Guidelines for clinical investigator involvement in industry-sponsored clinical trials. SAEM Research Committee.
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Advisory Committees↗
Biomedical subjects
E A Panacek
Publications and source records attributed to E A Panacek.
Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Fenoldopam Study Group.
OBJECTIVE: To compare the safeties and efficacies of IV fenoldopam (FNP) vs sodium nitroprusside (NTP) in severe acute hypertension. METHODS: A prospective, randomized, open-label, multicenter international trial, at 24 academic medical centers, was conducted. The participants were adult patients (21-80 years of age) who had supine diastolic blood pressures (DBPs) > or = 120 mm Hg, were capable of written informed consent, and did not have selected exclusion criteria. The subjects were randomized to either FNP or NTP therapy; DBP was titrated to 95-110 mm Hg, or a maximum reduction of 40 mm Hg for very high pressures. Infusions were maintained for at least six hours, then the patients were weaned off the IV therapy and oral medication was started. Measurements included BP, heart rate, and duration of study drug infusion and frequency of side effects or complications. RESULTS: A total of 183 patients (90 FNP, 93 NTP) were enrolled. Fifteen patients from each arm were excluded from efficacy analysis due to protocol violation. There was no significant difference in baseline characteristics. The two antihypertensive agents were equivalent in controlling and maintaining DBP. Systolic blood pressure (SBP) was reduced to a slightly greater degree for the NTP-treated patients during the initial (0.5-1-hr) study period, and both SBP and DBP were reduced more for the FNP-treated patients in the subset receiving infusions during the 12-24-hour period. The adverse effect profiles of the drugs were similar, as were the times to achieve target pressure, with no clinically relevant difference. CONCLUSIONS: For patients who had acute severe hypertension, FNP and NTP were equivalent in terms of efficacy and acute adverse events. Because of a unique mechanism of action, FNP may have advantages in selected subsets of patients. Further studies may be indicated in patient populations with pure "hypertensive emergencies."
Acute Disease↗
HA-1A in septic patients with ARDS: results from the pivotal trial.
OBJECTIVE: To evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients with ARDS. DESIGN: Substudy of a multicenter, double-blinded, placebo-controlled trial of HA-1A in septic patients. PATIENTS: 63 septic patients with ARDS at the time of study entry. INTERVENTION: A single intravenous injection of HA-1A (100 mg) or placebo. RESULTS: A quantitative radiographic score, the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3, 5 and 7 days after treatment. The duration of endotracheal intubation did not differ between the two groups. 15 of 30 HA-1A treated patients (50%) and 23 of 33 placebo-treated patients (69.7%) died within 28 days. The daily mortality was always lower in the HA-1A group, but this difference was not statistically significant at 28 days. The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different (p = 0.07). Using logistic regression, a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days (p = 0.03) but not at 14 and 28 days. CONCLUSION: A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival.
Adult↗
An evaluation of the hemodynamic effects of HA-1A human monoclonal antibody.
OBJECTIVES: We sought to determine whether there might be acute changes in hemodynamics attributable to HA-1A, a monoclonal antibody to endotoxin, in patients with presumed Gram-negative sepsis. DESIGN: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled study. PATIENTS: A total of 543 patients with severe sepsis presumed to be caused by Gram-negative bacteria who were enrolled in a clinical trial to evaluate the efficacy and safety of HA-1A human monoclonal antibody. INTERVENTIONS: Patients were randomly assigned to receive either 100 mg of HA-1A or placebo. MEASUREMENT AND MAIN RESULTS: Patients were grouped by the study drug, HA-1A, or placebo, and the presence or absence of Gram-negative bacteremia. Hemodynamic variables were monitored from before, until 72 hrs after infusion of the study drug. For the entire study population (n = 543), no changes over time attributable to study drug were noted in the mean arterial pressure (p > .19), heart rate (p > .53) or the need for vasopressor administration (p > .62). One hundred ninety-seven patients underwent pulmonary artery catheterization and had hemodynamic data available from before the infusion of HA-1A or placebo until at least 12 hrs after infusion. Evaluating all 197 patients on an intent to treat basis demonstrated no significant differences over time in cardiac index (p > .15), oxygen delivery index (p > .43), or left ventricular stroke work index (p > .48) between patients who received HA-1A and those patients receiving placebo. Grouping patients by the presence of Gram-negative bacteremia and study drug received also failed to demonstrate any significant difference attributable to HA-1A in mean arterial pressure (p > .54), heart rate (p > .84), cardiac index (p > .13), oxygen delivery index (p > .05), or left ventricular stroke work index (p > .48) between populations. CONCLUSION: There is no apparent relationship between the administration of HA-1A, the presence of Gram-negative bacteremia, and hemodynamic profiles over the 72-hr study period.
Antibodies, Monoclonal↗
Fenoldopam mesylate versus sodium nitroprusside in the acute management of severe systemic hypertension.
Thirty-three patients with severe systemic hypertension defined as a diastolic blood pressure (DBP) > or = 120 mm Hg were randomized in a single-blind fashion to be treated with either intravenous fenoldopam mesylate (FNP) or sodium nitroprusside (NTP). Fenoldopam mesylate and NTP infusion rates began at 0.1 microgram/kg/minute and 0.5 microgram/kg/minute, respectively and were titrated to achieve a goal DBP of between 95 and 110 mm Hg; or a reduction of at least 40 mm Hg if the baseline DBP was > 150 mm Hg. Fenoldopam mesylate (n = 15) reduced blood pressure from 217/145 +/- 6/5 to 187/112 +/- 6/3 mm Hg (P < .001) at an average infusion rate of 0.5 +/- 0.1 microgram/kg/minute. The average time to achieve goal DBP with FNP was 1.5 +/- 1.4 hours. Nitroprusside (n = 18) reduced blood pressure from 210/136 +/- 5/2 to 172/103 +/- 6/2 mm Hg (P < .001) at an average infusion rate of 1.2 +/- .24 micrograms/kg/minute. Nitroprusside response time averaged 2 +/- 2.5 hours. There was no significant difference between the magnitude of effect seen with either FNP or NTP; nor was there any difference observed in the adverse effect rates of the two agents. Fenoldopam mesylate and NTP demonstrate similar overall efficacy in the treatment of severe systemic hypertension.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group.
OBJECTIVES: To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody in severe sepsis. DESIGN: Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). SETTING: Twelve academic medical center intensive care units in the United States and Europe. PATIENTS: Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti-TNF antibody. INTERVENTIONS: Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. MEASUREMENTS AND MAIN RESULTS: The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. CONCLUSIONS: The murine anti-TNF-alpha monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.
Antibodies, Monoclonal↗
Pilot study of anti-lipopolysaccharide human monoclonal antibody MAB-T88 in patients with gram-negative sepsis.
MAB-T88 is a human monoclonal IgM antibody directed at the lipopolysaccharide of gram-negative bacteria. A protocol was designed to identify a group of septic patients with a very high likelihood of gram-negative bacteremia. All 6 patients entered in the protocol had a gram-negative source, and 4 of 6 had gram-negative bacteremia. In this patient population, MAB-T88 was shown to be safe with an effective half-life of 19.1 hours.
Aged↗
Report of nitropatch explosions complicating defibrillation.
Reports of complications associated with the use of electrical defibrillators have been relatively rare. In two patients, defibrillation performed over a nitroglycerin skin patch resulted in electrical arcing with a resultant flash of light and thermal injuries. Skin burns as a complication of defibrillation over nitropatches has not been previously reported. Such burn injuries respond to standard therapeutic measures. Healthcare professionals who may perform defibrillation should be aware of this potential complication.
Administration, Cutaneous↗
Spontaneous pneumomediastinum: clinical and natural history.
STUDY OBJECTIVE: To evaluate the clinical characteristics and natural history of patients presenting with spontaneous pneumomediastinum. DESIGN: A retrospective case series was conducted to identify patients diagnosed with spontaneous pneumomediastinum. ICD-9 discharge codes were used for 1984 to 1990 at two institutions, and emergency department records of a third hospital were reviewed for 1981 to 1986. Clinical features, interventions, complications, setting, etiology, symptoms, and length of hospital stay were recorded. SETTING: Three university tertiary care hospitals. PARTICIPANTS: All ED patients more than 12 years old with a diagnosis of spontaneous pneumomediastinum. INTERVENTIONS: None. RESULTS: Seventeen cases were identified. Age range was 15 to 41 years (mean, 25 years). Presenting symptoms were chest pain in eight (47%), dyspnea in three (18%), both symptoms in three (18%), and neither in three (18%). Three patients complained only of throat discomfort. Nine (52%) had a Hamman's crunch, 11 (65%) had subcutaneous emphysema, and two (11%) had a small pneumothorax. Five (29%) were smokers, and five (29%) had normal esophograms. Thirteen of 17 (76%) cases were associated with illicit inhalation drug use. Twelve cases (70%) had history of a "Valsalva-type" maneuver. All but three were admitted to a hospital, with a mean stay of 2.5 days (range, one to six). No patient suffered complications or required interventions for spontaneous pneumomediastinum. Specifically, no patient developed a subsequent pneumothorax or airway compromise. The three patients not admitted were followed up by telephone contact. All did well with rapid resolution of their symptoms. CONCLUSION: Most spontaneous pneumomediastinum cases occur in the setting of inhalational drug use. One hundred percent of patients will have a symptom directly related to the spontaneous pneumomediastinum, with 82% presenting with either dyspnea or chest pain. Most (88%) will present with either subcutaneous emphysema or a Hamman's crunch on examination. Simple spontaneous pneumomediastinum has a very benign course and does not require hospitalization. Serial radiographs, likewise, did not change the medical management of spontaneous pneumomediastinum.
Administration, Inhalation↗
Comparative assessment of the effect of lomefloxacin, ciprofloxacin, and placebo on cerebral blood flow, and glucose and oxygen metabolism in healthy subjects by positron emission tomography.
The mechanism by which the fluorinated quinolones produce central nervous system (CNS) effects is currently unknown. We measured the effect of lomefloxacin on cerebral blood flow and metabolism using positron emission tomography. Eighteen healthy, nonsmoking volunteers were randomized to receive lomefloxacin 400 mg, ciprofloxacin 750 mg, or placebo given in a single-blind fashion every 12 hours for 72 hours, the time window for maximum lomefloxacin CNS effects. Subjects receiving lomefloxacin had a mean (+/- SEM) cerebral blood flow (CBF) of 46 (2.9) ml/min/100 g, glucose metabolism (FDG) 4.7 (0.4) mg/min/100 g, oxygen metabolism (OM) 3.3 (0.3) ml/min/100 g, and oxygen extraction (%OM) 0.4 (0.04). Posttreatment values were 43 (3.6) ml/min/100 g, 4.2 (0.4) mg/min/100 g, 2.6 (0.3) ml/min/100 g, and 0.4 (0.03), respectively. Values for subjects receiving ciprofloxacin were CBF 44.8 (1.6) ml/min/100 g, FDG 4.9 (0.7) mg/min/100 g, OM 4.1 (0.4) ml/min/100 g, and %OM 0.6 (0.03) at baseline, and 40.3 (3.5), 4.5 (0.6), 3.4 (0.4), and 0.5 (0.09), respectively, after treatment. For placebo-treated subjects, baseline values were CBF 41.4 (1.9) ml/min/100 g, FDG 4.9 (0.5) mg/min/100 g, OM 3.3 (0.4) ml/min/100 g, and %OM 0.5 (0.07), and respective posttreatment values were 42.1 (2.3), 5.0 (0.6), 3.5 (0.3), and 0.5 (0.02). No effect was observed on visual (qualitative), blinded reading of the scans. No significant effect on cerebral blood flow or metabolism was detected. We conclude that short-term administration of lomefloxacin or ciprofloxacin to healthy volunteers does not have a significant effect on cerebral blood flow, or on oxygen or glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Drug-induced supraventricular tachycardia: a case report of fluoxetine.
We report the occurrence of supraventricular tachycardia and hypotension in a 54-year-old woman after maintenance therapy with fluoxetine. Although cases of tachycardia and palpitations have been reported, supraventricular tachycardia and hypotension have not been directly attributed to fluoxetine.
Electrocardiography↗
Comparison of the effect of temafloxacin, ciprofloxacin, or placebo on cerebral blood flow, glucose, and oxygen metabolism in healthy subjects by means of positron emission tomography.
STUDY OBJECTIVE: To determine the cause of the central nervous system effect of the fluorinated quinolones temafloxacin and ciprofloxacin by measuring cerebral blood flow and metabolism by use of positron emission tomography. DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study. PATIENTS: The patients were 13 healthy, nonsmoking volunteers whose ages ranged from 18 to 40 years. RESULTS: We measured brain blood flow and metabolism by use of positron emission tomography before and after a five-dose course of 750 mg ciprofloxacin, 600 mg temafloxacin, or placebo given every 12 hours. Quinolone administration produced no significant effect on visual (qualitative) reading of the positron emission tomography scans. CONCLUSIONS: We conclude that short-term administration of temafloxacin, ciprofloxacin, or placebo does not significantly alter cerebral glucose or oxygen metabolism. Subjects treated with ciprofloxacin demonstrated a significant decrease in brain blood flow compared with baseline and with temafloxacin- or placebo-treated subjects.
Adolescent↗
Neuromuscular blockage in emergency medicine.
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Atracurium↗
A multicenter study of physicians' knowledge of the pulmonary artery catheter. Pulmonary Artery Catheter Study Group.
We administered a 31-question multiple-choice examination to 496 physicians practicing in 13 medical facilities in the United States and Canada to assess their knowledge and understanding of the use of the pulmonary artery catheter and interpretation of data derived from it. The mean test score was 20.7 (67% correct), with an SD of 5.4 and a range of 6 to 31 (19% to 100%). Mean scores varied independently by training, frequency of use of pulmonary artery catheter data in patient treatment, frequency of inserting a pulmonary artery catheter, and whether the respondent's hospital was a primary medical school affiliate. Given the variability in physician understanding of the pulmonary artery catheter, we believe that credentialing policies should be reevaluated and that consideration should be given to restricting its use to individuals with documented competency.
Canada↗
Assessment of intravenous fenoldopam mesylate in the management of severe systemic hypertension.
To evaluate the acute BP response to iv fenoldopam mesylate (FNP), 14 patients with severe hypertension (diastolic BP 120 to 170 mm Hg) were studied in an open-label trial. Initial infusion rate of FNP was 0.1 microgram/kg.min. Titration to diastolic BP goal (95 to 110 mm Hg) was followed by a constant infusion phase (greater than or equal to 6 h), a detitration phase (2 h), and a postinfusion phase. FNP reduced BP by 27/29 mm Hg (p less than .001) with no significant effect on heart rate. Maintenance of the BP effect was noted through the 6 h of constant rate infusion. Mild, transient vasodilating-associated adverse effects were noted with FNP. We conclude that FNP is an effective, well-tolerated iv antihypertensive agent for acute BP reduction in a severely hypertensive population.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome.
HA-1A, a human monoclonal immunoglobulin M antibody that binds specifically to the lipid A domain of endotoxin, was administered to septic patients to evaluate the safety, pharmacokinetics, and immunogenicity of the antibody. Thirty-four patients received a single infusion of either 25 mg, 100 mg, or 250 mg, and were followed clinically for 14 to 21 days after treatment. HA-1A serum levels were measured before infusion and frequently after infusion with a radiometric assay. A one-compartment pharmacokinetic model was fit to the measured serum levels, and accurately described the changes in HA-1A level over time in each dose group (r2 = .99). The mean +/- SEM apparent volume of distribution of HA-1A was 48.5 +/- 4.5 ml/kg, and the mean serum clearance was 2.8 +/- 0.4 ml/kg.h. The mean serum half-life of HA-1A was 15.9 +/- 1.5 h. The mean serum level one hour after a 100-mg dose was 33.2 +/- 2.4 micrograms/ml, and the mean concentration 24 h later was 9.1 +/- 1.6 micrograms/ml. The dose administered and presence of Gram-negative bacterial infection did not significantly influence the volume of distribution or serum clearance. No adverse reactions to HA-1A were observed, and no antibodies against HA-1A were detected in any patient. These data indicate that the pharmacokinetics of HA-1A are well described by a one-compartment pharmacokinetic model, and that HA-1A is safe and nonimmunogenic in patients with sepsis.
Adult↗
Hyperventilation-induced reduction in cerebral blood flow: assessment by positron emission tomography.
The use of positron emission tomography (PET) has been well documented as a relatively noninvasive method of measuring cerebral blood flow (CBF), both globally and regionally. The utility of readily detecting alterations in CBF is apparent, particularly when applied to the evaluation of therapeutic interventions thought to influence CBF. We report the effects of hypocapnia, an experimental condition of known cerebral vasoconstriction, in ten normal volunteers. Subjects had brain blood flow evaluated utilizing H215O as the positron emitter before and after approximately five minutes of hyperventilation. Baseline CBF was measured as a mean +/- SD of 61.2 +/- 16.3 mL/min/100 g of tissue. Mean baseline arterial blood gas values were PaO2 107.4 +/- 14 mm Hg, PaCO2 37.7 +/- 0.89 mm Hg, and pH 7.39 (calculated from mean [H+]). Post hyperventilation, global CBF was measured as 31.1 +/- 10.8 mL/min/100 g. Mean arterial blood gas values were PaO2 141.7 +/- 21 mm Hg, PaCO2 19.7 +/- 5 mm Hg, and pH 7.63 (calculated from mean [H+]). CBF decreased by a mean of 49.5 +/- 11 percent. Data analysis using the Student's t-test showed a significant change over baseline in PaCO2 (p less than 0.001) and CBF (p less than 0.001), in the hyperventilated state. Correlations were noted between the decrease in CBF and change in PaCO2 (r = 0.81) as well as between hyperventilation PaCO2 and the change in CBF (r = 0.97). We conclude that, as measured by PET, CBF decreases significantly during a state of artificial hyperventilation to a degree consistent with results seen using other methods. PET appears to be a valuable tool in the assessment of interventions that could influence CBF.
Cerebrovascular Circulation↗
Comparative acute blood pressure reduction from intravenous fenoldopam mesylate versus sodium nitroprusside in severe systemic hypertension.
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Adult↗