Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam.

OBJECTIVE: To report a patient with a probable acute tubular necrosis (ATN) induced by chronic exposure to polyethylene glycol (PEG)-400 via long-term, massive dosage of intravenous lorazepam. CASE SUMMARY: A 57-year-old man with a history of alcohol abuse was admitted to the intensive care unit for acute respiratory failure. Lorazepam therapy was initiated in anticipation of alcohol withdrawal. Dosages up to 18 mg/h were required to provide adequate sedation and optimize ventilation. On day 43, the patient developed oliguric ATN of unknown etiology. The cumulative intravenous lorazepam dose was 4089 mg, equivalent to approximately 220 mL of PEG-400. Blood urea nitrogen concentrations followed a pattern that paralleled lorazepam dosage increases and decreases. Protein and granular casts were evident in urinalyses performed on days 12 and 29. The patient eventually experienced complete recovery. DISCUSSION: ATN associated with intravenous PEG was last reported in 1959 in 6 of 32 patients receiving a cumulative PEG-300 dose of 120-200 mL over 3-5 days via an intravenous nitrofurantoin preparation. Two of the 6 patients died. Chronic administration of intravenous PEG to rabbits over a 5-week period has caused cloudy swelling of the renal tubular epithelium, increased blood urea concentrations, and death in some animals. CONCLUSIONS: ATN probably resulted from chronic PEG exposure via massive doses of lorazepam injection, possibly enhanced by concurrent administration of vancomycin.

Unilateral gynecomastia associated with thoracotomy following resection of carcinoma of the lung.

A 66-year-old man developed right painful gynecomastia following resection of a well-differentiated squamous cell carcinoma from the right upper lobe. In 1979, he had a well-differentiated squamous cell carcinoma resected from the left lower lobe. Extensive investigation did not reveal any definite indication of metastases or residual carcinoma. There was no evidence for thyroid, liver, or renal disease. His plasma testosterone was 400 ng/dl, estradiol was 43 pg/ml, LH 3.5 ng/ml, FSH 13.1 mIU/ml and HCG less than 5 mIU/ml. Since no other cause of gynecomastia was apparent , it was attributed to the right thoracotomy.

Inhibition of platelet aggregation by oral digoxin and reversal with nifedipine.

To study the effect of cardiac glycosides on platelet function, we obtained serial blood samples from 18 normal male volunteers before and 3, 5, and 7 weeks after beginning digoxin therapy (0.375 mg daily). The combined effect of digoxin and nifedipine (mean dose, 57 mg/day) was assessed during the 5th week. Spontaneous platelet aggregation and platelet response to adenosine diphosphate (ADP) were measured in whole blood by electronic particle sizing. Digoxin (mean serum concentration, 0.9 ng/ml) caused significant reduction in total volume and mean size of platelet aggregates formed in response to ADP. However, with addition of nifedipine, the volume and mean size of aggregates returned to baseline measurements. In vitro administration of digoxin to whole blood failed to inhibit ADP-induced platelet aggregation. The volume of spontaneously induced aggregates decreased with digoxin; however, the decrease was not statistically significant. These data indicate that digoxin given in vivo for several weeks inhibits platelet response to ADP; this effect is reversed by the addition of nifedipine.

The kinetics of platelet aggregation induced by fluid-shearing stress.

The work herein examines in vitro the kinetics of platelet aggregation in response to the fluid-shearing stress imparted by a rotational viscometer. Aggregation is expressed through changes in particle size histograms and total particle count. Platelet aggregation commenced above 2000 sec-1 shear rate and was stable above 5000 sec-1. Activation by shear required less than 10 sec at all shear rates. At shear rates above 5000 sec-1, the particle count fell by one-half within 10 sec. By this point aggregates of 1000 platelets or more had appeared. Diluting the platelet suspensions suppressed shear-induced aggregation but not aggregation to ADP, supporting the hypothesis that shear-induced platelet aggregation proceeds through chemical release.

Intravascular microaggregation and in vitro platelet aggregation in coronary artery disease.

To investigate in vivo and in vitro microaggregation in coronary artery disease, we obtained blood samples from the coronary sinus (CS), pulmonary artery (PA), and aorta (AO) in patients undergoing cardiac catheterization. An electronic particle size analyzer was used to quantify microaggregates 13 to 81 mu in diameter in blood. In the first group of 58 patients, preformed circulating microaggregates and platelet responsiveness to ADP were assessed in AO and PA blood only. The coronary artery disease patients did not have significantly higher volumes of preformed in vivo aggregates in either AO or PA blood. However, the mean aggregate size in response to 0.2 microM ADP in vitro was larger in both AO and PA blood in patients with coronary disease [12.4 +/- 0.9 vs. 9.4 +/- 1.4 X 10(3) mu3 (AO); 12.5 +/- 0.9 vs. 8.3 +/- 0.7 0.7 X 10(3) mu3 (PA)]. In a second group of 46 patients, CS, AO and PA samples were compared using the same methods. The volume of microaggregates preformed in vivo was significantly greater in CS blood than in PA or AO blood in patients with and without coronary disease. The volume and mean size of aggregates induced by ADP in vitro were smaller in CS blood compared to PA. In conclusion, the volume of in vivo microaggregates is increased in CS blood, independent of coronary disease, but significant volumes are not found in PA or AO blood. Patients with coronary disease have more reactive platelets to in vitro aggregatory agents in AO and PA samples of similar hematocrit.

Defective platelet aggregation in patients undergoing surgical repair of cyanotic congenital heart disease.

Fifteen patients undergoing cardiopulmonary bypass for repair of cyanotic congenital defects were examined for evidence of platelet aggregation abnormalities by means of electronic particle sizing. Eight patients with polycythemia whose hematocrits were greater than or equal to 50% before bypass were compared with 7 patients without polycythemia whose hematocrits were less than 50%. Patients also were compared with 11 healthy volunteers. Before bypass, platelets in blood from the patients with polycythemia formed markedly smaller platelet aggregates (8.9 +/- 0.8 X 10(3) mu 3; mean +/- standard error of the mean) in response to adenosine diphosphate than those of the other group of patients (21.7 +/- 1.9 X 10(3) mu 3; p less than 0.001) or healthy volunteers (25.8 +/- 2.1 X 10(3) mu 3; p less than 0.001). Mean platelet aggregate sizes were not different between patients without polycythemia and normal volunteers (p greater than 0.05). In samples taken after bypass, patients with polycythemia again had smaller aggregates than the other group of patients (p less than 0.005). This platelet defect is quantitatively related to polycythemia, and may be a mechanical effect of the excess erythrocytes.

Effects of ethanol and hemolysis on in vivo and in vitro platelet aggregation.

In vivo and in vitro platelet function were measured in male rats after intravenous injection of ethanol or water. There was a dose-related ethanol suppression of platelet aggregation induced by extravasation. Increased volumes of preformed microaggregates were seen in samples taken directly from the vena cava after injection of ethanol in doses that caused hemolysis. Lower doses of ethanol produced no demonstrable microaggregates or hemolysis: however, extravasation-induced aggregation was inhibited. Hemolysis was noted after intravenous injection of water, which also reduced the total volume and mean aggregate size of platelet aggregates induced by extravasation. Blood drawn from the inferior vena cava after induction of hemolysis had an increased volume of microaggregates, regardless of the agent producing hemolysis. In vitro studies revealed changes in spontaneous and ADP-induced aggregation only at very high concentrations of ethanol (greater than 3,000 mg/dl) and no effects at ethanol levels that altered in vivo aggregation. Ethanol, in doses that do not hemolyze erythrocytes, decreases platelet aggregation.

Platelet aggregation during and after cardiopulmonary bypass: effect of two different cardiotomy filters.

Patients undergoing cardiopulmonary bypass with a membrane oxygenator were studied to determine the effects of two cardiotomy filters on platelet number and function. A Dacron wool filter removed significantly more microemboli than a 40 mu X 40 mu pore-mesh filter. Postoperatively, there were fewer platelets and a lower total volume of platelets in patients who had a Dacron wool filter in the extracorporeal circuit. However, the volume of adenosine diphosphate-induced aggregates was nearly identical in the two patient groups (p greater than 0.1). The study documents an increased number of circulating platelets after pore-mesh filtration, and suggests that the microaggregates reinfused during pore-mesh filtration represent aggregated platelets that dissociate and subsequently circulate in the patient but do not function.

Inhibition of platelet aggregation by verapamil: quantification by in vivo and in vitro techniques.

Platelet aggregation appears to play a prominent role in myocardial ischemia. Verapamil, a slow-channel blocking agent with important antiarrhythmic and vasodilating actions, has been shown to inhibit in vitro platelet aggregation. We used an electronic particle size analyzer to evaluate the effects of verapamil on platelet aggregation in vitro and in vivo in 88 rats. The intravenous injection of verapamil (0.4 mg/kg) did not change the platelet count compared to control animals receiving an equal volume of normal saline (verapamil, 1.1 +/- 0.04 x 10(6)/mm3, vs. control, 1.2 +/- 0.09 x 10(6)/mm3, (p greater than 0.05). The mean size of platelet aggregates induced by adenosine diphosphate (0.2 microM), was reduced by verapamil (verapamil, 15.3 +/- 1.2 x 10(3) micron3 vs. control 24.4 +/- 2.7 x 10(3) micron; p less than 0.01). Platelet aggregates induced in vivo, following a standardized technique of extravasation of right iliac artery blood into the peritoneal cavity, were also smaller following verapamil infusion (verapamil, 12.6 +/- 1.1 x 10(3)micron3, vs control, 17.3 +/- 0.9 x 10(3) micron3 p less than 0.001). We conclude that verapamil exerts and inhibitory effect on platelet aggregation both in vitro and in vivo. This property may add an important new dimension to its potential therapeutic usefulness in ischemic heart disease.

Evaluation of a new cardiotomy blood filter.

A new cardiotomy blood filter with a polycarbonate body, a polyester prefilter, and a nylon screen with 20 mu pores was compared with four other commercially available filters. The Optigard filter was found to function as a "surface filter," which effectively removes blood particles larger than its nominal pore size.

Effects of changes in arterial carbon dioxide tension on oxygen consumption during cardiopulmonary bypass.

The effects of changes in arterial carbon dioxide tension (PaCO2) on the oxygenation of tissues in 34 patients undergoing surgery for aortocoronary bypass were studied while temperature, systemic blood flow, and the delivery of oxygen to the peripheral tissues remained constant. Mixed venous and superior vena caval oxygen tensions (PvO2 and PsvcO2, respectively) and oxyhemoglobin saturations and the in vivo partial pressure of oxygen at which 50 percent of the hemoglobin is saturated (P50) increased with PaCO2, while peripheral vascular resistance, in vitro P50, the level of 2,3-diphosphoglyceric acid in the red blood cells, and the level of lactate in the blood remained constant. There was a close correlation between increases in PaCO2 and increases in PvO2 (r = 0.912; P less than 0.001) but not increases in PsvcO2 (r = 0.364; not significant). This indicated that the total-body consumption of oxygen diminished with increases in PaCO2 but that some regional redistribution of oxygen consumption occurred between the superior and inferior vena caval vascular beds. Since the level of lactate in the blood remained constant and since signs of metabolism acidosis did not develop, the reduced oxygen consumption due to increases in PaCO2 did not result in detectable increases in anaerobic metabolism.

Cardiopulmonary bypass surgery. Platelet aggregation during induction of anesthesia and following heparinization of patients.

Measurements of platelet count and platelet aggregation in response to adenosine diphosphate and epinephrine were made before and after administration of preanesthetic medications and at intervals during induction of anesthesia, before and after thoractomy, and before and after systemic heparinization in patients undergoing cardiopulmonary bypass operations. Substantial decreases in circulating platelet count occurred only after induction of anesthesia and following thoracotomy. There was no notable change in the percent of platelets involved in aggregation over the period studied, but the reactivity of platelets was increased after induction of anesthesia and after thoracotomy.

Total support of the circulation of a patient with post-cardiotomy stone-heart syndrome by a partial artificial heart (ALVAD) for 5 days followed by heart and kidney transplantation.

A patient with acute bacterial endocarditis in whom ischaemic contracture of the left ventricle (stone-heart syndrome) developed during aortic and mitral valve replacement had an emergency implantation of an intracorporeal partial artificial heart (an abdominal left-ventricular assist device of ALVAD). This device functioned as a total artificial heart for nearly 6 days, while a donor heart for transplantation was sought. The ALVAD was then removed, and the patient received allografts of a heart and a kidney. The transplanted heart functioned well, but the patient died 15 days later from gram-negative sepsis. There was no evidence of cardiac or renal allograft rejection.

An evaluation of several blood transfusion filters.

Several blood transfusion filters designed to remove microemboli were evaluated for filtration and flow characteristics, as well as for hemolysis and for release of particulate debris from the filter. The Dacron wool filter, a depth filter, was superior at removing microemboli measured with an electronic particle size analyzer. A 25 micrometer pore mesh filter was least effective at removing microemboli from stored blood, but demonstrated the most favorable flow rates and induced no apparent red blood cell destruction during filtration. In general, filter efficiency and filter induced hemolysis correlated inversely with flow rate. No filter tested released significant quantities of particulate debris when compared with unfiltered isotonic saline.

A simple method of intraoperative autotransfusion.

A new method of intraoperative blood collection and autotransfusion can be incorporated into an available suction system. It combines systemic heparinization with immediate extracorporeal citrate phosphate dextrose anticoagulation. Analysis of the autologous blood collected and its recipients indicates that it is safe. The preservation of platelets, coagulation factors and erythrocyte oxygen carrying capacity is better in this autologous blood than in homologous banked units. Potential problems of autotransfusion exist, but they are minimized when this system is used.

Clinical experience with the Teflo disposable membrane oxygenator.

A simple, inexpensive, highly efficient disposable membrane oxygenator with low priming volume and a microporous membrane recently has become available. Animal and clinical investigations of its use have been most satisfactory, and clinical experience now has been extended to include 285 patients. Its primary advantage has been the ability to control oxygenation and carbon dioxide separately. Disadvantages have included the somewhat increased complexity of the system as compared with bubble oxygenator systems, the necessity of converting pumps for its use, and excessive condensation of water vapor in the gas phase of the oxygenator unless certain precautions are followed.

Cardiopulmonary bypass. Microembolization and platelet aggregation.

Particulate microemboli and in vitro platelet aggregation were studied in blood of patients during cardiac operations with an electronic particle size analyzer. A small gradient of microemboli developed on passage of blood through a bubble oxygenator but not through a membrane oxygenator. However, with both types of oxygenators, there was a sustained increase in the volume of microemboli in cardiotomy return blood which was much greater than in aterial blood. After cardiopulmonary bypass with both oxygenators, there was a comparable reduction in the volume of circulating platelets which exceeded that of the hemoglobin concentration, indicating platelet loss exceeded that that expected from hemodilution alone. However, the total volume and mean size of platelet aggregates induced in blood of patients after membrane oxygenation was significantly greater than similar measurements after bubble oxygenation. This study shows that membrane oxygenation reduces particulate microembolization and preserves platelet function in patients undergoing cardiac operations when compared to bubble oxygenation.