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© 2000 International Anesthesia Research Society
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Abstract |
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We tested the possibility that large-dose isoflurane will produce a loss of brain tissue oxygen regulation in dogs. A total of 12 dogs were anesthetized with isoflurane, a craniotomy was performed, and a probe was inserted to measure brain tissue oxygen pressure (PtO2), carbon dioxide, and pH. Baseline measures were made during 1.5% end-tidal isoflurane with 30% oxygen ventilation, followed by 95% oxygen ventilation. Six dogs (Group 1) were treated with 3% isoflurane and 30% oxygen, followed by a second oxygen challenge with 95% O2. Six dogs (Group 2) received propofol to produce a similar suppression of the electroencephalogram as in Group 1, followed by 95% oxygen ventilation. Brain tissue oxygen reactivity was calculated by the increase in PtO2 divided by the increase in arterial PO2. During 1.5% isoflurane and propofol anesthesia, PtO2 increased from 42 to 62 mm Hg with oxygen ventilation, and brain tissue oxygen reactivity was 0.14% per mm Hg-1. Brain tissue oxygen reactivity did not change during propofol anesthesia. With 3% isoflurane, PtO2 increased from 52 to 113 mm Hg and brain tissue oxygen reactivity was 0.36% per mm Hg-1 (P < 0.05). These results suggest that the cerebrovasodilator and vasoplegic effects of large-dose isoflurane attenuate brain oxygen regulation.
Implications: We evaluated the ability of oxygen ventilation to increase brain tissue oxygen pressure in dogs anesthetized with 1.5% and 3% isoflurane and propofol. Increases in tissue oxygen were significantly greater during 3% isoflurane compared with 1.5% isoflurane and propofol.
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Introduction |
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Brain tissue oxygen reactivity is defined by the increase in brain tissue oxygen pressure (PtO2) produced by an increase in arterial oxygen pressure (1). In head-injured patients, investigators found that brain tissue oxygen reactivity was increased in subjects with a poor outcome (1–3). Because PtO2 is correlated with cerebral blood flow (3,4), a loss of oxygen regulation after head injury may be because of an increase in cerebral blood flow or a decrease in tissue oxygen demand. In support of this, we observed that in dogs, increases in PaCO2 increased brain tissue oxygen reactivity, whereas hypocapnia had the opposite effect (5). Another possible mechanism is regulation of cerebrovascular resistance. It is reported that cerebrovascular resistance increases during hyperoxia (6), and that brain injury is associated with loss of regulation of blood flow (7). If cerebral arteries are unable to regulate capillary perfusion during hyperoxia, brain oxygenation would be significantly increased. Because isoflurane will produce cerebrovasodilation and vasoplegia in large doses (8), we evaluated whether isoflurane, given in doses that produce burst suppression electroencephalogram (EEG) activity, increases brain tissue oxygen reactivity. Isoflurane was compared with propofol, a cerebrovasoconstrictor, given in doses that also produced burst suppression EEG.
In addition to measuring brain tissue gases and pH, we evaluated sagittal sinus blood gases. Cerebral venous oxygen is often used clinically to estimate brain oxygenation (9); however, the validity of this assumption may be questioned because of arteriovenous shunting (10). We determined whether brain venous and tissue oxygen reactivity are similar and how they are affected by large-dose isoflurane and propofol anesthesia.
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Methods |
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Our study was approved by our institutional animal care committee and experiments were performed at the West Side Veterans Administration Animal Research Facilities in Chicago. A total of 12 nonpurpose bred dogs were used in our study. Dogs were fasted overnight. On the day of the study, the dogs were anesthetized with pentothal, intubated, and their lungs ventilated with 2% isoflurane in an air/oxygen mixture. A heating pad was used to maintain rectal temperature at 38°C. Catheters were inserted into the femoral artery and vein and external jugular vein for blood pressure recording, blood gas sampling, and fluid and drug administration. For fluid maintenance, 4 mL · kg-1 · hr-1 IV sterile saline was infused. A 4-cm diameter craniotomy was performed over the left hemisphere and the dura incised and retracted.
A Neurotrend probe (Codman, New Bedford, MA) was calibrated on the day of the study by using precision gases. The probe is 0.5 mm in diameter and four sensors measuring brain tissue pH, carbon dioxide pressure (PtCO2), temperature, and PtO2 are contained in the final 2 cm. The probe was inserted 2 cm into the cortex, parallel to the surface of the brain. Care was taken to avoid blood vessels on insertion of the probe by visual inspection. All probes displayed a normal PtO2 range of 20–40 mm Hg and responsiveness to changes in PaO2 after equilibration, suggesting that a hematoma did not impair tissue measures. The sagittal sinus vein was catheterized with PE-50 tubing. When cerebral surgery was completed, the craniotomy site was packed with sterile gauze soaked with saline to exclude extraneous light. End-tidal isoflurane concentration was decreased to 1.5% and the dog was allowed to stabilize for 45 min.
Surface electrodes were applied to the skull on the right hemisphere contralateral to the craniotomy for recording the EEG. One-channel bipolar EEG was recorded by using an EEG monitor (A-1000; Aspect Medical Systems, Natick, MA). During large-dose isoflurane and propofol treatments, burst suppression was identified from the raw EEG signal by a bursting EEG pattern followed by periods of quiescence. Percent quiescence was calculated and displayed on the screen by the A-1000 monitor.
Dogs were randomly assigned to two groups. In Group 1 (n = 6), end-tidal isoflurane was adjusted to 1.5% for a 45 min equilibration period. Inspired oxygen was 30 ± 1% and end-tidal CO2 was adjusted to 38 ± 2 mm Hg. At the end of the equilibration period, mean arterial pressure (MAP), heart rate, PtO2, PtCO2, brain tissue pH, and temperature were recorded. Arterial and sagittal sinus blood samples were obtained to measure blood gases and pH, by using a blood gas analyzer (1202; Instrumentation Laboratories, Chicago, IL).
Inspired oxygen concentration was then increased to 95 ± 1%, maintaining all other experimental conditions constant. After a 10 min equilibration period, a second measurement of all variables was made. Inspired oxygen was decreased to 30% and end-tidal isoflurane increased to 3.0 ± 0.1%. This isoflurane concentration produced a burst suppression EEG with a quiescence measure of 80%–100%. Blood pressure was not controlled in this treatment. After a 10-minute equilibration at this isoflurane concentration, a third measure was obtained. An infusion of 3 to 10 µg/min IV phenylephrine was given to increase MAP to baseline levels, and a fourth measurement was made after a 10 min equilibration. Phenylephrine was chosen to support blood pressure because it has minimal direct cerebrovasoconstrictor effects (11). While maintaining blood pressure with phenylephrine, inspired oxygen was increased to 95% and the last measure was made after 10 min.
In Group 2, the baseline measure with 1.5% isoflurane and the second measure with 95% oxygen ventilation were the same as in Group 1. A 2 mg/kg IV propofol injection over 5 min was followed by an infusion of 100–200 µg · kg-1 · min-1 to maintain a burst suppression pattern with >80% quiescence. Isoflurane anesthesia was maintained at 1.5% during this treatment to maintain a similar background anesthetic in both treatment groups. After a 10 min equilibration, the third measure was made in these dogs. Propofol infusion was maintained with blood pressure support to baseline levels with phenylephrine (0.5–2 µg/min) in a fourth treatment and during 95% oxygen ventilation in a fifth treatment. At the end of the study, each dog was killed by using a euthanasia solution.
Tissue oxygen reactivity was calculated for each increase in oxygen concentration, relative to 30% oxygen by using the following formula of van Santbrink et al. (1): 
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Physiological shunt fraction was calculated from oxygen content in the artery, sagittal sinus, and capillary, by using the Neurotrend tissue value to estimate capillary partial pressures (10). Oxygen content was calculated from PaO2 and PvO2 in each case by using the oxygen dissociation curve for the dog with a correction for pH and temperature (12,13). Brain capillary oxygen content was calculated from PtO2 with a correction for pH and temperature. Capillary pH was estimated from PtCO2, assuming a normal CO2/pH relationship for each dog’s blood. Shunt fraction was calculated from oxygen content differences by using the following formula: O2 shunt fraction = (sagittal sinus - capillary)/(artery - capillary) x 100.
Differences in MAP, blood and tissue gases, and pH compared with baseline were determined by repeated measure analysis of variance with Tukey’s tests used for post hoc evaluation. PtO2 and oxygen reactivity differences between isoflurane and propofol treatments were compared by using Tukey’s tests. For shunt fraction, the two groups receiving 1.5% isoflurane were pooled to evaluate the effect of oxygen ventilation by using a paired t-test. The three treatments during 3% isoflurane were compared with the same treatments during propofol anesthesia by using an analysis of variance.
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Results |
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Cardiovascular and arterial blood gas changes in propofol and isoflurane anesthetized dogs are shown in Table 1. During 3% isoflurane, MAP decreased 50%. In contrast, the hypotensive effects of propofol to produce burst suppression EEG were modest. Significant increases in PaO2 were produced during 95% oxygen ventilation. Brain temperature was 38°C in all groups, with no difference between treatment conditions.
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Sagittal sinus and brain tissue gases and pH are presented in Table 2. Supporting blood pressure after treatment with 3% isoflurane produced a significant increase in venous and tissue oxygenation. When inspired oxygen was increased to 95%, PvO2 and PtO2 increased during baseline, propofol, and 3% isoflurane anesthesia. The magnitude of the increase was greater during 3% isoflurane compared with baseline and propofol anesthesia (P < 0.05).
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Oxygen reactivity, calculated by the change in PvO2 or PtO2 during 95% O2 inspiration, was higher in tissue compared with venous samples during baseline isoflurane anesthesia (P < 0.05, fig 1). There was no change in venous or tissue oxygen reactivity during propofol anesthesia. During 3% isoflurane, venous and tissue oxygen reactivity increased significantly compared with baseline and propofol treatment (P < 0.05).
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During baseline anesthesia with 1.5% isoflurane, the average shunt fraction was 25% and decreased to 13% during hyperoxia (Fig. 2). A similar decrease in shunt fraction was seen with oxygen ventilation during propofol anesthesia. Shunt fraction increased to 47% during 3% isoflurane, significantly higher than with propofol treatment. Hyperoxia had no effect on shunt fraction in 3% isoflurane anesthetized dogs.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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These results show that oxygen ventilation during 1.5% isoflurane anesthesia increases PtO2 by 40%. When end-tidal isoflurane is 3%, oxygen ventilation increases PtO2 by 120%. Loss of oxygen regulation during large-dose isoflurane is seen in both brain tissue and cerebral venous blood. In comparison to large-dose isoflurane, propofol given in doses that also produced burst suppression EEG had no effect on brain tissue oxygen reactivity. This indicates that cerebral metabolic depression is not the primary mechanism of increased PtO2. The loss of oxygen regulation with 3% isoflurane is consistent with other reports that brain tissue oxygen reactivity increases during other hyperperfusion states (1,2,5). A similar loss of brain tissue oxygen regulation after head injury may promote oxygen free radicals and neuronal damage during hyperoxia (14).
Previous studies indicate that brain tissue oxygen reactivity is increased after cerebral tissue injury. Meixensberger et al. (2) reported that PtO2 in normal brain tissue increased from 43 to 138 mm Hg during oxygen ventilation. In injured tissue, oxygen ventilation produced an increase from 45 to 352 mm Hg. They concluded that brain oxygen regulation is abolished after tissue injury. Van Santbrink et al. (15) reported that brain tissue oxygen reactivity was 0.91% per mm Hg-1 in head-injured patients with a bad outcome and 0.59% per mm Hg-1 in those with a good outcome. They suggested that oxygen regulation in the first 24 hours after head injury is a good indicator of patient outcome. This was confirmed by Menzel et al. (3) who found a significant relationship between oxygen regulation and outcome. The increase in brain tissue oxygen reactivity in head-injured patients may be related to hyperperfusion relative to oxygen consumption or a loss of cerebrovascular regulation (7). Impaired cerebral vascular reactivity is consistently associated with a poor outcome after traumatic brain injury (16,17).
Investigators report that hyperoxia will constrict cerebral arteries and decrease cerebral blood flow (6). This agrees with our finding that arteriovenous shunting is decreased during hyperoxia. Fan et al. (18) reported shunting of microspheres occurred primarily in cerebral vessels <15 micron in diameter and increased from 22% during normocapnia to 28% during hypercapnia. Physiological shunting, measured by differences in arterial, venous, and capillary oxygen content, increased from 10% during hypocapnia to 50% during hypercapnia (10). These findings indicate that brain arteriovenous shunting changes in the opposite direction to cerebral vascular resistance. It is reported that 2.8% isoflurane produces maximum cerebrovasodilation, similar to hypercapnia (8). This is consistent with our finding that shunt fraction increases from baseline measures of 25%–47% during 3% isoflurane. Shunting increases even when blood pressure is decreased and cerebral blood flow may not be increased. This suggests that shunting is related to cerebrovascular tone rather than to cerebral blood flow.
We observed that brain tissue oxygen reactivity is higher in brain tissue compared with veins during 1.5% isoflurane anesthesia. This is consistent with a previous finding in normocapnic dogs anesthetized with 1.7% isoflurane (5). Separate factors could affect tissue and venous oxygenation. Capillary perfusion and oxygenation and tissue metabolism would be primary factors regulating PtO2, whereas arterial to venous shunting could have a major impact on PvO2 (10,18). Although brain blood flow may decrease during hyperoxia (6), the amount of blood perfusing brain capillaries would be proportionally greater because of decreased shunting. This would enhance tissue oxygenation and attenuate increases in PvO2. The differential response of venous and tissue oxygen reactivity was abolished by 3% isoflurane. We previously observed that the difference between venous and tissue oxygen reactivity was also abolished by hypercapnia (5). This suggests that the cerebrovasodilator effects of 3% isoflurane and hypercapnia antagonize the regulation of PtO2 and PvO2 during hyperoxia.
A concern of ours is that there was a systematic treatment of each group, starting with baseline oxygen challenges followed by anesthetic treatment and hyperoxia. This may produce an error in measurement if the experimental preparation is not stable or an early treatment affected later measures. Arterial blood gases were similar between groups and were stable throughout the study. This is consistent with measures of cerebral venous and tissue pH and PCO2. Tissue PO2 is more difficult to interpret, because measures would be dependent on cerebral blood flow, perfusion pressure, and blood oxygenation. It is also clear that propofol treatment does not change normal PtO2 or the hyperoxia response compared with baseline measures. This supports the conclusion that the change in brain tissue oxygen reactivity and shunt fraction produced by 3% isoflurane is a direct result of that treatment, rather than a time-induced change in measurement.
In conclusion, our study shows that brain tissue oxygen reactivity is increased during 3% isoflurane compared with 1.5% isoflurane and propofol. Loss of oxygen regulation may be related to increases in cerebral blood flow or to the vasoplegic effects of 3% isoflurane. These changes may be related to increased brain tissue oxygen reactivity after head injury.
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Acknowledgments |
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We wish to thank Richard Ripper for his surgical and technical support in our study.
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References |
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- Van Santbrink H, Maas AIR, Avezaat CJJ. Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury. Neurosurgery 1996; 38: 21–31.[Web of Science][Medline]
- Meixensberger J, Dings J, Kuhnigk H, Roosen K. Studies of tissue PO2 in normal and pathological human brain cortex. Acta Neurochir 1993; 59 (Suppl): 58–63.
- Menzel M, Doppenburg EM, Zauner A, et al. Cerebral oxygenation in patients after severe head injury: Monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure. J Neurosurg Anesthesiol 1999; 11: 240–51.[Web of Science][Medline]
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- Hoffman WE, Edelman G, Wheeler P. Cerebral oxygen reactivity in the dog. Neurol Res. In press.
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