Differential effects of heparin on the early and late phases of hepatic ischemia and reperfusion injury in the pig.

The mechanisms by which heparin protects the liver during induced episodes of liver ischemia-reperfusion are poorly understood. Previous work in a swine model demonstrated that serum levels of glycohydrolases and lipid peroxide peaked within 3 h after 45 minutes of hepatic ischemia followed by reperfusion. Serum levels of lactate dehydrogenase and aspartate aminotransferase peaked 20-24 h later. The aim of this study was to evaluate the effect of heparin on these two-phases of enzyme release, using a pig model of hepatic ischemia-reperfusion injury. Twenty male swine were divided into control (n = 8) and heparin (n = 12) groups. In the heparin group, heparin was administered prior to and concurrent with ischemia-reperfusion. Following 45 min of hepatic ischemia, the levels of beta-galactosidase, beta-glucosidase, acid phosphatase, purine nucleoside phosphorylase, lipid peroxides, lactate dehydrogenase, and aspartate aminotransferase in serum were monitored for up to 166 h and compared to pre-ischemic and control levels. With heparin infusion, the peak levels of beta-galactosidase, beta-glucosidase, and the lipid peroxide were reduced to 50-60% of the control levels. Acid phosphatase and purine nucleoside phosphorylase activities in serum were reduced to 25% and 60%, respectively. The peak concentrations of lactate dehydrogenase and aspartate aminotransferase were reduced to about 25% of the control level. In addition, the serum enzymes of control pigs did not return to pre-ischemic levels until 2 weeks after hepatic ischemia, while they normalized in less than 1 week in the heparin-treated animals. Systemic heparinization had different protective effects on the first and secondary phases of liver injury. These differences may reflect heparin protection of different types of liver cells. The protection of the parenchymal cells may be the combined result of reduced sinusoidal cell injury and the anticoagulant properties of heparin.

Occult splenic abscess: an unrecognized complication of heroin abuse.

Despite increased recognition of surgical problems related to narcotic addiction, splenic abscess has not been commonly recognized as such a complication. Seven male patients with splenic abscess secondary to heroin abuse have been treated. Six had bacterial endocarditis. Symptoms were nonspecific. Splenomegaly in two patients was the only useful physical finding. Five patients had left pleural effusion, of which three were proven to be empyemas. Staphylococcus aureus was the predominant pathogen of of bacterial endocarditis and splenic abscess. The splenic scan was diagnostic. All patients recovered following curative splenectomy.

Hepatocellular function and nutrient blood flow in experimental peritonitis.

The pathophysiologic basis of organ failure and reduced oxygen consumption in peritoneal infection remains undefined. Plausible explanations include alteration of tissue nutrient blood flow and a primary cellular injury that impairs oxygen metabolism. To define this controversy, we created peritonitis in rats by cecal ligation and puncture. Controls had sham operation. Rats were sacrificed at 6 or 18 hours, liver mitochondria were isolated, and oxidative phosphorylation was studied polarographically. In additional animals indocyanine green (ICG) clearance was studied at low (5 mg/kg) or high (15 mg/kg) doses. The low-dose ICG clearance reflects total hepatic blood flow; a Lineweaver-Burk plot of clearance versus the dose permits extrapolation of clearance to an infinite dose as an indicator of cellular function. Mitochondria studied at 6 hours (n = 10) and 18 hours (n = 10) indicated no differences when compared to paired controls. ICG clearance was unchanged between peritonitis and control rats at 6 hours. However, at 18 hours peritonitis rats had a prolonged half-life of 2.49 +/- 0.31 minutes for the low-dose and 5.29 +/- 0.41 minutes for the high-dose compared to 1.65 +/- 0.07 and 4.34 +/- 0.10 minutes, respectively, for the controls. The Lineweaver-Burk plot of clearance versus dose resulted in peritonitis and control clearance rates intercepting each other at an extrapolated infinite dose. These data indicate that hepatocellular function measured by mitochondrial function and ICG clearance was unaltered. Low-dose ICG clearance indicated reduced total hepatic blood flow. The reduced oxygen consumption in peritonitis appears to have its genesis in altered nutrient blood flow.

The effects of acidosis on canine hepatic and renal oxidative phosphorylation.

The intracellular effects of acidosis remain poorly defined. To examine the effects of acidosis on oxidative phosphorylation, liver biopsies and weight nephrectomies were performed on 10 adult German shepherd dogs. The mitochondria were isolated from each tissue and their respiratory activity was studied by the polarographic technique with the pH of the reaction media varied from 5.5 to 8.0. Glutamate and succinate substrates were employed. Results showed a dramatic reduction in the efficiency of oxygen utilization by mitochondria with glutamate as the reaction medium became more acidic. The efficiency of succinate oxidation was significantly (P less than 0.01) preserved. These findings were confirmed by both the respiratory control indices and by ADP:O ratios. Acidosis appears to result in severe inhibition of NAD-linked energy substrate oxidation.

Effective organ blood flow and bioenergy status in murine peritonitis.

Whether organ dysfunction frequently encountered in overwhelming bacterial sepsis is a result of a direct cellular "toxic" effect or diminished cellular perfusion remains controversial. To assess the effects of peritonitis on cellular energy status and visceral blood flow, peritonitis was induced in rats by means of cecal ligation and perforation. Five, 10, or 20 hours after cecal ligation and perforation, cardiac outputs were determined by thermodilution, effective hepatic blood flow was determined by low-dose galactose clearance, and effective renal plasma flow was determined by paraminohippuric acid clearance. In similar groups of rats with peritonitis or sham controls, tissue samples of liver, kidney, and skeletal muscle were obtained by freeze-clamp technique for analysis of adenine nucleotides, energy charge, pyruvate, lactate, and pyruvate/lactate ratios (P/L). Despite an increase in cardiac output (p less than 0.05), results indicated in this model that effective hepatic blood flow and effective renal plasma flow were significantly reduced (p less than 0.05). The energy charge and P/L ratios of hepatic (p less than 0.01) and renal (p less than 0.05) tissues were also decreased. In contrast, skeletal muscle energy charge and P/L ratio were unchanged by 20 hours duration. These data support the hypothesis of diminished visceral perfusion as contributory to the cellular dysfunction observed in sepsis. Skeletal muscle appears either nonischemic or more tolerant of ischemia in sepsis.

Hepatic cellular hypoxia in murine peritonitis.

Reduced oxygen consumption and lactic acidosis were observed frequently in patients with peritonitis. This study was designed to evaluate whether reduced oxygen consumption is secondary to deficient oxygen delivery or is a function of primary injury to mitochondria. Peritonitis was produced in rats by cecal ligation and perforation. Animals were killed at 2, 4, and 6 hours and agonally. Oxygen utilization was studied polarographically in isolated hepatic mitochondria with glutamate, pyruvate, and succinate substrates. State 3, state 4, respiratory control index (RCI), and ADP:O ratios were determined. Whole tissue and isolated mitochondrial ultrastructure were examined by electron microscopy. Systemic blood pressure and oxygenation were monitored. Hepatic tissue oxygenation was examined using a surface oxygen electrode. Peritonitis resulted in acceleration of state 3 respiratory rates and increased respiratory control indices at all time intervals. Maximal respiratory control was observed at 4 hours with all substrates. Whole tissue mitochondria demonstrated mild swelling and thinning of membranes and matrix. Experimental and control isolates showed similar orthodox-to-condensed conformational changes. Hepatic tissue oxygenation declined to less than 10% of control by 6 hours, while arterial Po2 was unchanged. The conclusions of this study are that lethal peritonitis results in (1) no primary injury to the hepatic mitochondria, (2) increased efficiency of hepatic mitochondrial oxygen utilization, and (3) reduced hepatic tissue oxygenation. The exact mechanisms of defective oxygen delivery require further study.

Breast cancer survival and perioperative blood transfusion.

The effect of perioperative blood transfusion on disease-free and overall survival was studied in 812 patients with stages I and II breast cancer, followed up prospectively in a multicenter study. All patients initially underwent a modified radical mastectomy. Patients with axillary node-negative, stage I cancer were followed up without additional therapy. Patients with axillary node-positive, stage II cancer were randomized to receive adjuvant chemoendocrine therapy. Transfusion was done in 35.8% of the patients with stage I and in 37.3% of the patients with stage II cancer. For the patients with stage II cancer, perioperative blood transfusion did not affect disease-free or overall survival. For the patients with stage I cancer, perioperative blood transfusion resulted in a worse disease-free and overall survival (p = 0.05 and 0.02, respectively), which was particularly evident for those patients who received more than 1 unit. This study suggests that stage of disease, adjuvant therapy, number of transfusions, and duration of follow-up must be considered in further analyses.

Bioenergy metabolism of gastric mucosa during stress.

Previous studies have identified a cellular energy deficit in gastric mucosa after ischemia. We studied the processes of energy generation (mitochondrial function) and energy utilization (microsomal adenosine triphosphatase [ATPase] activity) in an experimental model of stress. Rabbits were divided into four groups: I, fed controls (n = 7); II, 24-hour fasted controls (n = 7); III, fasted, anesthetized, and cannulated controls (n = 7); and IV, fasted, anesthetized, cannulated, and bled rabbits. Bleeding consisted of 25 ml blood/kg into a reservoir for 60 minutes; the blood was then reinfused. Animals were killed 30 minutes after reinfusion; antral, corpus, and fundus mucosae were dissected; each region of mucosa was homogenized; and mitochondrial and microsomal fractions were isolated by differential centrifugation. No animals in group I or II had gastric ulcerations. Three of seven animals in group III and all group IV animals had corpus and fundus ulcers. No antral ulcers were seen in any group. The respiratory control index (RCI) of antral mitochondria was increased in groups II, III, and IV but was unchanged in all groups of corpus and fundus mitochondria. Studies of microsomal ATPase activity indicated increased activity of potassium-stimulated ATPase in the corpus mucosa. In the corpus mucosa, total ATPase activity was increased primarily as a consequence of increased potassium-stimulated ATPase. These data indicate that increased RCI is associated with gastric mucosal integrity in the antrum. Accelerated utilization of available adenosine triphosphate by corpus membrane ATPases may further compromise energy homeostasis during stress.

Effects of systemic hyperthermia on the growth patterns of experimental neoplasms.

Hyperthermia has been shown to have a detrimental effect on experimental and human neoplasms. A water bath immersion system is described to evaluate the effects of systemic hyperthermia (SH) on the growth patterns of the Morris hepatoma 7777 in male Buffalo rats. SH and anesthesia were observed to have no long-term detrimental effects on weight trends or chow consumption. Inhibition of growth was demonstrated for this experimental tumor model at extreme SH (41.5 degree to 42.0 degree C), and it was statistically different (P less than 0.01) from the patterns of tumor growth observed in controls and tumor-burdened animals treated with moderate SH (39..5 degree to 40.0 degree C). Cessation of extreme SH resulted in acceleration of tumor growth so that no difference in tumor volume or animal survival was identified SH resulted in retardation of tumor growth patterns, but its effects were not sustained once treatments were stopped.

Determinants of death in patients with intraabdominal abscess.

To better define determinants of death in patients with intraabdominal abscess, 143 patients from a 5-year hospital experience were reviewed. Abscesses were most commonly results of trauma, spontaneous gastrointestinal perforations, and technical errors. Clinical presentation of abscess was quite variable as were criteria to justify reoperation for drainage. Abscesses occurred most commonly in the subphrenic space, pelvis, or subhepatic space. Complete abdominal exploration was employed most frequently for drainage. Those factors that were associated with a fatal outcome were: organ failure (P < 0.001), lesser sac abscess (P < 0.001), positive blood culture (P < 0.01), recurrent and/or persistent abscess (P < 0.01), multiple abscesses (P pE 0.01), age > 50 years (P < 0.03), and subhepatic abscess (P < 0.03). These data suggest that deaths from abdominal abscess are consequences of ineffective surgical drainage and failure of host defense mechanisms.

Abdominal wall repair with polypropylene mesh in pregnancy.

A woman in her 34th week of gestation required emergency appendectomy for perforation, with postoperative wound dehiscence secondary to fasciitis and tension on the suture line. Polypropylene mesh was used to repair the abdominal wall. Fetal distress necessitated a cesarean section. The mother and child both survived without functional impairment. The indications, the disadvantages, and the unresolved issues concerning the use of polypropylene mesh during pregnancy are presented.

The reemergence of mycobacterial infections.

In the early half of this century, infections due to Mycobacterium tuberculosis were quite common and were frequent causes of death and morbidity among the world population. Surgeons in the 1930s were quite sensitive to making the diagnosis of tuberculosis. All surgeons had considerable experience with thoracic surgical procedures for pulmonary tuberculosis. Moreover, tuberculosis was a significant cause of occupational infection among surgeons and other physicians. Thus, being able to diagnose the disease quickly and accurately was not only in the patient's best interest, but also allowed appropriate precautions to be exercised so that occupational infections of the health care team could be minimized.

Antibiotic pharmacokinetics in surgery.

Pharmacokinetics is the study of variables that affect drug concentrations at the effector site. The descriptive terms peak concentration, elimination half-life, volume of distribution, and bioavailability are commonly used to express pharmacokinetic variability among drugs used in patient care. The pharmacokinetic characteristics of drugs are important for surgeons to understand because they represent differences that may assume clinical significance when selecting antibiotics for preoperative preventive indications. In addition, the changing hemodynamic pattern of the stressed and septic patient may result in changing pharmacokinetic patterns for an antibiotic, which, in turn, may require changes in the dosing regimen during the course of treatment.

Iatrogenic ureteral injury. Options in management.

Twenty-five patients sustained 27 iatrogenic ureteral injuries during various operative procedures. Injuries were managed by ureteroureterostomy in 11 injuries, ureteroneocystostomy in 11, nephrectomy in two, ureteral stent in one, cutaneous ureterostomy in one, and reimplantation into an ileal conduit in one. Four of 25 patients died, three as a result of the failure of ureteral repair and intra-abdominal sepsis. Short-term failure of repair occurred in five patients; long-term failure occurred in three. All patients with injuries missed during the primary operation had poor results of ureteral reconstruction. Immediate recognition of accidental ureteral injury provides optimum results. Injuries within 4 cm of the ureterovesical junction are managed by ureteroneocystostomy; injuries greater than 4 cm, by ureteroureterostomy. Crush injuries require immediate placement of a ureteral stent. Prior pelvic radiotherapy or intra-abdominal infection should preclude any attempt at primary reconstruction.

Serum kinetics of intraperitoneal moxalactam.

Continuous intraperitoneal administration of antibiotics has been recommended as treatment for peritonitis. The necessity of simultaneous systemic administration of antibiotics remains undefined but usually is performed. Moxalactam kinetics in serum were studied in dogs receiving 15 mg/kg intravenously; 15 mg/kg intraperitoneally; 5 mg/kg hourly with peritoneal lavage; 15 mg/kg intravenously followed by 5 mg/kg hourly intraperitoneally; 15 mg/kg intraperitoneally after 24 hours of peritonitis; and 5 mg/kg hourly by peritoneal lavage after 24 hours of peritonitis. Intraperitoneally administered moxalactam resulted in sustained serum levels compared with intravenously administered drugs. Repeated exchanges in lavage fluid resulted in progressively higher serum levels with each exchange. Peritonitis results in statistically higher levels of serum antibiotic concentration when compared with controls. Continuous intraperitoneal lavage with antibiotics would not appear to require concomitant systemic drug therapy.

Recombinant human tumor necrosis factor produces hemodynamic changes characteristic of sepsis and endotoxemia.

Tumor necrosis factor (TNF) is a macrophage-derived peptide mediator released during endotoxemia and sepsis. We examined the systemic and visceral hemodynamic response to low doses of human recombinant TNF in rats. Each animal received a 30-minute intravenous infusion of either saline solution (n = 8) or TNF (n = 8) in a dose of 0.25 mg/kg or 1.0 mg/kg. Thermodilution cardiac output, blood pressure, pulse, vascular resistance, effective hepatic blood flow (galactose clearance), and effective renal plasma flow (p-aminohippurate clearance) were determined at time = 2 hours. The 0.25-mg/kg dose had no apparent effect on systemic hemodynamics. The 1.0-mg/kg dose produced a hyperdynamic systemic circulatory response with an elevated cardiac output, tachycardia, and a diminished systemic vascular resistance. Effective hepatic blood flow was exquisitely sensitive to even the lowest dose of TNF, with a 29% reduction despite the normal cardiac output. Renal flow was unaffected by either dose. Tumor necrosis factor-induced systemic and visceral hemodynamic changes are remarkably similar to those seen in gram-negative sepsis, suggesting that TNF may occupy a proximal position in the pathogenesis of overwhelming infection.

Candida sepsis. Implications of polymicrobial blood-borne infection.

Eighty-three patients with 117 episodes of candidemia were reviewed to examine the clinically significant variables and the results of treatment for this problem. Mortality was 52%. Patients who had bacteremia either synchronously or metachronously in association with Candida species had poorer survival rates. Staphylococcal and enterococcal species were the most frequently associated bacteria. Patients with Candida parapsilosis had better survival rates than patients with other species. Portals of entry for fungemia were catheters, wounds, the urinary tract, and the peritoneal cavity, but were undefined in 54% of patients. Antifungal chemotherapy could not be identified as affecting the outcome in these patients. It is suggested that candidemia in most patients represents a failure of host defense, and that septicemia of either bacteria or fungi may arise from the gastrointestinal tract in critically ill, immunocompromised patients.

Early urgent relaparotomy.

We analyzed the indications for and implications of reoperation in 113 patients who required early urgent relaparotomy. Infection with intact organs was the most common indication, causing the most diagnostic difficulties, and presenting the most varied findings. Suture-line leaks and dehiscence were next in frequency. Bleeding caused the earliest relaparotomies and obstruction, the latest. In seven patients a technical error at the primary laparotomy was identified, and in 56 patients an error of some sort was presumed. High-mortality categories were identified, including the elderly, who were particularly susceptible if bleeding or after an emergency primary laparotomy. An aggressive policy of reoperation resulted in 59 survivors and seems to be the only practical approach in the treatment of these usually desperately ill patients.

Closure of an acute perforated peptic ulcer with the falciform ligament.

When management of a perforated peptic ulcer necessitates simple closure, the omentum may not be of adequate quality to buttress such a closure. In this unusual circunstance, we have found the falciform ligament to serve as an effective alternative to satisfactorily peptic perforations.

Systemic prophylactic antibiotics: need the 'cost' be so high?

To assess compliance with accepted principles, the use of prophylaxis with systemic antibiotics in selected specialty procedures was examined. The operations reviewed were aortofemoral bypass, pulmonary resections, open-hip procedures, and head-neck cancer procedures that involve the oropharyngeal cavity. Of all patients, 74% received antibiotics preoperatively and 79% received prophylaxis with antibiotics longer than 24 hours postoperatively. Evaluated against the criteria of preoperative initiation and limited postoperative administration (less than 24 hours) only 10% of the patients received appropriate prophylaxis. A 3% incidence of drug-associated complications was identified; each patient with complications had received antibiotics for a prolonged time postoperatively. Reduction in the length of postoperative prophylaxis with systemic antibiotics will reduce (1) the number of drug-associated complications, (2) selection pressures on the hospital microbial population, and (3) needless expense in hospitalized patients.