Neonates with functional single ventricle often require hypoxic or hypercapnic inspired gas mixtures to reduce pulmonary overcirculation and improve systemic perfusion. Although the impact of these treatments on arterial oxygen saturation has been described, the effects on cerebral oxygenation remain uncertain. This study examined the effect of these treatments on cerebral oxygen saturation and systemic hemodynamics.
Neonates with single ventricle mechanically ventilated with room air were enrolled in a randomized crossover trial of 17% inspired oxygen or 3% inspired carbon dioxide. Each treatment lasted 10 min, followed by a 10-20-min washout period. Cerebral and arterial oxygen saturation were measured by cerebral and pulse oximetry, respectively. Cerebral oxygen saturation, arterial oxygen saturation, and other physiologic data were continuously recorded.
Three percent inspired carbon dioxide increased cerebral oxygen saturation (56 +/- 13 to 68 +/- 13%; P < 0.01), whereas 17% inspired oxygen had no effect (53 +/- 13 to 53 +/- 14%; P = 0.8). Three percent inspired carbon dioxide increased the mean arterial pressure (45 +/- 8 to 50 +/- 9 mmHg; P < 0.01), whereas 17% inspired oxygen had no effect. And 3% inspired carbon dioxide decreased arterial pH and increased arterial carbon dioxide and oxygen tensions.
Inspired 3% carbon dioxide improved cerebral oxygenation and mean arterial pressure. Treatment with 17% inspired oxygen had no effect on either.
NEONATES with hypoplastic left heart syndrome and other single ventricle (SV) cardiac malformations depend on a patent ductus arteriosus for survival. The proportion of blood flow into the pulmonary (Q̇p) and systemic (Q̇s) circulation depends on the resistance of each of these circuits. Systemic arterial oxygen saturation (Sao2) is often used to gauge relative blood flows between these circuits. Sao2greater than 85% suggests excessive pulmonary blood flow at the expense of systemic blood flow, often resulting in insufficient vital organ perfusion and metabolic acidosis. 1Two strategies are used to counter excessive pulmonary blood flow, namely, inspiration of hypoxic or hypercapnic gas mixtures. 2Both strategies increase pulmonary vascular resistance and redirect blood flow to the systemic circulation.
Neonates born with SV disease sometimes experience neurologic complications in the form of seizures, impaired cognition, developmental delay, and cerebral palsy. 3,4Although these neurologic complications are clearly multifactorial in origin, a growing body of evidence indicates that many neonates with SV experience cerebral hypoxia–ischemia before surgery. 5,6Thus, the use of hypoxic gas mixtures raises the concern of contributing to this preoperative hypoxic–ischemic injury.
Near-infrared spectroscopy is a noninvasive optical technique used to monitor brain tissue oxygenation by measuring concentrations of oxyhemoglobin and deoxyhemoglobin, cerebral oxygen saturation (Sco2), or cytochrome aa3redox state. 7This technology has been used to examine cerebral oxygenation before and during congenital heart surgery 8,9and may also be used to examine cerebral oxygenation in response to medical therapies before and after surgery.
In this prospective, randomized, crossover trial, we examined the effect of 17% fraction of inspired oxygen (Fio2) and 3% fraction of inspired carbon dioxide (Fico2) on cerebral oxygenation and systemic hemodynamics in neonates with SV before the Norwood operation. We hypothesized that, although both treatments would improve systemic hemodynamics, 3% Fico2would increase Sco2, whereas 17% Fio2would decrease Sco2.
Materials and Methods
After obtaining institutional review board approval (Children's Hospital of Philadelphia, Philadelphia, PA), informed parental consent was obtained. This study was conducted between June and October 1999 at the Children's Hospital of Philadelphia. Eligibility criteria included a diagnosis of univentricular heart defect with Sao2greater than 80% (evidence of Q̇p/Q̇s > 1.0). Exclusion criteria were postnatal age greater than 1 month, preoperative seizures, associated craniofacial anomalies that precluded near-infrared spectroscopy monitoring, and participation in an investigational drug study. The study was conducted in the operating room after induction of anesthesia and before start of stage 1 Norwood surgery.
Per institutional practice, prostaglandin infusion was discontinued immediately before transport to the operating room. No premedication was administered. After placement of electrocardiogram, pulse oximeter, and arterial pressure monitors, the subjects received fentanyl citrate (20 μg/kg bolus, then 1 μg · kg−1· h−1) and pancuronium bromide (0.2 mg/kg), were nasally intubated, and mechanically ventilated to normocapnia with 21% Fio2using a Servo SV 300 ventilator (Siemens-Elema, Solna, Sweden) without positive end-expiratory pressure. Heart rate, systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure (MAP), Sao2and nasopharyngeal temperature were continuously monitored during the study.
To deliver 17% Fio2and 3% Fico2, nitrogen and carbon dioxide, respectively, were added to the inspiratory limb of the ventilator circuit. Nitrogen (size H tank) flow was adjusted to obtain 17% Fio2as measured in the inspired limb (MaxO2oxygen analyzer; Ceramatec, Salt Lake City, UT). Carbon dioxide (size E tank) was adjusted to achieve a partial pressure of 20 mmHg in the inspired limb (equivalent to 2.8% CO2, with a water vapor pressure of 47 mmHg at 37°C; measured using Nellcor Ultracap; Nellcor Inc., Pleasanton, CA). No changes were made to the minute ventilation during the study period.
Near-infrared Spectroscopy Methodology
The near-infrared cerebral oximeter used in this study (NIM Incorporated, Philadelphia, PA) was a prototype 3 wavelength frequency-domain device. 10This device uses laser diodes at measuring wavelengths of 754, 785, and 816 nm with an internal reference wavelength at 780 nm. The emitted light is sinusoidally oscillated at 200 MHz, and the phase-shift and intensity of the detected light relative to the emitted light were monitored by heterodyne frequency domain technology. Fiberoptic bundles mounted in soft rubber housing (optical probe) delivered the light to and from the head, and emitter and detector were separated by 3 or 4 cm. The probe, placed on the forehead below the hairline, monitors Sco2located in the frontal cerebrum; the scalp and skull do not contribute to the optical signal. 7,10The main unit housing the electronic hardware sends data to a computer for storage and analysis. Sco2is calculated from the phase shift signals. 10Instrument precision relative to cooximetry is 6% from 0 to 100%. Near-infrared spectroscopy Sco2represents predominantly oxygen saturation in the venous blood. 11
The protocol consisted of two treatment periods with three baseline periods (before and after each treatment). Treatments were 17% Fio2and 3% Fico2. Arterial blood gases, arterial pressure, saturation, and cerebral saturation were obtained at the end of each period. Arterial blood gases were drawn from an indwelling umbilical arterial catheter in all subjects. The sequence of treatment was assigned randomly from a previously generated chart. Each treatment was maintained for 10 min, followed by a 10–20-min baseline period.
Sample size calculation (n = 16) was based on a power of 0.8 and α= 0.01 to detect a 20% change in Sco2from baseline with treatment (3% Fico2or 17% Fio2). Data are presented as mean ± SD. Significance was set at 0.01 after Bonferroni correction for multiple comparisons.
The primary outcome measure was Sco2. Secondary outcome measures included heart rate, MAP, Sao2, p H, arterial carbon dioxide tension, arterial oxygen tension, and base excess. To examine the effect of period (time effect) and the order of treatment (carryover effects), independent two-sample t tests were conducted (SPSS Inc., Chicago, IL). In the absence of time and carryover effects, and differences between baseline and the two treatments were then examined by paired t tests for parametric data (data were normally distributed). Sco2values during the last 1-min of each period (baseline, 3% Fico2, 17% Fio2) were averaged by the computer to obtain the representative Sco2value for that period. Change in Sco2was the difference between treatment and the average of the baselines before and after the treatment.
Of the 16 patients enrolled, data from 15 were included in the analysis. One neonate was excluded for protocol violation (error in administering 3% Fico2). Table 1shows the demographic data of 15 subjects. Before the study, in the intensive care unit, all neonates had received prostaglandin infusion (0.025–0. 05 μg · kg−1· min−1), 10 had received dopamine (3–5 μg · kg−1· min−1), 13 had received digoxin and lasix, and 4 had inspired a hypoxic gas mixture (17–19% Fio2) by spontaneous ventilation in a hood. There were 12 full-term birth infants and 3 prematurely (< 37 weeks) born infants. None of the infants had neurologic abnormalities by history or physical examination.
During the study, 8 of 15 subjects received hypoxic mixture first followed by 3% Fico2. Because neither the order of treatments (crossover effect, P = 0.16) or time (period effect, P = 0.45) was statistically significant, data are presented by condition (i.e. , Fico2, Fio2, baseline) rather than by treatment order (baseline, 3% Fico2, baseline, 17% Fio2, baseline; or baseline, 17% Fio2, baseline, 3% Fico2, baseline). Mean data from the 15 subjects are shown in table 2, and the change from baseline (δ) in the MAP and Sco2for each subject is shown in table 3.
Heart rate, systolic arterial pressure, and Sao2did not change significantly with either Fico2or Fio2(table 2). With 3% Fico2, diastolic arterial pressure and MAP increased significantly by 12 and 10%, respectively. During 17% Fio2, diastolic arterial pressure and MAP did not change significantly (P = 0.02 and 0.11, respectively). With 3% Fico2, p H decreased and arterial carbon dioxide tension increased as intended, and arterial oxygen tension increased (P < 0.01); although the base excess increased, it was not significant (P = 0.09). With 17% Fio2, p H increased and arterial oxygen and carbon dioxide tensions decreased (although no alterations were made to the minute ventilation, adding nitrogen increased the minute ventilation;P < 0.01); the decrease in base excess was not significant (P = 0.3). Nasopharyngeal temperature remained unchanged during the study (36 ± 0.4 vs. 35.98 ± 0.4°C, start vs. end), as did hematocrit (42 ± 6 vs. 42.6 ± 6%, start vs. end).
Cerebral Oxygen Saturation
Figure 1shows a typical tracing of Sco2during the study in one subject, and table 4shows the results of the 15 subjects. Sco2increased significantly with 3% Fico2(P < 0.01), whereas it did not change with 17% Fio2(P = 0.85). In 8 of 15 subjects, 17% Fio2decreased Sco2, the largest decrease being 6.5%. By comparison , 3% Fico2increased Sco2in all subjects, the largest increase being 26%. At baseline, in two subjects Sco2was less than 40% (37 and 38.5%, respectively). In one of these subjects, Sco2decreased to 32% with 17% Fio2, whereas Sco2increased to 48% with 3% Fico2. In the other subject, Sco2did not change with 17% Fio2, but increased 10% during 3% Fico2administration.
Increase in Sco2began 2 ± 0.8 min after administration of 3% Fico2, and the increase was linear at a rate of 0.075 ± 0.05%· mmHg CO2−1· min−1(r2= 0.68). With the discontinuation of Fico2, Sco2returned to baseline by 8 ± 1.5 min. The relation between change in Sco2and MAP during Fico2was not significant (r2= 0.27, P = 0.048). The Sco2response to 3% Fico2in the premature (10 ± 3%) and full-term birth (13 ± 6) infants was similar.
There were no complications from the study.
In this group of neonates with SV heart defects, we found that Sco2and arterial pressure increased with 3% Fico2, whereas these parameters did not change significantly with 17% Fio2. These observations suggest that 3% Fico2provides better preoperative hemodynamics and cerebral oxygenation than 17% Fio2in this patient population.
Previous studies conducted in immature animal models of SV heart defects reported increases in pulmonary vascular resistance and a decrease in pulmonary to systemic blood flow ratios (Q̇p:Q̇s) with 10% Fio2and 5% Fico2. 12However, no cerebral oxygenation or vital organ blood flow data exist in either animal model or human neonates. In anesthetized, mechanically ventilated human neonates with SV heart defects, Tabbutt et al. 13compared the impact of 17% Fio2and 3% Fico2on systemic oxygen delivery after the same protocol as our study. 13They found that both treatments decreased Sao2and Q̇p:Q̇s similarly, although 3% Fico2increased systemic oxygen delivery, whereas 17% Fio2had no significant impact. These data suggest that 3% Fico2provides better systemic hemodynamics and oxygenation than 17% Fio2. Our observations support these conclusions. However, lower inspired oxygen concentrations, as in the animal models, might provide a similar hemodynamic result as 3% Fico2, with or without changes in cerebral oximetry.
Cerebral oximetry is an emerging technology to noninvasively monitor brain tissue oxygenation at the bedside. It is particularly applicable to the critically ill neonate and infant population, where the thin extra-cranial tissues do not interfere with brain monitoring, and in whom diagnosis of cerebral hypoxia–ischemia is otherwise problematic. At present, the instrumentation is based on continuous-wave or frequency-domain technologies. Continuous-wave devices have been commercially available for several years. They can monitor changes in Sco2over time but cannot determine baseline levels accurately. Frequency-domain devices (used in this study), a new technology using cellular phone technology, can accurately determine baseline Sco2as well as changes over time. It should be commercially available in the near future. However, the clinical utility of cerebral oximetry remains to be determined. Our study serves as an example of how the technology might be used clinically.
Cerebral oximetry and pulse oximetry differ in several respects. Although both use near-infrared light intensity signals, pulse oximetry monitors the pulsatile signal component reflecting the arterial circulation. Cerebral oximetry monitors the nonpulsatile signal component reflecting the gas-exchanging tissue circulation (capillaries, venules, arterioles), of which approximately 85% of the signal appears to originate from small venules. 11Pulse oximetry often fails with poor perfusion as the pulsatile signal diminishes. Cerebral oximetry is not susceptible to this failure, although it is subject to motion artifact like pulse oximetry. The critical cerebral oxygen saturation that results in brain damage remains uncertain. Studies in animal models suggest that the risk of brain damage increases as Sco2decreases to less than 40%, because electroencephalogram activity begins to slow, adenosine triphosphate decreases, and cytochrome aa3becomes reduced; these physiologic changes inevitably lead to neuronal necrosis. 14In our study, Sco2was less than this 40% threshold in two subjects at baseline (incidence, 2 of 15 [13%]), which decreased further with 17% Fio2in one subject, whereas Sco2increased above the threshold in both subjects with 3% Fico2. Based on this limited experience, 17% Fio2might increase the risk of cerebral hypoxia–ischemia before surgery in this patient population.
Cerebral oxygen saturation reflects a balance between cerebral oxygen delivery and cerebral oxygen consumption. Cerebral oxygen delivery is a product of cerebral blood flow (CBF) and arterial oxygen content. The latter depends on Sao2and hemoglobin. We did not measure hemoglobin, but during the study period there were no volume shifts; hence, use of hematocrit should be appropriate. During the study, Sao2and hematocrit remained constant; thus, a change Sco2resulted from changes in CBF or cerebral oxygen consumption. Hypercapnia and hypoxia in the magnitude used in our study do not alter cerebral oxygen consumption, 15nor do they alter the proportion of arterial to venous blood in the brain. 11Thus, changes in Sco2most likely reflect changes in CBF.
Treatment with 3% Fico2increased Sco2. The decrease in p H with hypercapnia would lead to a right shift in the oxygen dissociation curve (Bohr effect), which would lead to a decrease in Sco2and not an increase. There was a small (3 mmHg) but significant increase in arterial oxygen tension with 3% Fico2treatment; however, this cannot explain the 12% increase in Sco2we observed. Hence, it is most likely that hypercapnic cerebral vasodilatation led to an increase in CBF with an increase in Sco2.
Healthy adult volunteers breathing hypoxic mixtures (7–11% Fio2) during isocapnic conditions showed decreases in Sco2. 16We had therefore expected treatment with 17% Fio2to lead to a decrease in Sco2. However, the lack of change in Sco2reflects the fact that cerebral oxygen delivery was unchanged. Hypoxia can lead to cerebral vasodilatation, but 17% Fio2was an insufficient stimulus to evoke this. For example, in adult volunteers, CBF did not change with 18% Fio2, and it increased only 5% in response to 16% Fio2. 17
Cerebral blood flow may also increase if the MAP increases above the limits of autoregulation. The upper lower limit of autoregulation is uncertain in human neonates but is approximately 90 mmHg in neonatal animals. 18,19In our study, mean arterial pressure increased 10% in response to 3% Fico2but was still within the limits of autoregulation. Hence, an increase in CBF, and hence Sco2, on this basis was unlikely.
There are several limitations in our study that might not allow generalization of our findings to care of neonates with SV in the intensive care unit. Our subjects were anesthetized and mechanically ventilated. Their baseline and posttreatment Sao2and Sco2were greater than that of nonanesthetized, spontaneously breathing subjects. It is possible that the response to hypoxic or hypercapnic gas mixtures differs in nonanesthetized, spontaneously breathing subjects with lower Sao2and Sco2. Despite treatment with 3% Fico2and 17% Fio2, the Sao2remained greater than 90% in our subjects , indicating continued excessive pulmonary blood flow. Use of higher Fico2or lower Fio2might have reduced Sao2further. Time constraints did not permit us to test this hypothesis. Time constraints also limited each baseline and treatment period to 10–20 min. Previous work has shown the CBF response to hypercapnia and hypoxia to be completed by 5 and 6 min, respectively, with return to baseline by 1–2 min. 17,20Hence, treatment duration in our study should have been adequate to observe a response. However, chronic exposure (hours) might desensitize the cerebral response to hypoxia and hypercapnia.
In conclusion, we demonstrated that controlled ventilation with 3% Fico2increased the cerebral oxygen saturation as well as arterial pressure, whereas controlled ventilation with 17% Fio2maintained arterial pressure but did not change Sco2in most subjects, suggesting these treatments provide hemodynamic stability but affect cerebral oxygenation differently. The impact of 17% Fio2on cerebral oxygen saturation during spontaneous ventilation, prolonged administration of 17% Fio2and 3% Fico2, as well as higher Fico2remain to be studied.