Praveen Indraratna

Understanding the dose–response relationship of allopurinol: predicting the optimal dosage

AIMS The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODS Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTS Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONS A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .

Fractional clearance of urate: validation of measurement in spot-urine samples in healthy subjects and gouty patients

IntroductionHyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients.MethodsTimed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout.ResultsNo substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001).ConclusionsThe present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood.Trial RegistrationACTRN12611000743965

Transcatheter Aortic Valve Implantation versus Surgical Aortic Valve Replacement: Meta-Analysis of Clinical Outcomes and Cost-Effectiveness

OBJECTIVE Transcatheter aortic valve implantation (TAVI) has emerged as a feasible alternative treatment to conventional surgical aortic valve replacement (AVR) for high-risk patients with aortic stenosis. The present systematic review aimed to assess the comparative clinical and cost-effectiveness outcomes of TAVI versus AVR, and meta-analyse standardized clinical endpoints. METHODS An electronic search was conducted on 9 online databases to identify all relevant studies. Eligible studies had to report on either periprocedural mortality or incremental cost-effectiveness ratio (ICER) to be included for analysis. RESULTS The systematic review identified 24 studies that reported on comparative clinical outcomes, including three randomized controlled trials and ten matched observational studies involving 7906 patients. Meta-analysis demonstrated no significant differences in regards to mortality, stroke, myocardial infarction or acute renal failure. Patients who underwent TAVI were more likely to experience major vascular complications or arrhythmias requiring permanent pacemaker insertion. Patients who underwent AVR were more likely to experience major bleeding. Eleven analyses from 7 economic studies reported on ICER. Six analyses defined TAVI to be low value, 2 analyses defined TAVI to be intermediate value, and three analyses defined TAVI to be high value. CONCLUSION The present study demonstrated no significant differences in regards to mortality or stroke between the two therapeutic procedures. However, the cost-effectiveness and long-term efficacy of TAVI may require further investigation. Technological improvement and increased experience may broaden the clinical indication for TAVI for low-intermediate risk patients in the future.

Hyperuricemia, Cardiovascular Disease, and the Metabolic Syndrome

To the Editor: We read with great interest Dr. Neogi’s recent editorial on asymptomatic hyperuricemia1, as well as the correspondence from Drs. Marasini and Massarotti2. There are strong associations among hyperuricemia, cardiovascular disease, and the metabolic syndrome3,4. Still, the role of uric acid (UA) in the latter 2 conditions is lacking. Marasini and Massarotti state that “abdominal obesity has been found to be significantly related to serum uric acid levels probably because obesity interferes with urate synthesis and … Address correspondence to Prof. R.O. Day, Level 2, Xavier Building, St. Vincent’s Hospital, Darlinghurst NSW 2010, Australia. E-mail: R.Day{at}unsw.edu.au

Intra-operative cystoscopy in gynaecological surgery: a brief overview.

Recent studies using universal cystoscopy have demonstrated a higher rate of urinary tract injury at major gynaecological procedures than previously thought. These injuries are associated with significant medical and medico‐legal implications. The sensitivity of visual inspection is low and cystoscopic screening with intravenous dye improves detection. We review the evidence for intra‐operative cystoscopy in gynaecology, with emphasis on rates of urinary tract injury and the use of intravenous contrast dye.

Use of colchicine in pregnancy: a systematic review and meta-analysis

Objectives Colchicine is an anti-inflammatory agent used in the treatment of several rheumatological conditions. The use of colchicine in pregnancy is controversial. The current study aimed to systematically review and meta-analyse the existing data in the literature regarding the safety of colchicine in pregnancy. Methods A systematic review was carried out using six electronic databases, identifying all relevant studies where colchicine was administered to pregnant women, and where pregnancy-related outcomes were measured. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Results Four studies were included for meta-analysis. Use of colchicine throughout pregnancy was not associated with an increased incidence of miscarriage or major foetal malformations. The incidence of miscarriage was significantly lower in women who took colchicine compared with those that did not. In women with FMF who took colchicine throughout the pregnancy, there was no significant difference in birthweight or gestational age compared with those who did not take colchicine. When not limited to FMF, colchicine use was associated with a significantly lower birthweight and gestational age compared with a control group including healthy women who did not take colchicine. Conclusions Colchicine therapy did not significantly increase the incidence of foetal malformations or miscarriage when taken during pregnancy. Colchicine therapy for FMF should not be withheld on this basis during pregnancy.

Acute ST-Elevation Myocardial Infarction, a Unique Complication of Recreational Nitrous Oxide Use

A 28-year-old male was admitted to hospital with an acute ST-elevation myocardial infarction. This was in the context of recreational abuse of nitrous oxide. The prevalence of nitrous oxide use in Australia has not been formally quantified, however it is the second most commonly used recreational drug in the United Kingdom. Nitrous oxide has previously been shown to increase serum homocysteine levels. This patient was discovered to have an elevated homocysteine level at baseline, which was further increased after nitrous oxide consumption. Homocysteine has been linked to endothelial dysfunction and coronary atherosclerosis and this case report highlights one of the dangers of recreational abuse of nitrous oxide.

Bedside Teaching in Australian Clinical Schools: A National Study

Purpose. Bedside teaching (BST) of medical students has become less common in recent years; however, there have been strong recommendations made in the literature to continue this teaching modality for the valued benefits it provides. The purpose of the present study is to explore the perceptions and opinions of bedside teaching among senior Australian medical students. Methods. Medical students at Australian universities were surveyed by means of an electronic questionnaire. The results were collected and analysed. Results. A total of 517 responses were received from students at 15 universities and 94 different clinical sites. The percentage of students who identified BST as very important ranged from 62.5% in psychiatry to 90.4% in internal medicine. The optimal class size was nominated as 3-4 students, and students favoured a style where one individual performs a complete examination, with the remainder allowed to elicit the key sign afterwards. Students felt 3-4 hours of BST per week to be ideal. Advantages identified to BST included provision of feedback and elicitation of clinical signs. Disadvantages included time constraints and excessive class sizes. Conclusions. The unique benefits of BST result in its high demand by students, regardless of the discipline being taught.

Safety and efficacy of aerobic exercise commenced early after cardiac surgery: A systematic review and meta-analysis

Background Aerobic exercise is a critical component of cardiac rehabilitation following cardiac surgery. Aerobic exercise is traditionally commenced 2–6 weeks following hospital discharge and most commonly includes stationary cycling or treadmill walking. The initiation of aerobic exercise within this early postoperative period not only introduces the benefits associated with aerobic activity sooner, but also ameliorates the negative effects of immobilization associated with the early postoperative period. Methods A systematic review identified all studies reporting safety and efficacy outcomes of aerobic exercise commenced within two weeks of cardiac surgery. A meta-analysis was performed comparing functional, aerobic and safety outcomes in patients receiving early postoperative aerobic exercise compared with usual postoperative care. Results Six-minute walk test distance at hospital discharge was 419 ± 88 m in early aerobic exercise patients versus 341 ± 81 m in those receiving usual care (mean difference 69.5 m, 95% confidence interval (CI) 39.2–99.7 m, p < 0.00001). Peak aerobic power was 18.6 ± 3.8 ml·kg–1·min–1 in those receiving early exercise versus 15.0 ± 2.1 ml·kg–1·min–1 in usual care (mean difference 3.20 ml·kg–1·min–1, 95% CI 1.45–4.95, p = 0.0003). There was no significant difference in adverse events rates between the two groups (odds ratio 0.41, 95% CI 0.12–1.42, p = 0.16). Conclusion Aerobic exercise commenced early after cardiac surgery significantly improves functional and aerobic capacity following cardiac surgery. While adverse event rates did not differ significantly, patients included were very low risk. Further studies are required to adequately assess safety outcomes of aerobic exercise commenced early after cardiac surgery.