Biomedical subjects
Publications and source records attributed to H L Greene.
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Explore the source record for details and available documents.
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Anti-arrhythmic drug therapy is frequently used for the control of ventricular arrhythmias in the setting of heart disease. These agents have been used in many randomised clinical trials in an attempt to demonstrate improved survival. However, most studies have been disappointing, showing little or no improvement in survival, and, in some cases, deterioration. This report reviews ongoing clinical trials designed to evaluate survival in specific patient populations.
The current U.S. EPA standard for inorganic arsenic in drinking water is 50 ppb (microgram/L), dating to the National Interim Primary Drinking Water Regulation of 1976. The current EPA risk analysis predicts an increased lifetime skin cancer risk on the order of 3 or 4 per 1000 from chronic exposure at that concentration. Revision of the standard to only a few ppb, perhaps even less than 1 ppb, may be indicated by the EPA analysis to reduce the lifetime risk to an acceptable level. The cost to water utilities, and ultimately to their consumers, to conform to such a large reduction in the standard could easily reach several billion dollars, so it is particularly important to assess accurately the current risk and the risk reduction that would be achieved by a lower standard. This article addresses the major sources of uncertainty in the EPA analysis with respect to this objective. Specifically, it focuses on uncertainty and variability in the exposure estimates for the landmark study of Tseng and colleagues in Taiwan, analyzed using a reconstruction of the their exposure data. It is concluded that while the available dataset is suitable to establish the hazard of skin cancer, it is too highly summarized for reliable dose-response assessment. A new epidemiologic study is needed, designed for the requirements of dose-response assessment.
Whether patients with serious ventricular arrhythmias should be treated first with antiarrhythmic drugs or an implantable cardioverter-defibrillator (ICD) is not known. Many patients are ultimately treated with both an antiarrhythmic drug and on ICD. Early studies reported that 40-70% of patients who received an ICD were ultimately treated with an antiarrhythmic drug, although fewer patients are now being treated with both modalities. The beneficial interactions between antiarrhythmic drugs and an ICD are slowing of ventricular tachycardia, which yields improved hemodynamic tolerance; improved antitachycardia pacing and low energy cardioversion success; lowering of antiarrhythmic drug doses, which reduces the risk of side effects; limiting the number of arrhythmia episodes, which minimizes patients discomfort and prolongs ICD battery life; and preventing or slowing supraventricular tachyarrhythmias, which reduces the number of inappropriate shocks from the ICD. The disadvantages of combining pharmacologic therapy and the use of an ICD are the cost and side effects of both therapies. Adverse interactions between an ICD and antiarrhythmic drugs include slowed ventricular tachycardia, which may lead to failure to detect the arrhythmia; increased defibrillation and pacing thresholds; worsened hemodynamic tolerance of ventricular tachycardia; lengthened PR, QRS, or QT intervals causing multiple counting; and decreased size of the intracardiac electrogram, leading to failure to detect the ventricular tachycardia or fibrillation. Caution must be used when combining pharmacologic therapy with an ICD. Repeat electrophysiologic testing is frequently necessary after the initiation of antiarrhythmic drug therapy in a patient with an ICD to ensure successful therapy with the ICD.
Preterm infant formulas (PIFs) for very-low-birth-weight (VLBW) infants (birth weight, < 1,500 g) are augmented to provide daily riboflavin and pyridoxine at levels up to five-fold greater than in term infant formula and 18-fold greater than in human milk. We evaluated plasma riboflavin and pyridoxine concentrations in VLBW infants who received PIF during their first postnatal month. Eighty-eight plasma and 124 urine samples were collected for riboflavin- and pyridoxine-concentration measurements from 57 clinically healthy VLBW infants weekly during their first postnatal month. Concentrations were measured using high-performance liquid chromatography. At the time of the sample, patients were receiving > or = 80% of their total calories via enteral feedings. Plasma riboflavin concentrations rose from 45.3 +/- 7.3 ng/ml at baseline (mean +/- SEM) to 173.5 +/- 20.3 ng/ml by 1 week of age and remained at 177.3-199.7 ng/ml during the following three weekly measurements; values were up to 14-fold above baseline concentration. Urine riboflavin concentration increased from 534 +/- 137 ng/ml at baseline to 3,521 +/- 423 ng/ml by 1 week of age and remained at 4,451-5,216 ng/ml during the next 3 weeks. In a similar pattern, baseline plasma (69.4 +/- 10.4 ng/ml) and urine (145 +/- 30 ng/ml) pyridoxine concentrations were significantly increased by 1 week postnatal age; they remained at 163-248 ng/ml (plasma) and 1,573-2,394 ng/ml (urine) through the first postnatal month. Plasma and urine riboflavin and pyridoxine concentrations in enterally fed VLBW infants increased from baseline concentrations by 1 week of postnatal age and remained elevated for the first postnatal month. High daily intake and immature renal development are probable contributing causes of the elevated plasma riboflavin and pyridoxine concentrations. We suggest that lower daily enteral administration of riboflavin and pyridoxine should maintain adequate blood concentrations and minimize potential toxicity.
Holter data from the 17,609 postmyocardial infarction patients in the CAST Registry were analyzed to study the effect of age on VPC and VT incidence and frequency. Multivariable analysis demonstrated that age is an important independent predictor of increased ventricular ectopy, with the median rate of VPCs/hour increasing from 0.4 (patients aged < 50 years) to 4.0 (patients aged 75 to 80 years), and the prevalence of VT increasing from 7.3% (patients aged < 50 years) to 15.3% (patients aged 75 to 80 years).
All transthoracic defibrillators on the US market use nominally monophasic shock waveforms. However, biphasic waveforms have a lower defibrillation threshold than monophasic waveforms for transthoracic defibrillation of animals and for defibrillation of humans by implantable cardioverter defibrillators. The relative efficacies of Edmark monophasic and Gurvich biphasic transthoracic cardioversion waveforms (200 J into 50 omega) were compared for transthoracic cardioversion in 171 patients undergoing electrophysiologic study for evaluation of ventricular arrhythmias. Patients were randomized in a blinded fashion to receive either a monophasic or a biphasic waveform for the initial shock for conversion of induced ventricular arrhythmias (ventricular fibrillation [VF] = 53, monomorphic ventricular tachycardia [VT] = 80, polymorphic VT = 30, ventricular flutter = 8). Delivered energies for the Edmark and Gurvich waveforms were 215 +/- 11 and 171 +/- 11 J, respectively. There were no significant differences in patient characteristics, use of antiarrhythmic agents, arrhythmia cycle length, or duration of arrhythmia prior to shock for monophasic and biphasic waveform groups. The first shock for all arrhythmias was successful in 75 of 88 patients (85.2%) for the monophasic waveform compared with 81 of 83 patients (97.6%) for the biphasic waveform, p = 0.0054. The first shock for VF was successful in 22 of 28 patients (78.6%) for the monophasic waveform compared with 25 of 25 (100%) for the biphasic waveform, p = 0.0241. The Gurvich biphasic waveforms delivering a mean of 171 J were superior to Edmark monophasic waveforms delivering a mean of 215 J for transthoracic cardioversion of arrhythmias of short duration. This finding may have important implications for the development of future transthoracic defibrillators.
The Antiarrhythmics Versus Implantable Defibrillators (AVID) study compares a strategy of initial treatment with an implantable cardioverter-defibrillator (ICD) to a strategy of initial treatment with an antiarrhythmic drug to prevent death in patients with a history of ventricular fibrillation or hemodynamically compromising ventricular tachycardia, or both. Neither arrhythmia can have been due to a transient or correctable cause. The principle exclusions are a contraindication to amiodarone therapy and inability to undergo ICD implantation. Antiarrhythmic drug therapy includes empiric amiodarone and guided sotalol. The ICDs allowed are advanced generation devices, and most are implanted transvenously. The primary end point of the study is total mortality. Secondary end points are cost and quality of life. The study was designed in 2 phases. The pilot phase enrolled 200 patients between June 1993 and June 1994. Data collected during the pilot phase confirmed that the trial is feasible. An additional 1,000 patients will be enrolled between June 1994 and March 1997. It is anticipated that all 1,200 patients will be followed until September 1998, and will be included in the intention-to-treat analysis.
In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.
OBJECTIVES: We studied the relations between heart failure, ejection fraction, arrhythmia suppression and mortality. BACKGROUND: Both left ventricular ejection fraction and functional class of heart failure are strongly associated with mortality after acute myocardial infarction. Both are also related to the presence of ventricular arrhythmias and have been identified as factors related to the ability to suppress ventricular arrhythmias. Little has been reported about the relations between these two factors and arrhythmia suppression or mortality. METHODS: Baseline data from the Cardiac Arrhythmia Suppression Trial were used to define several categories of heart failure and to relate both the resulting categories and ejection fraction to arrhythmia suppression and mortality using logistic and survival regression analytic methodologies. RESULTS: Regardless of the prospective baseline definition of heart failure used, the data consistently showed that heart failure was a more powerful predictor of subsequent congestive heart failure events and arrhythmia suppression and was equally powerful in predicting death. However, each variable provided incremental information when included in the prediction model. Heart failure and ejection fraction appeared to be independent predictors of death. Interactions were observed: A low ejection fraction was more predictive of failure of arrhythmia suppression in patients with than without evidence of heart failure before or at baseline; a low ejection fraction was more predictive of subsequent congestive heart failure events in patients without than with evidence of heart failure before or at baseline. CONCLUSIONS: Although heart failure as a prognostic feature appears to be somewhat superior to ejection fraction, both are powerful predictors of arrhythmia suppression and cardiac events in patients with ventricular arrhythmia after myocardial infarction. Each provides incremental prediction.
OBJECTIVE: To improve breast cancer screening skills, practicing non-academic primary care physicians were offered an opportunity to participate in a one-hour private skills-assessment session with a patient instructor. Research questions included: would physicians in non-academic practice be interested in a skills course; would the course improve their skills in breast examination and/or in counseling for mammography; and if they did improve, would the effect endure? DESIGN: Pilot study with cohort follow-up. INTERVENTIONS: Physicians were offered an opportunity to have their counseling and physical examination skills evaluated in a one-on-one interaction with standardized patients. The protocol included patient instructors who were trained to use a uniform breast health history that emphasized their increased risk of breast cancer, scant knowledge of breast-cancer screening, and fear of medical tests and cancer. The standardized patients were trained using a 77-point checklist. They demonstrated a high degree of consistency and reproducibility. A critical part of the learning experience was immediate feedback to the physicians regarding their performances. Physicians who took the course were given an opportunity to repeat it approximately 18 months later. MEASUREMENTS AND MAIN RESULTS: Of the 82 primary care physicians in the community, 49 (60%) were eligible to have their skills evaluated. Of these, 38 (77.6%) participated in the intervention. Baseline skills had mean scores (correct responses) better than 50% in most aspects of the physical examination but less than 35% in several critical counseling areas: reviewing mechanics of getting mammography, actually recommending mammography, and directing the patient regarding scheduling. Of the 38 physicians, 15 repeated the course. There was a significant improvement in their overall performance: 49% vs 67% (p = 0.002). CONCLUSIONS: Primary care physicians in a non-academic practice are interested in reviewing and improving their counseling skills. They are capable of improving their skills after receiving background information, instruction, and brief feedback. They maintain these improvements over time.
The implantable cardiac defibrillator was first used in 1980 and has gained widespread acceptance. However, no randomized controlled trials have been reported that compare the implantable cardiac defibrillator with antiarrhythmic drugs. Most published studies have used historical control subjects or nonrandomized concurrent patients for comparison with patients who received an implantable defibrillator. To reduce bias, studies are needed that compare therapies randomized between antiarrhythmic drugs and implantable defibrillators. The Antiarrhythmics Versus Implantable Defibrillators (AVID) Study was designed to evaluate the nonthoracotomy, tiered-therapy implantable defibrillator compared with drug therapy (amiodarone or sotalol). Patients are eligible for randomization if they have a history of recent cardiac arrest caused by ventricular fibrillation or have hemodynamically serious ventricular tachycardia. A pilot study to enroll 200 patients began on June 1, 1993, before the start of the main study of 1000 patients. Analysis of the main study by intention to treat will assess the primary endpoint of total mortality.
OBJECTIVES: The purpose of this study was to assess the effect of antiarrhythmic drugs on the timing of arrhythmic death. BACKGROUND: Sudden cardiac death remains a problem of epidemic proportions. Delineating its pathophysiology is an important step in devising preventive measures. Previous studies have shown a circadian pattern of onset of sudden cardiac death. The effect of antiarrhythmic drugs on this pattern has not been systematically studied. METHODS: The Cardiac Arrhythmia Suppression Trial (CAST) was a multicenter double-blind, placebo-controlled study designed to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs (encainide, flecainide or moricizine) after acute myocardial infarction would reduce the incidence of arrhythmic death. RESULTS: The trial was terminated prematurely because of an unexpectedly high mortality rate in the active treatment group. The onset of arrhythmic death in this group (in patients not receiving beta-adrenergic blocking agents) displayed a bimodal variation, with significant peaks in midmorning and late afternoon/early evening. More than half of the symptomatic events were accompanied by anginalike symptoms. Approximately 30% of all events occurred within 2 h of awakening. CONCLUSIONS: Our data suggest the possibility of a complex interaction among antiarrhythmic drugs, sympathetic nervous system activation and acute myocardial ischemia. Planning of future antiarrhythmic drug trials will need to take this information into account.
The Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) study evaluated antiarrhythmic drug therapy in patients who had survived an episode of out-of-hospital ventricular fibrillation (VF) and who were thought to be at high risk for recurrence of VF. Therapy with empiric amiodarone was compared to therapy with other antiarrhythmic agents, guided by electrophysiologic testing and/or Holter recording. The study evaluated the endpoints of (1) cardiac death, (2) cardiac arrest from ventricular fibrillation with resuscitation, and (3) complete syncope followed by a shock from an automatic implanted defibrillator that restored consciousness. The study comprised 228 patients, 113 treated with amiodarone and 115 treated with conventional antiarrhythmic drug therapy. Most patients had coronary artery disease with a prior myocardial infarction, and one half of the population had a history of congestive heart failure. The mean left ventricular ejection fraction was 35%. Survival was better in patients treated with amiodarone than in patients treated with other antiarrhythmic agents. Patients treated with amiodarone were less likely to receive a shock from an implanted defibrillator, and syncope followed by a shock from a defibrillator was less common in patients treated with amiodarone. However, overall mortality was high, and side effects of therapy were common. Patients treated with amiodarone, even at the low doses used in this study, were still at risk for thyroid dysfunction (both hyperthyroidism and hypothyroidism) and for pulmonary toxicity.
An 18-month-old boy with Gaucher's disease, massive hepatosplenomegaly, and hypersplenism underwent partial (85%) splenectomy and recovered without complication. During the next 4 months, his residual splenic segment showed progressive enlargement from 2 to 6 cm below the left costal margin. By this time, genetic typing had indicated central nervous system involvement (type III). A compatible donor was not available for bone marrow transplantation. Complete splenectomy was not recommended despite continued enlargement of the organ into the pelvis and across the abdominal midline by 7 1/2 months postoperatively. The next week he presented to the emergency room in shock with an hematocrit of 6% and a platelet count of 18,000/mm3. During emergency surgery, massive intraabdominal hemorrhage was noted from a splenic rupture on the inferior pole that was opposite the site of prior division. He died in the operating room during attempted splenectomy. This is a report of fatal outcome after partial splenectomy for type III Gaucher's disease. Patients with subacute neuronopathic disease may not be candidates for subtotal splenectomy.
OBJECTIVES: The aim of this study was to determine the efficacy of implantable cardioverter-defibrillator (ICD) therapy in survivors of sudden cardiac death in whom no ventricular arrhythmias can be induced with programmed electrical stimulation. BACKGROUND: Survivors of sudden cardiac death in whom ventricular arrhythmias cannot be induced with programmed electrical stimulation remain at risk for recurrence of serious arrhythmias. Optimal protection to prevent sudden death in these patients is uncertain. This study compares survival in the subset of survivors of sudden cardiac death with that of patients treated with or without an ICD. METHODS: A retrospective study was performed on 194 consecutive survivors of primary sudden death who had < or = 6 beats of ventricular tachycardia induced with programmed electrical stimulation with at least three extrastimuli. Ninety-nine patients received an ICD and 95 did not. RESULTS: There were no significant differences between the two groups in presenting rhythm, number of prior myocardial infarctions or use of antiarrhythmic agents. Patients treated with an ICD were younger (55 +/- 16 vs. 59 +/- 11 years, p = 0.03) and had a lesser incidence of coronary artery disease (48% vs. 63%, p = 0.04) and a lower ejection fraction (0.43 +/- 0.16 vs. 0.48 +/- 0.18, p = 0.04). There were no significant differences between the groups in the use of revascularization procedures or antiarrhythmic agents after the sudden cardiac death. Patients treated with an ICD had an improvement in sudden cardiac death-free survival (p = 0.04) but the overall survival rate did not differ from that of the patients not so treated (p = 0.91). A multivariate regression analysis that adjusted for the observed differences between the groups did not alter these results. CONCLUSIONS: Survivors of sudden cardiac death in whom no arrhythmias could be induced with programmed electrical stimulation remained at risk for arrhythmia recurrence. Although the proportion of deaths attributed to arrhythmias was lower in the patients treated with an ICD, this therapy did not significantly improve overall survival.