1 Department of Anaesthesia and Intensive Care, 2 Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China*Corresponding author
Presented in part as a free paper at the 10th European Society of Anaesthesiologists and 24th European Academy of Anaesthesiology meeting, Nice, France, April 2002.
Accepted for publication: April 2, 2002
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Abstract |
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Methods. We randomized patients having elective Caesarean section to receive one of the following: FIO2 0.3, FIN2O 0.7 and end-tidal sevoflurane 0.6% (Group 30, n=20); FIO2 0.5, FIN2O 0.5 and end-tidal sevoflurane 1.0% (Group 50, n=20), or FIO2 1.0 and end-tidal sevoflurane 2.0% (Group 100, n=20) until delivery. Neonatal outcome was compared biochemically and clinically.
Results. At delivery, for umbilical venous blood, mean PO2 was greater in Group 100 (7.6 (SD 3.7) kPa) compared with both Group 30 (4.0 (1.1) kPa, P<0.0001) and Group 50 (4.7 (0.9) kPa, P=0.002) and oxygen content was greater in Group 100 (17.2 (1.6) ml dl1) compared with both Group 30 (12.8 (3.6) ml dl1, P=0.0001) and Group 50 (13.8 (2.6) ml dl1, P=0.0001). For umbilical arterial blood, PO2 was greater in Group 100 (3.2 (0.4) kPa) compared with Group 30 (2.4 (0.7) kPa, P=0.003), and in Group 50 (2.9 (0.8) kPa) compared with Group 30 (2.4 (0.7) kPa, P=0.04); oxygen content was greater in Group 100 (10.8 (3.5) ml dl1) than in Group 30 (7.0 (3.0) ml dl1, P<0.01). Apgar scores, neonatal neurologic and adaptive capacity scores, and maternal arterial plasma concentrations of epinephrine and norepinephrine before induction and at delivery were similar among groups. No patient reported intraoperative awareness.
Conclusions. Use of FIO2 1.0 during general anaesthesia for elective Caesarean section increased fetal oxygenation.
Br J Anaesth 2002; 89: 55661
Keywords: anaesthesia, depth; anaesthesia, obstetric; anaesthetics volatile, sevoflurane; oxygen, inspired concentration; partial pressure, oxygen
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Introduction |
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The different findings may result from differences in study design. Confounding factors that make interpretation of earlier studies difficult include lack of lateral uterine displacement,6 7 inclusion of both labouring and non-labouring patients,35 incomplete or undescribed methods of randomization3 58 and inadequate compensation for changes in anaesthetic depth when varying FIO2.3 68 Furthermore, previous studies used umbilical arterial and venous PO2 to calculate fetal haemoglobin oxygen saturation, taking into account the characteristics of the fetal oxyhaemoglobin concentration curve.5 No previous study has directly measured the effect of maternal FIO2 on umbilical cord blood oxygen content.
We set out to compare the effect of FIO2 of 0.3, 0.5 and 1.0 on umbilical cord blood oxygen content in patients having elective Caesarean section under general anaesthesia. To achieve equivalent depth of anaesthesia among groups, we calculated equipotent doses of inhaled anaesthetics and measured and closely regulated circuit anaesthetic concentrations. Because light anaesthesia can increase maternal circulating catecholamines and cause uteroplacental vasoconstriction,4 5 we measured maternal arterial plasma concentrations of epinephrine and norepinephrine before induction and at delivery. Neonatal outcome was compared biochemically by measurement of umbilical venous and arterial blood gases and oxygen content using co-oximetry, and clinically by assessment of neonatal Apgar scores and neurologic and adaptive capacity scores (NACS).
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Methods |
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Patients were given oral ranitidine 150 mg the night before and on the morning of surgery and 30 ml 0.3 M sodium citrate on arrival in the operating theatre. Standard monitoring included non-invasive arterial pressure measurement, electrocardiography and pulse oximetry. A wide-bore i.v. catheter was inserted under local anaesthesia and a slow infusion of lactated Ringers solution was started. Patients were then randomly allocated to one of three groups by drawing of sequentially numbered sealed envelopes that each contained a computer-generated randomization code. Each group received a different inspired oxygen fraction during the period from immediately after induction to delivery.
The circuit oxygen analyser was calibrated immediately before each case and lateral uterine displacement was achieved by tilting the operating table to the left. After pre-oxygenation, rapid sequence induction with cricoid pressure was achieved using thiopental 4 mg kg1 and succinylcholine 1.5 mg kg1. Atracurium was given as required for further muscle relaxation as indicated by a peripheral nerve stimulator. The lungs were ventilated to maintain end-tidal carbon dioxide concentration of 4.3 kPa. For maintenance of anaesthesia, we used sevoflurane9 as the volatile agent because of its low bloodgas partition coefficient. Concentrations of oxygen, nitrous oxide and sevoflurane were adjusted according to group allocation: Group 30 received FIO2 0.3, FIN2O 0.7 and sevoflurane adjusted to maintain end-tidal concentration of 0.6%; Group 50 received FIO2 0.5, FIN2O 0.5 and end-tidal sevoflurane 1.0%; and Group 100 received FIO2 1.0 and end-tidal sevoflurane 2.0%. These inspired fractions were chosen to provide approximately equivalent MAC values. A circle circuit with a fresh gas flow of 6 litre min1 was used and for all patients the sevoflurane vaporizer was initially set at 6% for the first 60 s in order to prime the circuit and was then adjusted as required to maintain the allocated end-tidal concentration. Oxygen and anaesthetic concentrations were measured using the modules integrated into the anaesthesia machine (Narkomed 4, North American Dräger, Telford, PA, USA). All monitoring data were downloaded to a Macintosh computer using software developed within our department.
Patients were not informed of the group allocation. One anaesthetist was responsible for controlling the delivery of the anaesthetic. Separate investigators were responsible for the blood sampling and analysis. To mask these investigators and the surgeon to the treatment, the anaesthesia machine was turned away so the monitors were not visible to them. Maternal arterial haemoglobin oxygen saturation was measured continuously using pulse oximetry. The contingency plan for any patient who developed an SpO2 95% was to increase the FIO2 to the next highest group, and for any patient who developed hypotension was to increase the rate of i.v. fluid administration. Times of skin incision, uterine incision and delivery were recorded by stopwatch.
Approximately 10 ml maternal arterial blood was taken by radial artery puncture before pre-oxygenation and at the time of delivery. Each sample was divided into aliquots for measurement of blood gases, oxygen content and plasma concentrations of epinephrine and norepinephrine. Samples of arterial and venous blood were taken from a double-clamped segment of umbilical cord for measurement of blood gases and oxygen content. After delivery, morphine 0.15 mg kg1 and oxytocin 10 IU were given i.v. Anaesthesia was then maintained using FIO2 0.3, FIN2O 0.7 and end-tidal sevoflurane 0.6% in all patients.
After delivery, the neonate was assessed by a paediatrician (KCM) who was not aware of the treatment, who recorded Apgar scores 1 min and 5 min after birth and NACS 15 min and 2 h after birth.
At the end of surgery, residual neuromuscular block was antagonized using neostigmine and atropine. Blood loss was assessed by measuring blood in the suction bottle minus liquor, weighing wet swabs and estimating blood on drapes and on the floor.
Each patient was visited on the first day after operation by a research nurse, who asked the patient if she was able to recall any intraoperative events or remembered any dreams during the operation.
Laboratory analyses
All blood samples were drawn into heparinized syringes. Samples for blood-gas and oxygen-content analysis were immediately placed in ice. Blood gases were measured using a Ciba-Corning 278 Blood Gas System blood gas analyser (Ciba-Corning, Medfield, MA, USA). Oxygen content and total haemoglobin concentration were measured using an IL 482 Co-oximeter (Instrumentation Laboratory, Lexington, MA, USA) with correction for 70% fetal haemoglobin. Blood samples for catecholamine analysis were immediately put into lithium-heparin tubes containing metabisulphite as an antioxidant and the tubes were immediately placed in ice. These were centrifuged at 4°C and the plasma was separated and stored at 70°C pending batch analysis. Norepinephrine and epinephrine were measured by high performance liquid chromatography. Catecholamines were extracted with alumina, analysed on a reverse-phase Ultrasphere IP C18 column (Beckman Instruments Inc., Altex Division, San Ramon, CA, USA) and detected by an electrochemical method on an ESA 5100A coulometric detector (Environmental Science Associates, Bedford, MA, USA). The within-day coefficients of variation for norepinephrine and epinephrine were 7.06% and 8.48%, respectively, and the between-day coefficients of variation were 10.69% and 12.69%, respectively. The assay was linear to the lower limit of detection, which was 25 pg ml1 for both norepinephrine and epinephrine.
Statistics
Prospective power analysis was based on data from our previously published work.10 The primary outcome was defined as the umbilical venous oxygen content. We calculated that a sample size of 17 patients per group would have 90% power to detect a 20% difference in oxygen content among groups with an alpha value of 0.05. To allow for possible difficulties with sample collection, we increased the sample size to 20 per group. Intergroup comparisons were made using analysis of variance with post-hoc pairwise comparisons using Scheffes procedure. Single-variable intragroup comparisons were made using the paired t-test. Nominal data were analysed using the chi square test and Fishers exact test. Analyses were performed using Statview for Windows 4.53 (Abacus Concepts Inc., Berkeley, CA, USA). P<0.05 was considered significant.
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Results |
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There was insufficient sample volume for analysis from one patient in Group 30 for umbilical venous blood, from one patient in Group 50 for maternal arterial blood and from two patients in Group 50 and three patients in Group 100 for umbilical arterial blood. The paediatrician investigator (KCM) was not available for three cases in Group 30, three in Group 50 and one in Group 100; in these cases the neonate was assessed by the duty paediatrician, who assessed Apgar scores but not NACS.
No patient reported recall of intraoperative events. One patient in Group 50 reported experiencing intraoperative dreams but was not distressed by this.
Maternal arterial blood gases, haemoglobin concentration and oxygen content are shown in Table 2. Values for PaO2 at delivery increased with increasing FIO2, but there was no difference in maternal arterial oxygen content among groups or between baseline and delivery values within groups.
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Discussion |
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These findings support the earlier work by Bogod, Piggott and colleagues,4 5 who also reported that the use of 100% oxygen improved fetal oxygenation compared with 50% oxygen. As 100% oxygen increased umbilical venous oxygen tension, they postulated that because of the high oxygen affinity of fetal haemoglobin, this should correspond to a significant increase in oxygen content. We have confirmed this by measuring oxygen content using co-oximetry. Bogod, Piggott and colleagues also emphasized the importance of adjusting the concentration of volatile anaesthetic to compensate for loss of the anaesthetic contribution from nitrous oxide. This was not done in previous studies6 7 and it was suggested that light anaesthesia could have increased plasma catecholamines and caused placental vasoconstriction.4 5 In our study we found no difference between groups in maternal arterial plasma concentrations of epinephrine and norepinephrine, making it unlikely that differences in depth of anaesthesia contributed to any differences in cord blood results. However, the small sample size should be noted in the interpretation of these data. Retrospective power analysis showed that our study had 80% power to detect a 44% difference in maternal arterial plasma norepinephrine concentration and a 65% difference in maternal arterial plasma epinephrine concentration in Group 100 compared with the other groups.
In our study, similar to those of Bogod, Piggott and colleagues, we calculated and administered equivalent MAC values of inhalational anaesthetics to each group. We also initially administered a high concentration of volatile agent to rapidly increase alveolar anaesthetic concentration. However, we limited this initial period of overpressure to only 1 min, compared with 5 min in the previous studies. Thereafter we titrated anaesthetic delivery according to end-tidal concentration, which was not done in the previous studies. This was facilitated by our choice of sevoflurane, because its low bloodgas partition coefficient results in rapid changes of alveolar concentration. In retrospect, we might have been further able to confirm equivalent depth of anaesthesia among groups by use of bispectral index (BIS) monitoring, although few data are available on BIS monitoring in pregnant patients.
Previously, Lawes and colleagues3 investigated different values of FIO2 during general anaesthesia for Caesarean section. In contrast to our findings, they found no difference in umbilical venous PO2 in patients who received an FIO2 of 0.33 compared with patients who received an FIO2 of 0.5. However, that study was not fully randomized and was only partially blinded, there was no compensatory adjustment of isoflurane concentration, and both labouring and non-labouring patients were included. Although the authors concluded that use of 33% oxygen appeared to be safe, they did not include a group that received an FIO2 of 1.0 for comparison.
Perreault and colleagues11 investigated administration of 100% oxygen during the period between hysterotomy and birth during general anaesthesia for Caesarean section. Compared with a group that received 50% oxygen, they found no difference in umbilical venous or arterial PO2. Notably, however, no adjustment of volatile anaesthetic was made after discontinuing nitrous oxide in the 100% group and four out of 10 patients reported intraoperative awareness. This serves to emphasize the importance of increasing the concentration of volatile agent and monitoring circuit concentration when using 100% oxygen. In that study, two infants in the 100% group had low early Apgar scores, which was not explained.
We found no difference in the clinical condition of the neonates, assessed using Apgar scores and NACS. However, significant differences would be difficult to detect in healthy uncomplicated elective cases in whom outcome was already expected to be favourable. Further research is required to determine whether the increase in oxygen delivery we found in elective cases could lead to differences in clinical outcome in emergency cases when there is fetal distress. Such an advantage was suggested by Piggott and colleagues5 who found that neonates born to mothers who received 100% oxygen during emergency Caesarean section had a smaller requirement for oxygen and positive-pressure ventilation compared with those delivered to mothers who received 50% oxygen. We chose to use NACS as a method of evaluating potential differences among groups exposed to different anaesthetic combinations, including relatively high concentrations of sevoflurane and found no difference between groups. Retrospective power analysis showed that our study had 80% power to detect a mean difference in NACS score of 4 points at 15 min and 3 points at 2 h in Group 100 compared with the other groups. However, since this study was planned, the validity of NACS has been questioned.12 13
Finally, although we have found that a high FIO2 improved fetal oxygenation, the potential harmful effects of oxygen should be considered. Maternal hyperoxia could provoke vasoconstriction in the fetoplacental unit.14 However, our finding that fetal oxygenation improved in the group that received the highest FIO2 suggests that this is not a significant concern in elective cases. Hyperoxia also increases the rate of formation of toxic reactive species by superoxide generation.15 In a previous study16 we found that a high FIO2 during regional anaesthesia for Caesarean section resulted in increased maternal and umbilical plasma concentrations of lipid peroxide markers of oxygen free-radical activity. The clinical importance of this is as yet undetermined. We are now investigating the effect of FIO2 on markers of free-radical generation during general anaesthesia for Caesarean section.
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Acknowledgements |
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References |
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