Measurement Of Urinary Catecholamines Research Articles

Association Between Urinary Catecholamine Excretion and Urine Volume.

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients' age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume.

Norepinephrine and T4 Are Predictors of Fat Mass Gain in Humans With Cold-Induced Brown Adipose Tissue Activation.

In healthy adults with detectable cold-induced brown adipose tissue activation (CIBA), the relationships between sympathetic nervous system (SNS) or thyroid activity during energy balance (EBL) with CIBA and body composition change are undetermined. To investigate the relationships between CIBA and thermoneutral catecholamines and thyroid hormones measured during EBL and to determine if CIBA, catecholamines, or thyroid hormones predict body composition changes. Twelve healthy volunteers (seven male and five female) with positive CIBA [>2 standardized uptake value (g/mL)] had 24-hour energy expenditure (24hEE) assessed during EBL via whole-room indirect calorimetry while residing on a clinical research unit. Positron emission tomography/computed tomography scans were performed after exposure to 16°C for 2 hours to quantify CIBA. CIBA, 24hEE during EBL, and thermoneutrality with concomitant measurement of urinary catecholamines and plasma free T3 and free T4. Body composition at baseline and 6 months by dual-energy X-ray absorptiometry. Lower urinary norepinephrine and free T4 were associated with higher CIBA (r = -0.65, P = 0.03; and r = -0.75, P < 0.01, respectively), but CIBA was not associated with 24hEE at thermoneutrality (P = 0.77). Lower CIBA (β = -3.5 kg/standardized uptake value; P < 0.01) predicted fat mass gain, whereas higher urinary norepinephrine and free T4 predicted future fat mass gain at 6 months (β = 3.0 kg per twofold difference in norepinephrine, P = 0.03; and β = 1.2 kg per 0.1-ng/dL difference in free T4, P = 0.03, respectively). Lower SNS and free thyroid measurements at baseline indicate a greater capacity for CIBA, which may be predictive against fat mass gain.

Development and validation of a liquid chromatography tandem mass spectrometry method for the measurement of urinary catecholamines in diagnosis of pheochromocytoma.

The measurement of catecholamines in human body fluids is requested frequently for the differential diagnosis and monitoring of pheochromocytoma. The methods in most clinical laboratories focus on high-performance liquid chromatography coupled with electrochemical detection, which suffers from high background noise, low sensitivity, and poor separation. We reported and developed a robust high-throughput liquid chromatography tandem mass spectrometry method in routine clinical laboratories for the measurement of urinary catecholamines for diagnosis of pheochromocytoma. The method was validated for consistent linearity, good recovery (88-112%), excellent stability and low carryover. Intra- and inter-assay precision values for catecholamines were all below 3.35 and 4.83% respectively. Dilution linearity was investigated with satisfactory linearly dependent coefficients (r > 0.9988). The reference intervals were obtained from 310 results derived from patients in which the diagnosis of pheochromocytoma was excluded. This method was successfully used in our laboratory. The clinical characteristics of patients have been explored with satisfactory sensitivity and specificity. Therefore, we have developed a reliable assay for the liquid chromatography tandem mass spectrometry measurement of catecholamines in a routine clinical laboratory. The assay requires a small volume of urine, and all analytes are measured simultaneously. The assay is rapid and reliable to be executed, offering the potential for routine clinical laboratories.

The Consistency in Macronutrient Oxidation and the Role for Epinephrine in the Response to Fasting and Overfeeding.

In humans, dietary vs intraindividual determinants of macronutrient oxidation preference and the role of the sympathetic nervous system (SNS) during short-term overfeeding and fasting are unclear. To understand the influence on metabolic changes of diet and SNS during 24 hours of overfeeding. While residing on a clinical research unit, 64 participants with normal glucose regulation were assessed during energy balance, fasting, and four 24-hour overfeeding diets, given in random order. The overfeeding diets contained 200% of energy requirements and varied macronutrient proportions: (1) standard (50% carbohydrate, 20% protein, and 30% fat); (2) 75% carbohydrate; (3) 60% fat; and (4) 3% protein. Twenty-four-hour energy expenditure (EE) and macronutrient oxidation rates were measured in an indirect calorimeter during the dietary interventions, with concomitant measurement of urinary catecholamines and free cortisol. EE decreased with fasting (-7.7% ± 4.8%; P < 0.0001) and increased with overfeeding. The smallest increase occurred during consumption of the diet with 3% protein (2.7% ± 4.5%; P = 0.001) and the greatest during the diet with 75% carbohydrate (13.8 ± 5.7%; P < 0.0001). Approximately 60% of macronutrient oxidation was determined by diet and 20% by intrinsic factors (P < 0.0001). Only urinary epinephrine differed between fasting and overfeeding diets (Δ = 2.25 ± 2.9 µg/24h; P < 0.0001). During fasting, higher urinary epinephrine concentrations correlated with smaller reductions in EE (ρ = 0.34; P = 0.01). Independent from dietary macronutrient proportions, there is a strong individual contribution to fuel preference that remains consistent across diets. Higher urinary epinephrine levels may reflect the importance of epinephrine in maintaining EE during fasting.

Resting Energy Expenditure and Blood Pressure: Evidence of Perpetual Association

A myriad of cross-sectional and prospective studies have evaluated the interrelationship between blood pressure (BP) levels and different traditional metabolic surrogates including body mass index (BMI). In addition, clinically meaningful conditions such as hypertension and the metabolic syndrome independently of treatment for either condition have shown a prospective bidirectional association among different ethnicities and age burdens. However, along with the positive association between BP and adverse metabolic phenotypes, the exact underlying pathophysiological background has not yet been fully elucidated. Resting energy expenditure (REE), a quantitative measurement of metabolic processes at rest, was found to be correlated with BP levels in different ethnicities after adjustment for potential confounders. The arising clinical question is whether the measurement of REE might be a predictor of increasing BP levels or incident hypertension later in life independently of confounders including body adiposity and common pathophysiological pathways such as enhanced sympathetic nervous drive and subclinical inflammatory processes. To address the above clinical question, a longitudinal study has to be projected. However, it is also important to validate the reproducibility of the association over time, ie, sequential longitudinal evaluation of REE and BP levels. In the current issue of The Journal of Clinical Hypertension, Sriram and colleagues evaluated the association of systolic BP with REE in a cohort of 229 originally overweight premenopausal women without comorbidities who were recruited to participate in a weight loss program to normalize their BMI. After BMIrelated target achievement, the cohort of “newly normoweight” women was observed annually for 4 years and different adiposity surrogates were assessed in combination with BP and REE measurements during each individual investigational visit. The constant association of REE with BP at several follow-up timeframes after adjustment for confounders highlighted the consistency of the results over time. As a general comment, and beyond the purpose of the study by Sriram and colleagues, a successful weight loss intervention of limited time once again was not able to retain BMI within normal levels during the follow-up period. Indeed, the subset of women returned at the last visit had the same weight as before the intervention. However, we should point out that the rate of women who returned for follow-up visits was progressively reduced. Only 30 women returned for the last follow-up laboratory visit compared with 140 women with normalized BMI after weight loss intervention. Thus, prospective changes of body adiposity and REE in relation to BP changes could not be addressed by the design of the present study mainly as a result of reduced power for longitudinal evaluation. Curiously, only systolic BP was used as a principal outcome in the investigational approach of Sriram and colleagues. Although previous reports have demonstrated a mild relationship between REE and diastolic BP, the present study did not explain whether even this mild association persists overtime. Moreover, from a clinical point of view, diastolic BP might be more important compared with systolic BP in middle-aged patients. Additionally, bias regarding the exact methodology for measuring laboratory BP should not be neglected. It would be interesting to know the 24-hour profile of BP and measures of BP variability across visits. Although 24-hour BP measurements might be far different than laboratory resting BP, the former better reflects the overall hemodynamic load and may overcome eventual white-coat phenomena. A step further, does variability in laboratory BP correlate with REE variability across the 3 days of each individual followup laboratory visit? The answer to this question might enable us to better understand the reciprocal temporal changes of BP and REE. Although the procedure of REE assessment seems adequate because it is performed in laboratory conditions of “complete quiescence” after an overnight stay at a general clinical research center, neither the duration nor the quality of sleep the night before testing are reported. Under the hypothesis that participants did not demonstrate respiratory disorders during sleep, REE at awaking could be modulated by sleep characteristics. The role of the sympathetic nervous system in the pathophysiology of obesity-related hypertension is well established. We believe that a more sophisticated measurement of sympathetic nervous system activity, namely muscle nerve sympathetic activity, might better define its confounding effect compared with the measurement of urinary catecholamines alone. Over and under the above methodological remarks, the study by Sriram and colleagues set the basis for the prospective evaluation of REE either on BP levels or on Address for correspondence: Costas Thomopoulos, MD, 2, Helena Venizelou sqr, 11521 Athens, Greece E-mail: thokos@otenet.gr

Effects of repeated short-term futsal practice games on urinary catecholamine levels

Introduction: Catecholamines have been known as an index of sympathetic nervous function, usually acting as a trigger for the adaptation of physical systems to the demands of exercise. A futsal game has high physical demands, which are known to act on stress hormone levels such as catecholamines. The non-invasive measurement of urinary catecholamines may offer a more suitable index than altered plasma catecholamines in sympathetic-adrenal activityduringvigorous intermittentexercise in futsal-specific condition. The purpose of this study was to determine the effects of repeated bouts of short-term futsal games on urinary catecholamine levels. Methods: Nine recreationally active male futsal players served as the subjects (age: 19.4±0.7 year; height: 170.0±4.4 cm; body mass: 61.7±7.6 kg; body fat: 15.5±5.1%; BMI: 21.3±2.1 kg/m2). The protocolwas composed of 5min ofwarm-up, six 7-min periods of game with 1min of rest, and cool-down. Spot urinary samples were obtained before (Pre) and after (Post) overall session for the later analysis of the urinary catecholamine levels (epinephrine, norepinephrine and dopamine). The urinary catecholamine levels were analyzed by high-performance liquid chromatography. Results: A Student’s t-test represented a significant elevation at the levels of urinary free norepinephrine (Pre: 97.7±57.7; Post: 432.9±190.0 g/L, p<0.05) and epinephrine (Pre: 18.1±9.8; Post: 65.9±29.0 g/L, p<0.05) except for dopamine (Pre: 572.9±245.4; Post: 1341.6±639.2 g/L) after exercise. Significant changes were found at the levels of urinary total protein after exercise compared to the baseline (Pre: 6.0±8.2; Post: 26.9±27.9mg/dL, p<0.05). Discussion and conclusions: Previous research has reported augmentation of urinary catecholamine levels following intermittent exercise. Thus, the concentration of urinary catecholamine may provide information about the psychological and physiological stress levels of athletes during training andcompetition. The results of the present study indicate that elevated urinary catecholamine levels may be useful to comprehensively understand exercise intensity during repeatedbouts of futsal-specific intermittent exercise.

Abstract LB-179: Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide.

Abstract Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. There is no curative treatment for children with relapsed NB, and the 5-year survival rate is &amp;lt;10%. These more aggressive forms of NB respond poorly to chemotherapeutic approaches, and there is a need for agents with novel mechanisms of action. Ornithine decarboxylase (ODC), a gene encoding for the ODC enzyme that is pivotal in polyamine biosynthesis, has been shown to be upregulated in NB. High polyamine content and elevated ODC activities have been associated with poor prognosis in NB. Suppression of polyamines in NB has been shown in preclinical studies to be effective to reduce tumor. Methods: The primary aim of this phase I study was to determine the safety and maximum tolerated dose (MTD) of DFMO as a single agent and in combination with etoposide in pediatric patients with refractory or recurrent NB. The secondary aims were to evaluate the pharmacokinetics of DFMO, the treatment response and biological correlates in urine. A dose escalation trial of daily oral DFMO for one 21-day cycle, followed by four 21 day cycles of DFMO and oral etoposide was completed. Response was evaluated by CT or MRI and MIBG imaging. Measurement of urinary catecholamines and bone marrow disease were used to determine a clinical response. Urinary polyamines were measured at day 1 of each cycle. Results: Twenty-one patients were enrolled between Mar 2010 and Oct 2012. The median age was 10 years old, with a range of 1-17 years old. Patients were enrolled at one of four escalating doses (500mg/m2-1500mg/m2 BID). No dose-limiting toxicities (DLTs) or serious adverse events (SAEs) were seen. The biological effect of urinary polyamine normalization was seen at these dose levels, therefore this study did not escalate to a final MTD. While a phase I study is not powered to evaluate anti-tumor efficacy, seventeen patients with NB were evaluable. Of these; 15 had stable disease and 2 had progressive disease. Of note, 1 subject obtained a complete response in their bone marrow while four patients have been on study progression free for over a year. Spot urine samples from patients had measurable levels of polyamines monoacetylspermidine (MASpd) and diacetylspermine (DASpm). Treatment was associated with decreased urinary MASpd over the first cycle for all patients. Patients with disease progression during the first 3-months of treatment had average increases in urinary DASpm and histamine over this time, while this parameter decreased over time in those patients exhibiting 3-month stabilization of disease. Conclusion: The biologically active dose of DFMO is 500-1500 mg/m2 BID and is well tolerated by pediatric patients. Prolonged stabilization of disease was seen with clinical benefit in greater than 50% of patients. Urine polyamines appear to be a marker for response to DFMO therapy. This biological correlate will be further explored in a Phase II study currently underway. Citation Format: Giselle L. Sholler, Eugene W. Gerner, Genevieve Bergendahl, Bonnie J. LaFleur, Alyssa VanderWerff, Takamaru Ashikaga, William Ferguson, William Roberts, Don Eslin, Joel Kaplan, Jacqueline M. Kraveka, Deanna Mitchell, Kathleen Neville, Randal Wada, Nehal Parikh, Leonard Sender, Timothy Higgins, Andre Bachmann. Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-179. doi:10.1158/1538-7445.AM2013-LB-179

Measurement of Urinary Catecholamines for Mice

A method for extraction of unconjugated catecholamines in 20μL urine samples has been developed using alumina extraction prior to separation by high performance liquid chromatography (HPLC) and electrochemical detection (ECD). Murine experiments tested the application of the procedure. In the first, collection occurred in the morning and evening prior to handling, and in the morning after three days of handling. In the second, passively obtained urine was compared to stressfully obtained urine in the same mice. Urine was extracted alongside 2,3‐dihydroxybenzoic acid internal standard via alumina and brought to pH 8.5 with tris buffer. Two wash steps preceded acid elution for analysis on HPLC with ECD. This method averaged 50 to 70% recovery. Differences were not seen when comparing small variations collection time, handling exposure, or collection technique. This procedure effectively measures sympathetic activity in micro samples, with a limit of detection in the attomole range.

Simultaneous liquid chromatography tandem mass spectrometric determination of urinary free metanephrines and catecholamines, with comparisons of free and deconjugated metabolites

ObjectiveWe introduce a novel liquid chromatographic tandem-mass spectrometric method for simultaneous measurements of urinary catecholamines and their free O-methylated metabolites, which we compare to the deconjugated metabolites. MethodsMethod performance was validated for recovery, linearity, precision and accuracy, analyte stability, ion suppression and carry over. Results from 53 patients with and 138 volunteers without pheochromocytoma were compared. ResultsAnalyte recoveries ranged from 60 to 96% and intra- and inter-assay coefficients of variation from 2.7 to 13.2%. The method showed excellent linearity over 3 orders of magnitude with analytical sensitivity sufficient to measure to 1.2nmol/L. Free O-methylated metabolites were excreted at less than 20% the rates of the deconjugated metabolites, but were easily measureable. Increases in urinary normetanephrine in pheochromocytoma patients relative to volunteers were higher for free than deconjugated metabolites and higher for both than for norepinephrine (10 vs 5.5 vs 3.7 fold increases). In contrast, relative increases in urinary free versus deconjugated metanephrine (2.7 and 3.2) and methoxytyramine (2.1 and 1.9) did not differ, but for methoxytyramine were larger than for dopamine (1.2). ConclusionMeasurements of urinary catecholamines and their free O-methylated metabolites by our method provide potential advantages over urinary deconjugated metanephrines for diagnosis of pheochromocytoma.

Measurement of urinary catecholamines in small samples for mice

IntroductionAnalysis of catecholamines in small samples of urine is difficult and sensitive to stress. Current techniques require pooling of samples or expensive separation by double mass spectrometry. A method for extraction of unconjugated catecholamines in 20μL urine samples has been developed using alumina extraction prior to separation by high performance liquid chromatography (HPLC) and electrochemical detection (ECD). MethodsThree murine experiments tested the application of the procedure. In the first, collection occurred in the morning and evening prior to handling, and in the morning after three days of handling. In the second, passively obtained urine was compared to stressfully obtained urine in the same mice. Finally, basal collections were compared to urinary catecholamine levels 15 and 30min into novel cage stress. Urine was extracted alongside 2,3-dihydroxybenzoic acid (DHBA) internal standard via alumina and brought to pH 8.5 with tris buffer. The mixture underwent two wash steps for depuration and eluted with perchloric acid for analysis on HPLC with ECD. ResultsThis novel extraction method using low amounts of urine yielded 48% recovery in the samples and 60% recovery in the standard extraction on average. With a signal to noise ratio of 3:1, the limit of detection (LOD) of a standard is 1.2pg/mL, which allows for the detection of 3.6pg/mL in urine or 72fg in a 20μL sample. Thus resting catecholamine levels are 216 times higher than the LOD. Unconjugated norepinephrine and epinephrine levels were significantly increased 15min after novel cage stress and epinephrine remained elevated after 30min, but did not show significant differences when comparing collection time, handling exposure, or specific collection technique. DiscussionThe technique is an effective measure for sympathetic activity in micro samples, with a limit of detection in the attomole range for 20μL samples.

Comparison of plasma metanephrines measured by a commercial immunoassay and urinary catecholamines in the diagnosis of pheochromocytoma

Background: The diagnosis of pheochromocytomas requires consideration among patients suffering from hypertension, unexplained spells, incidental adrenal masses, or a family history of pheochromocytoma. Accordingly, the diagnosis requires a biochemical test with high sensitivity and specificity. Aim: To compare plasma free metanephrines as measured by a commercial immunoassay and the 24-hour urinary excretion of catecholamines. Method: Plasma free metanephrines were measured in 185 patients suspected of pheochromocytoma. Concomitant measurements of urinary catecholamines were performed in 115 patients. Based on clinical findings, imaging and biochemistry 11 cases were found; 9 were diagnosed with pheochromocytoma, one patient with paraganglioma and one patient with ganglioneuroma. Results: All patients with pheochromocytoma/paraganglioma had abnormally elevated concentrations of either plasma metanephrine or normetanephrine. The patient with ganglioneuroma had normal plasma metanephrine levels, corresponding to a sensitivity of 91%. In two patients where pheochromocytoma was excluded, plasma metanephrin or normetanephrine was above the reference level, corresponding to a specificity of 99%. Urinary catecholamines were determined in 10 of 11 patients with a positive diagnosis, and all 10 showed elevated levels of either urinary epinephrine or norepinephrine, including the patient with ganglioneuroma (equivalent to a sensitivity of 100%). Seven patients, in whom pheochromocytoma was excluded, had elevated urinary catecholamines (equivalent to a specificity of 94%). Conclusion: Measurement of plasma free metanephrines by immunoassay appears to be a useful diagnostic test in patients suspected of pheochromocytoma, with a high specificity as compared with urinary catecholamines. The latter may result in fewer false-positive findings, an outcome which may be particularly troublesome.

Pheochromocytoma

Pheochromocytoma

A Phase 1 Study of Nifurtimox in Patients With Relapsed/Refractory Neuroblastoma

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.

Approach to the Patient with an Adrenal Incidentaloma

Unsuspected adrenal masses, or incidentalomas, are increasingly found with the widespread use of thoracic and abdominal imaging. These masses may be hormonally active or nonfunctional and malignant or benign. Clinicians must determine the nature of the mass to decide what treatment, if any, is needed. Measurement of precontrast Hounsfield units (HU) and contrast washout on computed tomography scan provide useful diagnostic information. All patients should undergo biochemical testing for pheochromocytoma, either with plasma or urinary catecholamine measurements. This is particularly important before surgical resection, which is routinely recommended for masses larger than 4 cm in diameter without a clear-cut diagnosis and for others with hormonal secretion or ominous imaging characteristics. Hypertensive patients should undergo biochemical testing for hyperaldosteronism. Patients with features consistent with Cushing's syndrome, such as glucose intolerance, weight gain, and unexplained osteopenia, should be evaluated for cortisol excess. Here, the dexamethasone suppression test and late-night salivary cortisol may be preferred over measurement of urine cortisol. The ability of surgical resection to reverse features of mild hypercortisolism is not well established. For masses that appear to be benign (<10 HU; washout, >50%), small (<3 cm), and completely nonfunctioning, imaging and biochemical reevaluation (pheochromocytoma and hypercortisolism only) at 1-2 yr (or more) is appropriate. For more indeterminate lesions, repeat evaluation for growth after 3-12 months is useful, with subsequent testing intervals based on the rate of growth.

Pediatric endocrine screening for von Hippel-Lindau disease: Benefits and the challenge of compliance

Fifteen children and adolescents (4 male) with a median age of 5.4 yr (range 1.2 -13.6 yr) were entered into a screening protocol to identify lesions of von Hippel-Lindau (VHL) disease. Fourteen had an affected first-degree relative and one had a previous VHL lesion. Screening during the period of 2000 to 2008 followed published guidelines and consisted of measurement of urinary catecholamines, adrenal and renal imaging and ophthalmological and central nervous system examinations and imaging. Screening identified 8 VHL lesions in 6 asymptomatic patients with confirmed genetic mutations. Five patients had elevated urinary noradrenaline excretion and in each case the presence of a pheochromocytoma was identified on adrenal magnetic resonance imagin scan. In one patient a left-sided tumor was identified 1 yr after a right-sided tumor had been removed. In a sixth patient a retinal capillary hemangioma and a cerebellar hemangioblastoma were identified. Patient compliance with the screening protocol was variable reflecting its time-intensive nature. A formal screening programme for this at-risk population of pediatric patients, despite being intensive, can identify VHL lesions during a pre-morbid phase and may thus have a beneficial impact on prognosis in this serious disorder.

Anaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial – The NeuroMorfeo trial

BackgroundMany studies have attempted to determine the "best" anaesthetic technique for neurosurgical procedures in patients without intracranial hypertension. So far, no study comparing intravenous (IA) with volatile-based neuroanaesthesia (VA) has been able to demonstrate major outcome differences nor a superiority of one of the two strategies in patients undergoing elective supratentorial neurosurgery. Therefore, current practice varies and includes the use of either volatile or intravenous anaesthetics in addition to narcotics. Actually the choice of the anaestesiological strategy depends only on the anaesthetists' preferences or institutional policies.This trial, named NeuroMorfeo, aims to assess the equivalence between volatile and intravenous anaesthetics for neurosurgical procedures.Methods/DesignNeuroMorfeo is a multicenter, randomized, open label, controlled trial, based on an equivalence design. Patients aged between 18 and 75 years, scheduled for elective craniotomy for supratentorial lesion without signs of intracranial hypertension, in good physical state (ASA I-III) and Glasgow Coma Scale (GCS) equal to 15, are randomly assigned to one of three anaesthesiological strategies (two VA arms, sevoflurane + fentanyl or sevoflurane + remifentanil, and one IA, propofol + remifentanil). The equivalence between intravenous and volatile-based neuroanaesthesia will be evaluated by comparing the intervals required to reach, after anaesthesia discontinuation, a modified Aldrete score ≥ 9 (primary end-point). Two statistical comparisons have been planned:1) sevoflurane + fentanyl vs. propofol + remifentanil;2) sevoflurane + remifentanil vs. propofol + remifentanil.Secondary end-points include: an assessment of neurovegetative stress based on (a) measurement of urinary catecholamines and plasma and urinary cortisol and (b) estimate of sympathetic/parasympathetic balance by power spectrum analyses of electrocardiographic tracings recorded during anaesthesia; intraoperative adverse events; evaluation of surgical field; postoperative adverse events; patient's satisfaction and analysis of costs.411 patients will be recruited in 14 Italian centers during an 18-month period.DiscussionWe presented the development phase of this anaesthesiological on-going trial. The recruitment started December 4th, 2007 and up to 4th, December 2008, 314 patients have been enrolled.

Tracing chameleon: thallium-201 SPECT/CT for pheochromocytoma.

A 61-year-old woman, in receipt of haemodialysis for 11 years, was diagnosed with a high-grade papillary urothelial carcinoma of the urinary bladder. Thallium-201 single photon emission computed tomography/computed tomography (SPECT/CT) was performed during the cancer work-up (Figure ​(Figure1).1). Unenhanced CT images of the SPECT/CT demonstrated a left adrenal mass (31.7 mm in size) with a homogeneous density of 62 HU. Scintigraphic SPECT images of the SPECT/CT showed an abnormal focus of increased radiotracer activity in the left upper quadrant of abdomen. The corresponding SPECT/CT fusion images confirmed the focus in the left adrenal medulla. The patient underwent a left adrenalectomy and the pathological findings indicated the histological characteristics of pheochromocytoma (Figure ​(Figure22). Fig. 1 New advance of image-rendering display: thallium-201 SPECT/CT. The coronal (left column), sagittal (middle column) and transaxial (right column) views of the CT images (top row) and corresponding SPECT images (middle row) fused to the SPECT/CT images ... Fig. 2 A pathological section of the left adrenal gland revealed a uniform proliferation of medullary cells, showing a nesting (Zellballen) pattern composed of well-defined cell clusters with amphophilic cytoplasm surrounded by fibrovascular stroma (haematoxylin ... Pheochromocytoma is a rare catecholamine-secreting tumour with a potential for cardiovascular devastation if the diagnosis is overlooked. The tumour may present with a diversity of imaging features that result from various histological degenerations including fibrosis, calcification, congestion, haemorrhage, necrosis and cystic change. Therefore, pheochromocytoma is often referred to as an epithet ‘imaging chameleon’ [1]. An adrenal mass with attenuation value >10 HU on CT usually suggests a radiological diagnosis of pheochromocytoma. Thallium-201, a widely used radiotracer for myocardial perfusion scintigraphy, has been proved effective in the diagnosis of various tumours through the mechanisms of increased vascularity and higher mitotic rate in tumour cells. Its uptake into tumour cells also reflects the cell membrane functions of the Na+/K+ ATPase pump, Tl+-Na+-2Cl− cotransport system and calcium-dependent ion channel. We firstly report a long-term haemodialysis patient whose pheochromocytoma is visualized through thallium-201 uptake within the left adrenal medulla by means of real-time functional SPECT and anatomical CT fusion images in tracing the site of pheochromocytoma. Diagnosis of pheochromocytoma in long-term haemodialysis patients is quite difficult since symptoms and signs implying pheochromocytoma are easily attributed to haemodialysis effects or complications of chronic renal disease. Measurement of urinary catecholamines and their metabolites is not feasible in anuric patients. Plasma catecholamines are also unreliable due to the impact of haemodialysis. With the help of advanced imaging fusion science, integrated thallium-201 SPECT/CT could be a promising paradigm for the diagnosis of pheochromocytoma in haemodialysis patients [2]. Conflict of interest statement. None declared.

Tamponade and the rule of tens

In February, 2007, a 32-year-old man presented with a 3week history of shortness of breath on exertion. He had no important medical history and was not taking any medication. His blood pressure was 100/80 mm Hg, he had a sinus tachycardia of 110 beats per min, and a respiratory rate of 18 breaths per min. His neck veins were distended and more pronounced on inspiration. On examination, his pulse was rapid and weak in character but did not alter with respiration. Heart sounds were quiet on auscultation of the praecordium. On the basis of these fi ndings, a clinical diagnosis of cardiac tamponade was suspected. A chest radiograph demonstrated an enlarged heart, and echocardiography showed a large pericardial eff usion with a mediastinal mass compressing the left atrium (fi gure, A), associated diastolic collapse, and severely impaired left ventricular function (ejection fraction 33%). Emergency pericardiocentesis was done and 1700 mL of blood-stained fl uid was drained; microscopy showed red blood cells and macrophages, but cytology and tumour markers were negative. CT of the chest and abdomen (fi gure, B) showed a 6∙4×7∙5×7∙5 cm vascular mediastinal mass with central necrosis and numerous feeding vessels. Subsequent cardiac catheterisation showed multiple feeding branches from the coronary arteries and a large bronchial vessel supplying part of the tumour. The combination of a pericardial eff usion, vascular mediastinal mass, and unexplained left ventricular dysfunction raised the diff erential diagnoses of arteriovenous malformation, haemangioma, thymoma, lymphoma, and phaeochromocytoma. Measurement of urinary catecholamines showed elevated levels of dopamine (12 674 nmol/24 h; normal range 70–1900) and noradrenaline (3281 nmol/24 h; 63–471) with normal adrenaline levels. A 123I-metaiodobenzylguanidine (MIBG) scan showed uptake in the region of the mass, confi rming that the lesion was an extra-adrenal phaeochromo cytoma, also known as a paraganglioma. Embolisation was done to de-vascularise the tumour before surgery; prior blockade with phenoxybenzamine and propranolol was done to control blood pressure and prevent tachyarrhythmias. During surgical excision a magnesium sulphate infusion achieved stable intraoperative haemodynamics. The tumour was successfully excised from the left atrial roof. The patient made an unremarkable post-operative recovery. Histology confi rmed the diagnosis of a paraganglioma. Within 6 weeks of surgery his left ventricular function had substantially improved (ejection fraction 54%). When last seen in June, 2007, the patient was asymptomatic. Cardiac tamponade is a life-threatening clinical syndrome requiring prompt recognition and management. The diagnosis is made clinically by raised jugular venous pressure or neck vein distension (Kussmaul’s sign if more pronounced on inspiration), hypotension, and muffl ed heart sounds. This combination is known as Beck’s triad and is observed in 10–40% of cases. Pulsus paradoxus may also be seen. Tamponade occurs when fl uid accumulation in the pericardial cavity causes a substantial rise in intra-pericardial pressure. At least 200 mL of fl uid must accumulate before the cardiac silhouette is aff ected on chest radiography. Echocardiography is a readily available, inexpensive, and easy to use tool to investigate cardiac tamponade and possible causes, for example mass infi ltration, as in our case. Extra-adrenal phaeochromocytomas are rare vascular tumours; it is useful to remember the rule of 10s: 10% of phaeochromocytomas are extra-adrenal, 10% are malignant, 10% are familial, and 10% are bilateral. MIBG scanning is a valuable technique for identifying tumour deposits in conjunction with CT and MRI. Features suggestive of malignancy include very high dopamine levels and vascular invasion. Close liaison between radiologists, oncologists, endocrinologists, geneticists, cardiologists, anaesthetists, and cardiothoracic surgeons is required to ensure optimum management. Underlying paraganglioma should be considered as a diff erential diagnosis in cases of cardiac tamponade, particularly in the young.

Selective solid-phase extraction of catecholamines by the chemically modified polymeric adsorbents with crown ether

A simple and selective one-step solid-phase extraction procedure using chemically modified polymer resin (Amberlite XAD-4) with crown ether was investigated for the measurement of urinary catecholamines. After loading the urine samples (adjusted to pH 4) on the synthesized adsorbent cartridge, the column was washed with methanol followed by water and then the adsorbed catecholamines were eluted by 1.0 mL of 6.0 M acetic acid. The effectiveness of sample clean-up method was demonstrated by reversed-phase ion-pair high-performance liquid chromatography with electrochemical detection. Under optimal condition, the recoveries of epinephrine, norepinephrine, and dopamine from spiked urine sample were >86% for all catecholamines. The detection limits ( n = 5) for epinephrine, norepinephrine, and dopamine were 37, 52, and 46 nmol/L, respectively.

Editorial

The challenges and uncertainties of working in the developing field of Acute Medicine have been a regular theme for editorial comment in this journal since I took the helm in 2002. Almost four years on, with sub-specialty status confirmed, over 200 consultants and many SpRs enrolled in higher specialist training programmes throughout the UK, Acute Medicine finds itself in a much stronger position than any could have predicted at that time. Enthusiasm for the field is clear from the numbers of applicants for training programmes at SpR level, as well as the dramatic rise in attendances at acute medicine meetings across the country in the last year. However, on-going challenges remain. Eighteen months from now, Modernising Medical Careers will send shockwaves throughout hospital medicine. The exact nature of the change to our training programmes remains unclear, and will probably have changed again between my writing this and its publication. However it is essential that Acute Medicine is ready for whatever comes our way. We must work closely with our colleagues in Emergency Medicine and Critical Care to develop common stem training schemes which allow doctors to choose the area of ‘front door’ medicine which suits them best. Where possible we should seek to encourage dual accreditation in two or more of these areas. But most of all we need to maintain the momentum which has carried us so far in such a short space of time, and which has the potential to make Acute Medicine one of the largest hospital specialties. This edition’s review articles cover a varied mix of common and less common conditions on the acute medical ‘take’. Most medical admission units will be faced with at least one patient presenting with a seizure in each 24 hour period. Dr Kinton emphasises the importance of a good history in the management of this problem, but also provides some useful tips to help distinguish seizures from other causes of blackout. Distinction from syncope can be a particular challenge, not least because of the differing implications for driving, the loss of which can have devastating consequences. Acute ischaemic stroke is another common problem, the management of which is comprehensively reviewed by David Jarrett and Hemang Dave. As well as summarising some of the major trial data for thrombolytic and antiplatelet therapy, this review includes some advice on some of the common clinical challenges which don’t usually feature in text book descriptions of this condition. Less common, but no less important, Acute liver failure must be distinguished from decompensated chronic liver disease – the former often requiring discussion with a regional liver unit. Phil Berry has included a useful checklist to have to hand before making this phone call. Headache, palpitations and sweating is a common problem on the post-take ward round – particularly amongst the junior staff completing a night shift. Fortunately most junior doctors do not have a phaeochromocytoma – in common with every patient for whom I have ever requested 24 hour urinary catecholamine measurement. Having read Dr Solomon’s thorough review of the acute management of this condition I will now feel equipped to manage this condition when I finally get a positive result back from the laboratory! Apologies that this edition has been a little delayed – I hope you consider it to have been worth waiting for….