Sedation and analgesia in neonatology

Abstracts

JUSTIFICATIVA E OBJETIVOS: A importância do estudo da dor em Neonatologia se deve ao fato de que a sensação de dor e estresse significa sofrimento e desconforto para os recém-nascidos e, apesar desse conhecimento, pouco tem sido feito para minimizá-los. Nessa revisão foram discutidas: a prevenção da dor, as medidas não-farmacológicas e farmacológicas para o seu tratamento e a sedação em recém-nascidos. CONTEÚDO: Várias são as medidas não-farmacológicas que podem ser tomadas com intuito de prevenir a dor nas Unidades de Terapia Intensiva Neonatal e também para tornar o ambiente mais humanizado e menos estressante para os pacientes e seus familiares. O tratamento da dor no recém-nascido consiste em medidas não-farmacológicas (sucção não-nutritiva, glicose) e farmacológicas (analgésicos não-opióides, opióides e anestésicos locais). A sedação em recém-nascidos é produzida por fármacos que agem diminuindo a atividade, a ansiedade e a agitação do paciente, podendo levar à amnésia de eventos dolorosos ou não-dolorosos. A sedação pode ser feita pela administração de hidrato de cloral, barbitúricos, propofol e benzodiazepínicos. CONCLUSÕES: A prevenção da dor e a indicação de analgesia devem ser individualizadas e sempre consideradas em todos os recém-nascidos portadores de doenças potencialmente dolorosas e/ou submetidos a procedimentos invasivos, cirúrgicos ou não.

ANALGÉSICOS, Opióides; ANALGÉSICOS, Não-opióides; ANESTÉSICOS; DOR, Tratamento; SEDAÇÃO

REVIEW ARTICLE

Sedation and analgesia in neonatology^*

Sedación y analgesia en neonatología

Yerkes Pereira e Silva^I; Renato Santiago Gomez, TSA^II; Thadeu Alves Máximo^III; Ana Cristina Simões e Silva^IV

^IAnestesiologista e Neonatologista do Hospital Life Center, Belo Horizonte, MG

^IIProfessor Adjunto do Departamento de Cirurgia da FM/UFMG

^IIIAluno de Graduação da FM/UFMG

^IVProfessora Adjunto do Departamento de Pediatria da FM/UFMG

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: The study of pain in neonatology is important because pain and stress mean suffering and discomfort for newborns and, despite it, very little has been done to minimize them. In this revision we discuss: prevention of pain, non-pharmacological and pharmacological treatment, and sedation in newborns.

CONTENTS: Several non-pharmacological measures can be taken to prevent pain in Neonatal Intensive Care Units, and to humanize and reduce the stress on the environment for patients and their families. Pain treatment in the newborn consists of non-pharmacological (non-nutritive suckling, glucose) and pharmacological (non-opioid analgesics, opioids, and local anesthetics) measures. Sedation in the newborn is achieved with drugs that decrease activity, anxiety, and agitation of the patient, and that could lead to amnesia of painful and non-painful events. Sedation can be accomplished with chloral hydrate, barbiturates, propofol, and benzodiazepines.

CONCLUSIONS: Prevention of pain and the indication of analgesia should be individualized and always considered in every newborn with potentially painful disorders and/or undergoing invasive procedures, surgical or not.

Key Words: ANALGESICS, Opioids: morphine, fentanyl, sufentanil, alfentanil, remifentanil; ANALGESICS: Non-opioids: paracetamol, dipyrone, indomethacin; ANESTHETICS: Local; PAIN, Treatment: non-pharmacologic, pharmacologic; SEDATION: newborn.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La importancia del estudio del dolor en neonatología se debe al hecho de que la sensación de dolor y de estrés significa sufrimiento e incomodidad para los recién nacidos y, a pesar de ese conocimiento poco se ha hecho para reducirlo. Dentro de esa revisión se discutieron: la prevención del dolor, las medidas no farmacológicas ye farmacológicas para su tratamiento y la sedación en recién nacidos.

CONTENIDO: Varias son las medidas no-farmacológicas que pueden ser tomadas con el objetivo de prevenir el dolor en Unidades de Terapia Intensiva Neonatal y también para hacer el ambiente más humanizado y menos estresante para los pacientes y sus familiares. El tratamiento del dolor en el recién nacido consiste en medidas no farmacológicas (succión no nutritiva, glicosis) y farmacológicas (analgésicos no-opioides, opioides y anestésicos locales). La sedación en recién nacidos es producida por fármacos que actúan disminuyendo la actividad, la ansiedad y la agitación del paciente, pudiendo conllevar a la amnesia de eventos dolorosos o no dolorosos. La sedación puede ser hecha a través del uso de hidrato de cloral, barbitúricos, propofol y benzodiazepínicos.

CONCLUSIONES: La prevención del dolor y la indicación de analgesia deben ser individualizadas y siempre consideradas en todos los recién nacidos portadores de enfermedades potencialmente dolorosas y/o sometidos a procedimientos invasivos, quirúrgicos o no.

INTRODUCTION

Pain relief and the comfort of the patient are basic missions of the physician, involving ethical and humanitarian issues of the medical practice. Therefore, pain in the newborn should also be recognized and treated ^1,2. The importance of the study of pain in neonatology derives from the fact that pain and stress mean suffering and discomfort for newborns and, despite of this, very little has been done to minimize them ³.

The indication of analgesia should be individualized and always considered in every newborn with potentially painful disorders and/or undergoing invasive procedures, surgical or not. Currently, there is a consensus about the importance of pain control in the newborn. However, several studies have indicated that physicians and nurses are usually incapable of identifying and treat pain in newborns and infants, who do not complaint verbally ^4-7. Thus, the lack of verbalization is one of the greatest obstacles for the diagnosis and proper treatment of pain in newborns in the intensive care unit ¹.

In 2001, the specialists in the area defined some general principles of sedation and analgesia in newborns ⁸: a) pain in the newborn is usually not recognized and, therefore, is undertreated, due to the incapacity of the children to verbalize it; b) if a procedure is painful in adults, it should be considered painful in newborns and premature neonates; c) compared with older children and adults, newborns, especially premature neonates, may have greater sensitivity to pain and may be more susceptible to the long-term effects of nociceptive stimulation; d) proper treatment of pain in newborns is associated with a reduction in morbidity and mortality; e) the appropriate use of environmental, behavioral, and pharmacological interventions can prevent, reduce, or eliminate pain in the newborn in many clinical situations; f) sedation does not offer pain relief, and may mask the response of the newborn to the painful stimulus; and g) health care professionals are responsible for evaluating, preventing, and managing pain in the newborn.

PREVENTION OF PAIN IN THE NEWBORN

Several behavioral measures (non-pharmacological) may be undertaken to prevent pain in the Neonatal Intensive Care Unit and to make the environment more humane and less stressful for patients and their families, such as: control the incidence of strong lights on the newborn; reduce the noise around the baby (alarms and conversation); rationalize patient handling (preserving free periods for sleep and avoiding several blood drawings, which should be made as a set), using protocols for minimal handling; stimulate the use of central catheters; decrease the amount of tape on the skin; adequate positioning of the tracheal tube, avoiding traction or unnecessary movement; care with monitoring devices (observe the adaptation of the blood pressure cuff, reducing the number of measuring intervals; electrocardiogram electrodes, and pulse oximetry sensors, alternating them); and, whenever possible, to promote skin contact between the newborn and its parents ^9,10.

TREATMENT OF PAIN IN THE NEWBORN

Non-Pharmacological Treatment

Use of Non-Nutritive Suckling

It can be used in small procedures. Although there are controversies on the use of pacifiers in neonatal units due to the possible association with decreased stimulation to maternal breastfeeding, non-nutritive suckling in premature neonates that are intensively handled seems to be of great value in the neurological and emotional organization of the newborn after the aggressor stimulus, decreasing physiological and behavioral repercussions ^1,10. Thus, it is believed that its use should be selectively stimulated in specific populations of neonates. It constitutes an adjuvant measure in pain treatment in the newborn, and it seems that it does not have intrinsic analgesic properties ¹¹.

Glucose Solution

In the past few years the use of water with sugar as analgesic has been discussed ¹². It has been demonstrate, in animal models, that the analgesic effect of glucose can be reversed by opioid antagonists, suggesting a mechanism of action involving the release of endorphins ¹³. The revision of the Cochrane Group ¹⁴ shows a significant reduction in pain indicators when glucose was used as an analgesic for blood drawing in premature and term newborns. The most consistent effect is the reduction in the total time of crying. Few studies consider adverse effects, emphasizing that they are minimal and include a temporary reduction in hemoglobin saturation. A consensus on the adequate dose of glucose to be used (0.012 to 0.12 g) is lacking, and it seems that repeated doses are more effective than a single dose. Besides, there seems to be a synergism between the use of pacifiers (non-nutritive suckling) and glucose ¹⁵. Therefore, it is possible to recommend the clinical use of oral glucose solutions one to two minutes before small procedures, such as capillary, venous, or arterial punctures.

Pharmacological Treatment

Non-Opioid Analgesics

Non-steroidal anti-inflammatories (NSAIDs) are the main group of drugs. They inhibit the cyclooxigenase, decreasing the synthesis of prostaglandins and, consequently, the inflammatory process ¹⁶. They are indicated in the treatment of mild pain, as adjuvant in the treatment of moderate and severe pain, or when pain is associated with an inflammatory process.

Paracetamol

Paracetamol is a safe drug to be used in neonates. It has a slow onset of analgesia, approximately one hour, having little efficacy in severe pain ¹. The doses recommended in neonatology are 10 to 15 mg.kg^-1 in newborns at term and 10 mg. kg^-1 in premature neonates, every 6 hours, and should not exceed 5 doses a day ¹. It should be administered orally, since intravenous paracetamol is not available in Brazil. It is indicated in the treatment of mild to moderate pain, it is useful as an adjuvant in postoperative analgesia in newborns because it does not interfere with platelet aggregation and does not cause gastric irritation ¹⁷. It has low hepatotoxicity in newborns, since enzymatic liver pathways responsible for the production of the toxic metabolite are immature. This drug is contra-indicated in newborns with deficiency of glucose-6-phosphate dehydrogenase ¹.

Dypirone

Due to the lack of clinical and pharmacological studies that validate its use, the drug is not recommended in this age group ¹. However, the large experience with its use in Brazil has demonstrated its safety and analgesic and antipyretic efficacy, including in the neonatal period, without an increased incidence of proven side effects ¹⁰. The dose recommended is 10 to 15 mg.kg^-1 every 6 hours, and it can be administered orally or intravenously ¹⁰.

Indomethacin

Its use is indicated in newborns for the treatment of patent ductus arteriosus, but there are no studies that justify its use as analgesic in the neonatal period ¹⁶.

Opioid Analgesics

They constitute the most important weapon for the treatment of pain in severely ill newborns. Opioid analgesics bind the three major groups of membrane receptors in the spinal cord and cortex: µ, k, and d. Stimulation of the receptors inhibits the transmission of the nociceptive stimulus to upper processing centers. Opioids inhibit afferent pain in the spinal cord and activate descending inhibitory pathways. Due to their action in other opioid receptors, they can cause respiratory depression, sedation, ileus, urinary retention, nausea, vomiting, and physical dependence ^18,19. The oral route is easier to use and provides constant serum levels, but it is not appropriate for severely ill patients or after large surgeries. In this case, the intravenous route should be used, preferentially in continuous infusion to avoid fluctuations in serum levels. Intramuscular administration should be avoided because it causes pain, but their administration can also be transdermal, transmucous, rectal, subcutaneous, intrathecal, and epidural ¹.

Morphine

Morphine is the standard among µ-receptors antagonists, it is a potent analgesic and sedative, and has a low cost ¹⁸. It has an onset of action of 3 to 5 minutes and T_1/2Ke0 (equilibrium half-life between the plasma and its site of action brain) of 30 minutes ²⁰. Pharmacokinetics studies after a bolus dose showed that, in premature neonates, younger than and older than 30 weeks of gestation, the elimination half-life is greater and more premature patients have reduced depuration, although both groups presented important individual variations ²¹. Evaluating the elimination half-life, depuration, and metabolism of morphine in newborns with 24 to 40 weeks, from the first to the 60^th day of life, a wide variation in pharmacokinetic parameters was noted, but the half-life tends to decrease and depuration to increase with increased gestational age ^21,22. All newborns excreted more than 20% of non-metabolized morphine and one third of them did not metabolized morphine in its primary metabolites ²². Considering the use of morphine in continuous infusion in newborns, pharmacokinetic studies also demonstrated an increase in clearance and elimination half-life when compared with adults ²³. The increase in morphine clearance in the first six months of life is due to an increase in glucuronidation rather than in changes in protein binding or percentage of sulfatation. Thus, the plasma concentration of morphine is twice to three times greater in newborns at term and four times greater in premature neonates than in older children. Besides, its plasma level tends to increase, even after it is discontinued, due to the enterohepatic recirculation ²⁴.

Very few researchers tried to characterize the minimum concentration of morphine necessary for analgesia in newborns. Chay et al. demonstrated that a concentration of morphine of 125 ng.mL^-1 was necessary to produce adequate sedation in 50% of newborns studied (at term and premature) ²⁵. Since concentrations of 4 to 65 ng.mL^-1 are considered analgesic in older children, an explanation for the discrepancy in the increased need of morphine in the neonatal period include low concentration of the metabolite morphine-6-glucuronide (M6G) produced and the immaturity of the opioid receptor system (reduction in receptor concentration and/or affinity for the receptors) in the brain of newborns¹⁸. Besides the collateral effects common to all opioids (respiratory depression, nausea, vomiting, and urinary retention), morphine triggers the release of histamine, and can cause bronchospasm in newborns with chronic pulmonary disease. The release of histamine and the inhibition of the adrenergic tone could lead to hypotension, especially in hypovolemic newborns. Tolerance and withdrawal syndrome could be present, depending on the duration of morphine use and the strategy used to discontinue the drug ¹⁸.

The recommended doses for the neonatal period are ¹:

–

intermittent intravenous administration of 0.05 to 0.20 mg.kg^-1 per dose up to every 4 hours.

–

continuous administration for newborns at term of 5 to 20 µg.kg^-1.h^-1 and 2 to 10 µg.kg^-1.h^-1 in premature neonates.

Fentanyl

Fentanyl is commonly used in neonatology for its capacity of providing fast analgesia with hemodynamic stability ¹⁶. It has faster onset of action and shorter duration (less than 2 hours) than morphine, its T_1/2Ke0 is 6.4 min, and a context sensitive half-life of 260 min after four hours of infusion ^20,23. It is redistributed from the opioid receptors to other tissues, such as muscles, stomach, and adipose tissue. Thus, transitory increases in plasma concentration can occur due to the redistribution of the drug from those tissues. It has a large hepatic metabolism and its clearance depends, primarily, on the liver blood flow ¹⁸. Its pharmacokinetics can be altered in the presence of increased intra-abdominal pressure because of decreased hepatic blood flow and cardiac output, allowing its accumulation in areas of poor perfusion and posterior recirculation ²⁴. Fast administration of high doses (above 5 µg.kg^-1) could cause muscle rigidity, especially in the thorax, hindering ventilation and inducing laryngeal spasm in newborns ²⁶. The recommended doses for the neonatal period are ¹⁰:

–

intermittent intravenous administration of 1 to 4 µg.kg^-1 every 2 to 4 hours.

–

continuous intravenous administration in newborns at term of 0.5 to 3 µg.kg^-1.h^-1 and 0.5 to 2 µg.kg^-1.h^-1 in premature neonates. The downside of the continuous infusion is the fast development of tolerance with the need of increasing doses to achieve the desired analgesia¹.

Sufentanil

Sufentanil is a synthetic opioid, potent agonist of m receptors, with a short half-life. It has a context sensitive half-life after four hours of infusion of 30 minutes, an elimination half-life of 2.2 to 4.6 hours, and a plasma-cerebral balance of 6.2 minutes ²³. Sufentanil is highly bound to alpha-1 acid glycoprotein, and its binding depends on the serum level of this protein. And since the plasma concentration of this protein is reduced in newborns, the levels of free drug are significantly higher in those patients than in older children ²⁷. Pharmacokinetic studies demonstrated results similar to fentanyl, with decreased clearance and increased elimination half-life in premature neonates when compared with newborns at term and older children ²⁴. It is recommended the administration of 0.5 to 1.5 µg.kg^-1 per dose. Fast administration could lead to thoracic rigidity, vomiting, and seizures ¹⁰.

Alfentanil

It is a synthetic opioid derived from fentanyl, with one fourth of its potency. The onset of action after venous infusion is immediate, and the peak occurs in one minute, with T_1/2Ke0 of 0.9 to 1.4 minutes ^20,23. It has a context sensitive half-life after four hours of infusion of 60 minutes, and the duration of action is approximately one third of that of fentanyl ^20,23. In general, the clearance of alfentanil is decreased in newborns and its half-life is prolonged ^18,20. The volume of distribution might be increased due to the greater percentage of body water and/or reduction in binding to proteins ^18,20.

Remifentanil

A synthetic opioid, agonist of µ receptors, it has the same potency as fentanyl. It has all the pharmacodynamic properties of its class (analgesia, hemodynamic stability, respiratory depression, and muscle rigidity); however, its pharmacokinetic profile is unique, due to the ester structure that makes it susceptible to the fast metabolism by non-specific plasma and tissue esterases, which is responsible for its ultra-short action ²⁸. It has a context sensitive half-life after four hours of infusion of four minutes, making the end of its action independent of the duration of infusion ²³. Thus, the recovery from the effects of remifentanil is fast (within 5 to 10 minutes), and a fix concentration level is achieved five to 10minutes after a change in the speed of infusion. It is estimated that 99.8% of remifentanil is eliminated during the distribution (0.9 minute) and elimination (6.3 minutes) half-lives. Therefore, unlike other fentanyl analogues, the duration of action of remifentanil does not increase with prolonged administration ²³. Besides, its pharmacokinetics does not change in the presence of liver or renal failure, unless the metabolism by non-specific esterases is not preserved ²⁹. The pharmacodynamic effects follow closely blood concentrations, allowing the direct correlation among dose, blood levels, and response ^30,31. Hemodynamic (hypotension and bradycardia), and respiratory (respiratory depression) changes; and muscular rigidity related to the dose and rate of infusion of a bolus dose might occur. On the other hand, histamine release is not seen with conventional doses ²³.

Samartino et al. evaluated the efficacy and safety of the continuous intravenous use of remifentanil in premature neonates undergoing laser therapy for the treatment of retinopathy of prematurity. Fast recovery and the return to preoperative status, associated with the absence of side effects and the excellent levels of analgesia and anesthesia, confirmed the efficacy and safety of the continuous administration of remifentanil in premature neonates, reinforcing the choice for this opioid ³².

The doses vary according to the objective ²³ and, in newborns, the initial dose varies from 1 to 3 µg.kg^-1 for a bolus and 0.1 to 5 µg.kg^-1.h^-1 for continuous infusion ³³.

Other Opioids

Tramadol and codeine are used for the treatment of moderate pain. Tramadol has 1/10 of the potency of morphine and its mechanism of action includes characteristics of opioids and non-opioids. It stimulates the release of serotonin from nerve endings and inhibits re-uptake of both serotonin and noradrenaline ³⁴. It causes little respiratory depression and constipation, besides having a lower potential to develop tolerance and to cause addiction ³⁴. Despite the potential advantages of its use, studies with this drug in children are rare and for this reason, its use in neonatology is limited. On the other hand, the use of meperidine for the treatment of pain is practically proscribed, mainly due to the formation of toxic metabolites (normeperidine) that can decrease the seizure threshold ¹⁰.

Local Anesthetics

EMLA^® (an eutectic mixture of lidocaine and prilocaine) produces anesthesia on the skin, is safe to be used in newborns when applied isolatedly in one procedure, being effective in reducing the pain caused by circumcision, and arterial, venous, and lumbar punctures ³⁵. Its disadvantages include the latency of approximately 60 minutes; vasoconstriction, which hinders venous puncture; and the risk of methemoglobinemia ³⁵. ELA-Max cream is also a topic local anesthetic, but it has an onset of action of 30 minutes. It causes less vasoconstriction than EMLA ³⁶.

Infiltration of a local anesthetic (lidocaine) is indicated in lumbar punctures, introduction of central catheters, thoracic drainage and, eventually, in arterial punctures. The onset of action is almost immediate and lasts from 30 to 60 minutes. The maximal dose of 5 mg.kg^{-1 10} should always be observed.

SEDATION IN THE NEWBORN

Sedation in the newborn is accomplished with drugs that decrease activity, anxiety, and agitation of the patient, and could lead to amnesia of painful and non-painful events ¹. However, those drugs usually do not reduce pain and, on the contrary, could potentiate it, although some opioids, like morphine, can also cause sedation ³⁷. Before prescribing a sedative, all possible causes of agitation should be sought and properly treated, such as pain, hunger, hypoxemia, hypothermia, hyperthermia, inflammatory lesions, and inadequacy of mechanical ventilation parameters, among others. The main indications of sedation in newborns include diagnostic procedures that require some degree of immobility (CT and MRI); aggressive ventilatory support in agitated newborns with persistent hypoxemia, and postoperative management of surgeries, such as closure of the abdominal wall ^1,38. Some scales are more appropriate than others to evaluate the degree of sedation in this age group, such as the COMFORT scale ³⁹.

Chloral Hydrate

Chloral hydrate is a sedative and hypnotic agent, being used in short diagnostic or therapeutic procedures. Its mechanism of action has not been elucidated yet and its elimination depends on the age of the patient, but is slow in newborns ³⁸. In premature neonates one can observe residual effects of the drug up to 64 hours after its administration. Its active metabolite, trichloroethanol, is mutagenic and can cause chromosomal damage. It can also increase blood levels of direct and indirect bilirubin and metabolic acidosis in newborns. It can cause gastric irritation with nausea, vomiting, diarrhea, and hallucinations, headache, and residual depression of the central nervous system with somnolence, myocardial depression with cardiac arrhythmias, obstruction of the airways, and respiratory depression. For this reason, its use is not recommended in the neonatal period ^1,40.

Barbiturates

Barbiturates are potent depressors of the central nervous system and also have an anticonvulsant effect ⁴⁰. They do not have intrinsic analgesic activity and can even intensify the sensation of pain ³⁷. The level of depression of the neurological activity depends on the pharmacokinetics of the drug, route of administration, clinical condition, and simultaneous use of other drugs ¹.

Propofol

Propofol is a potent depressor of the central nervous system, whose action is rapidly reversible without residual sedation ⁴¹. In general, the onset of action occurs one to three minutes after administration of the drug, lasting approximately 15 to 20 minutes. The drug has antiemetic activity, being indicated for sedation during diagnostic or therapeutic procedures, or for the induction of general anesthesia in older children and adults. It causes respiratory depression and hypotension that are potentiated by the concomitant administration of opioids, ketamine, or nitrous oxide. The safety to be used in neonates is still being studied ⁴². Propofol infusion syndrome is a concern when the drug is used in continuous infusion for a long time (more than 24 hours) and in high doses (more than 75 µg.kg^-1.h^-1) ^41,43.

Benzodiazepines

Benzodiazepines are the drugs used more often for sedation, anxiety, and induction of amnesia. They do not have any analgesic activity, and they can even have an anti-analgesic effect ⁴⁴. They can cause respiratory depression, obstruction of the airways, hypotension, and paradoxal excitation, and their effects are potentiated by the opioids ⁴⁰.

Diazepam

It is a potent anti-anxiety sedative and anticonvulsant. However, patients develop tolerance to its sedative effect very rapidly. It interferes with the binding of albumin-bilirubin, increasing the amount of free circulating bilirubin. It is rarely used in Neonatal Intensive Care Units, but for isolated doses to promote prolonged sedation, in the dose of 0.05 to 0.2 mg.kg^-1 intravenously, with fast onset of action, of 2 to 3 minutes, lasting 2 to 6 hours ⁴⁵.

Midazolam

It is a benzodiazepine with good sedative and hypnotic activities, being twice to four times more potent than diazepam, with fast onset of action, and can cause amnesia ⁴⁶. Its plasma-cerebral balance time (t_1/2Ke0) is between 0.9 and 5.6 minutes, and 87.5% of this balance occurs in 2.7 minutes ⁴⁶. The elimination half-life in severely ill newborns is prolonged (6.5 to 12 hours), and its clearance is decreased (0.07 to 0.12 L.h^-1.kg^-1). It can cause respiratory depression and hypotension, which are potentiated by the concomitant administration of opioids, and it can cause addiction if used continuously for more than 48 hours ¹. Although it is an effective sedative when compared with placebo, one cannot reach definitive conclusions about its safety in newborns ^47,48. Its bolus, intermittent, intravenous, doses vary from 0.05 to 0.20 mg.kg^-1 every 2 to 4 hours, with onset of action in 1 to 3 minutes, peak action in 3 to 5 minutes, and duration of 1 to 2 hours. The doses for continuous intravenous administration vary from 1 to 6 µg.kg^-1.min^{-1 1,10}. Intranasal administration is not recommended due to the risk of central nervous system toxicity when it is absorbed, since it is in direct contact with the olfactory nerve through the cribriform plate ⁴⁹. A possible side effect is the development of seizures with fast administration of elevated doses ⁵⁰. It can also reduce blood flow to the medial cerebral artery in premature neonates ^51,52, besides transient neurological effects (hypertonia, hypotonia, choreic movements, dyskinetic movements, myoclonia, and epileptic activity).

The data available is not enough to promote its continuous infusion as a sedative in neonates in Neonatal Intensive Care Units. Although midazolam is often used indiscriminately in Neonatal Intensive Care Units, alone or associated with fentanyl, it has been demonstrated that the continuous infusion in premature neonates is associated with severe adverse effects such as death, leucomalacia, and peri-intraventricular hemorrhage ⁴⁸.

Antagonists of Benzodiazepines and Opioids

The availability of specific antagonists of benzodiazepines and opioids increased the safety of sedation for procedures, because respiratory depression can be reversed immediately ¹⁰.

Naloxone is a non-selective opioid antagonist, extremely potent, and 1 to 4 µg.kg^-1 should be used to reverse the respiratory depression caused by opioids. Since it has a short half-life (elimination half-life of 60 minutes), most patients might need repeated doses, continuous infusion, or intramuscular deposit, besides monitoring, to avoid the rebound effect of sedation and respiratory depression. It counteracts not only respiratory depression, muscle rigidity, and gastrointestinal effects, but also sedation and analgesia ²³.

Flumazenil is a pure benzodiazepine antagonist that presents competitive inhibition of the GABA-diazepine complex in the central nervous system. It is used to reverse the sedative effects of benzodiazepines after sedation or intoxication. The duration of its action is shorter than most benzodiazepines. The antagonism begins one to two minutes after the intravenous administration, with a peak in six to 10 minutes. The dose varies from 4 to 20 µg.kg^-1, and its side effects include nausea, vomiting, tinnitus, headache, seizures, anxiety, and emotional lability ^1,53.

Newborn Withdrawal Syndrome

If during the withdrawal or after discontinuation of the drugs used for sedation and analgesia signs and symptoms of withdrawal, such as tachycardia, agitation, diaphoresis, nausea, vomiting, diarrhea, sleep disorders, and even rebound pain develop, one should consider instituting withdrawal treatment involving several therapeutic options like methadone, phenobarbital, lorazepam, or an association of those drugs ^8,10. Monitoring of withdrawal symptoms can be done using the proper scale, as the Finnegan scale ⁵⁴.

CONCLUSION

Morphine has been recommended as the drug of choice, according to a worldwide consensus on newborn sedation and analgesia. However, morphine is not always the best option for analgesia and sedation of premature neonates, since it has been observed in this age group (gestational age of 27 to 29 weeks) a statistically significant difference in the incidence of severe peri-intraventricular bleeding in patients who received continuous infusion of morphine ⁵⁵. Besides, morphine metabolism depends on renal and hepatic function, and residual sedation has been implicated in the delay to extubate those patients. Pharmacokinetic studies of morphine present considerable variability in term newborns and premature neonates, and morphine clearance is reduced in premature neonates ^56,57.

Besides, several studies have demonstrated the safety and efficacy of remifentanil in analgesia and anesthesia of newborns, at term and premature ^32,33,58. Since remifentanil does not have residual sedation after it is discontinued, it became an option for sedation and analgesia of premature neonates ^59,60.

REFERENCES

Submitted em 12 de julho de 2006

Accepted para publicação em 25 de junho de 2007

* Received from Hospital Life Center e Faculdade de Medicina da Universidade Federal de Minas Gerais (FM/UFMG), Belo Horizonte, MG

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Publication Dates

• Publication in this collection
  14 Sept 2007
• Date of issue
  Oct 2007

History

• Accepted
  25 June 2007
• Received
  12 July 2006