Metabolism and pharmacokinetics of morphine in neonates: A review.

Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords "morphine metabolism neonate" and "morphine pharmacokinetics neonate". The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

Metabolism and pharmacokinetics of morphine in neonates: A review

Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

Ibuprofen and indomethacin for the closure of the patent ductus arteriosus / Ibuprofen, indometacina e fechamento do canal arterial

The ductus arteriosus connects the pulmonary artery with the aorta and allows right ventricular blood to bypass the unexpanded lungs. In mature infants, the ductus arteriosus closes after birth. Patent ductus arteriosus occurs in 70% of preterm infants with a birth weight < 1,000 grams. Failure of the ductus arteriosus to close has been associated with intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leukomalacia, renal failure, and persistent pulmonary hypertension. The drugs used to treat the patent ductus arteriosus are ibuprofen and indomethacin which are potent non-selective inhibitors of cyclo-oxygenase (COX) and therefore inhibit prostaglandin E2 synthesis. Prostaglandin E2 relaxes smooth muscle and tends to inhibit the closure of the patent ductus arteriosus. Intravenous ibuprofen and indomethacin inhibit prostaglandin E2 synthesis and thereby close the patent ductus arteriosus with similar efficacy. Indomethacin reduces the blood flow velocity in kidneys, intestine and brain. Ibuprofen has less effect on blood flow velocity in these organs. There is a significant increase in serum creatinine after indomethacin administration but not after ibuprofen and infants treated with ibuprofen have higher creatinine clearance. Oliguria (urine output < 1 ml/kg/h) occurs more frequently with indomethacin than with ibuprofen. Indomethacin requires furosemide for urine output more often than ibuprofen. Ibuprofen reduces the risk of necrotizing enterocolitis and transient renal insufficiency and it is the drug of choice for closing the patent ductus arteriosus. Ibuprofen and indomethacin may be administered orally. In conclusion, intravenous ibuprofen and indomethacin close the patent ductus arteriosus at the same rate, but indomethacin is more toxic than ibuprofen.

O canal arterial conecta a artéria pulmonar com a aorta e permite que o sangue oriundo do ventrículo direito evite passar pelos pulmões fetais não expandidos. Em recém-nascidos maduros, o canal arterial se fecha após o nascimento. A persistência do canal arterial ocorre em 70% dos recém-nascidos prematuros com peso de nascimento < 1.000 gramas. O não fechamento do canal arterial associa-se a hemorragia intraventricular, enterocolite necrosante, displasia bronco-pulmonar, leucomalacia periventricular, insuficiência renal e hipertensão pulmonar persistente. Os medicamentos utilizados para tratar a persistência do canal arterial são o ibuprofeno e a indometacina. Ambos são potentes inibidores não seletivos da ciclo-oxigenase e inibem a síntese de prostaglandina E2. Esta relaxa a musculature vascular lisa e tende a inibir o fechamento do canal arterial. O ibuprofeno e a indometacina inibem a síntese de prostaglandina E2 e favorecem o fechamento do canal arterial. A indometacina reduz a velocidade do fluxo sanguíneo renal, intestinal e cerebral. O Ibuprofeno tem efeito menor sobre a velocidade do fluxo de sangue nesses órgãos. Há um aumento significativo da creatinina sérica após a administração de indometacina, mas não após o ibuprofeno; por isso, recém-nascidos tratados com ibuprofeno têm maior depuração da creatinina. A oligúria ocorre mais frequentemente com a indometacina vs. ibuprofeno. A indometacina requer furosemida para a produção de urina mais frequentemente do que o ibuprofeno. O ibuprofeno reduz o risco de enterocolite necrotizante e de insuficiência renal transitória e é a droga de escolha para o fechamento do canal arterial patente. O ibuprofeno e a indometacina podem ser ministrados por via oral. Em conclusão, o ibuprofeno e a indometacina fecham o canal arterial patente com a mesma velocidade, mas a indometacina é mais tóxica.

Clinical pharmacology of gentamicin in neonates: regimen, toxicology and pharmacokinetics / Farmacologia clínica da gentamicina em neonatos: modalidades de uso, toxicologia e farmacocinética

Gentamicin is an aminoglycoside antibiotic. It kills bacteria by inhibiting protein synthesis and to some extent by lysing the cell envelope. Gentamicin is frequently the first choice drug because of its reliability, but also because of the long experience with its use. In combination with β-lactam antibiotics it is recommended for the treatment of sepsis or pneumonia and is active against P. aeruginosa, Enterobacter, Klebsiella and Serratia. However, gentamicin is ototoxic and nephrotoxic. The human mitochondrial genetic variant m.1555A > G has been reported to be an important cause of non-syndromic hereditary hearing dysfunction and may cause permanent hearing loss. Even short courses of gentamicin therapy in healty newborn infants can lead to abnormalities of auditory function. It is active against very resistant bacteria at peak concentrations (> 10 mg/l) that are high enough to be potentially toxic. For safe therapeutic efficacy, peak plasma concentrations of gentamicin should range from 4 to 10 mg/l; but trough concentrations, immediately before a new drug administration, must be lower that 2 mg/L to avoid toxic effects. Pharmacokinetic parameters vary considerably in infants. Half-life ranges from 5.4 to 10.0 hours, clearance 0.50 to 1.71 ml/h/kg and distribution volume from 0.4 to 0.7 l/kg. Preterm infants have a longer half-life than full-term infants. Thus, it is mandatory to monitor gentamicin serum concentrations whenever infants are treated for 48 hours or more.

A gentamicina é antibiótico do grupo dos aminoglicosídeos. Destrói bactérias por inibição de síntese proteica e, em certa medida, por lise do envelope celular. A gentamicina é a droga de primeira escolha por causa de sua atividade confiável e em virtude de longa experiência com seu uso. Em combinação com antibióticos β-lactâmicos é recomendada para o tratamento de septicemia ou pneumonia e é ativa contra P. aeruginosa, Enterobacter, Klebsiella e Serratia. No entanto, a gentamicina é ototóxica e nefrotóxica. A variante genética mitocondrial humana m.1555A > G é tida como importante causa de disfunção auditiva hereditária não-sindrômica e pode causar perda permanente da audição. Até mesmo procedimentos terapêuticos de gentamicina de curta duração em recém-nascidos sadios podem levar a anormalidades da função auditiva. É ativa contra algumas espécies de bactérias apenas em concentrações de pico (> 10 mg/l) que são suficientemente altas para produzirem efeitos tóxicos. A gentamicina deve cair a concentrações mínimas menores que 2 mg/l para evitar efeitos tóxicos. Para produzir efeitos terapêuticos, as concentrações plasmáticas máximas de gentamicina deve variar de 4 a 10 mg/l. Os parâmetros farmacocinéticos variam consideravelmente em lactentes. A meia-vida varia entre 5,4-10,0 horas, o "clearance" varia entre 0,50 e 1,71 ml/h/kg e volume de distribuição de 0,4-0,7 l/kg. Em prematuros a meia-vida é mais longa do que a de crianças nascidas a termo. Por esses motivos, sempre que lactentes são tratadas durante 48 horas ou mais, monitorizar as concentrações séricas de gentamicina é essencial.

Effects of surfactants on preterm infant lungs / Efeitos de surfactantes nos pulmões de recém-nascidos prematuros

Lack of surfactant is the commonest cause of death in preterm infants. Their lungs may contain as little as 10 mg/ kg of surfactant at birth, a tenth of the amount normally found at term. Surfactants (animal origin or synthetic) can reduce mortality by 40% in infants with less than 30 weeks of gestation. Poractant is the surfactant derived from minced porcine lungs, Beractant from minced bovine lungs. Bronchoalveolar lavage with diluted poractant is effective in mechanically ventilated term infants with severe acute respiratory distress syndrome due to meconium aspiration syndrome. Nebulized surfactant and mask airway surfactant do not require intubation. Alternatively, surfactant may be administered via a thin catheter during spontaneous breathing. In conclusion, surfactants reduce the mortality in preterm infants.

RESUMO A falta de surfactante é a causa mais comum de morte em recém-nascidos prematuros. Os pulmões podem conter apenas 10% da quantidade encontrada a termo. Surfactantes (de origem animal ou sintética) podem reduzir a mortalidade em até 40% em crianças com menos de 30 semanas de gestação. O poractante é o surfactante derivado de pulmões suínos, o beractante e o calfactante derivam de pulmões bovinos. A lavagem bronco-alveolar com poractante diluído é eficaz em crianças nascidas a termo e sob ventilação mecânica com síndrome da angústia respiratória aguda grave secund´ria a aspiração de mecônio. Surfactante por nebulização e máscara de vias aéreas não necessitam de intubação. Como alternativa, o surfactante pode ser administrado através de um cateter fino durante a respiração espontânea. Em conclusão, os surfactantes reduzem a mortalidade em recém-nascidos prematuros.

Clinical pharmacology of paracetamol in neonates: a review.

Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks' gestation, 45 mg/kg/d in preterm infants of 34 weeks' gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted.

Clinical pharmacology of methadone in neonates and in their mothers. A review / Farmacologia clínica da metadona em neonatos e suas mães: revisão

The outstanding properties of methadone are its analgesic activity, its efficacy by oral route, its extended duration of action in suppressing of withdrawal symptoms in physically dependent individuals, and its tendency to show persistent effects with repeated administration. The analgesic activity of methadone, a racemate, is almost entirely the result of its R-methadone content. Respiratory depression is the chief hazard associated with methadone, and its peak respiratory depressant effects typically occur later, and persist for longer than its peak analgesic effect, particularly in the early dosing period. Methadone undergoes extensive metabolism in the liver and the major metabolic pathway is N-demethylation by CYP3A4 and CYP2B6. There is a remarkable interindividual variability in the rate of methadone metabolism. Mothers with opioid addiction are often placed on methadone before delivery in an attempt to reduce illicit opioid usage. Methadone is useful because it can be taken orally, only requires one or two daily doses and has a long-lasting effect. Weaning should not be attempted during pregnancy and, because of increased clearance, the dose of methadone may need to be increased in the last 3 months of pregnancy. Significant positive correlations were found for umbilical cord methadone concentrations, methadone mean daily dose, mean dose during the third trimester, and methadone cumulative daily dose. In conclusion, umbilical cord methadone concentrations were correlated to methadone dose. A total of 55-94% of infants born to opioid-dependent mothers in US show signs of opioid withdrawal. Methadone is useful to avoid use of opioid illicit drugs.

As mais importantes propriedades da metadona são sua atividade analgésica, a sua eficácia por via oral, a sua prolongada acão supressora de sintomas de abstinência em indivíduos fisicamente dependentes e a persistência de seus efeitos com administração repetida. A actividade analgésica de metadona, um racemato, é quase inteiramente o resultado do seu teor de R-metadona. A depressão respiratória é o principal risco associado a seu uso, e o pico de depressão respiratória normalmente ocorre tardiamente e persiste após o fim de seu efeito analgésico especialmente durante as fases iniciais de seu uso terapêutico. A metadona é metabolizada no fígado e a principal via metabólica é a N-desmetilação por CYP3A4 e CYP2B6. Há uma variabilidade interindividual notável em relação à sua taxa de metabolisacão. Mães com dependência de opiáceos são frequentemente colocadas em terapêutica com metadona antes do parto, na tentativa de reduzir o uso de opiáceos ilícitos. A metadona é útil porque pode ser tomada por via oral, só precisa de uma ou duas doses diárias e tem efeito de longa duração. O desmame não deve ser executado durante a gravidez; por causa do aumento da depuração, a dose de metadona pode precisar ser aumentada nos últimos três meses de gravidez. Correlações positivas significativas foram encontradas para a metadona entre os seguintes parâmetros: concentrações no cordão umbilical, dose média diria, dose durante o terceiro trimestre, e dose diária média cumulativa. Em conclusão, as concentrações de cordão umbilical de metadona foram correlacionados com a dose de metadona. Entre 55% e 94% dos recém-nascidos de mães dependentes de opiáceos nos Estados Unidos mostram sinais de abstinência a opiáceos. A metadona é útil para evitar o uso de drogas ilícitas opióides.

Clinical pharmacology of fentanyl in preterm infants. A review.

Fentanyl is a synthetic opioid that is very important in anesthetic practice because of its relatively short time to peak analgesic effect and the rapid termination of action after small bolus doses. The objective of this survey is to review the clinical pharmacology of fentanyl in preterm infants. The bibliographic search was performed using PubMed and EMBASE databases as search engines. In addition, the books Neofax: A manual of drugs used in neonatal care and Neonatal formulary were consulted. Fentanyl is N-dealkylated by CYP3A4 into the inactive norfentanyl. Fentanyl may be administered as bolus doses or as a continuous infusion. In neonates, there is a remarkable interindividual variability in the kinetic parameters. In neonates, fentanyl half-life ranges from 317 minutes to 1266 minutes and in adults it is 222 minutes. Respiratory depression occurs when fentanyl doses are >5 µg/kg. Chest wall rigidity may occur in neonates and occasionally is associated with laryngospasm. Tolerance to fentanyl may develop after prolonged use of this drug. Significant withdrawal symptoms have been reported in infants treated with continuous infusion for 5 days or longer. Fentanyl is an extremely potent analgesic and is the opioid analgesic most frequently used in the neonatal intensive care unit.

Differential renal adverse effects of ibuprofen and indomethacin in preterm infants: a review.

OBJECTIVE: The objective of this study was to evaluate the extent of renal adverse effects caused by ibuprofen or indomethacin in order to choose the safer drug to administer to preterm infants. METHODS: THE FOLLOWING THREE PARAMETERS OF RENAL FUNCTION WERE TAKEN INTO CONSIDERATION: 1) the urine output; 2) the serum creatinine concentration; and 3) the frequency of oliguria. The bibliographic search was performed using PubMed and Embase databases as search engines. RESULTS: Urine output ranged from 3.5±1.2 to 4.0±1.4 mL/kg/h after ibuprofen treatment, and from 2.8±1.1 to 3.6±1.4 mL/kg/h after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) higher than those for indomethacin. The serum creatinine concentrations ranged from 0.98±0.24 to 1.48±0.2 mg/dL after ibuprofen treatment, and from 1.06±0.24 and 2.03±2.10 mg/dL after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) lower than those for indomethacin. The frequency of oliguria ranged from 1.0% to 9.6% (ibuprofen) and from 14.8% to 40.0% (indomethacin), and was significantly lower following ibuprofen than indomethacin administration. In infants with body weight lower than 1,000 g, oliguria appeared in 5% (ibuprofen) and 40% (indomethacin; P=0.02). CONCLUSION: Indomethacin is associated with more severe renal adverse effects than ibuprofen. Ibuprofen is less nephrotoxic than indomethacin and should be used to treat patent ductus arteriosus in preterm infants. Immaturity increases the frequency of adverse effects of indomethacin.

Clinical pharmacology of ibuprofen and indomethacin in preterm infants with patent ductus arteriosus.

BACKGROUND: Ibuprofen and indomethacin are potent non-selective cyclo-oxygenase inhibitors and inhibit prostaglandin E2 synthesis. The patent ductus arteriosus (PDA) occurs in more than 70% of preterm infants weighing <1500 g. Prostaglandin E2 relaxes smooth muscle, tends to inhibit the closure of PDA, yields vasodilatation of the afferent renal arterioles and maintains glomerular filtration rate (GFR). Ibuprofen and indomethacin inhibiting prostaglandin E2 synthesis close PDA and reduce GFR with consequent decrease of urine output and increase of serum creatinine concentrations. AIMS: The aims of this study are to give the definitive estimates of PDA closure rate following ibuprofen or indomethacin treatment and to evaluate the extent of renal side effects following the administration of these drugs to preterm infants. Other aims are to review the metabolism and the pharmacokinetics of ibuprofen and indomethacin in preterm infants with PDA. METHODS: The bibliographic search was performed using PubMed and EMBASE databases as search engines, January 2013 was the cutoff point. RESULTS: The %PDA closed by ibuprofen (n=24) and indomethacin (n=24) is 77.7±14.1 and 77.3±11.0, respectively. For ibuprofen, the gestational age of the infants included in the study ranged from 25.0 to 39.0 weeks (mean±SD=29.3±3.1 weeks). The %PDA did not correlate with the gestational age (p=0.2516). For indomethacin, the gestational age of infants included in the study ranged from 25.0 and 39.0 weeks (mean±SD=29.4±2.9 weeks). The %PDA did not correlate with the gestational age (p=0.3742). The treatment with ibuprofen reduces the urine output and increases the serum creatinine concentrations less extensively than indomethacin. The half-life (t1/2) of ibuprofen and indomethacin is lengthened and the clearance is reduced in preterm infants as compared with fullterm infants. CONCLUSIONS: Ibuprofen and indomethacin are equally effective in closing PDA. Treatment with ibuprofen decreases the risk of renal failure. Ibuprofen has the most favourable risk/benefit ratio. The rate of metabolism is reduced and t1/2 is lengthened in prematures as compared with term infants.

Clinical pharmacology of midazolam in neonates and children: effect of disease-a review.

Midazolam is a benzodiazepine with rapid onset of action and short duration of effect. In healthy neonates the half-life (t 1/2) and the clearance (Cl) are 3.3-fold longer and 3.7-fold smaller, respectively, than in adults. The volume of distribution (Vd) is 1.1 L/kg both in neonates and adults. Midazolam is hydroxylated by CYP3A4 and CYP3A5; the activities of these enzymes surge in the liver in the first weeks of life and thus the metabolic rate of midazolam is lower in neonates than in adults. Midazolam acts as a sedative, as an antiepileptic, for those infants who are refractory to standard antiepileptic therapy, and as an anaesthetic. Information of midazolam as an anaesthetic in infants are very little. Midazolam is usually administered intravenously; when minimal sedation is required, intranasal administration of midazolam is employed. Disease affects the pharmacokinetics of midazolam in neonates; multiple organ failure reduces the Cl of midazolam and mechanical ventilation prolongs the t 1/2 of this drug. ECMO therapy increases t 1/2, Cl, and Vd of midazolam several times. The adverse effects of midazolam in neonates are scarce: pain, tenderness, and thrombophlebitis may occur. Respiratory depression and hypotension appear in a limited percentage of infants following intravenous infusion of midazolam. In conclusion, midazolam is a safe and effective drug which is employed as a sedative, as antiepileptic agent, for infants who are refractory to standard antiepileptic therapy, and as an anaesthetic.

Clinical pharmacology of theophylline in preterm infants: effects, metabolism and pharmacokinetics.

Recurrent apnea is common in preterm infants with consequent episodes of loss of effective breathing and the bronchodilator theophylline prevents apnea and reduces the number of apneic attacks. This drug also reduces hypoxaemic episodes. Theophylline acts on the lungs, kidneys and brain. Theophylline inhibits solute reabsorption in various segments of the nephron and a marked diuresis which occurs immediately after the administration of theophylline. This drug ameliorates kidney dysfunction and prophylaxis given early after birth, preventing vasomotor nephropathy. Theophylline reduces brain activity and reduces the spontaneous activity transients and alters the sleep-wake state in pre-term infants. Theophylline is extensively metabolized in premature infants and its major metabolic product is caffeine. The demethylation pathway occurring predominantly in adults is substituted by N-methylation to caffeine in premature infants. The halflife of theophylline is 5-fold longer in neonates than in adults and reaches the adult value at the age of 55 weeks. Theophylline may be administered trans-cutaneously by applying this drug to the back or abdomen of the infants and the mean fractional absorbance at 30 hours is 0.25. Theophylline is present in saliva and the concentration of this drug in saliva is similar to that in plasma, saliva may be used to monitor theophylline concentration. In conclusion, theophylline is a useful drug to treat apnea and ameliorate kidney dysfunction.

Clinical pharmacology of carbapenems in neonates.

Carbapenems are an effective tool to treat complicated bacterial infections. This review aims to summarize the available information on carbapenems in neonates to guide clinicians on drug choice and indications in neonates. Moreover, identification of knowledge gaps may stimulate researchers to design studies to further improve pharmacotherapy in neonates. To do so, a bibliographic search [infant/newborn and meropenem, imipenem, panipenem, ertapenem, doripenem or imipenem] was performed (PubMed, EMBASE) and public clinical trial registries (clinicaltrials.gov, EU registry) were searched to summarize the available information. Carbapenem clearance in neonates is low. Variability relates to maturation (weight, age) and renal function (creatinine clearance), while observations in neonates with renal failure are absent. Pharmacodynamics are almost exclusively limited to meropenem, and the available information will further increase (NeoMero-1-2, necrotizing enterocolitis, meningitis). Finally, there are also some ongoing doripenem pharmacokinetics (PK) studies in neonates. It was concluded that observations on carbapenems in neonates are limited, but studies (NeoMero, doripenem) are ongoing. Until this information becomes available, off label prescription of meropenem seems to be the most reasonable choice when a carbapenem is appropriate. Knowledge gaps relate to PK in neonates with renal failure and to the potential benefit of prolonged compared to short duration of infusion.

Clinical pharmacology of furosemide in neonates: a review.

Furosemide is the diuretic most used in newborn infants. It blocks the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na+ and Cl-. This article aimed to review the published data on the clinical pharmacology of furosemide in neonates to provide a critical, comprehensive, authoritative and, updated survey on the metabolism, pharmacokinetics, pharmacodynamics and side-effects of furosemide in neonates. The bibliographic search was performed using PubMed and EMBASE databases as search engines; January 2013 was the cutoff point. Furosemide half-life (t1/2) is 6 to 20-fold longer, clearance (Cl) is 1.2 to 14-fold smaller and volume of distribution (Vd) is 1.3 to 6-fold larger than the adult values. t1/2 shortens and Cl increases as the neonatal maturation proceeds. Continuous intravenous infusion of furosemide yields more controlled diuresis than the intermittent intravenous infusion. Furosemide may be administered by inhalation to infants with chronic lung disease to improve pulmonary mechanics. Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus arteriosus, and the administration of furosemide to any preterm infants should be carefully weighed against the risk of precipitation of a symptomatic patent ductus arteriosus. Infants with low birthweight treated with chronic furosemide are at risk for the development of intra-renal calcifications.

Clinical pharmacology of indomethacin in preterm infants: implications in patent ductus arteriosus closure.

Indomethacin is a non-steroidal anti-inflammatory drug that is a potent inhibitor of prostaglandin E(2) synthesis. After birth, the ductus arteriosus closes spontaneously within 2-4 days in term infants. The major factor closing the ductus arteriosus is the tension of oxygen, which increases significantly after birth. Prostaglandin E(2) has the opposite effect to that of oxygen; it relaxes smooth muscle and tends to inhibit the closure of the ductus arteriosus. In preterm infants with respiratory distress syndrome, the ductus arteriosus fails to close (patent ductus arteriosus [PDA]) because the concentration of prostaglandin E2 is relatively high. PDA occurs in more than 70 % of neonates weighing less than 1,500 g at birth. The aim of this article was to review the published data on the clinical pharmacology of indomethacin in preterm infants in order to provide a critical analysis of the literature and a useful tool for physicians. The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines and February 2012 was the cutoff point. A remarkable interindividual variability was observed for the half-life (t(½)), clearance (CL), and volume of distribution (V(d)) of indomethacin. Prophylactic indomethacin consists of a continuous infusion of low levels of indomethacin and may be useful in preterm infants. Extremely preterm infants are less likely to respond to indomethacin. Infants with a postnatal age of 2 months do not respond to treatment with indomethacin. Indomethacin has several adverse effects, the most common of which is renal failure. An increase in serum creatinine of ≥0.5 % mg/dL after indomethacin was observed in about 10-15 % of the patients and creatinine returns to a normal level about 1 week after cessation of therapy. Indomethacin should be administered intravenously by syringe pump for at least 30 min to minimize adverse effects on cerebral, gastrointestinal, and renal blood flow velocities. A prolonged course of indomethacin appears to reduce the risk of severe intracranial hemorrhage and renal impairment in patients with PDA. In conclusion, indomethacin is a useful drug to treat PDA.

Clinical pharmacokinetics of vancomycin in the neonate: a review.

Neonatal sepsis is common and is a major cause of morbidity and mortality. Vancomycin is the preferred treatment of several neonatal staphylococcal infections. The aim of this study was to review published data on vancomycin pharmacokinetics in neonates and to provide a critical analysis of the literature. A bibliographic search was performed using PubMed and Embase, and articles with a publication date of August 2011 or earlier were included in the analysis. Vancomycin pharmacokinetic estimates, which are different in neonates compared with adults, also exhibit extensive inter-neonatal variability. In neonates, several vancomycin dosing schedules have been proposed, mainly based on age (i.e., postmenstrual and postnatal), body weight or serum creatinine level. Other covariates [e.g., extracorporeal membrane oxygenation (ECMO), indomethacin or ibuprofen, and growth restriction] of vancomycin pharmacokinetics have been reported in neonates. Finally, vancomycin penetrates cerebrospinal fluid (range = 7-42%). Renal function drives vancomycin pharmacokinetics. Because either age or weight is the most relevant covariate of renal maturation, these covariates should be considered first in neonatal vancomycin dosing guidelines and further adjusted by renal dysfunction indicators (e.g., ECMO and ibuprofen/indomethacin). In addition to the prospective validation of available dosing guidelines, future studies should focus on the relevance of therapeutic drug monitoring and on the value of continuous vancomycin administration in neonates.

Clinical pharmacokinetics of vancomycin in the neonate: a review

Neonatal sepsis is common and is a major cause of morbidity and mortality. Vancomycin is the preferred treatment of several neonatal staphylococcal infections. The aim of this study was to review published data on vancomycin pharmacokinetics in neonates and to provide a critical analysis of the literature. A bibliographic search was performed using PubMed and Embase, and articles with a publication date of August 2011 or earlier were included in the analysis. Vancomycin pharmacokinetic estimates, which are different in neonates compared with adults, also exhibit extensive inter-neonatal variability. In neonates, several vancomycin dosing schedules have been proposed, mainly based on age (i.e., postmenstrual and postnatal), body weight or serum creatinine level. Other covariates [e.g., extracorporeal membrane oxygenation (ECMO), indomethacin or ibuprofen, and growth restriction] of vancomycin pharmacokinetics have been reported in neonates. Finally, vancomycin penetrates cerebrospinal fluid (range = 7-42%). Renal function drives vancomycin pharmacokinetics. Because either age or weight is the most relevant covariate of renal maturation, these covariates should be considered first in neonatal vancomycin dosing guidelines and further adjusted by renal dysfunction indicators (e.g., ECMO and ibuprofen/indomethacin). In addition to the prospective validation of available dosing guidelines, future studies should focus on the relevance of therapeutic drug monitoring and on the value of continuous vancomycin administration in neonates.

Clinical pharmacology of the loop diuretics furosemide and bumetanide in neonates and infants.

The loop diuretics furosemide and bumetanide are used widely for the management of fluid overload in both acute and chronic disease states. To date, most pharmacokinetic studies in neonates have been conducted with furosemide and little is known about bumetanide. The aim of this article was to review the published data on the pharmacology of furosemide and bumetanide in neonates and infants in order to provide a critical analysis of the literature, and a useful tool for physicians. The bibliographic search was performed electronically using PubMed and EMBASE databases as search engines and March 2011 was the cutoff point. The half-life (t(½)) of both furosemide and bumetanide is considerably longer in neonates than in adults and consequently the clearance (CL) of these drugs is reduced at birth. In healthy volunteers, plasma t(½) of furosemide ranges from 33 to 100 minutes, whereas in neonates it ranges from 8 to 27 hours. The volume of distribution (V(d)) of furosemide undergoes little variation during neonate maturation. The dose of furosemide, administered by intermittent intravenous infusion, is 1 mg/kg and may increase to a maximum of 2 mg/kg every 24 hours in premature infants and every 12 hours in full-term infants. Comparison of continuous infusion versus intermittent infusion of furosemide showed that the diuresis is more controlled with fewer hemodynamic and electrolytic variations during continuous infusion. The appropriate infusion rate of furosemide ranges from 0.1 to 0.2 mg/kg/h and when the diuresis is <1 mL/kg/h the infusion rate may be increased to 0.4 mg/kg/h. Treatment with theophylline before administration of furosemide results in a significant increase of urine flow rate. Bumetanide is more potent than furosemide and its dose after intermittent intravenous infusion ranges from 0.005 to 0.1 mg/kg every 24 hours. The t(½) of bumetanide in neonates ranges from 1.74 to 7.0 hours. Up to now, no data are available on the continuous infusion of bumetanide. Extracorporeal membrane oxygenation (ECMO) is used for a variety of indications including sepsis, persistent pulmonary hypertension, meconium aspiration syndrome, cardiac defects and congenital diaphragmatic hernia. There are two studies of furosemide in neonates undergoing ECMO and only one on the pharmacokinetics of bumetanide under ECMO. When ECMO was conducted for 72 hours, the total amount of furosemide administered was 7.0 mg/kg, and the urine production in the 3 days of treatment was about 6 mL/kg/h, which is the target value. The t(½) of bumetanide in neonates during ECMO was extremely variable. CL, t(½), and V(d) were 0.63 mL/min/kg, 13.2 hours, and 0.45 L/kg, respectively. Furosemide may be administered by inhalation and inhibits the bronco-constrictive effect of exercise, cold air ventilation and antigen challenge. However, inhaled furosemide is not active in infants with viral bronchiolitis and its effect on broncho-pulmonary dysplasia is still uncertain. Furosemide does not significantly increase the risk of failure of patent ductus arteriosus closure when indomethacin or ibuprofen have been co-administered. Infants with low birth weight treated long-term with furosemide are at risk for the development of intra-renal calcification. Furosemide therapy above 10 mg/kg bodyweight cumulative dose had a 48-fold increased risk of nephrocalcinosis. The use of furosemide in combination with indomethacin increased the incidence of acute renal failure. The maturation of the kidney governs the pharmacokinetics of furosemide and bumetanide in the infant. CL and t(½) are influenced by development, and this must be taken into consideration when planning a dosage regimen with these drugs.

Pharmacokinetics of cephalosporins in the neonate: a review.

The aim of this work was to review the published data on the pharmacokinetics of cephalosporins in neonates to provide a critical analysis of the literature as a useful tool for physicians. The bibliographic search was performed for articles published up to December 3, 2010, using PubMed. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum was consulted. The cephalosporins are mainly eliminated by the kidneys, and their elimination rates are reduced at birth. As a consequence, clearance is reduced and t1/2 is more prolonged in the neonate than in more mature infants. The neonate's substantial body water content creates a large volume of distribution (Vd) of cephalosporins, as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, the clearance of cephalosporins increases. The maturation of the kidney governs the pharmacokinetics of cephalosporins in the infant. Clearance and t1/2 are influenced by development, and this must be taken into consideration when planning a cephalosporin dosage regimen for the neonate.