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PEDIATRICS Vol. 111 No. 1 January 2003, pp. 123-128

Effects of Sufentanil on Electroencephalogram in Very and Extremely Preterm Neonates

Sylvie Nguyen The Tich, MD*, Marie-Françoise Vecchierini, MD{ddagger}, Thierry Debillon, MD§ and Yann Péréon, MD, PhD*

* Laboratoire d’Explorations Fonctionnelles, Hôtel-Dieu, Nantes, France
{ddagger} Laboratoire d’Explorations Fonctionnelles, Hôpital Bichat, and INSERM E9935, Paris, France
§ Service de Réanimation Pédiatrique, Hôpital de la Mère et de l’Enfant, Nantes, France

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. The electroencephalogram (EEG) is used in neonatal intensive care units to assess brain maturation and neurologic prognosis in preterm newborns. Most of these newborns are sedated by opioids because of long-term assisted ventilation. The aim of this study was to describe the effects of sufentanil on the EEG in preterm newborns and to evaluate the consequences of such a treatment on neurologic assessment.

Methods. Fifteen preterm newborns <28 days of extrauterine life were studied. All of them were sedated by sufentanil (initial bolus injection of 0.5 µg/kg, followed by continuous infusion of 0.2 µg/kg/h). Three EEGs were performed: the first before and during the bolus injection, the second in the 48 hours after the start of the continuous infusion, and the third at least 24 hours after the treatment was stopped. Qualitative and quantitative methods were used to analyze each EEG.

Results. EEG patterns were not affected by sufentanil treatment. Bolus injection and continuous infusion induced a significant increase of EEG discontinuity in preterm newborns affecting mean burst percentage and mean and maximum interburst duration.

Conclusions. The present data demonstrate that EEG is affected by bolus injection and continuous infusion of sufentanil. Sedation must therefore be considered to avoid misinterpretation of EEGs.

Key Words: analgesia • sedation • infants • opioids • electroencephalography

Abbreviations: EEG, electroencephalogram • NICU, neonatal intensive care unit • IBI, interburst interval • REM, rapid eye movement


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The electroencephalogram (EEG) represents a very useful tool in neonatal intensive care units (NICUs) for neurologic prognosis assessment in preterm newborns.1 It can be used to identify the gestational age within approximately 2 weeks, and preterm neonates at the same postconceptional age as term infants should have EEG patterns similar to the latter.2 Appropriate postconceptional age EEG patterns reflect the healthy medical status of an infant.3 The EEG also allows detection of abnormal patterns such as positive rolandic sharp waves, which are criteria for a poor neurologic prognosis.4–6

Preterm newborns frequently require mechanical ventilation, and synthetic opioids such as sufentanil are commonly used for analgesia and sedation.7–9 Although effects of morphine and synthetic opioids on EEG are well known in adults,10–12 very few studies have examined these effects in human neonates.13–15

Knowledge of the effects of drugs that may modify cerebral activity is critical for the electroencephalographer to avoid false interpretation. Therefore, the aims of this study were 1) to describe the effects of sufentanil on the EEG in preterm infants and 2) to evaluate the consequences of these effects on neurologic assessment in NICUs.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
Fifteen early preterm newborns (5 boys, 10 girls) who were <28 days of extrauterine life, admitted in the NICU of Nantes University Hospital, mechanically ventilated for respiratory distress, and needing sedative treatment for evidence of pain were included prospectively in the study. Patients’ mean postconceptional age was 29 ± 2.7 weeks (range: 26–34) at birth. Before proceeding, ethical approval was obtained from the hospital’s ethics committee as was a written informed consent from all parents. Newborns who received sedative drugs during the 48 hours before the study were excluded.

Anesthetic Management
All newborns were mechanically ventilated after tracheal intubation because of respiratory distress syndrome or hyaline membrane disease. The indication of sedation was a score above 5 on a clinical scale of pain for newborns.16 After a baseline EEG measurement, a bolus of 0.5 µg/kg sufentanil (Janssen Cilag, Berchem, Belgium) was administered over 10 minutes. It was followed by a continuous infusion of 0.2 µg/kg/h. Routine monitoring included heart rate with standard electrocardiography, arterial oxyhemoglobin saturation with a pulse oximeter (model N200; Nellcor, Hayward, CA), noninvasive arterial blood pressure by plethysmography, blood gases, serum lactate concentration, and clinical pain score. Serum concentrations of sufentanil were also determined in the 10 minutes after the end of the first 2 EEGs in 0.5- to 0.8-mL aliquots of serum using a standard radioimmunoassay technique (Janssen Biotech, Janssen-Cilag).17

EEG Recordings
EEGs were recorded in a mini-8 EEG machine (Alvar, REEGA, Paris, France) using 11 EEG electrodes (Fp2-C4-T4-O2, Fz-Cz-Oz, Fp1-C3-T3-O1) according to the International 10-20 System. The time constant was 0.3 seconds with a paper speed of 15 mm/sec and sensitivity was 10 µV/mm. Electrocardiogram and thoraco-abdominal respiration were also recorded on the EEG paper, and a specially trained nurse continuously observed the infants and noted the infants’ behavior and their eye and body movements. Data were inspected on-line and stored on paper for subsequent analysis.

Three EEGs were recorded for each patient. The first was a baseline measurement performed over 30 minutes before sufentanil bolus injection (state 1) and was continued for 20 minutes afterward (state 2). The second was performed for 30 minutes in the following 48 hours during the continuous sufentanil infusion (state 3), and the third was recorded at least 24 hours after treatment was stopped (state 4). The age of newborns by the time of the first EEG ranged from 1 day to 22 days (mean: 3 days). The last EEG (state 4) was performed at a mean age of 12 days of life (range: 5–36, depending on treatment duration).

EEG Analysis
Two physicians (M.F.V., S.N.T.T.) independently reviewed the EEGs; when results were discordant, the EEGs were reviewed by the 2 specialists together and the final interpretation was reached by consensus. The analysis of each EEG included both qualitative and quantitative parameters. Qualitative parameters assessed were physiologic patterns for the given postconceptional age using a standard textbook of neonatal electroencephalography,2 sleep states, pathologic figures (positive rolandic sharp waves or seizures), and unusual pattern for the given postconceptional age (eg, fast rhythms). Quantitative parameters were analyzed every 40-second epoch, and EEG activity was divided into burst or interburst interval (IBI). Bursts included any epoch with clear EEG activity (amplitude >10 µV) on any channel for >2 seconds. The IBI was defined as one with no clear EEG activity above 10 µV on all channels for >2 seconds. The following parameters were calculated: number of bursts and IBIs by epoch; mean duration of bursts and IBIs, maximum burst and IBI duration in each recording, and percentage of bursts during the whole recording.

Statistical Analysis
Qualitative data were analyzed by {chi}2 tests. Quantitative data were analyzed using a Wilcoxon signed rank test. Statistical significance was P <= .05. Results are reported as mean ± standard deviation. Linear regression was used for correlation between quantitative variables.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Forty-two EEGs were studied; 1 infant had only 1 EEG, another had 2. Typical EEG recordings are presented in Fig 1.



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  		Fig 1. A 20-second EEG epoch in a boy of 28-weeks’ postconceptional age. A, Before sufentanil treatment (first EEG, state 1). B, After bolus sufentanil injection (first EEG, state 2). Note the increased duration of the IBI.

 
Clinical and Laboratory Evaluation
The clinical pain score was significantly lower after treatment, demonstrating a favorable effect with sufentanil. Sufentanil concentrations were available for 10 of 15 infants after the bolus injection and for 11 of 14 infants during the continuous infusion. Range of sufentanil serum concentration was extremely wide despite that all patients received the same dose per kilogram (Fig 2). Sufentanil was not detectable in serum in 3 infants after the bolus and in 1 infant during the continuous infusion. There was no significant relationship between clinical pain score and serum concentration levels of sufentanil (R = 0.185; P = .527). Bolus sufentanil did not significantly modify blood pressure during the first 2 EEGs. However, a significant increase in blood pressure was found by the time of the final EEG recording (Table 1).



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  		Fig 2. Sufentanil concentration after bolus injection and during infusion in 11 patients. Note the wide range of values despite the same dose in µg/kg.

 

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  		TABLE 1. Clinical and Laboratory Results

 
EEG Analysis
Qualitative Parameters
Neither the initial bolus injection nor the continuous infusion qualitatively modified the physiologic EEG patterns for the given postconceptional age. However, the 2 distinct sleep states (active and quiet sleep) observed in 9 of the 15 preterm newborns before bolus injection could not be assessed later. In 7 of 9 infants, sleep states were again identified during the continuous sufentanil infusion on a short-duration EEG. Positive rolandic sharp waves, when present, persisted in 3 cases and appeared in 2 cases during sufentanil treatment. Two brief seizures were recorded in 1 infant before the bolus sufentanil injection but not after it. This infant did not have a second EEG because of hemodynamic instability and died at 5 days of age. No unusual EEG rhythms were identified during sufentanil treatment.

Quantitative Parameters
Both bolus injection and continuous infusion induced a significant decrease in burst percentage and an increase in the mean duration of IBIs (Fig 1). Moreover, bolus injection significantly decreased the maximum burst duration. Mean burst duration and number of bursts per epoch were not significantly affected. No significant correlation was found between the initial percentage of bursts and the marked decrease that occurred during treatment (R = 0.27; P = .32). There also was no correlation between the sufentanil concentration levels in the plasma and burst percentage decrease after bolus (R = 0.08; P = .77) and during continuous infusion (R = 0.46; P = .10). After sufentanil was withdrawn and ventilation was stopped, EEG activity increased significantly compared with baseline values, as expected with postconceptional age increase (Table 2).


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  		TABLE 2. EEG Quantitative Parameters

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Our results showed that both bolus sufentanil injection and continuous infusion had a significant effect on EEG features in preterm newborns. The mean IBI duration increased and the mean burst percentage decreased, leading to increased discontinuity; physiologic EEG rhythms were not altered. Furthermore, no unusual EEG features were found, and pathologic figures such as positive rolandic sharp waves when present were not suppressed by sufentanil. During continuous sufentanil infusion, quantitative modifications were less important than after bolus injection. All of these alterations were reversible after sufentanil withdrawal.

No relationship was found between EEG changes and serum concentration levels of sufentanil. A wide range of sufentanil plasma levels were noted in the infants without any definite relationship to postconceptional age or postnatal age. This variability had already been observed in neonates by pharmacokinetic studies of fentanyl,18 sufentanil,19,20 and alfentanil.21 Several factors may be involved. First, the volume of distribution is significantly greater in newborns than in children,22,23 inducing lower sufentanil concentrations for the same dose per kilogram. Second, opiates are metabolized in the liver by nonspecific monoamine oxidases, and inactive metabolites are excreted in urine.24 The immature hepatic and renal function of sick preterm newborns may induce individual metabolic variations with a significant effect on the metabolism of sufentanil.

Comparison between our baseline data (before sufentanil administration) about burst and IBI duration and results previously published about EEG maturational changes in premature infants is difficult because of some methodological differences. Indeed, computer analysis of the EEG, lower machine amplification, reduced number of EEG channels, and compressed time scale can be responsible for an overestimation of IBI.25,26 Moreover, the choice of quantitative (exact duration of burst and IBI in seconds) or qualitative parameters (classification of each epoch in continuous or discontinuous category27,28) is also critical. Taking these differences in account, our data about IBI duration before sufentanil administration are similar to those published previously.29–32

In adults, EEG variations as a result of opioids are mostly the occurrence of high-voltage slow {Delta} waves and a decrease in the faster {alpha} and ß rhythms. Sharp waves have been described, being not associated with clinical epileptic symptom and disappearing under midazolam infusion.12,33 Opioids have complex effects on seizure threshold.34 Both pro- and anticonvulsive actions have been reported depending on the exact experimental conditions. Morphine protects against seizures induced by electroconvulsive shock but increases the incidence and severity of seizures induced by bicuculline in rats.35 Recent works suggest that the proconvulsive effect of µ opioid receptor agonist is mediated by interference with {gamma}-aminobutyric acid transmission. This effect seems to be dose-dependent in rats and specific to µ receptors.36

Effects of sufentanil on EEG observed in our study were similar to those previously described with other sedative drugs. Automatic analysis of 2 EEG channels in preterm neonates after bolus of morphine or pethidine also demonstrated increased discontinuity.13,14 An excessive discontinuity constituting a suppression burst pattern is also reported after morphine continuous infusion by visual analysis of multichannel EEG in 20 preterm newborns of >30 weeks’ postconceptional age.15 Furthermore, these authors described transient sharp waves and epileptiform activity. In our study, neither unusual EEG rhythms nor seizures were observed. This discrepancy could be explained in part by patient age (present work: 29 weeks; Young’s work: 34 weeks).

The main effect of our study was an increased discontinuity leading to a "suppression-burst" like pattern. The suppression-burst pattern is produced in adults by a pharmacological disconnection of cerebral cortex and thalamus from the brainstem.37 This pattern has never been described in adults after opioid use, whereas it is commonly observed after barbiturate administration in adults as well as in children. The occurrence of such a pattern after opioid administration seems to be very specific to the preterm infant and is probably attributable to characteristics of brain electrogenesis at this age. The presence of discontinuous pattern is a prominent feature of EEG of preterm infants. Percentage of discontinuous pattern varies with postconceptional age and with sleep states. Discontinuity decreases with increased postconceptional age and is greater during quiet sleep than during active sleep.

In preterm newborns, identifying sleep state is difficult before 30 weeks’ postconceptional age because there is no strong correlation between EEG activity and ocular and body movements.38 However, the main state is active sleep, which is generally considered to be the precursor to adult rapid eye movement (REM) sleep.39 REM sleep is controlled by 2 main structures of the medial pontine reticular formation of the brainstem. The first one depends on the cholinergic system and is active during REM sleep. The second one, inactive during REM sleep, depends on the monoaminergic system. Opioid receptors are involved in pain control, but they also affect sleep cycles: REM sleep decreases after morphine administration with REM sleep rebound after morphine withdrawal.40 According to animal experimental studies in rat, this effect could be mediated by a decrease in acetylcholine levels in the medial pontine reticular formation.41

Considering cortex immaturity and preterm newborn head physical characteristics (head size and absence of skull ossification), EEG activity recorded via surface electrodes may arise from subcortical structures including the brainstem and should be constituted in part by the activity of neurons controlling REM sleep. Besides cortical explanation of EEG variations as a result of the action of sufentanil on opioid receptors, possible effect on the brainstem structures controlling sleep has to be considered in preterm infants. The excessive discontinuity induced by sufentanil could be explained by a direct action on opioid receptors located in the medial pontine formation of the brainstem inhibiting the cholinergic-dependent neurons active during REM sleep.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Our study demonstrates that the use of bolus sufentanil is responsible for significant effects on EEG activity in preterm infants, and less important effects are observed after continuous infusion. Sufentanil does not preclude the use of EEG for neurologic monitoring but electroencephalographers should take in account the administration of sedative drugs to avoid misinterpretation. This excessive discontinuity should reflect the action of sufentanil on opioid receptors located in the brain but also in the brainstem considering the origin of EEG activity at this age.


   FOOTNOTES
 
Received for publication Feb 25, 2002; Accepted Aug 5, 2002.

Reprint requests to (S.N.T.T.) Laboratoire d’Explorations Fonctionnelles, Hôtel-Dieu-University Hospital, F-44093 Nantes cedex, France; E-mail: snguyen{at}sante.univ-nantes.fr


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics



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L. Hellstrom-Westas, I. Rosen, L.S. de Vries, and G. Greisen
Amplitude-integrated EEG Classification and Interpretation in Preterm and Term Infants
NeoReviews, February 1, 2006; 7(2): e76 - e87.
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