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Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

Background Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids. Methods After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores. Results There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin. Conclusions Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.

Background Parecoxib, a cyclooxygenase-2-specific inhibitor with intended perioperative analgesic and antiinflammatory use, is a parenterally administered inactive prodrug undergoing rapid hydrolysis in vivo to the active cyclooxygenase-2 inhibitor valdecoxib. Both parecoxib and valdecoxib inhibit human cytochrome P450 2C9 (CYP2C9) activity in vitro. Thus, a potential exists for in vivo interactions with other CYP2C9 substrates, including propofol. This investigation determined the influence of parecoxib on the pharmacokinetics and pharmacodynamics of bolus dose propofol in human volunteers. Methods This was a randomized, balanced crossover, placebo-controlled, double-blind, clinical investigation. Twelve healthy 21- to 37-yr-old subjects were studied after providing institutional review board-approved written informed consent. Each subject received a 2-mg/kg intravenous propofol bolus 1 h after placebo (control) or 40 mg intravenous parecoxib on two occasions. Venous concentrations of propofol, parecoxib, and parecoxib metabolites were determined by mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical endpoints, cognitive function (memory, Digit-Symbol Substitution Tests), subjective self-assessment of recovery (Visual Analog Scale) performed at baseline, 15, 30, 60 min after propofol, and sedation depth measured by Bispectral Index. Results Propofol plasma concentrations were similar between placebo- and parecoxib-treated subjects. No significant differences were found in pharmacokinetic parameters (Cmax, clearance, elimination half-life, volume of distribution) or pharmacodynamic parameters (clinical endpoints [times to: loss of consciousness, apnea, return of response to voice], Bispectral Index scores, Digit-Symbol Substitution Test scores, memory, Visual Analog Scale scores, propofol EC(50)). Conclusions Single-bolus parecoxib, in doses to be used perioperatively, does not alter the disposition or the magnitude or time course of clinical effects of bolus propofol. Effects on a propofol infusion were not evaluated.

Background . The present study examines the long-term outcome of pediatric patients with cardiac disease who required mechanical circulatory support with extracorporeal membrane oxygenation or ventricular assist devices. Methods . Telephone interviews and questionnaires were administered to parents and physicians of pediatric cardiac patients who were in-hospital survivors after requiring mechanical circulatory support, with either extracorporeal membrane oxygenation or ventricular assist devices. Data was collected regarding these patients' general health, cardiac status, and neurologic outcome, and compared between the two modes of support. Results . Follow-up was available for 26 patients supported with extracorporeal membrane oxygenation (25 survivors, 96%) and 11 patients supported with ventricular assist devices (10 survivors, 91%); median follow-up 42 months, 11 to 92 months). More than 80% of survivors were in New York Heart Association class I or II. Of 31 patients for whom neurologic assessment data was available, moderate to severe neurologic impairment was more common for extracorporeal membrane oxygenation supported patients [13 of 21, 59%) than for ventricular assist device supported patients (2 of 10, 20% p = 0.03). Neurologic impairment was associated with small patient size and the use of circulatory arrest during cardiac surgical repair, but was not associated with in-hospital neurologic complications, carotid cannulation, or presupport cardiac arrest. Conclusions . The long-term survival and cardiac functional status of pediatric cardiac patients requiring mechanical circulatory support is favorable. Extracorporeal membrane oxygenation supported patients demonstrate higher rates of neurologic impairment than patients supported with ventricular assist devices. Poor neurologic outcomes are associated with institution of support in younger patients with more complex congenital heart disease.

Background: Mechanisms of cardiac dysfunction during endotoxemia are multiple and their targets uncertain. This study tested the hypothesis that endotoxin (LPS) induces abnormal calcium-activated contractile force in the heart. Methods: Adult rabbits were given LPS intravenously; 2 hours later hearts were studied in the Langendorff mode. Measurements included peak developed pressure (PDP), myocardial oxygen consumption (MVO2), high-energy phosphates by 31P-NMR, and beat-to-beat intracellular calcium (Cai) by fluorescence spectroscopy. Myofibrillar calcium sensitivity was assessed from the relationship of PDP to Cai and the rate of diastolic Cai removal (τCa) was quantified. Results: Force-calcium relationships were markedly depressed in LPS hearts despite increased Cai. MVO2 was increased in parallel with increased Cai. Taken together, these data denote myofilament calcium insensitivity and mechanical inefficiency. τCa was markedly prolonged in LPS hearts, indicating impaired calcium reuptake and/or extrusion. High-energy phosphates and intracellular pH were unaffected by LPS; however, inorganic phosphate (Pi) was significantly increased. Dobutamine further increased Cai and MVO2 in LPS hearts without significantly improving calcium-activated force. Pyruvate, an inotrope that reduces Pi, significantly improved contractility in LPS hearts. Conclusions: Endotoxemia rapidly induced futile calcium cycling and reduced myofibrillar calcium sensitivity. This state was resistant to β-agonist inotropic stimulation; inotropes that normalize the calcium-force relationship may be more effective. (Surgery 1999;126:231-8.)

Objective: The systemic inflammatory response is an important cause of organ dysfunction. The present study tested the hypothesis that 2 clinically used agents, amrinone and vesnarinone, would decrease inflammation and cardiac dysfunction in a relevant model of systemic inflammatory response activation. Methods: Rabbits received intravenous endotoxin, alone or in conjunction with amrinone or vesnarinone. Systemic effects were assessed by death, fever, behavior, and acidosis. Measures of inflammatory signaling were (1) plasma tumor necrosis factor-α and interleukin-1 β production, (2) lung tissue myeloperoxidase activity, and (3) myocardial inducible nitric oxide synthase activity. Indices of systolic and diastolic myocardial function were measured in Langendorff-perfused hearts. Results: Vesnarinone, in particular, reduced mortality rates (19% vs 61% for lipopolysaccharide alone, P = .01) and acidosis in lipopolysaccharide-treated rabbits. Both agents markedly reduced systemic tumor necrosis factor and interleukin-1 concentrations, lipopolysaccharide-mediated effects on myocardial systolic and diastolic function and on myocardial inducible nitric oxide synthase activity. Vesnarinone, but not amrinone, (1) decreased fever and lethargy, consistent with decreased central nervous system effects of endotoxin, and (2) decreased lung leukocyte infiltration. Conclusions: Vesnarinone and amrinone, which are used clinically for their inotropic and vasodilating properties, may be useful to limit inflammatory activation and consequent organ dysfunction. Structure-activity and/or pharmacokinetic between the compounds may be important, particularly in preventing inflamatory signaling within certain tissues. (J Thorac Cardiovasc Surg 1999;117:375-82)

Introduction: We have recently used extracorporeal membrane oxygenation as a means of rapidly resuscitating pediatric patients with heart disease after cardiopulmonary arrest, in whom conventional resuscitation measures have failed. Methods: We developed a fully portable extracorporeal membrane oxygenation circuit that is maintained vacuum and carbon dioxide–primed at all times. When needed, the circuit is crystalloid-primed and can be ready for use within 15 minutes. Since February 1996, we have used this rapid-deployment circuit to resuscitate 11 pediatric patients in full cardiopulmonary arrest. Results: The median age of the 11 patients was 120 days (2 days to 4.6 years). Nine patients had a cardiac arrest after cardiac surgery. One patient had a cardiac arrest during cardiac catheterization and one patient had a cardiac arrest before cardiac surgery. Median duration of cardiopulmonary resuscitation was 55 minutes (range 20 to 103 minutes), with no difference in the duration of cardiopulmonary resuscitation between survivors and nonsurvivors. Ten of 11 patients (91%) were weaned from extracorporeal membrane oxygenation and seven (64%) survived to hospital discharge. Six patients are long-term survivors, five of whom are in New York Heart Association class I; one survivor is in class II. Seven patients resuscitated with extracorporeal membrane oxygenation before the use of this rapid-deployment circuit had a median duration of cardiopulmonary resuscitation of 90 minutes, with two (28.6%) survivors. Conclusions: The use of rapid-deployment extracorporeal membrane oxygenation results in shorter resuscitation times and improved survival in pediatric patients with heart disease after cardiopulmonary arrest. (J Thorac Cardiovasc Surg 1998;116:305-11)

Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids.After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores.There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin.Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.

Parecoxib, a parenteral cyclooxygenase-2 inhibitor, is undergoing clinical development as an analgesic/antiinflammatory drug for perioperative use. Parecoxib, an inactive prodrug, is hydrolyzed in vivo to valdecoxib, a substrate for hepatic cytochrome P450 (CYP) 3A4. Thus, potential exists for interactions with other CYP3A4 substrates. In this investigation, we determined the influence of parecoxib on the pharmacokinetics and clinical effects of midazolam, a CYP3A4 substrate, in volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Twelve healthy subjects aged 23-41 yr were studied after providing IRB-approved informed consent. Midazolam 0.07 mg/kg IV infusion was administered 1 h after placebo (control) or parecoxib 40 mg IV. Venous midazolam concentrations were determined by using liquid chromatography-mass spectrometry/mass spectrometry assay. Pharmacokinetic variables were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical end-points, cognitive function (memory; digit symbol substitution tests), subjective self-assessment of recovery (visual analog scales), and bispectral index. Midazolam plasma concentrations were similar between placebo and parecoxib-treated subjects. No differences were found in midazolam pharmacokinetics (maximal observed plasma concentration, clearance, elimination half-life, volume of distribution) or pharmacodynamics (clinical end-points, digit symbol substitution tests, memory, visual analog scales, bispectral index). Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam infusion. Parecoxib did not affect CYP3A4 activity as assessed using midazolam clearance as the in vivo probe.Parecoxib, a parenteral cyclooxygenase-2 inhibitor intended for perioperative use as an analgesic/antiinflammatory drug, is a substrate for hepatic cytochrome P450 3A4. The potential for a drug interaction with midazolam, an in vivo CYP3A4 probe, was tested in healthy volunteers. Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam.

Background Bispectral Index (BIS) has been used to measure sedation depth. Ideally, to guide anesthetic management, range of BIS scores at different sedation levels should not overlap, and BIS should be independent of drug used. This study assessed ability of BIS to predict sedation depth between sevoflurane, propofol, and midazolam. Quality of recovery was also compared. Methods Patients undergoing surgery with local or regional anesthesia and sedation were randomized to sevoflurane (n = 23), midazolam (n = 21), or propofol (n = 22). Sedation was titrated to Observers's Assessment of Alertness-Sedation score of 3 (responds slowly to voice). BIS and Observers's Assessment of Alertness-Sedation were measured every 5 min. BIS prediction probability (PK) was compared between drugs. Recovery was assessed by BIS and Digit Symbol Substitution and memory tests. Results Bispectral Index of responders to voice was significantly different from nonresponders (86 +/- 10 vs. 74 +/- 14, mean +/- SD; P < 0.001) However, wide variability and overlap in BIS were observed (25th-75th percentile, responders vs. non-responders: 79-96 vs. 65-83). BIS of responders was different for sevoflurane versus propofol and midazolam. BIS was a better predictor of propofol sedation than sevoflurane or midazolam (PK = 0.87 +/- 0.11, 0.76 +/- 0.01, and 0.69 +/- 0.02, respectively; P < 0.05). At 10 min after the procedure, 76, 48, and 24% of sevoflurane, propofol, midazolam patients, respectively, returned to baseline Digit Symbol Substitution scores (P < 0.05). Excitement-disinhibition occurred in 70, 36, and 5% of sevoflurane, propofol, and midazolam patients, respectively (P < 0.05). Conclusion Individual BIS scores demonstrate significant variability, making it difficult to predict sedation depth. The relation between BIS and sedation depth may not be independent of anesthetic agent. Quality of recovery was similar between drugs, but excitement occurred frequently with sevoflurane.

Background Sedation for surgical procedures performed with regional or local anesthesia has usually been achieved with intravenous medications, whereas the use of volatile anesthetics has been limited. The use of sevoflurane for sedation has been suggested because of its characteristics of nonpungency, rapid induction, and quick elimination. The purpose of this investigation was to assess the quality, recovery, and side effects of sevoflurane sedation compared with midazolam. Methods One hundred seventy-three patients undergoing surgery with local or regional anesthesia were enrolled in a multicenter, open-label, randomized investigation comparing sedation with sevoflurane versus midazolam. Sedation level was titrated to an Observer's Assessment of Alertness--Sedation score of 3 (responds slowly to voice). Recovery was assessed objectively by Observer's Assessment of Alertness--Sedation, Digit Symbol Substitution Test (DSST), and memory scores, and subjectively by visual analog scales. Results Significantly more patients in the sevoflurane group had to be converted to general anesthesia because of excessive movement (18 sevoflurane and 2 midazolam; P = 0.043). Of remaining patients, 141 were assessable for efficacy and recovery data (93 sevoflurane and 48 midazolam). Sevoflurane and midazolam produced dose-related sedation. Sevoflurane patients had higher DSST and memory scores during recovery. Seventy-six percent (sevoflurane) compared with 35% (midazolam) returned to baseline DSST at 30 min postoperatively (P < 0.05). More frequent excitement-disinhibition was observed with sevoflurane (15 [16%] vs. midazolam; P = 0.008). Conclusions Sevoflurane for sedation produces faster recovery of cognitive function as measured by DSST and memory scores compared with midazolam. However, sevoflurane for sedation is complicated by a high incidence of intraoperative excitement.