Changes in vasopressin use and outcomes in surgical intensive care unit patients with septic shock.

INTRODUCTION: This study compares recent vasopressin use and outcomes to our early practice when vasopressin was introduced for septic shock. METHODS: Charts of Surgical Intensive Care Unit (SICU) patients receiving vasopressin for septic shock in 2005-2006 (05-06 cohort,) were retrospectively reviewed. Demographics, APACHE II, hemodynamic variables, and vasoactive drug data were compared to a similar 1999-2000 cohort (99-00 cohort). Statistical analysis included general linear model, Chi-square, t-test, and Cox-regression (p < 0.05 considered significant). RESULTS: Thirty-one SICU patients in the 05-06 cohort and twenty patients in the 99-00 cohort met study criteria. Age, weight, gender, intensive care length of stay and vasopressin treatment duration were similar in the two groups. APACHE II (23 +/- 7 versus 34 +/- 9), baseline vasopressin dose (2.2 +/- 1.4 units/hour versus 5.3 +/- 6.7 units/hour), and SICU survival rate (45% versus 15%) significantly changed between the two time periods (p < 0.01). The mean arterial pressure increased significantly from baseline at all measured time points in both groups (p < 0.05). Vasopressin and dopamine doses were significantly lower in the 05-06 cohort versus the 99-00 cohort (p < 0.05). By Cox regression analysis the survival function adjusted for APACHE II was significantly different between groups. CONCLUSIONS: Vasopressin is recently used at lower doses and in less severe septic shock. Patients recently treated with vasopressin have a higher SICU survival rate than the survival rate when vasopressin was first introduced for septic shock.

Tobramycin pharmacokinetics in morbidly obese patients.

Tobramycin kinetics were examined in 9 morbidly obese women following a single intravenous (120 mg) bolus. After the injection, serum elimination conformed to a 2-compartment open model with alpha and beta t1/2s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 1/kg ideal body weight (IBW) and 0.20 1/kg total body weight (TBW). To normalize Varea to 0.26 1/kg, 58% of the patients' adipose weight (TBW -- IBW) must also be taken into account.

The use of a cosyntropin stimulation test to predict adrenal suppression in renal transplant patients being withdrawn from prednisone.

Eighteen renal transplant patients were studied to identify predictors of steroid-induced adrenal suppression. A cosyntropin adrenal stimulation test was administered to each patient and the response was correlated with the past transplant course and their subsequent prognosis. Eight (44%) of the 18 patients studied had a suppressed cosyntropin stimulation test. The suppressed adrenal response could not be predicted accurately by any one factor, although a history of a total prednisone dose greater than 25 g or a duration of steroid therapy of more than 12 months occurred more often among the suppressed patients. Four of the five deaths occurred among the suppressed patients. These deaths occurred despite maintenance of steroid administration. The cosyntropin stimulation test can be easily performed to identify renal transplant patients at risk of steroid-induced adrenal suppression when rapid steroid tapering is desired. An unsuppressed response gives assurance that steroid withdrawal is safe.

A technique for porcine hepatocyte harvest and description of differentiated metabolic functions in static culture.

Current bioartificial liver devices are based on the use of a large mass of hepatocytes exhibiting differentiated metabolic function. The pig has become a source of interest for the acquisition of such cells-however, harvesting a large mass of highly viable cells has met with difficulty. This study describes a technique for harvesting large quantities of hepatocytes at viabilities greater than 90% and also describes several features documenting differentiated function. Pigs, 6 to 10 kg body weight, underwent in situ two-step whole liver perfusion (ethylene glycol tetraacetic acid and collagenase) and ex vivo cell harvest. Harvests yielded an average of 19.5 billion cells with an average viability of 94.6%. Hepatocytes were then entrapped in type I collagen (3 x 10(5) cells/well) and cultured in serum-free media for 5 days. Pig hepatocytes produced stable amounts of albumin and maintained cytochrome P-450 and glucuronidation activity over 5 days, as shown by the metabolism of lidocaine and 4-methylumbelliferone. These data indicate that pig hepatocytes can be harvested with high yields and can retain viability and differentiated function over at least 5 days of culture, and therefore should prove to be an excellent source of hepatocytes for bioartificial liver devices.

Extracorporeal application of a gel-entrapment, bioartificial liver: demonstration of drug metabolism and other biochemical functions.

Metabolic activity of a gel-entrapment, hollow fiber, bioartificial liver was evaluated in vitro and during extracorporeal hemoperfusion in an anhepatic rabbit model. The bioartificial liver contained either 100 million rat hepatocytes (n = 12), fibroblasts (n = 3), or no cells (n = 7) during hemoperfusion of anhepatic rabbits. Eight other anhepatic rabbits were studied without hemoperfusion as anhepatic controls, and three sham rabbits served as normal controls. Albumin production rates (mean +/- SEM) were similar during in vitro (17.0 +/- 2.8 micrograms/h) and extracorporeal (18.0 +/- 4.0 micrograms/h) application of the hepatocyte bioartificial liver. Exogenous glucose requirements were reduced (p < 0.01) and euglycemia was prolonged (p < 0.001) in anhepatic rabbits treated with the hepatocyte bioartificial liver. The maximum rate of glucose production by the hepatocyte bioartificial liver ranged from 50-80 micrograms/h. Plasma concentrations of aromatic amino acids, proline, alanine, and ammonia were normalized in anhepatic rabbits during hepatocyte hemoperfusion. Gel-entrapped hepatocytes in the bioartifical liver performed sulfation and glucuronidation of 4-methylumbelliferone. P450 activity was demonstrated during both in vitro and extracorporeal application of the BAL device by the formation of 3-hydroxy-lidocaine, the major metabolite of lidocaine biotransformation by gel-entrapped rat hepatocytes. In summary, a gel-entrapment, bioartificial liver performed multiple hepatocyte-specific functions without adverse side effects during extracorporeal application in an anhepatic, small animal model. With its potential for short term support of acute liver failure, scale-up of the current bioartificial liver device is indicated for further investigations in large animal, preclinical trials.

Selective gut decontamination reduces nosocomial infections and length of stay but not mortality or organ failure in surgical intensive care unit patients.

Suppression of the gut luminal aerobic flora to reduce nosocomial infections was tested in a prospective, randomized, double-blind, placebo-controlled clinical trial in patients in a surgical intensive care unit who had persistent hypermetabolism. Forty-six patients were randomized to receive either norfloxacin, 500-mg suspension every 8 hours, together with nystatin, 1 million units every 6 hours, or matching placebo solutions administered through a nasogastric tube within 48 hours of surgical intensive care unit admission. Selective gut decontamination with the experimental therapy or placebo solutions continued for at least 5 days or until the time of surgical intensive care unit discharge. Patients were monitored with routine surveillance cultures for the development of nosocomial infections, as defined by criteria from the Centers for Disease Control. All other therapy was given as clinically indicated, including systemic antibiotics. The selective gut decontamination group experienced a significant reduction in the incidence of nosocomial infections and a reduced length of stay. However, these results were not associated with a concomitant decrease in progressive multiple organ failure syndrome, adult respiratory distress syndrome, or mortality.

Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients.

We compared pharmacokinetic parameters derived from three aminoglycoside serum concentration sampling methods and evaluated their effects on recommended aminoglycoside dosing regimens in 60 critically ill surgery patients. Patients had presumed or documented gram-negative sepsis, and had at least 4 aminoglycoside serum concentrations measured. We used a one-compartment model for peak and trough, 3-point series, and 4-point series sampling methods. Dosing regimens were calculated for each patient based on values derived from each method. We found differences in regimens for nearly 50% of patients if either 4- or 3-point series sampling was used to calculate the recommended dosage rather than peak and trough sampling. However, the 3-point method required a clinically significant change in regimen in only 12% of patients compared with 4-point sampling. The variability of all values derived from 3-point sampling were well accounted for by the 4-point method (r2 > 0.80). In addition, we noted significantly greater relative precision for 3-point sampling than peak and trough sampling for estimates of clearance, elimination rate, recommended daily dosage, and recommended dosing frequency. We recommend three optimally timed samples be drawn instead of peak and trough levels in dosing aminoglycosides in critically ill surgery patients.

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis.

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacy technology of the ICU. Today and tomorrow.

This article takes a broad sweep at some of the forces that will impact pharmacy in the intensive care units of tomorrow. Each of the topics covered has journals or societies devoted to these issues. The incredible change from 10 years ago is that one can easily put these topics into a search engine on the Internet and receive more information than it is possible to read in one setting. The challenge to us all is to find ways to maintain a degree of knowledge about these changes that is both timely and considered. The old axiom of not being the first or the last to change is still a safe approach, but the speed at which the decision must be made is ever increasing. We must all put pressure on our professional societies and our employers to assure that we have adequate access to the rapidly developing technology and a level of expert review prior to its adoption. Future technology is already in our intensive care units but what we do with the technology and the information will determine the future healthcare outcomes of our patients.

Extended liver-specific functions of porcine hepatocyte spheroids entrapped in collagen gel.

The potential use of porcine hepatocytes in a bioartificial liver device requires large quantities of viable and highly active cells. To facilitate the scaling up of the system, liver specific activities of hepatocytes should be maximized. One way of enhancing the specific activities is to cultivate hepatocytes as multicellular spheroids. Freshly isolated porcine hepatocytes form spheroids when cultivated in suspended cultures. These spheroids exhibit higher activities for a number of liver specific functions compared to hepatocytes cultivated as monolayers. However, these activities decreased in a few days in culture. Entrappment of spheroids in collagen gel sustained their metabolic activities at a stable level over 21 days. Production of albumin and urea by spheroid hepatocytes entrapped in collagen gels were 2 to 3 times higher than those by freshly isolated single cells. P-450 activity was demonstrated by metabolism of lidocaine to its main metabolite, monoethylglycinexylidide. Phase II drug metabolism was demonstrated by glucuronidation of 4-methylumbelliferone. This work shows that porcine hepatocyte spheroids entrapped in collagen maintain differentiated functions for an extended time period. Such hepatocyte spheroid entrappment system may facilitate the development of a bioartificial liver support device.

Pharmacokinetic analysis verifies P450 function during in vitro and in vivo application of a bioartificial liver.

Lidocaine is a sensitive substrate for evaluating liver P450 function. In this study, metabolism of lidocaine by xenogeneic hepatocytes in a hollow fiber, bioartificial liver was measured under in vitro conditions (n = 6) and in an anhepatic rabbit model. Animals in the treatment group (n = 6) received hemoperfusion by a bioartificial liver that contained 100 million rat hepatocytes. Other anhepatic rabbits received no hemoperfusion (n = 3) or a bioartificial liver with no cells (n = 3). Lidocaine clearance was 7.0 +/- 0.6 ml/min, and the half-life of lidocaine was 5.6 +/- 0.8 hr under in vitro conditions. Conversion of lidocaine to 3-hydroxy-lidocaine was confirmed in vitro and accounted for 46% of lidocaine elimination in the hepatocyte bioartificial liver. During in vivo application of the bioartificial liver, pharmacokinetic parameters of lidocaine metabolism, including drug half-life and metabolite formation, were significantly improved in anhepatic rabbits. 3-Hydroxy-lidocaine profiles verified the activity of a P450 isozyme expressed preferentially by rat hepatocytes in the bioartificial liver. We conclude that hepatic P450 activity was provided by xenogeneic hepatocytes during in vitro and in vivo applications of a bioartificial liver.

Immunotherapy targets in critical care.

Advances in our understanding of the immune system and the body's normal response to injury have allowed for the development of innovative new therapies for critically ill patients. In the area of sepsis, significant information is being generated to support the concept that adjunctive immunotherapy can improve both morbidity and mortality. Investigational agents directed at immunotherapy targets that are currently being studied include colony stimulating factors, immunoglobulins, anticytokines, and opioid antagonists. This article reviews the basis for the use of such adjunctive immunotherapy in the critically ill patient.

Moricizine: a new class I antiarrhythmic.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.

Intrinsic sympathomimetic activity: physiological reality or marketing phenomenon.

Intrinsic sympathomimetic activity (ISA) describes the partial beta-adrenergic agonist responses elicited by a series of beta-adrenergic antagonists. The dual effect on the beta-adrenergic receptor appears to be related to structural specificity of the drugs allowing competitive binding to the receptor (antagonist activity) and partial interaction at the receptor's activation site (agonist activity). The clinical effects of a beta-adrenergic antagonist with ISA depend on the relative balance of the drug's inherent antagonist and agonist activity and on the degree of underlying sympathetic tone in the patient. Theoretically, the agonist activity may be beneficial in the patient in whom beta-adrenergic antagonists are indicated, but who has concomitant bradycardia and/or mild to moderate congestive heart failure or compromised pulmonary function, or in the patient being withdrawn from beta-adrenergic antagonist therapy. There is positive evidence from clinical trials that in select patient populations a few of these benefits of ISA are afforded without compromise to beta-adrenergic antagonist activity. However, predisposing factors such as acute illness and individual idiosyncrasies may interfere with the manifestations of the agonist effects. Further, maximal response to full beta-adrenergic agonists will be diminished by concurrent therapy with beta-adrenergic antagonists regardless of ISA presence. In summary, ISA does have a physiological basis and increased experience in larger patient populations will help to place it in proper clinical perspective.

Cefamandole distribution in serum, adipose tissue, and wound drainage in morbidly obese patients.

Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidly obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, wound drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p less than 0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p less than 0.01) postoperatively. The patients had a mean (+/- SD) volume of the central compartment of 10.3 (+/- 2.3) L, volume at steady state of 18.3 (+/- 3.9) L, and elimination rate constant of 1.67 (+/- 0.63) h-1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were less than 1 microgram/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 micrograms/ml during a dosing interval and dropped to 7 micrograms/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations greater than 1 microgram/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidly obese patients.

Effect of pH on disintegration and dissolution of ketoconazole tablets.

The effect of pH on the in vitro disintegration, dissolution, and solubility of ketoconazole tablets was studied. One 200-mg ketoconazole tablet was added to each of five different buffer solutions having pH values of 2 to 6;900 ml of each solution containing the ketoconazole was placed in a stationary basket dissolution device and stirred at 500 rpm at 37 degrees C for 60 minutes. Single 1-ml samples of each solution were obtained at 1,3, and 5 minutes after addition of the drug, and then every 5 minutes for the duration of the sampling period. This same procedure was repeated using two 200-mg tablets in the buffer solution at pH 3. The effect of pH on ketoconazole solubility was studied by gradually increasing the pH of a ketoconazole solution at pH 3 to pH 10. Samples of this solution were analyzed periodically after allowing a short period for equilibration of pH. All samples were assayed spectrophotometrically against blanks, and concentrations were determined by comparison with a standard curve. Disintegration of ketoconazole tablets occurred within 5 minutes in each buffer solution and was unaffected by pH. At pH 2 and 3, dissolution of ketoconazole was greater than 85% complete after five minutes, and all ketoconazole had dissolved after 30 minutes. As pH increased, the rate and extent of dissolution slowed; only 10% of ketoconazole was dissolved after 60 minutes at pH 6. Ketoconazole precipitated rapidly from solution as the pH of the dissolution medium exceeded 5.5. There was no difference in the rate or extent of dissolution of ketoconazole for the two doses studied at pH 3. In the buffer solutions tested, dissolution but not disintegration of ketoconazole tablets is pH-dependent. Dissolution characteristics of 200- and 400-mg doses of ketoconazole are similar at pH 3.

Acute renal failure.

Acute renal failure (ARF) is common among critically ill patients and renal dysfunction is often associated with the multisystem organ failure syndrome. The mortality of ARF remains high but animal data indicate that prevention and early treatment may decrease the morbidity and mortality. This review defines ARF based on urine volume, laboratory parameters, and clinical presentation. The pathophysiology of prerenal, postrenal, and intrinsic ART are differentiated and diagnostic criteria provided. Preventive therapy, supportive care, and proposed treatments are outlined. Studies examining the prevention and treatment of ARF in animal models and trials in humans are evaluated. Mannitol 0.5-1 g/kg, furosemide 0.5-1 mg/kg initially, and dopamine 1-5 micrograms/kg/min are effective in preventing or decreasing the severity of ARF in animal models. In humans these drugs are effective at maintaining urine output in various clinical situations and converting oliguria to nonoliguria in some patients; however, increased survival has not been adequately proven as of yet. Dialysis and experimental therapy are briefly discussed.

Effect of infusion pump fill-stroke flow interruption on response to sodium nitroprusside in surgical patients.

The influence of the piston-cassette pump fill stroke on the pharmacodynamic response to sodium nitroprusside was evaluated prospectively in 10 adult patients in the surgical intensive-care unit. Simultaneous analog recordings of blood pressure and fill stroke were made over three complete pump fill cycles in each patient. Sodium nitroprusside flow rates and concentrations were recorded throughout the data-collection period. Analysis was based on the maximum pressure obtained during the two-minute baseline period before a fill stroke (Pmax baseline), the pressure at the initiation of the fill stroke (P initial), and the maximum pressure obtained during the two-minute period after the fill stroke (Pmax postfill). The maximum systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) during the baseline and post-fill-stroke periods were significantly different. The mean (+/- S.D.) variability in pressure between the time periods Pmax baseline and Pmax postfill was 3.9 +/- 5.8 mm Hg for SBP (range, -8 to +16), 3.5 +/- 5.7 mm Hg for DBP (range, -7 to +13), and 3.6 +/- 5.6 mm Hg for MBP (range, -7 to +14). The likelihood of a pharmacodynamic change was inconsistent both between and within patients. Within patients the difference between cycles for the variability between time periods ranged from a minimum of 2 mm Hg to a maximum of 16 mm Hg for SBP, 2 mm Hg to 17 mm Hg for DBP, and 1 mm Hg to 17 mm Hg for MBP. The variability within the baseline period (Pmax baseline - P initial) in SBP was significantly greater than the variability between the time periods, while the differences for DBP and MBP were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)