Margaret Wood

Frequency of myocardial infarction, pulmonary embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty

Background There is limited information about the frequency of perioperative complications after elective primary orthopedic total hip and knee arthroplasty in contemporary practice. The purpose of this study was to determine the frequency of clinically relevant myocardial infarction, pulmonary embolism, deep venous thrombosis, and death within 30 days after elective primary hip or knee arthroplasty treated according to contemporary perioperative management. Methods The authors examined the medical records of consecutive patients undergoing hip or knee arthroplasty at their institution in a 10-yr period. Prospectively collected databases were used to identify patients with the diagnosis of myocardial infarction, pulmonary embolism, deep venous thrombosis, or death using strict validation criteria and diagnostic-certainty categories. Results A total of 10,244 patients underwent primary total hip or knee arthroplasty in the period of study. Of these, 224 patients had one or more adverse events (overall event rate: 2.2%; myocardial infarction: 0.4%; pulmonary embolism: 0.7%; deep venous thrombosis: 1.5%; death: 0.5%). Most adverse events (myocardial infarction, pulmonary embolism, and death) increased in frequency with older age, particularly for patients aged 70 yr or older. Myocardial infarction occurred more frequently in male patients. There were no differences in the overall event frequency between types of procedure. However, pulmonary embolism was highest in patients undergoing bilateral knee operations. Conclusions The overall frequency of serious complications within 30 days after primary total hip or knee arthroplasty with contemporary practice was 2.2%. Accurate knowledge of the perioperative risks associated with widely performed elective operations can be used to implement management strategies that may further improve patient outcomes and decrease cost.

Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein.

Background The efflux transporter P-glycoprotein, a member of the adenosine triphosphate–binding cassette superfamily, is a major determinant of the pharmacokinetics and pharmacodynamics of the opioid loperamide, a well-recognized antidiarrheal agent. Animal studies indicate that P-glycoprotein limits morphine entry into the brain. In this study, the authors examined whether other opioids of importance to anesthesiologists such as fentanyl, sufentanil, and alfentanil, and also morphine-6-glucuronide and morphine-3-glucuronide, are P-glycoprotein substrates and whether, in turn, these opioids act also as P-glycoprotein inhibitors. Methods The transcellular movement of the various opioids, including loperamide and morphine, was assessed in L-MDR1 (expressing P-glycoprotein) and LLC-PK1 cell monolayers (P-glycoprotein expression absent). A preferential basal-to-apical versus apical-to-basal transport in the L-MDR cells but not the LLC-PK1 cells is seen for P-glycoprotein substrates. In addition, the effect of the various opioids on the transcellular movement of the prototypical P-glycoprotein substrate digoxin was examined in Caco-2 cell monolayers. IC50 values were calculated according to the Hill equation. Results Loperamide was a substrate showing high dependence on P-glycoprotein in that basal–apical transport was nearly 10-fold greater than in the apical–basal direction in L-MDRI cells. Morphine also showed a basal-to-apical gradient in the L-MDR1 cell monolayer, indicating that it too is a P-glycoprotein substrate, but with less dependence than loperamide in that only 1.5-fold greater basal–apical directional transport was observed. Fentanyl, sufentanil, and alfentanil did not behave as P-glycoprotein substrates, whereas the morphine glucuronides did not cross the cell monolayers at all, whether P-glycoprotein was present or not. Loperamide, sufentanil, fentanyl, and alfentanil inhibited P-glycoprotein–mediated digoxin transport in Caco-2 cells with IC50 values of 2.5, 4.5, 6.5, and 112 &mgr;m, respectively. Morphine and its glucuronides (20 &mgr;m) did not inhibit digoxin (5 &mgr;m) transport in Caco-2 cells, and therefore IC50 values were not determined. Conclusions Opioids have a wide spectrum of P-glycoprotein activity, acting as both substrates and inhibitors, which might contribute to their varying central nervous system–related effects.

Plasma Drug Binding: Implications for Anesthesiologists

The measurement of plasma drug concentrations is now a therapeutic tool widely applied in drug dosage adjustment. It is customary to measure total drug concentrations in either blood or plasma. However, total drug concentration exists in two forms: that which is bound to plasma proteins and other plasma constituents, and that which is free or unbound. The factors influencing drug binding and the pharmacokinetic and pharmacodynamic consequences of altered drug binding will be addressed in subsequent sections of this review. After entry into the systemic circulation, drugs are transported by the blood to their sites of action, metabolism, and excretion. In blood, many drugs are bound to plasma proteins in a reversible manner which may be considered to obey the law of mass action,

The Apgar Score Has Survived the Test of Time

In 1953, Virginia Apgar, M.D. published her proposal for a new method of evaluation of the newborn infant. The avowed purpose of this paper was to establish a simple and clear classification of newborn infants which can be used to compare the results of obstetric practices, types of maternal pain relief and the results of resuscitation. Having considered several objective signs pertaining to the condition of the infant at birth she selected five that could be evaluated and taught to the delivery room personnel without difficulty. These signs were heart rate, respiratory effort, reflex irritability, muscle tone and color. Sixty seconds after the complete birth of the baby a rating of zero, one or two was given to each sign, depending on whether it was absent or present. Virginia Apgar reviewed anesthesia records of 1025 infants born alive at Columbia Presbyterian Medical Center during the period of this report. All had been rated by her method. Infants in poor condition scored 0-2, infants in fair condition scored 3-7, while scores 8-10 were achieved by infants in good condition. The most favorable score 1 min after birth was obtained by infants delivered vaginally with the occiput the presenting part (average 8.4). Newborns delivered by version and breech extraction had the lowest score (average 6.3). Infants delivered by cesarean section were more vigorous (average score 8.0) when spinal was the method of anesthesia versus an average score of 5.0 when general anesthesia was used. Correlating the 60 s score with neonatal mortality, Virginia found that mature infants receiving 0, 1 or 2 scores had a neonatal death rate of 14%; those scoring 3, 4, 5, 6 or 7 had a death rate of 1.1%; and those in the 8-10 score group had a death rate of 0.13%. She concluded that the prognosis of an infant is excellent if he receives one of the upper three scores, and poor if one of the lowest three scores.

Changes in plasma drug binding and α1-acid glycoprotein in mother and newborn infant

A number of drugs bind to α1‐acid glycoprotein in plasma. To determine whether age‐related changes in α1‐acid glycoprotein influence drug binding in mother and newborn infant and also the effects of sex, pregnancy, and oral contraceptives on drug binding, the binding of lidocaine, diazepam, propranolol, d‐tubocurarine, and metocurine was determined by equilibrium dialysis in 17 men, 16 nonpregnant women, 16 nonpregnant women on oral contraceptives, and 15 mothers and their newborn infants at delivery. The free fraction of d‐tubocurarine (p < 0.05), metocurine (p < 0.01), propranolol (p < 0.001), and lidocaine (p < 0.02) was higher in neonatal blood than in maternal blood, whereas the free fraction of diazepam was less in fetal cord blood than the mothers (p < 0.02), but higher than that in nonpregnant women (p < 0.001). The free fractions of diazepam, propranolol, and lidocaine were higher (p < 0.001) in pregnant women compared with nonpregnant women while the diazepam and lidocaine free fractions were higher (p < 0.05) in nonpregnant women on oral contraceptives than in women not using them. arAcid glycoprotein was lower in the fetus (15.3 ± 4.7 mg/100 ml) than the mother (49.6 ± 6.5 mg/100 ml) (p < 0.002). There was a positive correlation between plasma α1‐acid glycoprotein concentrations and the binding ratio (bound/free concentrations) of lidocaine (p < 0.001; r = 0.623) and propranolol (p < 0.001; r = 0.652), indicating that it is likely that the elevation of the free fraction of these drugs in the fetus is due in part to lower levels of α1‐acid glycoprotein.

Identification of Human Liver Cytochrome P-450 3a4 as the Enzyme Responsible for Fentanyl and Sufentanil N-dealkylation

Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-dealkylation in the liver. We have previously shown that cytochrome P-450 3A4 (CYP3A4) contributes significantly to human liver microsomal alfentanil oxidation. Since identification of specific drug-metabolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P-450 enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with 0.25 micro Meter3 H-fentanyl or3 H-sufentanil. Rates of N-dealkylated metabolite formation significantly correlated with nifedipine oxidation activity (a marker of CYP3A4 activity) for fentanyl and sufentanil (r = 0.93 and 0.87, n = 18, respectively), but not with the oxidation activity for ethoxyresorufin (CYP1A2), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2E1). Gestodene and troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhibitors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentanyl and sufentanil. Recombinant CYP3A4 expressed in Escherichia coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYP1A2, 2C10, and 2E1 enzymes did not. We conclude that CYP3A4 is responsible for fentanyl and sufentanil N-dealkylation in vitro. (Anesth Analg 1996;82:167-72)

Ethnic differences in response to morphine

Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy men after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end‐tidal Pco2. The slope of the ventilation/Pco2 response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a Pco2 of 55 mm Hg. The morphine‐induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.

Ultra‐short‐acting beta‐blockade: A comparison with conventional beta‐blockade

Esmolol is a β1‐selective adrenoceptor blocker that is rapidly metabolized by blood and liver esterases. The β‐receptor and hemodynamic effects of esmolol were determined in a group of 12 healthy men and were compared with those induced by both oral and intravenous propranolol. Esmolol was rapidly effective in inducing at least 90% of steady‐state β‐blockade within 5 minutes of either initiating or changing the esmolol infusion rate. More importantly, when esmolol infusion was discontinued the β‐blockade had totally disappeared by 18 minutes after esmolol, 300 µg/kg/min, and had been reduced by 50% after 750 µg/kg/min. In contrast, 30 minutes after discontinuation of a propranolol infusion, there was no change in the level of β‐blockade. Propranolol was much more potent at blocking isoproterenol‐induced tachycardia (dose ratio 33.5 ± 2.5) than was even the highest dose (750 µg/kg/min) of esmolol (dose ratio 13.1 ± 1.0). The same dose of intravenous propranolol was approximately equipotent to oral propranolol, 40 mg every 8 hours (dose ratio 33.5 ± 2.5 and 34.5 ± 3.6, respectively). In contrast, propranolol, 40 mg every 8 hours, and esmolol, 300 µg/kg/min, were equipotent in antagonizing exercise‐induced tachycardia (40.1% ± 2.3% and 42.7% ± 3.2%, respectively). Esmolol had striking hypotensive effects. Systolic blood pressure fell by 20 mm Hg during esmolol infusions of 750 µg/kg/min. Esmolol appears to be a potent β1‐selective adrenoceptor antagonist with a particularly strong hypotensive effect. It is likely to be very useful in the treatment of hemodynamically unstable patients and may be useful in the emergency treatment of hypertension.

Metabolism of cytochrome P4503A substrates in vivo administered by the same route: Lack of correlation between alfentanil clearance and erythromycin breath test

Because there is considerable interindividual variation in both microsomal CYP3A4 activity and CYP3A4 substrate disposition, an established probe of in vivo CYP3A4 activity would represent an important advance in clinical practice. In a previous study, no correlation was found between the 14C‐erythromycin breath test and urinary dapsone recovery ratio. However these drugs were administered by different routes, with the orally administered dapsone being exposed to presystemic metabolism by the gut and renal metabolism before the measurement of the urinary ratio. To overcome the variable of route of administration, the aim of this study was to determine whether the elimination of two intravenously administered CYP3A4 substrates (alfentanil and erythromycin) correlate. We compared the metabolism of alfentanil to its CYP3A4‐dependent metabolite, noralfentanil, with the erythromycin breath test in 14 young healthy white men. No significant correlation was found between alfentanil metabolism and the erythromycin breath test: alfentanil clearance versus erythromycin breath test, r = 0.45, p = 0.1; partial metabolic clearance to noralfentanil versus erythromycin breath test, r = 0.35, p = 0.23. Because these two CYP3A4 substrates were administered by the same (intravenous) route, we conclude that differences in the route of administration do not explain the lack of correlation between the erythromycin breath test and other probes of CYP3A4 metabolism.

Principles and practice of pharmacology for anaesthetists

Foreword to the First Edition. Preface. 1 Drug Absorption, Distribution and Elimination. 2 Pharmacokinetics. 3 Drug Action. 4 Drug Interaction. 5 Variability in Drug Response. 6 Adverse Drug Reactions. 7 Intravenous Anaesthetic Agents. 8 Inhalational Anaesthetic Agents. 9 Local Anaesthetics. 10 Drugs that act on the Neuromuscular Junction. 11 Analgesic Drugs. 12 Drugs used in Premedication and Antiemetic Agents. 13 Drugs and the Autonomic Nervous System. 14 Antihypertensive Agents: Drugs that Are Used to Induce Hypotension. 15 Antiarrhythmic and Antianginal Drugs. 16 Antiplatelet Drugs, Anticoagulants and Fibrinolytic Agents. 17 Corticosteroids and Hypoglycaemic Agents. Glossary. Index