Two-year outcome of laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity: results from a Swedish Nationwide Study (AMOS).

CONTEXT: The prevalence of obesity among adolescents has increased and we lack effective treatments. OBJECTIVE: To determine if gastric bypass is safe and effective for an unselected cohort of adolescents with morbid obesity in specialized health care. DESIGN, SETTING AND PATIENTS: Intervention study for 81 adolescents (13-18 years) with a body mass index (BMI) range 36-69 kg m(-2) undergoing laparoscopic gastric bypass surgery in a university hospital setting in Sweden between April 2006 and May 2009. For weight change comparisons, we identified an adult group undergoing gastric bypass surgery (n=81) and an adolescent group (n=81) receiving conventional care. MAIN OUTCOME MEASUREMENTS: Two-year outcome regarding BMI in all groups, and metabolic risk factors and quality of life in the adolescent surgery group. RESULTS: Two-year follow-up rate was 100% in both surgery groups and 73% in the adolescent comparison group. In adolescents undergoing surgery, BMI was 45.5 ± 6.1 (mean ± s.d.) at baseline and 30.2 (confidence interval 29.1-31.3) after 2 years (P<0.001) corresponding to a 32% weight loss and a 76% loss of excess BMI. The 2-year weight loss was 31% in adult surgery patients, whereas 3% weight gain was seen in conventionally treated adolescents. At baseline, hyperinsulinemia (>20 mU l(-1)) was present in 70% of the adolescent surgery patients, which was reduced to 0% at 1 year and 3% at 2 years. Other cardiovascular risk factors were also improved. Two-thirds of adolescents undergoing surgery had a history of psychopathology. Nevertheless, the treatment was generally well tolerated and, overall, quality of life increased significantly. Adverse events were seen in 33% of patients. CONCLUSIONS: Adolescents with severe obesity demonstrated similar weight loss as adults following gastric bypass surgery yet demonstrating high prevalence of psychopathology at baseline. There were associated benefits for health and quality of life. Surgical and psychological challenges during follow-up require careful attention.

Dominant role of nuclear progesterone receptor in the control of rat periovulatory granulosa cell apoptosis.

In this study, it was hypothesized that progesterone (P4) acts as a survival factor primarily by actions of the classic nuclear progesterone receptor (PGR) signaling pathway in rat periovulatory granulosa cells. Granulosa cells were isolated from immature female rats primed with equine chorionic gonadotropin/human chorionic gonadotropin and treated in vitro with PGR antagonists. As little as 10 nM of two different PGR antagonists (Org 31710 and RU 486) increased apoptosis measured as caspase 3/7 activity, which was reversed by cotreatment with the progestin R5020. Concurrently, P4 synthesis was decreased. Inhibition of P4 synthesis by cyanoketone similarly induced apoptosis but required greater inhibition of P4 synthesis than that seen after treatment with PGR antagonists. Therefore, the induction of apoptosis by PGR antagonists cannot be explained by decreased P4 synthesis alone. Low concentrations of R5020 also completely reversed the effects of cyanoketone. Inhibition of P4 synthesis was more effective in inducing apoptosis than treatment with PGR antagonists. However, cotreatment with PGR antagonists protected cells from the additional effects of cyanoketone, indicating partial agonist effects of the antagonists and a dominating role for PGR in P4-mediated regulation of apoptosis. Progesterone receptor membrane component 1 (PGRMC1) was expressed in granulosa cells; however, an anti-PGRMC1 antibody did not induce apoptosis in periovulatory granulosa cells. Neither anti-PGRMC1 nor P4 or cyanoketone affected apoptosis of immature granulosa cells. In conclusion, we show that P4 regulates apoptosis in periovulatory granulosa cells by acting via the classic nuclear receptor.

Long-term outcome of a large series of patients surgically treated for pheochromocytoma.

OBJECTIVE: To analyse the morbidity, mortality and long-term outcome in a consecutive series of surgically treated patients with pheochromocytoma (PC), or paraganglioma (PG), from the western region of Sweden between 1950 and 1997. PATIENTS: All patients (n = 121) who had been hospitalized and treated for PC/PG over 47 years. DESIGN: Retrospective review of patients with PC/PG regarding presenting symptoms, tumour characteristics, clinical management and long-term outcome after treatment. SETTING: One referral centre for all patients from the western region of Sweden. RESULTS: During an observation of 15 +/- 6 years, 42 patients died vs. 23.6 expected in the general population (P < 0.001). There was no intra- or post-operative mortality. Four patients with sporadic disease died of malignant PC and six with hereditary disease of associated neuroectodermal tumours. Five patients died of other malignancies, 20 of cardiovascular disease and seven of other causes. Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed risk factor for death (P = 0.02). At diagnosis 85% of the patients were hypertensive; one year after surgery more than half were still hypertensive. However, pre- and post-operative hypertension did not influence the risk for death versus controls. CONCLUSION: Pheochromocytoma/PG can be safely treated by surgery. Death of malignant PC/PG was unusual, but the patients as a group had an increased risk of death. We recommend life-long follow-up of patients treated for PC/PG with screening for recurrent tumour in sporadic cases and for associated tumours in hereditary cases. This strategy would also be helpful in diagnosing cardiovascular disease at an early stage.

Plasma metanephrines: a novel and cost-effective test for pheochromocytoma.

Pheochromocytomas are rare chromaffin cell tumors that nevertheless must be excluded in large numbers of patients who develop sustained or episodic hypertension as well as in many others with suggestive symptoms or with a familial history of pheochromocytoma. Diagnosis of pheochromocytoma depends importantly on biochemical evidence of excess catecholamine production by a tumor. Imperfect sensitivity and specificity of commonly available biochemical tests and the low incidence of the tumor among the tested population mean that considerable time and effort can be expended in confirming or ruling out pheochromocytoma in patients where the tumor is suspected. Measurements of plasma free metanephrines provide a superior test compared to other available tests for diagnosis of pheochromocytoma. In particular, the high sensitivity of plasma free metanephrines means that a normal test result reliably excludes all but the smallest of pheochromocytomas so that no other tests are necessary. Measurements of plasma free metanephrines, when systematically combined with other diagnostic procedures outlined in this review, provide a more efficient, reliable and cost-effective approach for diagnosis of pheochromocytoma than offered by previously available approaches.

Renal effects of amino acid infusion in cardiac surgery.

OBJECTIVE: To evaluate effects of amino acids on renal function and oxygen consumption and the role of individual amino acids on renal blood flow (RBF) changes. DESIGN: Prospective, randomized, controlled study. SETTING: Operating room in cardiothoracic surgery department, university hospital. PARTICIPANTS: Twenty-two male patients submitted to elective first-time coronary artery bypass surgery. INTERVENTIONS: A catheter was placed in the left renal vein for thermodilution RBF measurements and blood sampling. In 11 patients, a balanced mixed amino acid infusion was infused (200 mL/hr) for 30 minutes immediately after the operation. MEASUREMENTS AND MAIN RESULTS: RBF and glomerular filtration rate increased during amino acid infusion compared with the control group. Renal oxygen consumption increased in the amino acid group and correlated with the increase in RBF (r = 0.70, p<0.001). Amino acid infusion induced two- to fourfold increases in plasma concentrations of individual amino acid concentrations and promoted renal extraction of aspartate, glutamate, glycine, and histidine. No correlation was observed between arterial concentration or uptake of individual amino acids and RBF. CONCLUSIONS: The increase in RBF from a mixed amino acid infusion was associated with increased glomerular filtration rate and renal consumption of oxygen. Changes in RBF of a mixed amino acid infusion could not be linked to plasma level or renal uptake of any individual amino acids.

Splanchnic circulation and regional sympathetic outflow during peroperative PEEP ventilation in humans.

The splanchnic organs represent a major target for sympathetic outflow and an important region for haemodynamic effects on cardiovascular homeostasis. We have studied regional haemodynamic and sympathetic changes in the splanchnic bed during standardized circulatory stress from positive end-expiratory pressure ventilation (PEEP). We investigated eight patients undergoing major upper abdominal surgery using a radiotracer method to measure plasma spillover of norepinephrine as an index of sympathetic nerve activity using arterial, portal and hepatic venous blood sampling. Mesenteric and hepatic perfusion were measured by ultrasound transit time flowmetry and blood-gas analyses. Steady state measurements were performed before and during PEEP ventilation at 10 cm H2O. Plasma spillover of norepinephrine in the mesenteric and hepatic organs represented mean 49 (SEM 8)% and 7 (2)%, respectively, of systemic norepinephrine spillover at baseline, and PEEP ventilation did not cause any significant changes. However, PEEP ventilation significantly decreased portal venous blood flow while hepatic blood flow was preserved by a compensatory increase in hepatic arterial blood flow. Mesenteric and hepatic oxygen delivery changed according to blood flow, and there were no changes in regional oxygen consumption. Thus PEEP ventilation altered mesenteric and hepatic perfusion, independent of any change in corresponding sympathetic nerve activity. Regulation of hepatic blood supply, not related to sympathetic activity, maintained liver oxygenation during PEEP ventilation despite a simultaneous decrease in mesenteric perfusion.

Differential regulation of IGF-I, its receptor and GH receptor mRNAs in the right ventricle and caval vein in volume-loaded genetically hypertensive and normotensive rats.

It has been suggested, mainly by in vitro findings, that cardiovascular tissue in the spontaneously hypertensive rat (SHR) should be more prone to proliferate/hypertrophy than that of the Wistar-Kyoto rat (WKY). The present study tests the hypothesis that the tissue of the low-pressure compartment in SHR, being structurally similar to that of the WKY, shows an increased growth response due to activation of the GH-IGF-I system. An aortocaval fistula (ACF) was induced in 64 SHR and WKY male rats and 44 rats served as controls. They were all followed for 1, 2, 4 and 7 days after surgery. In separate groups of SHR (n=4) and WKY (n=3), central venous pressure was measured by telemetry recordings prior to opening of the fistula and for up to 16 h post-surgery. Systolic blood pressure was measured during the week post-surgery. The right ventricular (RV) and the caval vein IGF-I mRNA and RV IGF-I receptor and GH receptor mRNAs were quantitated by means of solution hybridisation assay. In rats with ACF the systolic blood pressure decreased, approximately 29% in SHR and 16% in WKY between 1 and 7 days post-surgery (P<0.05, n=5-6 in each group). SHR with ACF showed a transient elevation in central venous pressure vs WKY. Within the week following fistula induction both strains showed a similar, pronounced increase in RV hypertrophy. SHR with ACF showed a smaller, or even blunted, overall response with respect to activation of the GH-IGF-I system compared with WKY, the latter showing clear-cut elevation of gene expressions. Two days after shunt opening in SHR, RV and caval vein IGF-I mRNA increased by 57% and 108% (P<0.05 for both, n=5-6 in each group) respectively, and these expressions were then turned off, whereas RV GH receptor and IGF-I receptor mRNA expression remained unaffected compared with WKY rats. WKY rats showed on average a later and a greater response of GH-IGF-I system mRNA expression vs SHR. The present in vivo study suggests that the SHR requires less activation of the GH-IGF-I system for creating a given adaptive structural growth response.

[Plasma metanephrine measurements make the diagnosis of pheochromocytoma easier]. / Plasmametanefriner underlättar diagnostik av feokromocytom.

A study where plasma metanephrine and normetanephrine concentrations in 51 patients with hypertension and 62 healthy normotensives were compared with those in 52 patients with histologically confirmed phaeochromocytoma showed measurement of the two variables to constitute a test that reliably excludes the presence of phaeochromocytoma in cases where both values are normal. Other currently available tests (e.g., plasma catecholamine assay) can yield false-negative results in some patients with the tumour, and thus do not reliably exclude its presence in unaffected patients. Accordingly, as a missed diagnosis can have disastrous consequences for the patient, hitherto the exclusion of phaeochromocytoma has typically entailed multiple and repeated tests which are time-consuming and costly. The advantage of the plasma metanephrine-normetanephrine test is that, as it does not yield false-negative results, a negative test result reliably excludes the presence of phaeochromocytoma in suspected cases, and no further tests are necessary.

Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors.

This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of pheochromocytoma may result from production of free metanephrines within tumors. Presence in pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of pheochromocytoma.

Renal effects of alpha-ketoglutarate early after coronary operations.

BACKGROUND: Alpha-ketoglutarate (alpha-KG) is a Krebs cycle intermediate and the carbon skeleton of glutamate. Alpha-ketoglutarate has provoked interest in heart surgery because of its proposed critical role in myocardial metabolism. This study investigates the role of alpha-KG in renal function after cardiac surgical procedures. METHODS: Twenty-two patients with normal preoperative renal function were included in a prospective, randomized, and controlled study. Eleven patients received intravenous infusion of 30 g alpha-KG/hour after the operation. Measurements were performed before operation, immediately after operation, and after 30 minutes of alpha-KG infusion. RESULTS: Renal blood flow was higher during alpha-KG infusion, 297% +/- 97% (of preoperative value), than in controls, 125% +/- 20% (p < 0.05). Filtration fraction was lower (12.3% +/- 0.05% versus 17.2% +/- 1.1%, p < 0.01), which prevented a significant difference in glomerular filtration rate. The renal arteriovenous differences of lactate, glutamate, glutamine, and glycine changed toward a net release during alpha-KG infusion. CONCLUSIONS: Infusion of alpha-KG enhances renal blood flow early after coronary surgical procedures in patients with normal renal function. The mechanism is unclear, but could be associated with primarily metabolic effects, and may potentially convey a beneficial effect for renal function.

Inhibited expression of insulin-like growth factor I mRNA and attenuated cardiac hypertrophy in volume overloaded hearts treated with difluoromethylornithine.

The present study examined whether the previously reported hypertrophy and increased expression of insulin-like growth factor I (IGF-I) mRNA in the volume-overloaded right ventricle was dependent on an intact production of polyamines. Volume overload was created in normotensive Wistar rats by means of an aorto-caval fistula. Difluoromethylornithine (DFMO) 2%, which is a specific, irreversible blocker of ornithine decarboxylase, was administered in the drinking water to intervention groups and one sham group, respectively, 24 h prior to surgery and for up to 26 days. DFMO blocked transiently the early over-expression of right ventricular IGF-I mRNA and attenuated the rapid development of both right and left ventricular hypertrophy during volume overload. Expression of IGF-I mRNA in the right ventricle in the early phase of volume overload appears to be dependent on activation of ornithine decarboxylase, whereas other pathways are involved in the later phase of cardiac structural adaptation. Thus, these findings link together early and late growth responses potentially important for compensatory cardiac hypertrophy.

Rapid fall in sympathetic nerve hyperactivity in patients with heart failure after cardiac transplantation.

BACKGROUND: Severe heart failure is associated with an intense sympathetic nerve hyperactivity. After cardiac transplantation, neurochemical studies have indicated a normalization of sympathetic outflow. Intraneural recordings have, however, yielded varying results; both a normalization and a remaining hyperactivity have been obtained in cardiac transplant recipients, the latter being attributed to cyclosporine treatment. METHODS AND RESULTS: To circumvent the methodologic variation associated with different patient groups in cross-sectional studies, a longitudinal study design was employed in this study. Intraneural recordings of muscle sympathetic nerve activity in 21 heart failure patients were performed before, and repeatedly during the first year after, heart transplantation. Before surgery, muscle sympathetic nerve activity was augmented in all patients (78 +/- 4 bursts/min, 90 +/- 2 bursts/100 heartbeats). Both muscle sympathetic nerve activity burst frequency (burst/minute) and burst incidence (bursts/100 heartbeats) decreased rapidly following surgery. One month after surgery, burst frequency was reduced by 35% (51 +/- 5 bursts/min P < .05), whereas burst incidence decreased by 32% (61 +/- 5 bursts/100 heartbeats, P < .05). This decrease remained unchanged up to 1 year after surgery. The fall in posttransplant muscle sympathetic nerve activity was similar in transplant recipients who developed hypertension during the course of the study (n = 12) and those who remained normotensive (n = 9). CONCLUSIONS: The sympathoexcitation recorded in patients with heart failure was rapidly and substantially reduced after cardiac transplantation despite cyclosporine treatment, most likely reflecting improved central and peripheral hemodynamics.

Sympathetic discharge to mesenteric organs and the liver. Evidence for substantial mesenteric organ norepinephrine spillover.

This study using sampling of blood from the portal vein, in addition to arterial and hepatic sites, to estimate separately spillovers of norepinephrine from mesenteric organs and the liver in seven patients undergoing upper abdominal surgery. Conventional measurements in arterial and hepatic venous plasma provided a measure of net hepatomesenteric NE spillover (403 pmol/ml) that indicated a 13% contribution of these organs to total body spillover of NE into systemic plasma (3,071+/-518 pmol/min). The net hepatomesenteric spillover of NE into systemic plasma was much lower than the spillover of NE from mesenteric organs into portal venous plasma (1,684+/-418 pmol/min). This and the hepatic spillover of NE into systemic plasma (212+/-72 pmol/min) indicated a considerable combined spillover of NE from hepatomesenteric organs (1,896+/-455 pmol/min). The sum of the latter estimate with the difference between total body and net hepatomesenteric NE spillovers provided an adjusted total body spillover of NE into both systemic and portal venous plasma (4,564+/-902 pmol/min). Mesenteric organs made a 37% contribution, and the liver made a 5% contribution to the adjusted total body spillover of NE. Thus, a substantial proportion of total body sympathetic outflow is directed towards mesenteric organs; this is obscured by efficient hepatic extraction of NE (86+/-6%) when measurements are restricted to arterial and hepatic venous plasma.

Cardiac insulin-like growth factor I and growth hormone receptor expression in renal hypertension.

The aim of the present study was to investigate the role of insulin-like growth factor I in the development of cardiac hypertrophy in two-kidney, one clip hypertension by relating growth hormone receptor and insulin-like growth factor I receptor mRNA levels to insulin-like growth factor I gene transcription using a solution hybridization/RNase protection assay. Two-kidney, one clip hypertension was induced in male Wistar rats, and experiments were performed 2, 4, 7, and 12 days after surgery. Systolic blood pressure was elevated 2, 7, and 12 days after clipping (P < .001). Left ventricular weights were increased 2, 4, 7, and 12 days after surgery (P < .01). Associated with the rise in blood pressure, left ventricular insulin-like growth factor I mRNA was increased 2, 7, and 12 days after surgery (P < .01). Furthermore, growth hormone receptor and insulin-like growth factor I receptor gene expression increased specifically in the left ventricle of renal hypertensive rats (P < .05 and P < .001, respectively). Left ventricular growth hormone receptor mRNA peaked 7 days after induction of renal artery stenosis. These results show that insulin-like growth factor I, growth hormone receptor, and insulin-like growth factor I receptor mRNA increase in the pressure-overloaded left ventricle of two-kidney, one clip rats, suggesting a role for insulin-like growth factor I and the growth hormone/insulin-like growth factor I axis in the development of cardiac hypertrophy.

Regional myosin heavy chain expression in volume and pressure overload induced cardiac hypertrophy.

Although the overall shift towards the V3 myosin heavy chain (MHC) has been shown to be associated with cardiac hypertrophy, quantitative evidence describing regional expression is sparse. The aim of this study was to compare and contrast the regional ventricular myosin isoform expression in two distinct haemodynamic states: pressure and volume overload. Volume overload was achieved using an aortocaval fistula (ACF) model and pressure overload by two-kidney-one-clip (2K1C) hypertension. A separate group (UC-2K1C) had the clip removed 1 week prior to investigation. Sham operated rats (SHAM) served as controls. All groups were studied 4 weeks after surgery. Ventricular tissue samples (approximately 50 mg) were taken from the walls of the right ventricle (RV), septum and left ventricular (LV) free wall. Tissue samples (excluding RV) were divided into endocardium and epicardium, and myosin expression was determined using polyacrylamide gel electrophoresis. Cardiac hypertrophy was substantial in both LV (1.7-fold) and RV (1.9-fold) in ACF rats. The 2K1C rats had similar LV enlargement (1.6-fold) whereas RV hypertrophy was not as great (1.2-fold). Blood pressure (BP) was increased 65% in 2K1C rats, whereas there was no change in ACF rats with respect to SHAM animals. After unclipping (UC-2K1C), LV hypertrophy and BP had returned towards control levels. In general, V3 MHC expression was associated with increasing LV hypertrophy in both 2K1C and ACF models. However, there was a marked endo-epi differential (1.5:1) in the LV free wall and septum of 2K1C rats. In contrast, in ACF rats there was no differential V3 MHC expression in the LV or septal tissue, i.e. expression was similar in both endo- and epi-samples. Elevated expression of V3 MHC persisted despite normotension and regression of cardiac hypertrophy in UC-2K1C rats. Taken together with published results demonstrating that relative transmural myocyte hypertrophy in ACF rats (endo > epi) is in contrast to that seen in 2K1C rats (epi > endo), the present findings reveal that regional V3 myosin expression represents a distinct adaptational component of the overall cardiac hypertrophic response in both volume and pressure overload.

Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines.

Norepinephrine (NE) and epinephrine (E) are metabolized extraneuronally by catechol-O-methyl-transferase to the metanephrines (MNs), normetanephrine (NMN) and metanephrine (MN). Subjects in this study received infusions of tritium-labeled NE and E. Concentrations of MNs and catecholamines were measured in plasma flowing into and out of the heart, forearm, lungs, kidneys, mesenteric organs (gastrointestinal tract, spleen, and pancreas), liver, and adrenals to examine the regional production of MNs from circulating and locally released catecholamines. NE spillover from mesenteric organs and kidneys accounted for 64% of the spillover from all tissues. There was detectable spillover of E from most extraadrenal tissues, but 91% was from the adrenals. The production of MNs from locally released and circulating catecholamines varied widely among tissues. The liver made the largest contribution to removal of circulating NE (57%) and E (32%) and the largest contribution to the production of NMN (54%) and MN (37%) from metabolism of circulating catecholamines. In all other tissues more NMN was produced from locally released than from circulating NE. Thus, the metabolism of circulating NE was responsible for only 19% of the total production of NMN. An even smaller portion (6%) of plasma MN was derived from metabolism of circulating E. Most plasma MN (91%) was produced within the adrenals, which also provided the largest single source (23%) of NMN. The regional variation in extraneuronal production of MNs indicates considerable heterogeneity in how circulating and locally released catecholamines are handled by different tissues. The substantial contribution of the adrenals to the production of MNs explains the extraordinary sensitivity of these metabolites for the diagnosis of pheochromocytoma.

Plasma metanephrines in the diagnosis of pheochromocytoma.

OBJECTIVE: To examine whether tests for plasma metanephrines, the o-methylated metabolites of catecholamines, offer advantages for diagnosis of a pheochromocytoma over standard tests for plasma catecholamines or urinary metanephrines. DESIGN: Cross-sectional study. SETTING: 3 clinical specialist centers. PATIENTS: 52 patients with a pheochromocytoma; 67 normotensive persons and 51 patients with essential hypertension who provided reference values; and 23 patients with secondary hypertension and 50 patients with either heart failure or angina pectoris who served as comparison groups. MEASUREMENTS: Plasma concentrations of catecholamines (norepinephrine and epinephrine) and metanephrines (normetanephrine and metanephrine) were measured in all patients. The 24-hour urinary excretion of metanephrines was measured in 46 patients with pheochromocytoma. RESULTS: Pheochromocytomas were associated with increases in plasma concentrations of metanephrines that were greater and more consistent than those in plasma catecholamine concentrations. No patient with a pheochromocytoma had normal plasma concentrations of both normetanephrine and metanephrine. The sensitivity of these tests was 100% (52 of 52 patients [95% CI, 94% to 100%]), and the negative predictive value of normal plasma concentrations of metanephrines was 100% (162 of 162 patients). Tests for plasma catecholamines yielded eight false-negative results and a sensitivity of 85% (44 of 52 patients [CI, 72% to 93%]). The negative predictive value of normal plasma concentrations of catecholamines was 95% (156 of 164 patients). Tests for urinary metanephrines yielded five false-negative results and a sensitivity of 89% (41 of 46 patients [CI, 76% to 96%]). Because no statistical difference was noted in the number of false-positive results between tests for plasma metanephrines (15%) and tests for plasma catecholamines (18%), the specificities of the two tests did not differ. CONCLUSIONS: Normal plasma concentrations of metanephrines exclude the diagnosis of pheochromocytoma, whereas normal plasma concentrations of catecholamines and normal urinary excretion of metanephrines do not. Tests for plasma metanephrines are more sensitive than tests for plasma catecholamines or urinary metanephrines for the diagnosis of pheochromocytoma.

Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism?

1. The clinical utility of plasma metadrenalines for examination of sympatho-adrenal function and catecholamine metabolism was assessed from plasma measurements of these metabolites in a number of clinical conditions (hypertension, cardiac failure, bilateral adrenalectomy and X-chromosomal deletions of the gene for monoamine oxidase), and before and during activation of sympathetic outflow or infusions of noradrenaline and adrenaline. 2. Plasma concentrations of normetadrenaline were less than 25% of those of noradrenaline, concentrations of metadrenaline and adrenaline were similar and those of sulphate-conjugated metadrenalines were 20- to 30-fold higher than free metadrenalines. Hypertensive patients had elevated plasma concentrations of adrenaline, noradrenaline and conjugated but not free metadrenalines. Cardiac failure patients had 2- to 4-fold increases in plasma noradrenaline and free and conjugated normetadrenaline. Adrenalectomy resulted in undetectable plasma concentrations of adrenaline, 91-97% decreases in free and conjugated metadrenaline and a 40% decrease in normetadrenaline relative to noradrenaline. Patients with X-chromosomal deletions of the gene for monoamine oxidase had 6- and 16-fold increases in plasma free and conjugated normetadrenaline and 2- and 4-fold increases in free and conjugated metadrenaline. 3. Infusion of catecholamines increased plasma concentrations of free metadrenalines by less than 6% of increases in precursor amines, indicating that most plasma normetadrenaline (84%) and metadrenaline (90%) is derived from metabolism of catecholamines before their entry into the circulation. Considerable O-methylation of catecholamines within the adrenals explains why sympatho-adrenal activation resulted in smaller proportional increases in plasma metadrenalines than catecholamines. 4. Plasma metadrenalines provide supplementary information about sympatho-adrenal activity to that provided by catecholamines, but are more useful for examination of the extraneuronal inactivation of catecholamines, particularly detection of neurochemical phenotypes in genetic disorders of catecholamine metabolism. Significant formation of metadrenalines within chromaffin tissue explains why measurements of plasma metadrenalines provide an extraordinarily sensitive method for diagnosis of phaeochromocytoma.

Thoracic epidural anesthesia during coronary artery bypass surgery: effects on cardiac sympathetic activity, myocardial blood flow and metabolism, and central hemodynamics.

The effects of high thoracic epidural anesthesia (TEA) on cardiac sympathetic nerve activity, myocardial blood flow and metabolism, and central hemodynamics were studied in 20 patients undergoing coronary artery bypass grafting (CABG). In 10 of the patients, TEA (T1-5 block) was used as an adjunct to a standardized fentanyl-nitrous oxide anesthesia. Hemodynamic measurements and blood sampling were performed after induction of anesthesia but prior to skin incision and after sternotomy. Assessment of total and cardiac sympathetic activity was performed by means of the norepinephrine kinetic approach. Prior to surgery, mean arterial pressure (MAP), great cardiac vein flow (GCVF), and regional myocardial oxygen consumption (Reg-MVO2) were lower in the TEA group compared to the control group. During sternotomy there was a pronounced increase in cardiac norepinephrine spillover, MAP, systemic vascular resistance index (SVRI), pulmonary capillary wedge pressure (PCWP), GCVF, and Reg-MVO2 in the control group. These changes were clearly attenuated in the TEA group. None of the patients in the TEA group had metabolic (lactate) or electrocardiographic signs of myocardial ischemia. Three patients in the control group had indices of myocardial ischemia prior to and/or during surgery. We conclude that TEA attenuates the surgically mediated sympathetic stress response to sternotomy, thereby preventing the increase in myocardial oxygen demand in the pre-bypass period without jeopardizing myocardial perfusion.