The cortisol response to hypobaric hypoxia at rest and post-exercise.

High altitude exposure normally leads to a marked natriuresis and diuresis. Acute mountain sickness is often associated with fluid retention, to which an elevated cortisol may contribute. Most investigators report a rise in resting cortisol with ascent, but little data exist regarding the cortisol response to a day trekking. We therefore measured salivary cortisol during ascent to > 5000 m in a cohort of between 42-45 subjects following a 6-h trek (samples taken between 15:30-16:30 h) and between 15-20 subjects at rest (morning samples taken between 08:00-09:00 h). Morning resting cortisol [nmol/l, mean±sd, (range)] was 5.5±2.9 (2.13-13.61) at 1300 m; 4.7±6.8 (1.4-27.02) at 3400 m, and significantly (p=0.002) rose between 4270 m [3.5±2.1 (1.4-8.34)] and 5150 m [14.5±30.3 (1.9-123.1)]. Post-exercise cortisol [nmol/l, mean±sd, (range)] dropped between 3400 m [7±6 (1.5-33.3)] and 4270 m [4.2±4.8 (1.4-29.5)] (p=0.001) followed by a significant rise in post-exercise cortisol between 4270 m [4.2±4.8 (1.4-29.5)] and 5 150 m [9.2±10.2 (1.4-61.3)] (p<0.001). There were no significant associations between severity of acute mountain sickness and cortisol levels. There was a significant though weak correlation between cortisol post-exercise at 5150 m and oxygen saturation at 5150 m (rho= - 0.451, p=0.004). In conclusion, this is the largest cohort to have their resting and post-exercise cortisol levels ascertained at high altitude. We confirm the previous findings of an elevated resting morning cortisol at > 5000 m, but present the novel finding that the cortisol response to a day trekking at HA appears suppressed at 4270 m.

The effect of exogenous glucocorticoids on plasma catecholamines and metanephrines in patients without phaeochromocytomas.

The aim of the study was to evaluate the effects of steroid administration under standardised conditions in a range of patients both normal and with adrenal pathologies and to review the impact on plasma catecholamines and metanephrines. Corticosteroid administration has been linked to the development of hypertensive crises in patients with phaeochromocytoma, however a mechanism for this is not fully understood. We aimed to add useful information about the effect of steroids on levels of these hormones under usual circumstances. A prospective, observational cohort study of 50 patients undergoing the low-dose dexamethasone suppression test (LDDST) was undertaken. Additional blood samples were taken at the start and end of the standard LDDST. Biochemical analysis was carried out for plasma catecholamines and plasma free metanephrines. Demographic and hormonal data were acquired from review of the notes or measured at baseline. No significant changes in plasma catecholamines or metanephrines were seen at the end of the LDDST compared to baseline. This was also true of subgroup analysis, divided by age, gender, or type of underlying pathology. Our results suggest that hypertensive reaction responses, rare as they are, are unlikely to be related to normal adrenal physiology. Thus LDDST is likely to be safe under most circumstances, however caution should be exercised in patients with adrenal masses with imaging characteristics compatible with phaeochromocytoma. It may be prudent to defer glucocorticoid administration until functioning phaeochromocytoma has been excluded biochemically.

Evaluation of NT-proBNP to predict outcomes in advanced heart failure.

AIMS: To determine which factors predict outcomes in a group of patients with advanced heart failure, and in particular if NT-proBNP provides additional clinical and prognostic information to other haemodynamic and biochemical data. METHODS AND RESULTS: Ninety-one patients were studied who were being evaluated for heart transplantation, with 166 assessments. The patients had advanced heart failure as determined by median cardiac index of 2.0 l/min/m(2), left ventricular end-diastolic diameter of 7.0 mm and levels of NT-proBNP of 2473 pg/ml. Median follow-up time was 359 days. Clinicians were blinded to NT-proBNP levels. NT-proBNP significantly correlated with cardiac index (R = -0.44, p < 0.001), right atrial pressure (R = 0.40, p < 0.001), pulmonary arterial wedge pressure (R = 0.38, p < 0.001) and albumin (R = -0.52, p < 0.001), and total bilirubin with right atrial pressure (R = 0.59, p < 0.001). Cardiac index was the most important independent predictor of outcome (p = 0.0001), although bilirubin (p = 0.001) and NT-proBNP (p < 0.05) were also significant. In patients with a 50% increase in NT-proBNP, 64% had adverse outcomes, whereas those in whom levels were stable, 22% had adverse outcomes (p < 0.05). CONCLUSION: Cardiac index is the primary independent predictor of outcome in advanced heart failure when haemodynamic deterioration is evident. In situations where invasive haemodynamics are not available, total bilirubin (reflecting hepatic congestion) and NT-proBNP (related to haemodynamics) also provide important prognostic information.

A lifecourse study of bone resorption in men ages 49-51years: the Newcastle Thousand Families cohort study.

It has been suggested that bone health in adulthood is programmed by development in utero. Most previous investigations addressing this topic have focussed on bone mineral density or content, rather than other indicators of bone health, such as biochemical markers of bone turnover. This study investigated whether potential predictors, from different stages of life, influence bone resorption in men aged 49-51years in the Newcastle Thousand Families birth cohort. The cohort originally consisted of all 1142 births in the city of Newcastle upon Tyne, UK in May and June 1947. Detailed information was collected prospectively during childhood, including birth weight and socio-economic circumstances. At 49-51years of age, 574 study members completed a detailed 'Health and Lifestyle' questionnaire, including the European Prospective Investigation of Cancer (EPIC) food frequency questionnaire and 412 study members attended for clinical examination, including 172 men in whom bone resorption was assessed by measurement of serum beta C-telopeptide of type 1 collagen (CTX). A significant trend was seen between increasingly disadvantaged socio-economic status at birth and increased bone resorption (p=0.04, r-squared 2.6%). However, birth weight, standardised for sex and gestational age, was not associated with serum CTX (p=0.77, r-squared 0.05%). Significant trends were also seen between increasing total energy intake (p=0.03, r-squared 2.9%), dietary intake of saturated fat (p=0.02, r-squared 2.6%), protein (p=0.04, r-squared 2.5%) and carbohydrates (p=0.04, r-squared 2.6%) and higher serum CTX. However, on adjustment for total energy intake, none of the other dietary variables was significant at the univariate level maintained significance. Our findings suggest that early socio-economic disadvantage and later dietary factors may be associated with increased bone resorption in middle aged men. However, as little of the variance in serum CTX was explained by the variables included within this investigation, further longitudinal studies, with sufficient statistical power, are required to assess predictors of bone resorption in adulthood and their relative importance.

Smoking after cardiac transplantation.

Although smoking cessation is a prerequisite prior to listing for cardiac transplantation, some patients return to smoking after recovery. We have covertly assessed the smoking habits of our cardiac transplant recipients (with ethical approval) since 1993 by measuring urinary cotinine: a level of >500 ng/mL signifying continued tobacco use. We retrospectively analyzed survival, causes of death and the development of graft coronary artery disease (GCAD) with respect to the number of positive and negative cotinine levels. One hundred four of 380 (27.4%) patients tested positive for active smoking at some point posttransplant, and 57 (15.0%) tested positive repeatedly. Smokers suffered significantly more deaths due to GCAD (21.2% vs. 12.3%, p < 0.05), and due to malignancy (16.3% vs. 5.8%, p < 0.001). In univariate analysis, smoking after heart transplantation shortened median survival from 16.28 years to 11.89 years. After correcting for the effects of pretransplant smoking in time-dependent multivariate analysis, posttransplant smoking remained the most significant determinant of overall mortality (p < 0.00001). We conclude that tobacco smoking after cardiac transplantation significantly impacts survival by accelerating the development of graft vasculopathy and malignancy. We hope that this information will deter cardiac transplant recipients from relapsing, and intensify efforts in improving cessation rates.

Impact on renal function after endovascular aneurysm repair with uncovered supra-renal fixation assessed by serum cystatin C.

OBJECTIVE: Supra-renal fixation in endovascular aneurysm repair (SR-EVR) is used to improve the proximal seal of aortic stent grafts and appears to have minimal effect on serum creatinine. Serum cystatin C (CC) is a more sensitive marker of renal injury and, unlike creatinine, is unaffected by non-renal influence. The aim of this study was to assess the true renal effect of SR-EVR using this superior renal index. METHODS: Consecutive patients undergoing SR-EVR were prospectively recruited and compared to control groups undergoing open aneurysm repair (OR) and colorectal resection (CR). Serum CC and creatinine clearance (CrC) were determined pre-operatively and at 3, 6 and 12 months post-surgery. Renal function was compared using analyses of covariance (ANCOVA). RESULTS: Sixty-five patients (M:F; 52:13, median age 74 years) were enrolled (24 SR-EVR, 28 OR, 13 CR). Pre-operative renal function and risk factors were comparable (CC 1.04mg/l, SR-EVR; 0.96mg/l, OR; 0.97mg/l, CR). Adjusting for baseline renal function, there was no significant difference in CC or CrC between study and both control groups at 3, 6 or 12-months post-operatively. CONCLUSION: Using cystatin C as a more sensitive renal index, there was no detectable evidence of kidney dysfunction at up to one-year following EVR with uncovered bare-metal supra-renal fixation.

Comparison of HTK and hypertonic citrate to intraarterial cooling in human non-heart-beating kidney donors.

Intraarterial cooling (IAC) of non-heart-beating donors (NHBD) for renal donation requires a cheap, low-viscosity solution. HTK contains a high hydrogen ion buffer level that theoretically should reduce the observable acidosis associated with ongoing anaerobic metabolism. A retrospective comparison of all retrieved NHBD kidneys as well as of viability on the Organ Recovery Systems Lifeporter machine perfusion circuit was performed with respect to the preservation solution HTK or Marshall's HOC. Forty-two NHBD kidneys (19 HTK and 23 HOC) were machine perfused between February 2004 and May 2005. Most of the HTK kidneys were obtained from uncontrolled donors (12 vs 5; Fisher exact test, P = .01). As a consequence, the glutathione-s-transferase viability assay (411 vs 292 IU/L, P = .12) and the lactate concentrations (2.33 vs 1.94 mmol/L, P = .13) were higher among the HTK cohort. There was evidence of greater buffering capacity in HTK, since the lactate:hydrogen ion ratios were consistently lower during the first 2 perfusion hours (1 hour P = .03, 2 hour P = .02). A linear regression analysis confirmed that this was related to the IAC solution (ANCOVA, P < .001). All controlled donor kidneys passed viability testing and were transplanted. In contrast, 83% (10/12) of the uncontrolled donor kidneys preserved with HTK passed the viability test and were transplanted, compared with only 20% (1/5) of the HOC-treated comparators (Fisher exact test, P = .03). It may be concluded that the postulated advantages of improved pH buffering with HTK appear to have clinical relevance.

Phaeochromocytomas presenting as acute crises after beta blockade therapy.

OBJECTIVE: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period. RESULTS: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully. CONCLUSION: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Ischemia-reperfusion injury in cadaveric nonheart beating, cadaveric heart beating and live donor renal transplants.

PURPOSE: Ischemia-reperfusion injury is gaining importance in transplantation as being responsible for allograft dysfunction. Ischemia occurs during kidney procurement, which is shortest in LDs, and prolonged in cadaveric HBDs and NHBDs. MATERIALS AND METHODS: Renal transplants from 17 LDs, 15 HBDs and 19 NHBDs were assessed during reperfusion for biochemical markers of ischemia-reperfusion injury and assessed clinically. Central venous blood sampling was assayed for free radicals using electron spin resonance and tissue injury biomarkers, namely lactate dehydrogenase, fatty acid binding protein, alanine aminopeptidase, lactate and total antioxidants. RESULTS: The return to stable renal function was more rapid in LD renal transplants, while recovery continued from 3 months after hospital discharge in NHBD renal transplants. Injury markers, such as lactate dehydrogenase, fatty acid binding protein, alanine aminopeptidase and lactate, were raised at the time of reperfusion, especially in NHBD renal transplants. Free radical release measured by electron spin resonance showed 2 phase release, that is early (0 to 10-minute) and late (20 to 40-minute) release. In NHBD, HBD and LD renal transplants the index of free radical release in the early phase was 1.43, 1.36 and 1.20, and in the late phase it was 1.43, 1.38 and 0.97, respectively (each ANOVA p <0.05). CONCLUSIONS: NHBD renal transplants were accompanied by a greater release of free radicals at reperfusion (NHBD > HBD > LD), which was associated with an increase in tissue injury markers at reperfusion. This was reflected in a slower return to stable renal function in NHBD compared to HBD and LD renal transplants.

Reperfusion injury in renal transplantation: comparison of LD, HBD and NHBD renal transplants.

Comparison of reperfusion injury in kidneys transplanted from LD, HBD or NHBD donors is presented in the paper. Central venous blood samples (taken during perioperative period) was assessed for free radicals, total antioxidant activity and various markers of tissue injury. There was demonstrable ischemia reperfusion injury occurring at the time of revascularization, which was particularly notable in kidneys transplanted from NHBD donors.

A randomized controlled trial of calcium with vitamin D, alone or in combination with intravenous pamidronate, for the treatment of low bone mineral density associated with Crohn's disease.

BACKGROUND: Osteoporosis is a common complication of Crohn's disease. AIM: To study the effect on the bone mineral density of a bisphosphonate (pamidronate) given intravenously, in combination with oral calcium and vitamin D supplements, compared with oral calcium and vitamin D supplements alone. METHODS: Seventy-four patients with Crohn's disease and low bone mineral density at the lumbar spine and/or hip were randomized to receive either a daily dose of 500 mg of calcium with 400 IU of vitamin D alone or in combination with four three-monthly infusions of 30 mg of intravenous pamidronate over the course of 12 months. The main outcome measure was the change in bone mineral density at the lumbar spine and hip, measured by dual X-ray absorptiometry, at baseline and 12 months. RESULTS: Both groups gained bone mineral density at the lumbar spine and hip after 12 months. There were significant (P < 0.05) changes in the pamidronate group, with gains of + 2.6%[95% confidence interval (CI), 1.4-3.0] at the spine and + 1.6% (95% CI, 0.6-2.5) at the hip, compared with gains of + 1.6% (95% CI, - 0.1-3.2) and + 0.9% (95% CI, - 0.4-2.1) at the spine and hip, respectively, in the group taking vitamin D and calcium supplements alone. CONCLUSIONS: In patients with Crohn's disease and low bone mineral density, intravenous pamidronate significantly increases the bone mineral density at the lumbar spine and hip.

Vital capacity inhalation induction with sevoflurane: an alternative to standard intravenous induction for patients undergoing cardiac surgery.

OBJECTIVE: To determine the respiratory and cardiovascular effects of a high concentration vital capacity induction with sevoflurane compared with an intravenous induction with etomidate in patients scheduled for elective coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, randomized, double-blind, controlled clinical trial. SETTING: Cardiothoracic unit at a university hospital referral center. PARTICIPANTS: Twenty-two patients undergoing elective CABG surgery. INTERVENTIONS: The study group (group S) received a vital capacity gaseous induction with sevoflurane 8% (n = 12) and the control group (group E) were given etomidate, 0.2 to 0.3 mg/kg (n = 10). Anesthesia was supplemented with fentanyl, 8 microg/kg, and vecuronium, 0.1 mg/kg, in both groups. MEASUREMENTS AND MAIN RESULTS: The speed of induction of anesthesia was comparable between the groups. There was a significant increase in minute ventilation after induction of anesthesia in both groups. This increase was associated with a small reduction in PaCO2. There were no clinically significant changes in pH and PaO(2). The incidence of breath-holding and the need for an oropharyngeal airway were similar between the groups. Both groups had similar reductions in mean arterial pressure and cardiac output during the study period; however, a downward trend in mean pulmonary artery pressure was noted in group S, whereas in group E it remained unchanged. Absolute plasma epinephrine and norepinephrine values were low during the precardiopulmonary bypass period in both groups. CONCLUSIONS: The technique of vital capacity inhalation induction with 8% sevoflurane offers a rapid onset of anesthesia, satisfactory airway control, and a good hemodynamic profile. Consideration should be given to the benefits of single-agent anesthesia and lowered pulmonary artery pressure during the precardiopulmonary bypass period. In addition to CABG surgery, this technique could be considered in patients with coronary artery disease undergoing noncardiac surgery, particularly for procedures in which spontaneous ventilation is preferred.

Urinary free deoxypyridinoline by chemiluminescence immunoassay: analytical and clinical evaluation.

We evaluated an automated chemiluminescence immunoassay (CLIA) developed for the measurement of urinary free deoxypyridinoline (DPD). The new DPD method by CLIA is based on the competition of DPD with particle-bound pyridinoline for a limited amount of monoclonal mouse anti-DPD antibody. Total imprecision (CV) was 3.2-9.0% at 30-270 nmol/L. Regression analysis of urinary DPD concentration (second morning-void) measured by CLIA (y) and enzyme immunoassay (EIA) for adult volunteers (n = 449) with and without bone disease revealed a best fit equation of: y = 1.08 +/- 0.03x - 1.15 +/- 0.98 nmol/L (r = 0.964, S(y/x) = 14 nmol/L). CLIA and EIA methods were correlated with HPLC measurement of urinary free DPD (r = 0.846 and 0.871, respectively). For healthy adults, the creatinine-normalized excretion of DPD (mean +/- SD) measured by CLIA for 61 men (4.1 +/- 1.2 micromol DPD/mol creatinine) and 76 premenopausal women (5.3 +/- 1.8 micromol DPD/mol creatinine) did not differ significantly (P >0.05) from DPD excretion measured by EIA, and both immunoassays showed a significant gender difference (P <0.001) in reference intervals. In a clinical trial, DPD excretion (micromol DPD/mol creatinine) measured by CLIA differed substantially from the reference population for 54 untreated pagetic (12.7 +/- 8.0 SD), 255 untreated osteoporotic (7.5 +/- 4.1), 21 osteomalacic (12.4 +/- 8.5), 17 primary hyperparathyroid (9.4 +/- 4.4), and 14 secondary hyperparathyroid (9.2 +/- 5.1) patients. Clinical sensitivities of the CLIA and EIA methods range from 38% to 80% in bone disorders and limit the use of the DPD measurement in disease detection. DPD excretion after pamidronate treatment in a subgroup of the pagetic patients fell dramatically as assessed by CLIA or EIA. We conclude that the automated CLIA method for DPD is a convenient and reliable method that may aid in the evaluation and management of bone disease and is applicable to high volume testing in the routine clinical laboratory.

Benign transient hyperphosphatasemia of infancy and early childhood following cardiac transplantation.

The phenomenon of a transient very high rise in serum alkaline phosphatase, associated with either trivial illness or no symptoms, in early childhood has been described previously in otherwise normal children. We describe here what we believe are the first published reports in two children who have previously undergone orthotopic cardiac transplantation. They were found to have a very high serum alkaline phosphatase, with features consistent with a diagnosis of transient hyperphosphatasemia of infancy and early childhood. The importance of early recognition and avoidance of overinvestigation are discussed.

The prevalence of hereditary haemochromatosis in a diabetic population.

Hereditary haemochromatosis is an under-diagnosed and treatable cause of chronic liver disease. Its prevalence indicates that selective population screening may be worthwhile, but opinion differs as to whether diabetic patients constitute such a group. We studied 727 patients attending a teaching hospital diabetic clinic. On first testing, 7.4% had abnormally high iron indices, but only 3% remained abnormal on retesting. Of these patients, those at high risk were offered liver biopsy for histological assessment and iron assay. Only one had hereditary haemochromatosis, but all had abnormal liver histology--largely steatosis but some with fibrosis. These findings raise questions regarding the true prevalence of this disorder in North-East England, do not indicate that targeted screening of diabetic patients is worthwhile, and incidentally highlight the potential importance of diabetes as a cause of liver disease.