The NHL-15 protocol for aggressive non-Hodgkin's lymphomas: a sequential dose-dense, dose-intense regimen of doxorubicin, vincristine and high-dose cyclophosphamide.

BACKGROUND: The NHL-15 protocol is a novel, dose-intense, dose-dense, sequential chemotherapy program developed to improve outcome in advanced, aggressive non-Hodgkin's lymphomas. PATIENTS AND METHODS: The phase II NHL-15 protocol comprised: (i) induction [doxorubicin 60 mg/m(2) i.v. on weeks 1, 3, 5 and 7 plus vincristine 1.4 mg/m(2) i.v. (no cap) on weeks 1, 2, 3, 5 and 7]; and (ii) consolidation (cyclophosphamide 3000 mg/m(2) i.v. on weeks 9, 11 and 13 plus granulocyte colony-stimulating factor 5 microg/kg subcutaneous on days 3-10 following each cyclophosphamide dose). Patients with aggressive non-Hodgkin's lymphomas (working formulation: intermediate grade or immunoblastic), bulky stage I and stages II-IV, were eligible. RESULTS: There are 165 eligible patients with a 6.9-year median follow-up (range 0.5-141 months) and a median age of 48 years. For the entire group, 72.1% achieved complete remission, and at 5 years disease-free survival was 57.8% and overall survival (OS) was 62.2%. Ideal dose delivery was >90%. Acute and late toxicities of treatment were manageable and acceptable. Toxic death on treatment was 2.4%. When the diffuse large cell lymphoma histologies were grouped according to the International Prognostic Index (IPI), complete remission and OS in the low-intermediate (LI), and high-intermediate (HI) risk groups were improved by 5%-15% compared with historical CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). This improvement was also noted for LI and HI risk groups in the age-adjusted (aa)IPI analysis for patients < or =60 years of age. CONCLUSIONS: The NHL-15 program can be administered safely and effectively to achieve high rates of durable remission when used for the treatment of advanced stage, aggressive, non-Hodgkin's lymphomas. The 5%-15% improvement in 5-year OS compared with historical CHOP, according to the IPI/aaIPI model (in LI and HI risk groups), is encouraging. Further evaluation and prospective testing of the NHL-15 protocol appears to be warranted.

Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery.

OBJECTIVES: We sought to determine whether early prophylaxis with an L -type calcium channel blocker reduces the incidence and morbidity associated with atrial fibrillation/flutter and supraventricular tachyarrhythmia after major thoracic operations. METHODS: In this randomized, double-blind, placebo-controlled study, 330 patients were given either intravenous diltiazem (n = 167) or placebo (n = 163) immediately after lobectomy (> or =60 years) or pneumonectomy (> or =18 years) and orally thereafter for 14 days. The primary end point with respect to efficacy was a sustained (> or =15 minutes) or clinically significant atrial arrhythmia during treatment. RESULTS: Postoperative atrial arrhythmias (atrial fibrillation/flutter = 60; supraventricular tachyarrhythmias = 5) occurred in 25 (15%) of the 167 patients in the diltiazem group and 40 (25%) of the 163 patients in the placebo group (P = .03). When compared with placebo, diltiazem nearly halved the incidence of clinically significant arrhythmias (17/167 [10%] vs. 31/163 [19%], P = .02). The 2 groups did not differ in the incidence of other major postoperative complications or overall duration or costs of hospitalization. No serious adverse effects caused by diltiazem were seen. CONCLUSIONS: After major thoracic operations, prophylactic diltiazem reduced the incidence of clinically significant atrial arrhythmias in patients considered at high risk for this complication.

Perioperative alterations in plasma endothelin-1 and echocardiographic correlates of right heart function.

OBJECTIVE: To determine whether greater changes in plasma endothelin-1 (ET-1) concentrations and right ventricular systolic pressure occur after major thoracic surgery than after major abdominal operations. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Patients undergoing elective thoracotomies (n = 12) or laparotomies (n = 10). INTERVENTIONS: ET-1 was measured from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). Transthoracic echocardiography was performed before surgery and on postoperative day 2 to evaluate right-sided heart function. MEASUREMENTS AND MAIN RESULTS: After abdominal and thoracic surgery, systemic and estimated pulmonary vascular pressures were normal in both groups and unaffected by surgery. Plasma ET-1 concentrations decreased from baseline values during the first postoperative week with no differences between the groups. CONCLUSIONS: In patients without organic heart disease, plasma ET-1 levels do not increase in response to major abdominal or thoracic surgery. Whether or not plasma ET-1 concentrations are elevated in patients developing clinically significant postoperative pulmonary hypertension requires further study.

Signal-averaged P-wave duration does not predict atrial fibrillation after thoracic surgery.

BACKGROUND: Atrial fibrillation (AF) is the most common dysrhythmia seen early after major thoracic surgery but occurs infrequently after minor thoracic or other operations. A prolonged signal-averaged P-wave duration (SAPWD) has been shown to be an independent predictor of AF after cardiac surgery. The authors sought to determine whether a prolonged SAPWD alone or in combination with clinical or echocardiographic correlates predicts AF after elective noncardiac thoracic surgery. METHODS: Of the 250 patients enrolled, 228 were included in the final analysis. Preoperative SAPWD was obtained in 155 patients who had major thoracic surgery and in 73 patients undergoing minor thoracic or other operations who served as comparison control subjects. The SAPWD was recorded from three orthogonal leads using a sinus P-wave template. The filtered vector composite was used to measure total P-wave duration. Clinical, surgical, and echocardiographic parameters were collected and patients followed for 30 days after surgery for the development of symptomatic AF. RESULTS: Symptomatic AF developed in 18 of 155 (12%) patients undergoing major thoracic surgery and in 1 of 73 (1%) patients having minor thoracic or abdominal surgery, most commonly 2 or 3 days after surgery. In comparison with similar patients undergoing major thoracic surgery without AF, those who developed AF were older (66+/-8 vs. 62+/-10 yr; P = 0.04) but did not differ in SAPWD (145+/-17 vs. 147+/-16, ms) in standard electrocardiographic P-wave duration (105+/-7 vs. 107+/-10 mns), incidence of left-ventricular hypertrophy on 12-lead electrocardiography, male sex, history of hypertension, diabetes, or coronary heart disease. Thoracic-surgery patients at risk for postoperative AF did not differ from all other patients at low risk for AF in clinical or SAPWD parameters. CONCLUSIONS: Under the conditions of this study, SAPWD did not differentiate patients who did or did not develop AF after noncardiac thoracic surgery, and therefore its measurement cannot be recommended for the routine evaluation of these patients. Older age continues to be a risk factor for AF after thoracic surgery.

Persistent alterations of the autonomic nervous system after noncardiac surgery.

UNLABELLED: BACKGROUND. Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both beta-adrenergic receptor (betaAR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. METHODS: The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine betaAR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. RESULTS: After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol-stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol-stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. CONCLUSIONS: Persistent downregulation and desensitization of the lymphocyte betaAR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at-risk period after major surgery appears to be about 1 week or more.

Effects of diltiazem versus digoxin on dysrhythmias and cardiac function after pneumonectomy.

BACKGROUND: This prospective study was designed to determine whether diltiazem is superior to digoxin for the prophylaxis of supraventricular dysrhythmias (SVD) after pneumonectomy or extrapleural pneumonectomy (EPP) and to assess the influence of these drugs on perioperative cardiac function. METHODS: Seventy consecutive patients without previous SVD were randomly allocated immediately after pneumonectomy or EPP to receive diltiazem (n = 35) or digoxin (n = 35). Diltiazem-treated patients received a slow intravenous loading dose of 20 mg, followed by 10 mg intravenously every 4 hours for 24 to 36 hours, then 180 to 240 mg orally daily for 1 month. Digoxin-treated patients received a 1-mg intravenous loading in the first 24 to 36 hours, then 0.125 to 0.25 mg orally daily for 1 month. A concurrent prospective cohort of 40 patients without previous SVD, who did not participate in the study and underwent pneumonectomy or EPP without prophylaxis, served as a comparison group for SVD occurrence. Serial Doppler echocardiograms were performed to assess cardiac function and all patients were continuously monitored with Holter recorders for 3 days. Data were analyzed by intent-to-treat. RESULTS: In patients undergoing standard or intrapericardial pneumonectomy, diltiazem prevented the overall incidence of postoperative SVD when compared with digoxin, 0 of 21 patients versus 8 of 25 patients, respectively, p < 0.005. When EPP patients were included in the analysis, diltiazem decreased the incidence of all SVD from 11 of 35 patients (31%) to 5 of 35 patients (14%) when compared with digoxin, p = 0.09. Digoxin-treated patients had a similar incidence of all SVD (31%) as concurrent controls (11 of 40 patients [28%]). The two treated groups did not differ in right or left atrial size, left ventricular ejection fraction, or right heart pressure. When all patients were combined, those in whom SVD developed were significantly older (65 +/- 12 years versus 55 +/- 11 years, p = 0.004) and had a longer median hospital stay (9 versus 6 days, p = 0.03), when compared with those in whom SVD did not develop, respectively. The subset of patients undergoing EPP had a greater incidence of atrial fibrillation and electrocardiographic changes suggestive of postoperative pericarditis than all other pneumonectomy patients. CONCLUSIONS: Diltiazem was both safe and more effective than digoxin in reducing the overall incidence of SVD after standard or intrapericardial pneumonectomy. Digoxin therapy had no effect on the incidence of postoperative SVD and is not recommended for prophylaxis of SVD. Dysrhythmias after pneumonectomy or EPP occur in older patients and are associated with a greater length of hospital stay.

Value of perioperative Doppler echocardiography in patients undergoing major lung resection.

BACKGROUND: The effects of major lung resection on right heart function have not been well established. Our goal was to evaluate these effects using serial Doppler echocardiography in the perioperative period. METHODS: In 86 patients undergoing lobectomy (n = 47) and pneumonectomy (n = 39), we examined the effects of pulmonary resection on perioperative changes in right heart function by transthoracic echocardiography. Serial echocardiograms were performed preoperatively, on postoperative day 1, and again between postoperative days 2 and 6 (median, 3 days) to evaluate cardiovascular function and to estimate right ventricular systolic pressure by the tricuspid regurgitation jet Doppler velocity method. RESULTS: Right or left atrial size, right atrial pressure, and estimated right ventricular systolic pressure did not differ between groups on the preoperative or postoperative day 1 examinations. However, on postoperative days 2 through 6 patients who underwent pneumonectomy had higher (mean +/- standard deviation) right ventricular systolic pressure values than lobectomy patients (31 +/- 15 versus 25 +/- 10 mm Hg, respectively; p < 0.05 by analysis of variance). In the subset of patients with percent predicted forced expiratory volume in 1 second less than 60% undergoing pneumonectomy (9/39), preoperative right ventricular systolic pressure was inversely correlated with percent predicted forced expiratory volume in 1 second values (r = -0.78; p < 0.04). This correlation was not significant in corresponding lobectomy patients. Postoperative right ventricular enlargement determined by echocardiography occurred with similar frequency in both groups and was associated with poor short-term prognosis in patients in whom severe respiratory failure developed. CONCLUSIONS: Preoperative indices of right heart function were within the normal range in both groups. Pneumonectomy but not lobectomy was associated with mild postoperative pulmonary hypertension that was not accompanied by significant right ventricular systolic dysfunction. Postoperative echocardiography may be useful to evaluate right heart function in critically ill patients after lung resection.

Clinical and echocardiographic correlates of symptomatic tachydysrhythmias after noncardiac thoracic surgery.

BACKGROUND: Supraventricular tachydysrhythmias (SVTs) following thoracic surgery occur with significant frequency and may be associated with increased morbidity. Prospective data on the etiology and importance of these dysrhythmias are sparse. METHODS: In 100 patients undergoing pulmonary resection without history of atrial dysrhythmias or previous thoracic surgery, we examined the effects of predefined risk factors by history, pulmonary function, and echocardiography on the incidence of postoperative SVT. Serial echocardiograms were performed preoperatively, on postoperative day 1, and again between postoperative days 2 to 6 (median = 3) to evaluate cardiovascular function and to estimate right ventricular systolic pressure (RVSP) by the tricuspid regurgitation jet (TRJ) Doppler velocity method. RESULTS: Symptomatic postoperative SVT occurred in 18 (18%) of the 100 patients studied at a median of 3 days after surgery and was disabling in 12 of 18 (67%). Digoxin loading was ineffective in controlling the ventricular response in 16 of 17 episodes. In the patients developing SVT, postoperative echocardiography revealed significant elevation of TRJ Doppler velocity (2.7 +/- 0.6 m/s vs 2.3 +/- 0.6 m/s, p < 0.05) but not right atrial or ventricular enlargement or right atrial pressure increase when compared with patients without SVT. Independent correlates of SVT determined in a stepwise logistic regression included intraoperative blood loss > or = 1 L (p = 0.0001) and a postoperative TRJ Doppler velocity > or = 2.7 m/s (p < 0.05). Patients who developed SVT had a higher rate of intensive care unit admission (p < 0.004), a longer hospital stay (p < 0.02), and higher 30-day mortality (p < 0.02). CONCLUSIONS: These prospective data suggest that increased right heart pressure but not fluid overload or right heart enlargement predisposes to clinically significant SVT after pulmonary resection. SVT may be an important marker of poor cardiopulmonary reserve in patients who develop significant morbidity after thoracic surgery. Early interventions to reduce right heart pressure may decrease the incidence of postoperative SVT and potentially improve overall surgical outcomes.

Clinical and pharmacology study of chloroquinoxaline sulfonamide given on a weekly schedule.

The in vitro human tumor colony-forming assay identified chloroquinoxaline sulfonamide (CQS) as an active agent at human plasma concentrations of > 100 micrograms/ml. In the initial phase I trial of CQS given every 28 days, peak plasma concentrations > 500 micrograms/ml were associated with reversible dose-limiting hypoglycemia and occasional cardiac arrhythmias. Therefore, we evaluated whether a weekly schedule of treatment might minimize the drug-associated toxicity while maintaining potential therapeutic concentrations. CQS was given intravenously over 1 h once per week for 4 weeks to 12 patients, beginning at a dose of 2,000 mg/m2. All patients underwent monitoring for cardiac arrhythmias and hypoglycemia. Plasma drug levels were measured following each dose. Mild hypoglycemia was the most common adverse effect. A median nadir plasma glucose concentration of 56 mg/dl was observed at a weekly dose of 2,500 mg/m2. Two patients experienced cardiac dysrhythmia while on study. Continuous electrocardiographic monitoring failed to identify any significant infusion-related arrhythmia. The median CQS plasma concentration measured 24 h following a 2,000-mg/m2 dose of CQS was > 100 micrograms/ml, and the cumulative area under the concentration x time curve (AUC) determined at concentrations of > or = 100 micrograms/ml was similar to that observed with the every-28-day schedule. The weekly schedule described herein appears to maximize the plasma AUC with an acceptable margin of safety. The recommended phase II dose and schedule for CQS is 2,000 mg/m2 given once per week. Although severe hypoglycemia is unlikely, glucose monitoring is appropriate for 6 h following CQS administration.

Simultaneous gallium-67 citrate and technetium-99m sestamibi SPET in a case of myocardial lymphoma: comparison with echocardiography before and after chemotherapy.

A patient with diffuse large cell lymphoma involving the interventricular septum and the inferior ventricular wall was imaged with a simultaneous dual-isotope single-photon emission tomography (SPET) acquisition technique, using the radiotracers technetium-99m hexakis 2-methoxyisobutylisonitrile (sestamibi) and gallium-67 citrate, in conjunction with echocardiography, prior to and following the first course of chemotherapy. Simultaneous acquisition--with the advantage of displaying corresponding sets of SPET slices without any need for position correction--, supplemented by echocardiography, increased the accuracy of evaluation of the extent of disease and response to treatment.

Evaluation of suspected deep venous thrombosis in oncologic patients.

Impedance plethysmography (IPG) and duplex scanning with color flow Doppler were performed in 100 consecutive high-risk patients with clinically suspected deep venous thrombosis. Risk factors included recent surgery (< three weeks) in 23%, malignant disease in 91%, clotting abnormalities in 32%, and limited activity in 70%. Lower limb findings of either edema, calf tenderness, or both occurred in 92%. There was agreement between the two tests in 76 patients (29 positive and 47 negative). In 12 patients the IPG was positive and the duplex negative. Four of these had extensive pelvic disease, 2 had lung cancer with an obstructive profile, and 2 had heart failure, all of which are known to cause false-positive IPG results. In the other 12 patients the IPG was negative and the duplex positive; however, 3 of these patients had nonocclusive thrombi, 5 had pelvic disease, and 1 had a hemiparesis of the involved lower limb. In 15 patients (11 with positive duplex studies and 4 with negative) a venogram was obtained and confirmed the results. All patients were followed up clinically and none developed complications suggesting inaccurate duplex results. In conclusion, the IPG is of limited utility in this population with a sensitivity of 71%, specificity of 80%, and false-negative rate of 29% when duplex Doppler and clinical outcome are used as the standard. Where available, duplex Doppler should be preferred for evaluation of suspected deep venous thrombosis in patients with extensive medical disease.

Clinical cardiotoxicity of 5-fluorouracil.

5-Fluorouracil is widely known to be toxic to the hematopoietic and gastrointestinal systems. It also has cardiac toxicity, but this is perceived to be rare. During a 16-month period from January 1990 through April 1991, approximately 910 patients were treated with 5-fluorouracil. Five of these developed life-threatening toxicity consistent with coronary artery spasm for an incidence of .55%. The acute events occurred on the third or fourth day of the 5-day infusion and after the fourth intravenous bolus in the patient on bolus therapy. Each of the patients had ST elevation and ventricular arrhythmias, four had acute myocardial infarction, and two had cardiac arrests. In these cases and those previously reported, cardiac toxicity is consistent with drug- or metabolite-mediated increases in coronary vasomotor tone and spasm, leading to the full spectrum of signs and symptoms of myocardial ischemia in susceptible individuals.

Tricuspid valve thromboembolus with recurrent pulmonary embolism--a case report.

The authors describe a fifty-one-year-old man with multiple pulmonary emboli in whom two-dimensional echocardiography clearly showed a large mobile thrombus transiently entrapped in the chordal apparatus of the tricuspid valve, a location rarely noted except in autopsy specimens. Subsequent lung scan and echocardiograms documented clinically silent nonfatal embolization of this large thrombus to the lungs. Whereas most patients with this form of thromboembolic disease come to either surgery or autopsy, this case demonstrates how the combination of echocardiography and lung scanning can be used to differentiate the etiology of some right-heart masses.

First-third ejection fraction: is the first-pass radionuclide method accurate?

Previous reports have suggested that left ventricular first-third ejection fraction (EF) can be obtained from the left ventricular time-activity curve derived from first-pass radionuclide angiography based on Anger camera data. The validity of this technique was assessed by: a study of beat-to-beat variations in data from 15 patients in which electrocardiographic data were simultaneously recorded, and a computer simulation incorporating the application of Poisson statistics to appropriate count rate data. The results of patients studies showed no consistent trend in any first-third parameter obtained from consecutive beats in individual subjects, and unacceptably high statistical uncertainty in the calculation of the first-third ejection fraction. The weighted standard deviation of the first-third ejection fraction in each of 15 patients studied averaged 7.5 EF units, while first-third ejection fraction averaged 22.9 EF units. The relative error averaged 32%. The computer simulation indicated a high relative error of 47% associated with the first-third ejection fraction at typical end-diastolic count rates of 200 per frame from 1,000 computer Poisson randomizations of an appropriate analog volume curve. The results render the first-pass radiocardiographic method invalid for determining first-third ejection fraction.

Unusual clinical and echocardiographic features of severe isolated pulmonic insufficiency.

A 57-year-old psoriatic man had severe, isolated pulmonic regurgitation, with intractable right sided failure. Echocardiography showed flail pulmonic leaflet and premature opening of the valve. Cardiac catheterization documented severe pulmonic regurgitation. The right ventricular end-diastolic pressure was elevated above the pulmonary artery diastolic pressure, thus explaining the echocardiographic finding. The patient was treated successfully by pulmonic valve replacement.