Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.

A phase I study was designed to evaluate the toxicity of escalating doses of gemcitabine along with fixed-dose paclitaxel in patients heavily pretreated with chemotherapy or radiotherapy. All patients had no prior therapy with the study drugs and possessed both adequate performance and end organ function. Eighteen patients were entered in the study. Characteristics included a median age of 66 years (range, 41 to 77) and stage IV disease in all patients; there were six patients with colon cancer, two with bladder cancer, three with non-small-cell lung cancer, two with esophageal cancer, three with pancreatic cancer, and two with cancer of unknown primary. Paclitaxel (150 mg/m2 over 3 hours) was given on day 1 and gemcitabine (800, 900, and 1,000 mg/m2 over 15 minutes) was given in three separate dose-escalating cohorts (1-3) on days 1 and 8. The treatment cycled every 21 days. The dose-limiting toxicity (DLT) proved to be neutropenia. All nonhematologic toxicities were mild and included gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash), and neurologic (paresthesias) disturbances along with transient elevations of liver function tests. The combination of gemcitabine and paclitaxel seems to be well tolerated, and the recommended starting dose for a phase II study, in pretreated patients using a day 1/day 8 treatment schedule, should be 900 mg/m2 for gemcitabine (days 1 and 8) along with 150 mg/m2 for paclitaxel (day 1).

Efficacy of preoperative autologous blood donation: analysis of blood loss and transfusion practice in total hip replacement.

STUDY OBJECTIVE: To determine the frequency of allogeneic transfusion for total hip replacement (THR) surgery and to examine the efficacy of preoperative autologous blood donation (PABD) under specified, standardized blood transfusion guidelines. DESIGN: Prospective, nonrandomized study. SETTING: University medical center. PATIENTS: All ASA physical status I, II, III, and IV patients undergoing single, primary, THR surgery from April 1998 to March 1999. INTERVENTIONS: All patients received standardized transfusion and anticoagulation therapy. Demographic, blood loss, and transfusion data were collected and compared between all patients participating in PABD (donors) and patients not participating in PABD (nondonors). Overall allogeneic blood exposure was established. Since most anemic patients could not participate in PABD, allogeneic transfusion frequency was also examined in a subset of nonanemic patients (hemoglobin > or =12 g/dL) who were potentially able to participate in PABD. MEASUREMENTS AND MAIN RESULTS: n = 231 patients, 142 donors and 89 nondonors. Mean estimated blood volume (EBV) of donors was 4991 +/- 1042 mL versus nondonors 4631 +/- 1108 mL (p < 0. 01). ASA physical status I-II/III-IV among donors was 118/24 versus nondonors 61/28 (p < 0.01). Overall allogeneic blood exposure was 22% (51/231). Allogeneic transfusion frequency for all donors was 15% (22/142) versus nondonors 33% (29/89) (p < 0.05). Among nonanemic patients, donor versus nondonor EBV and ASA physical status I-II/III-IV were 5074 +/- 1019 mL versus 4743 +/- 1172 mL and 107/20 versus 48/15 (p = NS); allogeneic transfusion frequency reduced to 13% (16/127) versus 17% (11/63) (p = NS), respectively. CONCLUSIONS: Allogeneic blood exposure was >10% despite the use of PABD. The efficacy of PABD has been obscured by the fact that donors of autologous blood tend to be larger and healthier than nondonors. After exclusion of anemic patients, autologous donors and nondonors were clinically comparable and the difference in allogeneic blood exposure was not statistically significant. PABD offers only a modest, if any, benefit for THR surgery.

Effect of ketorolac tromethamine on bleeding and on requirements for analgesia after total knee arthroplasty.

The effect of ketorolac tromethamine, a non-steroidal anti-inflammatory drug, on postoperative blood loss and on the requirement for morphine was assessed after total knee arthroplasty, an operation in which blood loss is mainly measured rather than estimated. The purpose of this prospective, randomized, double-blind clinical trial was to determine whether administration of ketorolac in the perioperative period would increase bleeding related to the operation. Fifty-nine patients who had a total knee arthroplasty received either thirty milligrams of ketorolac or a placebo consisting of saline solution, intravenously, every six hours, in four doses. The first dose was administered about an hour before the end of the operation. Blood loss and use of morphine for pain control were measured for the first twenty-four hours postoperatively. The per cent change in the hematocrit and the amount of transfused blood were also recorded. The patients who received ketorolac used 27 per cent less morphine than those who received the placebo (40.0 +/- 23.4 milligrams compared with 55.1 +/- 23.5 milligrams [mean and standard deviation]); this difference was significant (p < 0.05). On the first day after the operation, the hematocrit decreased from 0.364 +/- 0.043 preoperatively to 0.278 +/- 0.032 in the patients who received ketorolac and from 0.363 +/- 0.046 to 0.298 +/- 0.030 in the patients who received the placebo. The 6 per cent greater decrease in the group that received ketorolac was significant (p < 0.05) but not clinically important.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma calcitonin gene-related peptide and atrial natriuretic peptide levels during resection of pheochromocytoma.

Calcitonin gene-related peptide (CGRP) and atrial natriuretic peptide (ANP) are potent hypotensive agents. To determine if they play a counterregulatory role in catecholamine excess in patients with pheochromocytoma, plasma levels were measured in four patients undergoing resection of sporadically occurring tumors. Each patient was prepared with phenoxybenzamine hydrochloride (Dibenzyline); two patients also received propranolol. Blood was obtained for plasma levels of epinephrine, norepinephrine, CGRP, and ANP at induction of anesthesia, skin incision, tumor manipulation, tumor removal, and 24 hours after operation. Baseline plasma norepinephrine and epinephrine levels were markedly elevated and increased significantly with tumor manipulation and decreased significantly 24 hours after operation. CGRP and ANP levels were slightly elevated throughout but did not change significantly with tumor manipulation or early after tumor resection. Circulating CGRP and ANP do not appear to have an acute counterregulatory role in catecholamine excess in patients with pheochromocytoma but may exert some influence on postoperative hypotension after tumor removal.

Atrial natriuretic peptide responses during anaesthesia in patients with refractory cardiomyopathies.

In patients with congestive heart failure, the release of atrial natriuretic peptide (ANP) is decreased. This study sought to determine the extent of ANP, sympathetic and haemodynamic responses to acutely increased atrial pressure in patients with cardiomyopathies undergoing orthotopic cardiac transplantation. Haemodynamic variables, plasma ANP, norepinephrine, and epinephrine concentrations were measured in 17 patients at five times before and after induction of anaesthesia using either ketamine 1.5 micrograms.kg-1 or sufentanil 3.6 +/- 0.3 micrograms.kg-1. Preinduction values in the ketamine and sufentanil groups were not significantly different. Compared with preinduction values, increases in mean arterial pressure (26%), pulmonary capillary wedge pressure (90%), right atrial pressure (107%), and heart rate (24%) occurred in the ketamine group while cardiac index decreased by 19% (P less than 0.05). Haemodynamic variables in the sufentanil group did not change at any of the times studied. Plasma concentrations of atrial natriuretic peptide were not different within or between treatment groups. Following tracheal intubation plasma norepinephrine levels increased by 116% in the ketamine group (P less than 0.05), but did not change in the sufentanil group. Plasma norepinephrine concentrations differed significantly between the ketamine and sufentanil groups. There were no differences in epinephrine concentrations in either group. Despite the anticipated haemodynamic and catecholamine differences found between the ketamine and sufentanil groups, the levels of plasma ANP were similar. Based upon these results, it is concluded that ANP exerts little influence in the control of fluid volume or blood pressure in patients with refractory cardiomyopathy.

Cardiac transplantation: a prospective comparison of ketamine and sufentanil for anesthetic induction.

The hemodynamic effects of ketamine, 1.5 mg/kg, or sufentanil, 3.4 +/- 0.3 micrograms/kg, were studied prospectively for the anesthetic induction of 20 patients with cardiomyopathies undergoing cardiac transplantation. Plasma epinephrine (EPI), norepinephrine (NE), and sufentanil levels were also obtained. Measurements were taken at various times before induction and following intubation. Following ketamine, progressive increases (P less than 0.05) in mean arterial pressure (28%, MAP), mean pulmonary artery pressure (56%, PAP), central venous pressure (109%, CVP), and pulmonary capillary wedge pressure (84%, PCWP) occurred over time, whereas the cardiac index (CI), stroke volume index (SVI), and stroke work index (SWI) remained unchanged or decreased. The use of sufentanil was associated with no significant changes in MAP, PAP, CVP, PCWP, CI, SVI, or SWI. The heart rate (HR) did not significantly change in either group. Plasma NE significantly increased (31%) in the ketamine group, peaking at 10 minutes; whereas EPI levels did not significantly change in either group. Plasma sufentanil did not reflect the microgram/kg or microgram/BSA administered dose, suggesting individualized distribution kinetics. Since perioperative morbidity and mortality did not differ between groups, both ketamine and sufentanil are acceptable drugs for the anesthetic induction for cardiac transplantation. However, the dissimilar hemodynamic effects caused by ketamine and sufentanil suggest that this conclusion may not be applicable to the patient with a cardiomyopathy undergoing noncardiac surgery.

Plasma catecholamine changes during excision of pheochromocytoma.

Sequential changes in plasma norepinephrine (NE) and epinephrine (EPI) concentration were correlated with changes in blood pressure and cardiac rate in 14 patients undergoing surgery because of pheochromocytoma. All patients had elevated preoperative plasma catecholamine levels that increased during induction of anesthesia, intubation, and skin incision, but mean values did not become significantly higher than preoperative values until tumor manipulation. Episodes of hypertension were associated with increased plasma catecholamine levels, and plasma catecholamine levels and blood pressure decreased dramatically after tumor resection. NE and EPI were usually secreted simultaneously, but release of either NE or EPI alone occurred on some occasions. There were marked variations in the concentration ratio of NE to EPI in plasma at different periods of observation, which suggests that pheochromocytomas release varying amounts of catecholamines in a random fashion. Studies of the effect of the duration of preoperative preparation on intraoperative blood pressure, pulse rate, and cardiac arrhythmias failed to demonstrate that treatment for 14 days or longer was more effective than treatment for 4 to 7 days. Neither the brief nor the prolonged period of therapy prevented development of severe hypertension during tumor manipulation.

Pheochromocytoma multisystem crisis. A surgical emergency.

Three of 27 patients treated for pheochromocytoma between 1974 and 1987 presented with pheochromocytoma multisystem crisis (PMC). This unusual presentation consists of multiple organ system failure, temperature often greater than 40 degrees C, encephalopathy, and hypertension and/or hypotension. Although urgent medical therapy achieved blood pressure control in all three patients, the other manifestations of PMC progressed rapidly in spite of alpha and even beta blockade. The first patient died during attempts to localize a septic focus. The other two patients underwent urgent adrenalectomy and had postoperative improvement in their multiple organ system failure. All three tumors were large and produced markedly elevated levels of epinephrine. In conclusion (1) PMC is an unusual presentation of pheochromocytoma; (2) its manifestations include multiple organ system failure, high fever, encephalopathy, and vascular lability; (3) it may result from increased epinephrine secretion; and (4) successful treatment of PMC demands prompt diagnosis, vigorous medical preparation, and emergency tumor removal if the patient's condition continues to deteriorate.

Investigation of midazolam's influence on physiological and hormonal responses to hypotension.

Midazolam differs from diazepam in that midazolam is water-soluble, more potent and has a shorter elimination half-life (t1/2). To date, it has been used primarily for induction of anesthesia and as an anesthetic supplement. Diazepam has been shown to decrease the catecholamine response to perioperative stress. This study determined the extent to which midazolam influences the physiological and hormonal responses that are evoked by a nitroprusside-induced hypotensive challenge. Plasma levels of epinephrine, norepinephrine (NE), cortisol, and renin activity, as well as hemodynamic performance were measured in dogs anesthetized with enflurane-nitrous oxide-oxygen. Midazolam 0.2 mg/kg i.v. administered prior to a 30% decrease in mean blood pressure statistically attentuates the increase in plasma catecholamines. The cortisol and renin increases that occurred in response to the hypotension were not affected appreciably by midazolam. Hemodynamic changes due to midazolam were minimal, with only a transient 8-10% decrease in mean blood pressure observed. The findings of this study demonstrate that midazolam, like diazepam and fentanyl, can reduce the physiological and hormonal response to hypotensive episodes that occurred during the course of anesthesia and surgery.

Qualitative evaluation of coronary flow during anesthetic induction using thallium-201 perfusion scans.

Qualitative distribution of coronary flow using thallium-201 perfusion scans immediately postintubation was studied in 22 patients scheduled for elective coronary artery bypass surgery. Ten patients received a thiopental (4 mg/kg) and halothane induction. Twelve patients received a fentanyl (100 micrograms/kg) induction. Baseline thallium-201 perfusion scans were performed 24 h prior to surgery. These scans were compared with the scans performed postintubation. A thallium-positive scan was accepted as evidence of relative hypoperfusion. Baseline hemodynamic and ECG data were obtained prior to induction of anesthesia. These data were compared with the data obtained postintubation. Ten patients developed postintubation thallium-perfusion scan defects (thallium-positive scan), even though there was no statistical difference between their baseline hemodynamics and hemodynamics at the time of intubation. There was no difference in the incidence of thallium-positive scans between those patients anesthetized by fentanyl and those patients anesthetized with thiopental-halothane. The authors conclude that relative hypoperfusion, and possibly ischemia, occurred in 45% of patients studied, despite stable hemodynamics, and that the incidence of these events was the same with two different anesthetic techniques.

Haemodynamic and catecholamine response to isoflurane anaesthesia in patients undergoing coronary artery surgery.

Haemodynamic and plasma catecholamine responses were evaluated during isoflurane anaesthesia in ten patients undergoing coronary artery bypass surgery. Following thiopentone induction the patients were anaesthetized with isoflurane 1.5-2.0 per cent in oxygen. The results show that after 10 minutes of isoflurane anaesthesia there was a significant increase from baseline in heart rate, 68 to 80; cardiac output, 3.75 to 4.61; and plasma epinephrine, 0.80 to 1.33 microgram/l. Conversely, there was a significant reduction in systemic vascular resistance index, 3388 to 2260, and plasma norepinephrine, 1.10 to 0.88 microgram/l. Twenty-five minutes later, after sternotomy, heart rate, cardiac output and the level of plasma epinephrine were still elevated, and systemic vascular resistance index and plasma norepinephrine remained lowered (p less than 0.05). This study demonstrates significant catecholamine responses during isoflurane anaesthesia. The increase in plasma epinephrine parallelled the increase in heart rate and cardiac output, and the decrease in plasma norepinephrine paralleled the decrease in systemic vascular resistance. Based upon these findings we conclude that catecholamine responses contribute to the cardiac and peripheral cardiovascular changes observed with isoflurane anesthesia.

Epidural triamcinolone and adrenal response to hypoglycemic stress in dogs.

The effect of an epidural steroid injection (triamcinolone) on plasma cortisol levels was studied in twelve beagle dogs following an insulin-induced hypoglycemic stress. The control group (n = 6) received epidural bupivacaine only. This group consistently increases their plasma cortisol values in response to the hypoglycemic stress induced by 0.6 units of insulin/kg administered intravenously. Dogs in the study group (n = 6) received epidural bupivacaine plus 2 mg/kg of triamcinolone. This group was unable to increase their plasma cortisol values in response to similar insulin-induced hypoglycemic stress for four weeks. Return to normal function occurred five weeks following epidural triamcinolone. The authors hypothesize that the inability of the dogs to respond to hypoglycemic stress by increasing their plasma cortisol may interfere with homeostasis and decrease their tolerance to other types of stress up to 4 weeks following epidural triamcinolone administration.

Effect of priming volume on serum catecholamines during cardiopulmonary bypass.

Several theories have been proposed to explain the transient hypotension which occurs upon the initiation of cardiopulmonary bypass. The present study investigated the possibility that addition of the lactated Ringer's solution pump priming volume to the circulation causes dilution of circulating catecholamines leading to the hypotension. Circulating epinephrine and norepinephrine levels were measured during cardiopulmonary bypass in patients anaesthetized with halothane. The results demonstrate dilution of circulating catecholamines at the start of bypass in conjunction with the observed hypotension. During the bypass period, mean blood pressure graudally recovered to normotensive levels even though circulating catecholamine levels remained significantly lowered, indicating a mechanism for the recovery of blood press which is not sympathoadrenal. The results obtained from this study demonstrate a temporal relationship between catecholamine dilution by the pump priming volume and the observed hypotension. Whether catecholamine dilution is the sole factor causing the hypotension remains to be determined.

Nitroglycerin and the neuromuscular blockade produced by gallamine, succinylcholine, d-tubocurarine, and pancuronium.

The finding in cats of prolonged pancuronium neuromuscular blockade in conjunction with intravenous infusion of nitroglycerin was previously reported by this laboratory. To expand on this finding the present study compared the effects of nitroglycerin on neuromuscular blockade produced by gallamine, d-tubocurarine, succinylcholine, and pancuronium, and further characterized the nitroglycerin-pancuronium interaction. The results indicate that of the relaxants studied only pancuronium neuromuscular blockade is prolonged, and that the prolongation is not due to altered plasma elimination of pancuronium. In vitro pancuronium blockade was not affected by nitroglycerin, suggesting the involvement of a metabolite in the block prolongation response. Reversibility of the prolonged pancuronium block by neostigmine is not influenced by nitroglycerin.

Prolongation of pancuronium-induced neuromuscular blockade by intravenous infusion of nitroglycerin.

Based upon clinical observation of undue prolongation of pancuronium-induced blockade in the presence of intravenous infusion of nitroglycerin, neuromuscular blockades produced by pancuronium, succinylcholine and d-tubocurarine were studied in 51 cats using the sciatic-gastrocnemius nerve-muscle preparation. Pancuronium-induced blockade was found to be significantly prolonged (P less than 0.1) in the presence of a nitroglycerin infusion of 1 microgram/kg/min (65 vs. 127 min). Less, but still significant, prolongation occurred when nitroglycerin, 0.5 microgram/kg/min, was infused. The intravenous infusion of nitroglycerin must be started prior to the pancuronium injection for the block to be prolonged. Neuromuscular blocks produced by succinylcholine and d-tubocurarine were not altered by nitroglycerin. In experiments using the isolated rat diaphragm preparation, the depth of pancuronium-induced block was found not to be changed by nitroglycerin, suggesting an effect of nitroglycerin on the process of recovery from blockade. These findings indicate a selective pancuronium-nitroglycerin interaction.