Francoise Marotta

The ventilatory response to carbon dioxide in high risk infants

PURPOSE To examine the ventilatory response to inspired carbon dioxide in infants considered to be at risk for sudden infant death syndrome or apnea. DESIGN Clinical data measurement. SETTING Infant apnea evaluation program of a university division of neonatology. PATIENTS Fifty nine infants were full term characterized by the following diagnoses; siblings of infants who had died from sudden infant death syndrome (SIDS) (n = 7), apparent life threatening event (ALTE) (n = 24), apnea/cyanosis in the newborn nursery (n = 21), and controls. Sixty-nine infants were preterm and consisted of patients suffering from idiopathic apnea (n = 61), and bronchopulmonary dysplasia (n = 8). MEASUREMENTS The ventilatory response to carbon dioxide was measured with a computerized waveform analyzer. MAIN RESULTS Among full term infants no significant differences in the ventilatory slope in response to CO2 was seen. The range of mean slope was 19.4 +/- 7.6 in siblings of SIDS and 36 +/- 17 in control infants. Greater number of sibling of SIDS had slopes less than 20 ml/kg/min/mmHg in comparison to control infants. Sibling of SIDS had less increase in minute ventilation and inspiratory flow in response to CO2 administration in comparison to control infants. Preterm infants had similar slopes with a mean of 33 ml/kg/min/mmHg in infants with idiopathic apnea and 28 ml/kg/min/mmHg in infants with bronchopulmonary dysplasia. CONCLUSIONS The large intragroup variability in the ventilatory response to inspired CO2, confirming previously reported data, comprises the benefit of this test. Thus, ventilatory response to CO2 administration is not useful in unselected patients at risk of SIDS or apnea.

PHARMACOKINETICS OF NALOXONE IN PREMATURE INFANTS

Rapid disappearance of naloxone was observed in a group of very low birthweight infants examined for naloxone kinetics. Five infants (BW 1.20±0.25kg, GA 29±1wk) received 0.04 mg/per kg of naloxone intravenously, four within the first week of life and one on day 26. Serial serum samples were obtained at specific time intervals and frozen for subsequent analysis. Serum naloxone concentrations were measured by the radioimmunoassay method of Berkowitz (1975).Serial naloxone concentration at 5 min. was 51.5±13.4pmole/ml, at 15 min. 36.7±4.0pmole/ml, at 30 min. 28.9±5.1 pmole/ml, at 60 min. 20.4±5.9pmole/ml, at 120 min. 7.3±2.4pmole/ml, and 240 min. 1.5±0.4pmole/ml. No naloxone was detected at the next sample time (12hrs). The elimination rate constant (Ke) calculated from the decay portion of the elimination curve was 0.823±0.130/hr. The calculated half life (t½) was 51.8±9.2min. No correlations were found between Ke and t½ and initial serum level, birthweight, gestational age, and postnatal age.This group of infants demonstrated rapid elimination of intravenous naloxone, consistent with results obtained in adults.

VENTILATORY RESPONSE TESTING IN PREMATURE INFANTS

We studied the reproducibility of ventilatory response to CO2 in a group of premature infants with real or potential disturbances in the control of ventilation. (Ten infants BW 2.0±0.8 kg, GA 35±4 wks) comprised the test population, 6 with idiopathic apnea, 3 siblings of SIDS, and 1 near miss. The group was examined at 42±6 wks postconceptual age with a computerized waveform analyzer providing ventilatory response data to inhaled CO2. A second test was done 30 minutes after completion of the first.Significant correlation was found between the slopes, but significant differences were observed between their means(P<0.01) Baseline Ve was significantly lower in the repeat test with six infants starting at a lower level. Seven infants aroused at a lower PCO2 in the second test but the PCO2s at arousal were not different.It appears that the infants in this study became more sensitive to CO2 in the second test, as suggested by a steeper slope, lower baseline ventilation, and earlier arousal. We postulate that the CO2 challenge of the first test affected the second,and an interval greater than 30 min. may be necessary to duplicate results.

THE EFFECT OF POSTNATAL AGE ON THE VENTILATORY RESPONSE TO C02

We studied the impact of postnatal age on baseline PCO2, slope, and position of the CO2 response curve in two groups of infants. Eight infants (Group I) with prolonged apnea (BW 1850±820g, GA 33±5wks) were tested twice at 42±7 and 55±9wks post-conceptual age (P<0.01). Seven (Group II) near miss infants (BW 3160±760g, GA 37±3 wks) were examined at 48±6 and 68±6wks (P<0.01). Ventilatory responses to CO2 were obtained by a computerized CO2 waveform analyzer with the capacity to measure breath-to-breath responses.There were no significant differences in PCO2, slope and curve position at Ve=300ml between the two evaluations in either group. Due to the large coefficient of variation of the slope measurement we examined these results in another manner. In Group I, 5 slopes were abnormal (<20mm/kg/min/mmHg BTPS) in the first test and 3 in the second. In Group II 5 first slopes and 3 second slopes were abnormal. While this analysis suggests slope change with advancing age, the differences did not reach statistical significance. These data suggest that the CO2 response curve characteristics change little in the patients and time periods examined.

ALVEOLAR PaC02 AFTER ADMINISTRATION OF EXOGENOUS CO2 IN PRETERM INFANTS: ACHIEVEMENT OF STEADY STATE

Rapid achievement of steady state of alveolar PaCO2 was noted in a group of infants evaluated for ventilatory response to CO2. Ten infants,BW: 2.10±1.18kg and GA 33±6wks, were tested at a postconceptual age of 39±5wks. Ventilatory response was obtained by a computerized CO2 waveform analyzer that measures breath by breath alveolar CO2 concentration. Steady state was defined as equal values of PaCO2 for a 15 second interval that was usually comprised of 7 to 12 breaths.After administration of 2% CO2 the time to steady state was 39±23 seconds (range 15-75 sec) and after 4% it was 39±15seconds (range 15-60 sec). Time to achieve steady state did not correlate with birthweight, gestational age or postconceptual age. In addition there was no correlation noted between the results obtained in 2% and 4% CO2.Alveolar PaCO2 reaches a stable level quickly during CO2 response testing. Data can be safely collected after a lag time of approximately one minute.

VENTILATORY RESPONSES TO C02 IN PREMATURE INFANTS WITH INTRAVENTRICULAR HEMORRHAGE

No significant differences were found in the ventilatory response to CO2 in a group of very low birthweight infants evaluated for apnea. Twenty-two infants were divided into two groups based on the presence or absence of IVH. Group I consisted of 11 infants (BW 1050±380g, GA 28±1 wk), 8 suffering from Grade III, and 3 from Grade IV IVH. Eleven infants (BW 1130 ±210g,GA 28±2 wk) comprised Group II, the control population. Group I was examined at 44±9 weeks postconceptual age, and Group II at 42±10 weeks (P 0.05). Ventilatory response to CO2 was measured by a computerized waveform analyzer.The results of the study are presented below:In the group of infants with apnea, IVH did not affect the slope or position of the CO2 response curve, the baseline data, nor the frequence of arousal prior to test completion. These responses did not correlate with IVH severity. The increased incidence of apnea with IVH does not seem to be related to a compromised response to CO2.

FOLLOW-UP OF TERM INFANTS AT RISK FOR SIDS

Home monitoring did not interfere in the developmental status of a group of term infants at risk for SIDS. Eleven infants (BW 3.50±0.80kg) were managed on home monitors due to the presence of specific risk factors (near miss, sibling of SIDS apnea). Evaluation included ventilatory response studies to CO2 with a computerized CO2 waveform analyzer. Five infants had abnormal (13.7±4 mm/kg/min/mmHg BTPS) and six normal (36.3±15.8 mm/kg/min/mmHg BTPS) responses (P 0.05).Follow up examinations occurred at 6 months postnatal age with the Bayley Scales of Infant Development. All infants had normal MDI and PDI. Comparing the groups with normal and abnormal ventilatory responses, we noted similar MDI (119±12 vs. 124±14), PDI (115±10 vs. 110±18), and absolute MDI-PDI differences (16±11 vs. 14±8). No correlations could be demonstrated between slope and any of the developmental factors.Home monitoring allows for the normal development of high risk infants. Abnormalities demonstrated early in the control of ventilation did not affect outcome in these infants.

THE RESPONSE TO CO2 IN INFANTS AT RISK FOR SIDS

Higher incidence of abnormal ventilatory response was found in two of three groups of infants tested with a computerized CO2 waveform analyzer that measures breath by breath responses. Forty nine infants (BW 1980±1010g, GA 33±5wks) with risk factors (prolonged apnea, BPD), 11 near miss (BW 3090±760g, GA 39±2wks), and 6 siblings of SIDS (BW 3310±1090g, GA 39±4wks) comprised the three groups. Age at evaluation was 44±10wks postconceptual age for risk infants, 54±14 wks for the near miss group, and 49±18 wks for siblings.The risk group slope was significantly greated that the sibling group slope (P<0.05). The difference between risk and near miss slopes did not reach statistical significance. Nine risk infants (18%), 6 near miss (54%), and 3 siblings (50%) were identified to have abnormal slopes, below 20 mm/kg/min/mmHg BTPS (P<0.05). Near miss and sibling infants demonstrated more blunted responses to CO2 that a group identified to be at risk.

RISK PREDICTORS FOR SIDS: C02 RESPONSE TESTING VS|[period]| THE PNEUMOCARDIOGRAM

Evaluation of the ventilatory response to CO2 is more accurate than the pneumocardiogram (PCG) in predicting well being in infants managed with home monitors. Twenty-two infants (BW 1150-3900g, GA 28-41 wks) were evaluated at 35-47 wks postconceptual age with CO2 response studies and PCGs due to presence of risk factors for SIDS (prolonged apnea, BPD). Abnormal CO2 response was defined by a slope below 20 mm/kg/min/mmHg BTPS, and abnormal PCG was based on the presence of excessive periodic breathing, apnea, and bradycardia. Nineteen infants had normal slopes (43.5±21.8 mm/kg/min/mmHg BTPS) while 3 were abnormal (10.6±3.2 mm/kg/min/mmHg BTPS). Ten infants had an abnormal PCG while 12 were considered to be normal. The relationship between CO2 response slope and PCG result are shown below.There were no correlations between slope and %PB, and frequency of apnea and bradycardia. All infants were followed to 5-6 month postnatal age, with no reported episodes requiring intervention. The specificity of the CO2 response was 86% and the PCG 54% in forecasting an uncomplicated course (P<0.05). In this group of patients ventilatory response studies were better predictors of well being during the time period studied.

THE EFFECT OF CAFFEINE ADMINISTRATION ON THE PNEUMOCARDIOGRAM IN HIGH RISK INFANTS

Caffeine therapy improved the pneumocardiogram (PCG) score of five infants identified to be at risk for sudden infant death syndrome. The patients (BW 1.89±0.95kg, GA 33±7 wks) were initially evaluated with the PCG at 37±5wks postconceptual age.Oral caffeine citrate was then administered with a loading dose of 20 mg/kg followed by a daily maintenance dose of 5mg/kg. A second PCG was done at 39±5wks postconceptual age, approximately 1 week after the start of therapy. Serum caffeine levels at this time ranged from 6.5 to 14ug/ml. The results of the comparison are shown below:The PCG following caffeine therapy had significantly lower % PB, total apnea and total bradycardia events. Serum caffeine concentration did not correlate with any of the observed factors. No infant suffered any side effect of treatment. In this group of infants caffeine was effective in improving their performance on the pneumocardiogram.