Ibuprofen inhibits granulocyte responses to inflammatory mediators. A proposed mechanism for reduction of experimental myocardial infarct size.

The use of nonsteroidal antiinflammatory agents to reduce myocardial infarct size has demonstrated a dichotomy between ibuprofen, which reduces myocardial infarct size, and aspirin, which does not. A feline model of coronary ischemia using ligation of the anterior descending artery demonstrated that intravenous ibuprofen (2.5-20 mg/kg) given immediately and 2 h after ligation significantly decreased (by about 40%) myocardial infarct size. In contrast, aspirin did not diminish infarct size at any achieved dose; in fact, at some doses it tended to increase infarct size. In vitro studies with purified granulocytes demonstrated a similar dichotomy between ibuprofen and aspirin. Ibuprofen inhibits granulocyte aggregation, superoxide production, lysosomal enzyme release, and granulocyte-mediated endothelial cytotoxicity, while aspirin is without effect on these modalities. We propose that ibuprofen's beneficial effect in experimental myocardial ischemia is related to its ability to inhibit activated granulocytes and thus to diminish myocardial cell death in experimental myocardial infarction.

Serum complement levels in canine endotoxin shock: relation to survival and to corticosteroid therapy.

Recent studies suggest prominent roles of the complement system in endotoxin shock and steroid-complement interactions in its treatment. To assess further the potential importance of the complement system in this condition, we measured serum total complement levels in dogs after an IV bolus of 1.5 mg/kg DIFCO E coli endotoxin. Dogs were assigned to control (C), dextran40 (LMD), or LMD + steroid groups. Corticosteroids, given IV 15 min after endotoxin, were 1) methylprednisolone sodium succinate (MPSS), 30 mg/kg; 2) dexamethasone sodium phosphate (DSP), 6 mg/kg; 3) hydrocortisone sodium succinate (HSS), 150 mg/kg; or 4) hydrocortisone sodium phosphate (HSP), 150 mg/kg. LMD was infused to maintain BP greater than 60% of preshock levels during the 4 h of monitoring. Survival rates at 48 h were C--7/24 (29%); LMD--3/12 (25%), MPSS--11/19 (59%) (P less than 0.1); DSP--9/14 (64%) (P less than 0.05); HSS--3/10 (30%) HSP--5/10 (50%). Within 15 min of endotoxin administration, serum complement titers fell at least 48% in all groups. Complement levels returned to the preshock range in only the LMD group. Mean complement levels of all survivors and nonsurvivors were nearly identical throughout the acute experiment. The results indicate that survival in canine endotoxin shock, with or without corticosteroid therapy, is not related to normalization of serum total complement titers during the first few hours after endotoxin injection.

The influence of megadose methylprednisolone on experimental myocardial infarct size.

Prior work in our laboratory demonstrated a significant reduction of infarct size following early or late administration of 30 mg/kg of methylprednisolone sodium succinate (MP). This study was designed to determine the influence of larger doses of MP on infarct volume. Healthy anesthetized mongrel dogs with similar cardiac anatomy underwent ligation of the distal third of the LAD coronary artery. Following ligation, animals were randomly placed into control or treatment groups. Treated dogs received an IV bolus of either 50 mg/kg MP at 15 minutes (MP-50) or 30 mg/kg MP at 15 minutes and 1 hour later (2MP-30). Animals were then monitored for 6 hours, sacrificed, and the heart removed. The left ventricle was dissected from the heart, weighed, sectioned, and incubated in nitro-blue tetrazolium solution, an LDH stain. Unstained tissue (infarct) was dissected from the slices and weighed, and infarct volume was calculated. Among 20 untreated animals the infarct size was 14.5% +/- 4.3% of the left ventricle. Treatment with 2MP-30 or MP-50 significantly reduced infarct volume to a similar degree (9.1%-9.6%). There was no difference in the effect on infarct size by "megadose" MP compared to previous results with one injection of 30 mg/kg MP. Therefore, the early use of MP at doses above 30 mg/kg confers no additional protection to the ischemic myocardium.

Influence of the salt moiety on the effectiveness of corticosteroid therapy in cardiogenic shock.

Using closed chest coronary artery microsphere embolization, myocardial infarction and subsequent shock were produced in healthy adult mongrel dogs. Following infarction animals were distributed among the following groups: (1) control; (2) methylprednisolone sodium succinate (MPSS); (3) methylprednisolone sodium phosphate (MPSP); (4) sodium phosphate (SP); and (5) sodium succinate (SS). Drug doses of equivalent anti-inflammatory activity were administered i.v. 15 min after infarction. Compared to control animals, only dogs treated with MPSS exhibited significant improvements in hemodynamic parameters and permanent survival. Survival in MPSS dogs was significantly (P = 0.02) better than that of either group treated with SP or SS and substantially (P = 0.02) better than that of either group treated with SP or SS and substantially (P = 0.065) better than the survival rate of dogs receiving MPSP. It appears that succinate is permissive, while phosphate is restrictive, with respect to efficacy of methylprednisolone in experimental cardiogenic shock. Possible explanations for these observations are discussed.

The timing of surgical treatment of pancreatic pseudocysts.

In an attempt to provide practical guidelines for the management of pancreatic pseudocysts, the results in 114 patients were analyzed from the perspective of the timing of operative intervention. Over-all, the patients undergoing surgical therapy during the first six weeks after pseudocyst formation had higher rates postoperatively of morbidity, mortality and recurrence than did those treated later in the course of the disease. However, further subdivision of the data revealed that the results in patients with uncomplicated pseudocysts were similar, irrespective of the timing of operative treatment. Operative intervention in patients with a pseudocyst who were acutely ill was risky at any time in the course of the disease. Based upon our results and upon information available in the literature, the optimal timing of the operation in patients with uncomplicated pseudocysts appears to be about four weeks after formation of the mass. The utility of ultrasound evaluation in making a surgical decision is also discussed.

Complement activation and neutropenia occurring during cardiopulmonary bypass.

Complement activation and pulmonary leukostasis with neutropenia occur in hemodialysis and filtration leukapheresis, with attendant pulmonary dysfunction. Wondering whether similar phenomena might attend cardiopulmonary bypass (CPB), we studied 34 patients undergoing coronary artery bypass operations. As in the other extracorporeal circulation systems, neutropenia (mean 44.7% +/- 4.3% SEM of prebypass PMN count) occurred during the first half hour of bypass and then a rebound neutrophilia followed. CH50 and C3H50 fell 22% to 25% (p for CH50 less than 0.01) during bypass, but C3 conversion and C5a were not demonstrable in patient plasmas. Nonetheless, polymorphonuclear neutrophils (PMNs) harvested late in bypass showed low adherence to nylon and selective chemotactic and aggregative insensitivity to C5a--functional aberrations which are seen after exposure to activated complement. Furthermore, smaller infusions of activated complement into animals produced neutropenia than were required to achieve a detectable [C5a] in the plasma. We conclude that neutropenia during CPB probably results from complement activation below the threshold of detection; complement-stimulated PMNs deserve study as possible mediators of tissue injury occurring during CPB.

Protective effects of epinephrine tolerance in experimental cardiogenic shock.

To evaluate the mechanism of protection of epinephrine tolerance in shock, we studied the hemodynamic and regional blood flow response to cardiogenic shock in dogs rendered tolerant to lethal doses of epinephrine. Shock was induced by coronary embolization. Regional organ perfusion was evaluated with radioactive microspheres. The survival of tolerant dogs following embolization was 8/12 (62%) compared to 5/31 (16%) in control dogs (P = 0.008). Heart and adrenal organ weights were significantly greater in the tolerant animals. Ventricular hypertrophy in the tolerant dogs was accompanied by greater myocardial blood flow and greater myocardial contractility both before and during cardiogenic shock. There was significantly greater regional flow to spleen, gastrointestinal tract, and pancreas during shock in the epinephrine-tolerant group.

Experiences with allopurinal in canine endotoxin shock.

Allopurinol, a xanthine-oxidase inhibitor and potential cell-stabilizing compound, was studied as a possible therapeutic agent in canine endotoxin shock. Circulatory collapse was produced in anesthetized mongrel dogs by IV administration of an LD75 dose of endotoxin. Treatment, with dextran alone, or with dextran and an IV bolus of allopurinol, was initiated 15 minutes after the onset of shock. The administration of 25, 50, or 100 mg/kg of IV allopurinol, accompanied by adequate volume replenishment, produced a significant reduction in the total peripheral vascular resistance and significant increases in cardiac output, blood glucose concentration, and arterial lactate concentration. Survival was not enhanced by allopurinol therapy, and allopurinol administration in normal dogs did not affect the vascular tone or the arterial lactic acid concentration. There was a transient hyperglycemic response and a decrease in the cardiac index in normal animals. The infusion of a postassium-insulin solution, in association with 100 mg/kg of allopurinol, did not significantly improve survival. In summary, although a number of potentially beneficial hemodynamic and metabolic effects were observed following allopurinol administration, survival in canine endotoxin shock was not enhanced.

Comparative effects of intravenous and intra-arterial methylprednisolone in cardiogenic shock.

This study was undertaken to determine if a portion of intravenously administered methylprednisolone sodium succinate (MPSS) might be metabolized by the lung during cardiogenic shock. With plastic microsphere coronary artery embolization, myocardial infarction and shock were produced in mongrel dogs. Animals were assigned to control, intra-arterial MPSS, and intravenous MPSS groups, with the treated dogs receiving 30 mg/kg of MPSS 15 minutes after infarction. Compared to control animals, the group receiving intra-arterial MPSS had significantly higher mean blood pressure, cardiac index, and blood glucose levels and a lower peripheral resistance during shock. Compared with the intravenous MPSS group, dogs treated with intra-arterial MPSS had significantly lower peripheral resistance and a nearly significantly higher cardiac index. Permanent survival rates were 26% in the control group, 60% in the intravenous MPSS group, and 50% in the intra-arterial MPSS group. Although treatment with intra-arterial MPSS was associated with a better hemodynamic profile than that following intravenous MPSS (suggesting the possibility of corticosteroid metabolism by the lung), survival was not enhanced. It was concluded that functionally insignificant amounts of corticosteroids given intravenously might be inactivated by the lung. Hence, intravenous MPSS injection is a practical and adequate means of administering this valuable agent in cardiogenic shock.

Resistance to experimental peritonitis induced by local nonspecific stimulation of the reticuloendothelial system.

Zymosan, a yeast cell wall preparation from Saccharomyces cerevisiae, stimulates the reticuloendothelial system (RES) in animals. Pretreatment with zymosan induces resistance to several types of shock. We have shown evidence that zymosan given intraperitoneally (IP) induces greater protection than intravenous (IV) zymosan against E coli peritonitis in the rat. Moreover, IP zymosan has few systemic RES effects, which are commonly associated with IV zymosan. IV and IP zymosan stimulation were compared for effectiveness against experimental fibrinopurulent peritonitis in dogs (a peritonitis model quite similar to clinical peritonitis). Ten dogs received zymosan IV (10 mg/kg), ten dogs received zymosan IP (10 mg/kg), and eight dogs received an equal volume of saline IP on three consecutive days. On day 4, a 7.5 cm length of terminal ileum was isolated and its blood supply ligated to create an infarcted, blind loop of bowel. This loop was left in the peritoneal cavity for five days. Five-day survival was 80% (8/10) for the zymosan IP (P less than 0.05), 60% (6/10) for the zymosan IV and 12.5% (1/8) for the saline controls. All survivors were sacrificed at five days and found to have an intact enteric anastomosis with varying degrees of walled-off abscess at the site of the necrotic loop. Histologic evaluation of intraabdominal organs, peritoneum, and abscess wall was carried out. The IP zymosan had no significant systemic RES effects, whereas the IV zymosan produced a marked increase in liver and spleen weights. These findings reinforce the hypothesis that local nonspecific RES stimulation could have a major role in the preparation of certain high-risk patients for abdominal surgery where the chance of peritoneal soilage is high.

Basic requirements of pancreatic mass for transplantation.

In canine pancreas autografts, more than 20% (30% to 40%) of the pancreatic mass (body and distal head or proximal tail) is required for the establishment of a satisfactory endocrine response. Transplantation of 20% of the pancreatic mass did not result in an adequate restoration of the endocrine function. We believe that this study gives a practical answer to the question of how much pancreatic mass is necessary for the establishment of normal functional response after transplantation. This autotransplantation model precludes the determination of the content and volume of transplanted pancreatic islets. Thus, our model indicates the requirements of the pancreatic mass of the specific anatomic areas that were transplanted, but does not indicate the actual amount of transplanted islets.

Effects of glucocorticosteroids in patients undergoing coronary artery bypass surgery.

Glucocorticosteroid, methylprednisolone sodium succinate (MPSS), 30 mg/kg of body weight, or dexamethasone sodium phosphate (DSP), 6 mg/kg of body weight, were given intravenously to 60 patients, divided into two groups of 30 45 minutes prior to cardiopulmonary bypass for coronary artery bypass. These two groups were compared with 30 patients in a control group receiving a placebo and undergoing the same surgery. The study was carried out in a double-lind fashion. Patients receiving MPSS had a significantly higher cardiac index in both the preoperative and postoperative periods. This was accompanied by a decreased peripheral resistance. Patients receiving either MPSS or DSP also showed some evidence for the "washout" phenomenon indicating the possibility of better microcirculatory flow. Gluconeogenesis may have been enhanced in both groups receiving MPSS or DSP, but the evidence was greater in thos patients receiving MPSS. There were no hospital deaths in any of the three groups totaling 90 patients.

Surgical treatment of pancreatic pseudocysts. Analysis of 119 cases.

A review was made of the hospital records of 119 patients with pancreatic pseudocysts. Alcoholism, biliary disease and abdominal trauma were the most common antecedent conditions. Abdominal pain was the most frequent symptom, and abdominal tenderness or mass were the most common physical findings. Abdominal echography and contrast study of the upper gastrointestinal tract were diagnostic in 90% of the patients examined. X-rays of the chest, colon, and biliary tract revealed pathology in 30--40% of the patients. Compared to patients with uncomplicated pseudocyst, patients who were acutely ill at the time of external drainage had twice the incidence of postoperative complications. Each subgroup experienced similar, high rates of postoperative death and pseudocyst recurrence. Both groups of patients treated by internal drainage had lower rates of postoperative morbidity, mortality, and pseudocyst recurrence than patients with uncomplicated pseudocysts undergoing external drainage. External drainage should be used in all patients with immature pseudocysts and in critically ill patients with mature pseudocysts not juxtaposed to a portion of the upper gastrointestinal tract. Internal drainage is a safer and more effective procedure in most other patients with mature pseudocysts, irrespective of the clinical status of the patient.