Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice.

BACKGROUND: Although pheochromocytomas are believed to account for fewer than 0.3% of all cases of hypertension, aggressive diagnostic and surgical intervention is recommended whenever a pheochromocytoma is suspected because uncontrolled catecholamine release from the tumors can lead to catastrophic consequences. Many biochemical diagnostic and imaging localization tests exist for detecting pheochromocytomas. We sought to evaluate the sensitivity of these tests used over a 35-year period at a single institution. METHODS: Thirty-five patients with complete medical records who had pathologically confirmed pheochromocytomas between 1962 and 1997 at the University of Chicago Hospitals were identified. Sensitivity and 95% confidence intervals were calculated for 12 laboratory diagnostic tests and 5 imaging studies. RESULTS: The most sensitive laboratory diagnostic tests in our study were plasma total catecholamines (95%) and urine total metanephrines (100%). Testing for urine vanillylmandelic acid, while less expensive and easier to perform than many other tests, had a slightly lower sensitivity (89%). The most sensitive imaging tests in the study were magnetic resonance imaging (100%) and iodine I-131 metaiodobenzylguanidine scintigraphy (100%). The more often used computed tomography had only 88% sensitivity. Localization was safely and successfully performed on two pregnant patients using magnetic resonance imaging and ultrasound. CONCLUSIONS: By properly choosing from the wide array of laboratory diagnostic and imaging tests, pheochromocytomas can be identified and localized with nearly 100% sensitivity. These tests should be performed in any patient for whom the diagnosis of pheochromocytoma is being considered.

The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastrointestinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single-blind oral placebo and intravenous placebo, followed by randomized, double-blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral-cecal transit time from 114.6 +/- 37.0 minutes (mean +/- SD) to 158.6 +/- 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine-induced increase in oral-cecal transit time (110.4 +/- 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single-blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine-induced delay in oral-cecal transit time (p < 0.005 compared with morphine alone), and a dose-dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long-term opioid use.

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine-induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold-pressor test. Morphine significantly increased oral-cecal transit time from 104.6 +/- 31.1 minutes (mean +/- SD) to 163.3 +/- 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine-induced increase in oral-cecal transit time (106.3 +/- 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine-induced delay in oral-cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid-induced constipation.

Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.

BACKGROUND: Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. METHODS: This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time. RESULTS: In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. CONCLUSION: Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

Ptosis in the rat following topically administered 2% epinephrine.

Commercially available 2% epinephrine instilled twice daily in one eye of 15 rats resulted in ptosis after 4 weeks treatment. The ptosis was indistinguishable from that observed following topical treatment with 6-hydroxydopamine 20% and surgical sympathectomy. Ptosis in both epinephrine- and 6-hydroxydopamine-treated rats was associated with a statistically significant depletion of ocular norepinephrine, as determined by a sensitive catecholamine radio enzyme assay. Ultrastructural evidence of nerve terminal degeneration was present near the smooth muscle of Müller within the eyelid of rats treated with epinephrine. This study provides further evidence epinephrine administration can result in chemical sympathectomy as has been described following 6-hydroxydopamine.

Guidelines, practice policies, and parameters: the case for geriatrics.

OBJECTIVE: As the population ages, the care of older persons becomes more important. At the same time, practice guidelines that provide recommendations for appropriate care are being published in greater numbers. The purpose of this work is to determine the proportion of guidelines that contain specific information about older persons. DESIGN: Through a random sample of published guidelines listed in the AMA Directory of Practice Parameters, 1992 Edition, we determined the proportion of guidelines that contain specific age-related information. We also determined if, over time, there was a difference in the proportion of practice guidelines containing information about older persons. RESULTS: 45.9% (95% CI, range 33.4-58.4) of guidelines that could conceivably pertain to older persons contain no age information; 24.6% (95% CI, range 13.8-35.4) of guidelines contain information only about persons less than 65 years of age; 29.5% (95% CI, range 18.1-41.0) of guidelines contain specific information about older persons. Moreover, there were no secular trends in the proportion of guidelines pertaining to older persons. CONCLUSIONS: Only a minority of practice guidelines contain information about older persons. Possible causes and solutions to this shortfall are discussed.

Intraoperative urinary output does not predict postoperative renal function in patients undergoing abdominal aortic revascularization.

To determine whether intraoperative urinary output was predictive of postoperative renal function, mean urinary output and lowest hourly urinary output were measured in 137 patients during operation for aortic reconstruction. Pulmonary capillary wedge pressure was kept within normal limits. If urinary output was less than 0.125 ml X kg-1 X hr-1, patients were given crystalloid solution, mannitol, furosemide (Lasix), or nothing. For each patient, serum creatinine and blood urea nitrogen (BUN) levels were assayed on postoperative days 1, 3, and 7. There was no significant correlation between intraoperative mean urinary output or lowest hourly urinary output and change from preoperative to postoperative levels of creatinine or BUN. Twenty-one patients had postoperative renal insufficiency; of these, 17 had had renal disease before operation. In these patients as well; mean urinary output and the lowest hourly urinary output did not correlate with change in BUN or creatinine levels. The position of the aortic cross-clamp did not affect these correlations. Therefore, intraoperative urinary output was not predictive of postoperative renal insufficiency in patients undergoing aortic reconstruction.

The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma.

To establish criteria for administration of the optimal dose of alpha-adrenergic receptor blocking drugs, we studied cardiac performance and tissue oxygen tension in three patients who underwent excision of pheochromocytoma. Subcutaneous oxygen tension was measured by the method of Niinikoski and Hunt. Cardiac function was assessed by thermodilution cardiac output, systemic and pulmonary arterial blood pressures, and continuous two-dimensional transesophageal echocardiography of a cross section of the left ventricle at the level of the papillary muscles. Despite large changes in cardiac output and systemic, pulmonary, and wedge pressures, intraoperative tissue oxygen tensions and ejection fractions remained normal (even at times of peak catecholamine excretion and very abnormal wedge pressures). Studies of healthy animals that received no alpha-adrenergic receptor blocking drugs showed major decrements of tissue oxygen in response to modest doses of epinephrine. We conclude that progressive administration of alpha-adrenergic receptor blocking drugs does not absolutely protect the patient from major changes in blood pressure during operation for pheochromocytoma, but that cardiac performance and oxygen supply to the tissues are unimpaired.

Simple computer measurement of pulmonary VCO2 per breath.

Measurements of the volume of CO2 exhaled per breath (VCO2/br) are preferable to end-tidal PCO2, when the exhaled flow and CO2 waveforms may be changing during unsteady states, such as during alterations in positive end-expiratory pressure or alterations in cardiac output. We describe computer algorithms that determine VCO2/br from digital measurements of exhaled flow (including discontinuous signals common in anesthesia circuits) and CO2 concentration at the airway opening. Fractional concentration of CO2 is normally corrected for dynamic response and transport delay (TD), measured in a separate procedure. Instead, we determine an on-line adjusted TD during baseline ventilation. In six anesthetized dogs, we compared the determination of VCO2/br with a value measured in a simultaneous collection of expired gas. Over a wide range of tidal volume (180-700 ml), respiratory rate (3-30 min-1), and positive end-expiratory pressure (0-14 cmH2O), VCO2/br was more accurate with use of the adjusted TD than the measured TD (P less than 0.05).

Gut motility and transit changes in patients receiving long-term methadone maintenance.

This study was conducted to survey gut motility and transit in 19 volunteers receiving methadone maintenance who were opioid-dependent, and to measure the oral-cecal transit time in these individuals using the lactulose hydrogen breath test. None of these patients reported constipation problems before use of illicit drugs. During current long-term methadone therapy, 58% of patients experienced some degree of constipation, and two of these 19 patients reported that constipation was a very serious problem. Mean +/- standard deviation (SD) oral-cecal transit time in these individuals was 159+/-49.2 minutes, which is significantly longer than the transit time recorded in two previous studies of healthy volunteers (P < 0.01). These results indicate that tolerance to opioids does not appear to extend to gastrointestinal motility and transit. It seems that patients receiving long-term methadone therapy are a good model for use in evaluating gastrointestinal effects of opioid antagonists.

Effects of low-dose morphine on gastric emptying in healthy volunteers.

Appropriate preoperative pain therapy for patients undergoing surgery may be withheld due to the fear that opioids will inhibit gastric emptying and increase the risk of aspiration. Previously, doses of 5 to 10 mg of morphine have been shown to delay gastric emptying time. However, the effect of lower doses of morphine on gastric emptying in humans has not been reported. In this study, the effects of intravenous morphine 0.05 mg/kg-3.5 mg for 70-kg body weight, a dose that can cause analgesia--on gastric emptying were evaluated in a double-blind, randomized, placebo-controlled study in 15 healthy human volunteers using the acetaminophen test. Our data indicated that this low dose of morphine significantly prolonged the gastric emptying time. Thus, even small doses of morphine inhibit gastric emptying. This effect may be important in patients undergoing surgery, in patients receiving other oral medications after surgery in ambulatory settings, and in instances of patient-controlled analgesia.

Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study.

N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.

Assessment of retrograde cardioplegia distribution using contrast echocardiography.

Retrograde cardioplegia has gained popularity in coronary and noncoronary cardiac operations. We have used contrast echocardiography in the open-chest canine model to compare the distribution of cardioplegia delivered antegrade in the aortic root versus retrograde through the coronary sinus, and to determine the effect of coronary occlusion on that delivery. With no coronary occlusion, antegrade cardioplegia was distributed to the entire left ventricle and septum whereas retrograde cardioplegia was distributed to the left ventricular free wall but had inconsistent delivery to the septum. Acute occlusion of the left circumflex coronary artery resulted in 57.06% +/- 9.52% of the left ventricle not being perfused by antegrade cardioplegia and occlusion of both the left circumflex and anterior descending coronary arteries caused a 65.46% +/- 18.5% reduction in perfusion by antegrade cardioplegia. Acute coronary occlusion had no effect on retrograde cardioplegia distribution. We conclude that retrograde cardioplegia is less homogeneous than antegrade cardioplegia in the intact coronary circulation but that retrograde cardioplegia preserves cardioplegia distal to acutely occluded coronary arteries. Furthermore, contrast echocardiography is a useful method of assessing myocardial perfusion and may have useful clinical applications.

Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine.

PURPOSE: Morphine can have either an emetic or an antiemetic effect. The emetic effect of morphine can be blocked by methylnaltrexone (MNTX), a quaternary opioid antagonist with peripheral action. In this study, we tested the hypothesis that administering MNTX to block the peripheral emetic effect of morphine would unmask the central antiemetic effect of the morphine. The net result, we hypothesized, would be a reduction in apomorphine- or cisplatin-induced emesis. METHODS: MNTX 0.25 mg/kg and morphine 1 mg/kg were administered to conscious dogs which were then challenged with the potent emetic agents apomorphine or cisplatin. Emesis was assessed by the presence of characteristic retching motions accompanied by the regurgitation of gastric contents. RESULTS: We observed that apomorphine challenges of 0.1 mg/kg and of 0.03 mg/kg produced 100% emesis in control animals. After pretreatment with MNTX and morphine, the frequency of emesis with the larger dose of apomorphine was reduced to 50% and with the smaller dose to 22%. MNTX alone did not block apomorphine-induced emesis. In animals challenged with cisplatin 3 mg/kg, the emetic response was 100%. Emesis did not occur in animals pretreated with MNTX 0.25 mg/kg and morphine 1 mg/kg before cisplatin. CONCLUSIONS: Our results demonstrate that MNTX combined with morphine reduces apomorphine-induced emesis and blocks cisplatin-induced emesis. These results support the hypothesis that the emetic effect of morphine is peripheral and its antiemetic action is central. In combination, MNTX and morphine may have a clinical role in the treatment of chemotherapy-induced emesis.

The effect of two anesthetic agents on norepinephrine and dopamine in discrete brain nuclei, fiber tracts, and terminal regions of the rat.

Catecholaminergic neurons have been implicated in the mechanism of general anesthesia, but previous attempts at measuring changes in adrenergic neuron function during anesthesia have been limited by techniques to whole brain. Microdissection techniques and sensitive radioisotopic-enzymatic assays were used to measure levels of catecholamines in 20 different nuclei, fiber tracts or nerve terminal regions in brains of rats anesthetized for 90-105 min with 1% halothane or 18% cyclopropane. These two anesthetics were chosen because of their diverse effects on the electroencephalogram and on the cardiovascular and respiratory systems. Of the areas examined, significant increases in norepinephrine content with both anesthetic agents were found only in the nucleus accumbens, locus coeruleus and central gray catecholamine areas. Only in the nucleus accumbens was the dopamine level increased by both anesthetics; cyclopropane, but not halothane anesthesia, also increased the dopamine content of the caudate nucleus, while halothane, but not cyclopropane anesthesia, significantly decreased the dopamine level of the ventral nucleus of the thalamus. Changes in levels of transmitters do not distinguish cause from effect of anesthesia, and further experiments are needed to delineate what role, if any, the specific areas play in muscle relaxation, analgesia, sleep or anesthesia. This study shows that a drug can affect one nucleus or region without significantly affecting other regions that contain the same transmitter substance, and that changes in transmitter levels can occur selectively in different regions of brain even if the nerve endings are derived from contiguous cell bodies.

Inhibition by halothane of release of norepinephrine, but not of dopamine-beta-hydroxylase, from guinea-pig vas deferens.

Halothane strikingly decreases spontaneous and electrically stimulated release of norepinephrine from the isolated guinea pig hypogastric nerve--vas deferens preparation. This depression of adrenergic discharge appears to be a direct action on the sympathetic nerve endings and may in part account for the cardiovascular depression seen during halothane administration. Although halothane depressed stimulation-induced release of norepinephrine, it did not proportionately diminish release of dopamine-beta-hydroxylase. Possible mechanisms of the dissociation between catecholamine and enzyme release are discussed.

Effect of prolonged treatment with adrenergic neuron blocking drugs on sympathoadrenal reactivity in rats.

The effects of repeated high doses of the adrenergic neuron blocking drug guanethidine or a hexahydropyrazinoindole compound (2-guanyl-1,2,3,10,10a, hexahydro-1,2,a-pyrazinoindole, EMD 21192) (30 mg/kg i.p., 21.5 mg/kg i.p. respectively, equimolar doses) on sympathoadrenal activity were investigated in normotensive adult rats. During treatment for 5 weeks with either guanethidine or EMD 21192 the systemic blood pressure fell steadily. Noradrenaline content in the heart and vas deferens were decreased markedly by guanethidine and to a much less degree by EMD 21192. EMD 21192 markedly lowers the catecholamine content of the adrenal medulla, presumably as a result of inhibition of dopamine-beta-hydroxylase. The plasma catecholamine concentrations reflected the different sites of action of the drugs in the sympathoadrenal system, i.e. guanethidine mainly reduced circulating norepinephrine and dopamine-beta-hydroxylase by more than 50%, whereas EMD 21192 decreased considerably by the total catecholamines (mainly epinephrine) without altering significantly in the plasma norepinephrine. Disappearance or reduction of fluorescent nerve endings in the iris and the heart and a decrease of the intensity of fluorescence in chromaffin cells of the adrenal gland caused by the drugs were consistent with the biochemical alteration. Whereas the repeated doses of guanethidine caused degeneration of sympathetic nerves, destruction of adrenergic neurons was not found after prolonged treatment with EMD 21192.

Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine.

Opioid compounds are commonly used analgesics. After opioid administration, troublesome subjective effects, such as dysphoria, dizziness, nausea, and pruritus, have been reported. While some if not all of these are believed to occur due to central nervous system effects of opioids, the anecdotal reports heard from volunteers in our other studies suggest that a peripheral opioid antagonist reduced some of these effects. In this double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone, a selective peripheral opioid receptor antagonist, to decrease subjective effects after administering morphine to normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on 'nauseous', 'skin itch', 'stimulated', and 'flushing'. Oral methylnaltrexone 19.2 mg/kg significantly decreased these four ratings. Plasma methylnaltrexone concentrations at two different oral doses were also measured to correlate between pharmacological effects of the compound and its plasma levels. Our results suggested that methylnaltrexone has a potential therapeutic value in decreasing some undesirable subjective effects associated with opioid medications.

The effect of educational gifts from pharmaceutical firms on medical students' recall of company names or products.

PURPOSE: To assess the influence of pharmaceutical advertising (in the form of books) directed at medical students and also to examine students' attitudes toward pharmaceutical representatives after interacting with them. METHOD: Two groups of fourth-year medical students were surveyed: 166 residency applicants to the Department of Anesthesia and Critical Care between 1991 and 1993, who were questioned during their personal interviews with the department chair, and 39 fourth-year students from the University of Chicago Pritzker School of Medicine in 1994-95, who were surveyed by telephone. The students were asked if they had ever received a book from a pharmaceutical representative and, if so, to name the book. Then they were asked to name the book-giving company or a product associated with the company. Responses were compared using chi-square analysis. RESULTS: In all, 90% of the students had received one or more books and accurately recalled titles for 89% of them. However, only 25% of the named books were accurately associated with a pharmaceutical company or product. The Pritzker students, asked to recall interactions with pharmaceutical representatives, reported being skeptical of representatives who ignored them because they were students, but they rated as helpful and informative those who conversed with them or gave them gifts. CONCLUSION: Although gifts to medical students do not necessarily engender company or product recall, attention paid to medical students by pharmaceutical representatives engenders goodwill toward the representatives and their messages.