Effect of rate of enteral nutrient supply on gut mass.

Early enteral feeding after injury is important for maintenance of gut integrity. However, enteral nutrients are frequently administered at low rates because of decreased gastrointestinal motility. These low rates are said to "maintain the gut." This study was performed to evaluate the effect of rate of enteral nutrient delivery on gut mass. Six male Sprague-Dawley rats had no surgery and served as controls (ad libitum rat chow diet). Twenty-four male Sprague-Dawley rats underwent abdominal surgery for placement of gastroduodenal feeding tubes (tip located 2 cm into intestine from pylorus) and were randomized (n = 6 per group) to ad libitum rat chow, 1/2 strength peptide diet (Reabilan HN, RHN) at 1 mL/h (1/2RHN-1 mL), full-strength peptide diet at 2 mL/h (RHN-2 mL), or full-strength peptide diet at 4 mL/h (RHN-4 mL). These diets supplied approximately 30%, 13%, 50%, and 100% of rat recommended daily allowances. The control animals gained weight (38 +/- 3 g over 5 days) whereas all postsurgery animals lost weight. Weight loss was greatest in the 1/2 RHN-1 mL (-55 +/- 3 g over 5 days) and RHN-2 mL (-52 +/- 6 g over 5 days) groups compared with the RHN-4 mL animals (-41 +/- 5 g over 5 days). All animals fed liquid enteral diets had reduced gut weights compared with chow-fed animals. Gut weights did not differ between control and postsurgery ad libitum chow animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of dopamine in healthy male subjects

BACKGROUND: Dopamine is an agonist of alpha, beta, and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model. METHODS: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 microg x kg(-1) x min(-1) for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 microg x kg(-1) x min(-1) for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine. RESULTS: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 microg x kg(-1) x min(-1). Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-microg x kg(-1) x min(-1) infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion. CONCLUSIONS: Despite a homogeneous population of healthy male subjects and weight-based dosing, there was 10- to 75-fold intersubject variability in plasma dopamine concentrations, making standard pharmacokinetic modeling of less utility than for other drugs. The data suggest marked intraindividual and interindividual variability in dopamine distribution and/or metabolism. Thus, plasma dopamine concentrations in patients receiving dopamine infusion at identical rates may vary profoundly. Our data suggest that dosing dopamine based on body weight does not yield predictable blood concentrations.     

Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow

Dexmedetomidine is a selective alpha(2)-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24-48 yr, were infused with a 1 micro g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 micro g. kg(-1). h(-1) (LOW DEX) and 0.6 micro g. kg(-1). h(-1) (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL. 100 g(-1). min(-1) [95% confidence interval, 72-114] to 64 mL. 100 g(-1). min(-1) [51-81] LOW DEX and 61 mL. 100 g(-1). min(-1) [48-76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524-732] to 380 pg/mL [253-507]). IMPLICATIONS: Dexmedetomidine-induced sedation decreased cerebral blood flow (CBF) by congruent with 33%, which could be due to direct alpha(2)-receptor cerebral smooth muscle vasoconstriction or to compensatory CBF changes caused by dexmedetomidine-induced decreases in the cerebral metabolic rate.     

The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers

Despite its long use in clinical medicine, protamine concentrations and pharmacokinetics in humans have not been reported. The occasional reoccurrence of anticoagulation after protamine reversal of heparin led us to hypothesize that protamine plasma concentrations decrease rapidly. We developed a method for the measurement of protamine in plasma. Eighteen fit volunteers gave their consent to receive 0.5 mg/kg protamine sulfate administered IV by an infusion pump over 10 min. Heart rate, mean arterial blood pressure, and cardiac output, all measured noninvasively, were recorded and blood samples obtained during and after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. The administration of protamine was associated with no significant changes in heart rate, mean arterial blood pressure, or cardiac output. Plasma protamine concentrations decreased rapidly, becoming nondetectable within approximately 20 min. Protamine elimination differed significantly between men and women: men had significantly larger areas under the concentration versus time curve. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution at steady state, 12.3 (6.9--63.1) L; clearance, 2.2 (1.1--12.1) L/min; and t1/2, 7.4 (5.9--9.3) min. Concentration versus time plots revealed an atypical pattern inconsistent with usual exponential models. The Schwartz-Bayesian criterion identified a one-compartment Michaelis-Menten model and a two-compartment exponential model with irreversible binding as performing better than conventional one- or two-compartmental exponential models; however, performance errors were large with both Michaelis-Menten and exponential models. All models described rapid decreases in protamine blood concentrations. IMPLICATIONS: We developed a method for measurement of protamine in human blood. In volunteers, protamine concentrations decreased rapidly after administration. The rapid disappearance of protamine from the circulation, as defined by a median half-life of 7.4 min, could contribute to cases of "heparin rebound" after initial adequate reversal of heparin.     

Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass

BACKGROUND: Despite long use of protamine in cardiac operations, neither protamine concentrations nor pharmacokinetics have been reported in patients. METHODS: Twenty-eight patients (age, 26 to 80 years) undergoing various cardiac surgical procedures gave their consent to receive 250 mg of protamine sulfate administered intravenously by an infusion pump during 5 minutes. Protamine was administered at the usual intraoperative time after separation from cardiopulmonary bypass for reversal of heparin. Timed arterial blood samples were obtained after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. Total (free + heparin-bound) protamine concentration versus time data were subjected to pharmacokinetic modeling. RESULTS: Twenty-six patients completed the study. Total plasma protamine concentrations declined rapidly. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution, 5.4 L (0.82 to 34 L); clearance, 1.4 L/min (0.61 to 3.8 L/min); and half-life, 4.5 min (1.9 to 18 min). Schwarz-Bayesian criterion identified a two-compartment exponential model with adjustment for weight in the central compartment volume of distribution as performing better than other compartmental or Michaelis-Menten models. CONCLUSIONS: Protamine has a very short (approximately 5 minutes) half-life after a single 250-mg dose in adult patients. This short half-life could underlie recurrent anticoagulation after initial apparent reversal of heparin.     

Men are more susceptible than women to direct pressure on unmyelinated ulnar nerve fibers

Ulnar nerve injury, the most common form of perioperative peripheral nerve injury, has a 3:1 male/female predominance. Neither the mechanism of perioperative ulnar nerve injury nor the reasons for the increased male susceptibility are well understood. We used an experimental model with arm flexion at the elbow, direct pressure on the ulnar nerve, and arm ischemia as distinct stress mechanisms to induce adverse changes in ulnar current perception thresholds (CPTs) on 3 groups of 40 male and 40 female volunteers (a total of 240 volunteers). CPT measurements were repeated at 2000-, 250-, and 5-Hz stimulating frequencies, specific to A-beta, A-delta, and unmyelinated C-fibers, respectively. Ischemia produced significant increases in CPT with all three stimulating frequencies, and there were no detectable differences between men and women. Flexion failed to produce significant CPT increases at any of the three stimulating frequencies, with no sex-based differences. Direct pressure produced significant CPT increases at 5 and 250 Hz, indicating inhibition of both unmyelinated C-fibers and myelinated A-delta fibers. C-fibers, but not A-delta fibers, demonstrated sex differences with direct pressure; there was a 1.7-fold (95% confidence interval, 1.2- to 2.4-fold) greater effect in men. Ischemia significantly inhibited the function of all three fiber types, perhaps sufficient to overwhelm gender differences. IMPLICATIONS: The ability of direct pressure to produce a greater inhibition of unmyelinated C-fibers in male subjects compared with female subjects is consistent with, and may help explain, the male increased susceptibility to perioperative ulnar nerve dysfunction.     

Ulnar Nerve Pressure: Influence of Arm Position and Relationship to Somatosensory Evoked Potentials

Background: Although the ulnar nerve is the most frequent site of perioperative neuropathy, the mechanism remains undefined. The ulnar nerve appears particularly susceptible to external pressure as it courses through the superficial condylar groove at the elbow, rendering it vulnerable to direct compression and ischemia. However, there is disagreement among major anesthesia textbooks regarding optimal positioning of the arm during anesthesia.

Methods: To determine which arm position (supination, neutral orientation, or pronation) minimizes external pressure applied to the ulnar nerve, we studied 50 awake, normal volunteers using a computerized pressure sensing mat. An additional group of 15 subjects was tested on an operating Table withtheir arm in 30 [degree sign], 60 [degree sign], and 90 [degree sign] of abduction, as well as in supination, neutral orientation, and pronation. To determine the onset of clinical paresthesia compared to the onset and severity of somatosensory evoked potential (SSEP) electrophysiologic changes, we studied a separate group of 16 male volunteers while applying intentional pressure directly to the ulnar nerve. Data are presented as mean (median; range).

Results: Supination minimizes direct pressure over the ulnar nerve at the elbow (2 mmHg [0; 0-23]; n = 50), compared with both neutral forearm orientation (69 mmHg [22; 0-220]; P < 0.0001), as well as pronation (95 mmHg [61; 0-220]; P < 0.0001). Neutral forearm orientation also results in significantly less pressure over the ulnar nerve compared to pronation (P or= to 20% in N9-N9' amplitude) were detected in 15 of 16 awake males during application of intentional pressure to the ulnar nerve. However, eight of these subjects did not perceive a paresthesia, even as SSEP waveform amplitudes were decreasing 23-72%. Two of these eight subjects manifested severe decreases in SSEP amplitude (>or= to 60%).     

Female Gender Associates with Increased Duration of Intubation and Length of Stay after Coronary Artery Surgery

Background: Females have worse outcome than do males after coronary artery bypass grafting; however, gender effects on length of stay (LOS) outcomes, such as duration of intubation or intensive care unit (ICU) LOS, have not been evaluated previously. The authors hypothesized that adjustment for pertinent preoperative covariates would eliminate any significant effect of gender on duration of intubation, LOS in the ICU after extubation, total ICU LOS, postoperative (exclusive of ICU) LOS, or total postoperative LOS.

Methods: Patients undergoing elective or urgent primary coronary artery bypass grafting surgery at 51 academic health centers in 1995 and 1997 were studied. Unique multivariable statistical models were developed for duration of intubation, ICU LOS after extubation, total ICU LOS, and postoperative (exclusive of ICU and total) LOS to test for independent associations with gender. Preoperative but not intraoperative or postoperative variables were included in the model. P >= 0.01 was considered significant.

Results: All LOSs were of significantly longer duration in females than in males in both the 1995 (n = 1,064) and 1997 (n = 910) data collections. After covariate adjustment, female sex remained associated with significantly longer duration ICU LOS and total postoperative LOS in both the 1995 (female:male ratios 1.30:1 and 1.13:1, respectively) and the 1997 (female:male ratios 1.19:1 and 1.12:1, respectively) data sets. After covariate adjustment, duration of intubation and ICU LOS after extubation were of significantly longer duration in women than men in 1995 (female:male ratios 1.22:1 and 1.39:1, respectively), but the differences were not significant in 1997.     

Magnesium inhibits the hypertensive but not the cardiotonic actions of low-dose epinephrine

Intravenous magnesium supplementation is often used to control cardiac arrhythmias and coronary artery vasospasm resulting from disturbances of magnesium homeostasis after coronary artery bypass surgery. Many such patients also require inotropic drug support of depressed myocardial function. However, increased serum magnesium concentrations directly depress cardiac contractility in animals and may interfere with catecholamine actions. To determine whether small intravenous doses of magnesium sulfate (MgSO4) interfere with the cardiotonic actions of epinephrine, we examined the hemodynamic effects of MgSO4 and epinephrine infusion in 17 cardiac surgical patients on their 1st postoperative day in a prospective, controlled study. In 11 patients, infusion of MgSO4 (7-mg.kg-1 bolus followed by 10 mg.kg-1.h-1 as a continuous infusion) increased serum magnesium concentrations by 44% (mean +/- standard error of the mean [SEM] of 0.8 +/- 0.1 to 1.2 +/- 0.1 mM; P less than 0.01) but had no significant effect on heart rate; mean arterial, central venous, or pulmonary arterial occlusion pressures; or cardiac output. Epinephrine infusion (30 ng.kg-1.min-1) significantly increased cardiac index (2.7 +/- 0.1 to 3.1 +/- 0.21.min-1.m-2; P less than 0.05); this effect was not altered by MgSO4 administration (n = 11). However, MgSO4 significantly blunted epinephrine's hypertensive action and prevented a significant increase in mean arterial pressure during concurrent MgSO4-epinephrine administration. Six placebo control patients were given two sequential infusions of epinephrine separated by a placebo infusion to rule out an effect of time on the hemodynamic response to epinephrine. Mean arterial pressure and cardiac index responses to epinephrine were identical before and after placebo infusion.(ABSTRACT TRUNCATED AT 250 WORDS)