Sedation level with midazolam: A pediatric surgery approach.

Midazolam (MDZ) is a short-acting benzodiazepine that is widely used to induce and maintain general anesthesia during diagnostic and therapeutic procedures in pediatric patients due to its sedative properties. The aim of this study was to perform a systematic review without a meta-analysis to identify scientific articles and clinical assays concerning MDZ-induced sedation for a pediatric surgery approach. One hundred and twenty-eight results were obtained. After critical reading, 37 articles were eliminated, yielding 91 publications. Additional items were identified, and the final review was performed with a total of 106 publications. In conclusion, to use MDZ accurately, individual patient characteristics, the base disease state, comorbidities, the treatment burden and other drugs with possible pharmacological interactions or adverse reactions must be considered to avoid direct alterations in the pharmacokinetics and pharmacodynamics of MDZ to obtain the desired effects and avoid overdosing in the pediatric population.

The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients. METHODS: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography. RESULTS AND DISCUSSION: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q25 0.01-Q75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q25 37.51-Q75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q25 0.01-Q75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q25 0.002-Q75 0.13) in patients with the normal genotype (CC), p = 0.042. WHAT IS NEW AND CONCLUSION: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug.

Influence of Age, Gender and Body Mass Index on Intravenous Pharmacokinetics of Buprenorphine in Children Undergoing Orthopedic Surgery.

Background: Buprenorphine (BPN) is a widely used analgesic in the pediatric population, although there are few studies on the pharmacokinetics and pharmacodynamics of this drug. Objective: The objective was to characterize the pharmacokinetics of BPN after intravenous administration and analyze the effect of age, gender, weight, height, body mass index (BMI), and drug-drug interactions as covariates. Methods: Ninety-nine children (2-10 years), who underwent orthopedic surgery under regional, general, or combined anesthesia were included. Patients evaluated according to the American Society of Anesthesiologists Physical Status Classification, who received intravenous BPN 2 µg/kg were enrolled. Blood was collected from 1-240 min. Drug plasma concentrations were determined by LC-MS/MS. Population pharmacokinetic parameters were obtained with Monolix 2021R1 software. Pearson's correlation and/or ANOVA were used for statistical analysis. Results: Age was associated with changes in clearance and central compartment volume and the female gender was associated with lower intercompartmental clearance, while BMI modified clearance, central and peripheral compartment volume. Concomitant administration of BPN with fentanyl and dexamethasone produced decreases in clearance. Conclusions: The covariates of sex, age, and BMI are directly related to the increase or decrease in BPN pharmacokinetic parameters.

Pharmacokinetic-Pharmacodynamic Modeling of Midazolam in Pediatric Surgery.

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.

Influence of Age and Sex on the Pharmacokinetics of Midazolam and the Depth of Sedation in Pediatric Patients Undergoing Minor Surgeries.

Whether age and sex influence the depth of sedation and the pharmacokinetics of midazolam is currently unknown. The influence of age and sex was investigated in 117 children (2 to 17 years) who required intravenous sedation for minor surgery (0.05 mg/kg). Plasma concentrations and sedation effects were simultaneously measured. The measured concentrations were analyzed using a two-compartment model with first-order elimination. Among the age ranges, significant differences were found (p < 0.05) between the volume of distribution (Vd) of the first compartment (V1) and that of the second (V2). With respect to sex, differences in V2 were found between age groups. At the administered dose, in patients younger than 6 years, a profound sedative effect (40-60 BIS) was observed for up to 120 min, while in older children, the effect lasted only half as long. The differences found in the Vd and bispectral index (BIS) in patients younger than 6 years compared to older patients may be due to immature CYP3A activity and body fat content; furthermore, the Vd varies with age due to changes in body composition and protein binding. Patients younger than 6 years require intravenous (IV) doses <0.05 mg/kg of midazolam for deep sedation. Dosage adjustments according to age group are suggested.

Sex and Age Influence on Association of CYP450 Polymorphism with Midazolam Levels in Critically Ill Children.

Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The present study aimed to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children. Seventy-two DNA samples were genotyped by real-time PCR. Children ≤ five years of age who carry the rs776746 (T) allele in CYP3A5 gene were associated with lower plasma midazolam levels. The concentration median in patients was 0.0 ng/mL, while in patients with the normal (C) allele, it was 438.17 ng/mL (Q25 135.75-Q75 580.24), p = 0.005. The midazolam plasmatic concentration in female patients with the minor (T) allele was 0.0 ng/mL (Q250.00-Q75204.3), while in patients with the normal (C) allele median it was 459.0 ng/mL (Q25296.9-Q75789.7), p = 0.002. Analysis of the dominant model for the rs2740574 variant in CYP3A4 revealed a median of 0.38 L/kg (Q250.02-Q751.5) for the volume of distribution parameter in female patients with the normal T allele, while female patients with the minor C allele showed a median of 18.1 L/kg (Q257.5-Q7528.7) p = 0.02. Our results suggest an altered midazolam metabolism due to the presence the allelic rs2740574 variants of CYP3A4 and rs776746 of CYP3A5, and also the strong influence of age and sex.

A reliable method of liquid chromatography for the quantification of acetaminophen and identification of its toxic metabolite N-acetyl-p-benzoquinoneimine for application in pediatric studies.

The aim of the present study was to develop a simple, selective and reliable method to quantify acetaminophen and its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) for pediatric studies using 100 µL plasma samples, by reverse-phase HPLC and UV detection. The assay was performed using a C18 column and an isocratic elution with water-methanol-formic acid (70:30:0.15; v/v/v) as mobile phase. Linearity of the method was assayed in the range of 1-30 µg/mL for acetaminophen and 10-200 µg/mL for NAPQI, with a correlation coefficient r = 0.999 for both compounds, and inter- and intra-day coefficients of variation of less than 13%. Several commonly co-administered drugs were analyzed for selectivity and no interference with the determinations was observed. The detection and quantification limits for acetaminophen and NAPQI were 0.1 and 1 µg/mL, and 0.1 and 10 µg/mL respectively. The present method can be used to monitor acetaminophen levels using 100 µL plasma samples, which may be helpful when very small samples need to be analyzed, as in pharmacokinetics determination or drug monitoring in plasma in children. This assay is also able to detect the NAPQI for drug monitoring in patients diagnosed with acetaminophen intoxication.

Effect of treatment and additional disease on pharmacokinetic of valproic acid in children with epilepsy.

BACKGROUND: Most of bayesian pharmacokinetic studies and the influence of clinical variables have been carried out in adults. PURPOSE: The aim was to estimate population-based pharmacokinetic of valproic acid (VPA) and to determine the effect of treatment and additional disease on its performance in children with epilepsy. MATERIAL AND METHODS: For the study steady-state serum concentrations of VPA were determined from 108 epileptic patients (44 females and 64 males) who were receiving the anticonvulsant as main drug of treatment with age range since 1 to 16 years (median 4y, 6m) and weight since 5.2 to 50 kg (median 17.5 kg). All patients had their renal, hepatic and nutritional functions normal. One compartment model using interactive two-stage Bayesian approach was employed in the analysis. RESULTS; Population estimates of CL/F and V/F for VPA were 0.022 +/- 0.013 L/h and 0.217 +/- 0.134 L/kg, respectively. These estimates were significantly affected by weight, age, carbamazepine (CBZ) and gastroesophageal reflux (GER). The final regression models were: CL/F (L/h) = 0.0696 + 0.0031 (Age) + 0.0075 (Weight); and V/F (L) = 0.674 + 0.0308 (Age) + 0.0756 (Weight). Prediction of VPA serum concentration in other validation group revealed an important improvement in the predictive performance of VPA concentrations in comparison with the basic model that did not include any co-variables. CONCLUSIONS: Based on a population model of children with epilepsy, the pharmacokinetic of VPA could be altered by weight, age and the administration of CBZ and additional GER to epilepsy.

Clinical evidence of the antiarrhythmic effect of a magistral suspension of propafenone: a case report.

Propafenone is an antiarrhythmic that has been used for the treatment of tachiarrytmias in both adults and children. The aim of this study was to analyze the pharmacologic effect of a magistral suspension of propafenone, due to lack of an adequate commercial formulation for use in children. In this study we present, a case of a 2-year-old boy that was diagnosed with Wolff-Parkinson White syndrome and treated with a magistral suspension of propafenone. He has now been one year with no symptoms, no tachycardia and no cyanosis. The clinical status of the patient under treatment with propafenone was improved through constant medical care in the Cardiological Health Care Unit. The use of a magistral formulation of propafenone developed in our laboratory offers a temporal solution due to lack of medicines for children.

Malformations in newborns associated to anticonvulsant consumption during pregnancy. experience in third level hospital of Mexico.

AIM: The purpose of the present study is to determine the relationship between the anticonvulsant drug use during pregnancy and the presence of malformations in the newborns. METHODS: The frequency of malformations in the neonates of epileptic mothers under anticonvulsant treatment was analyzed in two periods, one from 1988 to 1992, which included 76 epileptic mothers, and another from 1996 to 2003 with 170 patients. RESULTS: In the first period, 51 (67.1%) of mothers received monotherapy and 25 (32.9%) received polytherapy of phenytoin with carbamazepine, valproic acid or phenobarbital. In this period, 4 newborns (16%) with congenital malformations were registered. In the second period, 159 (93.5%) of the epileptic mothers received monotherapy and 11 (6.5%) received polytherapy of valproic acid with carbamazepine or phenytoin. During this period only 3 newborns 27.3% with malformations were registered. DISCUSSION: Clinical treatment should consider the risk of using polytherapy, mainly if phenytoin or valproic acid are combined with other anticonvulsants.

Buprenorphine and pain treatment in pediatric patients: an update.

INTRODUCTION: The usual management of moderate to severe pain is based on the use of opioids. Buprenorphine (BPN) is an opioid with an analgesic potency 50 times greater than that of morphine. It is widely used in various pain models and has demonstrated efficacy and safety in adult patients; however, there are insufficient clinical trials in pediatric populations. PURPOSE: The aim of this study was to perform an updated meta-analysis on the implementation of BPN in the treatment of pain in the pediatric population. METHODS: A bibliographic search was carried out in different biomedical databases to identify scientific papers and clinical trials with evidence of BPN use in children and adolescents. RESULTS: A total of 89 articles were found, of which 66 were selected. Analysis of these items revealed additional sources, and the final review included a total of 112 publications. CONCLUSION: Few studies were found regarding the efficacy and safety of BPN use in children. In recent years, the use of this drug in the pediatric population has become widespread, so it is imperative to perform clinical trials and pharmacological and pharmacovigilance studies, which will allow researchers to develop dosage schemes based on the evidence and minimize the risk of adverse effects.

Clinical evidence of an interaction between imipramine and acetylsalicylic acid on protein binding in depressed patients.

The binding of imipramine to plasma proteins was studied in 20 adult patients with endogenous depression, with the purpose of assessing the effect produced by its simultaneous administration with an analgesic. Patients were administered 150 mg/day imipramine for 5 days and the binding to plasma proteins was determined. This was repeated 2 days later, after simultaneous administration of imipramine with 1,000 mg/day acetylsalicylic acid (ASA). Adverse effects for each patient were registered during both phases and were classified as mild, moderate, or severe. Results showed 84.4 +/- 7.07% of imipramine bound to plasma proteins and 72.18 +/- 6.5% when imipramine was administered with ASA (p < 0.05). When imipramine was administered alone, 1.95 mild adverse events per patient were registered. When imipramine was administered with ASA, the mild adverse events increased to 3.1 (p < 0.01) and the severe adverse events increased from 0.6 to 1.5 (p < 0.01). The levels of free imipramine increased when ASA was administered, indicating a displacement on the binding to plasma proteins. When adverse events were compared for each treatment, the accumulation of the free fraction of imipramine caused an increase in adverse events as well as in their clinical severity.

Reliable method for the determination of ranitidine by liquid chromatography using a microvolume of plasma.

The aim of the present study was to develop a simple method to measure ranitidine, using 100 microL of plasma, by high-performance liquid chromatography with a Symmetry C(18) column and UV detection at 313 nm. Linearity was assessed in the range from 50 to 1500 ng ml(-1) and had a correlation coefficient of 0.999. The inter- and intra-day coefficients of variation were less than 7%. The limits of detection and quantitation were 5 and 15 ng ml(-1), respectively. Drug levels were determined satisfactorily in three patients. A simple and reliable method was developed which uses a microvolume of plasma, particularly useful in low-weight children.

Effects of gender and phase of the menstrual cycle on the kinetics of ranitidine in healthy volunteers.

The present study was undertaken to determine if differences exist in the pharmacokinetic parameters of oral ranitidine caused by gender and stage of the menstrual cycle. The study was performed in two steps, in the first a pharmacokinetic study was performed on 10 men (average age 35.5 yrs) and 10 women (average age 34.7 yrs) during the follicular phase, and in the second the pharmacokinetic study was performed only on the same women in their luteal phase. Subjects received a tablet dose of 300 mg ranitidine, and blood samples were drawn at several times after its ingestion. Plasma ranitidine concentration was determined by high performance liquid chromatography. Comparison of the pharmacokinetic parameters of women and men revealed statistically significant differences both in distribution volume (Vd) with values of 2.0 and 6.3 l/kg, Area Under Curve (AUC) with values of 7312.15 and 11471.94 ng/ml/h, and clearance (CLt) with values of 0.65 and 0.59 l/kg/h, respectively. Several pharmacokinetic parameters in women were different in the follicular compared to the luteal phase; for example, Vd was 2.0 and 5.6 l/kg, AUC was 7312.15 and 5195.83 ng/ml/h, and CLt was 0.65 and 0.97 l/kg/h, in the respective phases. Moreover, the maximum concentration (Cmax) was 1086 ng/ml in the follicular vs. 864 ng/ml in the luteal phase. The first study detected differences between men and women in several pharmacokinetic parameters, mainly those indicative of drug availability, for example, Vd, AUC, and CLt. Comparison of data obtained in the follicular phase with those obtained in the luteal phase revealed differences in most pharmacokinetic parameters, which is seemingly indicative of the characteristic physiological changes associated with the luteal phase that largely affect the kinetics and availability of drugs such as ranitidine. Although it has been postulated that hormonal fluctuation within the menstrual cycle phase is the primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs, further study of related factors is required to understand how gender and menstrual cycle rhythms affect the phannacokinetic process in their entirety.

Pharmacokinetics of digoxin in children with congestive heart failure aggravated by other diseases.

OBJECTIVE: To determine individual digoxin level variations and the effect of some common diseases those aggravate congestive heart failure (CHF) on digoxin pharmacokinetics in children. DESIGN: Digoxin pharmacokinetics was evaluated in 11 children with CHF and an additional disease, such as rheumatic fever, anemia or infections. Digoxin plasma levels were monitored in patients on multiple-dose regime. Setting. Third level pediatric hospital. RESULTS: Pharmacokinetic parameters showed extensive variation; median values were: elimination half-life 42.0 hrs (8.3-77.0), volume of distribution 1.01 L/kg (0.654-6.25), and clearance 15.0 mL/kg/h (6.0-331.8), which differed from results in patients with only CHF, reported previously. Dosage schemes in use at the Cardiology Service produced the following results: 40.5% of patients reached therapeutic levels, 10.8% toxic levels and 48.6% subtherapeutic levels. CONCLUSION: The range of dosage required in order to adjust individual treatments was very wide, leading us to the conclusion that therapeutic schemes for this population should be individualized based on their pharmacokinetic parameters, and therapeutic monitoring of drugs should be performed.

Comparative bioavailability of propafenone after administration of a magistral suspension vs. commercial tablets in healthy volunteers.

Propafenone (CAS 34183-22-7) is an effective antiarrhythmic drug used in children, although in some countries no specific pediatric formulation is available. The aim of this study is to compare the relative bioavailability of a magistral (MAG) preparation of propafenone versus its commercial (COM) presentation in a group of 16 Mexican healthy volunteers. Bioavailability was determined after crossover administration of the drugs, through a randomized two-phase trial. All volunteers had normal hepatic and renal functions, determined clinically at the beginning of the study, and received 150 mg of either COM (tablets) or MAG (suspension). Blood samples were drawn for a 24-h post-dose analysis by HPLC to measure plasma levels of propafenone. Subjects (mean 25.9 +/- 5.3 years and 66.1 +/- 12.4 kg) had the following pharmacokinetic parameters: Cmax 189.9 +/- 20.92 ng/mL, Tmax 1.5 h, AUC 322.4 +/- 36.28 ng x ml(-1) x h for COM. Values for MAG were Cmax 225.8 +/- 24.38 ng/mL, Tmax 1.7 h and AUC 359.3 +/- 27.90 ng x ml(-1) x h. These values yielded a relative bioavailability of 111.42% for MAG compared with COM. No electrocardiographic changes were recorded in any subject with respect to the baseline value, in both treatment schemes. Therefore, propafenone suspension prepared as a magistral formulation may be used as an alternative drug in pediatric patients.

Extemporaneous suspension of propafenone: attending lack of pediatric formulations in Mexico.

BACKGROUND: Physicians have frequently encountered difficulties when prescribing drugs not available in doses suitable for pediatric age groups. Furthermore, children have difficulty swallowing tablets. This study aimed to determine the stability of an oral propafenone suspension made from commercial tablets with a syrup vehicle and to establish its reliable use with children. METHODS: An extemporaneous suspension of propafenone 1.5 mg/ml was prepared with commercial tablets. Its physicochemical and microbiologic stability was established by constant monitoring during 90 days at room temperature (15 +/- 5 degrees C) and at refrigeration (3-5 degrees C). Plasma levels of propafenona were measured in two children with supraventricular tachycardia at steady state. RESULTS: The suspension was stable, maintaining its original physicochemical and microbiologic properties. Moreover, no apparent changes in color or odor were observed. Plasma levels of propafenone in patients demonstrated therapeutic concentrations after they had taken the suspension, with no unwanted outcome. CONCLUSIONS: The conservation of both physicochemical and microbiologic stability of the suspension represents an option for the administration of propafenone to children.

Pharmacovigilance and pharmacoepidemiology of drugs in a Mexican pediatric hospital. A proposed guide.

We describe the procedures of pharmacovigilance (PV) and pharmacoepidemiology (PE) of drugs in a pediatric hospital. These activities contribute to the detection and registration of adverse drug reactions and to determine the patterns of drug prescription among children attended at the hospital. The PV activities show that there is a relation between an increase in incidence of adverse drug reactions and the prescription of a larger number of drugs. The PE activities reveal that antibiotics are the most frequently prescribed drugs and next are drugs used for gastrointestinal diseases. Since PV and PE activities were initiated at our hospital, they have contributed to a more adequate use of drugs in children. As a conclusion of these activities, it could be that if the PE of a hospital is known, drug consumption can be optimally planned. PV and PE demonstrate that, if polytherapy is not necessary, it must be avoided. Finally, the present guide can be adopted to initiate PV and PE at a hospital.

Phenotypical expression of CYP2D6 in amerindians of tepehuano origin from Durango, Mexico.

Cytochrome P4502D6 (CYP2D6) shows genetic polymorphism, which is clinically important in the metabolism of drugs and other xenobiotics. Dextrometorphan (DM) has been used as a test compound to evaluate the in vivo activity of CYP2D6. Phenotypical frequencies of CYP2D6 have been determined in some populations, but little is known about them in native populations. The object of this study was to characterize the phenotypical expression of CYP2D6 in Amerindian subjects of Tepehuano origin from the State of Durango, using DM as metabolic marker, as well as the effect of age, sex and nutritional status on this activity. Three hr after oral administration of a single 30 mg dose of DM, the plasma concentration of DM and its metabolite dextrophan (DX) were determined with HPLC in 55 Tepehuano subjects. All subjects were extensive metabolizers (metabolic ratio MR < 0.3). No correlation of age, sex or nutritional status was found with the DM/DX metabolic ratio. However, we found a monoexponential relationship between the metabolic ratio of DM and DX, and their concentrations respectively, which can have clinical applications, since metabolic ratio can be predicted from a known DM or DX concentration. Three hr after ingestion of DM, 18 individuals showed DM plasma concentrations of 5 to 10 ng/mL, 15 subjects of 11 to 20 ng/mL, 8 subjects of 21 to 50 ng/mL and 14 subjects >51 ng/mL pointing out that DM concentrations and MR must be determined to establish toxicity risk levels.