Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies. METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined. RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates. CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population. IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.

Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy.

OBJECTIVE MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive method for thermal destruction of benign or malignant tissue that has been used for selective amygdalohippocampal ablation for the treatment of temporal lobe epilepsy. The authors report their initial experience adopting a real-time MRI-guided stereotactic platform that allows for completion of the entire procedure in the MRI suite. METHODS Between October 2014 and May 2016, 17 patients with mesial temporal sclerosis were selected by a multidisciplinary epilepsy board to undergo a selective amygdalohippocampal ablation for temporal lobe epilepsy using MRgLITT. The first 9 patients underwent standard laser ablation in 2 phases (operating room [OR] and MRI suite), whereas the next 8 patients underwent laser ablation entirely in the MRI suite with the ClearPoint platform. A checklist specific to the real-time MRI-guided laser amydalohippocampal ablation was developed and used for each case. For both cohorts, clinical and operative information, including average case times and accuracy data, was collected and analyzed. RESULTS There was a learning curve associated with using this real-time MRI-guided system. However, operative times decreased in a linear fashion, as did total anesthesia time. In fact, the total mean patient procedure time was less in the MRI cohort (362.8 ± 86.6 minutes) than in the OR cohort (456.9 ± 80.7 minutes). The mean anesthesia time was significantly shorter in the MRI cohort (327.2 ± 79.9 minutes) than in the OR cohort (435.8 ± 78.4 minutes, p = 0.02). CONCLUSIONS The real-time MRI platform for MRgLITT can be adopted in an expedient manner. Completion of MRgLITT entirely in the MRI suite may lead to significant advantages in procedural times.

Pharmacodynamic Analysis of Morphine Time-to-Remedication Events in Infants and Young Children After Congenital Heart Surgery.

OBJECTIVE: The aim of this study was to characterize the relationship between morphine plasma concentration and repeated time to postoperative remedication events in children undergoing cardiac surgery. METHODS: Data from our previously published study of morphine pharmacokinetics were utilized in this pharmacodynamic study. A population survival analysis based on hazard functions was undertaken in NONMEM(®). RESULTS: Hazard was best described by a Gompertz function changing in steps over time. Concentration and age were the only predictors of the hazard function. Concentration producing 50 % reduction in hazard was 19.6 (bootstrap 95 % confidence interval 5.90-49.5 ng/ml). The hazard ratio for a 1-year-old child to a 1-month-old child was 1.91 (1.35-2.86). Sensitivity to morphine decreased with age and leveled off after 1-year of life. Morphine sulfate doses >0.1 mg/kg did not noticeably increase tolerable pain durations. CONCLUSION: Time to remedication is a clinically useful endpoint for assessing opioid-induced analgesia. Sensitivity to morphine treatment is age-dependent. Morphine sulfate doses of 0.1-0.2 mg/kg are adequate for the management of postoperative pain in children. Our findings may help avoid unnecessary large morphine doses in children.

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery.

The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

Evaluation of sodium nitroprusside for controlled hypotension in children during surgery.

PURPOSE: (1) To define the onset and offset of the blood-pressure-lowering effects of sodium nitroprusside (SNP) for use in developing instructions for dose titration in children undergoing a surgical or medical procedure, and (2) to assess the safety of SNP administration in pediatric patients requiring controlled reduction of blood pressure. METHODS: We conducted a randomized, double-blind, parallel-group, dose-ranging, effect-controlled, multicenter study of intravenous (IV) infusions of SNP in pediatric patients <17 years, who required controlled hypotension for at least 2 h while undergoing a surgical or medical procedure. A blinded SNP dose of 0.3, 1, 2, or 3 µg/kg/min was infused for 30 min, followed by open-label administration for at least 90 min. Both infusions were titrated to effect. RESULTS: The final intent-to-treat group comprised 203 patients. Significant reductions in mean arterial pressure (MAP) from baseline were observed for all four doses at 20 and 25 min after the start of infusion (p ≤ 0.009 and p ≤ 0.010 for each time, respectively). Overall, 98.5% of the patients achieved the target MAP; 72.9% first achieved the target MAP during the blinded infusion. The mean infusion rate at target MAP was 1.07 µg/kg/min. CONCLUSION: We determined that 0.3 µg/kg/m is a reasonable starting dose for SNP in pediatric patients requiring controlled hypotension. The infusion rate can then be increased to achieve the desired reduction in blood pressure. On the basis of our results, we found an average infusion rate of 1 µg/kg/min might be appropriate. Of note, no cyanide toxicity was reported, and no measureable cyanide levels were detected in any blood samples obtained during the study. http://clinicaltrials.gov/show/NCT00135668.

Risk factors for respiratory depression in patients undergoing retrobulbar block for vitreoretinal surgery.

BACKGROUND AND OBJECTIVE: To determine the risk factors for respiratory depression during retrobulbar block administration before vitreoretinal surgery. PATIENTS AND METHODS: Prospective, observational case series of 113 patients undergoing monitored anesthesia care and retrobulbar block before vitreoretinal surgery at a tertiary medical center. RESULTS: Chin lift, jaw thrust, and bag mask ventilation were performed in eight (7.1%), nine (8%), and six (5.3%) patients, respectively. No patients required intubation. Age, sex, body mass index, history of obstructive sleep apnea, American Society of Anesthesiologists physical status level, and baseline oxygen saturation were not predictive of airway intervention. Of the four anesthetic agents utilized (midazolam, fentanyl, alfentanil, and propofol), only propofol and fentanyl were associated with an increased risk for clinically significant apnea. Use of three medications for sedation was associated with a 5.4-fold increase in the relative risk of requiring a respiratory rescue intervention. CONCLUSION: During preoperative sedation for retrobulbar block administration, the use of propofol, fentanyl, or a combination of three anesthetics is associated with a statistically significant increase in the risk for respiratory depression requiring resuscitation.

Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease.

BACKGROUND: Etomidate is a rapid-onset, short-acting hypnotic medication administered for the induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants are lacking. OBJECTIVE: The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery. METHODS: Four neonates and 16 infants, postnatal age 0.3-11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics. RESULTS: The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found significantly to impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 l/min/70 kg and 0.44 l/min/70 kg, respectively; central and peripheral distribution volume of 9.47 l/70 kgand 22.8 l/70 kg, respectively. Inter-individual variability was 94-142% for all parameters and the residual variability was 29%. CONCLUSIONS: The clearance of etomidate is lower in neonates and infants with congenital heart disease compared with published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population.

Predictors of arterial blood pressure control during deliberate hypotension with sodium nitroprusside in children.

BACKGROUND: Sodium nitroprusside (SNP) is used to decrease arterial blood pressure (BP) during certain surgical procedures. There are limited data regarding efficacy of BP control with SNP. There are no data on patient and clinician factors that affect BP control. We evaluated the dose-response relationship of SNP in infants and children undergoing major surgery and performed a quantitative assessment of BP control. METHODS: One hundred fifty-three subjects at 7 sites received a blinded infusion followed by open-label SNP during operative procedures requiring controlled hypotension. SNP was administered by continuous infusion and titrated to maintain BP control (mean arterial BP [MAP] within ±10% of clinician-defined target). BP was recorded using an arterial catheter. Statistical process control methodology was used to quantify BP control. A multivariable model assessed the effects of patient and procedural factors. RESULTS: BP was controlled an average 45.4% (SD 23.9%; 95% CI, 41.5%-49.18%) of the time. Larger changes in infusion rate were associated with worse BP control (7.99% less control for 1 µg·kg·min increase in average titration size, P = 0.0009). A larger difference between a patient's baseline and target MAP predicted worse BP control (0.93% worse control per 1-mm Hg increase in MAP difference, P = 0.0013). Both effects persisted in multivariable models. CONCLUSIONS: SNP was effective in reducing BP. However, BP was within the target range less than half of the time. No clinician or patient factors were predictive of BP control, although 2 inverse relationships were identified. These relationships require additional study and may be best coupled with exposure-response modeling to propose improved dosing strategies when using SNP for controlled hypotension in the pediatric population.

Pharmacokinetics of prophylactic cefazolin in parturients undergoing cesarean delivery.

The objectives of this work were (i) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (ii) to assess cefazolin transplacental transmission; (iii) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (iv) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g of cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 liters. [corrected] The values for pre- and postdelivery clearance were 7.18 and 4.12 liters/h, respectively. Computer simulations revealed that the probability of maintaining free cefazolin concentrations in plasma above 8 mg/liter during scheduled caesarean surgery was <50% in the cord blood when cefazolin was administered in doses of <2 g or when it was administered <1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates >5 h after birth. Cefazolin clearance increases during pregnancy, and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates than in adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates.

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

BACKGROUND: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). METHODS: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. RESULTS: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) . CONCLUSIONS: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children.

BACKGROUND: Sodium nitroprusside (SNP) is a potent vasodilator that has been used to induce deliberate hypotension in children during surgery involving significant blood loss, including craniofacial and spinal fusion procedures. SNP metabolism liberates cyanide, which may cause interference with cellular energy metabolism, leading to metabolic acidosis and central nervous system injury. We performed a retrospective, case-control study to determine whether the short-term intra-operative use of SNP for deliberate hypotension is associated with metabolic acidosis in children undergoing surgical procedures for craniofacial or spinal anomalies. Cyanide and thiocyanate concentrations were also recorded in patients who received SNP. METHODS: Data from 166 children undergoing craniofacial and spinal fusion surgery between 2005 and 2010 at Lucile Packard Children's Hospital (LPCH) at Stanford were analyzed. Records from 60 patients who received SNP (SNP group) as part of a multicenter, randomized, double-blind study were compared with records from 106 eligible patients who had blood pressure reduction using anesthetic agents and did not receive SNP (control group). Metabolic acidosis was defined as serum bicarbonate (HCO3) < 18.5 mEq/L. Whole blood CN, plasma thiocyanate and urinary thiocyanate concentrations were measured in patients in the SNP group. Differences in metabolic acidosis rates between the SNP and control groups were assessed through a test of noninferiority in the rate for the SNP group with a noninferiority threshold of 0.2. A z-test was used to test the null hypothesis. The alternative hypothesis was that the difference in these rates was less than 0.2. The same noninferiority threshold of 0.2 was also used to perform separate, secondary tests for noninferiority in the proportion of patients with HCO3 levels below 18.5 mEq/L and the proportion of patients who required HCO3 administration. RESULTS: Fewer patients in the SNP group experienced metabolic acidosis compared to the control group (31.7% vs. 36.8%, respectively; p < .001). No whole blood CN levels above the lower limit of quantification were detected in any of the 51 patients with validated CN data. Plasma and urinary thiocyanate levels were also low. CONCLUSIONS: Our findings suggest that SNP, when used for short-term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone. TRIAL REGISTRATION NUMBER: NCT00135668.

The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients.

BACKGROUND: Ketorolac tromethamine (ketorolac) administration reduces postoperative opioid requirements. The pharmacokinetic characteristics of intranasal ketorolac tromethamine in children have not been characterized. Our objective of this study was to determine the pharmacokinetics of a single intranasal dose of ketorolac in adolescent patients. METHODS: Twenty surgical patients, ages 12 to 17 years, were enrolled. After surgery, subjects received intranasal ketorolac 15 mg (weight ≤50 kg) or 30 mg (weight >50 kg) using a proprietary administration system. Blood samples were obtained for ketorolac assay at baseline (within 15 minutes before the dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose. A population analysis was undertaken using nonlinear mixed-effects models. Parameter estimates were standardized to a 70-kg person. RESULTS: The intranasal dosing in adolescents was well tolerated with minimal adverse effects. A 1-compartment model with first-order absorption and elimination was satisfactory to describe time-concentration profiles. Population parameter estimates (between subject variability) were clearance (CL/F) 2.05 L/h (60.5%), volume of distribution (V/F) 15.2 L (32.4%), absorption half-life (t(1/2)abs) 0.173 hour (25.0%). Time to peak concentration (Tmax) was 52 minutes (SD 6 minutes). CONCLUSION: Administration of ketorolac by the intranasal route resulted in a rapid increase in plasma concentration and may be a useful therapeutic alternative to IV injection in adolescents because plasma concentrations attained with the device are likely to be analgesic (investigational new drug no. 62,829).

Titration of sevoflurane in elderly patients: blinded, randomized clinical trial, in non-cardiac surgery after beta-adrenergic blockade.

BACKGROUND: Monitoring depth of anesthesia via the processed electroencephalogram (EEG) has been found useful in reducing the amount of anesthetic drugs, optimizing wake-up times, and, in some studies, reducing awareness. Our goal was to determine if titrating sevoflurane as the maintenance anesthetic to a depth of anesthesia monitor (SEDLine™, Masimo, CA) would shorten time to extubation in elderly patients undergoing non-cardiac surgery while on beta-adrenergic blockade. This patient population was selected because the usual cardiovascular signs of inadequate general anesthesia may be masked by beta-blocker therapy. METHODS: Surgical patients older than 65 years of age receiving beta-adrenergic blockers for a minimum of 24 h preoperatively were randomized to two groups: a group whose titration of sevoflurane was based on SEDLine™ data (SEDLine™ group) and a group whose titration was based on usual clinical criteria (control group) where SEDLine™ data were concealed. The primary endpoint was time from skin closure to time to extubation. Aldrete score, White Fast Track score and QoR-40 were also assessed. RESULTS: There was no significant difference in time to extubation [12.5 (SD 7.4) min in the control group versus 13.0 (SD 5.9) min for the treatment group]. The control group used more fentanyl [339 mcg (SD 205)] than did the treatment group [238 mcg (SD 123)] (P<0.02). There was no difference in sevoflurane utilization, Aldrete, White Fast Track scores, time to PACU discharge, or QoR-40 assessments between the groups. CONCLUSION: Use of the SEDLine™ monitor's data to titrate sevoflurane did not improve the time to extubation or change short-term outcome of geriatric surgical patients receiving beta-adrenergic blockers. (ClinicalTrials.gov number, NCT00938782).

ED(50) and ED(95) of intrathecal bupivacaine in morbidly obese patients undergoing cesarean delivery.

BACKGROUND: It has been suggested that morbidly obese parturients may require less local anesthetic for spinal anesthesia. The aim of this study was to determine the effective dose (ED(50)/ED(95)) of intrathecal bupivacaine for cesarean delivery in morbidly obese patients. METHODS: Morbidly obese parturients (body mass index equal to or more than 40) undergoing elective cesarean delivery were enrolled in this double-blinded study. Forty-two patients were randomly assigned to receive intrathecal hyperbaric bupivacaine in doses of 5, 6, 7, 8, 9, 10, or 11 mg (n = 6 per group) coadministered with 200 µg morphine and 10 µg fentanyl. Success (induction) was defined as block height to pinprick equal to or more than T6 and success (operation) as success (induction) plus no requirement for epidural supplementation throughout surgery. The ED(50)/ED(95) values were determined using a logistic regression model. RESULTS: ED(50) and ED(95) (with 95% confidence intervals) for success (operation) were 9.8 (8.6-11.0) and 15.0 (10.0-20.0), respectively, and were similar to corresponding values of a nonobese population determined previously using similar methodology. We were unable to measure ED(50)/ED(95) values for success (induction) because so few blocks failed initially, even at the low-dose range. There were no differences with regard to secondary outcomes (i.e., hypotension, vasopressor use, nausea, and vomiting). CONCLUSIONS: Obese and nonobese patients undergoing cesarean delivery do not appear to respond differently to modest doses of intrathecal bupivacaine. This dose-response study suggests that doses of intrathecal bupivacaine less than 10 mg may not adequately ensure successful intraoperative anesthesia. Even when the initial block obtained with a low dose is satisfactory, it will not guarantee adequate anesthesia throughout surgery.

Efficacy, safety, and pharmacokinetics of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in elderly patients.

BACKGROUND: The management of elderly patients can be challenging for anesthesiologists for many reasons, including altered pharmacokinetics and dynamics. This study compared the efficacy, safety, and pharmacokinetics of sugammadex for moderate rocuronium-induced neuromuscular blockade reversal in adult (aged 18-64 yr) versus elderly adult (aged 65 yr or older) patients. METHODS: This phase 3a, multicenter, parallel-group, comparative, open-label study enrolled 162 patients aged 18 yr and older, American Society of Anesthesiologists class 1-3, scheduled for surgery with general anesthesia and requiring neuromuscular blockade. After anesthesia induction, patients received rocuronium, 0.6 mg/kg, before tracheal intubation, with maintenance doses of 0.15 mg/kg as required. At the end of surgery, patients received sugammadex, 2.0 mg/kg, at reappearance of the second twitch of the train-of-four (TOF) for reversal. The primary efficacy variable was time from sugammadex administration to recovery of the TOF ratio to 0.9 or greater. Pharmacokinetics and safety were also evaluated. RESULTS: Overall, 150 patients were treated and had at least one postbaseline efficacy assessment; 48 were aged 18-64 yr (adult), 62 were aged 65-74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% confidence interval) from sugammadex administration to recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0-2.6) min (adults) to 2.9 (2.7-3.2) min (elderly/old-elderly groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults compared with patients aged 65 yr or older (P = 0.022). Sugammadex was well tolerated by all patients. CONCLUSION: Sugammadex facilitates rapid reversal from moderate rocuronium-induced neuromuscular blockade in adults of all ages.

The effectiveness of preemptive sphenopalatine ganglion block on postoperative pain and functional outcomes after functional endoscopic sinus surgery.

BACKGROUND: The sphenopalatine ganglion block (SPGB) with local anesthetic is used to treat facial pain and headache of various etiologies; it has been widely used during functional endoscopic sinus surgery (FESS). The purpose of this study was to investigate whether preemptive SPGB may positively impact postoperative pain and functional outcomes after FESS. METHODS: A prospective, double-blind, randomized, placebo-controlled study was performed. A total of 60 patients (18-70 years), undergoing general anesthesia for bilateral FESS, were randomly assigned to receive SPGB with either 2 mL 0.25% bupivacaine with epinephrine 1:100,000 (BP, treatment group) or normal saline (NS, control group). SPGB was performed preemptively 10 minutes before the start of surgery. Preoperative and postoperative (day 0, day 7, and day 30) visual analog pain scale, Sino-Nasal Outcome Test (SNOT-20), computed tomography (CT) and endoscopic scores were compared between the 2 groups. RESULTS: A total of 29 patients were enrolled in BP, and 27 were enrolled in NS. Three patients withdrew from the study, and 1 was withdrawn by the investigator due to severe hypertension after induction of anesthesia. There were no differences in patient demographic characteristics between the study groups. On day 7, the mean visual analog pain scales were 1.12 ± 0.3 in NS and 0.48 ± 0.23 in BP (p = 0.053). There were no statistical differences in other outcome measures (SNOT-20, CT and endoscopic scores) between the 2 groups. CONCLUSION: A limited trend toward reduced postoperative pain after FESS was noted with bupivacaine compared to saline, but statistical significance was not achieved. Preemptive SPGB may offer sinonasal symptomatic benefits for patients undergoing FESS, but larger studies are warranted.

Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty.

OBJECTIVES: Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic-pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants. METHODS/MATERIALS: We studied seven infants (age 0.3-1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM. RESULTS: A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l x min(-1) x 70 kg(-1) for clearance and 16.23 l x 70 kg(-1) for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E(max) model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC(50)) being 17.1 ng x ml(-1). CONCLUSIONS: Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng.ml(-1) would typically achieve a 30% decrease in MAP.

Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery.

BACKGROUND: The aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB). METHODS: We studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance. RESULTS: The pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively. CONCLUSION: Remifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 mug remifentanil followed by an infusion of 3.7 mug/min before, during and post-CPB, supplemented with a bolus dose of 25 mug given at the start of CPB.

Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children.

OBJECTIVES: Propofol is a sedative-hypnotic drug commonly used to anesthetize children undergoing esophagogastroduodenoscopy (EGD). Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist that has been utilized in combination with propofol to provide anesthesia. There is currently no information regarding the effect of intravenous dexmedetomidine on the propofol plasma concentration-response relationship during EGD in children. This study aimed to investigate the pharmacodynamic interaction of propofol and dexmedetomidine when used in combination for children undergoing EGD. METHODS: A total of 24 children undergoing EGD, ages 3-10 years, were enrolled in this study. Twelve children received dexmedetomidine 1 microg x kg(-1) given over 10 min as well as a continuous infusion of propofol delivered by a computer-assisted target-controlled infusion (TCI) system with target plasma concentrations ranging from 2.8 to 4.0 microg x ml(-1) (DEX group). Another group of 12 children undergoing EGD also received propofol administered by TCI targeting comparable plasma concentrations without dexmedetomidine (control group). We used logistic regression to predict plasma propofol concentrations at which 50% of the patients exhibited minimal response to stimuli (EC50 for anesthesia). RESULTS: The EC50 +/- SE values in the control and DEX groups were 3.7 +/- 0.4 microg x ml(-1) and 3.5 +/- 0.2 microg x ml(-1), respectively. There was no significant shift in the propofol concentration-response curve in the presence of dexmedetomidine. CONCLUSION: The EC50 of propofol required to produce adequate anesthesia for EGD in children was unaffected by a concomitant infusion of dexmedetomidine 1 microg x kg(-1) given over 10 min.

Pharmacokinetics And Pharmacodynamics Of Fenoldopam Mesylate For Blood Pressure Control In Pediatric Patients.

BACKGROUND: Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and side-effect profile of fenoldopam in children. METHODS: Seventy seven (77) children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv) for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure). Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints. RESULTS: Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p < 0.05) during the blinded interval, and doses of 1.0-1.2 mcg/kg/min resulted in continued control of blood pressure during the open-label interval. Doses greater than 1.2 mcg/kg/min during the open-label period resulted in increasing heart rate without additional reduction in blood pressure. Fenoldopam was well-tolerated; side effects occurred in a minority of patients. The PK/PD relationship of fenoldopam in children was determined. CONCLUSION: Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8-1.2 mcg/kg/min) than as labeled for adults (0.05-0.3 mcg/kg/min). The PK and side-effect profiles for children and adults are similar.