Developmental pharmacokinetics and pharmacodynamics of parenteral opioids and nonsteroidal anti-nflammatory drugs in neonates and infants

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Fuente: Lynn et al.<a class="elsevierStyleCrossRef" href="#bib0280">19</a>. Reproducida con autorización." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Lizabeth Martin, Nathalia Jimenez, Anne M. Lynn" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Lizabeth" "apellidos" => "Martin" ] 1 => array:2 [ "nombre" => "Nathalia" "apellidos" => "Jimenez" ] 2 => array:2 [ "nombre" => "Anne M." 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Source: Authors." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Edgar Cortés-Reyes, Katherine Parrado-Bermúdez, Franklin Escobar-Córdoba" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Edgar" "apellidos" => "Cortés-Reyes" ] 1 => array:2 [ "nombre" => "Katherine" "apellidos" => "Parrado-Bermúdez" ] 2 => array:2 [ "nombre" => "Franklin" "apellidos" => "Escobar-Córdoba" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S012033471630079X" "doi" => "10.1016/j.rca.2016.06.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S012033471630079X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2256208716300475?idApp=UINPBA00004N" "url" => "/22562087/0000004500000001/v1_201701060057/S2256208716300475/v1_201701060057/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Essay" "titulo" => "Developmental pharmacokinetics and pharmacodynamics of parenteral opioids and nonsteroidal anti-nflammatory drugs in neonates and infants" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "72" "paginaFinal" => "79" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Lizabeth Martin, Nathalia Jimenez, Anne M. Lynn" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Lizabeth" "apellidos" => "Martin" "email" => array:1 [ 0 => "Lizabeth.martin@seattlechildrens.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Nathalia" "apellidos" => "Jimenez" ] 2 => array:2 [ "nombre" => "Anne M." "apellidos" => "Lynn" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Seattle Children's Hospital, University of Washington, Department of Anesthesiology and Pain Medicine, Seattle, USA" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Seattle Children's Hospital, 4800 Sandpoint Way NE MB 11.500, Seattle, WA 98105, USA." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Farmacología del desarrollo de analgésicos opioides y no esteroideos en neonatos e infantes" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1022 "Ancho" => 1617 "Tamanyo" => 100885 ] ] "descripcion" => array:1 [ "en" => "Morphine clearance (ml/min−1/kg−1) vs age in infants receiving morphine. This figure was published in Pain, Lynn, A.M., Nespeca M.K., Bratton S., Shen D. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions, Pain 88(1):93, Copyright Elsevier (2000). Source: (19) Reproduced with permission." ] ] ] "textoCompleto" => "IntroductionPerioperative pain control and selection of analgesic medications is particularly important in infants and neonates. Emerging data suggest that adverse experiences including exposure to painful stimuli in the perinatal period may negatively impact long term emotional and behavioral well-being.<a class="elsevierStyleCrossRef" href="#bib0190">1</a> This must be carefully weighed with the increased side-effect profile of analgesic medications in this age group.This narrative review of the literature describes some of the features of neonatal and infant physiology that differ from adults and impact drug handling. Definitions of pharmacokinetic terms and a brief introduction to models for drug metabolism will be presented. Morphine and remifentanil will be used as examples to compare and contrast pharmacokinetics in infants and the pharmacodynamics particularly of respiratory effects in this vulnerable group. The kinetics of acetaminophen and of ketorolac (as examples of parenteral non-steroidal analgesics) in infants will be reviewed.The article is a summation of information presented at the annual Colombian Society for Anesthesia meeting in Cali, Colombia June, 2015. It is a selection from the literature rather than a comprehensive review of all literature of these drugs or drug classes. References to the authors’ own work is used for convenience and knowledge of study performance details, not to suggest other work is not equally important.PhysiologyThe physiology of the neonate and infant differs in many aspects from the adult; some of these differences are important factors for drug handling. Total body water is a higher percentage of body weight in infants, reaching adult values by age 8–10 years (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Liver and kidney function is not fully developed at birth which affects handling of many drugs. The maturation of function occurs over several months during the first year of life.<a class="elsevierStyleCrossRef" href="#bib0195">2</a> Drug development in the past 10–20 years has focused on agents whose metabolism is less dependent on normal renal and/or liver function as aging populations of adults have compromise in these organs. This is beneficial for infants who also have immature function. Remifentanil is the obvious example of this process in action.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Hepatic enzymes, including both the P450 system and the glucuronidation pathways, are immature at birth. Maturation occurs over the first few months of postnatal life, at different rates for different P450 variants. Drugs that are metabolized by glucuronidation (solubility increased for excretion) will have delayed removal in the first months of life. Sulfation then becomes more important as a metabolic pathway. There are also inherited variants for the CYP (P450) system that may impact drug handling. An example of this is seen with codeine, where conversion to the active morphine can occur faster, slower, or not at all, resulting in an unpredictable effect.<a class="elsevierStyleCrossRef" href="#bib0200">3</a> Reports of excessive effect in ultrarapid metabolizers have been associated with respiratory calamities.<a class="elsevierStyleCrossRefs" href="#bib0205">4,5</a>The kidney is important for eliminating drugs or their metabolites. In infants, glomerular filtration rates (GFR) start at approximately 10% of adult normal values, reaching these by 12 months of age. Renal tubular function also matures over the first 6 months. This decreased function can result in the accumulation of metabolites, and is particularly problematic with those metabolites that have active effects.PharmacokineticsPharmacokinetics is defined as the study of drug disposition by patients; it is affected by absorption (important for non-intravenous routes of administration), distribution, metabolism and elimination. Pharmacology terms are used commonly in studies of drug handling. Familiarity with these terms can be helpful when reviewing this literature.<a class="elsevierStyleCrossRef" href="#bib0215">6</a>Clearance (Cl) describes the removal of drug from a volume of plasma per unit of time (mL/min or L/h). This value is often reported as a normalized value, commonly as L/h/70kg or in older publications as mL/min/kg. Clearance reflects how efficiently the patient removes drug both by metabolism of drug and by excretion of unchanged drug.Volume of distribution (Vd), another volume term, describes the apparent volume that would be necessary to account for all drug if it were present at the same concentration as measured in plasma or serum (L/70kg or mL/kg in older work). Importantly, volume of distribution is a theoretical, rather than physiologic, volume. Its usefulness is to show how widely distributed a drug is in the body. Small Vd is found with drugs that are polar (difficult crossing lipid membranes as with aminoglycosides) or those bound to plasma proteins such as albumin or alpha-1 acid glycoprotein. Drugs with large Vd have high lipid solubility or are bound to tissue proteins, and blood concentration may poorly reflect how much drug is present in the body, as is seen with digoxin.Elimination half-life (t1/2) is the time needed to change blood concentration by 50% and is reported as minutes or hours. In 4–5 half-lives, 94–97% of drug is removed, respectively. Half-life is affected by both clearance and by volume of distribution. Drugs with a higher clearance and smaller volume of distribution have a shorter duration of action and are more titratable, which is often desirable in anesthesia practice.As novel anesthetic drugs with these features have been developed, the term context-sensitive half-time has come into use. This term refers to the time to change drug concentration by 50% (i.e. half-life) in the context of the duration of administration. Context-sensitive half-time pharmacokinetic models for intravenous anesthetic drugs have been described.<a class="elsevierStyleCrossRef" href="#bib0220">7</a> Many newer agents have been developed to achieve small context-sensitive half-times which are unchanged regardless of the duration of drug infusion.Limitations on blood sampling for pediatric patients, which is particularly significant in infants, have encouraged the development of computer generated pharmacokinetic mathematical modeling schemes which require sparse blood concentration data from pediatric patients. Population-based models exist which use factors such as age and weight as regular covariates, and introduce additional elements to improve the fit of the model in concentration vs. time graphs. Weight-based allometric models incorporate weight using exponential factors (0.75 for clearance, 1 for volume of distribution) based on enzyme functions. These models consider age-appropriate factors such as creatinine or bilirubin to improve fit. Both of these models have been used to study morphine and remifentanil handling in infants.<a class="elsevierStyleCrossRefs" href="#bib0225">8–10</a>There are genetic factors that influence metabolism of drugs and this is an active area of research. While the effect of genetic variants is sometimes difficult to extrapolate directly into clinical practice there are examples of important metabolic-genetic variants pertinent to pediatric populations.<a class="elsevierStyleCrossRef" href="#bib0240">11</a> Codeine as a pro-drug is entirely dependent on its metabolism for its analgesic effect. Its active metabolite morphine, is produced by O-demethylation by the CYP2D6 (Cytochrome P450 2D6) enzyme, which is highly polymorphic. Differences in CYP2D6 alleles can result in significant differences in handling of opiates because the activity level of the CYP2D6 enzyme is determined by the combination of alleles that each patient has, ranging from poor to ultrarapid metabolizers. In clinical practice patients who are poor metabolizers will not achieve any analgesia with codeine use, while patients who are ultrarapid metabolizers have higher risk of respiratory depression. Similar concerns have been reported with tramadol, hydrocodone and oxycodone resulting in the publication of dosing guidelines considering CYP2D6 genotypes.<a class="elsevierStyleCrossRef" href="#bib0245">12</a>The association of race, ethnicity, and the frequency of genetic polymorphism is an additional consideration. Using the previous example, CYP2D6 allele frequencies vary significantly between racial and ethnic groups. European Caucasians are more likely to carry normal function alleles compared with Asians and African-Americans.<a class="elsevierStyleCrossRef" href="#bib0250">13</a> East Africans (Ethiopians) on the other hand, are more likely to exhibit duplications of the CYP2D6-gene (indicative of ultrarapid metabolism), which predisposes them to serious adverse reactions.<a class="elsevierStyleCrossRef" href="#bib0255">14</a>MorphineStudies of morphine pharmacokinetics have been reported by several groups. The focus here will be on the author's work (AL) which is known in detail. In 1987, a small study in 10 infants showed they had different pharmacokinetic parameters than those reported in adults, with a lower clearance and large volume of distribution resulting in a prolonged elimination half-life.<a class="elsevierStyleCrossRef" href="#bib0260">15</a> The clearance appeared to increase quickly comparing infants aged 1–4 days to older infants. Study of a larger cohort of 49 infants and toddlers, all receiving morphine by infusion after cardiac surgery, showed the same pattern, with adult values for clearance being reached by age 6 months.<a class="elsevierStyleCrossRef" href="#bib0265">16</a> In a subsequent study of 26 infants who received morphine by iv infusion after non-cardiac surgeries, clearance in non-cardiac infants was found to be significantly greater than in infants post-cardiac surgery, with non-cardiac surgical infants reaching adult morphine clearance values by 1–3 months of age rather than 6 months.<a class="elsevierStyleCrossRef" href="#bib0270">17</a> In all these studies, interpatient morphine clearance was high, giving values 2–3 fold different for same aged infants, a problem seen with most “older” opiates.<a class="elsevierStyleCrossRefs" href="#bib0275">18–20</a>(<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) This variability makes it difficult to predict the duration of both desired and undesired morphine effects in any individual infant.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>PharmacodynamicsPharmacodynamics refers to the effects of the drug on the patient; these may be therapeutic or undesired (adverse). For most clinicians, pharmacodynamics drives our administration of drugs. Pharmacodynamics are affected by many factors; for opiates these include differences in receptor morphology (OPRM gene variant SNP 118 A/G), differences in target site concentrations of drug (ABCB 1/MDR 1 transporter), or effects downstream from drug reaching receptors and binding such as differences in COMT metabolism of catechols (472 G>A SNP). Studies of these genetic differences in different populations have been increasing and should continue to be an active area of research.Respiratory effects of opiates have been one of the factors limiting its use in infants. Studies linking drug concentrations to effects are few. In 1993, we recorded morphine concentrations at steady-state in 30 infants receiving intravenous morphine infusions after cardiac surgery, and found that a plasma morphine concentration of <20ng/mL was associated with hypercarbia in 15% versus 67% in those over 20ng/mL independent of age. This suggested that morphine infusions set to target a plasma concentration of 20ng/mL could minimize risk of respiratory depression in infants.<a class="elsevierStyleCrossRef" href="#bib0290">21</a> Unfortunately, the interpatient variability in morphine pharmacokinetics make predicting morphine concentration more difficult (see above discussion, <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).In 2000, a follow-up study of 83 infants demonstrated superior analgesia with morphine infusions compared to intermittent bolus dosing (high pain scores in 13% vs 32%).<a class="elsevierStyleCrossRef" href="#bib0280">19</a> There was no difference in continuous oximetry readings <90% in room air or time to oral intake. However, CO2 response curve slopes did show evidence of ventilatory depression in 4 of 57 (7%) infusion group infants. A suggested course to facilitate extubation at surgery end is to use 0.05mg/kg morphine as a loading dose, then infusion at 5–10mcg/kg/h in neonates, and 10–20mcg/kg/h in infants, adjusting to each individual's needs.RemifentanilThe unpredictable pharmacokinetics and potential for undesired respiratory depression with morphine has led to the investigation of opioids with clearance that is less reliant on hepatic or renal function. Remifentanil is an example of such an agent. Remifentanil is a mu-agonist, binding to the same opiate receptors as morphine or fentanyl. It is metabolized by tissue esterases, so its pharmacokinetics are unaffected by changes in hepatic or renal function. Important for use in infants, these tissue esterases are functional at birth so age-related changes are not seen. Onset and offset is rapid, so intravenous infusions are the most common administration route. The context-sensitive half-time is reported as 3–5min, independent of duration of infusion.<a class="elsevierStyleCrossRef" href="#bib0295">22</a> Eck did an early case report of 3 complex infants managed with remifentanil as an anesthetic adjuvant, and reported early extubation (7–20min from infusion off) in 2 of 3.<a class="elsevierStyleCrossRef" href="#bib0300">23</a> Davis did a multi-center trial in 60 infants undergoing pyloromyotomy, comparing nitrous oxide/remifentanil infusion at 0.55±0.2mcg/kg/min to nitrous oxide/halothane 0.4%. A field block with bupivacaine for postoperative analgesia was used in both groups. Although there was no difference in time to extubation, no infant in the remifentanil group had any new abnormality on postoperative pneumograms, where 3 patients in the volatile only group did.<a class="elsevierStyleCrossRef" href="#bib0305">24</a> Crawford et al. demonstrated that remifentanil can provide excellent conditions for orotracheal intubation in infants without use of muscle relaxants. 24 infants, pretreated with glycopyrrolate 10mcg/kg, were randomized to propofol/succinylcholine or propofol/remifentanil 3mcg/kg and intubating conditions were similar with no adverse events.<a class="elsevierStyleCrossRef" href="#bib0310">25</a> A subsequent study including 64 children 0–3 years of age, stratified in three age groups (0–3 months; 4–12 months and 1–3 years)<a class="elsevierStyleCrossRef" href="#bib0315">26</a> suggested that the age-specific bolus dose of remifentanil (ED50) to facilitate tracheal intubation, is slightly higher (3.7mcg/kg) among the infant group 4–12 months of age. In this study all patients were also pretreated with glycopyrrolate.Undesired effects including “chest wall rigidity” and bradycardia have been reported, as can be seen with other fentanyl derivatives. Nausea and vomiting is reported in ∼30% in adult studies. More importantly for anesthetic use, remifentanil analgesia is gone within 15–30min of stopping infusions. Some authors have suggested tachyphylaxis subsequently leading to higher opiate requirements, however this has not been reported in infants.Remifentanil avoids the challenges of pharmacokinetic variability that are seen with morphine, however it is relatively expensive and rapid offset can pose a challenge for post-operative analgesia. If postoperative pain can be approached with regional techniques, remifentanil seems a workable choice to allow early extubation after infant surgery. Studying ethnic, racial and genetic factors in opiate metabolism remains important in helping us individualize care for this vulnerable population.Depending on the patient and procedure, other categories of analgesics may be considered to complement or replace opioids. Description of the pharmacokinetics/dynamics in infants of acetaminophen (focusing on intravenous route) and of ketorolac (only widely available parenteral non-steroidal anti-inflammatory drug [NSAID] in US) will inform this next section. These agents may be of particular benefit in infants as they do not work via opiate receptors and do not have effects on respiration or consciousness.KetorolacKetorolac tromethamine is available in oral and parenteral forms. As the only widely available intravenous NSAID in the US, it has been used as an analgesic adjunct and has been shown to decrease opioid requirements in post-operative patients. It works by inhibiting the cyclooxygenase system which decreases prostaglandin synthesis and the inflammatory cascade. It does not affect consciousness or respiration but does have effects on gastric mucosa, renal perfusion and platelet function. Baseline renal or platelet dysfunction is a relative contraindication.A prospective randomized trial of 70 infants and children showed no difference in chest tube drainage or bleeding complications and no difference in median change in creatinine after congenital cardiac surgery with or without 48h of ketorolac therapy postoperatively.<a class="elsevierStyleCrossRef" href="#bib0320">27</a> To further explore the pharmacokinetic, safety and respiratory effects in infants, we did a single center randomized, blinded, placebo-control study in infants 6–18 months admitted after surgery. The kinetics were done for stereo-specific isomers since animal studies suggested the S-isomer was a more potent analgesic<a class="elsevierStyleCrossRef" href="#bib0325">28</a> and studies in children suggested differences in isomer handling.<a class="elsevierStyleCrossRefs" href="#bib0330">29,30</a> Thirty-seven infants were enrolled, 23 following craniectomy surgery. All received morphine for breakthrough pain. A marked difference in isomer clearance was found with the S-isomer cleared 4-fold faster than the R- (4.4±2.8ml/min/kg vs 1.0±0.6 respectively). The elimination t1/2 was 64±24min (S) vs 198±77min (R). Serum concentrations of the S-isomer fell below adult “therapeutic” values (as reported by Stanski et al.) by 4h. Modeling of doses of 0.5mg/kg or 1mg/kg showed complete clearance of the S-isomer by 4h, but accumulation of the R-isomer with each dose. As a single dose study, no adverse effects on renal function (creatinine and urine volume), gastric mucosa (guiac testing) or platelet function (drain amount in craniectomy babies) were observed. Continuous oximetry showed no episodes of desaturation in either placebo or ketorolac groups. Unanswered is the possibility that toxicity may relate to the R-isomer concentrations which rise with repeat dosing.<a class="elsevierStyleCrossRef" href="#bib0340">31</a>Safety data is lacking in neonates or infants at higher risk for renal dysfunction (post cardiac bypass, complex cardiac disease including single ventricle physiology) except in the Gupta study detailed above, and caution is advised in this patient population. In our institution we administer ketorolac 0.5mg/kg, every 6–8h for a maximum of 72h to infants older than 6 months and a single dose 0.5mg/kg for infants 1–6 months. Although retrospective review in 1–6 month age group suggests that scheduled dosing of ketorolac may be well-tolerated, pharmacokinetic and prospective safety data for this practice is lacking. If serial dosing is used in infants <6 months for 48–72h, monitoring of urine output, BUN/creatinine and stool guiac should be considered.AcetaminophenAcetaminophen (or paracetamol in European or UK literature) is the most widely used analgesic/antipyretic administered in oral or rectal forms. In 2002, propacetamol, an intravenous pro-drug, was developed and in 2009 an intravenous active form of acetaminophen became available in Europe. In the USA intravenous acetaminophen was approved by the FDA more recently, so many of the reports on its use come from European or UK sites. One advantage of this drug is its long history of use in the oral form, which means safety information in children and infants is available. Hepatic toxicity from overdose of acetaminophen and accumulation of the metabolite N-acetyl-p-benzoquinone imine (NAPQI) is very uncommon in infants because they have immature P450 enzyme function, specifically CYP2E1, and make much lower concentrations of this metabolite. The ideal analgesic concentration has been incompletely studied but Anderson reported acetaminophen concentrations of 10mg/L resulted in analgesia in children post-tonsillectomy.<a class="elsevierStyleCrossRef" href="#bib0345">32</a> This concentration is commonly targeted as therapeutic but whether it applies in all circumstances is unexplored.In 2005, Anderson reported a population pharmacokinetic study of intravenous propacetamol in children. He included 846 acetaminophen concentrations from 7 previous studies with a total of 144 children. The bioavailability was 0.5, clearance was 16L/h/70kg increasing from 1.27L/h/70kg in premature infants (gestation 27 weeks) to 84% of adult values by age 1y. Volume of distribution (peripheral) decreased from 45L/70kg in prematures (27 weeks) to adult values by age 6 months. He predicted that dosing propacetamol 30mg/kg every 6h would result in pediatric patients having acetaminophen concentrations of 10mg/L.<a class="elsevierStyleCrossRef" href="#bib0350">33</a>Allegeart (2004) reported kinetics of a single dose of intravenous acetaminophen in 30 neonates showing lower clearance in infants less than 37wk gestation (8.1L/h/70kg) compared to those 37–41wks gestation (11.9L/h/70kg), noting marked interpatient variability. Elimination half-life was prolonged at 277min in the premature group compared to 172min in the term infants, again with large variability noted.<a class="elsevierStyleCrossRef" href="#bib0355">34</a> Population pharmacokinetics of acetaminophen in infants was reported by Allegaert in 2011. She included 158 neonates (58 premature) from 4 studies, with 943 acetaminophen observations. Clearance from this larger group of infants was 5L/h/70kg, with adult clearance of 16.2L/h/70kg found at age 1y. Her suggestion was use of one loading dose of 20mg/kg followed by 10mg/kg every 6h to target an acetaminophen concentration of 11mg/L in infants aged 32–44wk gestation.<a class="elsevierStyleCrossRef" href="#bib0360">35</a>The safety profile and kinetics of intravenous acetaminophen was studied by Palmer in 50 neonates given repeated doses postoperatively. Clearance was 5.2L/h/70kg, with large volume of distribution of 76L/70kg. Elevated bilirubin correlated with decreased clearance. Daily hepatic enzyme levels remained normal in 49 of the 50 infants, increasing in one after 5 doses and recovering when acetaminophen was stopped. She suggests 15mg/kg/6h in term infants, with reduction for hyperbilirubinemia.<a class="elsevierStyleCrossRef" href="#bib0365">36</a>Ceelie did a blinded randomized controlled trial in 71 infants, aged 37wk gestation to 1y, treated after major abdominal or thoracic surgery. Infants received intravenous acetaminophen 30mg/kg/d in 4 doses or morphine infusions at 4–16mcg/kg/h after a standardized anesthetic with one dose of morphine 30min before surgery end. Rescue for pain was with morphine bolus dosing in both groups. Pain scores and the number needing rescue was the same in both groups. Total morphine was lower in the acetaminophen group (122mcg/kg over 48h vs. 357mcg/kg/48h); naloxone was given to 3 in morphine group, none in acetaminophen group (p=NS).<a class="elsevierStyleCrossRef" href="#bib0370">37</a>An overview of the pharmacokinetic considerations reviewed here are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. More detailed pharmacokinetic information is beyond the scope of this review, and can be found elsewhere.<a class="elsevierStyleCrossRef" href="#bib0215">6</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>ConclusionThe clinical application of pharmacokinetics and pharmacodynamics of opiates (morphine or remifentanil) or NSAIDS (ketorolac or iv acetaminophen) to our care of infants who require surgery has room for much further study. It seems reasonable to consider multimodal therapy to minimize undesirable opiate side effects. Variability of clearance of older opiates such as morphine support using small doses (0.05mg/kg morphine) and titrating for effect. Remifentanil avoids the variability issue but requires infusion to maintain effect and, analgesia is gone quickly (<30min) once it is discontinued, which may not be appropriate for the postoperative infant.Ketorolac in a single dose study did not show adverse effects on hepatic, gastrointestinal or renal function but raises the concern of accumulation of the R-isomer with repeated doses and its unknown relation to toxicity.Acetaminophen does have intravenous kinetic information for infants available to guide dosing so can be a part of a multimodal analgesic regime in most infants. Nonpharmacologic adjuncts should also be considered which we have not presented in this forum including use of regional anesthetic techniques, oral glucose, nonnutritive sucking and swaddling.FundingNo funding.Conflicts of interestAll authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres785831" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec784547" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres785832" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec784546" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Physiology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Pharmacokinetics" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Morphine" ] ] ] 7 => array:3 [ "identificador" => "sec0025" "titulo" => "Pharmacodynamics" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Remifentanil" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Ketorolac" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Acetaminophen" ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-09" "fechaAceptado" => "2016-10-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec784547" "palabras" => array:5 [ 0 => "Infant" 1 => "Infant care" 2 => "Analgesics, opioid" 3 => "Pharmacokinetics" 4 => "Pharmacology" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec784546" "palabras" => array:5 [ 0 => "Lactante" 1 => "Cuidado del lactante" 2 => "Analgésicos opióides" 3 => "Farmacocinética" 4 => "Farmacología" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionPharmacology of infants is understudied and different from other populations. ObjectiveTo 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 methodsThis 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. ConclusionsPharmacology 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." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa farmacología de los lactantes es poco estudiada y difiere de la farmacología de otras poblaciones. ObjetivoRevisar 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 métodosEste 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. ConclusionesLa 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." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Martin L, Jimenez N, Lynn AM. Farmacología del desarrollo de analgésicos opioides y no esteroideos en neonatos e infantes. Rev Colomb Anestesiol. 2017;45:72–79." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1257 "Ancho" => 1425 "Tamanyo" => 167311 ] ] "descripcion" => array:1 [ "en" => "Total body water, intracellular fluid and extracellular fluid percent body weight for age in children. This figure was published in Nelson Textbook of Pediatrics 17th edition. Richard E. Behrman, Robert M. Kliegman, H.B. Jenson. Pathophysiology of Body Fluids and Fluid Therapy, Chapter 45, Page 191, Copyright Elsevier (2004). Source: (2) Reproduced with permission." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1022 "Ancho" => 1617 "Tamanyo" => 100885 ] ] "descripcion" => array:1 [ "en" => "Morphine clearance (ml/min−1/kg−1) vs age in infants receiving morphine. This figure was published in Pain, Lynn, A.M., Nespeca M.K., Bratton S., Shen D. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions, Pain 88(1):93, Copyright Elsevier (2000). Source: (19) Reproduced with permission." ] ] 2 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Authors." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Medication \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Metabolism \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Metabolite \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Renal excretion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pharmacokinetic considerations \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical considerations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Morphine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes-active \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inter-individual variability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Titrate to effect, small doses 0.05mg/kg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Remifentanil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Plasma esterase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predictable duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No long-acting analgesia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ketorolac \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes-active \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R-isomer accumulation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Single dose <6 months, limit dosing to 72h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acetaminophen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes-toxic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV formulation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Q6h dosing interval preferred \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1306396.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Pharmacokinetic and clinical considerations of common analgesic medications in infants." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0190" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "More than anyone else: preemies need good analgesia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L. Vutskits" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ALN.0000000000001018" "Revista" => array:6 [ "tituloSerie" => "Anesthesiology" "fecha" => "2016" "volumen" => "124" "paginaInicial" => "758" "paginaFinal" => "760" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26808638" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0195" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathophysiology of body fluids and fluid therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L. Greenbaum" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Nelson textbook of pediatrics" "paginaInicial" => "267" "paginaFinal" => "268" "edicion" => "17th ed." "serieFecha" => "2004" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0200" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.G. Williams" 1 => "A. Patel" 2 => "R.F. Howard" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Anaesth" "fecha" => "2002" "volumen" => "89" "paginaInicial" => "839" "paginaFinal" => "845" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12453926" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0205" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Codeine, ultrarapid-metabolism genotype, and postoperative death" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C. Ciszkowski" 1 => "P. Madadi" 2 => "M.S. Phillips" 3 => "A.E. Lauwers" 4 => "G. Koren" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMc0904266" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2009" "volumen" => "361" "paginaInicial" => "827" "paginaFinal" => "828" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19692698" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0210" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "More codeine fatalities after tonsillectomy in North American children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.E. Kelly" 1 => "M. Rieder" 2 => "J. van den Anker" 3 => "B. Malkin" 4 => "C. Ross" 5 => "M.N. Neely" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.2011-2538" "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "2012" "volumen" => "129" "paginaInicial" => "e1343" "paginaFinal" => "e1347" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22492761" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0215" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacology of pediatric anesthesia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P. Davis" 1 => "A. Bosenberg" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Smith's anesthesia for infants and children" "paginaInicial" => "179" "paginaFinal" => "263" "edicion" => "8th ed." "serieFecha" => "2011" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0220" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.A. Hughes" 1 => "P.S. Glass" 2 => "J.R. Jacobs" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anesthesiology" "fecha" => "1992" "volumen" => "76" "paginaInicial" => "334" "paginaFinal" => "341" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1539843" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0225" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pediatric models for adult target-controlled infusion pumps" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B.J. Anderson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1460-9592.2009.03072.x" "Revista" => array:6 [ "tituloSerie" => "Paediatr Anaesth" "fecha" => "2010" "volumen" => "20" "paginaInicial" => "223" "paginaFinal" => "232" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19627530" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0230" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Are there still limitations for the use of target-controlled infusion in children?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B.J. Anderson" 1 => "B. Hodkinson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ACO.0b013e32833938db" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Anaesthesiol" "fecha" => "2010" "volumen" => "23" "paginaInicial" => "356" "paginaFinal" => "362" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20386438" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0235" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.H. Krekels" 1 => "J. DeJongh" 2 => "R.A. van Lingen" 3 => "C.D. van der Marel" 4 => "I. Choonara" 5 => "A.M. Lynn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/11536750-000000000-00000" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2011" "volumen" => "50" "paginaInicial" => "51" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27975238" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0240" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Personalizing pediatric pain medicine: using population-specific pharmacogenetics, genomics, and other – omics approaches to predict response" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Jimenez" 1 => "J.L. Galinkin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1213/ANE.0000000000000721" "Revista" => array:6 [ "tituloSerie" => "Anesth Analg" "fecha" => "2015" "volumen" => "121" "paginaInicial" => "183" "paginaFinal" => "187" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26086515" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0245" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.R. Crews" 1 => "A. Gaedigk" 2 => "H.M. Dunnenberger" 3 => "J.S. Leeder" 4 => "T.E. Klein" 5 => "K.E. Caudle" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/clpt.2013.254" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacol Ther" "fecha" => "2014" "volumen" => "95" "paginaInicial" => "376" "paginaFinal" => "382" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24458010" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0250" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L.D. Bradford" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/14622416.3.2.229" "Revista" => array:6 [ "tituloSerie" => "Pharmacogenomics" "fecha" => "2002" "volumen" => "3" "paginaInicial" => "229" "paginaFinal" => "243" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11972444" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0255" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E. Aklillu" 1 => "I. Persson" 2 => "L. Bertilsson" 3 => "I. Johansson" 4 => "F. Rodrigues" 5 => "M. Ingelman-Sundberg" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pharmacol Exp Ther" "fecha" => "1996" "volumen" => "278" "paginaInicial" => "441" "paginaFinal" => "446" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8764380" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0260" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Morphine pharmacokinetics in early infancy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.M. Lynn" 1 => "J.T. Slattery" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anesthesiology" "fecha" => "1987" "volumen" => "66" "paginaInicial" => "136" "paginaFinal" => "139" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3813075" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0265" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The maturation of morphine clearance and metabolism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.I. McRorie" 1 => "A.M. Lynn" 2 => "M.K. Nespeca" 3 => "K.E. Opheim" 4 => "J.T. Slattery" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Dis Child" "fecha" => "1992" "volumen" => "146" "paginaInicial" => "972" "paginaFinal" => "976" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1636668" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0270" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Lynn" 1 => "M.K. Nespeca" 2 => "S.L. Bratton" 3 => "S.G. Strauss" 4 => "D.D. Shen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anesth Analg" "fecha" => "1998" "volumen" => "86" "paginaInicial" => "958" "paginaFinal" => "963" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9585276" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0275" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence-based morphine dosing for postoperative neonates and infants" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.H. Krekels" 1 => "D. Tibboel" 2 => "S.N. de Wildt" 3 => "I. Ceelie" 4 => "A. Dahan" 5 => "M. van Dijk" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40262-014-0135-4" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2014" "volumen" => "53" "paginaInicial" => "553" "paginaFinal" => "563" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24496960" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0280" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.M. Lynn" 1 => "M.K. Nespeca" 2 => "S.L. Bratton" 3 => "D.D. Shen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pain" "fecha" => "2000" "volumen" => "88" "paginaInicial" => "89" "paginaFinal" => "95" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11098103" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0285" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N.J. Bouwmeester" 1 => "B.J. Anderson" 2 => "D. Tibboel" 3 => "N.H. Holford" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Anaesth" "fecha" => "2004" "volumen" => "92" "paginaInicial" => "208" "paginaFinal" => "217" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14722170" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0290" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.M. Lynn" 1 => "M.K. Nespeca" 2 => "K.E. Opheim" 3 => "J.T. Slattery" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anesth Analg" "fecha" => "1993" "volumen" => "77" "paginaInicial" => "695" "paginaFinal" => "701" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8214651" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0295" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.K. Ross" 1 => "P.J. Davis" 2 => "G. deL Dear" 3 => "B. Ginsberg" 4 => "F.X. McGowan" 5 => "R.D. Stiller" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Anesth Analg" "fecha" => "2001" "volumen" => "93" "paginaInicial" => "1393" "paginaFinal" => "1401" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11726413" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673614604608" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0300" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of remifentanil in infants" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.B. Eck" 1 => "A.M. Lynn" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Paediatr Anaesth" "fecha" => "1998" "volumen" => "8" "paginaInicial" => "437" "paginaFinal" => "439" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9742543" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0305" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "[table of contents]" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.J. Davis" 1 => "J. Galinkin" 2 => "F.X. McGowan" 3 => "A.M. Lynn" 4 => "M. Yaster" 5 => "M.F. Rabb" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anesth Analg" "fecha" => "2001" "volumen" => "93" "paginaInicial" => "1380" "paginaFinal" => "1386" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11726411" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0310" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dose–response of remifentanil for tracheal intubation in infants" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.W. Crawford" 1 => "J. Hayes" 2 => "J.M. Tan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1213/01.ANE.0000150940.57369.B5" "Revista" => array:6 [ "tituloSerie" => "Anesth Analg" "fecha" => "2005" "volumen" => "100" "paginaInicial" => "1599" "paginaFinal" => "1604" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15920180" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0315" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of age on the dose of remifentanil for tracheal intubation in infants and children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Hume-Smith" 1 => "J. McCormack" 2 => "C. Montgomery" 3 => "R. Brant" 4 => "S. Malherbe" 5 => "D. Mehta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1460-9592.2009.03190.x" "Revista" => array:6 [ "tituloSerie" => "Paediatr Anaesth" "fecha" => "2010" "volumen" => "20" "paginaInicial" => "19" "paginaFinal" => "27" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19968808" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0320" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prospective randomized trial of ketorolac after congenital heart surgery" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Gupta" 1 => "C. Daggett" 2 => "S. Drant" 3 => "N. Rivero" 4 => "A. Lewis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Cardiothorac Vasc Anesth" "fecha" => "2004" "volumen" => "18" "paginaInicial" => "454" "paginaFinal" => "457" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15365927" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0325" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.F. Jett" 1 => "C.S. Ramesha" 2 => "C.D. Brown" 3 => "S. Chiu" 4 => "C. Emmett" 5 => "T. Voronin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pharmacol Exp Ther" "fecha" => "1999" "volumen" => "288" "paginaInicial" => "1288" "paginaFinal" => "1297" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10027870" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0330" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Hamunen" 1 => "E.L. Maunuksela" 2 => "J. Sarvela" 3 => "R.E. Bullingham" 4 => "K.T. Olkkola" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Acta Anaesthesiol Scand" "fecha" => "1999" "volumen" => "43" "paginaInicial" => "1041" "paginaFinal" => "1046" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10593468" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0370410615003265" "estado" => "S300" "issn" => "03704106" ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0335" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.E. Kauffman" 1 => "M.W. Lieh-Lai" 2 => "H.G. Uy" 3 => "M.K. Aravind" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0009-9236(99)70131-1" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacol Ther" "fecha" => "1999" "volumen" => "65" "paginaInicial" => "382" "paginaFinal" => "388" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10223774" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0340" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2–6 months" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.M. Lynn" 1 => "H. Bradford" 2 => "E.D. Kantor" 3 => "M. Andrew" 4 => "P. Vicini" 5 => "G.D. Anderson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1460-9592.2010.03484.x" "Revista" => array:6 [ "tituloSerie" => "Paediatr Anaesth" "fecha" => "2011" "volumen" => "21" "paginaInicial" => "325" "paginaFinal" => "334" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21199130" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0345" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B.J. Anderson" 1 => "G.A. Woollard" 2 => "N.H. 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Farmacología del desarrollo de analgésicos opioides y no esteroideos en neonatos e infantes

Lizabeth Martin

Corresponding author

Lizabeth.martin@seattlechildrens.org

Corresponding author at: Seattle Children's Hospital, 4800 Sandpoint Way NE MB 11.500, Seattle, WA 98105, USA.

, Nathalia Jimenez, Anne M. Lynn

Seattle Children's Hospital, University of Washington, Department of Anesthesiology and Pain Medicine, Seattle, USA

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        "titulo" => "Farmacolog&#237;a del desarrollo de analg&#233;sicos opioides y no esteroideos en neonatos e infantes"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Morphine clearance &#40;ml&#47;min<span class="elsevierStyleSup">&#8722;1</span>&#47;kg<span class="elsevierStyleSup">&#8722;1</span>&#41; vs age in infants receiving morphine&#46; This figure was published in <span class="elsevierStyleItalic">Pain</span>&#44; Lynn&#44; A&#46;M&#46;&#44; Nespeca M&#46;K&#46;&#44; Bratton S&#46;&#44; Shen D&#46; Intravenous morphine in postoperative infants&#58; intermittent bolus dosing versus targeted continuous infusions&#44; <span class="elsevierStyleItalic">Pain</span> 88&#40;1&#41;&#58;93&#44; Copyright Elsevier &#40;2000&#41;&#46; Source&#58; &#40;19&#41; Reproduced with permission&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Perioperative pain control and selection of analgesic medications is particularly important in infants and neonates&#46; Emerging data suggest that adverse experiences including exposure to painful stimuli in the perinatal period may negatively impact long term emotional and behavioral well-being&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> This must be carefully weighed with the increased side-effect profile of analgesic medications in this age group&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">This narrative review of the literature describes some of the features of neonatal and infant physiology that differ from adults and impact drug handling&#46; Definitions of pharmacokinetic terms and a brief introduction to models for drug metabolism will be presented&#46; Morphine and remifentanil will be used as examples to compare and contrast pharmacokinetics in infants and the pharmacodynamics particularly of respiratory effects in this vulnerable group&#46; The kinetics of acetaminophen and of ketorolac &#40;as examples of parenteral non-steroidal analgesics&#41; in infants will be reviewed&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The article is a summation of information presented at the annual Colombian Society for Anesthesia meeting in Cali&#44; Colombia June&#44; 2015&#46; It is a selection from the literature rather than a comprehensive review of all literature of these drugs or drug classes&#46; References to the authors&#8217; own work is used for convenience and knowledge of study performance details&#44; not to suggest other work is not equally important&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Physiology</span><p id="par0020" class="elsevierStylePara elsevierViewall">The physiology of the neonate and infant differs in many aspects from the adult&#59; some of these differences are important factors for drug handling&#46; Total body water is a higher percentage of body weight in infants&#44; reaching adult values by age 8&#8211;10 years &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Liver and kidney function is not fully developed at birth which affects handling of many drugs&#46; The maturation of function occurs over several months during the first year of life&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> Drug development in the past 10&#8211;20 years has focused on agents whose metabolism is less dependent on normal renal and&#47;or liver function as aging populations of adults have compromise in these organs&#46; This is beneficial for infants who also have immature function&#46; Remifentanil is the obvious example of this process in action&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Hepatic enzymes&#44; including both the P450 system and the glucuronidation pathways&#44; are immature at birth&#46; Maturation occurs over the first few months of postnatal life&#44; at different rates for different P450 variants&#46; Drugs that are metabolized by glucuronidation &#40;solubility increased for excretion&#41; will have delayed removal in the first months of life&#46; Sulfation then becomes more important as a metabolic pathway&#46; There are also inherited variants for the CYP &#40;P450&#41; system that may impact drug handling&#46; An example of this is seen with codeine&#44; where conversion to the active morphine can occur faster&#44; slower&#44; or not at all&#44; resulting in an unpredictable effect&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a> Reports of excessive effect in ultrarapid metabolizers have been associated with respiratory calamities&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The kidney is important for eliminating drugs or their metabolites&#46; In infants&#44; glomerular filtration rates &#40;GFR&#41; start at approximately 10&#37; of adult normal values&#44; reaching these by 12 months of age&#46; Renal tubular function also matures over the first 6 months&#46; This decreased function can result in the accumulation of metabolites&#44; and is particularly problematic with those metabolites that have active effects&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pharmacokinetics</span><p id="par0035" class="elsevierStylePara elsevierViewall">Pharmacokinetics is defined as the study of drug disposition by patients&#59; it is affected by absorption &#40;important for non-intravenous routes of administration&#41;&#44; distribution&#44; metabolism and elimination&#46; Pharmacology terms are used commonly in studies of drug handling&#46; Familiarity with these terms can be helpful when reviewing this literature&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Clearance &#40;Cl&#41; describes the removal of drug from a volume of plasma per unit of time &#40;mL&#47;min or L&#47;h&#41;&#46; This value is often reported as a normalized value&#44; commonly as L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg or in older publications as mL&#47;min&#47;kg&#46; Clearance reflects how efficiently the patient removes drug both by metabolism of drug and by excretion of unchanged drug&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Volume of distribution &#40;Vd&#41;&#44; another volume term&#44; describes the apparent volume that would be necessary to account for all drug if it were present at the same concentration as measured in plasma or serum &#40;L&#47;70<span class="elsevierStyleHsp" style=""></span>kg or mL&#47;kg in older work&#41;&#46; Importantly&#44; volume of distribution is a theoretical&#44; rather than physiologic&#44; volume&#46; Its usefulness is to show how widely distributed a drug is in the body&#46; Small Vd is found with drugs that are polar &#40;difficult crossing lipid membranes as with aminoglycosides&#41; or those bound to plasma proteins such as albumin or alpha-1 acid glycoprotein&#46; Drugs with large Vd have high lipid solubility or are bound to tissue proteins&#44; and blood concentration may poorly reflect how much drug is present in the body&#44; as is seen with digoxin&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Elimination half-life &#40;<span class="elsevierStyleItalic">t</span>1&#47;2&#41; is the time needed to change blood concentration by 50&#37; and is reported as minutes or hours&#46; In 4&#8211;5 half-lives&#44; 94&#8211;97&#37; of drug is removed&#44; respectively&#46; Half-life is affected by both clearance and by volume of distribution&#46; Drugs with a higher clearance and smaller volume of distribution have a shorter duration of action and are more titratable&#44; which is often desirable in anesthesia practice&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">As novel anesthetic drugs with these features have been developed&#44; the term context-sensitive half-time has come into use&#46; This term refers to the time to change drug concentration by 50&#37; &#40;i&#46;e&#46; half-life&#41; in the context of the duration of administration&#46; Context-sensitive half-time pharmacokinetic models for intravenous anesthetic drugs have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">7</span></a> Many newer agents have been developed to achieve small context-sensitive half-times which are unchanged regardless of the duration of drug infusion&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Limitations on blood sampling for pediatric patients&#44; which is particularly significant in infants&#44; have encouraged the development of computer generated pharmacokinetic mathematical modeling schemes which require sparse blood concentration data from pediatric patients&#46; Population-based models exist which use factors such as age and weight as regular covariates&#44; and introduce additional elements to improve the fit of the model in concentration vs&#46; time graphs&#46; Weight-based allometric models incorporate weight using exponential factors &#40;0&#46;75 for clearance&#44; 1 for volume of distribution&#41; based on enzyme functions&#46; These models consider age-appropriate factors such as creatinine or bilirubin to improve fit&#46; Both of these models have been used to study morphine and remifentanil handling in infants&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">8&#8211;10</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">There are genetic factors that influence metabolism of drugs and this is an active area of research&#46; While the effect of genetic variants is sometimes difficult to extrapolate directly into clinical practice there are examples of important metabolic-genetic variants pertinent to pediatric populations&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> Codeine as a pro-drug is entirely dependent on its metabolism for its analgesic effect&#46; Its active metabolite morphine&#44; is produced by O-demethylation by the CYP2D6 &#40;Cytochrome P450 2D6&#41; enzyme&#44; which is highly polymorphic&#46; Differences in CYP2D6 alleles can result in significant differences in handling of opiates because the activity level of the CYP2D6 enzyme is determined by the combination of alleles that each patient has&#44; ranging from poor to ultrarapid metabolizers&#46; In clinical practice patients who are poor metabolizers will not achieve any analgesia with codeine use&#44; while patients who are ultrarapid metabolizers have higher risk of respiratory depression&#46; Similar concerns have been reported with tramadol&#44; hydrocodone and oxycodone resulting in the publication of dosing guidelines considering CYP2D6 genotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The association of race&#44; ethnicity&#44; and the frequency of genetic polymorphism is an additional consideration&#46; Using the previous example&#44; CYP2D6 allele frequencies vary significantly between racial and ethnic groups&#46; European Caucasians are more likely to carry normal function alleles compared with Asians and African-Americans&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> East Africans &#40;Ethiopians&#41; on the other hand&#44; are more likely to exhibit duplications of the CYP2D6-gene &#40;indicative of ultrarapid metabolism&#41;&#44; which predisposes them to serious adverse reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Morphine</span><p id="par0075" class="elsevierStylePara elsevierViewall">Studies of morphine pharmacokinetics have been reported by several groups&#46; The focus here will be on the author&#39;s work &#40;AL&#41; which is known in detail&#46; In 1987&#44; a small study in 10 infants showed they had different pharmacokinetic parameters than those reported in adults&#44; with a lower clearance and large volume of distribution resulting in a prolonged elimination half-life&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> The clearance appeared to increase quickly comparing infants aged 1&#8211;4 days to older infants&#46; Study of a larger cohort of 49 infants and toddlers&#44; all receiving morphine by infusion after cardiac surgery&#44; showed the same pattern&#44; with adult values for clearance being reached by age 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> In a subsequent study of 26 infants who received morphine by iv infusion after non-cardiac surgeries&#44; clearance in non-cardiac infants was found to be significantly greater than in infants post-cardiac surgery&#44; with non-cardiac surgical infants reaching adult morphine clearance values by 1&#8211;3 months of age rather than 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> In all these studies&#44; interpatient morphine clearance was high&#44; giving values 2&#8211;3 fold different for same aged infants&#44; a problem seen with most &#8220;older&#8221; opiates&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18&#8211;20</span></a>&#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; This variability makes it difficult to predict the duration of both desired and undesired morphine effects in any individual infant&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Pharmacodynamics</span><p id="par0080" class="elsevierStylePara elsevierViewall">Pharmacodynamics refers to the effects of the drug on the patient&#59; these may be therapeutic or undesired &#40;adverse&#41;&#46; For most clinicians&#44; pharmacodynamics drives our administration of drugs&#46; Pharmacodynamics are affected by many factors&#59; for opiates these include differences in receptor morphology &#40;OPRM gene variant SNP 118 A&#47;G&#41;&#44; differences in target site concentrations of drug &#40;ABCB 1&#47;MDR 1 transporter&#41;&#44; or effects downstream from drug reaching receptors and binding such as differences in COMT metabolism of catechols &#40;472 G&#62;A SNP&#41;&#46; Studies of these genetic differences in different populations have been increasing and should continue to be an active area of research&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Respiratory effects of opiates have been one of the factors limiting its use in infants&#46; Studies linking drug concentrations to effects are few&#46; In 1993&#44; we recorded morphine concentrations at steady-state in 30 infants receiving intravenous morphine infusions after cardiac surgery&#44; and found that a plasma morphine concentration of &#60;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with hypercarbia in 15&#37; versus 67&#37; in those over 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL independent of age&#46; This suggested that morphine infusions set to target a plasma concentration of 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL could minimize risk of respiratory depression in infants&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> Unfortunately&#44; the interpatient variability in morphine pharmacokinetics make predicting morphine concentration more difficult &#40;see above discussion&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In 2000&#44; a follow-up study of 83 infants demonstrated superior analgesia with morphine infusions compared to intermittent bolus dosing &#40;high pain scores in 13&#37; vs 32&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a> There was no difference in continuous oximetry readings &#60;90&#37; in room air or time to oral intake&#46; However&#44; CO<span class="elsevierStyleInf">2</span> response curve slopes did show evidence of ventilatory depression in 4 of 57 &#40;7&#37;&#41; infusion group infants&#46; A suggested course to facilitate extubation at surgery end is to use 0&#46;05<span class="elsevierStyleHsp" style=""></span>mg&#47;kg morphine as a loading dose&#44; then infusion at 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#47;h in neonates&#44; and 10&#8211;20<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#47;h in infants&#44; adjusting to each individual&#39;s needs&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Remifentanil</span><p id="par0095" class="elsevierStylePara elsevierViewall">The unpredictable pharmacokinetics and potential for undesired respiratory depression with morphine has led to the investigation of opioids with clearance that is less reliant on hepatic or renal function&#46; Remifentanil is an example of such an agent&#46; Remifentanil is a mu-agonist&#44; binding to the same opiate receptors as morphine or fentanyl&#46; It is metabolized by tissue esterases&#44; so its pharmacokinetics are unaffected by changes in hepatic or renal function&#46; Important for use in infants&#44; these tissue esterases are functional at birth so age-related changes are not seen&#46; Onset and offset is rapid&#44; so intravenous infusions are the most common administration route&#46; The context-sensitive half-time is reported as 3&#8211;5<span class="elsevierStyleHsp" style=""></span>min&#44; independent of duration of infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> Eck did an early case report of 3 complex infants managed with remifentanil as an anesthetic adjuvant&#44; and reported early extubation &#40;7&#8211;20<span class="elsevierStyleHsp" style=""></span>min from infusion off&#41; in 2 of 3&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> Davis did a multi-center trial in 60 infants undergoing pyloromyotomy&#44; comparing nitrous oxide&#47;remifentanil infusion at 0&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;2<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#47;min to nitrous oxide&#47;halothane 0&#46;4&#37;&#46; A field block with bupivacaine for postoperative analgesia was used in both groups&#46; Although there was no difference in time to extubation&#44; no infant in the remifentanil group had any new abnormality on postoperative pneumograms&#44; where 3 patients in the volatile only group did&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> Crawford et al&#46; demonstrated that remifentanil can provide excellent conditions for orotracheal intubation in infants without use of muscle relaxants&#46; 24 infants&#44; pretreated with glycopyrrolate 10<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#44; were randomized to propofol&#47;succinylcholine or propofol&#47;remifentanil 3<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg and intubating conditions were similar with no adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">25</span></a> A subsequent study including 64 children 0&#8211;3 years of age&#44; stratified in three age groups &#40;0&#8211;3 months&#59; 4&#8211;12 months and 1&#8211;3 years&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">26</span></a> suggested that the age-specific bolus dose of remifentanil &#40;ED50&#41; to facilitate tracheal intubation&#44; is slightly higher &#40;3&#46;7<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#41; among the infant group 4&#8211;12 months of age&#46; In this study all patients were also pretreated with glycopyrrolate&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Undesired effects including &#8220;chest wall rigidity&#8221; and bradycardia have been reported&#44; as can be seen with other fentanyl derivatives&#46; Nausea and vomiting is reported in &#8764;30&#37; in adult studies&#46; More importantly for anesthetic use&#44; remifentanil analgesia is gone within 15&#8211;30<span class="elsevierStyleHsp" style=""></span>min of stopping infusions&#46; Some authors have suggested tachyphylaxis subsequently leading to higher opiate requirements&#44; however this has not been reported in infants&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Remifentanil avoids the challenges of pharmacokinetic variability that are seen with morphine&#44; however it is relatively expensive and rapid offset can pose a challenge for post-operative analgesia&#46; If postoperative pain can be approached with regional techniques&#44; remifentanil seems a workable choice to allow early extubation after infant surgery&#46; Studying ethnic&#44; racial and genetic factors in opiate metabolism remains important in helping us individualize care for this vulnerable population&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Depending on the patient and procedure&#44; other categories of analgesics may be considered to complement or replace opioids&#46; Description of the pharmacokinetics&#47;dynamics in infants of acetaminophen &#40;focusing on intravenous route&#41; and of ketorolac &#40;only widely available parenteral non-steroidal anti-inflammatory drug &#91;NSAID&#93; in US&#41; will inform this next section&#46; These agents may be of particular benefit in infants as they do not work via opiate receptors and do not have effects on respiration or consciousness&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ketorolac</span><p id="par0115" class="elsevierStylePara elsevierViewall">Ketorolac tromethamine is available in oral and parenteral forms&#46; As the only widely available intravenous NSAID in the US&#44; it has been used as an analgesic adjunct and has been shown to decrease opioid requirements in post-operative patients&#46; It works by inhibiting the cyclooxygenase system which decreases prostaglandin synthesis and the inflammatory cascade&#46; It does not affect consciousness or respiration but does have effects on gastric mucosa&#44; renal perfusion and platelet function&#46; Baseline renal or platelet dysfunction is a relative contraindication&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">A prospective randomized trial of 70 infants and children showed no difference in chest tube drainage or bleeding complications and no difference in median change in creatinine after congenital cardiac surgery with or without 48<span class="elsevierStyleHsp" style=""></span>h of ketorolac therapy postoperatively&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a> To further explore the pharmacokinetic&#44; safety and respiratory effects in infants&#44; we did a single center randomized&#44; blinded&#44; placebo-control study in infants 6&#8211;18 months admitted after surgery&#46; The kinetics were done for stereo-specific isomers since animal studies suggested the S-isomer was a more potent analgesic<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">28</span></a> and studies in children suggested differences in isomer handling&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">29&#44;30</span></a> Thirty-seven infants were enrolled&#44; 23 following craniectomy surgery&#46; All received morphine for breakthrough pain&#46; A marked difference in isomer clearance was found with the S-isomer cleared 4-fold faster than the R- &#40;4&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;kg vs 1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6 respectively&#41;&#46; The elimination <span class="elsevierStyleItalic">t</span>1&#47;2 was 64<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>min &#40;S&#41; vs 198<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>77<span class="elsevierStyleHsp" style=""></span>min &#40;R&#41;&#46; Serum concentrations of the S-isomer fell below adult &#8220;therapeutic&#8221; values &#40;as reported by Stanski et al&#46;&#41; by 4<span class="elsevierStyleHsp" style=""></span>h&#46; Modeling of doses of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg or 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg showed complete clearance of the S-isomer by 4<span class="elsevierStyleHsp" style=""></span>h&#44; but accumulation of the R-isomer with each dose&#46; As a single dose study&#44; no adverse effects on renal function &#40;creatinine and urine volume&#41;&#44; gastric mucosa &#40;guiac testing&#41; or platelet function &#40;drain amount in craniectomy babies&#41; were observed&#46; Continuous oximetry showed no episodes of desaturation in either placebo or ketorolac groups&#46; Unanswered is the possibility that toxicity may relate to the R-isomer concentrations which rise with repeat dosing&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">31</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Safety data is lacking in neonates or infants at higher risk for renal dysfunction &#40;post cardiac bypass&#44; complex cardiac disease including single ventricle physiology&#41; except in the Gupta study detailed above&#44; and caution is advised in this patient population&#46; In our institution we administer ketorolac 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; every 6&#8211;8<span class="elsevierStyleHsp" style=""></span>h for a maximum of 72<span class="elsevierStyleHsp" style=""></span>h to infants older than 6 months and a single dose 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg for infants 1&#8211;6 months&#46; Although retrospective review in 1&#8211;6 month age group suggests that scheduled dosing of ketorolac may be well-tolerated&#44; pharmacokinetic and prospective safety data for this practice is lacking&#46; If serial dosing is used in infants &#60;6 months for 48&#8211;72<span class="elsevierStyleHsp" style=""></span>h&#44; monitoring of urine output&#44; BUN&#47;creatinine and stool guiac should be considered&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Acetaminophen</span><p id="par0130" class="elsevierStylePara elsevierViewall">Acetaminophen &#40;or paracetamol in European or UK literature&#41; is the most widely used analgesic&#47;antipyretic administered in oral or rectal forms&#46; In 2002&#44; propacetamol&#44; an intravenous pro-drug&#44; was developed and in 2009 an intravenous active form of acetaminophen became available in Europe&#46; In the USA intravenous acetaminophen was approved by the FDA more recently&#44; so many of the reports on its use come from European or UK sites&#46; One advantage of this drug is its long history of use in the oral form&#44; which means safety information in children and infants is available&#46; Hepatic toxicity from overdose of acetaminophen and accumulation of the metabolite N-acetyl-p-benzoquinone imine &#40;NAPQI&#41; is very uncommon in infants because they have immature P450 enzyme function&#44; specifically CYP2E1&#44; and make much lower concentrations of this metabolite&#46; The ideal analgesic concentration has been incompletely studied but Anderson reported acetaminophen concentrations of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;L resulted in analgesia in children post-tonsillectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> This concentration is commonly targeted as therapeutic but whether it applies in all circumstances is unexplored&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In 2005&#44; Anderson reported a population pharmacokinetic study of intravenous propacetamol in children&#46; He included 846 acetaminophen concentrations from 7 previous studies with a total of 144 children&#46; The bioavailability was 0&#46;5&#44; clearance was 16<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg increasing from 1&#46;27<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg in premature infants &#40;gestation 27 weeks&#41; to 84&#37; of adult values by age 1<span class="elsevierStyleHsp" style=""></span>y&#46; Volume of distribution &#40;peripheral&#41; decreased from 45<span class="elsevierStyleHsp" style=""></span>L&#47;70<span class="elsevierStyleHsp" style=""></span>kg in prematures &#40;27 weeks&#41; to adult values by age 6 months&#46; He predicted that dosing propacetamol 30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 6<span class="elsevierStyleHsp" style=""></span>h would result in pediatric patients having acetaminophen concentrations of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Allegeart &#40;2004&#41; reported kinetics of a single dose of intravenous acetaminophen in 30 neonates showing lower clearance in infants less than 37<span class="elsevierStyleHsp" style=""></span>wk gestation &#40;8&#46;1<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg&#41; compared to those 37&#8211;41<span class="elsevierStyleHsp" style=""></span>wks gestation &#40;11&#46;9<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg&#41;&#44; noting marked interpatient variability&#46; Elimination half-life was prolonged at 277<span class="elsevierStyleHsp" style=""></span>min in the premature group compared to 172<span class="elsevierStyleHsp" style=""></span>min in the term infants&#44; again with large variability noted&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a> Population pharmacokinetics of acetaminophen in infants was reported by Allegaert in 2011&#46; She included 158 neonates &#40;58 premature&#41; from 4 studies&#44; with 943 acetaminophen observations&#46; Clearance from this larger group of infants was 5<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg&#44; with adult clearance of 16&#46;2<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg found at age 1<span class="elsevierStyleHsp" style=""></span>y&#46; Her suggestion was use of one loading dose of 20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg followed by 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 6<span class="elsevierStyleHsp" style=""></span>h to target an acetaminophen concentration of 11<span class="elsevierStyleHsp" style=""></span>mg&#47;L in infants aged 32&#8211;44<span class="elsevierStyleHsp" style=""></span>wk gestation&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">35</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The safety profile and kinetics of intravenous acetaminophen was studied by Palmer in 50 neonates given repeated doses postoperatively&#46; Clearance was 5&#46;2<span class="elsevierStyleHsp" style=""></span>L&#47;h&#47;70<span class="elsevierStyleHsp" style=""></span>kg&#44; with large volume of distribution of 76<span class="elsevierStyleHsp" style=""></span>L&#47;70<span class="elsevierStyleHsp" style=""></span>kg&#46; Elevated bilirubin correlated with decreased clearance&#46; Daily hepatic enzyme levels remained normal in 49 of the 50 infants&#44; increasing in one after 5 doses and recovering when acetaminophen was stopped&#46; She suggests 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;6h in term infants&#44; with reduction for hyperbilirubinemia&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Ceelie did a blinded randomized controlled trial in 71 infants&#44; aged 37<span class="elsevierStyleHsp" style=""></span>wk gestation to 1<span class="elsevierStyleHsp" style=""></span>y&#44; treated after major abdominal or thoracic surgery&#46; Infants received intravenous acetaminophen 30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d in 4 doses or morphine infusions at 4&#8211;16<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#47;h after a standardized anesthetic with one dose of morphine 30<span class="elsevierStyleHsp" style=""></span>min before surgery end&#46; Rescue for pain was with morphine bolus dosing in both groups&#46; Pain scores and the number needing rescue was the same in both groups&#46; Total morphine was lower in the acetaminophen group &#40;122<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg over 48<span class="elsevierStyleHsp" style=""></span>h vs&#46; 357<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg&#47;48<span class="elsevierStyleHsp" style=""></span>h&#41;&#59; naloxone was given to 3 in morphine group&#44; none in acetaminophen group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>NS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">An overview of the pharmacokinetic considerations reviewed here are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; More detailed pharmacokinetic information is beyond the scope of this review&#44; and can be found elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusion</span><p id="par0160" class="elsevierStylePara elsevierViewall">The clinical application of pharmacokinetics and pharmacodynamics of opiates &#40;morphine or remifentanil&#41; or NSAIDS &#40;ketorolac or iv acetaminophen&#41; to our care of infants who require surgery has room for much further study&#46; It seems reasonable to consider multimodal therapy to minimize undesirable opiate side effects&#46; Variability of clearance of older opiates such as morphine support using small doses &#40;0&#46;05<span class="elsevierStyleHsp" style=""></span>mg&#47;kg morphine&#41; and titrating for effect&#46; Remifentanil avoids the variability issue but requires infusion to maintain effect and&#44; analgesia is gone quickly &#40;&#60;30<span class="elsevierStyleHsp" style=""></span>min&#41; once it is discontinued&#44; which may not be appropriate for the postoperative infant&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Ketorolac in a single dose study did not show adverse effects on hepatic&#44; gastrointestinal or renal function but raises the concern of accumulation of the R-isomer with repeated doses and its unknown relation to toxicity&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Acetaminophen does have intravenous kinetic information for infants available to guide dosing so can be a part of a multimodal analgesic regime in most infants&#46; Nonpharmacologic adjuncts should also be considered which we have not presented in this forum including use of regional anesthetic techniques&#44; oral glucose&#44; nonnutritive sucking and swaddling&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">No funding&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">All authors declare no conflicts of interest&#46;</p></span></span>"
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    "fechaRecibido" => "2016-06-09"
    "fechaAceptado" => "2016-10-21"
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          "clase" => "keyword"
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            0 => "Infant"
            1 => "Infant care"
            2 => "Analgesics&#44; opioid"
            3 => "Pharmacokinetics"
            4 => "Pharmacology"
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            0 => "Lactante"
            1 => "Cuidado del lactante"
            2 => "Analg&#233;sicos opi&#243;ides"
            3 => "Farmacocin&#233;tica"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pharmacology of infants is understudied and different from other populations&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review the unique features of neonatal and infant physiology that impact drug handling and the pharmacokinetics of analgesics&#44; including opioids&#44; ketorolac and acetaminophen&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This article is a narrative review of the literature from the authors&#39; point of view that constitutes a summary of the information presented at the annual Colombian Society for Anesthesia meeting in Cali&#44; Colombia June 2015&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Pharmacology in neonates and infants is unique and must be considered in this vulnerable population&#46; Recommendations for administration of these analgesics are presented based on their unique pharmacokinetic properties&#46; Individual patient variation and clinical response must also be taken into account&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0005"
            "titulo" => "Introduction"
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          1 => array:2 [
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            "titulo" => "Objective"
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            "titulo" => "Materials and methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La farmacolog&#237;a de los lactantes es poco estudiada y difiere de la farmacolog&#237;a de otras poblaciones&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Objetivo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Revisar las caracter&#237;sticas &#250;nicas de la fisiolog&#237;a de los neonatos e lactantes que afectan el manejo del f&#225;rmaco y la farmacocin&#233;tica de los anest&#233;sicos&#44; incluyendo opioides&#44; ketorolaco y acetaminof&#233;n&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Materiales y m&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Este art&#237;culo es una revisi&#243;n narrativa de la literatura&#44; desde el punto de vista de las autoras&#44; y constituye un resumen de la informaci&#243;n presentada en la reuni&#243;n anual de la Sociedad Colombiana de Anestesiolog&#237;a y Reanimaci&#243;n en Cali&#44; Colombia&#44; en junio de 2015&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La farmacolog&#237;a en neonatos e lactantes es &#250;nica y debe ser considerada en esta poblaci&#243;n vulnerable&#46; Las recomendaciones presentadas para la administraci&#243;n de esos analg&#233;sicos est&#225;n basadas en sus propiedades farmacocin&#233;ticas &#250;nicas&#46; Tambi&#233;n deben tenerse en cuenta las variaciones individuales y la respuesta cl&#237;nica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Martin L&#44; Jimenez N&#44; Lynn AM&#46; Farmacolog&#237;a del desarrollo de analg&#233;sicos opioides y no esteroideos en neonatos e infantes&#46; Rev Colomb Anestesiol&#46; 2017&#59;45&#58;72&#8211;79&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Total body water&#44; intracellular fluid and extracellular fluid percent body weight for age in children&#46; This figure was published in <span class="elsevierStyleItalic">Nelson Textbook of Pediatrics 17th edition</span>&#46; Richard E&#46; Behrman&#44; Robert M&#46; Kliegman&#44; H&#46;B&#46; Jenson&#46; Pathophysiology of Body Fluids and Fluid Therapy&#44; Chapter 45&#44; Page 191&#44; Copyright Elsevier &#40;2004&#41;&#46; Source&#58; &#40;2&#41; Reproduced with permission&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Morphine clearance &#40;ml&#47;min<span class="elsevierStyleSup">&#8722;1</span>&#47;kg<span class="elsevierStyleSup">&#8722;1</span>&#41; vs age in infants receiving morphine&#46; This figure was published in <span class="elsevierStyleItalic">Pain</span>&#44; Lynn&#44; A&#46;M&#46;&#44; Nespeca M&#46;K&#46;&#44; Bratton S&#46;&#44; Shen D&#46; Intravenous morphine in postoperative infants&#58; intermittent bolus dosing versus targeted continuous infusions&#44; <span class="elsevierStyleItalic">Pain</span> 88&#40;1&#41;&#58;93&#44; Copyright Elsevier &#40;2000&#41;&#46; Source&#58; &#40;19&#41; Reproduced with permission&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Metabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Metabolite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Renal excretion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Pharmacokinetic considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Morphine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes-active&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inter-individual variability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Titrate to effect&#44; small doses 0&#46;05<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Remifentanil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Plasma esterase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predictable duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No long-acting analgesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ketorolac&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes-active&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R-isomer accumulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single dose &#60;6 months&#44; limit dosing to 72<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acetaminophen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes-toxic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV formulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Q6<span class="elsevierStyleHsp" style=""></span>h dosing interval preferred&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Pharmacokinetic and clinical considerations of common analgesic medications in infants&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:37 [
            0 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "More than anyone else&#58; preemies need good analgesia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "L&#46; Vutskits"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/ALN.0000000000001018"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesthesiology"
                        "fecha" => "2016"
                        "volumen" => "124"
                        "paginaInicial" => "758"
                        "paginaFinal" => "760"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26808638"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathophysiology of body fluids and fluid therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "L&#46; Greenbaum"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "Nelson textbook of pediatrics"
                        "paginaInicial" => "267"
                        "paginaFinal" => "268"
                        "edicion" => "17th ed&#46;"
                        "serieFecha" => "2004"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;G&#46; Williams"
                            1 => "A&#46; Patel"
                            2 => "R&#46;F&#46; Howard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Anaesth"
                        "fecha" => "2002"
                        "volumen" => "89"
                        "paginaInicial" => "839"
                        "paginaFinal" => "845"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12453926"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Codeine&#44; ultrarapid-metabolism genotype&#44; and postoperative death"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Ciszkowski"
                            1 => "P&#46; Madadi"
                            2 => "M&#46;S&#46; Phillips"
                            3 => "A&#46;E&#46; Lauwers"
                            4 => "G&#46; Koren"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMc0904266"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2009"
                        "volumen" => "361"
                        "paginaInicial" => "827"
                        "paginaFinal" => "828"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19692698"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "More codeine fatalities after tonsillectomy in North American children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;E&#46; Kelly"
                            1 => "M&#46; Rieder"
                            2 => "J&#46; van den Anker"
                            3 => "B&#46; Malkin"
                            4 => "C&#46; Ross"
                            5 => "M&#46;N&#46; Neely"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1542/peds.2011-2538"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "2012"
                        "volumen" => "129"
                        "paginaInicial" => "e1343"
                        "paginaFinal" => "e1347"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22492761"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacology of pediatric anesthesia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Davis"
                            1 => "A&#46; Bosenberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "titulo" => "Smith&#39;s anesthesia for infants and children"
                        "paginaInicial" => "179"
                        "paginaFinal" => "263"
                        "edicion" => "8th ed&#46;"
                        "serieFecha" => "2011"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;A&#46; Hughes"
                            1 => "P&#46;S&#46; Glass"
                            2 => "J&#46;R&#46; Jacobs"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesthesiology"
                        "fecha" => "1992"
                        "volumen" => "76"
                        "paginaInicial" => "334"
                        "paginaFinal" => "341"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1539843"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pediatric models for adult target-controlled infusion pumps"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46;J&#46; Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1460-9592.2009.03072.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Paediatr Anaesth"
                        "fecha" => "2010"
                        "volumen" => "20"
                        "paginaInicial" => "223"
                        "paginaFinal" => "232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19627530"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Are there still limitations for the use of target-controlled infusion in children&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46;J&#46; Anderson"
                            1 => "B&#46; Hodkinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/ACO.0b013e32833938db"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Anaesthesiol"
                        "fecha" => "2010"
                        "volumen" => "23"
                        "paginaInicial" => "356"
                        "paginaFinal" => "362"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20386438"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of &#40;preterm&#41; neonates&#44; infants and children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;H&#46; Krekels"
                            1 => "J&#46; DeJongh"
                            2 => "R&#46;A&#46; van Lingen"
                            3 => "C&#46;D&#46; van der Marel"
                            4 => "I&#46; Choonara"
                            5 => "A&#46;M&#46; Lynn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/11536750-000000000-00000"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2011"
                        "volumen" => "50"
                        "paginaInicial" => "51"
                        "paginaFinal" => "63"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27975238"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Personalizing pediatric pain medicine&#58; using population-specific pharmacogenetics&#44; genomics&#44; and other &#8211; omics approaches to predict response"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Jimenez"
                            1 => "J&#46;L&#46; Galinkin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1213/ANE.0000000000000721"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "2015"
                        "volumen" => "121"
                        "paginaInicial" => "183"
                        "paginaFinal" => "187"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26086515"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy&#58; 2014 update"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;R&#46; Crews"
                            1 => "A&#46; Gaedigk"
                            2 => "H&#46;M&#46; Dunnenberger"
                            3 => "J&#46;S&#46; Leeder"
                            4 => "T&#46;E&#46; Klein"
                            5 => "K&#46;E&#46; Caudle"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/clpt.2013.254"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "2014"
                        "volumen" => "95"
                        "paginaInicial" => "376"
                        "paginaFinal" => "382"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24458010"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CYP2D6 allele frequency in European Caucasians&#44; Asians&#44; Africans and their descendants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "L&#46;D&#46; Bradford"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1517/14622416.3.2.229"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenomics"
                        "fecha" => "2002"
                        "volumen" => "3"
                        "paginaInicial" => "229"
                        "paginaFinal" => "243"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11972444"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46; Aklillu"
                            1 => "I&#46; Persson"
                            2 => "L&#46; Bertilsson"
                            3 => "I&#46; Johansson"
                            4 => "F&#46; Rodrigues"
                            5 => "M&#46; Ingelman-Sundberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pharmacol Exp Ther"
                        "fecha" => "1996"
                        "volumen" => "278"
                        "paginaInicial" => "441"
                        "paginaFinal" => "446"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8764380"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Morphine pharmacokinetics in early infancy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;M&#46; Lynn"
                            1 => "J&#46;T&#46; Slattery"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesthesiology"
                        "fecha" => "1987"
                        "volumen" => "66"
                        "paginaInicial" => "136"
                        "paginaFinal" => "139"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3813075"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The maturation of morphine clearance and metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "T&#46;I&#46; McRorie"
                            1 => "A&#46;M&#46; Lynn"
                            2 => "M&#46;K&#46; Nespeca"
                            3 => "K&#46;E&#46; Opheim"
                            4 => "J&#46;T&#46; Slattery"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Dis Child"
                        "fecha" => "1992"
                        "volumen" => "146"
                        "paginaInicial" => "972"
                        "paginaFinal" => "976"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1636668"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clearance of morphine in postoperative infants during intravenous infusion&#58; the influence of age and surgery"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Lynn"
                            1 => "M&#46;K&#46; Nespeca"
                            2 => "S&#46;L&#46; Bratton"
                            3 => "S&#46;G&#46; Strauss"
                            4 => "D&#46;D&#46; Shen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "1998"
                        "volumen" => "86"
                        "paginaInicial" => "958"
                        "paginaFinal" => "963"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9585276"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence-based morphine dosing for postoperative neonates and infants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;H&#46; Krekels"
                            1 => "D&#46; Tibboel"
                            2 => "S&#46;N&#46; de Wildt"
                            3 => "I&#46; Ceelie"
                            4 => "A&#46; Dahan"
                            5 => "M&#46; van Dijk"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40262-014-0135-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacokinet"
                        "fecha" => "2014"
                        "volumen" => "53"
                        "paginaInicial" => "553"
                        "paginaFinal" => "563"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24496960"
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              "identificador" => "bib0280"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intravenous morphine in postoperative infants&#58; intermittent bolus dosing versus targeted continuous infusions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;M&#46; Lynn"
                            1 => "M&#46;K&#46; Nespeca"
                            2 => "S&#46;L&#46; Bratton"
                            3 => "D&#46;D&#46; Shen"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pain"
                        "fecha" => "2000"
                        "volumen" => "88"
                        "paginaInicial" => "89"
                        "paginaFinal" => "95"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11098103"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "20"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Developmental pharmacokinetics of morphine and its metabolites in neonates&#44; infants and young children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "N&#46;J&#46; Bouwmeester"
                            1 => "B&#46;J&#46; Anderson"
                            2 => "D&#46; Tibboel"
                            3 => "N&#46;H&#46; Holford"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Anaesth"
                        "fecha" => "2004"
                        "volumen" => "92"
                        "paginaInicial" => "208"
                        "paginaFinal" => "217"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14722170"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0290"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Respiratory effects of intravenous morphine infusions in neonates&#44; infants&#44; and children after cardiac surgery"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;M&#46; Lynn"
                            1 => "M&#46;K&#46; Nespeca"
                            2 => "K&#46;E&#46; Opheim"
                            3 => "J&#46;T&#46; Slattery"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "1993"
                        "volumen" => "77"
                        "paginaInicial" => "695"
                        "paginaFinal" => "701"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8214651"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;K&#46; Ross"
                            1 => "P&#46;J&#46; Davis"
                            2 => "G&#46; deL Dear"
                            3 => "B&#46; Ginsberg"
                            4 => "F&#46;X&#46; McGowan"
                            5 => "R&#46;D&#46; Stiller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "2001"
                        "volumen" => "93"
                        "paginaInicial" => "1393"
                        "paginaFinal" => "1401"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11726413"
                            "web" => "Medline"
                          ]
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                        "itemHostRev" => array:3 [
                          "pii" => "S0140673614604608"
                          "estado" => "S300"
                          "issn" => "01406736"
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                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of remifentanil in infants"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;B&#46; Eck"
                            1 => "A&#46;M&#46; Lynn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Paediatr Anaesth"
                        "fecha" => "1998"
                        "volumen" => "8"
                        "paginaInicial" => "437"
                        "paginaFinal" => "439"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9742543"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0305"
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                0 => array:3 [
                  "comentario" => "&#91;table of contents&#93;"
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                    0 => array:2 [
                      "titulo" => "A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy&#46; I&#46; Emergence and recovery profiles"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;J&#46; Davis"
                            1 => "J&#46; Galinkin"
                            2 => "F&#46;X&#46; McGowan"
                            3 => "A&#46;M&#46; Lynn"
                            4 => "M&#46; Yaster"
                            5 => "M&#46;F&#46; Rabb"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "2001"
                        "volumen" => "93"
                        "paginaInicial" => "1380"
                        "paginaFinal" => "1386"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11726411"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0310"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dose&#8211;response of remifentanil for tracheal intubation in infants"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;W&#46; Crawford"
                            1 => "J&#46; Hayes"
                            2 => "J&#46;M&#46; Tan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1213/01.ANE.0000150940.57369.B5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anesth Analg"
                        "fecha" => "2005"
                        "volumen" => "100"
                        "paginaInicial" => "1599"
                        "paginaFinal" => "1604"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15920180"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of age on the dose of remifentanil for tracheal intubation in infants and children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Hume-Smith"
                            1 => "J&#46; McCormack"
                            2 => "C&#46; Montgomery"
                            3 => "R&#46; Brant"
                            4 => "S&#46; Malherbe"
                            5 => "D&#46; Mehta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1460-9592.2009.03190.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Paediatr Anaesth"
                        "fecha" => "2010"
                        "volumen" => "20"
                        "paginaInicial" => "19"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19968808"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prospective randomized trial of ketorolac after congenital heart surgery"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46; Gupta"
                            1 => "C&#46; Daggett"
                            2 => "S&#46; Drant"
                            3 => "N&#46; Rivero"
                            4 => "A&#46; Lewis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cardiothorac Vasc Anesth"
                        "fecha" => "2004"
                        "volumen" => "18"
                        "paginaInicial" => "454"
                        "paginaFinal" => "457"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15365927"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0325"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;F&#46; Jett"
                            1 => "C&#46;S&#46; Ramesha"
                            2 => "C&#46;D&#46; Brown"
                            3 => "S&#46; Chiu"
                            4 => "C&#46; Emmett"
                            5 => "T&#46; Voronin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pharmacol Exp Ther"
                        "fecha" => "1999"
                        "volumen" => "288"
                        "paginaInicial" => "1288"
                        "paginaFinal" => "1297"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10027870"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Stereoselective pharmacokinetics of ketorolac in children&#44; adolescents and adults"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46; Hamunen"
                            1 => "E&#46;L&#46; Maunuksela"
                            2 => "J&#46; Sarvela"
                            3 => "R&#46;E&#46; Bullingham"
                            4 => "K&#46;T&#46; Olkkola"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Acta Anaesthesiol Scand"
                        "fecha" => "1999"
                        "volumen" => "43"
                        "paginaInicial" => "1041"
                        "paginaFinal" => "1046"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10593468"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0370410615003265"
                          "estado" => "S300"
                          "issn" => "03704106"
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                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;E&#46; Kauffman"
                            1 => "M&#46;W&#46; Lieh-Lai"
                            2 => "H&#46;G&#46; Uy"
                            3 => "M&#46;K&#46; Aravind"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0009-9236(99)70131-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "1999"
                        "volumen" => "65"
                        "paginaInicial" => "382"
                        "paginaFinal" => "388"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10223774"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ketorolac tromethamine&#58; stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2&#8211;6 months"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "A&#46;M&#46; Lynn"
                            1 => "H&#46; Bradford"
                            2 => "E&#46;D&#46; Kantor"
                            3 => "M&#46; Andrew"
                            4 => "P&#46; Vicini"
                            5 => "G&#46;D&#46; Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1460-9592.2010.03484.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Paediatr Anaesth"
                        "fecha" => "2011"
                        "volumen" => "21"
                        "paginaInicial" => "325"
                        "paginaFinal" => "334"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21199130"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Acetaminophen analgesia in children&#58; placebo effect and pain resolution after tonsillectomy"
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                          "etal" => false
                          "autores" => array:3 [
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                            1 => "G&#46;A&#46; Woollard"
                            2 => "N&#46;H&#46; Holford"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Pharmacol"
                        "fecha" => "2001"
                        "volumen" => "57"
                        "paginaInicial" => "559"
                        "paginaFinal" => "569"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11758634"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pediatric intravenous paracetamol &#40;propacetamol&#41; pharmacokinetics&#58; a population analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            4 => "E&#46; Boccard"
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                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1460-9592.2005.01455.x"
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                        "tituloSerie" => "Paediatr Anaesth"
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                        "volumen" => "15"
                        "paginaInicial" => "282"
                        "paginaFinal" => "292"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15787918"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of single dose intravenous propacetamol in neonates&#58; effect of gestational age"
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "C&#46;D&#46; Van der Marel"
                            2 => "A&#46; Debeer"
                            3 => "M&#46;A&#46; Pluim"
                            4 => "R&#46;A&#46; Van Lingen"
                            5 => "C&#46; Vanhole"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dis Child Fetal Neonatal Ed"
                        "fecha" => "2004"
                        "volumen" => "89"
                        "paginaInicial" => "F25"
                        "paginaFinal" => "F28"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14711849"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0360"
              "etiqueta" => "35"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The pharmacokinetics of intravenous paracetamol in neonates&#58; size matters most"
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                            0 => "K&#46; Allegaert"
                            1 => "G&#46;M&#46; Palmer"
                            2 => "B&#46;J&#46; Anderson"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/adc.2010.204552"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dis Child"
                        "fecha" => "2011"
                        "volumen" => "96"
                        "paginaInicial" => "575"
                        "paginaFinal" => "580"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21317433"
                            "web" => "Medline"
                          ]
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                ]
              ]
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                    0 => array:2 [
                      "titulo" => "I&#46;V&#46; acetaminophen pharmacokinetics in neonates after multiple doses"
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Article information

ISSN: 22562087
Original language: English

DOI:10.1016/j.rcae.2016.11.011

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	11	0	11
2024 October	58	7	65
2024 September	56	9	65
2024 August	53	6	59
2024 July	57	5	62
2024 June	49	5	54
2024 May	52	5	57
2024 April	53	9	62
2024 March	67	12	79
2024 February	73	15	88
2024 January	89	9	98
2023 December	60	16	76
2023 November	57	11	68
2023 October	65	11	76
2023 September	51	6	57
2023 August	32	6	38
2023 July	25	3	28
2023 June	30	7	37
2023 May	74	6	80
2023 April	74	2	76
2023 March	46	7	53
2023 February	23	9	32
2023 January	32	5	37
2022 December	55	14	69
2022 November	59	12	71
2022 October	38	15	53
2022 September	69	21	90
2022 August	46	12	58
2022 July	32	9	41
2022 June	52	5	57
2022 May	74	16	90
2022 April	93	15	108
2022 March	153	16	169
2022 February	158	10	168
2022 January	135	12	147
2021 December	86	14	100
2021 November	87	7	94
2021 October	62	18	80
2021 September	53	11	64
2021 August	33	12	45
2021 July	36	10	46
2021 June	31	10	41
2021 May	61	5	66
2021 April	174	11	185
2021 March	106	11	117
2021 February	51	8	59
2021 January	64	12	76
2020 December	38	7	45
2020 November	24	11	35
2020 October	14	57	71
2020 September	17	13	30
2020 August	20	12	32
2020 July	14	9	23
2020 June	14	14	28
2020 May	22	5	27
2020 April	17	10	27
2020 March	16	3	19
2020 February	9	7	16
2020 January	10	3	13
2019 December	8	7	15
2019 November	9	4	13
2019 October	10	5	15
2019 September	4	1	5
2019 August	2	0	2
2019 July	1	3	4
2019 June	4	6	10
2019 May	1	14	15
2019 January	2	0	2
2018 December	1	0	1
2018 September	1	0	1
2018 June	10	1	11
2018 May	42	7	49
2018 April	98	10	108
2018 March	181	14	195
2018 February	123	15	138
2018 January	89	10	99
2017 December	104	15	119
2017 November	62	10	72
2017 October	37	9	46
2017 September	35	11	46
2017 August	17	11	28
2017 July	22	10	32
2017 June	34	13	47
2017 May	39	17	56
2017 April	68	12	80
2017 March	61	12	73
2017 February	30	10	40
2017 January	38	14	52
2016 December	7	15	22

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