Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

AIMS: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry-based enantiomer-specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S- and R-ketorolac exposure. RESULTS: S- and R-ketorolac PK were best described with a 3- and a 2-compartment model, respectively. The allometry-based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S-ketorolac concentration of 0.057 mg/L, but a mean S-ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S-ketorolac-concentration (0.057 mg/L) in typical infants, the EC50-racemic should be increased to 0.41 mg/L. CONCLUSION: Enantiomer-specific changes in ketorolac PK yield different concentrations and S- and R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.

Enrollment challenges in multicenter, international studies: The example of the GAS trial.

INTRODUCTION: Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. METHODS: We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. RESULTS: A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. CONCLUSION: The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

Hemodynamic instability during prone spine surgery in a patient with merosin-deficient congenital muscular dystrophy.

Trans-esophageal echocardiography (TEE) and/or central venous pressure (CVP) monitoring are important in the anesthetic management of spine fusion of pediatric patients with severe muscular weakness. This case highlights an unusual situation of apparent acute right ventricular mechanical obstruction after prone positioning and its prompt recognition with CVP monitoring. The anesthetic management of a patient with congenital muscular dystrophy, an uncommon neuromuscular disorder, is presented. Good communication and planning between the anesthesiology and surgical teams allowed completion of the procedure using a lateral approach.

CT-guided percutaneous lung biopsy under general anesthesia: a pediatric case series and literature review.

We describe 14 consecutive children who received computed tomography-guided percutaneous lung biopsy (CT-PLB) under general anesthesia over an 18-month period at our institution. Pulmonary hemorrhage (occurring in 36%) and pneumothorax (29%) were the two most common complications; the overall complication rate was 64%. When complications did occur, immediate airway management was facilitated by the presence of an endotracheal tube (ETT). We conclude as follows: (i) CT-PLB in our series is associated with a high risk of both overall and severe complications; (ii) risk of complications is increased by both patient and procedure-related factors; (iii) airway management with ETT may be preferable should a complication arise; (iv) severe complications may necessitate ICU admission, which should be available before proceeding.

Acupuncture therapy for infants: a preliminary report on reasons for consultation, feasibility, and tolerability.

OBJECTIVES/AIMS: The aim of this retrospective review was to determine the feasibility, safety, and potential therapeutic effects of acupuncture in an inpatient infant population and to obtain data that would support the design of a randomized, controlled trial of acupuncture in infants. BACKGROUND: Hospitalized infants are often exposed to sedative and analgesic medications to facilitate intensive and invasive medical care. With increasing concern about the potential neurotoxic effects of common analgesic and sedative medications, minimizing an infant's exposure to such agents is desirable. Acupuncture can be therapeutic in adults and children, but data in infants are lacking. METHODS/MATERIALS: We performed a retrospective chart review of infants who received acupuncture during hospitalizations between 2008 and 2010. Demographic data, diagnoses, reason for acupuncture consult, ventilator settings, sedative/analgesic medication regimens, details of acupuncture therapy, and adverse effects were among data collected. RESULTS: Ten infants were identified in this review, seven of whom had agitation issues, two of whom had feeding difficulties, and one had both symptoms. Six of the eight infants with agitation had a decrease in the use of sedative and analgesic medications over the acupuncture therapy period, and four of five initially requiring mechanical ventilation were successfully weaned. One of the three infants with oral aversion transitioned rapidly to oral intake. Acupuncture therapy was well tolerated, and there were no complications observed. CONCLUSIONS: In this small group of hospitalized infants, acupuncture was found to be safe, well tolerated, and therapeutic. More studies are warranted to define the role of acupuncture in this population.

Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy.

OBJECTIVES/AIMS: To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. BACKGROUND: Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. METHODS: Prospective cohort study in L and NL children, 3-17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6- and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed. RESULTS: We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. CONCLUSIONS: We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.

Successful implementation of a pediatric sedation protocol for mechanically ventilated patients.

OBJECTIVE: To evaluate the effect of a nursing-driven sedation protocol for mechanically ventilated pediatric patients on duration of use of analgesic and sedative medications. We hypothesized that a protocol would decrease length of sedation use and decrease days of mechanical ventilation and length of stay. DESIGN: Retrospective cohort study with historical controls. SETTING: Thirty-one-bed tertiary care, medical-surgical-cardiac pediatric intensive care unit in a metropolitan university-affiliated children's hospital. PATIENTS: Children requiring mechanical ventilation longer than 48 hrs not meeting exclusion criteria. INTERVENTIONS: Before protocol implementation, sedation was managed per individual physician orders. During the intervention period, analgesia and sedation were managed by nurses following an algorithm-based sedation protocol based on a comfort score. MEASUREMENTS AND MAIN RESULTS: The observation group included consecutive patients admitted during the 12-month period before protocol education and implementation (n = 153). The intervention group included patients admitted during the 12 months following protocol implementation (n = 166). The median duration of total sedation days (intravenous plus enteral) was 7 days for the observation period and 5 days for the intervention period (p = .026). Specifically, the median duration of morphine infusion was 6 days for the observation period and 5 days for the intervention period (p = .015), whereas the median duration of lorazepam infusion was 2 days for the observation period and 0 days for the intervention period. After adjusting for severity of illness with the pediatric risk of mortality III (PRISM III) score, the Cox proportional hazards regression analysis demonstrated that at any point in time, patients in the intervention group were 23% more likely to be off all sedation (heart rate 0.77, p = .020). Additionally, the intervention group tended to be associated with fewer days of mechanical ventilation (heart rate 0.81, p = .060) and decreased pediatric intensive care unit length of stay (heart rate 0.81, p = .058), although these associations did not quite reach statistical significance. CONCLUSION: A pediatric sedation protocol can significantly decrease days of benzodiazepine and opiate administration, which may improve pediatric intensive care unit resource utilization.

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months.

OBJECTIVE: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. BACKGROUND: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. METHODS: This double-blinded, placebo-controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6-18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg(-1), or 1 mg·kg(-1) ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-h postdosing. Analysis used noncompartmental and compartmental population modeling methods. RESULTS: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6-18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min(-1). Those of the S (-) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min(-1). Typical elimination half-lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (-) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter-patient variability and was not different between groups. CONCLUSION: Stereo-isomer-specific clearance of ketorolac in infants (aged 2-6 months) shows rapid elimination of the analgesic S (-) isomer as reported in infants aged 6-18 months. No adverse effects were seen after a single IV ketorolac dose.

Acute unilateral enlargement of the parotid gland immediately post craniotomy in a pediatric patient: a case report.

A temporary acute unilateral enlargement of the parotid gland or "anesthesia mumps" has been described in both surgical and anesthesia literature. It has been described in elderly, dehydrated, poorly nourished, and post-operative patients. We present a 5-year-old patient who underwent a left temporal craniotomy for seizure focus resection and quadriceps muscle biopsy. Immediately post procedure, he was noted to have an acute unilateral enlargement of the right parotid gland. We report acute unilateral parotitis as a possible, but uncommon, complication of positioning in the pediatric population and to discuss possible pathophysiology and prevention, as well as a review of the available literature.

Feasibility of Acupuncture to Induce Sleep for Brainstem Auditory Evoked Response Testing.

Purpose Brainstem auditory evoked response (BAER) testing is often performed under general anesthesia for children unable to complete behavioral audiologic evaluation. Alternatively, acupuncture treatment may be considered appropriate for BAER. Reports of acupuncture treatment in pediatric patients are scarce but are needed to demonstrate effectiveness. This study had 2 main objectives: (a) to examine the feasibility and effectiveness of acupuncture to achieve sleep to perform diagnostic BAER testing in medically complex (Cohort I) and nonmedically complex (Cohort II) children and (b) to assess acceptability to parents and audiologists of acupuncture as an alternative to anesthesia for BAER testing. Method A prospective feasibility study at Seattle Children's Hospital Outpatient Audiology Clinic from August 2015 through December 2018 was performed. A total of 31 pediatric patients were included. The median age for Cohort I was 29 months (interquartile range: 19-37 months), and the median age for Cohort II was 25.5 months (interquartile range: 16-32 months). Variables included number of BAER thresholds obtained, sleep indicators, and acceptability. The cost of BAER with acupuncture and the cost of BAER under anesthesia were compared. Results Acupuncture treatment effectively contributed to an adequate sleep state to obtain BAER results for most patients in both cohorts. Across cohorts, most patients (81%) fell asleep after acupuncture treatment. Complete test results were obtained in 48% of patients. Audiologists and parents reported high satisfaction rates with this procedure (87%). There were no adverse safety effects. Acupuncture treatment was less costly than anesthesia for BAER testing. Conclusions Acupuncture to induce sleep for BAER testing is effective, safe, and cost-efficient in small samples of medically and nonmedically complex pediatric patients. This procedure allowed earlier detection of hearing status and avoided potential adverse effects of anesthesia. Audiologists and parents reported that acupuncture treatment was an acceptable alternative to anesthesia for the BAER procedure.

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations.

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

Postoperative ketorolac tromethamine use in infants aged 6-18 months: the effect on morphine usage, safety assessment, and stereo-specific pharmacokinetics.

BACKGROUND: Nonsteroidal antiinflammatory drugs have been useful for treating postoperative pain in children. The only parenteral nonsteroidal antiinflammatory drug currently available in the United States is ketorolac tromethamine with cyclooxygenase-1 and cyclooxygenase-2 effects. Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing difficult. Ketorolac is administered as a racemic mixture with the S(-) isomer responsible for the analgesic effect. In this study, we describe the population pharmacokinetics of ketorolac in a group of 25 infants and toddlers who received a single IV administration of racemic ketorolac and evaluate the potential influence of patient covariates on ketorolac disposition. METHODS: In this double-blind, placebo-controlled study, ketorolac pharmacokinetic, safety, and analgesic effects were studied in 37 infants and toddlers (aged 6-18 mo) postoperatively. On postoperative day 1, infants were randomized to receive placebo, 0.5, or 1 mg/kg ketorolac as a 10-min IV infusion. Blood samples were collected up to 12-h after dosing. The data were analyzed using noncompartmental and compartmental (nonlinear mixed-effects model) means. The patient covariates, including body weight, age, and surgical procedure, were analyzed in a stepwise fashion to identify their potential influence on ketorolac pharmacokinetics. RESULTS: The data were best described by a two-compartmental model. Inclusion of covariates did not significantly decrease the nonlinear mixed-effects model objective function values and between-subject variability in the pharmacokinetic parameters of nested models. The mean and standard error of the estimates of the R(+) isomer were central volume of distribution 1200 +/- 163 mL (coefficient of variation of interindividual variability, 13.6%), peripheral volume of distribution 828 +/- 108 mL (13.0%), clearance from the central compartment 7.52 +/- 0.7 mL/min (9.3%), and extrapolated elimination half-life 238 +/- 48 min. Those of the S(-) isomer were 2320 +/- 34 (14.6%), 224 +/- 193 mL (86.2%), 45.3 +/- 5.5 mL/min (12.1%), and 50 +/- 42 min respectively. Dosing simulations, using population pharmacokinetic parameters, showed no accumulation of S(-) ketorolac but steady increases in R(+) ketorolac. Safety assessment showed no adverse effects on renal or hepatic function tests, surgical drain output, or continuous oximetry between placebo and ketorolac groups. Cumulative morphine administration showed large interpatient variability and was not different between groups. CONCLUSION: The stereo-isomer-specific clearance of ketorolac in infants and toddlers (aged 6-18 mo) shows rapid elimination of the analgesic S(-) isomer. No adverse effects on surgical drain output, oximetry measured saturations, renal or hepatic function tests were seen. Simulation of single dosing at 0.5 or 1 mg/kg every 4 or 6 h does not lead to accumulation of S(-) ketorolac, the analgesic isomer, but does result in increases in R(+) ketorolac. Shorter dose intervals may be needed in infants older than 6 mo.

A review of perioperative anesthesia and analgesia for infants: updates and trends to watch.

This review focuses on pharmacokinetics and pharmacodynamics of opioid and non-opioid analgesics in neonates and infants. The unique physiology of this population differs from that of adults and impacts drug handling. Morphine and remifentanil are described as examples of older versus recently developed opiates to compare and contrast pharmacokinetics and pharmacodynamics in infants. Exploration of genetics affecting both pharmacokinetics and pharmacodynamics of opiates is an area of active research, as is the investigation of a new class of mu-opiate-binding agents which seem selective for analgesic pathways while having less activity in pathways linked to side effects. The kinetics of acetaminophen and of ketorolac as examples of parenteral non-steroidal analgesics in infants are also discussed. The growth in regional anesthesia for peri-operative analgesia in infants can fill an important role minimizing intra-operative anesthetic exposure to opioids and transitioning to post-operative care. Use of multi-modal techniques is recommended to decrease undesirable opiate-related side effects in this vulnerable population.

A comparison of a needle-free injection system for local anesthesia versus EMLA for intravenous catheter insertion in the pediatric patient.

Placement of IV catheters is a painful and stressful procedure for children. J-Tip is a needle-less Food and Drug Administration approved injection system that can be used for delivery of local anesthetic before IV cannulation. In this study, we compared the effectiveness of J-Tip versus eutectic mixture of local anesthetics (EMLA) to facilitate IV cannulation and provide adequate analgesia before IV placement. Children 7-19 years of age (n = 116) were randomized to receive 0.25 mL of 1% buffered lidocaine with J-Tip (n = 57) or 2.5 g of EMLA (n = 59) before IV cannulation. Measurements of success of cannulation (number of attempts for IV placement) and pain (0-10 visual analog scale) at application of local anesthetic and at cannulation were performed. There was a significant (P = 0.0001) difference in pain ratings during IV cannulation between EMLA (median = 3) and the J-Tip (median = 0). Eighty-four percent of patients reported no pain at the time of J-Tip lidocaine application compared to 61% in the EMLA group at the time of dressing removal (P = 0.004). We did not find differences in the number of attempts for IV cannulation. J-Tip application of 1% buffered lidocaine before IV cannulation is not painful and has better anesthetic effectiveness compared with EMLA.

The Feasibility of Developing an Inpatient Acupuncture Program at a Tertiary Care Pediatric Hospital.

OBJECTIVES: Use of complementary and integrative health approaches has increased significantly in recent decades, with hospital-based acupuncture programs becoming more common. This article presents the feasibility of developing an inpatient acupuncture program at a pediatric hospital. DESIGN AND SETTING: In January 2014, Seattle Children's Hospital, a tertiary care pediatric hospital serving patients from a five-state region, began a 6-month pilot project offering inpatient acupuncture. During the pilot, inpatient acupuncture and related manual therapies were provided to pediatric patients age 0-23 years who were admitted to Seattle Children's Hospital or were seen for an outpatient surgical procedure. MEASURES: The following data were collected: the reason for the acupuncture consult, type and number of treatments provided, any reported response to treatment, and any reported adverse events. Patients and referring providers gave feedback via questionnaires. RESULTS: During the pilot program, 338 treatments were provided to 87 patients. High interest, demand, and positive feedback from hospital providers, patients, and families led to the development of a full-time inpatient acupuncture program. CONCLUSIONS: The positive response to Seattle Children's inpatient acupuncture program with feasibility and acceptability demonstrated by increasing consults and patient and provider questionnaire data suggest that similar programs may be of interest to other pediatric hospitals.

Anesthesia and analgesia during and after surgery in neonates.

BACKGROUND: Historically, the use of anesthetics and analgesics in neonates and infants has been based on extrapolations from studies performed in adults and older children. Over the past 20 years, there has been a growing body of research on the clinical pharmacology and clinical outcomes of these agents in neonates and infants. OBJECTIVE: This article summarizes clinical pharmacology and clinical outcomes studies of opioids, opioid antagonists, sedative-hypnotics, nonsteroidal anti-inflammatory drugs and acetaminophen, and local anesthetics in neonates and infants to highlight gaps in the available knowledge, review some concerns about study design, and identify drugs that should receive high priority for future study. METHODS: Relevant studies were identified through a search of MEDLINE and a review of textbooks, conference proceedings, and abstracts. The available literature was subjected to expert committee-based review. CONCLUSIONS: There is a growing body of information on analgesic and anesthetic pharmacokinetics, pharmacodynamics, and clinical outcomes in neonates and infants, permitting safe and effective use in some clinical settings. Major gaps in knowledge persist, however. Future research may involve a combination of clinical trials and preclinical studies in suitable infant animal surrogate models.

Analgesia and anesthesia for neonates: study design and ethical issues.

OBJECTIVE: The purpose of this article is to summarize the clinical, methodologic, and ethical considerations for researchers interested in designing future trials in neonatal analgesia and anesthesia, hopefully stimulating additional research in this field. METHODS: The MEDLINE, PubMed, EMBASE, and Cochrane register databases were searched using subject headings related to infant, newborn, neonate, analgesia, anesthesia, ethics, and study design. Cross-references and personal files were searched manually. Studies reporting original data or review articles related to these topics were assessed and critically evaluated by experts for each topical area. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were abstracted and synthesized in a systematic manner and refined by group members. Data synthesis and results were reviewed by a panel of independent experts and presented to a wider audience including clinicians, scientists, regulatory personnel, and industry representatives at the Newborn Drug Development Initiative workshop. Recommendations were revised after extensive discussions at the workshop and between committee members. RESULTS: Designing clinical trials to investigate novel or currently available approaches for analgesia and anesthesia in neonates requires consideration of salient study designs and ethical issues. Conditions requiring treatment include pain/stress resulting from invasive procedures, surgical operations, inflammatory conditions, and routine neonatal intensive care. Study design considerations must define the inclusion and exclusion criteria, a rationale for stratification, the confounding effects of comorbid conditions, and other clinical factors. Significant ethical issues include the constraints of studying neonates, obtaining informed consent, making risk-benefit assessments, defining compensation or rewards for participation, safety considerations, the use of placebo controls, and the variability among institutional review boards in interpreting federal guidelines on human research. For optimal study design, investigators must formulate well-defined study questions, choose appropriate trial designs, estimate drug efficacy, calculate sample size, determine the duration of the studies, identify pharmacokinetic and pharmacodynamic parameters, and avoid drug-drug interactions. Specific outcome measures may include scoring on pain assessment scales, various biomarkers and their patterns of response, process outcomes (eg, length of stay, time to extubation), intermediate or long-term outcomes, and safety parameters. CONCLUSIONS: Much more research is needed in this field to formulate a scientifically sound, evidence-based, and clinically useful framework for management of anesthesia and analgesia in neonates. Newer study designs and additional ethical dilemmas may be defined with accumulating data in this field.

Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions.

Eighty-three infants received i.v. morphine following surgery as a continuous infusion to a targeted morphine concentration of 20 ng ml(-1) (n = 56) or as intermittent bolus doses as needed (n = 27). Ventilation was compared in the two groups by continuous pulse oximetry, by venous blood gases on postoperative day 1 (POD 1) and by CO2 response curves. Infant pain scores were done to assess analgesia every 4 h. Both groups achieved pain scores consistent with analgesia but the bolus group showed a higher percentage of pain scores indicating distress (32 vs. 13%, P < 0.001). Room air saturations of < 90% were seen for 2.3% of POD1 in infusion-treated infants and for 2.5% of POD1 in bolus-treated infants. Mean venous PCO2S were normal in the two groups. Four infants showed ventilatory effects in the infusion group (4/ 56 = 7%); venous hypercarbia in two (2 days, 36 days), oximetry desaturation in one (240 days), both effects in one (6 days). Ventilatory effects were not statistically different between the intermittent bolus-treated and infusion-treated infants but may be clinically important. Monitoring with continuous oximetry is necessary. Morphine clearance increased with age. Infants with detectable morphine also had measurable morphine-6-glucuronide in both groups. Oral intake began at 16 h in both groups and other side effects were infrequent.

Farmacología del desarrollo de analgésicos opioides y no esteroideos en neonatos e infantes / Developmental pharmacokinetics and pharmacodynamics of parenteral opioids and nonsteroidal anti-nflammatory drugs in neonates and infants

Abstract Introduction: Pharmacology of infants is understudied and different from other populations. Objective: To review the unique features of neonatal and infant physiology that impact drug handling and the pharmacokinetics of analgesics, including opioids, ketorolac and acetaminophen. Materials and methods: This article is a narrative review of the literature from the authors' point of view that constitutes a summary of the information presented at the annual Colombian Society for Anesthesia meeting in Cali, Colombia June 2015. Conclusions: Pharmacology in neonates and infants is unique and must be considered in this vulnerable population. Recommendations for administration of these analgesics are presented based on their unique pharmacokinetic properties. Individual patient variation and clinical response must also be taken into account.

Resumen Introducción: La farmacología de los lactantes es poco estudiada y difiere de la farmacología de otras poblaciones. Objetivo: Revisar las características únicas de la fisiología de los neonatos e lactantes que afectan el manejo del fármaco y la farmacocinética de los anestésicos, incluyendo opioides, ketorolaco y acetaminofén. Materiales y métodos: Este artículo es una revisión narrativa de la literatura, desde el punto de vista de las autoras, y constituye un resumen de la información presentada en la reunión anual de la Sociedad Colombiana de Anestesiología y Reanimación en Cali, Colombia, en junio de 2015. Conclusiones: La farmacología en neonatos e lactantes es única y debe ser considerada en esta población vulnerable. Las recomendaciones presentadas para la administración de esos analgésicos están basadas en sus propiedades farmacocinéticas únicas. También deben tenerse en cuenta las variaciones individuales y la respuesta clínica.

Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children.

BACKGROUND AND OBJECTIVE: Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model. METHODS: Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model. RESULTS: The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH. CONCLUSION: The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.