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Context: Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages.Objective: To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients.Design, Setting, and Patients: Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU.Interventions: Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days.Main Outcome Measures: Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events.Results: There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02).Conclusions: There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia.Trial Registration: clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56). [ABSTRACT FROM AUTHOR]

Aims: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients., Methods: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA)., Results: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months)., Conclusions: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months)., (© 2024 British Pharmacological Society.)

Objective: Ecallantide is a recombinant peptide in the same class as aprotinin that inhibits plasma kallikrein, a major component of the contact coagulation and inflammatory cascades. Therefore, ecallantide was expected to reduce blood loss associated with cardiac surgery requiring cardiopulmonary bypass., Methods: This prospective multinational, randomized, double-blind trial enrolled patients undergoing cardiac surgery using cardiopulmonary bypass for procedures associated with a high risk of bleeding. Patients were randomly assigned to ecallantide (n = 109) or tranexamic acid (high dose, n = 24; low dose, n = 85). Efficacy was assessed from the volume of packed red blood cells administered within the first 12 hours after surgery., Results: The study was terminated early after the independent data safety and monitoring board observed a statistically significantly higher 30-day mortality in the ecallantide group (12%) than in the tranexamic acid groups (4%, P = .041). Patients receiving ecallantide received more packed red blood cells within 12 hours of surgery than tranexamic acid-treated patients: median = 900 mL (95% confidence interval, 600-1070) versus 300 mL (95% confidence interval, 0-523) (P < .001). Similar differences were seen at 24 hours and at discharge. Patients treated with the higher tranexamic acid dose received less packed red blood cells, 0 mL (95% confidence interval, 280-600), than the group treated with the lower dose, 400 mL (95% confidence interval, 0-400) (P = .008). No deaths occurred in the higher dose tranexamic acid group., Conclusions: Ecallantide was less effective at reducing perioperative blood loss than tranexamic acid. High-dose tranexamic acid was more effective than the low dose in reducing blood loss., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: To determine the relationship between the number of delirium days experienced by intensive care patients and mortality, ventilation time, and intensive care unit stay., Design: Prospective cohort analysis., Setting: Patients from 68 intensive care units in five countries., Patients: Three hundred fifty-four medical and surgical intensive care patients enrolled in the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial received a sedative study drug and completed at least one delirium assessment., Interventions: Sedative drug interruption and/or titration to maintain light sedation with daily arousal and delirium assessments up to 30 days of mechanical ventilation., Measurements and Main Results: The primary outcome was all-cause 30-day mortality. Multivariable analysis using Cox regression incorporating delirium duration as a time-dependent variable and adjusting for eight relevant baseline covariates was conducted to quantify the relationship between number of delirium days and the three main outcomes. Overall, delirium was diagnosed in 228 of 354 patients (64.4%). Mortality was significantly lower in patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%]; p<.001). Similarly, the median time to extubation and intensive care unit discharge were significantly shorter among nondelirious patients (3.6 vs. 10.7 days [p<.001] and 4 vs. 16 days [p<.001], respectively). In multivariable analysis, the duration of delirium exhibited a nonlinear relationship with mortality (p=.02), with the strongest association observed in the early days of delirium. In comparison to 0 days of delirium, an independent dose-response increase in mortality was observed, which increased from 1 day of delirium (hazard ratio, 1.70; 95% confidence interval, 1.27-2.29; p<.001), 2 days of delirium (hazard ratio, 2.69; confidence interval, 1.58-4.57; p<.001), and ≥3 days of delirium (hazard ratio, 3.37; confidence interval, 1.92-7.23; p<.001). Similar independent relationships were observed between delirium duration and ventilation time and intensive care length of stay., Conclusions: In ventilated and lightly sedated intensive care unit patients, the duration of delirium was the strongest independent predictor of death, ventilation time, and intensive care unit stay after adjusting for relevant covariates.

Objective: To compare the intensive care unit costs and determine factors influencing these costs in mechanically ventilated patients randomized to dexmedetomidine or midazolam by continuous infusion., Design: Cost minimization analysis of a double-blind, multicenter clinical trial randomizing patients 2:1 to receive dexmedetomidine or midazolam from the institutional perspective., Setting: Sixty-eight intensive care units in the United States, Australia, New Zealand, Brazil, and Argentina., Patients: A total of 366 intubated intensive care unit patients anticipated to require sedation for >24 hrs., Measurements and Main Results: Intensive care unit resource use was compared within the two treatment arms, using the U.S. representative costs for these resources. The analyses characterized patient costs from start of study drug until intensive care unit discharge including costs associated with the intensive care unit stay, costs during mechanical ventilation, study drug acquisition cost, and costs of treating adverse drug reactions probably or possibly related to study drugs. Blinded to treatment group, costs were calculated using Medicare reimbursement schedules, average IMS drug costs, expert opinion, and peer-reviewed literature. Censored lengths of intensive care unit stay and mechanical ventilation were imputed, using a nonparametric adjustment algorithm. Crude and multivariate median regressions were performed to relate intensive care unit cost and treatment. Including drug acquisition cost, sedation with dexmedetomidine was associated with a median total intensive care unit cost savings of $9679 (confidence interval, $2314-$17,045) compared with midazolam. The primary cost drivers were reduced costs of intensive care unit stay (median savings, $6584, 95% confidence interval, $727-$12,440) and reduced costs of mechanical ventilation (median savings, $2958, 95% confidence interval, $698-$5219)., Conclusions: Continuous sedation with dexmedetomidine results in significantly lower total intensive care unit costs compared with midazolam infusion for intensive care unit sedation, primarily due to decreased intensive care unit stay costs and reduced mechanical ventilation costs.

Background: Dexmedetomidine (DEX) is increasingly being used as a sedative for monitored anesthesia care (MAC) because of its analgesic properties, "cooperative sedation," and lack of respiratory depression. In this randomized, multicenter, double-blind, Phase III Food and Drug Administration study, we evaluated the safety and efficacy of two doses of DEX for sedation of patients undergoing a broad range of surgical or diagnostic procedures requiring MAC., Methods: Three hundred twenty-six patients were randomized 2:2:1 to DEX 0.5 microg/kg, DEX 1 microg/kg, or saline placebo initial loading dose, followed by a maintenance infusion of 0.2-1.0 microg x kg(-1) x h(-1) of DEX (or equivalent volume of saline) titrated to a targeted level of sedation (< or = 4 on the Observer's Assessment of Alertness/Sedation Scale [OAA/S]). Study drug was started at least 15 min before placement of regional or local anesthetic block. Midazolam was given for OAA/S > 4 and fentanyl for pain. The primary end-point was the percentage of patients not requiring rescue midazolam., Results: Significantly fewer patients in the 0.5- and 1-microg/kg DEX groups required supplemental midazolam compared with placebo (59.7% [80/134], 45.7% [59/129] vs 96.8% [61/63], respectively; P < 0.001) and at lower doses to achieve an OAA/S < or = 4 before and during surgery compared with the saline group (1.4 and 0.9 mg vs 4.1 mg, respectively; P < 0.001, each group compared with placebo). Both DEX groups required significantly less fentanyl (84.8 and 83.6 microg vs 144.4 microg, respectively; P < 0.001, for both DEX groups versus placebo) for all surgical subtypes. Anesthesiologists indicated significantly increased ease of achieving and maintaining targeted sedation in both DEX groups compared with placebo with midazolam (P < 0.001). Patient satisfaction was significantly higher with DEX (P < or = 0.009, both groups versus placebo). Common adverse events with DEX were protocol-defined bradycardia and hypotension that were predominately mild to moderate in severity. The incidence of clinically significant respiratory depression (defined as a respiratory rate of < 8 or an oxygen saturation of < 90%) was lower in DEX-treated patients (P = 0.018, for both groups versus placebo)., Conclusions: DEX is an effective baseline sedative for patients undergoing MAC for a broad range of surgical procedures providing better patient satisfaction, less opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl.

Background: The pathophysiology of neurocognitive dysfunction and developmental delay after cardiopulmonary bypass (CPB) in infants is not known. It is known that head trauma, stroke, and seizures cause dysfunction of the blood brain barrier (BBB) that is associated with increased inducible transcription factor gene expression in the cells of the barrier. The purpose of this study was to determine the effects of CPB and hypothermic circulatory arrest on expression of the transcription factor FOS and the function of the BBB in an infant animal model., Methods: Infant lambs (n = 36; 10-12 days) were exposed to 0, 15, 30, 60, or 120 minutes of normothermic (38 degrees C) CPB or 2 hours of hypothermic circulatory arrest at 16 degrees C. After terminating bypass 15 animals had their brains perfusion-fixed and removed for immunohistochemical analysis of expression of the transcription factor FOS. The other animals were perfused with fluorescent albumin to visualize the brain microvasculature. Brain sections were analyzed with a laser scanning confocal microscope., Results: Control animals (n = 6, sham operated and cannulated) exhibited normal vasculature with negligible leakage and no FOS protein expression in neurons or endothelial cells anywhere in the brain. Significant FOS expression in barrier-associated structures including the blood vessels, choroid plexus, and ependyma but not neurons occurred at all times on bypass. CPB caused leakage of fluorescent albumin from blood vessels in all animals. Two hours of normothermic CPB (n = 4) caused significant (p < 0.01) leakage in the cerebellum, cortex, hippocampus, and corpus callosum. Animals exposed to circulatory arrest experienced severe leakage throughout the brain (p < 0.001) and FOS expression in all cells., Conclusions: These experiments indicate that the BBB is dysfunctional after all time points on normothermic CPB, BBB dysfunction is worsened by hypothermic circulatory arrest, and BBB dysfunction is associated with intense molecular activity within the barrier-forming cells. Dysfunction of the BBB may contribute to neurologic complications after heart surgery.

Background: This study was undertaken to determine whether soluble human complement receptor type 1 (TP10), a potent inhibitor of complement activation, would reduce morbidity and mortality in high-risk patients undergoing cardiac surgery on cardiopulmonary bypass (CPB)., Methods: This was a randomized multicenter, prospective, placebo-controlled, double-blind study in which 564 high-risk patients undergoing cardiac surgery on CPB received an intravenous bolus of TP10 (1, 3, 5, 10 mg/kg) or placebo immediately before CPB. The primary endpoint was the composite events of death, myocardial infarction (MI), prolonged (> or =24 hours) intra-aortic balloon pump support (IABP), and prolonged intubation., Results: TP10 significantly inhibited complement activity after 10 to 15 minutes of CPB and this inhibition persisted for 3 days postoperatively. However, there was no difference in the primary endpoint between the 2 groups (33.7% placebo versus 31.4% TP10; P=0.31). The primary composite endpoint was, however, reduced in all male TP10 patients by 30% (P=0.025). TP10 reduced the incidence of death or MI in males by 36% (P=0.026), the incidence of death or MI in CABG males by 43% (P=0.043) and the need for prolonged IABP support in male CABG and valve patients by 100% (P=0.019). There was, however, no improvement seen in female TP10 patients. There were no significant differences in adverse events between the groups., Conclusions: TP10 effectively inhibits complement activation during CPB; however, this was not associated with an improvement in the primary endpoint of the study. Nevertheless, TP10 did significantly decrease the incidence of mortality and MI in male patients.

Unlabelled: The glial-derived protein S100B is a serum marker of cerebral ischemia and correlates with negative neurological outcome after cardiopulmonary bypass (CPB) in adults. We sought to characterize the S100B release pattern before and after CPB in neonates and infants with congenital heart disease and correlate it with surgical mortality. Serum was collected before surgery and at 24 postoperative h from 109 neonates and infants with congenital heart disease. All patients had presurgical transthoracic echocardiograms and CPB with or without hypothermic circulatory arrest. S100B concentrations were determined using a two-site immunoluminometric assay (Sangtec 100). Thirty-day surgical mortality was observed. All neonates had significantly increased S100B concentrations before surgery that decreased by 24 postoperative h. Preoperative S100B concentrations in 32 neonates with hypoplastic left heart syndrome correlated inversely with the forward flow and size of the ascending aorta and postoperative mortality (r(2) = -0.63; P = 0.03). Among infants, increased pulmonary blood flow was associated with higher S100B levels before surgery than cyanosis. There was no correlation with postoperative S100B and time on CPB, hypothermic circulatory arrest, or 30-day surgical mortality. In conclusion, preoperative S100B concentrations correlate inversely with the size of the ascending aorta in hypoplastic left heart syndrome and may serve as a marker for preexisting brain injury and mortality., Implications: Neonates with hypoplastic left heart syndrome and no forward flow in the ascending aorta may have brain injury at birth before heart surgery.

Differences in brain neuroarchitecture have been extensively studied and recent results demonstrated that regional differences in the physiological properties of glial cells are equally common. Relatively little is known on the topographic differences in vascular supply, distribution and density of brain capillaries in different CNS regions. We developed a simple method consisting of intravascular injection of fluorescent dyes coupled to immunocytochemical techniques that allows for simultaneous observation of glia-neuronal-vascular interactions in immersion-fixed brain specimens from small rodents. This technique permits quantitative evaluation of regional differences in glial/neuronal distribution and the study of their relationship to vascular densities. Variations of this technique also allow the detection of abnormal microvasculature (i.e. 'leaky' vessels), a useful feature for studies of blood-brain barrier function in health and disease. By use of quantitative confocal microscopy, the three-dimensional geometry of cortical and hippocampal structures revealed remarkable differences in vascularization between cortical gray/white matter junction, and hippocampal formation (CA1 and CA3 regions). Significant differences were also observed within the same investigative region: CA1 was characterized by low capillary density compared to neighboring CA3. Following an ischemic insult, CA1 vessels had more extensive blood-brain barrier leakage than CA3 vessels. We conclude that in addition to neuronal and glial heterogeneity, cortical structures are also endowed with region-specific vascular patterns characterized by distinct pathophysiological responses.

Background: Cardiopulmonary bypass (CPB) in neonates induces a cytokine-mediated capillary leak syndrome that can cause organ dysfunction. Removing harmful cytokines after CPB may attenuate this response. This study measured the concentrations of serum and peritoneal fluid (PF) cytokines after CPB to determine if harmful cytokines can be removed with peritoneal catheters., Methods: Neonates (n = 18) had cardiac surgery using CPB with circulatory arrest. Peritoneal catheters were placed at the end of surgery to drain excess fluid. Serum samples were obtained before and after CPB, and PF after CPB. Cytokines were measured by enzyme-linked immunosorbent assay., Results: Tumor necrosis factor-alpha and interleukin-1beta (IL-1beta) were not detected in any serum or PF sample. Serum concentrations of IL-6, IL-8, and IL-10 increased significantly after CPB. PF concentrations of IL-6 and IL-8 exceeded serum concentrations, whereas IL-10 concentrations were higher in the serum. There was a significant negative correlation between serum and PF concentrations of IL-6 after CPB (r = -0.63; p<0.05)., Conclusions: PF has very high concentrations of the proinflammatory cytokines, IL-6 and IL-8, after CPB but not the antiinflammatory cytokine IL-10. The PF may be a depot for the harmful inflammatory cytokines after CPB, and removing the PF could lower serum concentrations.

Background: N-methyl-d-aspartate (NMDA) receptor antagonists are neuroprotective in animal models of cerebral ischemia, but adverse cardiovascular and neurobehavioral effects have precluded their clinical use. The authors present the neuroprotective, anesthetic, and cardiovascular effects of a novel NMDA antagonist, CNS 5161A., Methods: Lambs, 4.0-6.5 kg, were anesthetized with isoflurane, intubated, and ventilated and had thermodilution catheters placed in the pulmonary artery and 20-g catheters placed in the femoral artery. The minimum alveolar concentration (MAC) of isoflurane was determined using the "bracketing technique." CNS 5161A was given as a bolus and then as an infusion at three doses. Cardiovascular measurements were determined every 15 min. Other lambs (n = 25) were subjected to cardiopulmonary bypass (CPB) with hypothermic circulatory arrest (HCA) for 120 min. Eighteen received CNS 5161A, and seven received saline vehicle. One hour after CPB, brains were perfusion-fixed and removed for in situ hybridization and immunohistochemistry analysis in half of the animals. The other half survived 48 h before their brains were examined for neuronal degeneration., Results: Isoflurane at MAC significantly decreased blood pressure, heart rate, cardiac output, and systemic vascular resistance by 30-48% (n = 16; P < 0.05). CNS 5161A (n = 12) had no significant cardiovascular effects. All concentrations of CNS 5161A caused a significant reduction (21-29%) of the MAC of isoflurane (n = 12; P < 0.05). CNS 5161A, at serum concentrations greater than 25 ng/ml, completely inhibited c-fosmRNA and c-FOS protein expression in hippocampal neurons after 120 min of HCA, attenuated neuronal degeneration, and improved functional outcome by 47% (P < 0.05)., Conclusions: CNS 5161A at neuroprotective concentrations before CPB-HCA significantly reduces the MAC of isoflurane without cardiovascular effects.

Purpose: Accurate haemodynamic assessment during surgical repair of scoliosis is crucial to the care of the patient. The purpose of this study was to compare transoesophageal echocardiography (TEE) with central venous pressure monitoring in patients with spinal deformities requiring surgery in the prone position., Methods: Twelve paediatric patients undergoing corrective spinal surgery for scoliosis/kyphosis in the prone position were studied. Monitoring included TEE, intra-arterial and central venous pressure monitoring (CVP). Haemodynamic assessment was performed prior to and immediately after positioning the patient prone on the Relton-Hall table. Data consisted of mean arterial blood pressure (mBP), heart rate (HR), CVP, left ventricular end-systolic and end-diastolic diameters (LVESD and LVEDD respectively) and fractional shortening (FS). Right ventricular (RV) function and tricuspid regurgitation (TR) were assessed qualitatively. Analysis was performed using descriptive statistics, Student's t test, sign rank, and correlation analysis., Results: There was an increase in CVP (8.7 mmHg to 17.7 mmHg; P < .01), and decreases in LVEDD (37.1 mm to 33.2 mm; P < .05), and mean blood pressure (75.0 mmHg to 65.7 mmHg; P < .05) when patients were placed in the prone position. Fractional shortening, LVESD, and HR did not change from the supine to the prone position. Right ventricular systolic function and tricuspid regurgitation were unchanged., Conclusion: These data indicate that the CVP is a misleading monitor of cardiac volume in patients with kyphosis/scoliosis in the prone position. This is consistent with previous studies. In this clinical situation, TEE may be a more useful monitoring tool to assess on-line ventricular size and function.

Background: This study determined the induction profiles of immediate-early genes in the ovine brain after cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA), and the effects of the noncompetitive N-methyl-D-aspartate antagonist, aptiganel, on immediate-early gene expression, neuronal necrosis, and functional outcome., Methods: Cannulas were inserted into isoflurane-anesthetized neonatal lambs undergoing CPB. One group received 2.5 mg/kg intravenous aptiganel. Animals underwent 90 or 120 min of HCA at 16 degrees C, were rewarmed to 38 degrees C, and were weaned from CPB. One hour after CPB was discontinued, brain perfusion was fixed and removed for immunohistochemical analysis in one half of the animals. The other half survived 2 or 3 days before their brains were evaluated for neuronal degeneration. Data were analyzed using analysis of variance; P < 0.05 was considered significant., Results: Cardiopulmonary bypass and HCA differentially induced c-Jun and Fos proteins in the hippocampal formation, with c-Jun expression increasing with the duration of HCA, whereas Fos protein expressions were greatest after 90 min of HCA. The c-Jun protein was expressed in all neurons except the dentate gyrus. The Fos proteins were expressed in all neurons, including the dentate gyrus. Neuronal necrosis was observed in CA1 (73%) and CA3 (29%) neurons but not in the dentate gyrus after 120 min of HCA. Aptiganel completely inhibited c-Jun expression (P < 0.001) but not Fos, improved functional outcome, and attenuated neuronal necrosis (P < 0.05)., Conclusions: The c-Jun and c-Fos proteins are expressed differentially in hippocampal neurons after CPB and HCA. Expression of c-Jun is associated with neuronal necrosis, whereas Fos protein expression is associated with survival. Aptiganel inhibits c-Jun expression, attenuates neuronal necrosis, and improves outcome.

A case of branch retinal artery occlusion due to an embolus from a retained left atrial catheter is presented. Removal was accomplished by reoperation. Prompt removal of any retained intracardiac catheter is recommended.

Background: Altered gene expression occurs in the brain after global ischemia. We have developed a model to examine the effects of cardiopulmonary bypass and hypothermic circulatory arrest (HCA) on the induction of the immediate-early gene c-fos in the brains of neonatal lambs. We then tested the effects of the noncompetitive N-methyl-D-aspartate antagonist, aptiganel hydrochloride (Cerestat), on c-fos expression and neuronal injury., Methods: Neonatal lambs (weight, 4 to 6 kg) anesthetized with isoflurane were supported by cardiopulmonary bypass, subjected to 90 or 120 minutes of HCA at 15 degrees C, and rewarmed on bypass to 38 degrees C. One hour after cardiopulmonary bypass was terminated, the brains were perfusion fixed and removed for in situ hybridization and immunohistochemical analysis. Some animals survived 3 days before their brains were removed to examine for neuronal necrosis. One group of lambs (n = 20) received aptiganel (2.5 mg/kg). A second group (n = 25) received saline vehicle only., Results: Increasing duration of HCA induced a corresponding increase in c-fos messenger RNA expression throughout the hippocampal formation and cortex. However, Fos protein synthesis peaked after 90 minutes of HCA and decreased significantly (p < 0.01) after 120 minutes of HCA. Aptiganel administration caused a significant decrease in (p < 0.001) c-fos messenger RNA expression and Fos protein synthesis after 90 minutes of HCA and preserved Fos protein synthesis after 120 minutes of HCA. Neuronal necrosis was observed in the brains of vehicle-treated lambs after 120 minutes of HCA but was significantly decreased (p < 0.05) in the lambs given aptiganel., Conclusions: These experiments indicate that the transcriptional processes of immediate-early genes remain intact, whereas translational processes are impaired after prolonged HCA. The inability to synthesize Fos proteins after 120 minutes of HCA was associated with neuronal degeneration. Aptiganel preserved translational processes and caused a significant improvement in the neurologic outcome.

Background: Cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA) are associated with neurological injury. Altered immediate-early gene expression occurs rapidly in the brain in response to ischemia, hypoxia, and severe metabolic stress, which results in long-term changes in the molecular phenotype of neurons. This study determined the effects of CPB and HCA on the expression of the immediate-early gene c-fos., Methods: Neonatal lambs were subjected to 2 h of CPB at 38 degrees C (n = 4) or 60 min (n = 6), 90 min (n = 7), and 120 min (n = 6) of HCA at 15 degrees C. One hour after terminating CPB at 38 degrees C, the brains were analyzed for FOS-encoding mRNA and FOS-like immunoreactivity in the hippocampal formation. Other animals (n = 15), subjected to the same CPB and HCA protocol, were allowed to survive 3-5 days before their brains were examined for dead neurons., Results: Minimal c-fos mRNA and FOS proteins were observed in neurons of animals subjected to normothermic bypass and of those that served as controls. Non-neuronal FOS proteins were observed in the choroid plexus, ependyma, and blood vessels at all times, including normothermic CPB, but not in the control animals without CPB. The magnitude of c-fos mRNA expression in hippocampal neurons increased directly with the duration of HCA. In contrast, expression of FOS proteins peaked after 90 min of HCA and declined significantly thereafter. Dead neurons were seen in surviving animals after 2 h of HCA only., Conclusions: Cardiopulmonary bypass and HCA alter immediate-early gene expression in the brain. Translational processes are impaired after 120 min of HCA and correlate with neuron death in the hippocampus.

Study Objective: To measure serum CK-MB, a market of myocardial infarction (MI), in elderly men before and after cryoprostatectomy., Design: Serum CK-MB was measured on each patient before and after cryoprostatectomy. Each patient's preoperative result was used as control measurement for comparison with measurements made after cryoprostatectomy., Setting: Inpatient operating room and postanesthetic recovery unit of a university-affiliated general hospital., Patients: 38 male patients, mean (SEM) age 69.1 +/- 1.4 years, undergoing cryoprostatectomy., Interventions: All patients had a 12-lead ECG prior to surgery, in the recovery room, and 24 hours after surgery. Serum CK-MB was measured prior to induction of anesthesia, on arrival in the recovery room, and at 8 and 24 hours after surgery. Lactate dehydrogenase (LDH) and isoenzymes also were measured in 10 patients before and after cryoprostatectomy., Measurements and Main Results: All patients underwent uneventful cryoprostatectomy. No patients had new ECG changes after surgery. All patients had normal serum CK and CK-MB concentrations before surgery. Serum CK and CK-MB were significantly elevated after cryoprostatectomy (p < 0.001). Enzyme values were greatest 8 hours after surgery: total CK mean 1453 +/- 145 U/L (range 199 to 3,356 U/L); CK-MB mean 52 +/- 3 ng/ml (range 12 to 114 ng/ml) or 5.0 +/- 0.5% of total CK (range 1.6% to 12.4%). All patients had significant elevations of LDH after cryoprostatectomy but did not show an increase in the ratio of LDH1 to LDH2 isoenzymes. Finally, unlike patients with an acute MI, the activity of CK-MB isoenzyme when measured by gel electrophoresis was two to three times greater (mean, 2.6 +/- 0.7) than the concentration measured with the monoclonal antibody assay in patients after cryoprostatectomy., Conclusion: Serum CK-MB is an unreliable test to diagnose an MI in patients who have undergone cryoprostatectomy.

Adult patients who smoke are known to have airway complications during general anesthesia. The objective of this study was to explore the relationship between environmental tobacco smoke (ETS) exposure in the home and laryngospasm during general anesthesia in pediatric patients. A retrospective, cohort study was performed on pediatric ambulatory patients in the day surgery center and main operating room of a university hospital. We studied 310 consecutive pediatric patients (all ASA physical status I) who underwent an outpatient elective ear, nose, and throat or urologic surgical procedure in the spring and summer of 1994, and received inhalation induction by mask with halothane. Laryngospasm was identified from quality management and anesthetic records, and included only those patients whose records indicated that succinylcholine was given because of oxygen desaturation and inability to ventilate. Patients' families were questioned within 1 wk after surgery as to the number of smokers in each child's household. Of 96 children with ETS exposure, 9 (9.4%) developed laryngospasm. Of the 214 patients without domestic ETS exposure, 2 (0.9%) developed laryngospasm. The relative risk for developing laryngospasm was 10 times higher in the ETS-exposed patients compared with the non-ETS-exposed group (95% confidence interval = 2.2-45.6; P < 0.001). We conclude that ETS exposure is a strong risk factor for laryngospasm in infants and children during general anesthesia.

Background: Dextromethorphan (DM), a widely used antitussive agent, has been shown to possess both anticonvulsant and neuroprotective properties functionally related to its inhibitory effects on glutamate-induced neurotoxicity. The current study was designed to determine whether DM administration prevents delayed neuronal degeneration in central nervous system areas after global forebrain ischemia and whether this correlates with inhibition of induction of the immediate early gene c-fos., Methods: Mongolian gerbils, anesthetized with 2% halothane in air at 37 degrees C, received either 0.9% sodium chloride (vehicle, n = 9) or 50 mg/kg DM in vehicle (n = 9) by intraperitoneal injection before bilateral carotid artery occlusion. After 1 h of reperfusion under anesthesia, the animals were killed and the brains removed. Immunohistochemistry was used to detect neurons expressing Fos protein. Computer-assisted image analysis quantified changes in the number of labeled neurons as a function of drug treatment. To determine the extent of delayed neuronal degeneration within the hippocampus, other animals were treated with either DM (n = 7) or vehicle (n = 6) before carotid artery occlusion and allowed to survive for 1 week., Results: Global forebrain ischemia produced consistent patterns of Fos-like immunoreactivity in the hippocampus and neocortex of vehicle-treated animals. DM inhibited the induction of c-fos from 65% to 91%. DM also protected against delayed neuronal degeneration in the CA1 region of the hippocampus (P < 0.001)., Conclusions: The induction of nuclear-associated Fos protein represents a sensitive marker of cellular responses to ischemia and a method to assay the effectiveness of pharmacologic interventions. DM markedly inhibited ischemia-induced Fos expression and prevented cell death in CA1. DM given before conditions of ischemia or decreased central nervous system perfusion may be highly beneficial.

Ninety-two adult patients scheduled for automated percutaneous discectomy (PERC) were assigned to receive either local anesthesia supplemented with monitored i.v. analgesia (MIVA) or general endotracheal anesthesia (GA-LITE). Patients were examined 1 week post-PERC for the presence of new paresthesias, and they completed a questionnaire 6-18 weeks after PERC about changes in their pain. Sixty-four percent of MIVA patients and 83% of GA-LITE patients had diminished pain following PERC. Results did not show any difference between the two groups for new paresthesias after PERC. There were no differences in postoperative pain medication requirements, but the GA-LITE group reported more postoperative nausea, vomiting, and sore throat. GA-LITE patients averaged 1.06 +/- 0.3 h in the recovery room compared with 0.70 +/- 0.3 h for MIVA patients. Although the use of general anesthesia for PERC has been contraindicated because of fear of damaging the nerve root in the sleeping patient, we conclude that general anesthesia does not increase nerve injuries attributable to instrumentation. However, general anesthesia did cause a higher incidence of minor complications such as nausea, vomiting, and sore throat in the immediate postoperative period than did MIVA.

The pharmacokinetics of lidocaine were studied in 1-2-month-old lambs with surgically created, intracardiac right-to-left shunts (RLS) and in age-matched control lambs. Shunts were prepared by anastomosing the pulmonary artery to the left atrial appendage to achieve arterial oxygen saturation of 65-75%. Catheters were implanted both in the right atrium for drug infusion and in the ascending aorta for blood sampling. Lidocaine, 1 mg/kg, injected as a rapid bolus, or 12 mg/kg, injected as a continuous infusion over 15 min, was delivered into the right atrium. Serial samples of arterial blood were obtained every 2.5 s for 1 min following the bolus injection and up to 4 h following the continuous infusion. Samples were analyzed for lidocaine by gas chromatography. Peak arterial whole blood concentration of lidocaine in the shunted animals was 37.0 +/- 2.1 micrograms/ml compared to 21.1 +/- 0.1 microgram/ml in the control animals; P less than .01. The peak arterial concentrations during the lidocaine infusion were 12.6 +/- 3.5 micrograms/ml in the RLS and 5.8 +/- 1.5 micrograms/ml in the controls. Total body clearance of lidocaine was decreased in the shunted animals to 30.7 +/- 13.2 ml.kg-1.min-1 from 68.1 +/- 12.1 ml.kg-1.min-1 in the control animals; P less than .001. The steady-state volume of distribution was also decreased in the shunted animals, 1.0 +/- 0.2 l/kg versus 2.0 +/- 0.7 l/kg in the controls; P less than .02. To induce convulsions 4.75 +/- 0.46 mg/kg of lidocaine was required in the shunted animals and 7.37 +/- 0.44 mg/kg in the control animals (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Lidocaine solutions with different concentrations of CO2, NaOH, and HCl in two buffering systems were applied to frog sciatic nerves. The peak of the compound action potential (APc) and the firing threshold for single axons were measured. The amount of lidocaine required at steady state to double the firing threshold of single fibers or to reduce the peak of the APc by 40% was used as the index of potency. Acidification with CO2 increased potency (less lidocaine was needed to achieve either criterion), whereas acidification with HCl diminished potency, as compared with alkaline conditions. These results were true whether or not the perineurium was present. Frequency-dependent block (Bf) increased in acid conditions produced by CO2, whereas Bf was less under acid conditions produced with HCl (P less than 0.02). The experiments indicate that CO2 potentiates conduction block with lidocaine either by a direct effect on the membrane or by its indirect action on intracellular pH, but not from effects on the extracellular pH.

Experiments were done to assess the relationship of the chemical properties of local anesthetics to their ability to block neuronal impulse conduction, using a series of hitherto unavailable homologs of lidocaine. These molecules varied in the number and arrangement of alkyl groups attached to the tertiary amine nitrogen. Each compound was applied to desheathed sciatic nerves of frogs (Rana pipiens) mounted in a sucrose gap recording chamber. Compound action potentials (AP) were recorded at room temperature (20-23 degrees C) and the potency of each anesthetic determined from the concentration required to produce a 40% reduction in the amplitude of the AP at low-frequency stimulation: 1 min-1. This reduction was called Bt. An additional Bt was measured from the further decrease in amplitude of the AP during high-frequency stimulation (10 and 40 Hz). Tonic and phasic blocking potencies were analyzed as functions of the calculated drug partition coefficients, and the known molecular weights, molecular configurations and pKa values. Potency for Bt increased with increasing length of n-alkyl groups attached to the terminal amine, whereas it decreased as the length of the alkyl group connecting the amide bond to the terminal amine was increased. However, when considered in terms of their physicochemical properties, the homologs showed a potency for Bt that increased uniformly with increasing partition coefficient. This analysis revealed a strong positive correlation between tonic potency and partitioning into octanol for both neutral and protonated anesthetic species but little correlation with molecular weight or pKa. However, Bt did not depend uniquely on hydrophobicity, as predicted if lipophilic partitioning alone determined potency.(ABSTRACT TRUNCATED AT 250 WORDS)