| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
From the Departments of *Anesthesiology and Surgery, Duke University Medical Center, Durham, North Carolina; Department of Surgery, University of Missouri-Columbia, Columbia, Missouri; and CAS Medical Systems, Incorporated, Branford, Connecticut.
Address correspondence and reprint requests to James D. Reynolds, PhD, Departments of Anesthesiology and Surgery, Research Director, Division of Women's Anesthesia, Duke University Medical Center, Durham, NC 27710. Address e-mail to reyno010{at}mc.duke.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Variables were monitored in previously instrumented preterm pregnant sheep before, during, and after 4 h of general anesthesia. Isoflurane produced moderate fetal hypotension and bradycardia, whereas extubation was accompanied by increases in fetal heart rate and mean arterial blood pressure.
RESULTS: We observed an initial increase in fetal Sao2 followed by a gradual decline to baseline. Within the fetal brain, oxygenated hemoglobin changed by <10% (nonsignificant) and deoxygenated hemoglobin and total hemoglobin varied by <5%. Overall, although O2 levels within the preterm fetal brain were not independently enhanced by isoflurane (as occurs in the older fetus and in the adult), they did remain constant even as fetal mean arterial pressure decreased by more than 20%. By extension, we failed to identify changes in cerebral oxygenation that could be construed as injurious.
CONCLUSION: Any adverse preterm fetal response to maternal surgery should not be attributed solely to the actions of general anesthesia upon the fetus.
|
Introduction |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
One aspect that was unclear from our midterm insufflation study was the role of anesthesia in the fetal responses. This point has taken on added importance in light of recent debate on the potential for common anesthetics to injure the developing brain (3,4). Although we (5) have determined that a standard general anesthetic regimen actually has a positive effect on systemic and central oxygenation of the near-term fetus, it is uncertain how such drug exposure affects the immature conceptus. We attempted to answer this question in the present study. Experiments were conducted on instrumented pregnant sheep at 90 days of gestation (term between 145 and 155 days), a developmental time point roughly equivalent to the human second trimester. We used a standard anesthetic regimen (midazolam, thiopental, and isoflurane); the duration of exposure was 4 h, a period that would encompass most, if not all, of the surgical procedures conducted on gravid patients. The primary end-points were changes in fetal systemic (arterial blood gas and cardiovascular changes) and central [cerebral oxygenation monitored with near-infrared spectroscopy, NIRS (6)] physiologic status.
|
METHODS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Maternal/Fetal Instrumentation
Instrumentation and catheterization of the ewe and fetus were performed at a mean gestational age of 90 ± 1 days and was conducted in a manner identical to that already described for the near-term fetus (5). In brief, appropriately anesthetized ewes and their fetuses were instrumented with a series of arterial catheters. In addition, a perivascular flowprobe (S-series with either a 6 or 8 mm window; ±15% absolute accuracy; Transonic Systems, Ithaca NY) was placed around the left uterine artery, an amniotic catheter was secured to the fetus, and a NIRS fiberoptic bundle was attached onto the fetal brain. Throughout the procedure, ewes were kept in the left semilateral position to prevent aortocaval compression (7).
Upon completion of the surgery (3–4 h), bupivacaine (0.25%, s.c.) was infused around the incision sites and the animal returned to its pen. Nalbuphine hydrochloride, up to 1.0 mg/kg IM, (or similar opioid) was administered to the ewe as needed to control postsurgical pain. In addition to Pen G, prophylactic antibiotic therapy involved two doses of gentamicin (ewe 80 mg IV; fetus 40 mg via the amniotic catheter) and daily maternal IV infusions of sulfamethoxazole-trimethoprim (800 mg/160 mg in 250 mL of 5% glucose). All animals were allowed at least 48 h to recover from instrumentation before conducting the anesthetic exposure experiment.
Maternal General Anesthesia
On the day of experimentation, the ewe was placed in a support harness (Munks Livestock Sling Manufacturing Company, Anacortes, WA) within a transportation cart. The arterial catheters were flushed with heparinized saline and then attached to force transducers (Transpac®; Abbott Laboratories, North Chicago, IL); maternal and fetal cardiovascular data and amniotic pressures along with uterine blood flow (UBF) were recorded using a 16-channel PowerLab system (ADInstruments, CO Springs, CO). Fetal arterial blood pressure measurements were corrected for variations in intrauterine pressure by subtracting the simultaneously measured amniotic fluid pressure. Fetal cerebral oxygenation, as measured by changes in oxygenated, deoxygenated, and total hemoglobin (oxyHb, deoxyHb, and totalHb, respectively), was continuously recorded using a NIRS monitor (CAS Medical Systems, Branford, CT) adapted for in utero fetal sheep use.
After a baseline awake recording period (30–60 min), the ewe was sedated with midazolam (1 mg/kg, IV). Surgical anesthesia was induced with sodium thiopental (7 mg/kg, IV) and the lungs intubated. Surgical anesthesia was maintained at 1.5% isoflurane in O2 delivered by a Narkomed 2B ventilation system (North American Dräger, Telford, PA); isoflurane concentration was measured by an airway gas monitor (Datex Instrumentation Corporation, Helsinki, Finland). The ewe's ventilation was actively managed to keep ETco2 below 35 mm Hg; other standard operative monitoring devices (e.g., pulse oximetry) were also used. Body temperature was monitored with an esophageal probe and maintained at 39.5 (±1°C) with the use of a Bair Hugger body warming system (Arizant Healthcare Incorporated, Eden Prairie, MN). Supportive fluid therapy was provided during anesthetic exposure (IV saline at approximately 250 mL/h). Inhaled anesthesia was delivered for 4 h after which the vaporizer was turned off. Extubation occurred when the swallowing reflex appeared and the ewe resumed a normal respiratory pattern. To monitor for postanesthetic effects, the maternal and fetal physiologic recordings continued overnight. During the study, maternal and fetal arterial blood samples were obtained at regular intervals; blood gas status was quantitated with a Gem Premier 3000 blood gas analyzer (Instrumentation Laboratory, Lexington, MA).
Data Analysis
Arterial blood gas data are presented as group means ± sd. After determining fetal arterial O2 saturation and partial pressure along with Hb content, fetal arterial blood O2 content was calculated using the formula (8):
|
|
The constant 0.003 is the solubility coefficient for O2 in blood. The O2 capacity constant K is 1.36 for fetal sheep (9).
For the NIRS data, baseline values of fetal cerebral oxyHb, deoxyHb, and totalHb were calculated for each anesthetized animal by averaging the measurements taken during the preintubation period. Measurements taken during and after anesthesia were divided by these values and expressed as percent of baseline. Similar calculations were performed on the UBF data. With respect to the other cardiovascular variables, maternal and fetal heart rates and mean arterial blood pressures (MAP) were averaged at 1 min intervals for each animal and presented as group means.
The statistical analyses focused on the three primary end-points, viz. fetal changes in cerebral oxygenation, cardiovascular status, and arterial blood gas status. Data for the maternal responses are presented, but to preserve statistical power these parameters were not analyzed. Our initial power analysis (based on the near-term NIRS data) indicated that with 15 animals we would have a 90% power to detect a 15% change from baseline in oxyHb, deoxyHb, or totalHb; 80% power would be obtained with 10 animals. All fetal analyses were conducted using SAS® version 9.1 software (SAS Institute, Cary, NC). For cerebral oxygenation, changes in oxyHb, deoxyHb, and totalHb during and after anesthesia were assessed by calculating the duration above or below baseline as well as the average distance from baseline. (Distance was defined as the difference between each minute's measure minus baseline). For each animal, the average of these minute-by-minute distances was taken as a summary measure representing how far above or below baseline the measure was, and for how long. Mean distances during and after anesthesia (along with 95% confidence intervals) were calculated and compared with baseline using t-tests. A similar methodology was used to test for changes in fetal heart rate and fetal MAP. To assess for changes in fetal blood gas status, a mixed-model repeated-measures analysis of variance was used. Measurement times were treated categorically to allow post hoc comparisons to baseline with Dunnett's test adjusting as needed for multiple comparisons. A follow-up analysis treating minutes numerically in a test for time effect was also conducted to confirm the initial results. For all end-points, P values of <0.05 were considered significant.
|
RESULTS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
On the maternal side, the cardiovascular responses to general anesthesia (Fig. 1) were identical to what we observed in the near-term sheep (5). There was an initial period of bradycardia and hypotension along with a modest decrease in UBF (basal UBF was 175 ± 65 mL/min); 30–45 min into the exposure these variables returned to baseline. Extubation produced marked increases in maternal heart rate and MAP, and fluctuations in UBF, all of which resolved during the overnight monitoring period. With respect to respiratory status (top part of Table 1), the ewes were well-ventilated throughout the procedure with average ETco2 staying below the preset limit of 35 mm Hg. As expected, maternal Sao2 increased to 100% during anesthesia and then returned to the preintubation level of 98% after extubation; anesthesia produced a slight decline in arterial pH and a minor increase in Pco2; the latter occurred even as ETco2 stayed constant. Mean standard base excess changed little during or after isoflurane exposure.
|
|
The effects of general anesthesia on fetal arterial blood gas status, cardiovascular variables, and cerebral oxygenation are presented in Table 1 (bottom part) and Figures 2 and 3, respectively. There was an initial increase in O2 saturation and blood O2 content (both P < 0.05) that reversed by the 180 min time point after which neither marker of systemic oxygenation was significantly different from baseline. In contrast, Pco2 and pH were both statistically different from baseline (higher and lower, respectively) for the duration of anesthetic exposure; these differences resolved within 30 min of extubation. Mean standard base excess values fluctuated during the study, but no single time point was different from baseline. There were no significant changes in fetal Hb concentration, which confirmed that the blood sampling regimen did not produce hypovolemia. General anesthesia also produced changes in fetal cardiovascular status (Fig. 2). Both fetal heart rate and MAP declined as the exposure period progressed; nadirs of 152 ± 13 bpm and 35 ± 9 mm Hg were reached immediately before terminating the exposure (P < 0.001 for both versus baseline). Extubation was accompanied by a sudden increase in both variables. In this case, MAP returned to the baseline level (P = 0.58) while heart rate significantly overshot the baseline level (P = 0.036) and remained increased for several hours before gradually decreasing during the overnight period (data not shown).
|
|
|
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
The maternal responses to general anesthesia at this gestational time point were essentially identical to those we observed in the near-term ewes (5). The initial alterations in maternal cardiovascular status did not negatively impact the fetus because fetal arterial O2 saturation and blood O2 content increased during the time when UBF was lowest. One point of interest was the progressive divergence between the end-tidal and maternal arterial Pco2 measurements (Table 1). We have previously commented on this difference (1) and the present findings would lend additional support for monitoring both ETco2 and arterial blood gas status of pregnant patients.
These experiments relied on our ability to continually monitor changes in Hb oxidation status within the fetal brain. We used a NIRS device of our own design optimized for in utero applications (6). The technology is based on the ability of light within the near-infrared spectra (700–1000 nm) to pass through bone and tissue but, within this 300 nm bandwidth, Hb has specific absorption spectra dependent upon its oxidation state (10). NIRS sees Hb in the microvasculature (arterioles, venuoles, and capillaries); larger blood vessels blind or highly absorb the NIRS light. As a result, the NIRS interrogates approximately 30% arterial and 70% venous blood in the microvasculature. By placing fiberoptic probes that transmit (and other fiberoptic bundles that receive) near-infrared light at specific wavelengths on the skull, changes in attenuation can be converted to real-time measures of fetal cerebral oxyHb, deoxyHb, and totalHb concentrations. Our previous validation of the system involved recording changes in these fetal variables in response to controlled reductions in systemic oxygenation produced by partial to full umbilical cord occlusion; 5%–7% reductions in fetal arterial blood O2 saturation produced quantifiable alterations in fetal cerebral oxygenation (6).
In combination with our near-term isoflurane study (5), we have used the NIRS system to identify gestational age-dependent differences in the fetal cerebrovascular response to maternal general anesthesia. Cerebral autoregulation is an important means of ensuring that the developing brain receives an adequate supply of O2 and nutrients, even under conditions of altered fetal cardiovascular status or when maternal-fetal exchange is impaired (e.g., during umbilical cord occlusion). Multiple factors participate in this control of blood flow. As the fetus matures, these factors also change, including alterations in ion channel activity (11), cytoskeletal protein expression (12), and nitric oxide synthase activity (NOS). (13) Overt in utero physiologic/pharmacologic consequences of these changes include gestational age-dependent differences in autoregulatory capacity (14), effects of vasoactive drugs (15), and cerebral blood flow responses to changes in fetal intracranial pressure (16). To this list we would add the fetal cerebrovascular response to general anesthesia, specifically to isoflurane.
Isoflurane can alter blood flow to various organs, including the brain. Within the central nervous system, isoflurane increases oxygenation via an increase in cerebral blood flow coupled with an isoflurane-mediated reduction in O2 metabolism. The ability of isoflurane to augment cerebral oxygenation by these actions has been well documented in adult humans (17,18), a variety of adult experimental animal preparations (19–21) and by us in the near-term sheep fetus (5). In contrast, we observed no such augmentation of cerebral oxygenation in the preterm fetus during maternal isoflurane exposure. One possible reason for this lack of effect is the developmental differences in NOS activity. The development of NOS in the fetal sheep brain is temporally dependent (13). In vitro measurements have shown that within the parietal cortex, NOS activity is measurable at gestational day 70, it has doubled by day 92, and then exponentially increased to adult levels of activity by gestational day 135 (22). In vivo assessments of markers of NOS activity (i.e., nitrate/nitrite concentration) have confirmed higher levels in the mature fetal sheep brain (23). The ontogenic profile of NOS is relevant to the present finding because isoflurane increases the formation of nitric oxide within the brain (24,25), which presumably contributes to the isoflurane-mediated increases in cerebral blood flow (26). By extension, the lower level of NOS activity observed in the preterm fetal brain would limit this response. Another possible contributor is a gestational difference in calcium channel activity (11), because isoflurane appears to suppress calcium movement in vascular smooth muscle (27). Neither of these mechanisms is mutually exclusive, and it is quite possible that NOS and calcium channel activities interact with other factors to mediate the gestational age-dependent responses to isoflurane.
The lack of an isoflurane-induced increase in preterm fetal cerebral oxygenation does not mean that local regulation of cerebral blood flow is completely absent at this gestational time point. Indeed quite the opposite is true: the fetus maintained cerebral oxyHb and totalHb (the latter an index of blood flow) at their pretreatment levels even when fetal MAP decreased to a nadir of 35 mm Hg during maternal anesthesia. This observation is consistent with a previous report that demonstrated fetal sheep at a gestational age of 110 days could maintain a constant level of cerebral perfusion, even when fetal MAP was varied (via drug infusions) between 20 and 48 mm Hg (14). Although not a specific end-point of the present study, it is reasonable to propose that 18 days earlier in gestation, the fetus has already developed the capacity to maintain cerebral blood flow between systemic pressures of 35 and 45 mm Hg.
An impetus for the current study was our previous finding that maternal pneumoperitoneum produces a significant and prolonged decrease in systemic oxygenation along with hypercarbia and acidosis in preterm fetal sheep (1). We can now argue that these adverse effects resulted from the surgical procedure (i.e., insufflating the maternal abdomen with CO2), either alone or in combination with the anesthetic drugs, and were not exclusively the result of general anesthesia. The other issue of anesthetic neurotoxicity is left unanswered. Certainly we failed to identify changes in fetal cerebral oxygenation or other fetal (and maternal) physiologic variables that could be construed as injurious to the developing central nervous system. However, we were also not in a position to conduct histologic assessments of the preterm brains after maternal general anesthesia. Although we failed to find evidence of histologic injury in the near-term fetus following this same anesthetic regimen (5), the development differences we have identified argue for caution in extending the negative near-term histology results to encompass other gestational ages.
In addition to the unanswered question of anesthetic neurotoxicity at this developmental age, our study has other limitations. For instance, we elected to administer isoflurane in O2, whereas pregnant patients may not always receive a continual high level of supplemental O2. This was done to eliminate an experimental variable (i.e., to ensure all ewes had the same oxygenation status) as opposed to titrating O2 delivery during the exposure period. We do not believe this affected our results (nor the applicability of these findings to the clinical situation), as changes in maternal (e.g., UBF) and fetal (e.g., blood O2 content) variables were documented independent of maternal O2 status. It is also worth noting that some researchers support maternal hyper-oxygenation during general anesthesia as a means of increasing fetal oxygenation (28), although the present study would suggest that the fetal increase is only transitory. Another limitation is body position. Anesthesia was administered while the ewe was in a sling, and not supine. This was done to allow for continual cardiovascular and fetal cerebral oxygenation monitoring. The ewe's position did not appear to alter the fetal responses, because the observed changes in blood gases and cardiovascular status were similar to those we recorded in our preterm insufflation study after induction, but before initiating pneumoperitoneum (1). Other limitations include the absence of intra- or postexposure narcotics and restricting our study to a single volatile anesthetic. These omissions were financially driven. The cost of the instrumented sheep preparation limited us to studying a single anesthetic paradigm. And although the literature suggests that opioid administration has only modest fetal effects (as shown in Ref. 29), and that different volatile anesthetics such as sevoflurane induce responses similar to isoflurane (30), both warrant further assessments using a preparation that allow for monitoring of fetal systemic and central physiologic status.
In summary, maternal general anesthesia with isoflurane (in the absence of any surgical manipulation) does not alter cerebral oxygenation within the preterm fetal brain. At the same time, the cerebrovasculature has developed sufficiently by this time point to maintain a constant level of oxygenation and blood flow even when fetal MAP decreased by more than 20%. As a result, any adverse preterm fetal response to maternal surgery should not be attributed solely to the actions of general anesthesia upon the fetus.
|
Footnotes |
|---|
Supported by National Institutes of Health Grants NS 042664 and HD 042471; and by Duke Anesthesiology Research Fund and Duke Endosurgery Center.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
