Background: In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the “InSurE” procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known.
Objective: To evaluate the effects of the “InSurE” procedure in infants with RDS on regional cerebral oxygen saturation (rScO2) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG).
Methods: Sixteen infants with RDS, treated with the “InSurE” procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), rScO2, cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the “InSurE” procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods.
Results: MABP was not different between groups on all time points. rScO2 and cFTOE were comparable between groups, but there was a trend towards lower rScO2 and higher cFTOE 30 minutes after opioid administration in the “InSurE” infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in “InSurE” infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05).
Conclusion: In the present study, the “InSurE” procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time.
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Respiratory distress syndrome (RDS) is a common and serious problem in the preterm infant. Neonates with moderate to severe RDS often need mechanical ventilation and treatment with surfactant.1 2 However, mechanical ventilation has been increasingly recognised for its damaging effects on the immature lung, leading to chronic lung disease.3 4 Because nasal continuous positive airway pressure (nCPAP) devices have become more efficient,5 6 moderate and even severe RDS is treated more often with nCPAP and short-term intubation if surfactant administration is necessary: the so called “InSurE” procedure (intubation, surfactant, extubation).2 5 7 8 During this procedure, opioids are administered to the baby for sedation. It is feasible that less damage to the lungs will occur using the “InSurE” method.2 5 7 8 9 The acute effects of endotracheal surfactant instillation on cerebral haemodynamics and oxygenation10 11 and on electrical brain activity12 have already been investigated. These studies indicated that surfactant administration was not associated with cerebral injury and/or neurological deficits.13 14 However, it is not yet known whether the “InSurE” procedure has acute and/or sustained effects on cerebral oxygenation and electrical brain activity. Perturbation of cerebral oxygenation is known to be related to damage to the immature brain. Because the “InSurE” procedure must be repeated if the first dose of surfactant is not sufficiently effective,5 7 there may be an additional risk of brain damage.
We performed a prospective case–controlled study to examine the effects of the “InSurE” procedure on cerebral saturation and oxygen extraction using near infrared spectroscopy (NIRS) and electrical brain activity using amplitude-integrated electroencephalography (aEEG).
Patients and methods
Preterm infants of gestational age less than 32 weeks with moderate to severe RDS, consecutively admitted to our neonatal intensive care unit were included in the study. Infants treated with nCPAP and endotracheal surfactant replacement by the “InSurE” procedure (see below) were assigned to the treatment group. Infants treated with inotropic support because of hypotension or infants who needed ventilatory support in combination with sedation within 12 h after the “InSurE” procedure were excluded.
Sixteen preterm infants with RDS fulfilled the entry criteria of the study. They were compared with 16 infants who only needed nCPAP for mild RDS and/or recurrent apnoeas and matched for gestational age, birth weight and postnatal age (control group). Informed parental consent was obtained in all cases. The study was approved by the Medical Ethical Committee of the University Medical Center Utrecht.
Obstetric and intrapartum data were collected from the hospital records and neonatal data were collected prospectively. Arterial blood pressure was monitored via an indwelling arterial catheter (umbilical, radial or posterior tibial artery) in all infants. Arterial oxygen saturation (SaO2) was continuously measured by pulse oximetry.
RDS was defined as respiratory distress in a preterm infant with the characteristic clinical signs of RDS on x ray, the need of nCPAP and surfactant therapy. Treatment decisions were made by the attending neonatologist. Surfactant was administered according to the guidelines used in our neonatal intensive care unit (fractional inspired oxygen >0.4).
The “InSurE” procedure is defined as intubation, the administration of surfactant through an endotracheal tube and extubation within minutes after surfactant instillation.7 8 Before starting the procedure, infants in the “InSurE” group were sedated with opioids: morphine 0.1 mg/kg or pethidin 1 mg/kg as a single intravenous bolus and if necessary were briefly ventilated with a bag and mask and extra oxygen to maintain normal SaO2 values (85–97%). After intubation, surfactant (Curosurf 100 mg/kg; Chiesi Farmaceutici SpA, Parma, Italy) was endotracheally instilled as a bolus via a side port. Subsequently, infants were ventilated for 10–15 minutes and fractional inspired oxygen was tapered off dependent on SaO2 values. Meanwhile, the opioid antagonist naloxone 0.01 mg/kg was administered. When showing an adequate pattern of breathing, the infant was extubated and nCPAP was restarted. The average duration of the entire “InSurE” procedure was 20 minutes.
What this study adds
Although a limited number of preterm infants is investigated, the present study showed that the “InSurE” procedure caused no perturbations on cerebral oxygenation.
However, a sustained negative effect was detected on aEEG-measured electrical brain activity.
Monitoring cerebral oxygenation
NIRS was used to determine regional cerebral oxygen saturation (rScO2) to estimate changes in regional cerebral oxygenation.15 16 rScO2 reflects oxygen saturation in veins (70–80%), capillaries (5%) and arteries (15–25%), and can be used as a surrogate for oxygen saturation in jugular venous blood.17 18 Although at this stage NIRS-monitored rScO2 lacks the precision to be used as a quantitative variable, it can be used as a trend monitor in the individual patient when substantial changes of rScO2 and consequently of relative cerebral fractional tissue oxygen extraction (cFTOE) (see below) can give important clinical information.16 Because absolute values are provided, rScO2 is less dependent on movement artefacts and comparisons over time are possible.16 An INVOS 5100 near infrared spectrometer (Somanetics Corp, Troy, Michican, USA) was used. A transducer, containing a light-emitting diode and two distant sensors, was attached to the frontoparietal side of the head. rScO2 was calculated from the differential signals obtained from these two sensors, expressed as the venous-weighted percentage of oxygenated haemoglobin (oxygenated haemoglobin/total haemoglobin). Total haemoglobin = oxygenated haemoglobin + deoxygenated haemoglobin.16 To investigate the balance between oxygen delivery and oxygen consumption, relative cFTOE can be calculated as: (SaO2 − rScO2)/SaO2. An increase in cFTOE indicates either reduced oxygen delivery to the brain, with constant or increased oxygen consumption by the brain or increased oxygen consumption not matched by an appropriate increase in oxygen delivery. A decrease in cFTOE suggests a decrease in oxygen extraction of the brain because of less use of oxygen or a constant oxygen consumption of the brain with an increased oxygen delivery to the brain.15
Monitoring electrical brain activity
To monitor electrical brain activity as an indicator of cerebral function, a single-channel electroencephalography machine (Cerebral Function Monitor, CFM 4640; Lectromed, Devices Ltd, Oxford, UK) was used. aEEG electrodes were applied by a qualified nurse to the head of the neonate. The aEEG was recorded from two parietal electrodes, as earlier described by Toet et al.19
For quantitative analysis the minimum, mean and maximum voltage of amplitude (μV) in 4-s periods of the aEEG signal were determined and repeated 15 times. The median of these 15 values for minimum, mean and maximum μV was calculated and averaged over the selected 10-minute periods (ie, average amplitude values). Independently Burdjalov scores were assessed as a qualitative method for interpretation of the aEEG in selected time periods (see study design).20 The separately scored values, record continuity, presence of cyclic changes in electrical activity, amplitude of lower border and bandwidth, were summed.
As part of an ongoing prospective clinical study, consecutively admitted preterm infants (gestational age <32 weeks) were simultaneously monitored for arterial blood pressure, SaO2, rScO2, cFTOE and aEEG, starting as soon as possible after birth up to 72 h of life depending on the availability of a NIRS device and parental consent. Each infant who underwent the “InSurE” procedure and fulfilled the above-mentioned entry criteria was enrolled in the present study. All variables were collected and stored on a personal computer for offline analysis (Poly 5 software; Inspektor Research Systems, Amsterdam, The Netherlands), with a sampling frequency of 10 Hz. From mean arterial blood pressure (MABP), SaO2, rScO2, cFTOE and aEEG values, 10-minute periods were selected and averaged at 120 minutes and 20 minutes before the start of the “InSurE” procedure (ie, the administration of opioids), during the administration of opioids, during the intubation procedure and at 30 minutes, 60 minutes and at 2, 6, 12 and 24 h after the start of the “InSurE” procedure (ie, the administration of opioids). In the matched controls, the above-mentioned variables were determined at the same postnatal ages as in the study group.
The aEEG was analysed in two different ways for the most optimal interpretation. First, the aEEG was analysed quantitatively by average amplitude values, determined in μV/10 minutes (see above). Second, the Burdjalov score as qualitative analysis was determined by an independent investigator (MT) over a 60-minute period at 2 h before and at 1, 6, 12 and 24 h after the “InSurE” procedure or at the equivalent postnatal age in the control group (see above).20
Data are expressed as mean values (SD) or as median values and ranges when appropriate. The Mann–Whitney U test and analysis of variance were used to assess differences between groups at the various time points; differences among MABP, SaO2, rScO2 and cFTOE within groups (shown as box-and-whisker plots) were evaluated by analysis of variance for repeated measurements to assess changes within groups over time. Adjustments for multiple comparisons were made by a post hoc test (Bonferroni). A p value of less than 0.05 was considered statistically significant. SPSS version 12.0 was used for analysis.
The patient characteristics of the “InSurE” and control infants are shown in table 1.
The control group did not differ from the “InSurE” group in any item, except for the severity of RDS. None of the infants had signs of a patent ductus arteriosus.
Mean arterial blood pressure and arterial saturation
MABP was stable, within normal ranges and not different between groups (fig 1A). SaO2 was significantly lower in the “InSurE” infants compared with the controls, but always within normal ranges. Figure 1B shows the patterns of median SaO2 values and ranges of both groups over time.
Cerebral saturation and cerebral oxygen extraction
rScO2 was comparable between groups and was not different even during surfactant administration. Figure 2A shows the patterns of rScO2 in both groups. cFTOE did not differ between “InSurE” and control infants either (fig 2B).
Amplitude integrated electroencephalography
Figure 3A and B show the patterns of the Burdjalov scores and of the amplitude values (μV) in both groups. Before the “InSurE” procedure, no differences were detected in the aEEG between groups. After the “InSurE” procedure amplitude values were significantly lower in the “InSurE” infants compared with controls up to 24 h after the procedure. Burdjalov scores were significantly lower in the study group up to 24 h after opioid administration compared with the controls.
Figure 4 shows a representative pattern of the higher, lower and mean amplitude values of an infant undergoing the “InSurE” procedure. For comparison, values of MABP, SaO2 and rScO2 are also shown. Note the initial drop in electrical brain activity upon opioid administration, the subsequent apparent normalisation during surfactant instillation and the second sustained drop in amplitude after the procedure. During intubation and surfactant administration, rScO2 and MABP remained within normal limits.
This prospective study in a small group of infants revealed no negative effects of the “InsurE” procedure on cerebral oxygen delivery and cerebral oxygen extraction in the preterm infant with moderate to severe RDS. However, we observed a prolonged episode of reduced electrical brain activity, which we cannot entirely explain.
The results of the present study concerning the pattern of cerebral oxygenation are partly in conflict with reports of earlier studies, which investigated cerebral oxygenation and perfusion. An earlier study of our own group described a short-lasting, but substantial drop in cerebral oxygenation and increased cerebral blood volume upon endotracheal sufactant instillation. This response was largely related to the volume instilled.11 In the present study, we used a low dose and thus a low volume of surfactant, which may explain why we did not observe changes in cerebral oxygenation. Skov et al10 also reported a short-lasting decrease in cerebral oxygenation with a rapid recovery. However, Roll et al22 found no change in cerebral oxygenation after surfactant instillation. Interestingly Roll et al22 used a low dose and volume regimen that was comparable with the present study. These results suggest that the amount of fluid instilled endotracheally plays an important role with respect to possible changes in cerebral oxygenation due to surfactant treatment.
Interestingly, we observed that the “InsurE” infants displayed lower aEEG amplitude and “Burdjalov” scores from surfactant instillation up to 24 h after this procedure compared with the control group. This is in contrast to earlier studies reporting only a short period of low aEEG amplitudes in response to surfactant therapy.12 13 However, in these earlier studies no opioids were used, and opioids are known to cause changes in cerebral haemodynamics in preterm neonates after bolus administration.13 23 24 25 Only two studies reported a change in the aEEG-monitored background pattern in (preterm) neonates receiving morphine.25 26 Our own experience with therapeutic dosages of morphine confirms that often a change in background pattern occurs from a continuous pattern to a discontinuous pattern (unpublished findings). However, if the change in aEEG pattern was a direct result of opioid treatment, we would have expected an immediate drop in aEEG amplitude after the intravenous morphine bolus of 0.1 mg/kg and a subsequent normalisation of the aEEG amplitude after the opioid antagonist naloxone, which was not the case in the present study. Nonetheless, we postulate that the sustained depression in the aEEG amplitude/background pattern originates from the opioid medication. Maybe the arousal accompanying the first part of the “InsurE” procedure, ie, endotracheal intubation (including the preparation) and the actual instillation of surfactant may have prevented the immediate occurrence of lower brain activity after opioid administration. In addition, it is possible that the dose of naloxone was too low to neutralise the effect of morphine, as the half-life of naloxone is much shorter than that of most opioids. Moreover, naloxone has a high affinity for the μ-opioid receptor, which is more potent in restoring respiratory depression than sedation, which is mediated via the κ-opioid receptor.
As there was normal blood pressure during the entire study period it seems unlikely that hypotension was responsible for the sustained decrease in aEEG.
The discongruence between the aEEG activity change and apparently unchanged rScO2 and cFTOE, respectively, is not unexpected; it is well known that in the (more mature) brain as shown in several studies of near and full-term lambs27 acute changes in metabolic demands of the brain are met by changes in cerebral blood flow. Therefore, we suggest that a decrease in cerebral oxygen metabolism, as indicated by the significant decrease in aEEG activity, gives rise to a concomitant decrease in cerebral blood flow allowing the oxygen delivery (ie, rScO2) and extraction (ie, cFTOE) to remain unchanged. It remains, however, to be determined whether this mechanism is already operative in the preterm infant.
In summary, as far as changes in NIRS-monitored rScO2 and cFTOE estimate changes in cerebral oxygenation, no important perturbation occurred during and after the “InsurE” procedure in infants with RDS in need of surfactant. However, the rather long-lasting decrease in electrical brain activity warrants further research.
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed.
Ethics approval The study was approved by the Medical Ethical Committee of the University Medical Center Utrecht.
Patient consent Obtained.