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Nasotracheal intubation in the neonate: Physiologic responses and effects of atropine and pancuronium
Nasotracheal intubation in the neonate." Physiologic responses and effects of atropine and pancuronium Thirty infants with birth weights from 580 to 3450 gm (25 to 40 weeks gestation) were prospectively studied during nasotracheal intubation. The infants were randomized to receive atropine 0.01 mg/kg, atropine 0.01 mg/kg plus pancuronium 0.1 mg/kg, or no medication (controls) prior to intubation. There was a significant decrease in transcutaneous Poe (27.3 torr, P < 0.02), associated with significant increases in mean arterial blood pressure (57%, P < 0.01) and intracranial pressure (mean increase 18.9 cm HeO, P < 0.01) with intubation in all three groups o f infants. Only in control infants and infants receiving atropine was there significant decrease in heart rate (52.2 and 36.2 bpm, respectively, P < 0.01) during intubation. Control infants experienced a significantly greater decrease in heart rate and demonstrated the lowest mean heart rate, compared with the other two groups. Pancuronium plus atropine was associated with lesser increases in intracranial pressu~'e and with the least changes in heart rate in response to intubation. There was no significant difference between the groups for changes in systemic blood pressure or transcutaneous Poe. Further studies are required to determine the clinical consequences, i f any, o f these responses, and the use o f Pretreatment in the neonate requiring intubation. (J PEDIATR 105:303, 1984)
Marc A. Kelly, M.B., B.S., and Neil N. Finer, M.D., F.R.C.P.(C) Edmonton,
Alta., Canada
INTUBATION OF THE TRACHEA for the provision of mechanical ventilation is frequently required in the critically ill neonate. Although the physiologic responses to this procedure have not been systematically studied in neonates, it is well established that laryngoscopy and tracheal intubation after induction of anesthesia and muscle relaxation in adults without known heart disease can be associated with a 50% to 70% increase in mean arterial pressure and 20% to 38% increases in heart rate) -3 Adults with preexisting cardiovascular disease or hypertension can develop up to 85% increases in mean arterial blood pressure with intubation: Preoperative tracheal intubation of infants has been associated with significant elevations in intracranial pressure, an average increase of 70 cm water being reported in
From the Department o f Newborn Medicine, Royal Alexandra Hospital; and Department o f Pediatrics, University o f Alberta. Submitted for publication Aug. 15, 1983; accepted Feb. 17, 1984. Reprint requests: Neil N.Finer, M.D., Department o f Newborn Medicine, Royal Alexandra Hospital, 10240 Kingsway Ave., Edmonton, Alta. T5H 3V9, Canada.
four infants who underwent tracheal intubation while awake, compared to a ! 9.5 cm increase in five infants who had received D-tubocurare prior to intubation: Neonates respond to various noxious procedures involving nasopharyngeal stimulation with bradycardia, 6 which may represent a maturational imbalance of parasympathetic over sympathetic t o n e : ANOVA CPAP ICP
One-way analysis of variance Continuous positive airway pressure Intracranial pressure
The critically ill neonate who requires tracheal intubation is often hypoxic and needs high inspired oxygen concentrations (FIO2). Intubation in such infants can be associated with bradycardia, hypoxia, and elevations in arterial blood pressure and intracranial pressure. We sought to answer two questions: Does the neonate have physiologic responses similar to those in the adult during intubation? And what mitigating effects on these responses occur with prior injection of atropine alone and with atropine plus pancuronium?
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Table. Clinical data in study infants
Birth weight (gin) Gestatianalage(wk) Study age(hr) Apgar scores at 1 and 5 rnin F102 pH Po2(torr) Pco2(torr) Initial intubation (n) Reintubation (n)
Group 1 Control
Group 2 Atropine
Group 3 Atropine + pancuronium
1833.0 + 1034.0 31.9 • 5.4 39.7 ___ 60.8 4, 7 0.49 • 0.25 7,.29 • 0.07 64.4 • 28.5 45.2 _+ 8.7 6 4
1752.0 • 882.0 31.8 • 5.5 23.0 • 48.0 4, 6 0.56 • 0.28 7.33 • 0.11 64.1 • 42.6 37.0 • 11.9 6 4
2227.0 • 580.0 34.2 • 2.6 I2.5 • 24.3 5, 8 0.46 _+ 0.15 7.28 • 0.12 7.7 • 45.1 41.9 • 13.7 5 5
METHODS All infants were born in the Royal Alexandra Hospital between July 1982 through March 1983 and were admitted to the neonatal intensive care unit. In our nursery we have used nasotracheal intubation in all infants requiring .mechanical ventilation, and any infant requiring nasotracheal intubation during the study period in whom an umbilical or radial artery catheter was in place was eligible for inclusion. The usual indications for intubation were a requirement for mechanical ventilation because of immatilrity, apnea, progressive respiratory distress with rising arterial carbon dioxide tension despite the use Of continuous positive airway pressure, or intractable hypoxia unresponsive to CPAP. In infants who were resuscitated and required intubation in the delivery area, orotracheal tubes were placed, and these infants were studied when the orotracheal tube was replaced by a nasotracheal tube. In all remaining instances, the infants were studied during the insertion Of the initial nasotracheal tube in the NICU. Infants requiring urgent intubation and who could not be stabilized while the recording apparatus was set up were not included in the study. NO infant was studied on more than one occasion. The infant's heart rate was obtained by means of a bedside monitor (Model 78342-A, Hewlett Packard, Waltham, Mass.), and blood pressure was recorded from an umbilical artery catheter placed at T8-T10 or from a radial artery angiocatheter (24- or 22-gauge, Jelco, Critikon, Tampa, Fla.) using a blood pressure transducer (Models 1280 and 1290, Hewlett Packard; or Model 4-327-i, Bell & Howell Instrumentation Division, Pasadena, Calif.). A transcutaneous electrode (Model 633, Roche Medical Electronics, Cranbury, N.J.) was placed on the right side of the upper chest, with the electrode temperature set at 43.5 ~ C; and intracranial pressure was monitored by means of a fiberoptic sensor (Model 1004, Ladd Research Industries, Burlington, Vt.) applied to the infant's shaved anterior fontanelle, with an ECG electrode
(Model 01-0115, NDM, Dayton, Ohio), from which the electrode sponge and gel had been removed and replaced with a small wad of cotton batting.8 Immediately after identification of an infant suitable for study, his or her arterial blood pressure transducer was calibrated, the I C P probe was placed on the anterior fontaneUe, and all four previously mentioned variables were then recorded (Model 7404A, Hewlett Packard). A stable baseline record was obtained with the infant in the position for tracheal intubation for a minimum of 5 minutes prior to the procedure or to any drug administration. The recording was then carried out continuously throughout the procedur e , which included the actual intubation and taping of the endotracheal tube, and was followed by a further 5-minute stabilization period. All intubations were performed by us. All infants received high inspired oxygen concentrations until the transcutaneous Po2 (tcPo2) was at least 80 torr (when possible) immediately before the beginning of the intubation procedure. When necessary, this was accomplished by using a Jackson-Rees bag and mask. Every attempt was made during the procedure to be gentle, to avoid hyperextension of the neck, and to keep the infant's head in the midline position. During intubation, all infants were placed under an overhead radiant warmer, with the temperature servocontrolled to 36.8 ~ C and the bed in the level position. We used a no. 0 straight-bladed laryngoscope (No. 68500, Welch Allyn, Skan Falls, N.Y.) and a pediatric Magill forceps, with a 3.0 or 3.5 French endotracheal tube (Portex Blueline, Wilmington, Mass.). The intubation procedure began with the insertion of the endotracheal tube into the nostril, and ended when the tube was introduced into the trachea. A flow of oxygen through the endotracbeal tube at 3 to 5 L / m i n was maintained during the intubation procedure. The endotracheal tube was taped in position by means of a circumferential tape around the head and over the upper lip and endotracheal tube.
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The study was designed as a nonblinded prospective randomized evaluation of 30 neonates requiring intubation, of whom 10 would be controls (group I) and 10 each would receive pretreatment intravenous by with atropine (group 2) atropine plus pancuronium bromide (group 3). Patients were randomized prospectively into the three groups by computer program. Group 2 patients received atropine 0.01 mg/kg I V at least 3 minutes prior to the Procedure. Group 3 infants received atropine 0.01 mg/kg IV at least 3 minute s prior to intubation, plus pancuronium 0.1 mg/kg IV at least 2 minutes prior to intubation. No p!acebo was used. Statistical analysis was by Student paired t test, onewaY analysis of variance, chi-square, and Pearson correlation coefficient, with P < 0.05 being significant. Infant characteristics and measurements obtained for each study were entered into a 40 X 75 cell matrix, and an A N O V A was calculated for each of the 75 variables. All values reaching statistical significance are reported. A Scheffe test Was appl!ed to all statistically significant values by A N O V A to determine significant intergroup differences. The study protocol was approved by the Clinical Investigation Committee of the Royal Alexandra Hospital. RESULTS The birth weight, gestational age, Apgar scores, age at the time of the study, FIO2, and arterial blood gas values prior to the beginning of the study (before preoxygenation preceding the intubation) were compared for the three groups (Table). Although there were large clinical differences in birth weight and gestation, there were no significant differences in any of these categories between groups (ANOVA, all f values <1.9), no doubt secondary to the large standard errors. There were similar numbers of infants in each group studie d during an initial endotracheal insertion or during a change from an orotracheal to a nasotracheal tube. Heart rate. The baseline heart rate was similar in all
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Fig. 2. Comparison of the response to endotracheal intubation in an infant given atropine (A) and in a control infant (B). The infant who received atropine had a lesser decrease in heart rate, and both infants experienced significant increases in intracranial pressure and blood pressure and decrease in Po2. In neither infant did Poz fall below 40 torr during the procedure. JR, Manual ventilation with Jackson-Rees bag and mask.
groups. Infants receiving atropine did have small but significant increases in heart rate from the stable baseline period prior to drug administration, compared with heart rate just prior to the intubation (mean increase 10.6 bpm, P < 0.05), as did infants receiving atropine and pancuronium (mean increase 13.6 bpm, P < 0.01). The highest heart rate observed during the study was 210 bpm, and no arrhythmias were noted. Heart rates recorded during intubation were compared with those present immediately prior to initiating the intubation procedure, rather than with baseline values. This comparison was thought to be more representative of the actual effect on heart rate of the procedures themselves. A statistically significant decrease in heart rate was associated with intubation in infants in both group l and group 2, whereas infants in group 3 experienced no significant decreases (7.3 bpm, P > 0.05, Fig. 1). The decrease in heart rate was significantly greater for both the control group (52.2 bpm) and group 2 (36.2 bpm) compared with group 3 (7.3 bpm, 7.45, P < 0.01). Whereas no infants who received atropine or atropine plus pancuronium had heart rate <80 bpm during the procedure, three of the 10 control infants had rates of 60, 68, and 72 bpm, and this difference was significant (X2 = 6.67, P = 0.035). The temporal relationship for the response to intubation between changes in heart rate and changes in other measurements is demonstrated in Fig. 2
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Fig. 4. Changes in blood pressure with endotracheal intubation compared with baseline, with all increases being statistically significant. T; Standard error of the mean.
(response in a control infant compared with that in a neonate receiving atropine). ' There were no significant associations between any of the clinical variables, including birth weight and gestational and study age, versus the measured physiologic responses, including baseline heart rate and changes in heart rate during intubation. tePo2. There was .a significant decrease in tcPo2 in infants in all three groups (mean 27.3 torr) (Fig. 3, all P values <0.02), and the fall in tcPo: was not significantly different for any of the groups. The lowest preintubation tcPo2 value was 78 t o r r , ' a n d the lowest value during intubation was 36 torr. There were no significant relationships between the decrease in tcPo2 and any of the clinical variables, including birth weight and gestational and study age, or the measured physiologic responses. Blood pressure. All infants experienced an increase in mean blood pressure during the intubation procedure. The increase from the baseline for blood pressure (systolic, diastolic, and mean) was statistically significant in all three groups, with increases of systolic, diastolic, and mean arterial pressure, respectivelY, of 28.3, 21.9, and 24.0 mm Hg in group 1; 24.7, 18.6, and 18.4 mm Hg in group 2; and 17.8, 14.6, and 17.2 mm Hg in group 3 (P < 0.01 for all groups, Fig. 4). These changes represented an average 57% increase in mean arterial pressure. The increase in blood pressure began with the insertion of the endotracheal tube through the nose (Fig. 2). The mean blood pressure was >20% above the baseline for an average of 25.5 seconds during the intubation, and was similar in all the groups. The smallest infant (group 1, birth weight 580 gm, who underwent intubation at 2 hours of age during a change from orotracheal to nasotracheal tube) was the only one to
demonstrate a decrease in blood pressure. This infant had a rapid onset of bradycardia associated with a rise in pulse pressure and a fall in diastolic and mean blood pressure during the insertion of the tube through the vocal cords; a similar response was noted during palpation of the endotracheal tube position in the trachea (Fig. 5). Significant intermittent elevations in blood pressure values (28, 21, and 21.4 mm Hg for systolic, diastolic, and mean arterial pressure respectively, P < 0.001) associated with sustained elevations in intracranial pressure (22.2 cm H20, P < 0.01) were seen in all five infants in group 3 who required bag and mask ventilation just prior to intubation. These were infants undergoing initial intubation, as compared With the other five infants, in whom an orotracheal tube was changed for a nasotracheal tube. In these infants manual ventilation was performed with the bag and mask to allow at least 2 minutes between pancuronium bromide administration and initial intubation to ensure complete muscle relaxation) A maximum of 15 seconds was found sufficient to allow ICP and blood pressure changes to return to baseline prior to initiating the intubation procedure. lntraeranial pressure. ICP increased in all infants studied with the exception of three infants in group 3 (mean overall increase 18.9 cm H20). The average increase in ICP compared with baseline premedication values was 19.8 cm in the control infants, 24.8 cm in the infants given atropine, and 11.6 cm in infants receiving pancuronium; all of these changes were significant when compared with baseline (P < 0.01 for all groups, Fig. 6). The infants in group 3 demonstrated a significantly lesser rise in tCP with intubation (f2,27 = 3.37, P < 0.05). There were no significant associations between either ICP or
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Fig. 5. Response to endotracheal intubation in a 850 gm infant in group 1. Immediately after passage of the endotracheal tube through this infant's vocal cords, there was rapid onset of bradycardia associated with a brief decrease in blood pressure and an associated increase in pulse pressure. At palpation of the tip of the infant's endotracheal tube (P), there was another rapid onset episode of bradycardia and an associated brief decrease in blood pressure. JR, Manual ventilation with Jackson-Rees bag and mask. blood pressure changes during intubation and any clinical or physiologic measure, including birth weight and gestational and study age. Infants undergoing intubation for the first time were compared with infants undergoing reintubation, and no significant intragroup or intergroup differences were noted. The average duration of intubation, from insertion of the endotracheal tube in the nose until it was placed in the trachea, was 32 _+ 13.2 seconds, and the time from insertion of the laryngoscope in the mouth to the insertion through the vocal cords was 26 _+ 10.4 seconds; there were no significant differences among the three groups. DISCUSSION Our data demonstrate that nasotracheal intubation in the neonate is associated with significant increases in blood pressure and intracranial pressure and significant decreases in heart rate and tcPo2. The mean increase in blood pressure seen in our patients is similar to that previously reported in adults without preexisting hypertension or cardiovascular disease undergoing intubationY-n These adults were studied after induction of anesthesia while receiving muscle relaxants, demonstrating that the muscle relaxants did not alter the blood pressure response to intubation, similar to our observations in neonatesY ~ The cardiovascular response to intubation in adults is most probably a sympathetic
llosellne
Intu~lion
Group I
Group II
Group III
Fig. 6. Changes in intracranial pressure associated with endotracheal intubation. All changes are statistically significant. T, Standard error of mean. response to stimulation of the upper respiratory tract. This hypothesis is supported by the observations of Tomori and Widdicombe, ~ who noted significant tachycardia and hypertension associated with enhanced cervical sympathetic efferent activity after stimulation of the epipharynx and laryngopharyngeal regions in cats. Prys-Roberts et al. ~2 subsequently established that practolol, a B-blocker, effectively attenuated the cardiovascular reaction to laryngoscopy and intubation in adults. However, the cardiovascular response to intubation in neonates more closely parallels the response in the newborn lamb with laryngeal chemoreceptor stimulation elicited by injecting water into the larynx, and to stimulation of the trigeminal diving reflex by cooling of the snout. The newborn lamb responds to such stimulation with immediate apnea associated with hypertension, bradycardia, decrease in cardiac output proportional to the decrease in heart rate, and a significant increase in systemic vascular resistance.~3 The typical response to intubation in our series was an overall increase in arterial blood pressure in the face of a decreasing heart rate. Rudolph and Heymann TM have shown a linear relationship for both right and left ventricular outputs in response to changes in heart rate in the fetal lamb. The ability of the fetus to make compensatory changes in stroke volume is severely restricted because of the immaturity of the myocardium and the lack of sympathetic innervation to the ventriclesY Thus cardiac output will decrease in response to the decrease in heart rate during intubation, and the observed increase in blood pressure is most likely the result of an increase in systemic vascular resistance similar to that in the newborn lamb in response to the laryngeal chemoreflex and trigeminal diving reflex. In lambs, the apnea and associated cardio-
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vascular changes can be prevented by prior administration of a fl~-agonist, whereas these changes are aggravated by propranolol. 13 In view of these observations, the use of fl-blocking agents to alter the pressor response to intubation in neonates cannot be recommended. In our study, mean blood pressure increased by 57% over the entire group, with no attenuating effect noted from premedication with either atropine or atropine plus pancuronium. A hypertensive response was noted to laryngoscopy and to the endotracheal tube being inserted through the vocal cords. In the majority of circumstances, these responses could not be separated. Stoelting ~ has shown a relationship between the duration of direct laryngoscopy and the increase in mean arterial blood pressure in adults. As a result, prolonged laryngoscopy associated with difficult intubations may be associated with greater rises in blood pressure in neonates. We found no association between the duration of intubation and rise in blood pressure. The observed rise in blood pressure during endotracheal intubation may be significant in the pathogenesis of intraventricular hemorrhage, which has been detected after sudden increases in blood pressure associated with pneumothorax ~5 and ductus ligation, ~6 although these increases were less than those we observed. Wimberley et al) 7 observed that infants of <1500 gm who developed intraventricular hemorrhage had higher peak mean arterial blood pressure values when compared with matched control infants on the second and third days of life. The infants who received atropine or atropine plus pancuronium (n -- 20) did show a small but significant rise in heart rates prior to drug administration when compared with those just prior to the intubation procedure. This change was not seen in our control infants, and therefore confirms a drug effect. Pancuronium can cause an increase in heart rate?. ~8although the increase we noted was similar in groups 2 and 3 and was no doubt more a result of the atropine administered. Although bradycardia can occur in a reflex fashion from pharyngeal stimulation, 6 heart rate can also decrease in response to a decreased oxygen saturation, an effect thought to be mediated through the carotid chemoreceptor arch. 19 The bradycardia we observed was almost always of rapid onset (Fig. 2), suggesting a parasympathetic response to stimulation of the larynx and pharynx or trigeminal region. The group 3 infants had significantly fewer marked decreases in heart rate, suggesting synergism between these two agents consistent with the observations that pancuronium, like atropine, blocks cardiac muscarinic receptors? ~ The neonate can become rapidly hypoxic in response to a variety of procedures, such as suctioning, physiotherapy, and weighing, a~ and the decrease tcP02 observed with
The Journal of Pediatrics August 1984
intubation is consistent with these observations. The greater amplitude of this decrease may be explained by the less effective oxygen administration during the procedure and the general instability of infants studied. Our observed lag time in the response of the tcP02 electrode to a fall in oxygen was in the range of 8 to 14 seconds, consistent with the observations of others. 22 The decrease in skin perfusion associated with an increase in systemic vascular resistance may have contributed to some of the decrease in tcP02 during intubation. However, we have observed similar decreases in Pa02 during intubation as measured by an umbilical artery catheter tip electrode (G. D. Searle, Bucks, England), which is unaffected by alterations in systemic vascular resistance. We have previously shown that pancuronium will reduce the spikes in intracranial pressure >25 cm and durations of high ICP, as well as reduce periods of hypoxia and hyperoxia in the critically ill neonate during ventilation. 1~ White et al. 23 demonstrated that intravenously administered succinylcholine abolished the ICP response to endotracheal tube suctioning in adults, compared with thiopental, lidocaine, or fentanyl given intravenously or lidocaine endotracheally, whereas none of the drug therapies prevented a significant rise in blood pressure. Fisher et al. 14 studied nine children, all of whom were receiving neuromuscular blockage, and demonstrated a mean increase of 7 mm Hg in mean arterial pressure associated with a 6 mm Hg increase in ICP during suctioning of the endotracheal tube, similar to the mean increase in ICP seen in our group 3 infants. They also noted a small but significant increase in end-tidal Pc02 during the 30 seconds that the ventilator was disconnected, and postulated that part of the increase in ICP may have been a result of an increase in cerebral blood flow secondary to the increased Paco~) 5 The increase in ICP associated with laryngoscopy and intubation is probably influenced by many factors. There may be a slight but significant increase in Pat02 during intubation, with a resultant increase in cerebral blood flow and ICP. The infant's intrathoracic pressure may rise as a consequence of struggling, leading to an increase in cerebrovenous pressure. In addition, hyperextension of the neck may also impede venous return, increasing ICP. The three infants with no change in ICP during intubation all had received pancuronium, supporting the role of struggling and motor activity in the ICP increase. There was no association between the increase in ICP and the increase in blood pressure associated with intubation; in our group 3 infants increases in blood pressure were similar to those in the other infants, but increases in ICP were markedly lower. Intracranial pressure as measured by the Ladd fiberoptic sensor has been shown to correlate well with direct
Volume 105 Number 2
Physiologic responses to intubation in neonates
m e a s u r e m e n t s obtained at l u m b a r p u n c t u r e a n d ventriculostomy. 26 M e y e r b e r g et al. 27 reported a m a x i m u m response time with this device of 1.6 c m H 2 0 per second. W e recorded a m a x i m u m response of 1.57 c m H 2 0 per second when c o m p a r e d with t h a t recorded with o t h e r s t a n d a r d transducers ( S t a t h a m P M - 1 3 1 - T C , Gould M e d i cal I n s t r u m e n t s , Oxnard, Calif.; and Hewlett P a c k a r d Model 1280). This sensor markedly underestimates t h e m a x i m a l response seen during these procedures, as well as the m a x i m a l rate of rise. O u r d a t a suggest t h a t the physiologic changes associated with endotracheal intubation represent b o t h reflex cardiovascular responses, including b r a d y c a r d i a a n d hypertension, a n d nonreflex responses, which m a y represent struggling and mechanical effects. F u r t h e r studies are required to determine the clinical significance of the alterations in h e a r t rate, intracranial pressure, a n d blood pressure, a n d should include diagnostic cranial ultrasound studies immediately before and after intubation. We thank the medical and nursing staffs of the neonatal intensive care unit for their cooperation; Dr. P. Etches and Dr. E. G. King for their thoughtful review and criticism; Miss K. Peters for technical assistance and advice; and Mrs. C. Gadallah and Mrs. M. Shelling for secretarial assistance in preparation of the manuscript.
10.
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13. 14.
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18. 19.
REFERENCES 1. Stoelting RK: Circulatory changes during direct laryngoscopy and tracheal intubation: Influence of duration of laryngoscopy with or without prior Lidocaine. Anesthesiology 47:381, 1977. 2. Abou-Madi M, Keszler H, Yacoub O: A method for prevention of cardiovascular reactions to laryngoscopy and intubation. Can Anaesth Soe J 22:316, 1975. 3. Kautto UM: Attenuation of the circulatory response to laryngoscopy and intubation by fentanyl. Acta Anaesthesiol Scand 26:217, 1982. 4. Martin DE, Rosenberg H, Aukburg S J, Bartkowski RR, Edwards MW, Greenhow ED, Klineberg PL: Low-dose fentany] blunts circulatory responses to tracheal intubation. Anesth Analg 61:680, 1982. 5. Raju RNK, Vidyasagar D, Torres C, Grundy D, Bennett E J: Intracraniat pressure during intubation and anesthesia in infants. J PEDIArR 96:860, 1980. 6. Cordero L Jr, Hon EH: Neonatal bradycardia following nasopharyngeal stimulation. J PEDIATR 78:441, 1971. 7. Friedman WF: The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15:87, 1972. 8. Finer NN: Never trendsin continuous monitoring of critically ill infants and children. Pediatr Clin North Am 27:553, 1980. 9. Nugent SK, Laravuso R, Rogers MC: Pharmacology and use
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of muscle relaxants in infants and children. J PEDIATR 94:481, 1979. Finer NN, Tomney PM: Controlled evaluation of muscle relaxation in the ventilated neonate. Pediatrics 67:641, 1981. Tomori Z, Widdicombe JG: Muscular, bronchomotor and cardiovascular reflexes elicited by mechanical stimulation of the respiratory tract. J Physiol 200:25, 1969. Prys-Roberts C, Foex P, Biro GP, Roberts JG: Studies of anaesthesia in relation to hypertension. V. Adrenergic betareceptor blockade. Br J Anaesth 45:671, 1973. Grogaard J, Sundell H: Effect of beta-adrenergic agonists on apnea reflexes in newborn lambs. Pediatr Res 17:213, 1983. Rudolph AM, Heymann MA: Cardiac output in the fetal lamb: The effects of spontaneous and induced changes of heart rate on right and left ventricular output. Am J Obstet Gynecol 124:183, 1976. Hill A, Perlman JM, Volpe J J: The relationship of pneumothorax to the occurrence of intraventricular hemorrhage in the premature newborn. Pediatrics 69:144, 1981. Marshall TA, Marshall F lI, Reddy PP: Physiologic changes associated with ligation of the ductus arteriosus in preterm infants. J PEDIATR 101:749, 1982. Wimberley PD, Lou HC, Pedersen H, Hejl M, Lassen NA, Friis-Hansen B: Hypertensive peaks in the pathogenesis of intraventricular hemorrhage in the newborn, abolition by phenobarbitone sedation. Acta Paediatr Scand 71:537, 1982. Bennett, E J, Ramamurthy S, Dalal FY, Salem MR: Pancuronium and the neonate. Br J Anaesth 47:75, 1975. Levy MN, DeGeest H, Zieske H: Effects of respiratory center activity on the heart. Circ Res 18:67, 1966. Bowman WC: Non-relaxant properties of neuromuscular blocking drugs. Br J Anaesth 54:147, 1982. Danford DA, Miske S, Headley J, Nelson RM: Effects of routine care procedures on transcutaneous oxygen in neonates: A quantitative approach. Arch Dis Child 58:20, 1983. Abu-Osba YK, Thach BT, Brouillette RT: Evaluation of response time of a transcutaneous oxygen tension electrode. Pediatr Res 15:143, 1981. White PF, Schlobohm RM, Pitts LH, Lindauer JM: A randomized study of drugs for preventing increases in intracranial pressure durig endotracheal suctioning. Anesthesiology 57:242, 1982. Fisher DM, Frewen T, Swedlow DB. Increase in intracranial pressure during suctioning: Stimulation vs. rise in Paco2. Anesthesiology 57:416, 1982. Smith AL, Wollman H: Cerebral blood flow and metabolism: Effects of anesthetic drugs and techniques. Anesthesiology 36:378, 1972. Hill A, Volpe J J: Measurement of intracranial pressure using the Ladd intracranial pressure monitor. J PEDIATR 98:974, 1981. Myerberg DZ, York C, Chaplin ER, Gregory GA: Comparison of noninvasive and direct measurements of intracraniat pressure. Pediatrics 65:473, 1980.
Marc A. Kelly, M.B., B.S., and Neil N. Finer, M.D., F.R.C.P.(C) Edmonton,
Alta., Canada
INTUBATION OF THE TRACHEA for the provision of mechanical ventilation is frequently required in the critically ill neonate. Although the physiologic responses to this procedure have not been systematically studied in neonates, it is well established that laryngoscopy and tracheal intubation after induction of anesthesia and muscle relaxation in adults without known heart disease can be associated with a 50% to 70% increase in mean arterial pressure and 20% to 38% increases in heart rate) -3 Adults with preexisting cardiovascular disease or hypertension can develop up to 85% increases in mean arterial blood pressure with intubation: Preoperative tracheal intubation of infants has been associated with significant elevations in intracranial pressure, an average increase of 70 cm water being reported in
From the Department o f Newborn Medicine, Royal Alexandra Hospital; and Department o f Pediatrics, University o f Alberta. Submitted for publication Aug. 15, 1983; accepted Feb. 17, 1984. Reprint requests: Neil N.Finer, M.D., Department o f Newborn Medicine, Royal Alexandra Hospital, 10240 Kingsway Ave., Edmonton, Alta. T5H 3V9, Canada.
four infants who underwent tracheal intubation while awake, compared to a ! 9.5 cm increase in five infants who had received D-tubocurare prior to intubation: Neonates respond to various noxious procedures involving nasopharyngeal stimulation with bradycardia, 6 which may represent a maturational imbalance of parasympathetic over sympathetic t o n e : ANOVA CPAP ICP
One-way analysis of variance Continuous positive airway pressure Intracranial pressure
The critically ill neonate who requires tracheal intubation is often hypoxic and needs high inspired oxygen concentrations (FIO2). Intubation in such infants can be associated with bradycardia, hypoxia, and elevations in arterial blood pressure and intracranial pressure. We sought to answer two questions: Does the neonate have physiologic responses similar to those in the adult during intubation? And what mitigating effects on these responses occur with prior injection of atropine alone and with atropine plus pancuronium?
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Table. Clinical data in study infants
Birth weight (gin) Gestatianalage(wk) Study age(hr) Apgar scores at 1 and 5 rnin F102 pH Po2(torr) Pco2(torr) Initial intubation (n) Reintubation (n)
Group 1 Control
Group 2 Atropine
Group 3 Atropine + pancuronium
1833.0 + 1034.0 31.9 • 5.4 39.7 ___ 60.8 4, 7 0.49 • 0.25 7,.29 • 0.07 64.4 • 28.5 45.2 _+ 8.7 6 4
1752.0 • 882.0 31.8 • 5.5 23.0 • 48.0 4, 6 0.56 • 0.28 7.33 • 0.11 64.1 • 42.6 37.0 • 11.9 6 4
2227.0 • 580.0 34.2 • 2.6 I2.5 • 24.3 5, 8 0.46 _+ 0.15 7.28 • 0.12 7.7 • 45.1 41.9 • 13.7 5 5
METHODS All infants were born in the Royal Alexandra Hospital between July 1982 through March 1983 and were admitted to the neonatal intensive care unit. In our nursery we have used nasotracheal intubation in all infants requiring .mechanical ventilation, and any infant requiring nasotracheal intubation during the study period in whom an umbilical or radial artery catheter was in place was eligible for inclusion. The usual indications for intubation were a requirement for mechanical ventilation because of immatilrity, apnea, progressive respiratory distress with rising arterial carbon dioxide tension despite the use Of continuous positive airway pressure, or intractable hypoxia unresponsive to CPAP. In infants who were resuscitated and required intubation in the delivery area, orotracheal tubes were placed, and these infants were studied when the orotracheal tube was replaced by a nasotracheal tube. In all remaining instances, the infants were studied during the insertion Of the initial nasotracheal tube in the NICU. Infants requiring urgent intubation and who could not be stabilized while the recording apparatus was set up were not included in the study. NO infant was studied on more than one occasion. The infant's heart rate was obtained by means of a bedside monitor (Model 78342-A, Hewlett Packard, Waltham, Mass.), and blood pressure was recorded from an umbilical artery catheter placed at T8-T10 or from a radial artery angiocatheter (24- or 22-gauge, Jelco, Critikon, Tampa, Fla.) using a blood pressure transducer (Models 1280 and 1290, Hewlett Packard; or Model 4-327-i, Bell & Howell Instrumentation Division, Pasadena, Calif.). A transcutaneous electrode (Model 633, Roche Medical Electronics, Cranbury, N.J.) was placed on the right side of the upper chest, with the electrode temperature set at 43.5 ~ C; and intracranial pressure was monitored by means of a fiberoptic sensor (Model 1004, Ladd Research Industries, Burlington, Vt.) applied to the infant's shaved anterior fontanelle, with an ECG electrode
(Model 01-0115, NDM, Dayton, Ohio), from which the electrode sponge and gel had been removed and replaced with a small wad of cotton batting.8 Immediately after identification of an infant suitable for study, his or her arterial blood pressure transducer was calibrated, the I C P probe was placed on the anterior fontaneUe, and all four previously mentioned variables were then recorded (Model 7404A, Hewlett Packard). A stable baseline record was obtained with the infant in the position for tracheal intubation for a minimum of 5 minutes prior to the procedure or to any drug administration. The recording was then carried out continuously throughout the procedur e , which included the actual intubation and taping of the endotracheal tube, and was followed by a further 5-minute stabilization period. All intubations were performed by us. All infants received high inspired oxygen concentrations until the transcutaneous Po2 (tcPo2) was at least 80 torr (when possible) immediately before the beginning of the intubation procedure. When necessary, this was accomplished by using a Jackson-Rees bag and mask. Every attempt was made during the procedure to be gentle, to avoid hyperextension of the neck, and to keep the infant's head in the midline position. During intubation, all infants were placed under an overhead radiant warmer, with the temperature servocontrolled to 36.8 ~ C and the bed in the level position. We used a no. 0 straight-bladed laryngoscope (No. 68500, Welch Allyn, Skan Falls, N.Y.) and a pediatric Magill forceps, with a 3.0 or 3.5 French endotracheal tube (Portex Blueline, Wilmington, Mass.). The intubation procedure began with the insertion of the endotracheal tube into the nostril, and ended when the tube was introduced into the trachea. A flow of oxygen through the endotracbeal tube at 3 to 5 L / m i n was maintained during the intubation procedure. The endotracheal tube was taped in position by means of a circumferential tape around the head and over the upper lip and endotracheal tube.
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The study was designed as a nonblinded prospective randomized evaluation of 30 neonates requiring intubation, of whom 10 would be controls (group I) and 10 each would receive pretreatment intravenous by with atropine (group 2) atropine plus pancuronium bromide (group 3). Patients were randomized prospectively into the three groups by computer program. Group 2 patients received atropine 0.01 mg/kg I V at least 3 minutes prior to the Procedure. Group 3 infants received atropine 0.01 mg/kg IV at least 3 minute s prior to intubation, plus pancuronium 0.1 mg/kg IV at least 2 minutes prior to intubation. No p!acebo was used. Statistical analysis was by Student paired t test, onewaY analysis of variance, chi-square, and Pearson correlation coefficient, with P < 0.05 being significant. Infant characteristics and measurements obtained for each study were entered into a 40 X 75 cell matrix, and an A N O V A was calculated for each of the 75 variables. All values reaching statistical significance are reported. A Scheffe test Was appl!ed to all statistically significant values by A N O V A to determine significant intergroup differences. The study protocol was approved by the Clinical Investigation Committee of the Royal Alexandra Hospital. RESULTS The birth weight, gestational age, Apgar scores, age at the time of the study, FIO2, and arterial blood gas values prior to the beginning of the study (before preoxygenation preceding the intubation) were compared for the three groups (Table). Although there were large clinical differences in birth weight and gestation, there were no significant differences in any of these categories between groups (ANOVA, all f values <1.9), no doubt secondary to the large standard errors. There were similar numbers of infants in each group studie d during an initial endotracheal insertion or during a change from an orotracheal to a nasotracheal tube. Heart rate. The baseline heart rate was similar in all
~i '
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200 P020
Tc (torr) ~
Fig. 2. Comparison of the response to endotracheal intubation in an infant given atropine (A) and in a control infant (B). The infant who received atropine had a lesser decrease in heart rate, and both infants experienced significant increases in intracranial pressure and blood pressure and decrease in Po2. In neither infant did Poz fall below 40 torr during the procedure. JR, Manual ventilation with Jackson-Rees bag and mask.
groups. Infants receiving atropine did have small but significant increases in heart rate from the stable baseline period prior to drug administration, compared with heart rate just prior to the intubation (mean increase 10.6 bpm, P < 0.05), as did infants receiving atropine and pancuronium (mean increase 13.6 bpm, P < 0.01). The highest heart rate observed during the study was 210 bpm, and no arrhythmias were noted. Heart rates recorded during intubation were compared with those present immediately prior to initiating the intubation procedure, rather than with baseline values. This comparison was thought to be more representative of the actual effect on heart rate of the procedures themselves. A statistically significant decrease in heart rate was associated with intubation in infants in both group l and group 2, whereas infants in group 3 experienced no significant decreases (7.3 bpm, P > 0.05, Fig. 1). The decrease in heart rate was significantly greater for both the control group (52.2 bpm) and group 2 (36.2 bpm) compared with group 3 (7.3 bpm, 7.45, P < 0.01). Whereas no infants who received atropine or atropine plus pancuronium had heart rate <80 bpm during the procedure, three of the 10 control infants had rates of 60, 68, and 72 bpm, and this difference was significant (X2 = 6.67, P = 0.035). The temporal relationship for the response to intubation between changes in heart rate and changes in other measurements is demonstrated in Fig. 2
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Fig. 4. Changes in blood pressure with endotracheal intubation compared with baseline, with all increases being statistically significant. T; Standard error of the mean.
(response in a control infant compared with that in a neonate receiving atropine). ' There were no significant associations between any of the clinical variables, including birth weight and gestational and study age, versus the measured physiologic responses, including baseline heart rate and changes in heart rate during intubation. tePo2. There was .a significant decrease in tcPo2 in infants in all three groups (mean 27.3 torr) (Fig. 3, all P values <0.02), and the fall in tcPo: was not significantly different for any of the groups. The lowest preintubation tcPo2 value was 78 t o r r , ' a n d the lowest value during intubation was 36 torr. There were no significant relationships between the decrease in tcPo2 and any of the clinical variables, including birth weight and gestational and study age, or the measured physiologic responses. Blood pressure. All infants experienced an increase in mean blood pressure during the intubation procedure. The increase from the baseline for blood pressure (systolic, diastolic, and mean) was statistically significant in all three groups, with increases of systolic, diastolic, and mean arterial pressure, respectivelY, of 28.3, 21.9, and 24.0 mm Hg in group 1; 24.7, 18.6, and 18.4 mm Hg in group 2; and 17.8, 14.6, and 17.2 mm Hg in group 3 (P < 0.01 for all groups, Fig. 4). These changes represented an average 57% increase in mean arterial pressure. The increase in blood pressure began with the insertion of the endotracheal tube through the nose (Fig. 2). The mean blood pressure was >20% above the baseline for an average of 25.5 seconds during the intubation, and was similar in all the groups. The smallest infant (group 1, birth weight 580 gm, who underwent intubation at 2 hours of age during a change from orotracheal to nasotracheal tube) was the only one to
demonstrate a decrease in blood pressure. This infant had a rapid onset of bradycardia associated with a rise in pulse pressure and a fall in diastolic and mean blood pressure during the insertion of the tube through the vocal cords; a similar response was noted during palpation of the endotracheal tube position in the trachea (Fig. 5). Significant intermittent elevations in blood pressure values (28, 21, and 21.4 mm Hg for systolic, diastolic, and mean arterial pressure respectively, P < 0.001) associated with sustained elevations in intracranial pressure (22.2 cm H20, P < 0.01) were seen in all five infants in group 3 who required bag and mask ventilation just prior to intubation. These were infants undergoing initial intubation, as compared With the other five infants, in whom an orotracheal tube was changed for a nasotracheal tube. In these infants manual ventilation was performed with the bag and mask to allow at least 2 minutes between pancuronium bromide administration and initial intubation to ensure complete muscle relaxation) A maximum of 15 seconds was found sufficient to allow ICP and blood pressure changes to return to baseline prior to initiating the intubation procedure. lntraeranial pressure. ICP increased in all infants studied with the exception of three infants in group 3 (mean overall increase 18.9 cm H20). The average increase in ICP compared with baseline premedication values was 19.8 cm in the control infants, 24.8 cm in the infants given atropine, and 11.6 cm in infants receiving pancuronium; all of these changes were significant when compared with baseline (P < 0.01 for all groups, Fig. 6). The infants in group 3 demonstrated a significantly lesser rise in tCP with intubation (f2,27 = 3.37, P < 0.05). There were no significant associations between either ICP or
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Physiologic responses to intubation in neonates
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Fig. 5. Response to endotracheal intubation in a 850 gm infant in group 1. Immediately after passage of the endotracheal tube through this infant's vocal cords, there was rapid onset of bradycardia associated with a brief decrease in blood pressure and an associated increase in pulse pressure. At palpation of the tip of the infant's endotracheal tube (P), there was another rapid onset episode of bradycardia and an associated brief decrease in blood pressure. JR, Manual ventilation with Jackson-Rees bag and mask. blood pressure changes during intubation and any clinical or physiologic measure, including birth weight and gestational and study age. Infants undergoing intubation for the first time were compared with infants undergoing reintubation, and no significant intragroup or intergroup differences were noted. The average duration of intubation, from insertion of the endotracheal tube in the nose until it was placed in the trachea, was 32 _+ 13.2 seconds, and the time from insertion of the laryngoscope in the mouth to the insertion through the vocal cords was 26 _+ 10.4 seconds; there were no significant differences among the three groups. DISCUSSION Our data demonstrate that nasotracheal intubation in the neonate is associated with significant increases in blood pressure and intracranial pressure and significant decreases in heart rate and tcPo2. The mean increase in blood pressure seen in our patients is similar to that previously reported in adults without preexisting hypertension or cardiovascular disease undergoing intubationY-n These adults were studied after induction of anesthesia while receiving muscle relaxants, demonstrating that the muscle relaxants did not alter the blood pressure response to intubation, similar to our observations in neonatesY ~ The cardiovascular response to intubation in adults is most probably a sympathetic
llosellne
Intu~lion
Group I
Group II
Group III
Fig. 6. Changes in intracranial pressure associated with endotracheal intubation. All changes are statistically significant. T, Standard error of mean. response to stimulation of the upper respiratory tract. This hypothesis is supported by the observations of Tomori and Widdicombe, ~ who noted significant tachycardia and hypertension associated with enhanced cervical sympathetic efferent activity after stimulation of the epipharynx and laryngopharyngeal regions in cats. Prys-Roberts et al. ~2 subsequently established that practolol, a B-blocker, effectively attenuated the cardiovascular reaction to laryngoscopy and intubation in adults. However, the cardiovascular response to intubation in neonates more closely parallels the response in the newborn lamb with laryngeal chemoreceptor stimulation elicited by injecting water into the larynx, and to stimulation of the trigeminal diving reflex by cooling of the snout. The newborn lamb responds to such stimulation with immediate apnea associated with hypertension, bradycardia, decrease in cardiac output proportional to the decrease in heart rate, and a significant increase in systemic vascular resistance.~3 The typical response to intubation in our series was an overall increase in arterial blood pressure in the face of a decreasing heart rate. Rudolph and Heymann TM have shown a linear relationship for both right and left ventricular outputs in response to changes in heart rate in the fetal lamb. The ability of the fetus to make compensatory changes in stroke volume is severely restricted because of the immaturity of the myocardium and the lack of sympathetic innervation to the ventriclesY Thus cardiac output will decrease in response to the decrease in heart rate during intubation, and the observed increase in blood pressure is most likely the result of an increase in systemic vascular resistance similar to that in the newborn lamb in response to the laryngeal chemoreflex and trigeminal diving reflex. In lambs, the apnea and associated cardio-
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vascular changes can be prevented by prior administration of a fl~-agonist, whereas these changes are aggravated by propranolol. 13 In view of these observations, the use of fl-blocking agents to alter the pressor response to intubation in neonates cannot be recommended. In our study, mean blood pressure increased by 57% over the entire group, with no attenuating effect noted from premedication with either atropine or atropine plus pancuronium. A hypertensive response was noted to laryngoscopy and to the endotracheal tube being inserted through the vocal cords. In the majority of circumstances, these responses could not be separated. Stoelting ~ has shown a relationship between the duration of direct laryngoscopy and the increase in mean arterial blood pressure in adults. As a result, prolonged laryngoscopy associated with difficult intubations may be associated with greater rises in blood pressure in neonates. We found no association between the duration of intubation and rise in blood pressure. The observed rise in blood pressure during endotracheal intubation may be significant in the pathogenesis of intraventricular hemorrhage, which has been detected after sudden increases in blood pressure associated with pneumothorax ~5 and ductus ligation, ~6 although these increases were less than those we observed. Wimberley et al) 7 observed that infants of <1500 gm who developed intraventricular hemorrhage had higher peak mean arterial blood pressure values when compared with matched control infants on the second and third days of life. The infants who received atropine or atropine plus pancuronium (n -- 20) did show a small but significant rise in heart rates prior to drug administration when compared with those just prior to the intubation procedure. This change was not seen in our control infants, and therefore confirms a drug effect. Pancuronium can cause an increase in heart rate?. ~8although the increase we noted was similar in groups 2 and 3 and was no doubt more a result of the atropine administered. Although bradycardia can occur in a reflex fashion from pharyngeal stimulation, 6 heart rate can also decrease in response to a decreased oxygen saturation, an effect thought to be mediated through the carotid chemoreceptor arch. 19 The bradycardia we observed was almost always of rapid onset (Fig. 2), suggesting a parasympathetic response to stimulation of the larynx and pharynx or trigeminal region. The group 3 infants had significantly fewer marked decreases in heart rate, suggesting synergism between these two agents consistent with the observations that pancuronium, like atropine, blocks cardiac muscarinic receptors? ~ The neonate can become rapidly hypoxic in response to a variety of procedures, such as suctioning, physiotherapy, and weighing, a~ and the decrease tcP02 observed with
The Journal of Pediatrics August 1984
intubation is consistent with these observations. The greater amplitude of this decrease may be explained by the less effective oxygen administration during the procedure and the general instability of infants studied. Our observed lag time in the response of the tcP02 electrode to a fall in oxygen was in the range of 8 to 14 seconds, consistent with the observations of others. 22 The decrease in skin perfusion associated with an increase in systemic vascular resistance may have contributed to some of the decrease in tcP02 during intubation. However, we have observed similar decreases in Pa02 during intubation as measured by an umbilical artery catheter tip electrode (G. D. Searle, Bucks, England), which is unaffected by alterations in systemic vascular resistance. We have previously shown that pancuronium will reduce the spikes in intracranial pressure >25 cm and durations of high ICP, as well as reduce periods of hypoxia and hyperoxia in the critically ill neonate during ventilation. 1~ White et al. 23 demonstrated that intravenously administered succinylcholine abolished the ICP response to endotracheal tube suctioning in adults, compared with thiopental, lidocaine, or fentanyl given intravenously or lidocaine endotracheally, whereas none of the drug therapies prevented a significant rise in blood pressure. Fisher et al. 14 studied nine children, all of whom were receiving neuromuscular blockage, and demonstrated a mean increase of 7 mm Hg in mean arterial pressure associated with a 6 mm Hg increase in ICP during suctioning of the endotracheal tube, similar to the mean increase in ICP seen in our group 3 infants. They also noted a small but significant increase in end-tidal Pc02 during the 30 seconds that the ventilator was disconnected, and postulated that part of the increase in ICP may have been a result of an increase in cerebral blood flow secondary to the increased Paco~) 5 The increase in ICP associated with laryngoscopy and intubation is probably influenced by many factors. There may be a slight but significant increase in Pat02 during intubation, with a resultant increase in cerebral blood flow and ICP. The infant's intrathoracic pressure may rise as a consequence of struggling, leading to an increase in cerebrovenous pressure. In addition, hyperextension of the neck may also impede venous return, increasing ICP. The three infants with no change in ICP during intubation all had received pancuronium, supporting the role of struggling and motor activity in the ICP increase. There was no association between the increase in ICP and the increase in blood pressure associated with intubation; in our group 3 infants increases in blood pressure were similar to those in the other infants, but increases in ICP were markedly lower. Intracranial pressure as measured by the Ladd fiberoptic sensor has been shown to correlate well with direct
Volume 105 Number 2
Physiologic responses to intubation in neonates
m e a s u r e m e n t s obtained at l u m b a r p u n c t u r e a n d ventriculostomy. 26 M e y e r b e r g et al. 27 reported a m a x i m u m response time with this device of 1.6 c m H 2 0 per second. W e recorded a m a x i m u m response of 1.57 c m H 2 0 per second when c o m p a r e d with t h a t recorded with o t h e r s t a n d a r d transducers ( S t a t h a m P M - 1 3 1 - T C , Gould M e d i cal I n s t r u m e n t s , Oxnard, Calif.; and Hewlett P a c k a r d Model 1280). This sensor markedly underestimates t h e m a x i m a l response seen during these procedures, as well as the m a x i m a l rate of rise. O u r d a t a suggest t h a t the physiologic changes associated with endotracheal intubation represent b o t h reflex cardiovascular responses, including b r a d y c a r d i a a n d hypertension, a n d nonreflex responses, which m a y represent struggling and mechanical effects. F u r t h e r studies are required to determine the clinical significance of the alterations in h e a r t rate, intracranial pressure, a n d blood pressure, a n d should include diagnostic cranial ultrasound studies immediately before and after intubation. We thank the medical and nursing staffs of the neonatal intensive care unit for their cooperation; Dr. P. Etches and Dr. E. G. King for their thoughtful review and criticism; Miss K. Peters for technical assistance and advice; and Mrs. C. Gadallah and Mrs. M. Shelling for secretarial assistance in preparation of the manuscript.
10.
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REFERENCES 1. Stoelting RK: Circulatory changes during direct laryngoscopy and tracheal intubation: Influence of duration of laryngoscopy with or without prior Lidocaine. Anesthesiology 47:381, 1977. 2. Abou-Madi M, Keszler H, Yacoub O: A method for prevention of cardiovascular reactions to laryngoscopy and intubation. Can Anaesth Soe J 22:316, 1975. 3. Kautto UM: Attenuation of the circulatory response to laryngoscopy and intubation by fentanyl. Acta Anaesthesiol Scand 26:217, 1982. 4. Martin DE, Rosenberg H, Aukburg S J, Bartkowski RR, Edwards MW, Greenhow ED, Klineberg PL: Low-dose fentany] blunts circulatory responses to tracheal intubation. Anesth Analg 61:680, 1982. 5. Raju RNK, Vidyasagar D, Torres C, Grundy D, Bennett E J: Intracraniat pressure during intubation and anesthesia in infants. J PEDIArR 96:860, 1980. 6. Cordero L Jr, Hon EH: Neonatal bradycardia following nasopharyngeal stimulation. J PEDIATR 78:441, 1971. 7. Friedman WF: The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15:87, 1972. 8. Finer NN: Never trendsin continuous monitoring of critically ill infants and children. Pediatr Clin North Am 27:553, 1980. 9. Nugent SK, Laravuso R, Rogers MC: Pharmacology and use
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of muscle relaxants in infants and children. J PEDIATR 94:481, 1979. Finer NN, Tomney PM: Controlled evaluation of muscle relaxation in the ventilated neonate. Pediatrics 67:641, 1981. Tomori Z, Widdicombe JG: Muscular, bronchomotor and cardiovascular reflexes elicited by mechanical stimulation of the respiratory tract. J Physiol 200:25, 1969. Prys-Roberts C, Foex P, Biro GP, Roberts JG: Studies of anaesthesia in relation to hypertension. V. Adrenergic betareceptor blockade. Br J Anaesth 45:671, 1973. Grogaard J, Sundell H: Effect of beta-adrenergic agonists on apnea reflexes in newborn lambs. Pediatr Res 17:213, 1983. Rudolph AM, Heymann MA: Cardiac output in the fetal lamb: The effects of spontaneous and induced changes of heart rate on right and left ventricular output. Am J Obstet Gynecol 124:183, 1976. Hill A, Perlman JM, Volpe J J: The relationship of pneumothorax to the occurrence of intraventricular hemorrhage in the premature newborn. Pediatrics 69:144, 1981. Marshall TA, Marshall F lI, Reddy PP: Physiologic changes associated with ligation of the ductus arteriosus in preterm infants. J PEDIATR 101:749, 1982. Wimberley PD, Lou HC, Pedersen H, Hejl M, Lassen NA, Friis-Hansen B: Hypertensive peaks in the pathogenesis of intraventricular hemorrhage in the newborn, abolition by phenobarbitone sedation. Acta Paediatr Scand 71:537, 1982. Bennett, E J, Ramamurthy S, Dalal FY, Salem MR: Pancuronium and the neonate. Br J Anaesth 47:75, 1975. Levy MN, DeGeest H, Zieske H: Effects of respiratory center activity on the heart. Circ Res 18:67, 1966. Bowman WC: Non-relaxant properties of neuromuscular blocking drugs. Br J Anaesth 54:147, 1982. Danford DA, Miske S, Headley J, Nelson RM: Effects of routine care procedures on transcutaneous oxygen in neonates: A quantitative approach. Arch Dis Child 58:20, 1983. Abu-Osba YK, Thach BT, Brouillette RT: Evaluation of response time of a transcutaneous oxygen tension electrode. Pediatr Res 15:143, 1981. White PF, Schlobohm RM, Pitts LH, Lindauer JM: A randomized study of drugs for preventing increases in intracranial pressure durig endotracheal suctioning. Anesthesiology 57:242, 1982. Fisher DM, Frewen T, Swedlow DB. Increase in intracranial pressure during suctioning: Stimulation vs. rise in Paco2. Anesthesiology 57:416, 1982. Smith AL, Wollman H: Cerebral blood flow and metabolism: Effects of anesthetic drugs and techniques. Anesthesiology 36:378, 1972. Hill A, Volpe J J: Measurement of intracranial pressure using the Ladd intracranial pressure monitor. J PEDIATR 98:974, 1981. Myerberg DZ, York C, Chaplin ER, Gregory GA: Comparison of noninvasive and direct measurements of intracraniat pressure. Pediatrics 65:473, 1980.