Heparin versus citrate regional anticoagulation during autotransfusion in a porcine intra-abdominal hemorrhage model.

Our objective was to determine the effects of anticoagulants and blood loss on hemodynamic, hematologic, and coagulation parameters following autotransfusion in an animal model of intraabdominal hemorrhage. We performed a prospective, randomized observational animal study at an animal research laboratory at a university medical center. Eight Landrace, domestic pigs, weighing 17-23 kg, each underwent jugular venous and iliac arterial catheterization and laparotomy with retroperitoneal dissection for aortic exposure to simulate an operative environment. Following baseline laboratory and hemodynamic determinations, intra-abdominal hemorrhage was accomplished via aortotomy in three sequential 10 mL/kg blood volumes. After allowing pooling in the exposed retroperitoneum to ensure tissue contact, the shed blood was suctioned, processed, and washed in an autotransfusion device utilizing either heparin (n = 4) or acid-citrate-dextrose (n = 4) as a system anticoagulant. Prior to autologous transfusion, each pig received a 20 mL/kg intravenous bolus of 0.9 per cent saline to treat shock. The processed blood was then infused, and laboratory and hemodynamic measurements were repeated following each cycle of hemorrhage and autotransfusion. Sequential fixed volume hemorrhage resulted in significant reductions in mean arterial pressure. Despite crystalloid infusion and transfusion of processed shed blood, postresuscitation mean arterial pressure did not return to baseline values, with no difference noted between anticoagulant groups. Infusion of increasing volumes of autologous blood resulted in significant reductions in hematocrit, platelet count, fibrinogen, antithrombin III, ionized calcium, and total protein. The decrease in concentration of each variable was independent of the choice of anticoagulant with the exception of antithrombin III, with higher levels noted in animals receiving blood anticoagulated with acid-citrate-dextrose. Prothrombin time and partial thromboplastin time were unaffected by volume of autologous transfusion or choice of anticoagulant. We conclude that changes in hemodynamic, hematologic, and coagulation parameters associated with hemorrhage and autotransfusion appear related more to the volume of blood loss and the cumulative pheresis of plasma than to the choice of anticoagulant.

Pharmacodynamics of antimicrobial therapy in surgery.

INTRODUCTION: "Pharmacodynamics" refers to the relationship of drug concentrations in serum or tissues to effects on biologic systems. Concepts used to describe antimicrobial pharmacodynamics include the minimal inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), and serum bactericidal titers (SBT), as well as post-antibiotic effect. METHODS: Pertinent published literature was identified through a MEDLINE search. RESULTS: Aminoglycosides have a concentration-dependent effect on bacteria killing and possess a relatively long postantibiotic effect. Given these characteristics, single-daily dosing, where the total daily dose with a traditional aminoglycoside regimen is given as one dose, may be more efficacious compared with more frequent dosing. For beta-lactam antimicrobials, bacterial killing is related to the duration of time that the free drug concentration exceeds the bacterial MIC. Beta-lactam antimicrobials have been shown to have no, or a short postantibiotic effect. Beta-lactam antimicrobials may be more effective when administered as continuous intravenous infusions. CONCLUSIONS: Pharmacodynamic variation may result from differences in drug sensitivity among individuals and the nature of the interaction between antimicrobials and microorganisms. Proper use of pharmacokinetic and pharmacodynamic principles can result in more effective and less toxic antimicrobial regimens.

Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation.

OBJECTIVES: Reconstituted human high-density lipoprotein (HDL) can inhibit lipopolysaccharide effects in vivo. The major objectives of this study were to characterize the pharmacokinetics of reconstituted HDL in a stressed large-animal model and to provide preclinical tolerance information in support of use of reconstituted HDL in humans. DESIGN: A randomized, blinded, placebo-controlled trial where each animal received either reconstituted human HDL at a dose of 100 mg/kg (apolipoprotein A-I) or placebo, immediately after hemorrhagic shock and resuscitation. SETTING: Animal laboratory. SUBJECTS: Twelve immature female swine (18 to 25 kg) were studied. INTERVENTIONS: Six to 8 days before shock and study drug administration, animals were anesthesized and catheters were placed in the external jugular vein and abdominal aorta. These catheters were secured to the dorsal surface. On the day of shock, the animals were sedated (alpha-chloralose) and 50 mL/kg of arterial blood was removed over 0.5 hr. One half hour after blood removal, shed blood was infused, which was immediately followed by study drug (reconstituted HDL or placebo), and then by 1 L of lactated Ringer's solution. MEASUREMENTS AND MAIN RESULTS: Physiologic (arterial blood pressure, heart rate, respiratory rate) and laboratory (serum chemistries, hematologic and coagulation studies, and blood gases) measurements were determined intermittently for 96 hrs after the induction of shock. Blood was collected intermittently for 48 hrs after shock for assay of apolipoprotein A-I and phosphatidylcholine in plasma. Reconstituted HDL was well tolerated and did not appear to alter the physiologic responses to shock and resuscitation. HDL transient increase in aspartate aminotransferase concentration was noted in the reconstituted group but this increase normalized by 24 hrs after drug administration. Mean apolipoprotein A-I pharmacokinetic parameters were as follows: half-life 24.5+/-5.3 (SD) hrs; clearance 41.9+/-10 mL/hr; and volume of distribution 1.39+/-0.08 L. The apparent mean half-life of phosphatidylcholine was 5.4+/-0.8 hrs. CONCLUSIONS: Reconstituted human HDL was well tolerated in animals that had undergone hemorrhagic shock with resuscitation. The apolipoprotein component of reconstituted HDL had a relatively long half-life, with distribution limited to the vascular space. These findings support the investigational use of this product in humans.

Combination antibiotic therapy in the management of intra-abdominal infection.

Combination antimicrobial regimens consisting of an agent with activity against gram-negative bacilli (an aminoglycoside) plus an agent with anaerobic activity (usually clindamycin or metronidazole) have traditionally been accepted as the standards for the treatment of intra-abdominal infection. Because of the problems of nephrotoxicity and ototoxicity in patients treated with aminoglycosides, clinical trials have been conducted using alternative combination therapy (e.g., aztreonam plus clindamycin) or single beta-lactam antimicrobial agents. Most clinical trials of intra-abdominal infections have been conducted in relatively small patient populations with a variety of low- and high-risk patients. The newer regimens have demonstrated efficacy equivalent to traditional combination therapy in selected patient populations. When selecting an antimicrobial regimen for treatment of intra-abdominal infection, multiple issues should be considered, including demonstrated efficacy in clinical trials, potential for adverse effects, and cost.

Whole-bowel irrigation for mechanical colon cleansing.

The physiology, solution composition, indications, efficacy, and safety of whole-bowel irrigation (WBI) for mechanical bowel cleansing are reviewed. WBI with isotonic electrolyte solutions produces diarrhea when the infusion rate exceeds the capacity of the intestine to distend and absorb the solution. A number of solutions are used for WBI, including 0.9% sodium chloride, balanced electrolyte solutions, lactated Ringer's, mannitol, and electrolyte solutions containing polyethylene glycol 3350 (PEG). WBI solution administration rates vary from 15-90 mL/min, by oral ingestion or nasogastric tube, with total volumes ranging from 1 to 20 L. The onset of diarrhea occurs as soon as 20 minutes with clearing of the effluent as early as 90 minutes. Faster administration rates appear to shorten overall cleansing time. Two PEG-electrolyte lavage solutions (ELSs) have recently gained FDA approval. The recommended dosage rate is 1.2-1.8 L/hr orally or by nasogastric tube until rectal effluent is clear. In most patients, this requires a maximum of 4-6 L. Initial data indicate that PEG-ELSs are safe for elderly patients and for patients who have an increased risk of fluid overload, but these solutions have not been evaluated in children, pregnant women, or patients with inflammatory bowel disease. WBI is an effective alternative to other regimens for removing fecal material and reducing bowel lumen bacterial counts before colonoscopy and colorectal surgery. Retention of bacterial counts before colonoscopy and colorectal surgery. Retention of excess WBI solution may interfere with the quality of barium enema radiographs; this can be minimized by completing the irrigation the evening before the examination. Gastrointestinal side effects occur in about one third of the patients following WBI, but do not generally require discontinuing the irrigation. Solutions containing PEG with sodium sulfate as the primary electrolyte result in the least net water and electrolyte movement and are preferred over other solutions.