Biomedical subjects

J Butterworth

Publications and source records attributed to J Butterworth.

At least 19 recordsLinked to original sources

PubMed2001

Similar neurobehavioral outcome after valve or coronary artery operations despite differing carotid embolic counts.

OBJECTIVES: The interrelationships among coronary and valvular operations, microemboli, and neurobehavioral outcome are unclear. We hypothesized that adult patients undergoing cardiac valve operations would have more total emboli delivered to the brain than patients undergoing coronary artery bypass grafting and that this would associate with worse neurobehavioral outcomes. METHODS: One hundred ninety-three patients undergoing coronary artery bypass grafting and 73 patients undergoing cardiac valve operations were compared. Patients received neurologic, neuro-ophthalmologic, and 11 standardized neurobehavioral tests preoperatively and 5 to 7 days, 1 month, and 6 months postoperatively. Left common carotid Doppler ultrasonographic embolus detection was performed intraoperatively. Repeated measures and logistic regression analyses of outcome were performed. RESULTS: Patients undergoing either coronary or valve operations were well matched by age (61 +/- 10 and 59 +/- 12 years, respectively), but a significantly greater fraction of patients undergoing valve operations were female, diabetic, or had undergone previous cardiac operations. Neurobehavioral scores of patients undergoing either coronary artery bypass grafting or cardiac valve operations did not differ significantly at any time. Total embolus counts differed significantly: the median was 105 during coronary artery bypass grafting and 479 during cardiac valve operations (geometric means of 104 and 412, respectively; P =.0001). Significantly more emboli were detected in the patients undergoing cardiac valve operations after removal of the left ventricular vent and after separation from cardiopulmonary bypass, but comparable numbers of emboli were seen in the 2 groups before cardiopulmonary bypass. In both groups decreased neurobehavioral performance was apparent at 5 to 7 days, with improvement at 1 and 6 months. Increasing numbers of carotid emboli significantly associated with worse performance on the letter cancellation test. There were no significant differences between patients undergoing valve and coronary operations in neurobehavioral outcomes, strokes, transient ischemic attacks, or deaths. CONCLUSIONS: The significantly greater number of emboli in the group of patients undergoing cardiac valve operations is likely the result of the entrainment of intracardiac air. The greater numbers of emboli during cardiac valve operations do not appear associated with a commensurately greater risk of adverse neurologic or neurobehavioral outcome.

Adult↗

PubMed2001

Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs.

UNLABELLED: There is no information comparing the ability to reverse the cardiotoxic effects associated with incremental overdosage of bupivacaine (BUP) to levobupivacaine (LBUP), ropivacaine (ROP), or lidocaine (LIDO). Open-chest dogs were randomized to receive incremental escalating infusions of BUP, LBUP, ROP, and LIDO to the point of cardiovascular collapse (mean arterial pressure [MAP] < or = 45 mm Hg). Hypotension and arrhythmias were treated with epinephrine, open-chest massage, and advanced cardiac life support protocols, respectively. Outcomes were defined as the following: successful (stable rhythm and MAP > or = 55 mm Hg for 20 min), successful with continued therapy (stable rhythm and MAP <55 mm Hg after 20 min), or death. Continued therapy was required in 86% of LIDO dogs compared with only 10%-30% of the other dogs (P < 0.002). Mortality from BUP, LBUP, ROP, and LIDO was 50%, 30%, 10%, and 0%, respectively. Myocardial depression was primarily responsible for the profound hypotension, as the occurrence of lethal arrhythmias preceding resuscitation was not different among local anesthetics. Epinephrine-induced ventricular fibrillation occurred more frequently in BUP-intoxicated dogs than in dogs given LIDO or ROP (P < 0.05). The unbound plasma concentrations at collapse were larger for ROP, 19.8 microg/mL (10-39 microg/mL), compared with BUP, 5.7 microg/mL (3-11 microg/mL); whereas the concentrations of LBUP, 9.4 microg/mL (5-18 microg/mL) and BUP were not significantly different from each other. IMPLICATIONS: There were consistent differences among the local anesthetics, the sum of which suggests that larger doses and blood concentrations of ropivacaine (ROP) and lidocaine will be tolerated as compared with bupivacaine (BUP) and levobupivacaine (LBUP). Lidocaine intoxication results in myocardial depression from which resuscitation is consistently successful but will require continuing drug support. After BUP, LBUP, or ROP, resuscitation is not always successful, and the administration of epinephrine may lead to severe arrhythmias. The unbound plasma concentrations at collapse were larger for ROP compared with BUP, whereas the concentrations of LBUP and BUP were not significantly different from each other. Furthermore, larger plasma concentrations of ROP than BUP are present after resuscitation, suggesting a wider margin of safety when large volumes and large concentrations are used to establish upper or lower extremity nerve blocks for surgical anesthesia and during long-term infusions for pain management.

Amides↗

PubMed2001

Do pulmonary artery catheters cause or increase tricuspid or pulmonic valvular regurgitation?

UNLABELLED: There are few quantitative data on the extent or mechanism of pulmonary artery catheter (PAC)-induced valvular dysfunction. We hypothesized that PACs cause or worsen tricuspid and pulmonic valvular regurgitation, and tested this hypothesis by using transesophageal echocardiography. In 54 anesthetized adult patients, we measured color Doppler jet areas of tricuspid regurgitation (TR) in two planes (midesophageal [ME] 4-chamber and right ventricular inflow-outflow views) and pulmonic insufficiency (PI) in one plane (ME aortic valve long-axis view), both before and after we advanced a PAC into the pulmonary artery. Regurgitant jet areas and hemodynamic measurements were compared by using paired t-test. There were no significant changes in blood pressure or heart rate after passage of the PAC. After PAC placement, the mean PI jet area was not significantly increased. The mean TR jet area increased significantly in the right ventricular inflow-outflow view (+0.37 +/- 0.11 cm(2)) (P = 0.0014), but did not increase at the ME 4-chamber view. Seventeen percent of patients had an increase in TR jet area > or =1 cm(2); 8% of patients had an increase in PI jet area >/=1 cm(2). IMPLICATIONS: In patients without pulmonic or tricuspid valvular pathology, placement of a pulmonary artery catheter (PAC) worsened tricuspid regurgitation, which is consistently visualized in the right ventricular inflow-outflow view, and often not seen in the midesophageal 4-chamber view. This is consistent with malcoaptation of the anterior and posterior leaflets. PAC-induced pulmonic insufficiency was rarely detected in the midesophageal aortic valve long-axis view. We conclude that a PAC is very unlikely to be the sole cause of severe tricuspid regurgitation or pulmonic insufficiency.

Aged↗

PubMed2001

Gender does not influence epsilon-aminocaproic acid concentrations in adults undergoing cardiopulmonary bypass.

Epsilon-aminocaproic acid (epsilon-ACA) is administered to cardiac surgery patients to reduce blood transfusions. Highly water-soluble drugs, such as epsilon-ACA, often have larger distribution volumes in males than in females. We hypothesized that epsilon-ACA concentrations using this dosing scheme would differ by gender because of differences in body composition and weight-adjusted volumes of distribution. Ten men and 10 women undergoing elective coronary artery surgery with cardiopulmonary bypass (CPB) received a 50 mg/kg epsilon-ACA initial dose over 20 min and a 25 mg. kg(-1) x h(-1) epsilon-ACA maintenance infusion for 4 h. The area under the epsilon-ACA arterial concentration versus time curves was compared by using analysis of variance. Measured epsilon-ACA concentrations were smaller than predicted by the published model, but the area under the concentration versus time curves was not significantly different between men and women. Combining the present concentration data with that previously published, our updated two-compartment model included the following estimated population pharmacokinetic values: V(1) (11.8 L pre-CPB, 14.9 L during and after CPB), V(2) (12.0 L pre-CPB, 15.0 L during and after CPB), Cl(1) (0.125 L/min pre-CPB, 0.037 L/min during CPB, 0.156 L/min after CPB), Cl(2) (0.155 L/min pre-CPB, 0.013 L/min during CPB, 0.193 L/min after CPB).

Aged↗

PubMed2001

Reduced regional and global cerebral blood flow during fenoldopam-induced hypotension in volunteers.

UNLABELLED: Dopamine has a wide spectrum of receptor and pharmacologic actions that may affect cerebral blood flow (CBF). A new, selective dopamine-1 agonist, fenoldopam, is a potent systemic vasodilator with moderate alpha(2)-receptor affinity. However, the effects of fenoldopam on the cerebral circulation are undefined. We therefore hypothesized that infusion of fenoldopam would decrease mean arterial blood pressure (MAP) and might concurrently decrease CBF via vascular alpha(2)-adrenoreceptor activation in awake volunteers. We studied nine healthy normotensive subjects, using positron emission tomography to measure CBF in multiple cortical and subcortical regions of interest. In addition, bioimpedance cardiac output and middle cerebral artery blood flow velocity were determined during fenoldopam-induced hypotension. Three men and four women, aged 25-43 yr, completed the study. Fenoldopam infused at 1.3 +/- 0.4 microg. kg(-1). min(-1) (mean +/- SD) reduced MAP 16% from baseline: from 94 (89-100) mm Hg (mean [95% confidence interval]) to 79 [74-85] mm Hg (P < 0.0001). During the fenoldopam infusion, both cardiac output (+39%), and heart rate (+45%) increased significantly, whereas global CBF decreased from baseline, 45.6 [35.6-58.5] mL. 100 g(-1). min(-1), to 37.7 [33.9-42.0] mL. 100 g(-1). min(-1) (P < 0.0001). Despite restoration of baseline MAP with a concurrent infusion of phenylephrine, global CBF remained decreased relative to baseline values at 37.9 [34.0-42.3] mL. 100 gm(-1). min(-1) (P < 0.0001). Changes in middle cerebral artery velocity did not correlate with positron emission tomography-measured changes of CBF induced by fenoldopam, with or without concurrent phenylephrine. IMPLICATIONS: In awake volunteers with (presumably) intact cerebral autoregulation,fenoldopam-induced hypotension significantly decreased global cerebral bloodflow (CBF). Clinicians should be aware of these pharmacodynamic effects when choosing a vasodilator to control blood pressure, especially in situations where control of CBF, cerebral blood volume, and intracranial pressure are therapeutic priorities.

Adolescent↗

PubMed2000

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues.

The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.

Administration, Oral↗

PubMed2000

Inverse agonism by Dmt-Tic analogues and HS 378, a naltrindole analogue.

The potent delta-opioid receptor antagonist H-2',6-L-tyrosine(Dmt)-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic-OH) exhibited partial inverse agonism (EC(50)=6.35 nM, E(max)=-18.87%) for [35S]GTPgammaS binding and H-Dmt-Tic-NH(2) was a neutral antagonist (no effect up to 30 microM). In contrast N,N(CH(3))(2)-Dmt-Tic-NH(2) was a full inverse agonist (EC(50)=2.66 nM, E(max)=-35.95%) similar to ICI 174864 ([N,N-diallyl-Tyr(1),Aib(2,3),Leu(5)]enkephaline) but with a 3.5-fold higher EC(50). In comparison, naltrindole was a neutral antagonist while its analogue HS 378 was a partial inverse agonist (E(max)=-12.99%).

Benzamides↗

PubMed2000

Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists.

A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the delta opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the delta versus mu opioid receptor and proved to be delta receptor antagonists.

Benzamides↗

PubMed2000

Neural regulation of alpha-dystroglycan biosynthesis and glycosylation in skeletal muscle.

Alpha-dystroglycan (alpha-DG) is part of a complex of cell surface proteins linked to dystrophin or utrophin, which is distributed over the myofiber surface and is concentrated at neuromuscular junctions. In laminin overlays of muscle extracts from developing chick hindlimb muscle, alpha-DG first appears at embryonic day (E) 10 with an apparent molecular mass of 120 kDa. By E15 it is replaced by smaller (approximately 100 kDa) and larger (approximately 150 kDa) isoforms. The larger form increases in amount and in molecular mass (>200 kDa) as the muscle is innervated and the postsynaptic membrane differentiates (E10-E20), and then decreases dramatically in amount after hatching. In myoblasts differentiating in culture the molecular mass of alpha-DG is not significantly increased by their replication, fusion, or differentiation into myotubes. Monoclonal antibody IIH6, which recognizes a carbohydrate epitope on alpha-DG, preferentially binds to the larger forms, suggesting that the core protein is differentially glycosylated beginning at E16. Consistent with prior observations implicating the IIH6 epitope in laminin binding, the smaller forms of alpha-DG bind more weakly to laminin affinity columns than the larger ones. In blots of adult rat skeletal muscle probed with radiolabeled laminin or monoclonal antibody IIH6, alpha-DG appears as a >200-kDa band that decreases in molecular mass but increases in intensity following denervation. Northern blots reveal a single mRNA transcript, indicating that the reduction in molecular mass of alpha-DG after denervation is not obviously a result of alternative splicing but is likely due to posttranslational modification of newly synthesized molecules. The regulation of alpha-DG by the nerve and its increased affinity for laminin suggest that glycosylation of this protein may be important in myofiber-basement membrane interactions during development and after denervation.

Animals↗

PubMed2000

Effect of alkalinization of lidocaine on median nerve block.

Median nerve blocks were performed in 10 volunteers in a randomized, double-blind, crossover study to compare the effects of 1% plain lidocaine with 1% lidocaine in sodium bicarbonate 0.1 mmol litre-1. Sensations of hot, cold, pinprick and light touch, compound motor and sensory nerve action potentials, and skin temperature were assessed at 2-min intervals. pH was 6.4 +/- 0.1 for plain lidocaine and 7.7 +/- 0.2 for alkalinized lidocaine (P < 0.001). Alkalinized lidocaine produced more rapid inhibition of compound motor action potentials than plain lidocaine (median 4 (range 2-6) vs 9 (2-14) min) (P = 0.039). Alkalinized lidocaine also produced more rapid onset of inhibition of compound motor than sensory nerve action potentials (4 (2-6) vs 8 (4-12) min) (P = 0.0039). There was no significant difference in any other sensory modality between alkalinized and plain lidocaine. These data suggest that addition of bicarbonate to lidocaine for median nerve block significantly increased the rate of motor block without changing the onset or extent of sensory block.

Anesthetics, Local↗

PubMed2000

Bupivacaine suppresses [Ca(2+)](i) oscillations in neonatal rat cardiomyocytes with increased extracellular K+ and is reversed with increased extracellular Mg(2+).

UNLABELLED: Lidocaine is used to treat cardiac arrhythmias, whereas bupivacaine is noted for its cardiotoxicity. A precise mechanism for these differences is unclear, and there is no well defined antidote for local anesthetic cardiotoxicity. Our study compares the effect of lidocaine and bupivacaine on oscillations of intracellular Ca(2+) coupled with contractions in neonatal rat cardiomyocytes by using digital imaging. In medium containing 5.6 mM K(+), both 42 microM lidocaine and 5.5 microM bupivacaine significantly reduced the oscillation rate. The oscillatory patterns were highly irregular, and the rates were increased in the presence of bupivacaine in 7.6 mM K(+) medium, eventually degenerating into a loss of oscillations after several minutes of bupivacaine exposure. Irregular oscillations did not occur with lidocaine until the K(+) concentration was increased to 10 mM. Increasing the Mg(2+) and Ca(2+) concentrations by 2 mM each recovered oscillation that had been suppressed by bupivacaine in high K(+) buffer. Evaluation of intracellular Ca(2+) oscillations in neonatal rat suggests that increased extracellular K(+) may be an important component of bupivacaine cardiotoxicity. IMPLICATIONS: Evaluation of intracellular Ca(2+) oscillations in neonatal rat myocytes suggests that increased extracellular K(+) may be an important component of bupivacaine cardiotoxicity.

Anesthetics, Local↗

PubMed2000

Ventricular arrhythmias with or without programmed electrical stimulation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine.

UNLABELLED: It is unclear whether the mechanism of death from local anesthetic (LA) intoxication is primarily a consequence of cardiac arrhythmias or myocardial contractile depression, and whether LAs might differ in this susceptibility to these two mechanisms. By using programmable electrical stimulation (PES) protocols in anesthetized, ventilated dogs, we compared the arrhythmogenic potential of bupivacaine (BUP), ropivacaine (ROP), levobupivacaine (LBUP), and lidocaine (LIDO). Open-chest dogs were randomized to receive escalating incremental infusions of the four local anesthetics until cardiovascular collapse. We assumed a concentration relationship of 4:1 for LIDO/BUP, LBUP, and ROP. The effective refractory period did not change significantly until the dose increment corresponding to target concentrations of 8 and 32 microg/mL for BUP, LBUP, ROP, and LIDO, respectively. Thirty percent to 50% increases in effective refractory period occurred in surviving dogs at this dose. The incidence of spontaneous or PES-induced ventricular tachycardia and ventricular fibrillation did not differ among groups. Compared with LIDO, the incidence of PES-induced extrasystoles was more frequent for BUP- and LBUP-treated dogs (P: < 0.05). ROP-treated dogs did not differ from LIDO-treated dogs with respect to PES-induced extrasystoles. At the dose increment preceding cardiovascular collapse, all LAs produced significant increases in heart rate and reductions in blood pressure compared with their respective baseline values. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with BUP does not differ from the incidence that occurs with the single S:(-) enantiomers LBUP and ROP, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity. IMPLICATIONS: Progressive bupivacaine intoxication in anesthetized, ventilated dogs does not produce early arrhythmogenic events. The incidence of programmable electrical stimulation-induced ventricular tachycardia and fibrillation with bupivacaine does not differ from the incidence that occurs with the single S:(-) enantiomers levobupivacaine and ropivacaine, providing further evidence against stereoselective arrhythmogenesis as a primary component of local anesthetic-induced cardiotoxicity.

Amides↗

PubMed2000

Female gender associates with increased duration of intubation and length of stay after coronary artery surgery. CABG Clinical Benchmarking Database Participants.

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> or =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. CONCLUSIONS: Even in the context of accelerated recovery programs, these analyses show that female sex has powerful associations with increased LOS intervals for coronary artery bypass grafting surgery, even after adjustment for preoperative covariates. These effects could result from differences in the ways in which men and women respond to coronary artery disease, anesthesia, and coronary artery bypass grafting surgery, or to bias on the part of healthcare workers.

Aged↗

PubMed2000

Workplace culture, social interactions, and supports for transition-age young adults.

The role of the workplace and its culture in supporting social inclusion and workplace support for employees with disabilities is discussed and results of a qualitative study of the workplace experiences of 8 young adults with developmental disabilities presented. Data were collected using participant observation and semi-structured interviews. Four characteristics of supportive workplaces were identified: (a) multiple context relationships, (b) specific social opportunities, (c) a personal and team-building management style, and (d) interdependent job designs. The more supportive workplaces had all of these characteristics, suggesting that collectively they represent key features of a supportive workplace culture. Implications for job development and job creation are identified.

Adolescent↗

PubMed1999

Characterization of [125I]AR-M100613, a high-affinity radioligand for delta opioid receptors.

AR-M100613 ([I]-Dmt-c[-D-Orn-2-Nal-D-Pro-D-Ala-]) is the iodinated analog of a cyclic casomorphin previously shown to be a potent antagonist at the delta opioid receptor. Specific [125I]AR-M100613 binding to rat whole brain membranes was saturable, reversible, and best fit to a one-site model (Kd = 0.080 +/- 0.008 nM, Bmax = 45.2 +/- 4.4 fmol/mg protein). [125I]AR-M100613 binding was displaced with high affinity by the delta opioid receptor ligands SNC-80, Deltorphin II and DPDPE but not the mu or kappa-selective receptor ligands DAMGO and U69593. Residual non-selective binding of [125I]AR-M 100613 to mu opioid receptors is blocked by the addition of CTOP to the assay buffer. [35S]GTPgammaS binding assays indicate that AR-M100613 is a potent, selective, and reversible antagonist for delta opioid receptors in rat brain membranes. The high-affinity, high specific activity, low nonspecific binding and antagonist profile of [125I]AR-M100613 favor its use as a radiochemical probe for delta opioid receptors.

Animals↗

PubMed1999

The safety and effectiveness of esmolol in the perioperative period in patients undergoing abdominal aortic surgery.

OBJECTIVES: To determine (1) if perioperative use of esmolol in major vascular surgery patients provides strict heart rate (HR) control, (2) what doses of esmolol are required to do this, and (3) does this control influence myocardial ischemia or result in adverse consequences. DESIGN: Prospective study of 40 patients randomized to two groups: The HR was controlled to either less than 80 beats/min (group 80) or less than 110 beats/min (group 110) using esmolol. Patients were monitored continuously for electrocardiographic changes perioperatively. HR control began after induction of anesthesia and continued for 48 hours thereafter. SETTING: Operating room and intensive care unit. PATIENTS: Patients undergoing abdominal vascular surgery involving aortic cross-clamping. INTERVENTIONS: Esmolol was titrated until the target HR was met. MEASUREMENTS AND RESULTS: Only one patient demonstrated an adverse effect. The median infusion rates were 100 and 12.5 microg/kg/min for groups 80 and 110. Target HR was met less in group 80 than in group 110, primarily in the postoperative period. Ischemia patterns were not significantly different between groups. CONCLUSION: Using esmolol for HR control in the intraoperative period for abdominal vascular surgery patients is effective and safe. HR control was much less effective in the postoperative period, but esmolol is safe when used at recommended doses. Further study with a larger number of patients is necessary to determine whether strict HR control with esmolol affects the incidence of myocardial ischemia or infarction in this patient population.

Adrenergic beta-Antagonists↗

PubMed1999

A randomized, blinded trial of the antioxidant pegorgotein: no reduction in neuropsychological deficits, inotropic drug support, or myocardial ischemia after coronary artery bypass surgery.

OBJECTIVE: To determine whether patients receiving pegorgotein preoperatively would be less likely than patients receiving placebo to demonstrate postoperative cerebral or myocardial dysfunction and thus would be less likely to (1) demonstrate a decline in neuropsychologic testing after cardiopulmonary bypass, (2) receive inotropic drug support, or (3) demonstrate electrocardiographic signs of ischemia or infarction. DESIGN: Prospective, randomized, blinded clinical trial. SETTING: University teaching hospital and clinics. PARTICIPANTS: Sixty-seven patients with normal left ventricular function undergoing elective, primary coronary artery bypass surgery. INTERVENTIONS: Six to 18 hours before aortic cross-clamping, patients received a single dose of placebo (n = 22); pegorgotein, 2,000 IU/kg intravenously (n = 23); or pegorgotein, 5,000 IU/kg intravenously (n = 22). MEASUREMENTS AND MAIN RESULTS: Patients in the three groups were similar; the mean ages were 65, 66, and 67 years, and there were seven, eight, and seven women in the placebo; pegorgotein, 2,000 IU/kg; and pegorgotein, 5,000 IU/kg groups. Fifty-one of 67 patients demonstrated neuropsychologic deficit 5 to 7 days postoperatively (n = 17, 19, and 15 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = NS). Median duration of cardiopulmonary bypass was longer in patients with two or more deficits at 4 to 6 weeks than in those with fewer than two deficits (121 v. 98 minutes; p = 0.04). No patient demonstrated a perioperative stroke. Twenty-seven patients required inotropic drug support after cardiopulmonary bypass (n = 8, 11, and 8 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = NS). Inotropic drug support was associated with history of angina (p = 0.01) and increasing weight (p = 0.03). Nine patients demonstrated early postoperative ischemia or infarction (n = 1, 7, and 1 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = 0.07). CONCLUSIONS: This study showed no positive influence of pegorgotein on the incidence of any of the findings and showed a trend toward an increased incidence of myocardial ischemia or infarction.

Aged↗

PubMed1999

Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing aortocoronary bypass surgery.

BACKGROUND: Epsilon-aminocaproic acid (EACA) is commonly infused during cardiac surgery using empiric dosing schemes. The authors developed a pharmacokinetic model for EACA elimination in surgical patients, tested whether adjustments for cardiopulmonary bypass (CPB) would improve the model, and then used the model to develop an EACA dosing schedule that would yield nearly constant EACA blood concentrations. METHODS: Consenting patients undergoing elective coronary artery surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or 100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose before CPB and a 10 mg x kg(-1) x h(-1) maintenance infusion continued for 4 h during and after CPB (n = 7). Two patients with renal failure received EACA in the manner of group III. Blood concentrations of EACA, measured by high-performance liquid chromatography, were subjected to mixed-effects pharmacokinetic modeling. RESULTS: The EACA concentration data were best fit by a model with two compartments and corrections for CPB. The elimination rate constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011 after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1 varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB. Two patients with renal failure demonstrated markedly reduced clearance. Using their model, the authors predict that an EACA loading infusion of 50 mg/kg given over 20 min and a maintenance infusion of 25 mg x kg(-1) x h(-1) would maintain a nearly constant target concentration of 260 microg/ml. CONCLUSIONS: EACA clearance declines and volume of distribution increases during CPB. The authors' model predicts that more stable perioperative EACA concentrations would be obtained with a smaller loading dose (50 mg/kg given over 20 min) and a more rapid maintenance infusion (25 mg x kg(-1) x h(-1)) than are typically employed.

Adolescent↗