Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients.

Eight patients with refractory ovarian cancer were treated on a pilot protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH). This trial was based on our previous laboratory studies which demonstrated that Adriamycin resistance in human ovarian cancer cell lines could be partially reversed by exposure of the cells to high concentrations of verapamil (3,000 ng/mL). Patients were treated in an intensive care unit with continuous cardiovascular monitoring. The dose of verapamil was escalated in each patient until hypotension or heart block developed, and this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused over 24 hours during the second day of the verapamil infusion and verapamil alone was administered on the third day in an effort to block efflux from drug-resistant cells. This intensive approach led to a median plasma verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high infusion rates of verapamil (9 micrograms/kg/min) required to achieve these plasma levels produced an unacceptable degree of cardiac toxicity. Two patients developed transient atropine-responsive complete heart block and four patients developed transient congestive heart failure with increases in pulmonary capillary wedge pressure. There was no evidence that the noncardiac toxicities of Adriamycin were enhanced by verapamil. There were no objective responses to therapy. Future studies should use less cardiotoxic calcium channel blockers that can be safely administered to produce the plasma levels required for in vitro sensitization of drug resistant cells.

Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer.

PURPOSE: To increase the taxol dose beyond the current standard dose intensity of 175 mg/m2 per 21 days in patients with refractory ovarian cancer. PATIENTS AND METHODS: Fifteen patients who had platinum-refractory or recurrent advanced-stage ovarian cancer were treated with taxol in a phase I trial and were given granulocyte-colony stimulating factor (G-CSF). Taxol was administered at doses of 170, 200, 250, and 300 mg/m2 every 3 weeks. G-CSF was given as a daily subcutaneous injection that started 24 hours after the completion of the taxol infusion. RESULTS: Four patients required either taxol dose reduction or delay. The dose-limiting toxicity (DLT) was peripheral neuropathy, and it occurred at 300 mg/m2. This toxicity was manifested clinically as a stocking-and-glove sensory disturbance that primarily affected proprioception, and was associated with objective changes on nerve conduction studies in affected individuals. Mucositis was rarely observed. Substantial myelosuppression was observed, but was not dose-limiting. Five of 14 assessable patients experienced an objective response to therapy, with another five individuals who experienced a 30% to 45% reduction in tumor mass. CONCLUSION: Taxol can be safely administered in doses up to 250 mg/m2 with G-CSF support, which may make it possible to study taxol dose intensification.

Dynamic limitation of coronary vasodilator reserve in patients with dilated cardiomyopathy and chest pain.

Twenty-six patients with dilated cardiomyopathy and angiographically normal coronary arteries, 12 of whom gave a history of anginal chest pain, underwent noninvasive and invasive hemodynamic study. During treadmill exercise testing, patients with a history of angina demonstrated worse effort tolerance (7.4 +/- 4.9 versus 13.6 +/- 5.1 minutes, p less than 0.005) and a lower end-exercise systolic blood pressure-heart rate product (17.9 +/- 3.4 versus 23.6 +/- 4.9 mm Hg.beats/min x 10(3), p less than 0.005) compared with patients without a history of angina. During rapid atrial pacing after ergonovine, 0.15 mg intravenously, 11 of the 12 patients with a history of angina experienced their typical chest pain, in contrast to only 1 of 12 patients without a history of angina. The angina group, compared with the nonangina group, had significantly lower great cardiac vein flow (118 +/- 24 versus 160 +/- 43 ml/min, p less than 0.01), and higher coronary resistance (0.87 +/- 0.21 versus 0.66 +/- 0.25 mm Hg.min/ml, p less than 0.05), significant widening of the arterial--great cardiac vein oxygen difference and a significant fall in cardiac index during pacing. Further, ergonovine resulted in higher coronary resistance during pacing in the angina group compared with pacing alone (+0.16 +/- 0.16 mm Hg min/ml, p less than 0.01), in the absence of significant reduction in epicardial coronary artery luminal diameter. After dipyridamole, 0.5 to 0.75 mg/kg intravenously, to 21 patients, the 7 patients with a history of angina had significantly lower flow (149 +/- 37 versus 218 +/- 73 ml/min, p less than 0.05) and higher coronary resistance (0.59 +/- 0.09 versus 0.43 +/- 0.17 mm Hg.min/ml, p less than 0.05) than did the nonangina group. It is concluded that patients with dilated cardiomyopathy and chest pain unrelated to epicardial coronary artery disease exhibit impaired vasodilator responses to both metabolic and pharmacologic stimuli, and an increased sensitivity to the vasoconstrictor effects of ergonovine. Whether these findings are of etiologic or long-term prognostic significance is unknown.

Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome.

The prevalence of myocarditis was retrospectively evaluated in 71 consecutive necropsy patients who died from acquired immunodeficiency syndrome (AIDS) between 1982 and 1986. Myocarditis was found in 37 cases (52%). Biventricular dilation at necropsy was present in seven cases (10%) and was accompanied by myocarditis in each case; fatal congestive heart failure occurred in four of these seven cases. Although viral, protozoan, bacterial, fungal and mycobacterial opportunistic pathogens were present in myocardial sections of 7 of 37 myocarditis cases, the etiology of myocarditis in the majority of these patients with AIDS remained idiopathic. Thus, myocarditis is a frequent finding at necropsy in patients with AIDS and may contribute to the development of biventricular dilation.

Erysipelothrix rhusiopathiae bacteremia presenting as septic shock.

Erysipelothrix rhusiopathiae rarely causes bacteremia, and it has never been reported to cause septic shock. A 58-year-old man with fulminant hyperdynamic shock associated with E. rhusiopathiae bacteremia is described. Erysipelothrix must be considered when a patient with an appropriate history presents with septic shock.

Frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immune deficiency syndrome.

To evaluate possible relations between clinical and histopathologic cardiac findings in patients with the acquired immune deficiency syndrome (AIDS), 58 consecutively autopsied AIDS patients were reviewed retrospectively. Twenty-six (45%) had histopathologic myocarditis. Fifteen of these 26 (58%) had greater than or equal to 1 clinical cardiac abnormalities: 6 had congestive heart failure or left ventricular (LV) dysfunction, or both, 4 had ventricular tachycardia (VT), 10 had electrocardiographic abnormalities and 4 had pericardial abnormalities. Of the 32 patients without myocarditis, 6 (19%) had pericardial or electrocardiographic abnormalities, or both, but none had congestive heart failure, LV dysfunction or VT. Overall, clinical cardiac abnormalities were found in 21 patients (36%). Patients with myocarditis had a significantly higher incidence of clinical cardiac abnormalities than patients without myocarditis (58 vs 19%, p less than 0.01). All patients with congestive heart failure, LV dysfunction or VT had myocarditis. Thus, serious clinical cardiac abnormalities were common in patients with AIDS and were associated with myocarditis.

The effect of tumor necrosis factor on vascular smooth muscle. In vitro studies using rat aortic rings.

The mechanisms of vasodilation in septic shock have not been well elucidated. We used isolated rat aortic rings as an in vitro model of vascular reactivity to assess the acute, direct effects on vascular smooth muscle relaxation of four cytokines: interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), and tumor necrosis factor (TNF). The rings were precontracted with catecholamines and then test cytokines were added. The changes in tension with IL-1 at 1,000 U/ml, IL-2 at 1,000 U/ml, and IL-6 at 500 U/ml differed from controls by -67 +/- 59, -5 +/- 42, and 8 +/- 56 mg/mg of tissue, respectively (for each, n = 10, p = NS). The change in tension with TNF at 1,000 U/ml differed from controls by -176 +/- 42 mg/mg of tissue (n = 20), p less than 0.001). Chemical removal of the endothelium with deoxycholate diminished TNF-induced vasodilation to -62 +/- 14 mg/mg of tissue (p less than 0.05). The relaxation with TNF occurred in a concentration-dependent fashion and was unaffected by indomethacin. This study demonstrates that TNF has an acute, concentration-dependent, cyclooxygenase-independent, vasodilatory effect on vascular smooth muscle. The effect of TNF was partially, but not fully, dependent on the presence of an intact endothelium, implying that TNF acts on both the endothelium and the smooth muscle. These findings suggest that TNF may play an important role in the vasodilation characteristic of septic shock.

Late recurrent Candida endocarditis.

Late recurrent Candida endocarditis (LRCE) developed on a prosthetic mitral valve 22 months after treatment for primary native mitral valve endocarditis. The LRCE was difficult to diagnose; results of two dimensional echocardiography and repeated blood cultures were negative. Only transesophageal echocardiography revealed a vegetation and only lysis centrifugation blood cultures demonstrated candidemia. Postmortem examination revealed a large Candida vegetation on the prosthetic valve and Candida in the mitral valve ring. This case and a review of the literature indicate that Candida endocarditis treated with amphotericin B and prosthetic valve replacement may recur months after treatment, and that LRCE, which is difficult to diagnose and treat, may be best prevented by lifelong antifungal suppressive therapy.

A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock.

Using spontaneously beating rat myocardial cells as an in vitro model of myocardial depression, recent studies demonstrated that septic shock patients' sera frequently contain a myocardial depressant substance (MDS) that is associated with a reversible decrease in left ventricular ejection fraction (LVEF). To further characterize MDS, 50 consecutive patients with possible septic shock were studied serially from shock onset until recovery or death. Thirty-four patients had criteria diagnostic of septic shock, and 16 had a nonseptic critical illness. Of the 34, 14 met strict criteria for circulating MDS, with a mean inhibition of 35 percent (range 20 percent to 62 percent). Compared with those patients not exhibiting significant MDS activity, the 14 MDS-positive patients had a lower mean minimal EF (28 percent vs 39 percent, p less than 0.01), a greater mean decrease in EF (22.1 percent vs 8.8 percent, p = 0.002), a higher pulmonary artery wedge pressure (16.8 vs 11.9 mm Hg, p less than 0.01), greater LV dilatation (162 vs 118 ml/m2, p = 0.02), and a higher circulating mean peak lactic acid (6.9 vs 2.7 mmol/L, p less than 0.01). In the 14 MDS-positive patients, the in vitro myocardial cell depression had a negative correlation with the in vivo EF (r = -060, p less than 0.05). These findings suggest that a circulating MDS is a cause of the myocardial depression frequently accompanying human septic shock.

Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin.

Endotoxin is a major mediator of the life-threatening cardiovascular dysfunction that characterizes Gram-negative sepsis. In animal models of endotoxemia, pretreatment with ibuprofen or pentoxifylline attenuates some of these cardiovascular changes. To evaluate the effects of these agents on the human cardiovascular response to endotoxemia, hemodynamic variables were measured serially in 24 normal subjects who were given intravenous endotoxin. The subjects were randomized to receive oral ibuprofen (n = 9), pentoxifylline (n = 10), or no medication before endotoxin administration (n = 5). The subjects were volume loaded 3-5 h after endotoxin administration, and hemodynamic measurements were reassessed. Core temperature after endotoxin alone or endotoxin-pentoxifylline approached a maximum at 3 h (greater than or equal to 38.6 degrees C), while the endotoxin-ibuprofen group remained afebrile. At 3 and 5 h, all three groups had significant increases in heart rate, cardiac index, oxygen delivery, and oxygen consumption, while systemic vascular resistance index decreased significantly from baseline. The oxygen extraction ratio remained unchanged. After volume loading, the left ventricular ejection fraction and left ventricular end-diastolic and end-systolic volume indexes did not differ among the groups. The hyperdynamic cardiovascular response to endotoxin in humans occurs in the absence of fever and is not significantly ameliorated by oral cyclooxygenase or phosphodiesterase inhibition.

Endothelial and vascular smooth muscle function in sepsis.

The vascular abnormalities that arise during sepsis imply disturbances in the delicately tuned homeostatic mechanisms of vascular endothelium and smooth muscle. In the microvasculature, smooth muscle tone represents a complex equilibrium among metabolic stimuli, hemodynamic forces, and neurohumoral influences. Local tissue perfusion also is modulated by vasoactive mediators that can be produced locally, through endothelium-dependent adhesion and activation of inflammatory cells, or at a distance. In sepsis, derangement of normal autoregulation of perfusion, together with toxic effects of mediators, may be severe enough to result in organ dysfunction. Recent advances in vascular biology have illuminated a variety of targets, such as adhesion molecules, platelet activating factor, and inducible nitric oxide synthase for potential therapeutic intervention in sepsis.

Validation of continuous thermodilution cardiac output in critically ill patients with analysis of systematic errors.

PURPOSE: Bolus thermodilution cardiac output (BCO) measurements are affected by variations in injectate volume, rate, and temperature. These variations are eliminated when CO is measured by a continuous automated thermal technique (CCO). Further, CCO eliminates the need for fluid boluses, reduces contamination risk, requires no operator, and provides a continuous CO trend. We prospectively evaluated CCO versus BCO in a population of critically ill adults with low, normal, and high CO states. We sought to discern any systematic effects of temperature fluctuations or signal-to-noise-ratios (SNR) on disparities between BCO and CCO measurements and also sought to assess the relative cost effectiveness of the CCO system. MATERIALS AND METHODS: Pulmonary artery catheterizations were performed in a convenience sample of 20 patients over 6 months. BCO data were obtained using a standardized protocol. Three bolus injections of 5% dextrose were given when each CO was within 10% of the median before averaging; otherwise five boluses were given, with the high and low values eliminated before averaging. Injectates were administered randomly through the respiratory cycle and at 1-minute intervals. CCO measurements were recorded from a Vigilance monitor pre and post BCO measurements, yielding an average CCO value. Also recorded were pre- and post-core temperatures and SNR during the first CCO measurement. Cost data included estimates of operator time for BCO determinations as well as costs of Intellicath (Baxter-Edwards, Irvine, CA) pulmonary artery catheters, Vigilance (Baxter-Edwards, Irvine, CA) monitors, conventional catheters, and injectates. RESULTS: Of the 20 patients, 15 were mechanically ventilated. A total of 306 paired CO values were obtained for analysis. CCO ranged from 2.5 to 14.4 L/min and BCO from 2.4 to 13.3 L/min. Absolute differences between CCO and BCO measurements increased with increasing CO, but percentage differences did not. Of the paired values, 77% were within 1 L/min of one another. Temperature instability and SNR independently had weak correlations with CCO/BCO disparities. The Vigilance system had a slightly higher net cost than conventional BCO, although no economical value was assigned to the clinical usefulness of continuous, as opposed to intermittent, CO monitoring. CONCLUSIONS: Continuous CO is a reliable and cost-effective alternative to bolus thermodilution CO for critically ill patients in low, normal, and high CO states.

Septic shock.

Although our understanding of molecular events in septic shock is growing exponentially, bedside management has changed only incrementally over the last 20 years. In pediatric and adult patients alike, treatment continues to be largely supportive. Morbidity and mortality, though gradually improving, continue to be high. The major similarities, as well as the minor differences, between pediatric and adult septic shock are reviewed in this article, with an emphasis on current clinical practice and recent clinical investigations of novel therapies.

Myocardial dysfunction in sepsis.

The characteristic hemodynamic profile of human septic shock consists of a normal or elevated cardiac index and a decreased systemic vascular resistance index. When a patient with septic shock has a low cardiac index, concomitant hypovolemia is usually present. Within 48 hours of the onset of septic shock, most patients develop marked dilatation of both ventricles, depressed ejection fractions, and alterations of the Frank-Starling and diastolic pressure-volume relationships; stroke volume typically is well maintained. In surviving patients, cardiac function returns to normal within 10 days. An identical sequence of hemodynamic abnormalities occurs in an experimental canine model of sepsis that employs intraperitoneal implantation of infected fibrin clots. This myocardial dysfunction is not due to global myocardial ischemia; instead, there appear to be one or more circulating myocardial depressant substances. The chemical nature of these circulation mediators is under intensive investigation clinically, in vitro, and in the canine model.

Tachyphylaxis to the vasopressor effects of endothelin in rat aortic rings.

Endothelin-1 (ET-1), a potent vasoconstrictor peptide released by endothelial cells, binds with high affinity to surface receptors and is highly resistant to dissociation. We observed tachyphylaxis to the pressor effects of a second application of ET-1 in rat aortic rings and investigated the mechanism of this effect. Developed tension increased progressively with doses of ET-1 ranging from 1 to 500 nM (P < 0.001), and tensions with rechallenge were correspondingly decreased (P < 0.001). In response to 500 nM ET-1, tension increased 1,599 +/- 72 (SE) mg/mg ring wt. Rechallenge with 500 nM ET-1 led to contraction of only 33 +/- 40 mg/mg ring wt. Tachyphylaxis was seen up to 6 h after initial challenge. Pretreatment with nicardipine, lidoflazine, nitroglycerin, and sphingosine did not affect tachyphylaxis. Pretreatment with 500 microM dansylcadaverine (an inhibitor of endothelin internalization) markedly inhibited ET-1-induced contraction and also inhibited tachyphylaxis to ET-1. Further studies with radiolabeled ET-1 suggested that subsequent ET-1 binding is markedly decreased after an initial ET-1 challenge. Dansylcadaverine inhibited ET-1 internalization and also inhibited the decreased binding seen with ET-1 rechallenge. Rat aortic rings demonstrate tachyphylaxis to the pressor effect of a second dose of ET-1. The mechanism appears to be related to binding and subsequent internalization of endothelin-receptor complexes. This effect suggests a possible mechanism for sustained decreases in systemic vascular resistance.