxidation.