0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Article |

Prolonged Sedation and/or Analgesia and 5-Year Neurodevelopment Outcome in Very Preterm Infants:  Results From the EPIPAGE Cohort FREE

Jean-Christophe Rozé, MD, PhD; Sophie Denizot, MD; Ricardo Carbajal, MD, PhD; Pierre-Yves Ancel, MD, PhD; Monique Kaminski, MD, PhD; Catherine Arnaud, MD, PhD; Patrick Truffert, MD, PhD; Stéphane Marret, MD, PhD; Jaqueline Matis, MD; Gérard Thiriez, MD; Gilles Cambonie, MD, PhD; Monique André, MD; Béatrice Larroque, MD, PhD; Gérard Bréart, MD, PhD
[+] Author Affiliations

Author Affiliations: INSERM CIC004 and Department of Neonatal Medicine, Nantes University Hospital (Drs Rozé and Denizot); Centre National de Ressources de Lutte Contre la Douleur, Hôpital D'enfants Armand-Trousseau (Dr Carbajal); INSERM UMR S149, IFR69, Epidemiological Research Unit on Perinatal and Women's Health, Tenon University Hospital and Pierre et Marie Curie University, Paris (Drs Ancel, Kaminski, Larroque, and Bréart); Institut National de la Santé et de la Recherche Medicale, U558 Département de Santé Publique, Faculté de Médecine, Toulouse (Dr Arnaud); Department of Neonatal Medicine, Lille University Hospital, Lille (Dr Truffert); Department of Neonatalogy, Rouen University Hospital, Rouen (Dr Marret); Department of Neonatalogy, Strasbourg University Hospital, Strasbourg (Dr Matis); Department of Neonatal Medicine, Besancon University Hospital, Besancon (Dr Thiriez); Department of Neonatal Medicine, Montpellier University Hospital, Montpellier (Dr Cambonie); and Maternité Régionale, Nancy University Hospital, Nancy, France (Dr André).


Arch Pediatr Adolesc Med. 2008;162(8):728-733. doi:10.1001/archpedi.162.8.728.
Text Size: A A A
Published online

Objective  To describe the long-term outcome of very preterm infants receiving prolonged sedation and/or analgesia and examine the relationship between prolonged sedation and/or analgesia and this long-term outcome.

Design  A prospective population-based study (Etude EPIdémiologique sur les Petits Ages GEstationnels [EPIPAGE]). To reduce bias, the propensity score method was used.

Setting  Nine regions of France.

Participants  The study population included very preterm infants of fewer than 33 weeks' gestational age, born in 1997, who received mechanical ventilation and/or surgery.

Main Exposure  Prolonged exposure to sedative and/or analgesic drugs in the neonatal period, defined as exposure of more than 7 days to sedative and/or opioid drugs.

Main Outcome Measure  Presence of moderate or severe disability at 5 years of age.

Results  The analysis concerns 1572 premature infants who received mechanical ventilation for whom information about exposure to prolonged sedation and/or analgesia in the neonatal period was available. A total of 115 were exposed and 1457 were not exposed. There was no significant difference between the number of patients lost to follow-up from the group of very preterm infants who were exposed to prolonged sedation and/or analgesia and the group who were not. Exposed very preterm infants had severe or moderate disability at 5 years (41/97; 42%) more often than those who were not exposed (324/1248; 26%). After adjustment for gestational age and propensity score, this association was no longer statistically significant (adjusted relative risk, 1.0; 95% confidence interval, 0.8-1.2).

Conclusion  Prolonged sedation and/or analgesia is not associated with a poor 5-year neurological outcome after adjustment for the propensity score.

Very preterm neonates are exposed to many painful procedures.1 Repeated and prolonged pain exposure may affect the subsequent development of pain systems and potentially contribute to altered long-term development and behavior in very preterm infants.28 This knowledge has provided evidence-based arguments for the development of professional guidelines on preventing and managing infant pain.9,10

Recently, the short- and long-term effects of sedation and/or analgesia have been discussed. The Neopain study11 and a Dutch study12 revealed that continuous morphine therapy given for a maximum of 14 or 7 days, respectively, does not increase neonates' poor short-term neurological outcome or neonatal death. The Neopain study showed, however, that continuous morphine infusion was associated with a higher rate of severe intraventricular hemorrhage or a composite outcome, including neonatal death, intraventricular hemorrhage, and periventricular leukomalacia in a subgroup of very preterm infants born at 27-29 weeks' gestation and in those who were very hypotensive before morphine therapy.11,13 The only published study to date regarding long-term effects suggests that exposure to morphine in the neonatal period for fewer than 7 days does not seem to have adverse effects on intelligence or motor function.14 Regarding sedation, midazolam is widely used in neonatal intensive care units. However, a recent meta-analysis has concluded that further research on the effectiveness and safety of midazolam in neonates who received mechanical ventilation is needed before its routine use can be recommended in clinical practice.15

Although data on adverse effects are still controversial, analgesia and/or sedation therapies are routinely used in neonatal intensive care units worldwide, and some very preterm infants may receive prolonged treatment with sedation and/or anesthesia for more than 7 days. Given the lack of data regarding the neurological development outcome of these very preterm infants, we have performed an analysis to evaluate the relationship between prolonged sedation and/or analgesia exposure and the 5-year cognitive and neuromotor outcome of a large French cohort of very preterm infants.

DATA SOURCE AND PATIENTS

We included all surviving very preterm infants enrolled in the Etude EPIdémiologique sur les Petits Ages GEstationnels (EPIPAGE) cohort study who received mechanical ventilation and/or surgery. The EPIPAGE study is a prospective population-based cohort study including all infants born between 22 and 32 weeks' gestation in 1997 in the maternity wards of 9 French regions, accounting for about one-third of all births in France.16 Initial data about pregnancy, delivery, and medical care of infants was collected from medical records in the maternity and neonatal units with the intention of testing the association between obstetric and neonatal management and outcome. One aspect of these data concerned “exposure to prolonged sedative and/or analgesic drugs,” defined as exposure of more than 7 days to sedative and/or opioid drugs, with infants receiving sedation each day. The status “no prolonged sedation/analgesia” included children who received no sedation and/or analgesia at all or for whom sedation and/or analgesia was administered for fewer than 7 days.

ASSESSMENT

Once consent was obtained from the parents, the infants were enrolled in a longitudinal follow-up until 5 years of age. At 2 years children were examined by a physician who completed a standardized questionnaire. At 5 years children were evaluated with a clinical examination performed by a trained pediatrician and a neuropsychological assessment performed by a trained psychologist. The neuropsychological assessment was performed using the Kaufman Assessment Battery for Children.17 This assessment was carried out when appropriate for the patient's condition and when accepted by the patient. The Kaufman Assessment Battery for Children yields 4 global test scores, including the Mental Processing Composite (MPC), which is a global measure of cognitive ability. The MPC score was standardized to a mean (SD) of 100 (15), based on results in children born in the late 1970s. Mental Processing Composite scores of less than 70 define severe cognitive impairment and scores of between 70 and 85 indicate moderate cognitive impairment.

The main outcome criteria were the presence of disability at 5 years of age or death after discharge. Children were classified into 3 groups: no disability, moderate disability, and severe disability. Disabilities were assessed in 4 areas: neuromotor, cognition, hearing, and vision. A disability was defined as severe if it was considered likely to make the child highly dependent on caregivers and included nonambulant cerebral palsy, an MPC score of less than 70, profound bilateral sensorineural hearing loss (> 70 dB), blindness, or attending a special-needs school. Cerebral palsy was defined as a nonprogressive central nervous system disorder, as proposed by the European Cerebral Palsy Network.18 The severe disability group also included children who were classified into the cerebral palsy group at 2 years of age and were lost to follow-up at 5 years. A disability was defined as moderate if reasonable independence was likely to be reached, including ambulant cerebral palsy, independent walking with abnormal gait, age of walking greater than 24 months, an MPC score between 70 and 84 (< 1 SD), hearing loss less than 70 dB, or unilateral impaired vision without blindness.

STATISTICAL ANALYSIS

Median and quartiles are reported for continuous variables and frequencies for categorical variables. The Mann-Whitney U test and χ2 test with a Yates correction, if necessary, were used to compare infant characteristics and 5-year outcome between the group of infants who received prolonged sedation and/or exposure to analgesia during the neonatal period and the group who did not.

Because EPIPAGE is an observational study, we used the propensity score method to reduce bias.1923 The propensity score is defined as a conditional probability between 0 and 1 that a patient will be treated, based on an observed group of covariates. This score is then used as if it were the only confounding covariate. Thus, the collection of predictors is collapsed into a single predictor, which may better adjust covariates between the groups and reduce bias. A full nonparsimonious logistic regression model was developed to derive a propensity score for prolonged sedation and/or analgesia exposure. This model included true confounders, variables that are potentially associated with both treatment assignment and outcome.23 The variables included characteristics of the newborns (gestational age, birth weight, malformation, Clinical Risk Index for Babies score), characteristics of pregnancy (antenatal corticosteroids, multiple pregnancies, complications of pregnancy), place of birth (inborn/outborn, large maternity, region of birth), and characteristics of neonatal hospitalization (duration of ventilation, patent ductus arteriosus, severe respiratory failure including air leak and refractory hypoxemia, hemodynamic failure, necrotizing enterocolitis, neonatal surgery, bronchopulmonary dysplasia defined by supplemental oxygen at 36 weeks, and postnatal corticotherapy). Patients with missing data were excluded from multivariable analysis. The Hosmer-Lemeshow goodness-of-fit test and the area under the curve were used to assess model fit.

We have used a log-binomial model to estimate adjusted relative risk (RR) of disability.24 As described above, we integrated the propensity score into the analysis. The propensity score itself was included with exposure as a covariate in a log-binomial model predicting outcome, with gestational age as an additional covariate, and we estimated the adjusted RR of disability with 95% confidence intervals (CI). This was performed for all infants for whom propensity scores were calculated. Finally, we carried out 2 other analyses to independently estimate the adjusted RR of the risk of neuromotor disability and the risk of an MPC score of less than 85. All P values were based on 2-tailed tests. All analyses were performed using SPSS 15.0 (SPSS Inc, Chicago, Illinois).

PATIENT CHARACTERISTICS AND OUTCOME

Of the 1956 very preterm infants hospitalized in neonatal intensive care units who received mechanical ventilation and/or surgery, the status of prolonged sedation and/or exposure to analgesia was known for 1941 (99%) of the infants; of these, 369 died and 1572 survived. Prolonged sedation and/or exposure to analgesia was more frequent among infants who died during hospitalization than among survivors (72 of 369 [19.5%] vs 115 of 1572 [7.3%]; P < .001). Of the 1572 survivors, infants who were exposed to prolonged sedation and/or analgesia (n = 115) had significantly lower gestational ages, lower birth weights, and higher Clinical Risk Index for Babies scores than infants who did not (n = 1457) (Table 1). In the exposed group, antenatal corticosteroids, multiple pregnancies, birth in a large maternity (a maternity hospital in which > 98 very preterm infants are delivered per year), and presence of congenital malformations were significantly more frequent (P < .05). Prolonged sedation and/or analgesia was also significantly associated with neonatal complications such as severe respiratory failure, bronchopulmonary dysplasia, patent ductus arteriosus requiring treatment, hemodynamic failure, necrotizing enterocolitis, longer duration of mechanical ventilation, postnatal corticotherapy, and surgery (Table 1). Prolonged sedation and/or analgesia exposure rates varied according to region of birth from 0% to 9.3% (P < .001). Data on long-term outcome were available for 86% of the 1572 infants (84% in the exposed group vs 86% in the nonexposed group; P = .46). Disability rates in the exposed and nonexposed groups were 42.3% and 26.0%, respectively (P < .001).

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Mechanically Ventilated Very Preterm Infants Exposed or Not Exposed to Prolonged Sedation and/or Analgesia
PROPENSITY SCORE

It was possible to calculate the propensity score for the very preterm infants receiving prolonged sedation and/or analgesia for 1497 of the 1572 very preterm infants receiving mechanical ventilation and/or surgery who were alive at the time of discharge from the hospital and whose status regarding exposure to prolonged sedation and/or analgesia exposure and outcome were known. Of the 1497 infants with a propensity score, 113 were exposed to prolonged sedation and/or analgesia and 1384 were not. The propensity scores ranged from 0.000 to 0.975. The Hosmer-Lemeshow goodness-of-fit test was 6.2 (P = .62). The receiver operating characteristic curve area was 0.92. Among the 20 variables included in the score, 6 were significantly associated with prolonged sedation and/or exposure to analgesia: surgery (P < .001), duration of mechanical ventilation (P = .002), postnatal corticotherapy (P < .006), severe respiratory failure (P < .02), multiple pregnancies (P < .003), and region of birth (P = .001) (Table 2).

Table Graphic Jump LocationTable 2. Associations Between Variables Included in Calculation of Propensity Score and Prolonged Sedation and/or Analgesia
PROLONGED SEDATION AND/OR EXPOSURE TO ANALGESIA AND RISK OF DISABILITY

Of the 1497 very preterm infants for whom propensity scores were calculated, data on long-term outcome was available for 87% of the 1384 infants in the exposed group vs 86% of the 113 in the nonexposed group (P = .73). Disability rates in the exposed and nonexposed groups were 42.3% and 25.7%, respectively (P < .001). Relative risks of disability for prolonged sedation and/or analgesia are indicated on Table 3.

Table Graphic Jump LocationTable 3. Association Between Sedation and/or Analgesia and Disability: Crude and Adjusted RR

To limit bias, 2 log-binomial models were constructed. The first model included 3 covariates: gestational age, propensity score, and prolonged sedation and/or exposure to analgesia. Prolonged sedation and/or analgesia exposure was not associated with an increased risk of survival with any disability or risk of death after discharge (adjusted RR, 1.0; 95% CI, 0.8-1.2; P = .57), but propensity score was (adjusted RR, 2.2; 95% CI, 1.3-3.8; P = .005). The second model included the 3 previous covariates and 8 other covariates significantly associated with outcome: intrauterine growth, maternal socioeconomic status, maternal educational status, sex of preterm infant, surgery, duration of ventilation, postnatal corticotherapy, and presence of malformation. Prolonged sedation and/or analgesia exposure was not significantly associated with disability (adjusted RR, 1.0; 95% CI, 0.8-1.2).

To better assess the relationship between disability and prolonged sedation and/or analgesia exposure, we conducted 2 other analyses where the dependant variables were an MPC score lower than 85 and neuromotor disability. The covariates were the 11 previous covariates. Prolonged sedation and/or analgesia exposure was not associated with an increased risk of survival with neuromotor impairment (adjusted RR, 1.1; 95% CI, 0.9-1.2), an MPC score of less than 85 (adjusted RR, 1.0; 95% CI, 0.7-1.2), or an MPC score lower than 85 or not available (adjusted RR, 1.1; 95% CI, 0.9-1.2).

In this observational study, univariate analysis showed that very preterm infants requiring prolonged sedation and/or analgesia during neonatal hospitalization had a higher risk of developing a disability. Prolonged sedation and/or exposure to analgesia was also significantly associated with need for surgery, congenital malformation, necrotizing enterocolitis, severe respiratory failure, hemodynamic failure, and duration of ventilatory support. It is likely that these factors were the reason for the use of prolonged sedation and/or analgesia. The association of some of these factors with a poor outcome is well known.25,26 Because the prolonged sedation and/or analgesia treatment assignment in this observational study may have been subject to bias, we used the propensity score method to reduce it. The propensity score method is a way of ensuring that the effect of a treatment is compared only between individuals who are equally likely to receive it.21,22 After adjustment for gestational age and propensity score, we did not observe any association between prolonged sedation and/or analgesia exposure and poor outcome, whereas most of the nonexposed infants did not receive any analgesic or sedative drugs in 1997.

We cannot rule out the possibility that prolonged sedation and/or analgesia exposure has an effect on outcome for 4 reasons. First, our findings should be interpreted with caution, because this study has several limitations. Despite the large size of this cohort, the power of this study was not high enough to detect small differences between the groups, because exposure to prolonged sedation and/or analgesia is a relatively rare event. Thus, this study did not have the power to detect a difference of 10% in the rate of disability. Like regression modeling, propensity score methods cannot control for unknown confounders. Some covariates, like the duration of mechanical ventilation, could be the cause of prolonged sedation and/or analgesia as well as the consequence. Nevertheless, we performed a model without including duration of ventilation in propensity score, bronchopulmonary dysplasia, and hemodynamic failure, and we observed similar results. Second, the odds ratio of the risk of developing a disability increased as the propensity score increased. This association could be the result of an insufficient reduction of bias by the propensity score or a cumulative effect of prolonged sedation and/or analgesia exposure that appeared when the severity of illness increased. Third, MPC scores were similar between exposed and nonexposed infants, while white matter damage was observed less frequently. One hypothesis could be that prolonged sedation and/or exposure to analgesia reduced the rate of cerebral lesions but itself had an effect on cerebral development. No difference was observed between groups when we included all preterm infants. Fourth, we cannot differentiate and assess the potential effect of any individual sedative or anesthetic agent in this study.

Our results suggest that prolonged sedation and/or analgesia exposure has no major effect on neurological outcome. This is currently a critical and controversial issue, because the recent understanding that the neonate is capable of sensing pain and mounting a stress response after a surgical stimulus27 has led to widespread use of anesthesia and analgesia for painful procedures; however, exposure to opiates, anesthetics, or sedatives may have adverse effects on neurological neonatal outcome.28 Several investigators have demonstrated that prolonged administration of opiates29,30 and other anesthetic drugs produce increased neurodegeneration in rat pups.31 Similarly, repetitive pain in newborn rat pups leads to long-term changes in behavior, and some of these changes are prevented by analgesic therapy.3235 This data suggests that the long-term effects of anesthetics and analgesic drugs depend on whether they are given in the presence or absence of painful stimulation.28 Extrapolation of animal data are problematic, because a rat brain develops over a matter of weeks, while a human brain develops over years. Six hours of anesthesia in a neonatal rat pup is thought to be equivalent to a month in a human infant.36 Moreover, this rodent data has not been replicated in monkeys.37 Therefore, cautious interpretation of experimental data is prudent before extrapolating data across species. Although the animal data may not be applicable to human beings, it would be unwise to ignore it.36 Evidence must be sought from human data. MacGregor et al14 have assessed the outcome at 5 to 6 years in a cohort of neonates born before 34 weeks' gestation to determine whether brief exposure to exogenous opiates had an effect on subsequent neurological or behavioral performance. Their results are reassuring; morphine did not show a detrimental effect on the intelligence of children who received it in the first days of neonatal life. Our data are consistent with these results, though it pertained to a population that was sicker and exposed to more prolonged sedation and/or analgesia.

In this population-based cohort study, prolonged sedation and/or analgesia exposure was not associated with a poor 5-year neurological outcome after adjustment for the propensity score.

Correspondence: Jean-Christophe Rozé, Department of Neonatal Medicine and Centre d’Investigation Clinique INSERM CIC004, Hôpital de la Mère et l’Enfant, Boulevard Jean Monet, 44000 Nantes, France (jcroze@chu-nantes.fr).

Accepted for Publication: January 24, 2008.

Author Contributions:Study concept and design: Rozé, Kaminski, Truffert, André, Larroque, and Bréart. Acquisition of data: Rozé, Arnaud, Truffert, Marret, Matis, Thiriez, Cambonie, André, Larroque, and Bréart. Analysis and interpretation of data: Rozé, Denizot, Carbajal, Ancel, Kaminski, Arnaud, Thiriez, Larroque, and Bréart. Drafting of the manuscript: Rozé, Denizot, Carbajal, Ancel, and Bréart. Critical revision of the manuscript for important intellectual content: Carbajal, Ancel, Kaminski, Arnaud, Truffert, Marret, Matis, Thiriez, Cambonie, André, Larroque, and Bréart. Statistical analysis: Rozé, Carbajal, Ancel, Kaminski, and Bréart. Obtained funding: Kaminski, Larroque, and Bréart. Administrative, technical, and material support: Carbajal, Marret, and Larroque. Study supervision: Kaminski, Cambonie, André, Larroque, and Bréart.

Additional Contributions: Etude EPIdémiologique sur les Petits Ages GEstationnels (EPIPAGE) Study Group: B. Larroque (national coordinator), P. Y. Ancel, B. Blondel, G. Bréart, M. Dehan, M. Garel, M. Kaminski, F. Maillard, C. du Mazaubrun, P. Missy, F. Sehili, K. Supernant, INSERM U149, Paris; M. Durand, J. Matis, J. Messer, A. Treisser, Hôpital de Hautepierre, Strasbourg; A. Burguet, L. Abraham-Lerat, A. Menget, P. Roth, J.-P. Schaal, G. Thiriez, CHU of Nantes, Besançon; C. Lévêque, S. Marret, L. Marpeau, Hôpital Charles Nicolle, Rouen; P. Boulot, J.-C. Picaud, Hôpital Arnaud de Villeneuve, Montpellier; A.-M. Donadio, B. Ledésert, Observatoire Regional de la Santé Montpellier; M. André, J. Fresson, J. M. Hascoët, Maternité Régionale, Nancy; C. Arnaud, S. Bourdet-Loubère, H. Grandjean, INSERM U558, Toulouse; M. Rolland, Hôpital des Enfants, Toulouse; C. Leignel, P. Lequien, V. Pierrat, F. Puech, D. Subtil, P. Truffert, Hôpital Jeanne de Flandre, Lille; G. Boog, V. Rouger-Bureau, J.-C. Rozé, Hôpital Mère-Enfant, Nantes; P. Y. Ancel, G. Bréart, M. Kaminski, C. du Mazaubrun, INSERM U149, Paris; M. Dehan, V. Zupan-Simunek, Hôpital Antoine Béclère, Clamart; M. Vodovar, M. Voyer, Institut de Puériculture, Paris, France.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants from Institut National de la Santé et de la Recherche Médicale (French National Institute of Health and Medical Research), Merck-Sharp, Dohme-Chibret, Medical Research Foundation, Directorate General for Health of the French Ministry for Social Affairs, and the French Hospital Program of Clinical Research, Paris, France.

Carbajal  RRousset  AMarchand  A  et al.  Number of invasive procedures and corresponding analgesic therapy in neonates admitted to NICUs and PICUs: The EPIPPAIN Multicenter Study. Paper presented at: Pediatric Academic Societies' Annual Meeting May2007; Toronto, CanadaPublication 6281.3
Fitzgerald  M The development of nociceptive circuits. Nat Rev Neurosci 2005;6 (7) 507- 520
PubMed Link to Article
Anand  KJSCarr  DB The neuroanatomy, neurophysiology and neurochemistry of pain, stress and analgesia in newborns and children. Pediatr Clin North Am 1989;36 (4) 795- 822
PubMed
Simons  SHTibboel  D Pain perception development and maturation. Semin Fetal Neonatal Med 2006;11 (4) 227- 231
PubMed Link to Article
Simons  SHVan Dijk  MAnand  KS  et al.  Do we still hurt newborn babies? a prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157 (11) 1058- 1064
PubMed Link to Article
Grunau  R Early pain in preterm infants: a model of long-term effects. Clin Perinatol 2002;29 (3) 373- 394
PubMed Link to Article
Anand  KJS Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998;73 (1) 1- 9
PubMed Link to Article
Sternberg  WFRidgway  CG Effects of gestational stress and neonatal handling on pain, analgesia, and stress behavior of adult mice. Physiol Behav 2003;78 (3) 375- 383
PubMed Link to Article
Anand  KJS Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001;155 (2) 173- 180
PubMed Link to Article
American Academy of Pediatrics Committee on Fetus and Newborn Committee, Prevention and management of pain and stress in neonate. Pediatrics 2000;105 (2) 454- 461
PubMed Link to Article
Anand  KJHall  RWDesai  N  et al.  Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004;363 (9422) 1673- 1682
PubMed Link to Article
Simons  SHVan Dijk  MVan Lingen  RA  et al.  Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290 (18) 2419- 2427
PubMed Link to Article
Hall  RWKronsberg  SSBarton  BA  et al.  Morphine, hypotension and adverse outcomes among preterm neonates: who's to blame? secondary results from the NEOPAIN trial. Pediatrics 2005;115 (5) 1351- 1359
PubMed Link to Article
MacGregor  REvans  DSudgen  D  et al.  Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed 1998;79 (1) F40- F43
PubMed Link to Article
Ng  ETaddio  AOhlsson  A Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2000;2 (2) CD002052
PubMed
Larroque  BBréart  GKaminski  M  et al.  Survival of very preterm infants: EPIPAGE a population based study. Arch Dis Child Fetal Neonatal Ed 2004;89 (2) F139- F144
PubMed Link to Article
Kaufman  ASKaufman  NL Kaufman Assessment Battery for Children.  Circle Pines, Minnesota American Guidance Service1983;
Surveillance of Cerebral Palsy in Europe, Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers Dev Med Child Neurol 2000;42 (12) 816- 824
PubMed
Blackstone  EH Comparing apples and oranges. J Thorac Cardiovasc Surg 2002;123 (1) 8- 15
PubMed Link to Article
Rubin  DB Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127 (8 pt 2) 757- 763
PubMed Link to Article
D’agostino  RB  Jr Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17 (19) 2265- 2281
PubMed Link to Article
Austin  PCGrootendorst  PAnderson  GM A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 2007;26 (4) 734- 753
PubMed Link to Article
Newgard  CDHedges  JRArthur  MMullins  RJ Advanced statistics: the propensity score—a method for estimating treatment effect in observational research. Acad Emerg Med 2004;11 (9) 953- 961
PubMed
McNutt  LAWU  CXuE  XHafner  JP Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol 2003;157 (10) 940- 943
PubMed Link to Article
Short  EJKlein  NKLewis  BA  et al.  Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003;112 (5) e359
PubMed Link to Article
Adams-Chapman  IStoll  BJ Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006;19 (3) 290- 297
PubMed Link to Article
Anand  KJHickey  PR Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317 (21) 1321- 1329
PubMed Link to Article
Soriano  SGAnand  KJ Anesthetics and brain toxicity. Curr Opin Anaesthesiol 2005;18 (3) 293- 297
PubMed Link to Article
Hammer  RP  JrRicalde  AASeatriz  JV Effects of opiates on brain development. Neurotoxicology 1989;10 (3) 475- 483
PubMed
Tempel  A Visualization of mu opiate receptor downregulation following morphine treatment in neonatal rat brain. Brain Res Dev Brain Res 1991;64 (1-2) 19- 26
PubMed Link to Article
Jevtovic-Todorovic  VHartman  REIzumi  Y  et al.  Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23 (3) 876- 882
PubMed
Anand  KJSoriano  SG Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 2004;101 (2) 527- 530
PubMed Link to Article
Bhutta  ATRovnaghi  CSimpson  PMGossett  JMScalzo  FMAnand  KJ Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav 2001;73 (1-2) 51- 58
PubMed Link to Article
Ruda  MALing  QDHohmann  AGPeng  YBTachibana  T Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000;289 (5479) 628- 631
PubMed Link to Article
Sternberg  WFScorr  LSmith  LDRidgway  CGStout  M Long-term effects of neonatal surgery on adulthood pain behavior. Pain 2005;113 (3) 347- 353
PubMed Link to Article
Davidson  ASoriano  S Does anaesthesia harm the developing brain: evidence or speculation? Paediatr Anaesth 2004;14 (3) 199- 200
PubMed Link to Article
Paule  MGFogle  CMAllen  RRPearson  ECHammond  TGPopke  EJ Chronic exposure to NMDA receptor and sodium channel blockers during development in monkeys and rats: long-term effects on cognitive function. Ann N Y Acad Sci 2003;993116- 122
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Mechanically Ventilated Very Preterm Infants Exposed or Not Exposed to Prolonged Sedation and/or Analgesia
Table Graphic Jump LocationTable 2. Associations Between Variables Included in Calculation of Propensity Score and Prolonged Sedation and/or Analgesia
Table Graphic Jump LocationTable 3. Association Between Sedation and/or Analgesia and Disability: Crude and Adjusted RR

References

Carbajal  RRousset  AMarchand  A  et al.  Number of invasive procedures and corresponding analgesic therapy in neonates admitted to NICUs and PICUs: The EPIPPAIN Multicenter Study. Paper presented at: Pediatric Academic Societies' Annual Meeting May2007; Toronto, CanadaPublication 6281.3
Fitzgerald  M The development of nociceptive circuits. Nat Rev Neurosci 2005;6 (7) 507- 520
PubMed Link to Article
Anand  KJSCarr  DB The neuroanatomy, neurophysiology and neurochemistry of pain, stress and analgesia in newborns and children. Pediatr Clin North Am 1989;36 (4) 795- 822
PubMed
Simons  SHTibboel  D Pain perception development and maturation. Semin Fetal Neonatal Med 2006;11 (4) 227- 231
PubMed Link to Article
Simons  SHVan Dijk  MAnand  KS  et al.  Do we still hurt newborn babies? a prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157 (11) 1058- 1064
PubMed Link to Article
Grunau  R Early pain in preterm infants: a model of long-term effects. Clin Perinatol 2002;29 (3) 373- 394
PubMed Link to Article
Anand  KJS Clinical importance of pain and stress in preterm neonates. Biol Neonate 1998;73 (1) 1- 9
PubMed Link to Article
Sternberg  WFRidgway  CG Effects of gestational stress and neonatal handling on pain, analgesia, and stress behavior of adult mice. Physiol Behav 2003;78 (3) 375- 383
PubMed Link to Article
Anand  KJS Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med 2001;155 (2) 173- 180
PubMed Link to Article
American Academy of Pediatrics Committee on Fetus and Newborn Committee, Prevention and management of pain and stress in neonate. Pediatrics 2000;105 (2) 454- 461
PubMed Link to Article
Anand  KJHall  RWDesai  N  et al.  Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004;363 (9422) 1673- 1682
PubMed Link to Article
Simons  SHVan Dijk  MVan Lingen  RA  et al.  Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290 (18) 2419- 2427
PubMed Link to Article
Hall  RWKronsberg  SSBarton  BA  et al.  Morphine, hypotension and adverse outcomes among preterm neonates: who's to blame? secondary results from the NEOPAIN trial. Pediatrics 2005;115 (5) 1351- 1359
PubMed Link to Article
MacGregor  REvans  DSudgen  D  et al.  Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed 1998;79 (1) F40- F43
PubMed Link to Article
Ng  ETaddio  AOhlsson  A Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2000;2 (2) CD002052
PubMed
Larroque  BBréart  GKaminski  M  et al.  Survival of very preterm infants: EPIPAGE a population based study. Arch Dis Child Fetal Neonatal Ed 2004;89 (2) F139- F144
PubMed Link to Article
Kaufman  ASKaufman  NL Kaufman Assessment Battery for Children.  Circle Pines, Minnesota American Guidance Service1983;
Surveillance of Cerebral Palsy in Europe, Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers Dev Med Child Neurol 2000;42 (12) 816- 824
PubMed
Blackstone  EH Comparing apples and oranges. J Thorac Cardiovasc Surg 2002;123 (1) 8- 15
PubMed Link to Article
Rubin  DB Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127 (8 pt 2) 757- 763
PubMed Link to Article
D’agostino  RB  Jr Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17 (19) 2265- 2281
PubMed Link to Article
Austin  PCGrootendorst  PAnderson  GM A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 2007;26 (4) 734- 753
PubMed Link to Article
Newgard  CDHedges  JRArthur  MMullins  RJ Advanced statistics: the propensity score—a method for estimating treatment effect in observational research. Acad Emerg Med 2004;11 (9) 953- 961
PubMed
McNutt  LAWU  CXuE  XHafner  JP Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol 2003;157 (10) 940- 943
PubMed Link to Article
Short  EJKlein  NKLewis  BA  et al.  Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003;112 (5) e359
PubMed Link to Article
Adams-Chapman  IStoll  BJ Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr Opin Infect Dis 2006;19 (3) 290- 297
PubMed Link to Article
Anand  KJHickey  PR Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317 (21) 1321- 1329
PubMed Link to Article
Soriano  SGAnand  KJ Anesthetics and brain toxicity. Curr Opin Anaesthesiol 2005;18 (3) 293- 297
PubMed Link to Article
Hammer  RP  JrRicalde  AASeatriz  JV Effects of opiates on brain development. Neurotoxicology 1989;10 (3) 475- 483
PubMed
Tempel  A Visualization of mu opiate receptor downregulation following morphine treatment in neonatal rat brain. Brain Res Dev Brain Res 1991;64 (1-2) 19- 26
PubMed Link to Article
Jevtovic-Todorovic  VHartman  REIzumi  Y  et al.  Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23 (3) 876- 882
PubMed
Anand  KJSoriano  SG Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 2004;101 (2) 527- 530
PubMed Link to Article
Bhutta  ATRovnaghi  CSimpson  PMGossett  JMScalzo  FMAnand  KJ Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav 2001;73 (1-2) 51- 58
PubMed Link to Article
Ruda  MALing  QDHohmann  AGPeng  YBTachibana  T Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000;289 (5479) 628- 631
PubMed Link to Article
Sternberg  WFScorr  LSmith  LDRidgway  CGStout  M Long-term effects of neonatal surgery on adulthood pain behavior. Pain 2005;113 (3) 347- 353
PubMed Link to Article
Davidson  ASoriano  S Does anaesthesia harm the developing brain: evidence or speculation? Paediatr Anaesth 2004;14 (3) 199- 200
PubMed Link to Article
Paule  MGFogle  CMAllen  RRPearson  ECHammond  TGPopke  EJ Chronic exposure to NMDA receptor and sodium channel blockers during development in monkeys and rats: long-term effects on cognitive function. Ann N Y Acad Sci 2003;993116- 122
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 40

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Neurodevelopmental care in the NICU. Ment Retard Dev Disabil Res Rev 2002;8(4):298-308.
JAMAevidence.com