- Email: [email protected]
Intubation in the delivery room: Experience with nasal midazolam
Early Human Development 90 (2014) 39–43
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Intubation in the delivery room: Experience with nasal midazolam☆ Julien Baleine, Christophe Milési, Renaud Mesnage, Aline Rideau Batista Novais, Clémentine Combes, Sabine Durand, Gilles Cambonie ⁎ Neonatal Intensive Care Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, Montpellier University Hospital Center, 34000 Montpellier, France
a r t i c l e
i n f o
Article history: Received 14 May 2013 Received in revised form 22 October 2013 Accepted 29 October 2013 Keywords: Comfort Delivery room Intubation Midazolam Nasal mucosa Newborn
a b s t r a c t Background: Neonates are often intubated in the delivery room (DR) without anesthesia because vascular access is impossible. Aims: To assess neonatal comfort and adverse events after use of nasal midazolam (nMDZ) for intubation in the DR. Study design: Prospective data collection over 6 months on the intubation of neonates with respiratory distress requiring tracheal instillation of surfactant. Subjects: Twenty-seven neonates with median (Q25–75) gestational age and birthweight of, respectively, 29 (27–33) weeks and 1270 (817–1942) g received a 0.1 mg/kg dose of nMDZ, and intubation was performed at the onset of tonus resolution or apnea. Outcome measures: Comfort was assessed with a scale of hetero-pain assessment and electrical skin conductance monitoring. Continuous pulse oximetry was recorded in the first postnatal hour, with oscillometric blood pressure measurement every 10 min. Results: Seventy percent of the patients required a single dose, with intubation performed 4.8 (3–9) min after administration. Combined electro-clinical assessment found adequate comfort during the procedure in 68% of neonates. Mean blood pressure decreased from 39 (34–44) mm Hg before to 31 (25–33) mm Hg 1 h following nMDZ (p = 0.011). Conclusion: nMDZ provided rapid and effective sedation to intubate neonates in the DR but potentially exposed them to hypotension, thus requiring close hemodynamic monitoring. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neonatal endotracheal intubation is a very painful procedure that is commonly performed in the delivery room (DR). Except for intubations occurring in emergency situations, such as resuscitation, relieving and preventing pain are a therapeutic priority. Indeed, intubation in vigorous infants can cause systemic and pulmonary hypertension, bradycardia, intracranial hypertension and hypoxia [1]. Multiple attempts have also been implicated in upper airway injuries involving the pharyngoesophageal, laryngeal and tracheal regions [2,3]. Although this message has been widely disseminated to all concerned medical and nursing staff, the pain management of neonates intubated in the DR is still
Abbreviations: nMDZ, nasal midazolam; DR, delivery room; NICU, neonatal intensive care unit; GA, gestational age; CPAP, continuous positive airway pressure; RTC scale, reactivity, tonus and consciousness scale; FANS, faceless acute neonatal pain scale; MABP, mean arterial blood pressure. ☆ This work was carried out in the delivery room of Arnaud de Villeneuve Hospital, CHU Montpellier, F-34000 France. ⁎ Corresponding author at: Neonatal Intensive Care Unit, CHU de Montpellier, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen G. Giraud, 34295 Montpellier Cedex 5, France. Tel.: +33 467 336 609; fax: +33 467 336 228. E-mail address: [email protected] (G. Cambonie). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2013.10.007
frequently inadequate [4]. A recent survey in our country indicated that sedatives or analgesics in DRs were used in only 21% of the centers [5]. Sevoflurane and nitrous oxide inhalation have been proposed as an alternative to intravenous anesthesia, but this technique requires specific material or skills rarely found in the DR [6,7]. In cases of difficult vascular access, drug administration via nasal mucosa may also be considered [1]. Since 2009, we have used nasal midazolam (nMDZ) to intubate neonates in the DR, particularly premature neonates requiring rescue surfactant treatment. We were prompted to adopt this protocol because anesthesia before intubation was rarely administered in this situation due to the difficulty of accessing peripheral veins and the time required to place an umbilical venous catheter in sterile conditions. Furthermore, nMDZ has pharmacokinetic features that make it compatible with use in cases of urgent intubation; i.e., rapid action and high bioavailability [8]. Previous studies have also demonstrated nMDZ efficacy in reducing procedural anxiety [9] and treating acute seizures or status epilepticus in children [10,11]. Yet concerns have been raised about the safety of midazolam in neonates, with reports of altered hemodynamics, including decreases in heart rate, blood pressure and cerebral blood flow velocities [12,13]. These effects were nevertheless inconstant [14], transient [15] or of variable clinical significance [12,16] following an intravenous bolus. The findings on safety, particularly regarding neurologic outcome, remain contradictory in cases of
40
J. Baleine et al. / Early Human Development 90 (2014) 39–43
prolonged infusion [17,18], and safety has never been assessed after a single intranasal administration. Our purpose was thus to document our experience with this sedative regimen, particularly regarding neonatal comfort and adverse events occurring after nMDZ administered to intubate neonates in the DR. 2. Methods 2.1. Patients This prospective observational study was performed in the DR and the level 3 neonatal intensive care unit (NICU) of a university hospital. Data were collected over 6 months, from February to September 2010. In accordance with our protocol, neonates received nMDZ when they met the following conditions: (i) inborn preterm neonates spontaneously breathing at 5 min of life, sometimes after a brief period of manual ventilation; (ii) neonatal respiratory distress, defined by a Silverman– Anderson retraction score [19] N 3 in less than 30 week gestational age (GA) neonates and N5 in 30–34 week GA neonates; (iii) surfactant requirement, defined by a fractional inspired oxygen (FiO2) N 0.3 for less than 30 week GA and N0.4 for 30–34 week GA neonates; and (iv) normal blood pressure, defined as mean blood pressure N 10th percentile of the reference range for GA or birthweight in the presence of intrauterine growth retardation. nMDZ was not considered for neonates requiring immediate intubation; i.e., for Apgar scores b 4, meconium aspiration syndrome, or major malformation like congenital diaphragmatic hernia. The efficacy of nMDZ was not evaluated for births occurring at night (6:30 pm to 8:30 am) or on holidays. 2.2. Protocol Immediate postdelivery care was provided under a radiant warmer; the Apgar timer was started and a pulse oximeter sensor (Masimo low noise optical probe Neo) was placed on the infant's right hand or wrist as soon as possible and was then connected to an oximeter (Radical 7, Masimo, Irvine, CA, USA). After suction of nasal and oropharyngeal secretions, intermittent positive-pressure ventilation was provided, if necessary. Then, + 5 cmH2O continuous positive airway pressure (CPAP) ventilation was delivered using a device with a t-piece that attaches to a mask and a flow-controlled pressure-limited delivery system (Neopuff, Fisher & Paykel Healthcare, Auckland, NZ). Initial FiO2 was 21% and was then adapted to obtain preductal pulse oximetry (SpO2) between 60% and 65% at 1 min, 65% and 70% at 2 min, 70% and 75% at 3 min , 75% and 80% at 4 min , 80% and 85% at 5 min, and 85% and 92% at 10 min. When the clinician decided to treat the respiratory distress at least 5 min after birth, nMDZ was administered using a 1-mL syringe at a dose of 0.1 mg/kg (0.1 mL/kg). After 5 s, CPAP was again started and maintained until the observation of hypnosis, clear muscular relaxation, or apnea, requiring intratracheal intubation. A second, similar dose of nMDZ was authorized if the neonate became aroused at the introduction of the tube in the nostril or if a neonate with persistent respiratory distress and FiO2 requirements was excessively awake 5 min after the first dose. Blood pressure was monitored before any additional nMDZ dose. After intubation and verification of the adequate placement of the endotracheal tube, 200 mg/kg of poractant alfa (Curosurf, Chiesi, Parma, Italy) was administered.
intubation were collected by a single observer (JB), who was not involved in patient care. 2.3.1. Clinical scales The newborns were videotaped for 3 min before intubation and throughout the procedure, with a light and a field of vision allowing the observation of the entire body. The sound was set at a level that made any potential moaning or screaming easily audible. The videotapes were anonymized and then viewed by two independent observers. Each observer was blinded to the data collected by the other. Two scales were completed. The Reactivity, Tonus and Consciousness (RTC) scale is a practical tool developed by a highly specialized team for neonatal transport in the Parisian region (SAMU 92). Reactivity, tonus and consciousness are quantified to define the depth of sedation just before intubation. Values range from 0, corresponding to an infant without reaction, clearly hypotonic and asleep when his head is positioned for intubation, to 8 in a patient with spontaneous movements, hypertonia, and full alertness in the same conditions [http://pediadol.org/IMG/pdf/Actes2006_137.pdf]. The Faceless Acute Neonatal pain Scale (FANS) was constructed and validated by our team [20] to assess pain in situations where observation of facial expression is not easy, which is precisely the case during intubation. This instrument evaluates both behavioral items, like body movements and vocal expression, and physiological items, like variation in heart rate, bradycardia or desaturation (Table 1). To increase the specificity of this scale, behavioral elements are given particular weighting, as they are strongly associated with acute pain in the preterm baby. 2.3.2. Skin conductance Electrical skin conductance monitoring was performed via a Pain Monitor (Medstorm Innovations, Oslo, Norway). The electrodes were positioned as follows: measurement and counter on either side of the ankle, and reference on the sole of the foot. The equipment used an alternating current of 50 Hz and an applied voltage of 240 VAC (highest density 36 μA). The software automatically calculates the fluctuations in skin conductance activity and the frequency of the peaks reflecting the magnitude of the nociceptive stimulation [21]. The monitor was connected to a personal computer using an RS-232 serial communication port. A data sampling rate of 15 s, with a monitor refresh rate of 1 s, was selected, following the manufacturer's recommendations. 2.4. Outcomes The main outcome was neonatal comfort during the procedure. To this end, we used clinical scales and skin conductance as follows: – RTC score during intubation; – FANS score before and during intubation; – Electrical skin conductance data, from 2 min before nMDZ instillation to 2 min after intubation;
Table 1 Faceless Acute Neonatal pain Scale (FANS). Adapted with permission. Heart rate variation
Acute discomfort Limb movements
2.3. Monitoring and comfort assessment during intubation Monitoring included continuous pulse oximetry-derived heart rate and oxygen saturation and oscillometric blood pressure measurement (IntelliVue, Philips Medical Systems, Eindhoven, the Netherlands) before nMDZ administration and then every 10 min during the first postnatal hour. Clinical scales, skin conductance monitoring, and data on
Vocal expression
0: b10% 1: N10% 2: N50% 1: Bradycardia (FC b100 bpm) or desaturation SpO2 b85% 0: Calm, slight 1: Mild intermittent with return to calm 2: Moderate 3: Marked, continuous 4: Global hypotonia 0: Absent 1: Brief moaning, anxious 2: Intermittent screaming 3: Constant screaming
J. Baleine et al. / Early Human Development 90 (2014) 39–43
– Electro-clinical score, combining the high positive predictive value of FANS [20] and the high negative predictive value (97%) of skin conductance [22]. Comfort was estimated as adequate for a number of peaks per second of skin conductance b0.21, inadequate for a FANS score N3, and undetermined but probably insufficient for a FANS score ≤3 with a peak frequency ≥0.21. Secondary outcomes included: – Intubation features, including the number of doses of nMDZ, the time to adequate sedation, and the duration of glottis exposure; – Adverse events occurring in the 24 h following nMDZ, with specific attention to the cardiovascular (mainly blood pressure and cardiac rhythm) and central nervous (mainly seizures and paradoxical reactions) systems. 2.5. Data analysis Quantitative variables are expressed as medians (Q25–75). Qualitative variables are expressed in numbers and percentages. The qualitative variables were compared with the chi 2 test or Fisher's exact test if appropriate. Repeated-measures analysis of variance was used to compare changes over the course of the study period. Significance was set at 5% for all tests. Statistical analysis was conducted with the SAS software package, version 9 (SAS Institute, Cary, N.C.). 2.6. Ethical considerations The procedures reported in this observational study, including respiratory distress management and monitoring, use of nMDZ for intubation, and use of skin conductance and scales to assess pain and discomfort in neonates, had all been in routine use in the DR and NICU for more than 1 year before the study began. Informed parental consent was sought before delivery. Written authorization, including for videotaping their children, was obtained from the two parents, and the study protocol was approved by the local ethics committee. 3. Results
41
median GA and birthweight of, respectively, 29 (27–33) weeks and 1270 (817–1942) g. Their main characteristics are described in Table 2. 3.2. Comfort assessment during intubation 3.2.1. Clinical scales The RTC score was 3 (0–4), with 75% of the neonates having a score ≤3 during intubation. The FANS score increased from 0 (0–1) before to 2 (1–3) during intubation, p b 0.01. Given that the pain threshold is 3 with this scale, comfort was judged as adequate in 85% of the cases. The patients with a FANS score above the threshold value also had higher RTC scores [6.5 (6–7) vs 3 (0–3), p = 0.001]. 3.2.2. Skin conductance In 5 patients, the recordings could not be interpreted because of an unsatisfactory baseline signal. In the remaining patients, skin conductance increased during intubation, from 0.07 (0–0.13) to 0.13 (0.07– 0.27) peak/s, p = 0.044, and tended to decrease immediately after to 0.10 (0–0.2) peak/s. Given that the pain threshold is 0.21 peak/s with this monitor, comfort was judged as adequate in 68% of the cases. 3.2.3. Electro-clinical score (Fig. 1) In the 22 infants with the combined assessment, comfort was estimated as adequate in 68%, inadequate in 18%, and undetermined but probably insufficient in 14%. 3.3. Intubation features Intubation was performed after a single dose of nMDZ in 70% of the cases, and the maximum number was 2 doses. The delay between nMDZ instillation and the intubation attempt was 4.8 (3–9) min. The duration of glottis exposure was 31 (23–55) s. 3.4. Adverse events 3.4.1. Before intubation nMDZ induced immediate discomfort in 8 (30%) of the patients, who showed transitory increases in FANS and skin conductance scores to,
3.1. Population Seventy neonates were intubated in the DR. Among them, 43 (61%) were excluded for (i) management during duty periods in 34 neonates, and (ii) emergency intubation for an Apgar score b 4 and/or meconium aspiration in the other 9. Data were collected for 27 neonates, with
Table 2 Patient characteristics. N = 27 Antenatal steroids, % Cesarean delivery, % Gestational age, weeks Birthweight, g Male, % Intrauterine growth retardation, % Maternal anesthesia, % Regional (epidural and/or spinal) General None Apgar score 1-min 5-min CRIB Length of invasive ventilation, hours Values are median (Q25–Q75) or absolute frequencies (percentage). CRIB: Clinical Risk Index for Babies.
18 (72) 21 (78) 29 (27–33) 1270 (817–1942) 15 (56) 8 (30) 23 (85) 3 (11) 1 (4) 5 (4–8) 8 (7–9) 5 (1–6) 28 (8.5–192)
Fig. 1. Combined assessment of comfort during nasal midazolam administration in 22 preterm neonates, using the Faceless Acute Neonatal pain Scale (FANS, x axis), and electrical skin conductance (y axis). Comfort was classified as adequate for conductance values b0.21 (15 neonates, gray circle), inadequate for FANS N3 (4 neonates, black triangle), and undetermined for FANS ≤3 with peak frequencies ≥0.21 (3 neonates, pale gray square).
42
J. Baleine et al. / Early Human Development 90 (2014) 39–43
respectively, 2 (1–5), and 0.2 (0.07–0.38) peaks/s. Return to baseline values was observed after 15 (8–22) s. 3.4.2. During intubation Maximal heart rate increased from 160 (150–170) to 174 (164– 184) bpm, p b 0.01. No case of bradycardia b100 bpm was observed. Minimal SpO2 was 85 (69–90)%. 3.4.3. Following intubation Mean arterial blood pressure (MABP) decreased from 39 (34– 44) mm Hg at baseline to 35 (30–39) mm Hg 20 min after nMDZ administration and 31 (26–37) mm Hg 1 h after administration (p = 0.011, Fig. 2). Comparable changes were observed for systolic and diastolic pressures (data not shown). MABP was b 10th percentile in 9 (33%) patients during the first postnatal hour. On admission to the NICU, 4 (15%) received a loading dose of 20 ml/kg normal saline fluid for persistent hypotension. The GA was lower in neonates demonstrating low blood pressure after nMDZ [28 (27–30) vs 31 (29–34) weeks, p = 0.035]. A paradoxical reaction, including agitation, myoclonus, and hypertension, was observed in a 27-week-old boy in the hour following a single nMDZ administration. Venous MDZ concentration was 192 ng/ml 30 min after instillation. These manifestations resolved spontaneously after 40 min. Two additional patients presented unsustained myoclonus, with fewer than 10 myoclonic contractions, immediately after nMDZ instillation. MDZ blood concentration was not monitored in these patients. 4. Discussion This observational study suggested that administration of nMDZ to neonates in the DR rapidly induced a state compatible with intubation, thus contributing to adequate comfort during the procedure in most patients. The main side effect was decreased MABP in the hour following nMDZ, which required fluid boluses in the more immature infants. Neonatal comfort has rarely been documented in infants receiving an induction agent for endotracheal intubation. Indeed, the scales used for neonates are for the most part dependent on the study of facial expression, an element certainly discriminating in the evaluation of pain but particularly difficult to assess during intubation [23]. To overcome this difficulty, Welzing et al. developed their own scoring system rating limb movements, coughing and breathing [24]. Our team validated a simple and easy-to-use scale specifically adapted to scoring pain in preterm newborns when facial expression is not accessible [20]. However, experience is still very limited with this tool, which was compared with a reference scale for moderately painful procedures. We therefore completed FANS with the RTC scale, widely used by emergency physicians in their daily practice to evaluate the intubating conditions for
Fig. 2. Change in the mean arterial blood pressure (MABP) following nasal midazolam administration. Values are expressed as means (SEM). p = 0.011 for all four groups (Kruskal–Wallis test); *p b 0.05, **p b 0.01 vs baseline (paired t test).
infants. These two scales showed consistent results, suggesting an appropriate depth of sedation just before intubation in 75% to 85% of our patients. Clinical evaluation was associated with a physiological measure of the emotional state of the newborns. Skin conductance monitors the changes in the activity of the sympathetic nervous system and reflects the stress response to a transitory nociceptive stimulation [25]. The variation in peak frequency has been used to monitor pain at various ages, including premature infants [25,26], and in a range of clinical situations, including endotracheal suctioning [21]. Recordings in infants during sleep showed a frequency of the skin conductance response varying from 0 to 0.04 peak/s [27], and wide variations during a heel lance procedure from 0.08 to 0.25 peak/s [26,28]. We chose a short 15-s analyzing window because, given that pain during intubation may last only a few seconds, a longer window might average this increase and thereby underestimate the pain. Moreover, the cut-off value of 0.21 peak/s, i.e., 5 times higher than the maximum recorded during sleep, was recommended as the criterion for moderate to severe pain in children [29]. On this basis, the electro-clinical score indicated adequate comfort using nMDZ for tracheal intubation in nearly 70% of the cases. The group of patients with undetermined comfort level suggests the usefulness of skin conductance to unmask pain in patients treated with benzodiazepines only, because these agents blunt the body movements strongly associated with acute pain in neonates. Although nMDZ may be an alternative to intravenous or inhaled anesthesia for neonatal sedation before intubation in the DR, we are well aware that it is no magic bullet. First, as suggested above, comfort has to be improved in 18–32% of premature infants, and efficacy needs to be evaluated in near term and term infants. Second, the intranasal route irritates the mucosa because of the low pH [30], which was a source of transient pain in some of our patients. Chiaretti et al. suggested the interest of combining intranasal lidocaine spray and midazolam to cancel the nasal discomfort in children [31]. However, the safety of this procedure has not been established in neonates. Third, we observed a significant decrease in blood pressure after nMDZ administration. Previous studies found significant hemodynamic alteration with both substantial (0.2 mg/kg) and more moderate (0.1 mg/kg) intravenous loading doses of midazolam in ventilated premature infants [12,13]. However, a drop in peripheral vascular resistance following nasal administration of the drug could not be ascertained from this work. Our baseline values, measured soon after birth, were relatively high, given the mean GA of the population. Indeed, blood pressure has rarely been studied in the DR, and our data could be explained by the catecholamine surge at birth [32]. Hence, the 15% prevalence of hypotension requiring a fluid bolus on admission to the NICU was comparable to the 20% we previously observed in less than 32 week GA neonates [33]. Our observational study has several limitations, including a short period of observation and a limited number of infants. nMDZ was already standard practice in the DR before this work was started, and thus randomization with and without treatment was not feasible. We were therefore unable to confirm that all our results were the exclusive consequence of the intervention. Duration of mechanical ventilation was rather high in our patients, but immediate extubation was not a policy in the NICU during the study period and some of our patients also received continuous intravenous sedation and analgesia to aid in tolerating invasive assisted ventilation following their admission to the unit. Further trials are required to assess the efficacy and safety of nMDZ for strategies such as prophylactic surfactant administration or the intubation–surfactant–extubation procedure. In conclusion, most experts and academic societies have taken a stand for premedication in all newborns before endotracheal intubation, but debate is still open regarding the most adequate protocol, especially in the DR. The main advantage of nMDZ compared with other anesthesia modes is the simplicity and rapidity of administration. However, MDZ lacks analgesic properties, which is a drawback for the objective of achieving optimal sedation–analgesia, whatever the administration route.
J. Baleine et al. / Early Human Development 90 (2014) 39–43
Further randomized trials are required to determine the optimal premedication regimen for intubation in the DR.
Conflict of interest statement The authors report no conflict of interest.
References [1] Barrington KJ, Canadian Paediatric Society, Fetus and Newborn Committee. Premedication for endotracheal intubation in the newborn infant. Paediatr Child Health 2011;16(3):159–64. [2] Schuman TA, Jacobs B, Walsh W, Goudy SL. Iatrogenic perinatal pharyngoesophageal injury: a disease of prematurity. Int J Pediatr Otorhinolaryngol 2010;74(4):393–7. [3] Mahieu HF, de Bree R, Ekkelkamp S, Sibarani-Ponsen RD, Haasnoot K. Tracheal and laryngeal rupture in neonates: complication of delivery or of intubation? Ann Otol Rhinol Laryngol 2004;113(10):786–92. [4] Sarkar S, Schumacher RE, Baumgart S, Donn SM. Are newborns receiving premedication before elective intubation? J Perinatol 2006;26(5):286–9. [5] Walter-Nicolet E, Flamant C, Négréa M, Parat S, Hubert P, Mitanchez D. Premedication before tracheal intubation in French neonatal intensive care units and delivery rooms. Arch Pediatr 2007;14(2):144–9. [6] Hassid S, Nicaise C, Michel F, Vialet R, Thomachot L, Lagier P, et al. Randomized controlled trial of sevoflurane for intubation in neonates. Paediatr Anaesth 2007;17(11):1053–8. [7] Milesi C, Pidoux O, Sabatier E, Badr M, Cambonie G, Picaud JC. Nitrous oxide analgesia for intubating preterm neonates: a pilot study. Acta Paediatr 2006;95(9):1104–8. [8] Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics 2010;126(3):532–7. [9] Ljungman G, Kreuger A, Andréasson S, Gordh T, Sörensen S. Midazolam nasal spray reduces procedural anxiety in children. Pediatrics 2000;105(1 Pt 1):73–8. [10] Harbord MG, Kyrkou NE, Kyrkou MR, Kay D, Coulthard KP. Use of intranasal midazolam to treat acute seizures in paediatric community settings. J Paediatr Child Health 2004;40(9–10):556–8. [11] Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med 2006;24(3):343–6. [12] Harte GJ, Gray PH, Lee TC, Steer PA, Charles BG. Haemodynamic response and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates. J Paediatr Child Health 1997;33(4):335–8. [13] van Alfen-van der Velden AA, Hopman JC, Klaessens JH, Feuth T, Sengers RC, Liem KD. Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants. Biol Neonate 2006;90(3):197–202. [14] VanLooy JW, Schumacher RE, Bhatt-Mehta V. Efficacy of a premedication algorithm for nonemergent intubation in a neonatal intensive care unit. Ann Pharmacother 2008;42(7):947–55.
43
[15] van Straaten HL, Rademaker CM, de Vries LS. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn. Dev Pharmacol Ther 1992;19(4):191–5. [16] Shekerdemian L, Bush A, Redington A. Cardiovascular effects of intravenous midazolam after open heart surgery. Arch Dis Child 1997;76(1):57–61. [17] Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2003(1):CD002052. [18] Rozé JC, Denizot S, Carbajal R, Ancel PY, Kaminski M, Arnaud C, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. Arch Pediatr Adolesc Med 2008;162(8):728–33. [19] Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics 1956;17(1):1–10. [20] Milesi C, Cambonie G, Jacquot A, Barbotte E, Mesnage R, Masson F, et al. Validation of a neonatal pain scale adapted to the new practices in caring for preterm newborns. Arch Dis Child Fetal Neonatal Ed 2010;95(4):F263–6. [21] Gjerstad AC, Wagner K, Henrichsen T, Storm H. Skin conductance versus the modified COMFORT sedation score as a measure of discomfort in artificially ventilated children. Pediatrics 2008;122(4):e848–53. [22] Hullett B, Chambers N, Preuss J, Zamudio I, Lange J, Pascoe E, et al. Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children? Anesthesiology 2009;111(3):513–7. [23] Anand KJ. Pain assessment in preterm neonates. Pediatrics 2007;119(3):605–7. [24] Welzing L, Kribs A, Eifinger F, Huenseler C, Oberthuer A, Roth B. Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates. Paediatr Anaesth 2010;20(7):605–11. [25] Storm H. Skin conductance and the stress response from heel stick in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;83(2):F143–7. [26] Hellerud BC, Storm H. Skin conductance and behaviour during sensory stimulation of preterm and term infants. Early Hum Dev 2002;70(1–2):35–46. [27] Røeggen I, Storm H, Harrison D. Skin conductance variability between and within hospitalised infants at rest. Early Hum Dev 2011;87(1):37–42. [28] Harrison D, Boyce S, Loughnan P, Dargaville P, Storm H, Johnston L. Skin conductance as a measure of pain and stress in hospitalised infants. Early Hum Dev 2006;82(9):603–8. [29] Storm H. Pain assessment in neonates. In: Chen W, Bambang Oetomo S, Feijs L, editors. Neonatal Monitoring Technologies: Design for Integrated Solutions. Hershey: IGI Global; 2012. p. 278–302. [30] Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet 2006;367(9512):766–80. [31] Chiaretti A, Barone G, Rigante D, Ruggiero A, Pierri F, Barbi E, et al. Intranasal lidocaine and midazolam for procedural sedation in children. Arch Dis Child 2011;96(2):160–3. [32] Hägnevik K, Faxelius G, Irestedt L, Lagercrantz H, Lundell B, Persson B. Catecholamine surge and metabolic adaptation in the newborn after vaginal delivery and caesarean section. Acta Paediatr Scand 1984;73(5):602–9. [33] Cambonie G, Dupuy AM, Combes C, Vincenti M, Mesnage R, Cristol JP. Can a clinical decision rule help ductus arteriosus management in preterm neonates? Acta Paediatr 2012;101(5):e213–8.
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Intubation in the delivery room: Experience with nasal midazolam☆ Julien Baleine, Christophe Milési, Renaud Mesnage, Aline Rideau Batista Novais, Clémentine Combes, Sabine Durand, Gilles Cambonie ⁎ Neonatal Intensive Care Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, Montpellier University Hospital Center, 34000 Montpellier, France
a r t i c l e
i n f o
Article history: Received 14 May 2013 Received in revised form 22 October 2013 Accepted 29 October 2013 Keywords: Comfort Delivery room Intubation Midazolam Nasal mucosa Newborn
a b s t r a c t Background: Neonates are often intubated in the delivery room (DR) without anesthesia because vascular access is impossible. Aims: To assess neonatal comfort and adverse events after use of nasal midazolam (nMDZ) for intubation in the DR. Study design: Prospective data collection over 6 months on the intubation of neonates with respiratory distress requiring tracheal instillation of surfactant. Subjects: Twenty-seven neonates with median (Q25–75) gestational age and birthweight of, respectively, 29 (27–33) weeks and 1270 (817–1942) g received a 0.1 mg/kg dose of nMDZ, and intubation was performed at the onset of tonus resolution or apnea. Outcome measures: Comfort was assessed with a scale of hetero-pain assessment and electrical skin conductance monitoring. Continuous pulse oximetry was recorded in the first postnatal hour, with oscillometric blood pressure measurement every 10 min. Results: Seventy percent of the patients required a single dose, with intubation performed 4.8 (3–9) min after administration. Combined electro-clinical assessment found adequate comfort during the procedure in 68% of neonates. Mean blood pressure decreased from 39 (34–44) mm Hg before to 31 (25–33) mm Hg 1 h following nMDZ (p = 0.011). Conclusion: nMDZ provided rapid and effective sedation to intubate neonates in the DR but potentially exposed them to hypotension, thus requiring close hemodynamic monitoring. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neonatal endotracheal intubation is a very painful procedure that is commonly performed in the delivery room (DR). Except for intubations occurring in emergency situations, such as resuscitation, relieving and preventing pain are a therapeutic priority. Indeed, intubation in vigorous infants can cause systemic and pulmonary hypertension, bradycardia, intracranial hypertension and hypoxia [1]. Multiple attempts have also been implicated in upper airway injuries involving the pharyngoesophageal, laryngeal and tracheal regions [2,3]. Although this message has been widely disseminated to all concerned medical and nursing staff, the pain management of neonates intubated in the DR is still
Abbreviations: nMDZ, nasal midazolam; DR, delivery room; NICU, neonatal intensive care unit; GA, gestational age; CPAP, continuous positive airway pressure; RTC scale, reactivity, tonus and consciousness scale; FANS, faceless acute neonatal pain scale; MABP, mean arterial blood pressure. ☆ This work was carried out in the delivery room of Arnaud de Villeneuve Hospital, CHU Montpellier, F-34000 France. ⁎ Corresponding author at: Neonatal Intensive Care Unit, CHU de Montpellier, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen G. Giraud, 34295 Montpellier Cedex 5, France. Tel.: +33 467 336 609; fax: +33 467 336 228. E-mail address: [email protected] (G. Cambonie). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2013.10.007
frequently inadequate [4]. A recent survey in our country indicated that sedatives or analgesics in DRs were used in only 21% of the centers [5]. Sevoflurane and nitrous oxide inhalation have been proposed as an alternative to intravenous anesthesia, but this technique requires specific material or skills rarely found in the DR [6,7]. In cases of difficult vascular access, drug administration via nasal mucosa may also be considered [1]. Since 2009, we have used nasal midazolam (nMDZ) to intubate neonates in the DR, particularly premature neonates requiring rescue surfactant treatment. We were prompted to adopt this protocol because anesthesia before intubation was rarely administered in this situation due to the difficulty of accessing peripheral veins and the time required to place an umbilical venous catheter in sterile conditions. Furthermore, nMDZ has pharmacokinetic features that make it compatible with use in cases of urgent intubation; i.e., rapid action and high bioavailability [8]. Previous studies have also demonstrated nMDZ efficacy in reducing procedural anxiety [9] and treating acute seizures or status epilepticus in children [10,11]. Yet concerns have been raised about the safety of midazolam in neonates, with reports of altered hemodynamics, including decreases in heart rate, blood pressure and cerebral blood flow velocities [12,13]. These effects were nevertheless inconstant [14], transient [15] or of variable clinical significance [12,16] following an intravenous bolus. The findings on safety, particularly regarding neurologic outcome, remain contradictory in cases of
40
J. Baleine et al. / Early Human Development 90 (2014) 39–43
prolonged infusion [17,18], and safety has never been assessed after a single intranasal administration. Our purpose was thus to document our experience with this sedative regimen, particularly regarding neonatal comfort and adverse events occurring after nMDZ administered to intubate neonates in the DR. 2. Methods 2.1. Patients This prospective observational study was performed in the DR and the level 3 neonatal intensive care unit (NICU) of a university hospital. Data were collected over 6 months, from February to September 2010. In accordance with our protocol, neonates received nMDZ when they met the following conditions: (i) inborn preterm neonates spontaneously breathing at 5 min of life, sometimes after a brief period of manual ventilation; (ii) neonatal respiratory distress, defined by a Silverman– Anderson retraction score [19] N 3 in less than 30 week gestational age (GA) neonates and N5 in 30–34 week GA neonates; (iii) surfactant requirement, defined by a fractional inspired oxygen (FiO2) N 0.3 for less than 30 week GA and N0.4 for 30–34 week GA neonates; and (iv) normal blood pressure, defined as mean blood pressure N 10th percentile of the reference range for GA or birthweight in the presence of intrauterine growth retardation. nMDZ was not considered for neonates requiring immediate intubation; i.e., for Apgar scores b 4, meconium aspiration syndrome, or major malformation like congenital diaphragmatic hernia. The efficacy of nMDZ was not evaluated for births occurring at night (6:30 pm to 8:30 am) or on holidays. 2.2. Protocol Immediate postdelivery care was provided under a radiant warmer; the Apgar timer was started and a pulse oximeter sensor (Masimo low noise optical probe Neo) was placed on the infant's right hand or wrist as soon as possible and was then connected to an oximeter (Radical 7, Masimo, Irvine, CA, USA). After suction of nasal and oropharyngeal secretions, intermittent positive-pressure ventilation was provided, if necessary. Then, + 5 cmH2O continuous positive airway pressure (CPAP) ventilation was delivered using a device with a t-piece that attaches to a mask and a flow-controlled pressure-limited delivery system (Neopuff, Fisher & Paykel Healthcare, Auckland, NZ). Initial FiO2 was 21% and was then adapted to obtain preductal pulse oximetry (SpO2) between 60% and 65% at 1 min, 65% and 70% at 2 min, 70% and 75% at 3 min , 75% and 80% at 4 min , 80% and 85% at 5 min, and 85% and 92% at 10 min. When the clinician decided to treat the respiratory distress at least 5 min after birth, nMDZ was administered using a 1-mL syringe at a dose of 0.1 mg/kg (0.1 mL/kg). After 5 s, CPAP was again started and maintained until the observation of hypnosis, clear muscular relaxation, or apnea, requiring intratracheal intubation. A second, similar dose of nMDZ was authorized if the neonate became aroused at the introduction of the tube in the nostril or if a neonate with persistent respiratory distress and FiO2 requirements was excessively awake 5 min after the first dose. Blood pressure was monitored before any additional nMDZ dose. After intubation and verification of the adequate placement of the endotracheal tube, 200 mg/kg of poractant alfa (Curosurf, Chiesi, Parma, Italy) was administered.
intubation were collected by a single observer (JB), who was not involved in patient care. 2.3.1. Clinical scales The newborns were videotaped for 3 min before intubation and throughout the procedure, with a light and a field of vision allowing the observation of the entire body. The sound was set at a level that made any potential moaning or screaming easily audible. The videotapes were anonymized and then viewed by two independent observers. Each observer was blinded to the data collected by the other. Two scales were completed. The Reactivity, Tonus and Consciousness (RTC) scale is a practical tool developed by a highly specialized team for neonatal transport in the Parisian region (SAMU 92). Reactivity, tonus and consciousness are quantified to define the depth of sedation just before intubation. Values range from 0, corresponding to an infant without reaction, clearly hypotonic and asleep when his head is positioned for intubation, to 8 in a patient with spontaneous movements, hypertonia, and full alertness in the same conditions [http://pediadol.org/IMG/pdf/Actes2006_137.pdf]. The Faceless Acute Neonatal pain Scale (FANS) was constructed and validated by our team [20] to assess pain in situations where observation of facial expression is not easy, which is precisely the case during intubation. This instrument evaluates both behavioral items, like body movements and vocal expression, and physiological items, like variation in heart rate, bradycardia or desaturation (Table 1). To increase the specificity of this scale, behavioral elements are given particular weighting, as they are strongly associated with acute pain in the preterm baby. 2.3.2. Skin conductance Electrical skin conductance monitoring was performed via a Pain Monitor (Medstorm Innovations, Oslo, Norway). The electrodes were positioned as follows: measurement and counter on either side of the ankle, and reference on the sole of the foot. The equipment used an alternating current of 50 Hz and an applied voltage of 240 VAC (highest density 36 μA). The software automatically calculates the fluctuations in skin conductance activity and the frequency of the peaks reflecting the magnitude of the nociceptive stimulation [21]. The monitor was connected to a personal computer using an RS-232 serial communication port. A data sampling rate of 15 s, with a monitor refresh rate of 1 s, was selected, following the manufacturer's recommendations. 2.4. Outcomes The main outcome was neonatal comfort during the procedure. To this end, we used clinical scales and skin conductance as follows: – RTC score during intubation; – FANS score before and during intubation; – Electrical skin conductance data, from 2 min before nMDZ instillation to 2 min after intubation;
Table 1 Faceless Acute Neonatal pain Scale (FANS). Adapted with permission. Heart rate variation
Acute discomfort Limb movements
2.3. Monitoring and comfort assessment during intubation Monitoring included continuous pulse oximetry-derived heart rate and oxygen saturation and oscillometric blood pressure measurement (IntelliVue, Philips Medical Systems, Eindhoven, the Netherlands) before nMDZ administration and then every 10 min during the first postnatal hour. Clinical scales, skin conductance monitoring, and data on
Vocal expression
0: b10% 1: N10% 2: N50% 1: Bradycardia (FC b100 bpm) or desaturation SpO2 b85% 0: Calm, slight 1: Mild intermittent with return to calm 2: Moderate 3: Marked, continuous 4: Global hypotonia 0: Absent 1: Brief moaning, anxious 2: Intermittent screaming 3: Constant screaming
J. Baleine et al. / Early Human Development 90 (2014) 39–43
– Electro-clinical score, combining the high positive predictive value of FANS [20] and the high negative predictive value (97%) of skin conductance [22]. Comfort was estimated as adequate for a number of peaks per second of skin conductance b0.21, inadequate for a FANS score N3, and undetermined but probably insufficient for a FANS score ≤3 with a peak frequency ≥0.21. Secondary outcomes included: – Intubation features, including the number of doses of nMDZ, the time to adequate sedation, and the duration of glottis exposure; – Adverse events occurring in the 24 h following nMDZ, with specific attention to the cardiovascular (mainly blood pressure and cardiac rhythm) and central nervous (mainly seizures and paradoxical reactions) systems. 2.5. Data analysis Quantitative variables are expressed as medians (Q25–75). Qualitative variables are expressed in numbers and percentages. The qualitative variables were compared with the chi 2 test or Fisher's exact test if appropriate. Repeated-measures analysis of variance was used to compare changes over the course of the study period. Significance was set at 5% for all tests. Statistical analysis was conducted with the SAS software package, version 9 (SAS Institute, Cary, N.C.). 2.6. Ethical considerations The procedures reported in this observational study, including respiratory distress management and monitoring, use of nMDZ for intubation, and use of skin conductance and scales to assess pain and discomfort in neonates, had all been in routine use in the DR and NICU for more than 1 year before the study began. Informed parental consent was sought before delivery. Written authorization, including for videotaping their children, was obtained from the two parents, and the study protocol was approved by the local ethics committee. 3. Results
41
median GA and birthweight of, respectively, 29 (27–33) weeks and 1270 (817–1942) g. Their main characteristics are described in Table 2. 3.2. Comfort assessment during intubation 3.2.1. Clinical scales The RTC score was 3 (0–4), with 75% of the neonates having a score ≤3 during intubation. The FANS score increased from 0 (0–1) before to 2 (1–3) during intubation, p b 0.01. Given that the pain threshold is 3 with this scale, comfort was judged as adequate in 85% of the cases. The patients with a FANS score above the threshold value also had higher RTC scores [6.5 (6–7) vs 3 (0–3), p = 0.001]. 3.2.2. Skin conductance In 5 patients, the recordings could not be interpreted because of an unsatisfactory baseline signal. In the remaining patients, skin conductance increased during intubation, from 0.07 (0–0.13) to 0.13 (0.07– 0.27) peak/s, p = 0.044, and tended to decrease immediately after to 0.10 (0–0.2) peak/s. Given that the pain threshold is 0.21 peak/s with this monitor, comfort was judged as adequate in 68% of the cases. 3.2.3. Electro-clinical score (Fig. 1) In the 22 infants with the combined assessment, comfort was estimated as adequate in 68%, inadequate in 18%, and undetermined but probably insufficient in 14%. 3.3. Intubation features Intubation was performed after a single dose of nMDZ in 70% of the cases, and the maximum number was 2 doses. The delay between nMDZ instillation and the intubation attempt was 4.8 (3–9) min. The duration of glottis exposure was 31 (23–55) s. 3.4. Adverse events 3.4.1. Before intubation nMDZ induced immediate discomfort in 8 (30%) of the patients, who showed transitory increases in FANS and skin conductance scores to,
3.1. Population Seventy neonates were intubated in the DR. Among them, 43 (61%) were excluded for (i) management during duty periods in 34 neonates, and (ii) emergency intubation for an Apgar score b 4 and/or meconium aspiration in the other 9. Data were collected for 27 neonates, with
Table 2 Patient characteristics. N = 27 Antenatal steroids, % Cesarean delivery, % Gestational age, weeks Birthweight, g Male, % Intrauterine growth retardation, % Maternal anesthesia, % Regional (epidural and/or spinal) General None Apgar score 1-min 5-min CRIB Length of invasive ventilation, hours Values are median (Q25–Q75) or absolute frequencies (percentage). CRIB: Clinical Risk Index for Babies.
18 (72) 21 (78) 29 (27–33) 1270 (817–1942) 15 (56) 8 (30) 23 (85) 3 (11) 1 (4) 5 (4–8) 8 (7–9) 5 (1–6) 28 (8.5–192)
Fig. 1. Combined assessment of comfort during nasal midazolam administration in 22 preterm neonates, using the Faceless Acute Neonatal pain Scale (FANS, x axis), and electrical skin conductance (y axis). Comfort was classified as adequate for conductance values b0.21 (15 neonates, gray circle), inadequate for FANS N3 (4 neonates, black triangle), and undetermined for FANS ≤3 with peak frequencies ≥0.21 (3 neonates, pale gray square).
42
J. Baleine et al. / Early Human Development 90 (2014) 39–43
respectively, 2 (1–5), and 0.2 (0.07–0.38) peaks/s. Return to baseline values was observed after 15 (8–22) s. 3.4.2. During intubation Maximal heart rate increased from 160 (150–170) to 174 (164– 184) bpm, p b 0.01. No case of bradycardia b100 bpm was observed. Minimal SpO2 was 85 (69–90)%. 3.4.3. Following intubation Mean arterial blood pressure (MABP) decreased from 39 (34– 44) mm Hg at baseline to 35 (30–39) mm Hg 20 min after nMDZ administration and 31 (26–37) mm Hg 1 h after administration (p = 0.011, Fig. 2). Comparable changes were observed for systolic and diastolic pressures (data not shown). MABP was b 10th percentile in 9 (33%) patients during the first postnatal hour. On admission to the NICU, 4 (15%) received a loading dose of 20 ml/kg normal saline fluid for persistent hypotension. The GA was lower in neonates demonstrating low blood pressure after nMDZ [28 (27–30) vs 31 (29–34) weeks, p = 0.035]. A paradoxical reaction, including agitation, myoclonus, and hypertension, was observed in a 27-week-old boy in the hour following a single nMDZ administration. Venous MDZ concentration was 192 ng/ml 30 min after instillation. These manifestations resolved spontaneously after 40 min. Two additional patients presented unsustained myoclonus, with fewer than 10 myoclonic contractions, immediately after nMDZ instillation. MDZ blood concentration was not monitored in these patients. 4. Discussion This observational study suggested that administration of nMDZ to neonates in the DR rapidly induced a state compatible with intubation, thus contributing to adequate comfort during the procedure in most patients. The main side effect was decreased MABP in the hour following nMDZ, which required fluid boluses in the more immature infants. Neonatal comfort has rarely been documented in infants receiving an induction agent for endotracheal intubation. Indeed, the scales used for neonates are for the most part dependent on the study of facial expression, an element certainly discriminating in the evaluation of pain but particularly difficult to assess during intubation [23]. To overcome this difficulty, Welzing et al. developed their own scoring system rating limb movements, coughing and breathing [24]. Our team validated a simple and easy-to-use scale specifically adapted to scoring pain in preterm newborns when facial expression is not accessible [20]. However, experience is still very limited with this tool, which was compared with a reference scale for moderately painful procedures. We therefore completed FANS with the RTC scale, widely used by emergency physicians in their daily practice to evaluate the intubating conditions for
Fig. 2. Change in the mean arterial blood pressure (MABP) following nasal midazolam administration. Values are expressed as means (SEM). p = 0.011 for all four groups (Kruskal–Wallis test); *p b 0.05, **p b 0.01 vs baseline (paired t test).
infants. These two scales showed consistent results, suggesting an appropriate depth of sedation just before intubation in 75% to 85% of our patients. Clinical evaluation was associated with a physiological measure of the emotional state of the newborns. Skin conductance monitors the changes in the activity of the sympathetic nervous system and reflects the stress response to a transitory nociceptive stimulation [25]. The variation in peak frequency has been used to monitor pain at various ages, including premature infants [25,26], and in a range of clinical situations, including endotracheal suctioning [21]. Recordings in infants during sleep showed a frequency of the skin conductance response varying from 0 to 0.04 peak/s [27], and wide variations during a heel lance procedure from 0.08 to 0.25 peak/s [26,28]. We chose a short 15-s analyzing window because, given that pain during intubation may last only a few seconds, a longer window might average this increase and thereby underestimate the pain. Moreover, the cut-off value of 0.21 peak/s, i.e., 5 times higher than the maximum recorded during sleep, was recommended as the criterion for moderate to severe pain in children [29]. On this basis, the electro-clinical score indicated adequate comfort using nMDZ for tracheal intubation in nearly 70% of the cases. The group of patients with undetermined comfort level suggests the usefulness of skin conductance to unmask pain in patients treated with benzodiazepines only, because these agents blunt the body movements strongly associated with acute pain in neonates. Although nMDZ may be an alternative to intravenous or inhaled anesthesia for neonatal sedation before intubation in the DR, we are well aware that it is no magic bullet. First, as suggested above, comfort has to be improved in 18–32% of premature infants, and efficacy needs to be evaluated in near term and term infants. Second, the intranasal route irritates the mucosa because of the low pH [30], which was a source of transient pain in some of our patients. Chiaretti et al. suggested the interest of combining intranasal lidocaine spray and midazolam to cancel the nasal discomfort in children [31]. However, the safety of this procedure has not been established in neonates. Third, we observed a significant decrease in blood pressure after nMDZ administration. Previous studies found significant hemodynamic alteration with both substantial (0.2 mg/kg) and more moderate (0.1 mg/kg) intravenous loading doses of midazolam in ventilated premature infants [12,13]. However, a drop in peripheral vascular resistance following nasal administration of the drug could not be ascertained from this work. Our baseline values, measured soon after birth, were relatively high, given the mean GA of the population. Indeed, blood pressure has rarely been studied in the DR, and our data could be explained by the catecholamine surge at birth [32]. Hence, the 15% prevalence of hypotension requiring a fluid bolus on admission to the NICU was comparable to the 20% we previously observed in less than 32 week GA neonates [33]. Our observational study has several limitations, including a short period of observation and a limited number of infants. nMDZ was already standard practice in the DR before this work was started, and thus randomization with and without treatment was not feasible. We were therefore unable to confirm that all our results were the exclusive consequence of the intervention. Duration of mechanical ventilation was rather high in our patients, but immediate extubation was not a policy in the NICU during the study period and some of our patients also received continuous intravenous sedation and analgesia to aid in tolerating invasive assisted ventilation following their admission to the unit. Further trials are required to assess the efficacy and safety of nMDZ for strategies such as prophylactic surfactant administration or the intubation–surfactant–extubation procedure. In conclusion, most experts and academic societies have taken a stand for premedication in all newborns before endotracheal intubation, but debate is still open regarding the most adequate protocol, especially in the DR. The main advantage of nMDZ compared with other anesthesia modes is the simplicity and rapidity of administration. However, MDZ lacks analgesic properties, which is a drawback for the objective of achieving optimal sedation–analgesia, whatever the administration route.
J. Baleine et al. / Early Human Development 90 (2014) 39–43
Further randomized trials are required to determine the optimal premedication regimen for intubation in the DR.
Conflict of interest statement The authors report no conflict of interest.
References [1] Barrington KJ, Canadian Paediatric Society, Fetus and Newborn Committee. Premedication for endotracheal intubation in the newborn infant. Paediatr Child Health 2011;16(3):159–64. [2] Schuman TA, Jacobs B, Walsh W, Goudy SL. Iatrogenic perinatal pharyngoesophageal injury: a disease of prematurity. Int J Pediatr Otorhinolaryngol 2010;74(4):393–7. [3] Mahieu HF, de Bree R, Ekkelkamp S, Sibarani-Ponsen RD, Haasnoot K. Tracheal and laryngeal rupture in neonates: complication of delivery or of intubation? Ann Otol Rhinol Laryngol 2004;113(10):786–92. [4] Sarkar S, Schumacher RE, Baumgart S, Donn SM. Are newborns receiving premedication before elective intubation? J Perinatol 2006;26(5):286–9. [5] Walter-Nicolet E, Flamant C, Négréa M, Parat S, Hubert P, Mitanchez D. Premedication before tracheal intubation in French neonatal intensive care units and delivery rooms. Arch Pediatr 2007;14(2):144–9. [6] Hassid S, Nicaise C, Michel F, Vialet R, Thomachot L, Lagier P, et al. Randomized controlled trial of sevoflurane for intubation in neonates. Paediatr Anaesth 2007;17(11):1053–8. [7] Milesi C, Pidoux O, Sabatier E, Badr M, Cambonie G, Picaud JC. Nitrous oxide analgesia for intubating preterm neonates: a pilot study. Acta Paediatr 2006;95(9):1104–8. [8] Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics 2010;126(3):532–7. [9] Ljungman G, Kreuger A, Andréasson S, Gordh T, Sörensen S. Midazolam nasal spray reduces procedural anxiety in children. Pediatrics 2000;105(1 Pt 1):73–8. [10] Harbord MG, Kyrkou NE, Kyrkou MR, Kay D, Coulthard KP. Use of intranasal midazolam to treat acute seizures in paediatric community settings. J Paediatr Child Health 2004;40(9–10):556–8. [11] Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med 2006;24(3):343–6. [12] Harte GJ, Gray PH, Lee TC, Steer PA, Charles BG. Haemodynamic response and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates. J Paediatr Child Health 1997;33(4):335–8. [13] van Alfen-van der Velden AA, Hopman JC, Klaessens JH, Feuth T, Sengers RC, Liem KD. Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants. Biol Neonate 2006;90(3):197–202. [14] VanLooy JW, Schumacher RE, Bhatt-Mehta V. Efficacy of a premedication algorithm for nonemergent intubation in a neonatal intensive care unit. Ann Pharmacother 2008;42(7):947–55.
43
[15] van Straaten HL, Rademaker CM, de Vries LS. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn. Dev Pharmacol Ther 1992;19(4):191–5. [16] Shekerdemian L, Bush A, Redington A. Cardiovascular effects of intravenous midazolam after open heart surgery. Arch Dis Child 1997;76(1):57–61. [17] Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2003(1):CD002052. [18] Rozé JC, Denizot S, Carbajal R, Ancel PY, Kaminski M, Arnaud C, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. Arch Pediatr Adolesc Med 2008;162(8):728–33. [19] Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics 1956;17(1):1–10. [20] Milesi C, Cambonie G, Jacquot A, Barbotte E, Mesnage R, Masson F, et al. Validation of a neonatal pain scale adapted to the new practices in caring for preterm newborns. Arch Dis Child Fetal Neonatal Ed 2010;95(4):F263–6. [21] Gjerstad AC, Wagner K, Henrichsen T, Storm H. Skin conductance versus the modified COMFORT sedation score as a measure of discomfort in artificially ventilated children. Pediatrics 2008;122(4):e848–53. [22] Hullett B, Chambers N, Preuss J, Zamudio I, Lange J, Pascoe E, et al. Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children? Anesthesiology 2009;111(3):513–7. [23] Anand KJ. Pain assessment in preterm neonates. Pediatrics 2007;119(3):605–7. [24] Welzing L, Kribs A, Eifinger F, Huenseler C, Oberthuer A, Roth B. Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates. Paediatr Anaesth 2010;20(7):605–11. [25] Storm H. Skin conductance and the stress response from heel stick in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;83(2):F143–7. [26] Hellerud BC, Storm H. Skin conductance and behaviour during sensory stimulation of preterm and term infants. Early Hum Dev 2002;70(1–2):35–46. [27] Røeggen I, Storm H, Harrison D. Skin conductance variability between and within hospitalised infants at rest. Early Hum Dev 2011;87(1):37–42. [28] Harrison D, Boyce S, Loughnan P, Dargaville P, Storm H, Johnston L. Skin conductance as a measure of pain and stress in hospitalised infants. Early Hum Dev 2006;82(9):603–8. [29] Storm H. Pain assessment in neonates. In: Chen W, Bambang Oetomo S, Feijs L, editors. Neonatal Monitoring Technologies: Design for Integrated Solutions. Hershey: IGI Global; 2012. p. 278–302. [30] Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet 2006;367(9512):766–80. [31] Chiaretti A, Barone G, Rigante D, Ruggiero A, Pierri F, Barbi E, et al. Intranasal lidocaine and midazolam for procedural sedation in children. Arch Dis Child 2011;96(2):160–3. [32] Hägnevik K, Faxelius G, Irestedt L, Lagercrantz H, Lundell B, Persson B. Catecholamine surge and metabolic adaptation in the newborn after vaginal delivery and caesarean section. Acta Paediatr Scand 1984;73(5):602–9. [33] Cambonie G, Dupuy AM, Combes C, Vincenti M, Mesnage R, Cristol JP. Can a clinical decision rule help ductus arteriosus management in preterm neonates? Acta Paediatr 2012;101(5):e213–8.