Target Plasma Concentration Research Articles

Effect of dexmedetomidine on quality of intraoperative wake-up test in patients undergoing balloon occlusion test of the internal carotid artery

Objective To evaluate the effect of dexmedetomidine on the quality of intraoperative wake-up test in the patients undergoing balloon occlusion test of the internal carotid artery. Methods Forty-two patients of either sex with intracranial aneurysm, aged 57-78 yr, weighing 53-86 kg, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, scheduled for elective balloon occlusion test of the internal carotid artery under general anesthesia, were assigned into 2 groups(n=21 each)using a random number table: propofol combined with remifentanil group(group PR)and dexmedetomidine combined with propofol and remifentanil group(group DPR). In group DPR, dexmedetomidine was intravenously infused over 15 min in a loading dose of 0.5μg·kg-1 before induction of anesthesia, followed by an infusion of 0.3 μg·kg-1·h-1 throughout surgery.Propofol and remifentanil were given by target-controlled infusion(TCI)after infusion of the loading dose.The patients were mechanically ventilated after placement of the laryngeal mask airway.Maintenance of anesthesia was as follows: propofol and remifentanil were given by TCI with the target plasma concentrations of 0.5-1.0 μg/ml and 1-3 ng/ml, respectively, in group DPR; propofol and remifentanil were given by TCI with the target plasma concentrations of 3-5 μg/ml and 3-6 ng/ml, respectively, in group PR.Bispectral index(BIS)value was maintained at 40-60.Before wake-up test, propofol infusion was stopped and the target plasma concentration of remifentanil was decreased to 0.5 ng/ml in two groups, and the infusion rate of dexmedetomidine was decreased to 0.1 μg·kg-1·h-1 in group DPR.The wake-up time was recorded and the wake-up quality was assessed.After admission to the operating room(T0, baseline), at 10 min before wake-up test(T1), immediately after patients were wakened(T2), at 10 min after patients were wakened(T3)and at the end of wake-up test(T4), the mean blood pressure(MAP), heart rate, respiratory rate(RR), SpO2 and BIS values were recorded.The development of intraoperative awareness, emergence time, postoperative agitation, nausea and vomiting, regurgitation and aspiration and severe pain was recorded. Results MAP, heart rate, SpO2 and RR were all within the normal range during wake-up period in two groups.Compared with the baseline at T0, MAP was significantly decreased at T1, 3, 4 in group PR, and BIS value was decreased at T1-4 in DPR and PR groups(P 0.05). No cardiovascular events, respiratory depression, intraoperative awareness, postoperative nausea and vomiting, regurgitation and aspiration or severe pain was found in two groups. Conclusion Dexmedetomidine can raise the quality of intraoperative wake-up test in the patients undergoing balloon occlusion test of the internal carotid artery. Key words: Dexmedetomidine; Monitoring, intraoperative; Carotid artery, internal; Embolization, therapeutic; Wake-up test

Effects of different doses of dexmedetomidine administered intranasally on EC50 of propofol inhibiting responses to laryngeal mask airway insertion in pediatric patients

Objective To evaluate the effects of different doses of dexmedetomidine administered intranasally on the median effective target plasma concentration(EC50)of propofol inhibiting responses to laryngeal mask airway(LMA)insertion in the pediatric patients. Methods American Society of Anesthesiologists physical statusⅠor Ⅱ pediatric patients of both sexes, aged 1-3 yr, with body mass index of 20-26 kg/m2, scheduled for elective surgery under general anesthesia, were divided into 3 groups using a random number table: control group(group C), dexmedetomidine 1 μg/kg group(group D1)and dexmedetomidine 2 μg/kg group(group D2). At 20 min before induction of anesthesia, dexmedetomidine 1 and 2 μg/kg(diluted to 1 ml in normal saline)were intranasally administered in DI and D2 groups, respectively, and the equal volume of normal saline was intranasally administered in group C. Children were separated from their parents at 20 min after intranasal administration and admitted to the operating room.The target plasma concentration of propofol was determined by modified Dixon′s up-and-down method.The initial target plasma concentration of propofol was set at 5.4 μg/ml.The target plasma concentration of propofol was increased/decreased by 10% in the next patient according to the response to LMA insertion, and the ratio between the two successive concentrations was 1.1.Patients′ sedation status and LMA acceptance were evaluated when patients were separated from their parents.Patient′s satisfaction with sedation and with LMA acceptance was recorded.Probit analysis was used to calculate the EC50 of propofol inhibiting responses to LMA insertion. Results Compared with group C, the satisfactory rates of sedation and LMA acceptance were significantly increased, and EC50 of propofol inhibiting responses to LMA insertion was decreased in D1 and D2 groups(P<0.05). Compared with group D1, the satisfactory rates of sedation and LMA acceptance were significantly increased, and the EC50 of propofol inhibiting responses to LMA insertion was decreased in group D2(P<0.05). Conclusion Dexmedetomidine 1 and 2 μg/kg administered intranasally both can decrease the EC50 of propofol inhibiting responses to LMA insertion in the pediatric patients, and 2 μg/kg produces better efficacy. Key words: Dexmedetomidine; Administration, intranasal; Propofol; Dose-response relationship, drug; Laryngeal masks; Child

Median effective target plasma concentration of remifentanil inhibiting responses to skull-pin placement when combined with propofol in female patients undergoing neurosurgery

Objective To determine the median effective target plasma concentration (EC50) of remifentanil inhibiting responses to skull-pin placement when combined with propofol in the female patients undergoing neurosurgery. Methods Sixteen female patients, aged 20-60 yr, with body mass index of 18-30 kg/m2, of American Society of Anesthesiologists physical status Ⅰor Ⅱ, scheduled for elective neurosurgery under general anesthesia, were enrolled in this study.Anesthesia was induced with propofol and remifentanil given by target-controlled infusion and iv rocuronium 0.6 mg/kg.The target plasma concentration (Cp) of remifentanil and propofol was set at 5 ng/ml and 3 μg/ml, respectively.At 3 min after tracheal intubation, the target Cp of remifentanil was adjusted and set at 5 ng/ml in the first patient.The skull-pin was placed after the target effect-site and plasma concentrations were balanced.The Cp increased/decreased by 20% each time in the next patient depending on whether or not the response to skull-pin placement was positive.The ratio between the two successive concentrations was 1.2.The response to skull-pin placement was defined as positive when heart rate and/or mean arterial pressure increased by 20% of the baseline value within 1 min after placement.The EC50 and 95% confidence interval of remifentanil required to inhibit responses to skull-pin placement were calculated when combined with propofol. Results The EC50 (95% confidence interval) of remifentanil required to inhibit responses to skull-pin placement was 3.74 (3.43-4.09) ng/ml when combined with propofol. Conclusion When combined with propofol, the EC50 of remifentanil inhibiting responses to skull-pin placement is 3.74 ng/ml in the female patients undergoing neurosurgery. Key words: Piperidines; Propofol; Female; skull-pin; Dose-response relationship, drug; Drug delivery systems

Dose-response relationship of sufentanil blunting responses to double-lumen endotracheal intubation when combined with propofol given by TCI in patients with pulmonary tuberculosis

Objective To determine the dose-response relationship of sufentanil blunting responses to double-lumen endotracheal intubation when combined with propofol given by target-controlled infusion (TCI) in patients with pulmonary tuberculosis. Methods One hundred patients of both sexes with pulmonary tuberculosis, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, aged 24-58 yr, with body mass index 20% of the baseline value and/or heart rate > 90 bpm within 5 min after intubation.The median effective dose (ED50), ED95 and 95% confidence interval (95% CI) of sufentanil blunting the responses to double-lumen endotracheal intubation were calculated by Probit analysis. Results The ED50 (95% CI) and ED95 (95% CI) of sufentanil blunting the responses to intubation were 0.411 (0.370-0.441) μg/kg and 0.635 (0.556-0.888) μg/kg, respectively, when combined with propofol given by TCI. Conclusion When combined with propofol given by TCI(target plasma concentration 3.5 μg/ml), the ED50 and ED95 of sufentanil blunting the responses to double-lumen endotracheal intubation are 0.411 and 0.635 μg/kg, respectively, in patients with pulmonary tuberculosis. Key words: Propofol; Sufentanil; Dose-response relationship, drug; Tuberculosis, pulmonary; Intubation, intratracheal

Sedative interaction between dexmedetomidine and propofol

Objective To evaluate the sedative interaction between dexmedetomidine and propofol. Methods Sixty-four American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients, aged 20-60 yr, with body mass index of 19.0-25.0 kg/m2, scheduled for elective surgery under general anesthesia, were allocated into 4 groups (n=16 each) using a random number table: different target concentrations of dexmedetomidine groups (D1-4 groups). Dexmedetomidine was administered by target-controlled infusion (TCI) with the Markku model.The target plasma concentrations of dexmedetomidine were 0, 0.4, 0.6 and 0.8 ng/ml in D1-4 groups, respectively.At 15 min of dexmedetomidine TCI, propofol was given by TCI with Schnider model, and the initial target effect-site concentration was set at 1.0 μg/ml.After the target effect-site and plasma concentrations were balanced, the target effect-site concentration of propofol was gradually increased in increments of 0.2 μg/ml until loss of consciousness (Observer′s Assessment of Alertness/Sedation Scale score was 1). The model of pharmacodynamic interaction was used to analyze the sedative interaction between the two drugs. Results There was no statistically significant difference in residual sums of squares fitted by using the model of pharmacodynamic interaction between the target effect-site concentration of propofol and target plasma concentration of dexmedetomidine at loss of consciousness (P> 0.05). The linear dimensionless parameter of pharmacodynamic interaction was 0.The median effective effect-site concentration of propofol was 2.38 μg/ml at loss of consciousness, and the median effective plasma concentration of dexmedetomidine was 2.03 ng/ml at loss of consciousness. Conclusion Dexmedetomidine and propofol interact additively in terms of sedation. Key words: Dexmedetomidine; Propofol; Conscious sedation; Drug interactions

Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral therapy: analysis from a randomized placebo-controlled trial

BackgroundThe prevalence of bipolar disorder in HIV-infected patients is higher than the general population. Lithium is the most effective mood stabiliser, while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy (ART). Both TDF and lithium are associated with renal tubular toxicity, which could be additive, or a pharmacokinetic interaction may occur at renal transporters with a decrease in TDF elimination.ObjectiveWe report on the change in estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease formula in participants who received ART including TDF and were enrolled in a 24 week randomised trial of lithium versus placebo in patients with HIV-associated neurocognitive impairment.MethodsWe included HIV-infected adults with cognitive impairment established on ART for at least 6 months with a suppressed viral load attending public sector ART clinics in Cape Town, South Africa. We excluded participants with an eGFR <60 mL/min and treated with medications predisposing to lithium toxicity. We reviewed participants weekly for the first month for adverse events followed by 4 weekly visits for renal function assessment, adverse event monitoring and adherence. Lithium dose was titrated to achieve the maintenance target plasma concentration of between 0.6 and 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo.ResultsWe included 23 participants allocated to the lithium arm and 30 participants allocated to the placebo arm. Baseline characteristics were not statistically different with a mean age of 37.7 and 40.8 years, a median time on ART of 33 and 40 months and an eGFR of 139.3 and 131.0 mL/min in the lithium and placebo arms respectively. There was no statistical significant difference in the reduction in eGFR or increase in potassium between the two arms during the 24 weeks.ConclusionsWe found that 24-week treatment of HIV-infected patients with lithium and TDF did not result in increased nephrotoxicity.Trial registration The study was registered on the Pan African Clinical Trials Registry (PACTR) with the identifier number PACTR201310000635418. Registered 11 October 2013 before the first participant was enrolled

Comparative Total and Unbound Pharmacokinetics of Cefazolin Administered by Bolus Versus Continuous Infusion in Patients Undergoing Major Surgery

Abstract Background Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. Methods Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h−1) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics® software. Calculations of PTA and FTA were performed for common pathogens. Results Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44–80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean (sd) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h−1. Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. Conclusions Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. Clinical trial registration NCT02058979.

Target-controlled Infusion Propofol Versus Sevoflurane Anaesthesia for Emergency Traumatic Brain Surgery: Comparison of the Outcomes.

The choice of anaesthetic techniques is important for the outcome of traumatic brain injury (TBI) emergency surgery. The objective of this study was to compare patient outcomes for target-controlled infusion (TCI) of propofol and sevoflurane anaesthesia. A total of 110 severe TBI patients, aged 18-60, who underwent emergency brain surgery were randomised into Group T (TCI) (n = 55) and Group S (sevoflurane) (n = 55). Anaesthesia was maintained in Group T with propofol target plasma concentration of 3-6 μg/mL and in Group S with minimum alveolar concentration (MAC) of sevoflurane 1.0-1.5. Both groups received TCI remifentanil 2-8 ng/mL for analgesia. After the surgery, patients were managed in the intensive care unit and were followed up until discharge for the outcome parameters. Demographic characteristics were comparable in both groups. Differences in Glasgow Outcome Scale (GOS) score at discharge were not significant between Group T and Group S (P = 0.25): the percentages of mortality (GOS 1) [27.3% versus 16.4%], vegetative and severe disability (GOS 2-3) [29.1% versus 41.8%] and good outcome (GOS 4-5) [43.6% versus 41.8%] were comparable in both groups. There were no significant differences in other outcome parameters. TCI propofol and sevoflurane anaesthesia were comparable in the outcomes of TBI patients after emergency surgery.

Comparison of development of postoperative cognitive dysfunction using different methods of anesthesia in elderly patients

Objective To compare the development of postoperative cognitive dysfunction (POCD) under total inhalation anesthesia with sevoflurane versus total intravenous anesthesia with propofol in elderly patients. Methods Sixty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 65-77 yr, weighing 43-78 kg, with preoperative Mini-Mental State Examination (MMSE) score≥25, scheduled for elective surgery for oral and maxillofacial carcinoma, were divided into 2 groups (n=30 each) using a random number table: total inhalation anesthesia with sevoflurane group (group S) and total intravenous anesthesia with propofol-based anesthesia group (group P). The patients were tracheally intubated under local infiltration anesthesia.In group S, anesthesia was induced with inhalation of 8% sevoflurane (oxygen flow rate 8 L/min), rocuronium 0.9 mg/kg was injected intravenously when the bispectral index (BIS) value reached 45, and the patients were mechanically ventilated; anesthesia was maintained with inhalation of sevoflurane with the end-tidal concentration of 2%-3%.In group P, anesthesia was induced with iv propofol 2 mg/kg and sufentanil 0.3 μg/kg, rocuronium 0.9 mg/kg was injected intravenously when the BIS value reached 45, and the patients were mechanically ventilated; anesthesia was maintained with target-controlled infusion of propofol (target plasma concentration 3-5 μg/ml) and remifentanil (target plasma concentration 3-5 ng/ml). In both groups, intermittent iv boluses of cisatracurium 0.04 mg/kg were given to maintain muscle relaxation during operation, and BIS value was maintained at 40-60 during operation.Before intubation (T1), immediately after onset of intubation (T2), at 10 min of intubation (T3), immediately after begninning of skin incision (T4), while operating on the base of tongue or sawing the lower jaw (T5), at the end of operation (T6) and on the morning of the postoperative day 1 (T7), blood samples from the elbow vein were collected for determination of plasma norepinephrine and epinephrine concentrations by high-performance liquid chromatography and electrochemistry.At T1-7 and on the morning of the postoperative day 3 (T8), blood samples from the elbow vein were collected for measurement of plasma cortisol concentrations by radioimmunoassay.MMSE was used to assess the cognitive function on the postoperative day 7.MMSE score < 24 was defined as POCD, and the occurrence of POCD was recorded. Results Compared with group S, the plasma concentrations of norepinephrine and epinephrine were significantly decreased at T4 and T5, the plasma cortisol concentration was significantly decreased at T4-7 (P 0.05). Conclusion Although the probability of the development of POCD is low when the two anesthetic methods are used, total intravenous anesthesia with propofol-based anesthesia induces a marked decrease in perioperative stress responses when compared with total inhalation anesthesia with sevoflurane. Key words: Anesthesia, intravenous; Anesthesia, inhalation; Propofol; Anesthetics, inhalations; Aged; Cognition disorders; Stress

Moderate to severe HIV-associated neurocognitive impairment: A randomized placebo-controlled trial of lithium.

HIV-associated neurocognitive disorder (HAND) remains highly prevalent despite effective anti-retroviral therapy (ART). A number of adjunctive pharmacotherapies for HAND have been studied with disappointing results, but preliminary data suggest that lithium may provide clinical benefit. In addition, the low cost of lithium would facilitate access in low- and middle-income countries which carry the greatest burden of HIV. Our objective was to evaluate the 24-week efficacy and safety of lithium in patients with moderate to severe HAND. Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, whereas our secondary endpoint was the change in proton magnetic resonance spectroscopy (H-MRS) brain metabolite concentrations. We conducted a 24-week randomized placebo-controlled trial of lithium as adjunctive pharmacotherapy. We enrolled participants with moderate to severe HAND, on ART for at least 6 months, with suppressed viral loads and attending public sector primary care clinics in Cape Town, South Africa. We randomized 66 participants to lithium (n = 32) or placebo (n = 34). Lithium or placebo was dosed 12-hourly and titrated to achieve the maintenance target plasma concentration of 0.6 to 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. Totally 61 participants completed the study (lithium arm = 30; placebo arm = 31). Participants at enrolment had a mean age of 40 years and a median CD4+ T-cell count of 500 cells/μL. The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); P = 0.716. The improvement remained similar when analyzed according to age, severity of impairment, CD4+ count, time on ART, and ART regimen. Standard H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. Six serious adverse events occurred, but none were considered related to the study drug. Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment.

Effects of ketamine on brain function during smooth pursuit eye movements.

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block-design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self-ratings of psychosis-like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis-like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047-4060, 2016. © 2016 Wiley Periodicals, Inc.

Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV-Infected African Children.

Owing to insufficient evidence in children, target plasma concentrations of efavirenz are based on studies in adults. Our analysis aimed to evaluate the pediatric therapeutic thresholds and characterize the determinants of virological suppression in African children. We analyzed data from 128 African children (aged 1.7-13.5 years) treated with efavirenz, lamivudine, and one among abacavir, stavudine, or zidovudine, and followed up to 36 months. Individual pharmacokinetic (PK) measures [plasma concentration 12 hours after dose (C12h), plasma concentration 24 hours after dose (C24h), and area under the curve (AUC0-24)] were estimated using population PK modeling. Cox multiple failure regression and multivariable fractional polynomials were used to investigate the risks of unsuppressed viral load associated with efavirenz exposure and other factors among 106 initially treatment-naive children, and likelihood profiling was used to identify the most predictive PK thresholds. The risk of viral load >100 copies per milliliter decreased by 42% for every 2-fold increase in efavirenz mid-dose concentration [95% confidence interval (CI): 23% to 57%; P < 0.001]. The most predictive PK thresholds for increased risk of unsuppressed viral load were C12h 1.12 mg/L [hazard ratio (HR): 6.14; 95% CI: 2.64 to 14.27], C24h 0.65 mg/L (HR: 6.57; 95% CI: 2.86 to 15.10), and AUC0-24 28 mg·h/L (HR: 5.77; 95% CI: 2.28 to 14.58). Children older than 8 years had a more than 10-fold increased risk of virological nonsuppression (P = 0.005); among children younger than 8 years, boys had a 5.31 times higher risk than girls (P = 0.007). Central nervous system adverse events were infrequently reported. Our analysis suggests that the minimum target C24h and AUC0-24 could be lowered in children. Our findings should be confirmed in a prospective pediatric trial.

Clinical effects of midazolam or lidocaine co-induction with a propofol target-controlled infusion (TCI) in dogs

ObjectiveTo evaluate the propofol requirement, cardiovascular and respiratory variables using midazolam or lidocaine with a propofol target-controlled infusion (PTCI) for induction of anaesthesia in healthy dogs. Study designProspective, randomized, controlled blinded clinical trial. AnimalsSixty client-owned dogs [American Society of Anesthesiologists (ASA) I–II] undergoing surgical procedures. MethodsThirty minutes after premedication with acepromazine (0.03 mg kg−1) and morphine (0.2 mg kg−1), PTCI was started and maintained at a plasma target concentration of 1 μg mL−1. Three minutes later, dogs (n = 20 per group) received either 5 mL 0.9% sodium chloride (SG), 2 mg kg−1 of lidocaine (LG) or 0.2 mg kg−1 of midazolam (MG) intravenously (IV) as a co-induction agent. Two minutes later, suitability for endotracheal intubation was assessed. If intubation was not possible, the propofol target was increased by 0.5 μg mL−1 every 60 seconds until it was successfully achieved. Heart rate (HR), respiratory rate (fR), and oscillometric systolic arterial pressure (SAP), mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were recorded immediately prior to commencing PTCI (B0), prior to intubation (BI), immediately after (T0), and at 3 (T3) and 5 (T5) minutes post-intubation. End-tidal partial pressures of carbon dioxide (PE′CO2) were recorded at T0, T3 and T5. The occurrence of excitement at any time point was noted. ResultsThe median (range) propofol target concentration for endotracheal intubation was significantly lower in MG, 1.5 (1.0–4.0) μg mL−1 compared with LG, 2.5 (1.5–4.5) μg mL−1 or SG, 3.0 (2.0–5.0) μg mL−1. Heart rate, MAP, fR and PE′CO2 were similar in the three groups at all time points. No excitement was reported in any dog. Conclusions and clinical relevanceMidazolam, but not lidocaine, provided a significant reduction in PTCI requirement for induction of anaesthesia thereby allowing successful intubation. However, cardiovascular and respiratory effects were not different between the groups.

Abstract PR256

Background & Objectives: To evaluate the feasibility of bispectral index (BIS) guided closed-loop target controlled infusion (TCI) of propofol for general anesthesia in children. Materials & Methods: Twenty children aged 1-12 years old, ASA gradeI-II, scheduled to elective surgery under general anesthesia, were dived into 2 groups according to their age: group A, aged 1-3 yrs, and group B, aged 4-12yrs (n = 10). The BIS monitor (VISTA, Aspect Medical System, Inc., USA) was connected to a closed-loop TCI system (CONCERT-CL, VERYARK Technology Co., Ltd., Guang Xi, China), and the system automatically regulated the plasma target concentration of propofol to achieve a target BIS of 50 during maintenance of anesthesia. Results: There were 68.3% ± 11.8% and 90.4% ± 6.7% of time with BIS between 40-60 in group A and B respectively (P < 0.05); The MEAPE, Wobble and global score (GS, GS = (MEAPE + Wobble)/% of time of BIS 40-60) were higher in group A than in group B (13.5 ± 2.5 vs 7.8 ± 1.7, 10.7 ± 2.2 vs 7.1 ± 1.8 and 35.2 ± 8.1 vs 16.8 ± 5.1 respectively, P < 0.05). The heart rate and blood pressure were maintained stable (fluctuation less than 20% of the baseline) in both groups. No significant differences in propofol dose (11.5 ± 3.3 vs 11.2 ± 3.5 mg·kg-1·h-1), time to tracheal extubation(17.4 ± 4.9 vs 14.0 ±4.6 min), eyes opening(27.8 ± 7.2 vs 20.0 ± 8.2 min), and recovery of consciousness(30.2 ± 7.6 vs 25.3 ± 9.4 min) were observed between group A and B (P > 0.05). Conclusion: This study demonstrated the feasibility of BIS guided closed-loop target controlled infusion of propofol for general anesthesia in children, and the efficiency of the system was better in children aged over 4 years old. Disclosure of Interest: None declared

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion

Background: Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known. Objective: To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA). Methods: Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml. Results: The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion. Conclusion: Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion.

Critical contribution of KV1 channels to the regulation of coronary blood flow.

Ion channels in smooth muscle control coronary vascular tone, but the identity of the potassium channels involved requires further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P<0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch-clamp experiments demonstrated significant correolide-sensitive (1-10µM) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n=5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3-3µM targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P<0.05). Dobutamine (0.3-10µg/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3µM) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P<0.001). Coronary artery occlusions (15s) elicited reactive hyperemia and correolide (3µM) reduced the flow volume repayment by approximately 30% (P<0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and, perhaps, vasodilation in response to increased metabolism and transient ischemia.

Placental transfer and mammary excretion of a novel angiotensin receptor blocker fimasartan in rats.

BackgroundFimasartan (FMS) is a potent angiotensin receptor blocker for the treatment of mild to moderate hypertension. This study aimed to evaluate the transfer of FMS to fetus and breast milk in rats.MethodsIn order to study the transfer to the fetus and nursing pup, pregnant and nursing maternal rats were administered with FMS by a constant intravenous infusion to reach target plasma concentrations of 200 ng/mL and 100 ng/mL. The concentrations of FMS in plasma, placenta, amniotic fluid, fetus, and milk were determined by a validated LC-MS/MS assay.ResultsUpon constant intravenous infusion, the plasma FMS concentration reached the target steady state concentrations (Css = 200 ng/mL and 100 ng/mL) in 24 h. The tissue-to-plasma partition coefficients (Kp) for placenta, amniotic fluid, and milk were obtained based on the observed FMS concentrations in the tissues and Css. The Kp values for all tissues were not different between high (Css = 200 ng/mL) and low (Css = 100 ng/mL) dose groups. While the mean Kp of the placenta was 44.6–59.0 %, the mean Kp was 1.3–1.7 % for the amniotic fluid and 14.9–17.0 % for fetus. The mean Kp of milk was 10.4–15.2 %.ConclusionsPlacental transfer and milk excretion of FMS was relatively lower compared to other angiotensin receptor blockers.

Preliminary Intraoperative Validation of the Nociception Level Index: A Noninvasive Nociception Monitor.

The nociception level (NoL) index is an index of nociception based on nonlinear combination of heart rate, heart rate variability, photoplethysmograph wave amplitude, skin conductance, skin conductance fluctuations, and their time derivatives. The authors evaluated the abilities of the NoL index and other measures of nociception to discriminate between noxious and nonnoxious stimuli, to progressively respond to graded stimuli, and to respond to opioid administration. Intraoperative NoL was compared to heart rate, pulse plethysmograph amplitude, noninvasive blood pressure, and the surgical pleth index around five specific stimuli: tetanic stimulation with and without fentanyl analgesia, intubation, first incision/trocar insertion, and a nonnoxious period. The response around first incision was analyzed at two target plasma concentrations of remifentanil. In 58 patients, the NoL index responded progressively to increased stimulus intensity and remained unchanged in response to nonnoxious stimuli. Compared to other accepted measures of nociception, the NoL index better discriminated noxious from nonnoxious stimuli with an area under the curve of 0.93 (95% CI, 0.89 to 0.97) and a sensitivity of 87% at a specificity of 84%. The NoL index was the only measure that reliably reflected two different analgesic concentrations of remifentanil during initial skin incision or trocar insertion. The NoL index changes proportionately with patients' response to various clinical and experimental noxious stimuli and discriminates noxious from nonnoxious stimuli with high sensitivity and specificity. The NoL index also responds progressively to increasing stimuli intensity and is appropriately blunted by analgesic administration. The NoL index was superior to other compared measures and appears to accurately characterize nociception during general anesthesia.

Propofol target-controlled infusion modeling in rabbits: Pharmacokinetic and pharmacodynamic analysis.

This study aimed to establish a new propofol target-controlled infusion (TCI) model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and propofol (10 mg/kg) was administrated intravenously. Artery blood samples were collected at various time points after injection, and plasma concentrations of propofol were measured. Pharmacokinetic modeling was performed using WinNonlin software. Propofol TCI within the acquired parameters integrated was conducted to achieve different anesthetic depths in rabbits, monitored by narcotrend. The pharmacodynamics was analyzed using a sigmoidal inhibitory maximal effect model for narcotrend index (NI) versus effect-site concentration. The results showed the pharmacokinetics of propofol in Japanese white rabbits was best described by a two-compartment model. The target plasma concentrations of propofol required at light anesthetic depth was 9.77±0.23 μg/mL, while 12.52±0.69 μg/mL at deep anesthetic depth. NI was 76.17±4.25 at light anesthetic depth, while 27.41±5.77 at deep anesthetic depth. The effect-site elimination rate constant (ke0) was 0.263/min, and the propofol dose required to achieve a 50% decrease in the NI value from baseline was 11.19 μg/mL (95% CI, 10.25-13.67). Our results established a new propofol TCI animal model and proved the model controlled the anesthetic depth accurately and stably in rabbits. The study provides a powerful method for exploring general anesthetic mechanisms at different anesthetic depths in vivo.

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5–1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2–0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5–1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.