Cardiovascular and Neurophysiologic Changes during Graded Duration of Apnea in Piglets

003 1-3998/88/2304-0402$02.00/0 PEDIATRIC RESEARCH Copyright O 1988 International Pediatric Research Foundation, Inc. Vol. 23, No. 4, 1988 Printed in U.S. A. Cardiovascular and Neurophysiologic Changes during Graded Duration of Apnea in Piglets U. M. SANOCKA, D. F. DONNELLY, AND G. G. HADDAD Department of Pediatrics (Neonatal and Pulmonary Divisions), Columbia University, College of Physicians and Surgeons, New York, New York 10032 ABSTRACT. To examine the interrelationship between the duration of apnea and changes in oxygen saturation, blood pressure, electroencephalogram (EEG), and heart rate, reflex apnea of 10, 20, 40, and 60 s duration was induced by stimulating the superior laryngeal nerves. Piglets (n = 11, age 5-14 days) were chronically instrumented for continuous monitoring of SaOz and blood pressure and for sampling arterial blood. Ventilation was recorded using whole body plethysmography and EEG and electrocardiogram were measured by acutely placed subcutaneouselectrodes. Central apnea produced an immediate rise in blood pressure and a decrease in SaOz by 20 s. By 30 s into the apnea, EEG amplitude had already decreased. Major cardiac slowing did not occur until 80 s after the start of apnea. Hyperoxia delayed the start of desaturation, hypertension, and EEG attenuation. These data suggest that during superior laryngeal nerve-induced apnea in young piglets: 1) desaturation can reach profound levels rapidly, 2) EEG amplitude decreases substantially and becomes nearly isoelectric within 1 min, and 3) bradycardia is a late manifestation when compared to changes in oxygen saturation, blood pressure, and EEG. (Pediatr Res 23:402407,1988) tion is variable. Bradycardia may occur early into an apnea, at a time before significant desaturation (3, 11, 12), but also can occur late in 40% of protracted apneas (13) or after the onset of EEG supression (14). The purpose herein was to examine the sequence of neurologic and cardiovascular consequences of graded periods of apnea. Prolonged neonatal apnea can be of variable etiology such as central nervous system immaturity, infection, metabolic disturbances, IVH, airway obstruction, and vagal reflex. For our studies, we used laryngeal stimulation to induce a central apnea secondary to reflex effect. In this way, apnea duration could be controlled by the duration of stimulus presentation and the cause for central apnea was consistent among experimental animals. Experiments were conducted in piglets because they have a similar time course of brain development and cardiovascular control systems as infants. Inasmuch as unterminated respiratory pauses up to 80 s duration were examined, similar studies on human infants could not ethically be undertaken. We hypothesized that in healthy animals, significant desaturation and neurologic electroencephalographic alterations occur during the course of an apnea and that bradycardia may be a poor indicator of an apneic period. Abbreviations MATERIALS AND METHODS SLN, superior laryngeal nerves EEG, electroencephalogram SaOz, arterial oxygen saturation MAP, mean arterial blood pressure EKG, electrocardiogram IVH, intraventricular hemorrhage Apnea is a common problem in neonatal intensive care units with an incidence of 80-90% in infants weighing less than 1000 g (1,2). The importance of this phenomenon stems from the fact that apnea has been associated with cyanosis, bradycardia, altered neurologic state (3-7), and recently, with decreased cereL-21 blood flow (8). Despite the importance of apnea as a potentially detrimental phenomenon (9), the time of onset and the sequence of physiologic changes associated with apnea are unclear. Some infants require intervention at 10-15 s into an apnea, whereas some observations suggest that hypotonia and other indications of cerebral dysfunction do not occur until 45 s (3, 10). Similarly, the latency of bradycardia and its relationship to oxygen saturaReceived May 19, 1987; accepted December 11, 1987. Correspondence Ulana Sanocka, M.D., Department of Pediatrics, Babies Hospital, Room 115, 3959 Broadway, New York, NY 10032. Supported by HL-33783. DFD is Parker B Francis Fellow. GGH is an Established Investigator of the American Heart Association. Eleven farm bred newborn piglets were used. The animals were bottle fed pig milk replacer every 4-5 h for the first five days of life and then allowed to feed ad libitum from a bowl. Environmental temperature was maintained between 30.5-32" C. Piglets were weighed daily and an increase in weight was noted in all. Electrode and catheter placement. On day 4- 13 of life, surgery was performed under sterile conditions using Halothane anesthesia. A no. 5 Oxymetrix oxygen saturation catheter was inserted into the carotid artery. This allowed us to make continuous recordings of O2 saturation and blood pressure and to take intermittent samples for blood gas analysis. Both SLN were exposed and isolated along their path from larynx to nodose ganglia. The nerves were cut at the entrance to the larynx and placed in individual cuff electrodes that were sutured to the neighboring laryngeal muscles. These electrodes were constructed by sewing a pair of Teflon insulated steel wires (7 strands no. 44 wire, Medwire Corp., Mt. Vernon, NY) circumferentially within silastic tubes and separated by 2 mm. Because the fine wires allowed for a tight closure of the wound, the site of exteriorization could be kept free from infection. The piglets were then allowed to recover for 24 h. Experiments were performed 1-2 days after surgery at which time piglets were sedated with penobarbital (20 mg/kg, intraarterially). Pentobarbital was used to suppress periodic breathing that is observed during SLN stimulation in awake, unanesthetized animals (15). Throughout the experimental period the animal was maintained under a light level of anesthesia as assessed by withdrawal from nocioceptive stimuli. 4(32 403 CARDIOVASCULAR EFFECTS OF APNEA Physiologic measurements. Respiration was measured using barometric plethysmography (16, 17). In brief, the animal is placed in a closed chamber and tidal volume is calculated from pressure changes due to humidification and heating of inspired air. The chamber air is circulated through a scrubbing system to remove expired C 0 2and control for humidity. The total volume of the chamber and scrubbing system is 51 liters. Oxygen was added periodically to maintain an FiO, between 0.19 and 0.22. Oxygen saturation and blood pressure were measured continuously through a carotid artery catheter. Heart rate was monitored by inserting pins subcutaneously and attaching these to electrode wires (17). Similarly, pins were inserted subcutaneously over the temporoparietal cortex to measure the electroencephalogram. A hot water bottle was used to maintain the temperature in the box at 32" C. After the animal was placed in the chamber, which was carefully sealed to avoid any leakage of air, baseline recordings were o (...truncated)