M. A. Bureau

The ventilatory response to hypoxia in the newborn lamb after carotid body denervation

Neonates of various species including lambs respond to hypoxia by a transient hyperventilation followed by a VE depression (diphasic response). To better delineate the role of the carotid chemoreceptors and that of the central depressive/inhibitive effect of hypoxia on minute ventilation, we have studied the VE response of 4-day-old carotid body-deprived lambs (CBD) during successive exposure to moderate and severe (0.12 and 0.07 FIO2) hypoxia. The carotid body denervation was done to abolish most of the chemoreceptor stimulating effect on VE during hypoxia and to allow for central depression/inhibition of VE during hypoxia. In the CBD lambs, baseline VE was 461 +/- 81 (SE) ml X (kg X min)-1. It increased to 532 +/- 79 ml X (kg X min)-1 and to 541 +/- 75 ml X (kg X min)-1, to 0.12 FIO2 and 0.07 FIO2. These VE increases did not reach level of significance (P greater than 0.05). After 2-5 min of both levels of hypoxia VE dropped respectively to 460 +/- 60 ml X (kg X min)-1 and to 459 +/- 38 ml X (kg X min)-1. No marked ventilatory depressions were noted but VE had only returned to baseline. It is concluded that, in the denervated newborn lamb, the centrally mediated depressive effect of hypoxia is small and not sufficient to explain the diphasic VE response of the intact lamb to steady state hypoxia. Analysis of the magnitude of the hyperventilation and the VE damping pre-hypoxic levels occurring with sustained hypoxia in newborns of various species suggests that the immaturity of the O2-sensitive chemoreceptor rather than the central effect of hypoxia is the determinant factor of the diphasic response of newborn mammals to hypoxic hypoxia.

Influence of vagal afferents on diphasic ventilatory response to hypoxia in newborn lambs.

The effect of vagal afferents on the ventilatory response to hypoxia was studied in eleven awake newborn lambs. Tests were repeated before and after vagotomy in the same lambs in two conditions: with intact upper airways and after intubation. During hypoxia, a diphasic pattern of ventilatory response was observed in both vagotomized and intact lambs. However, face mask-breathing vagotomized lambs had a blunted increase in ventilation (VI) to hypoxia as compared with intact lambs (P = 0.0001) and they showed an expiratory braking during all hypoxic time. Furthermore, the normal increase in frequency (f) to hypoxia was abolished after vagotomy. After intubation, expiratory braking disappeared and, consequently, magnitude of the VI response to hypoxia was similar in intact and vagotomized lambs. These changes were due to improved tidal volume response in vagotomized intubated lambs (P < 0.002) with no significant change in f response. We concluded that, in awake newborn lambs, vagal afferents are essential for maintaining the pattern and the magnitude of the ventilatory response to hypoxia, the latter by controlling the motor output to the larynx.

Interactive Ventilatory Effects of Two Respiratory Stimulants, Caffeine and Doxapram, in Newborn Lambs

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30 min. In the first group, ventilation increased after the caffeine loading dose from 566 +/- 55 to 680 +/- 74 ml/kg/min (plasma caffeine = 14.7 +/- 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram up to 1,000 +/- 108 ml/kg/min at 2.5 mg/kg of doxapram (p less than 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 +/- 50 to 936 +/- 75 (p less than 0.002 and p less than 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 +/- 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.

BLOOD PRESSURE CHANGES AFTER BOLUS INFUSION OF DOXAPRAM IN NEWBORN LAMBS

Doxapram (Dox) has been recently used in the treatment of apnea of the newborn. Currently Dox is given by continuous I.V. low dose infusion; this usually implies a slow onset of action. A bolus infusion as a loading dose should accelerate this onset of action, and in theory repeated boluses could be used for administration. However, increases in blood pressure (BP) have been identified when a continuous I.V. infusion is used. The objective of this study was to define the changes in BP following bolus doses of Dox: 1, 2.5, 5 and 10mg/kg given over 1 min. Seven lambs were studied at 2 and at 15 days of age. After 1 mg/kg, 2 of the 7 two-day old lambs had no change in BP, the 5 others had a transient (<1 min) increase of a maximum of 10 mmHg from baseline; at 15 days of age, 2 had no change in BP, 2 had an increase of 5 to 10 mmHg (<1 min) and 3 had an increase of 10 to 20 mmHg (<2 min). After 2.5 mg/kg a maximum increase of 15 mmHg (<30 sec) was seen in 2 of the 2 day old lambs and in the 15 day old lambs a maximum increase of 30 mmHg (<1 min) was seen in 1 of the 7 lambs. For doses of 5 and 10 mg/kg the same magnitude of increase was seen but for a longer duration (5 to 30 minutes). In summary, only a transient mild increase in BP was seen with a rapid (1 min) bolus dose of 2.5 mg/kg or less of Dox. The safety of even these apparently small increases in BP is not yet known. Further, the effect of a less rapid infusion rate needs to be determined.

VENTILATORY (VE) RESPONSE TO INTRAVENOUS BOLUS OF DOXAPRAM (DOX) IN NEWBORN LAMBS

The VE response to I.V. bolus infusion of Dox is largely unkown, although Dox is used parenterally in the treatment of apnea of infancy. The objectives of this study were 1) to determine if VE response to Dox changes with postnatal age 2) to characterize the VE response to graded bolus doses of Dox (1 to 10 mg/kg) 3) to partition the peripheral versus the central chemoreceptor response to Dox. Seven intact lambs were studied at 2 and at 15 days of age. Two lambs had carotid body denervation (CBD) at 2 days and were studied at 7 days of age. The animals were studied awake and unsedated. VE was recorded before and continuously for 30 min. after 1 mg/kg Dox I.V. bolus. The study was repeated using 2.5, 5 and 10 mg/kg. The VE response was characterized by a diphasic pattern, an early peak and a late plateau. In the 2 day old VE increases rapidly from 550 to 900 ml/kg/min with 1 mg/ kg, returning to near baseline plateau in 10-12 min. With 2.5 mg/kg, the peak VE was 1000 ml/kg/min. With 5 and 10 mg/kg, the peak VE did not increase further but the plateau VE was shifted to higher VE levels. The same dose response and pattern was seen in the 15 day old lambs. The CBD lambs showed a similar pattern, but the peak response was decreased by more than 50%. Conclusions: 1) no postnatal maturational change was seen in the VE response to Dox 2) Doses >2.5 mg/kg did not increase the peak VE 3) the diminution of the VE by CBD suggests that the peak response is mediated by the peripheral chemoreceptors.

Effects of phenobarbital on cerebral blood flow in the newborn piglet

To determine the neonatal cerebrovascular effect of a therapeutic dose and a high dose of phenobarbital (Pb), the effect of Pb on cerebral blood flow (CBF) and total brain oxygen consumption (CMRO2) was studied in three groups of awake newborn piglets (aged 1-3.5 days). Group I (control n = 9) received normal saline solution, group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.) and group III (n = 9) received a high Pb dose (45 mg/kg i.v.). Four CBF measurements per piglet using radioactive microspheres (141Ce, 85Cr, 95Nb, 46Sc), arterial blood gases, O2 content, hematocrit and plasma glucose were obtained at 0, 15, 30, 60 min after saline or Pb injections. In all groups, pH, PaO2, PaCO2, blood pressure, heart rate, temperature and plasma glucose remained unchanged except a 14% decrease (p < 0.01) in blood pressure and an increase (p < 0.05) in PaCO2, 60 min after drug injection in groups II and III. Total CBF in group II decreased by 14% (p < 0.05) 15 min after drug injection and was significantly lower (p < 0.05) than control (group I) but returned to baseline after 30 min. High Pb dose progressively lowered CBF by 11% 15 min after drug injection and produced a significant decrease by 20% (p < 0.01) 30 min after drug injection with return to baseline after 60 min. Similar effects were noted in different brain regions (cerebrum and thalamus). CMRO2 remained unchanged in the control group; however, it was decreased by 35% (< 0.01 p > 0.05) 15 min after drug injection and returned to baseline after 60 min. In group III, high Pb dose lowered CMRO2 by 31% 30 min (p = 0.02) after drug injection. Data indicate that Pb exerts a minimal but transient dose-dependent effect on CBF and CMRO2.

346 VENTILATORY RESPONSE TO HYPOXIA AND HYPERCARBIA AFTER CAFFEINE INFUSION IN THE NEWBORN LAMB: CONTRIB UTION OF THE PERIPHERAL CHEMORECEPTORS

Caffeine is a methylxanthine currently used in the prevention of disorders in the control of breathing in the pediatric age group. Despite this wide acceptance, the mechanisms implicated in the respiratory action of caffeine are still unclear. The current study has evaluated the effect of caffeine on O2 and CO2 drive of breathing. Seven awake, non-premedicated, non-intubated lambs (mean age 53h) were used for this study. Before and after caffeine therapy (10 mg/kg), progressive isocarbic hypoxia was used to assess the peripheral chemoreceptors, and hyperoxic rebreathing hypercapnea was used for the central receptors. The output of these chemoreceptors was measured by changes in minute ventilation (VE), mean inspiratory flow (Vt/Ti) and timing of respiration (Ii/Ttot). Mean plasma level of caffeine was 13.2mg/ L. Caffeine increased the ventilatory response to isocarbic hypoxia (FiO2: 0.21 to 0.06); the difference was particularly significant with low FiO2. At FiO2= 0.06, VE was 915 before and 1213 ml/kg/min after caffeine (p<0.02); Vt/Ti was 30.9 before and 40.2 ml/kg/s after caffeine (p<0.03). No significant change was induced by caffeine infusion on the CO2 response curve. We conclude that in the newborn lamb, caffeine potentiates the response of the peripheral chemoreceptors; no central effect of caffeine was observed in our study.

EFFECT OF PHENOBARBITAL ON CEREBRAL BLOOD FLOW AND TOTAL BRAIN OXYGEN CONSUMPTION IN NEWBORN PIGLETS

The effect of phenobarbital (Pb) on cerebral blood flow (CBF) and total brain oxygen consumption (TBOC) was studied in 3 groups of awake newborn piglets (ages 1-3.5 d). Group I (control n-9) received saline, Group II (n=9) received low Pb dose (15 mg/kg IV) and Group III (n-9) received high Pb dose (45 mg/kg IV). Four CBF and cardiac output measurements per piglet using radioactive microspheres (141Ce,85Sr,95Nb,46Sc) arterial blood gases, 02 content hematocrit and plasma glucose were obtained at 0,15,30,60 min after saline or Pb injections. In all groups, pH, PO2, PCO2, blood pressure, heart rate, temperature and plasma glucose remained unchanged except a 14% decrease (p<0.05) in BP and an increase (p<0.05) in PCO2 (3 torr) at 60 min in Groups II and III. Total cerebral blood flow (TCBF) in Groups II and III decreased by 13% and 11.5% respectively (p<0.05) at 15 min and was significantly lower (p<0.05) than Group I but returned to baseline 30 min after drug injection. Similar findings were noted in different areas (cerebrum, thalamus, brain stem and eyes). TCBF and TBOC remained unchanged in Group I. In Group II, TBOC decreased by 35% (p<0.01) at 15 min and returned to baseline at 60 min. In Group III, high Pb dose lowered TBOC by 34% at 30 min (p<0.01) which persisted to 60 min. We conclude that therapeutic Pb dose produced only a transient decrease in TCBF and TBOC, but a high dose produced a more important and sustained decrease in TCBF and TBOC.

EFFECT OF CAFFEINE ON VENTILATION DURING POST-NATAL MATURATION OF BREATHING IN AWAKE LAMBS

Caffeine is an efficient respiratory stimulant during the neonatal period, but its action on respiration beyond this period remains unclear. This study was performed to evaluate the effect of caffeine on ventilation in relation to post-natal maturation. Nineteen lambs divided in 3 groups of different ages were studied;I: 7 lambs with a mean age of 1 week;II: 6 lambs, mean age of 2 1/2 months and III: 6 sheep, 6 months old. After a baseline period, saline (as a control infusion) then, 10 minutes later, caffeine 10 mg/kg I.V. were injected to the animals. Ventilation was measured using a mask adapted to the animals facial contour and connected to a pneumotachograph; on-line values of VE (minute ventilation), Vt/Ti, (mean inspiratory flow) and Ti/Ttot (timing of respiration) were derived from the flow signal using a computerized system.No response was seen after saline;but in all three groups, VE (ml/min/kg) increased significantly after caffeine; this increase was 36% in group I; 46% in group II; and was 48% in group III. This increase in VE was due mainly to an increase in Vt/Ti (ml/sec/kg), which increased in groups I,II,III by 36,41 and 26%. Ti/Ttot did not change significantly at any time. The plasma concentrations were 9.7,8.8,10.0 mg/1 in groups I,II,III. We conclude that: the magnitude of the ventilatory response and the strategy of breathing in response to the therapeutic blood concentration of caffeine persists without major difference between 1 week to 6 months of age in lambs.