A. Craig Eddy

The mechanism of the interaction between amiodarone and warfarin in humans

Amiodarone decreased the total body clearance of both (R)‐ and (S)‐warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)‐warfarin to (R,S)‐warfarin alcohol‐1 and the oxidation of both (R)‐ and (S)‐warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)‐warfarin is more strongly inhibited than that of (R)‐warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P‐450 primarily responsible for the conversion of (S)‐warfarin to its major metabolite, (S)‐7‐hydroxywarfarin.

Empyema thoracis in patients undergoing emergent closed tube thoracostomy for thoracic trauma

The vast majority of thoracic trauma victims require only observation or tube thoracostomy for definitive treatment of their thoracic injury. Although tube thoracostomy is generally considered a limited intervention, 2 to 25 percent of patients who undergo this procedure develop infectious complications. To determine the incidence and risk factors for the development of empyema thoracis after tube thoracostomy, a retrospective study was undertaken. We found that the development of empyema thoracis was increased in patients whose pleural space was incompletely drained and whose thoracic catheters were in place for a prolonged period.

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: In vitro/in vivo correlation

On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (<1 mmol/L) and valpromide (<10 µmol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (K1 = 5 µmol/L) was 100 times more potent than valproic acid (K1 = 550 µmol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration ≈ 113 µmol/L) and 67% by valpromide (blood concentration < 10 µmol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.

The sensitivity of vital signs in identifying major thoracoabdominal hemorrhage

Prehospital and emergency room recordings of hemodynamic vital signs frequently play a major role in the evaluation and treatment of trauma victims. Guidelines for resuscitation and treatment are affected by absolute cutoffs in hemodynamic parameters. To determine the sensitivity of various strata of systolic blood pressure and heart rate in identifying patients with major thoracoabdominal hemorrhage, a 1-year retrospective review was conducted. A third of all patients presented to the emergency department with a normal blood pressure and over three-quarters attained a normal blood pressure during the emergency department evaluation. Although the sensitivity of vital signs in identifying this group of patients improved as the variance from normal increased, standard cutoffs were relatively insensitive. We conclude that normal postinjury vital signs do not predict the absence of potentially life-threatening hemorrhage and abnormal vital signs at any point after injury require investigation to rule out significant blood loss.

Right ventricular dysfunction in multiple trauma victims

We studied 17 victims of multiple trauma and found that right ventricular function can be reliably monitored at the bedside using the thermodilution method. In addition, we noted that right ventricular dysfunction occurred early in victims of major trauma without affecting the left ventricular function. If right ventricular function does not improve, the patient is likely to die. Further studies are needed to determine if early intervention aimed at improving right ventricular function can improve survival.

Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol.

Summary: The inhibitory effect of stiripentol (STP) on disposition of carbamazepine (CBZ) and carbamazepine‐10,11‐epoxide (CBZE) was quantitated to establish CBZ dosage reduction guidelines for future clinical add‐on efficacy trials of STP. In seven epileptic patients, STP (1,500‐3,000 mg/day for 2 weeks) inhibited CBZ clearance by 50± 16% (p = 0.001) and reduced the CBZE/ CBZ plasma ratio by 45 ± 14% (p = 0.0005). The inhibitory effect was gradually manifested over a period of 7–10 days after initiation of STP therapy. In contrast to inhibition of CBZE formation, STP had no effect (p ± 0.05) on elimination clearance or half‐life (t1/2) of CBZE in six healthy volunteers. STP most likely exerts inhibitory effects through inhibition of cytochrome P‐450. This hypothesis was confirmed in the present study by the finding that a therapeutic concentration of STP (7 (μg/mL) inhibited 10,11‐epoxidation of CBZ in human liver microsomes by 40–50%. On the basis of results from this study, we propose that (a) CBZ dosage should be reduced in steps over a period of 7–10 days after initiation of STP, and (b) a CBZ dosage of 4.3 to 8.7 mg/kg/day will maintain therapeutic CBZ plasma levels of 5–10 (μg/mL.

Tricuspid valve repair for tricuspid valve endocarditis: Tricuspid valve “recycling”

Tricuspid valve endocarditis traditionally has been treated with either valve excision or valve replacement. To avoid implantation of foreign material in an infected field, we have applied the principles of mitral valve repair to 4 patients with tricuspid valve endocarditis. On preoperative echocardiography, all patients had 3 to 4+ tricuspid regurgitation, evidence of progressive right ventricular enlargement, and mobile vegetations. In each case, up to three quarters of the anterior leaflet was excised en bloc with infected chordae and papillary muscle heads. Surgical procedures included standard quadrangular resection, conversion to a bicuspid valve, and pericardial patch replacement of the anterior leaflet with mobilization of basal chordae to replace resected marginal chordae. On postoperative echocardiography, tricuspid regurgitation and right ventricular dimensions were reduced in 2 of 4 patients in spite of loss of leaflet tissue. All excised valve tissue demonstrated bacteria on Gram stain or culture. Nonetheless, all repaired valves were successfully sterilized without recurrent infections. Tricuspid valve repair can allow eradication of infection with potential for improving valve competency in complicated tricuspid valve endocarditis.

Influence of Dexmedetomidine and Clonidine on Human Liver Microsomal Alfentanil Metabolism

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of cimetidine on acetaminophen disposition in humans

The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N‐Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3‐hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect.

Anterior sternal retraction for reoperative median sternotomy

The incidence of reoperative median sternotomy for repeat cardiac surgery is increasing. Reoperative median sternotomy is associated with a higher morbidity and mortality than first-time cardiac surgery. A portion of this morbidity and mortality may be due to direct injury to the heart and great vessels in the process of reopening the sternum. We report a new technique utilizing anterior sternal retraction that allows division of adhesions between the undersurface of the sternum and the heart and great vessels under direct vision. This technique enables the surgeon to minimize the risk of serious injury to these underlying structures during reoperative cardiac surgery.