Effects of high inspired oxygen fraction during elective Caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation
K. S. Khaw*,1,
C. C. Wang2,
W. D. Ngan Kee1,
C. P. Pang3 and
M. S. Rogers2
1Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China. 2Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China. 3Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China*Corresponding author: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
This article is accompanied by Editorial II.
Accepted for publication: July 27, 2001
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Abstract
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Background. Oxygen supplementation is given routinely to parturients undergoing Caesarean section under regional anaesthesia. While the aim is to improve fetal oxygenation, inspiring a high oxygen fraction (FIO2) can also increase free radical activity and lipid peroxidation in both the mother and baby. In this prospective, randomized, double-blind study, we investigated the effect of high inspired oxygen fraction (FIO2) on maternal and fetal oxygenation and oxygen free radical activity in parturients having Caesarean section under spinal anaesthesia.
Methods. Forty-four healthy parturients were randomized to breathe either 21% (air group) or 60% oxygen (oxygen group) intraoperatively via a ventimask. Maternal arterial blood was collected at 5-min intervals from baseline until delivery, and umbilical arterial and venous blood was collected at delivery. We measured blood gases and the products of lipid peroxidation (8-isoprostane, malondialdehyde (MDA), hydroperoxide (OHP)) and purine metabolites.
Results. At delivery, the oxygen group had greater maternal arterial PO2 [mean 30.0 (SD 6.3) vs 14.2 (1.9) kPa; mean difference 15.8 kPa, 95% confidence interval 12.918.7 kPa, P<0.001] and greater umbilical venous PO2 [4.8 (1.0) vs 4.0 (1.4) kPa; mean difference 0.8 kPa, 95% confidence interval 0.01.5 kPa, P=0.04] compared with the air group. Maternal and umbilical plasma concentrations of lipid peroxides (8-isoprostane, MDA, OHP) were greater in the oxygen group than in the air group (P<0.05).
Conclusions. We conclude that breathing high FIO2modestly increased fetal oxygenation but caused a concomitant increase in oxygen free radical activity in both mother and fetus.
Br J Anaesth 2002; 88: 1823
Keywords: anaesthetic techniques, subarachnoid; anaesthesia, obstetric, Caesarean section; oxygen, supplement; oxygen, free radical activity
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Introduction
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During spinal anaesthesia, changes in respiratory function occur1 and oxygen supplementation is commonly given to prevent maternal oxyhaemoglobin desaturation and to optimize fetal oxygenation. Some studies have shown improvement in the umbilical blood gas and acidbase parameters under general and epidural anaesthesia.25 However, Kelly and colleagues showed that administration of 35% oxygen during spinal anaesthesia did not improve fetal umbilical vein PO2 or pH.1 Few data are available on the efficacy of administering a greater inspired oxygen fraction (FIO2). Moreover, high FIO2 induces maternal hyperoxia and this may promote the formation of free radicals and lipid peroxidation.
In this randomized, double-blinded study, we investigated the effect of administration of a high FIO2 on maternal and neonatal oxygenation and free radical formation in women having Caesarean section under spinal anaesthesia. The main outcomes we assessed were maternal arterial and umbilical cord blood gases and maternal and neonatal plasma concentrations of markers of oxygen free radical activity.
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Materials and methods
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This study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. We recruited 44 ASA III non-labouring, term parturients scheduled for elective Caesarean section under spinal anaesthesia after informed written consent. Patients were premedicated with ranitidine 150 mg orally the night before and on the morning of surgery. On arrival at the operating theatre, i.v. access was secured, standard monitoring was attached and a radial arterial cannula was inserted in the non-dominant forearm under local anaesthesia. Patients were then randomized, by drawing shuffled coded opaque envelopes, to breathe either 21% (air group) or 60% oxygen (oxygen group) intraoperatively. Air or oxygen was supplied from the anaesthetic machine (Narkomed 4; North American Dräger, Telford, PA, USA) to a high-flow venturi-type facemask (Intersurgical, Wokingham, UK) to provide the assigned FIO2. The oxygen analyser of the anaesthesia machine was used to confirm the FIO2 from the facemask before each use.
Spinal anaesthesia was then performed. After i.v. preload with lactated Ringers solution 20 ml kg1, 0.5% hyperbaric bupivacaine 2.0 ml and fentanyl 15 µg were injected intrathecally with the patient in the right lateral position. The patient was then turned supine with left lateral tilt. Preparation and surgery started after checking that the level of the block was adequate. Our contingency for patients in the air group who developed a pulse oximetry reading of <94% was to increase the FIO2to 28%. Hypotension, defined as a decrease in systolic arterial pressure of more than 20% from baseline or to less than 100 mm Hg,6 was treated with i.v. boluses of ephedrine, as required. Nausea and vomiting were treated with metoclopramide 10 mg i.v. once hypotension had been excluded. The times from starting oxygen supplementation to delivery, skin incision to delivery (ID) and uterine incision to delivery (UD) were recorded using a stopwatch. After delivery, a blinded paediatrician assessed Apgar scores.
Maternal arterial (MA) blood samples were taken before the start of anaesthesia, with the patient breathing room air, and at 5-min intervals after applying the facemask until delivery of the baby. The investigator who performed all the blood analyses was blinded to the FIO2 and did not participate in patient care. Fetal umbilical arterial (UA) and venous (UV) blood samples were collected from a segment of umbilical cord, double-clamped before the infants first breath. For each blood sample, blood gas analysis was performed immediately using a Corning 278 pH/blood gas analyser (Medfield, MA, USA). The remainder of the sample was centrifuged and the plasma was stored at 70°C for subsequent batch analysis for 8-isoprostaglandin F2
(8-isoprostane), malondialdehyde (MDA), organic hydroperoxides (OHP) and metabolites of oxidative purine metabolism.
Plasma concentrations of MDA were estimated as reactive substances by a thiobarbituric acid adduction method as described by Richard and colleagues7 with partial modification.8 An enzymatic technique9 was used to determine OHP. For the measurement of purine and pyrimidine metabolites, the concentrations of cytosine, uracil, cytidine, hypoxanthine, xanthine, uric acid, guanine, uridine, thymine, adenine, inosine, guanosine and adenosine were determined simultaneously by reverse-phase high-performance liquid chromatography modified partially from previously described techniques.10 Total free and esterified 8-isoprostane was estimated with an enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI, USA) with a precision of 97.9%.
Statistical analysis
In a previous study, we found that the mean and standard deviation of UA plasma concentrations of MDA and OHP during elective Caesarean section were 0.580 (0.029) and 0.135 (0.058) µmol l1 respectively.11 Using these data, we calculated that a sample size of 22 patients in each group yielded >80% power to detect a difference of 0.05 µmol l1 of MDA or OHP with a type I error probability of 0.05. Data were tested initially for equality of variances using Levenes test, and the normal probability plot was used subsequently to test for normality. On the basis of these findings, statistical comparison was performed using either Students t-test or the MannWhitney U-test. The
2 test was used to compare equality of proportions, and the association between PaO2, 8-isoprostane MDA and OHP in maternal and umbilical blood was compared using the Spearman rank correlation. Results are presented as mean and standard deviation or median and range where appropriate. P<0.05 was considered significant.
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Results
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All patients completed the study. The indications for surgery are summarized in Table 1. Maternal and fetal characteristics, duration of oxygen exposure, timed intervals to delivery from skin incision (ID) and uterine incision (UD) were similar between groups (Tables 2 and 3). No treatment for arterial desaturation was required and the incidence of hypotension was similar in the two groups.
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Table 2 Maternal characteristics and arterial blood gas (ABG) data. Mean (SD), median (range). n.s. = not significant
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Maternal blood analysis
The MA blood gases data are summarized in Table 2. Baseline parameters while breathing room air were similar. Compared with the air group, the oxygen group had greater arterial PaO2intraoperatively [mean 31.8 (SD 5.9) vs 14.3 (2.5) kPa, mean difference 17.5 kPa, 95% confidence interval 16.318.4 kPa, P<0.001] and at delivery [mean 30.0 (6.3) vs 14.2 (1.9) kPa; mean difference 15.8 kPa, 95% confidence interval 12.918.7 kPa, P<0.001]. There were no differences in the other parameters (pH, PaCO2 and base excess). Mean intraoperative plasma concentrations of MDA were greater in the oxygen group than in the air group [1.26 (0.22) vs 0.89 (0.16) µmol l1, P<0.05]. The increase in MDA was significant within 10 min of exposure to the higher FIO2 (Fig. 1) and at birth both isoprostane and MDA were higher in the oxygen than in the air group (Table 4). The concentrations of OHP and purine metabolites were similar between groups.

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Fig 1 Maternal plasma concentrations of malondialdehyde at 10-min intervals. Data are mean (95% confidence interval) concentration for each interval after commencement of oxygen supplementation +P<0.05; *P<0.001.
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Table 4 Maternal and umbilical lipid peroxide concentrations. Values are mean (SD); units are µmol litre1. n.s. = not significant; N/A=not available
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Apgar scores and umbilical cord blood analysis
Apgar scores were similar between groups, with all scores >7 at 1 min and >9 at 5 min. The umbilical cord blood gases are summarized in Table 3. Umbilical venous PaO2 was greater in the oxygen than in the air group [4.8 (1.0) vs 4.0 (1.4) kPa; mean difference 0.7 kPa, 95% confidence interval 0.01.5 kPa, P=0.04]. There was a positive correlation between UV PaO2 and maternal arterial PaO2 at delivery (r=0.516, P<0.001) (Fig. 2). Other umbilical venous and arterial blood gas variables were similar between groups.
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Table 3 Fetal characteristics, timed intervals, Apgar scores and umbilical cord blood gas data. Values are mean (SD), median (range) or number (%). ID = interval from skin incision to delivery. UD = interval from uterine incision to delivery. n.s. = not significant
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Fig 2 Scatter-plot of maternal arterial PaO2 at delivery and umbilical venous PaO2. Data from air and oxygen groups are presented. r=0.516, P<0.001.
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Plasma concentrations of lipid peroxides were greater in both the UA and UV samples of the oxygen than in the air group (Table 4). In both groups, there was a positive correlation between the MA PaO2 and the UV concentrations of 8-isoprostane (r=0.87, P<0.001) (Fig. 3), OHP (r=0.61, P<0.001) (Fig. 4) and MDA (r=0.56, P<0.001) (Fig. 5). Paired comparison of plasma concentrations of MDA showed significant increases as early as in the first 10 min after starting oxygen supplementation (Fig. 1). A weak correlation was found between the MA and the UV concentrations of MDA (r=0.38, P<0.05) and OHP (r=0.29, P=0.61), and plasma UA and UV concentrations of purine and pyrimidine metabolites were similar between groups.

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Fig 3 Scatter-plot of maternal arterial PaO2 at delivery and umbilical venous concentration of 8-isoprostane. Data from air and oxygen groups are presented. r=0.870, P<0.001.
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Fig 4 Scatter plot of maternal arterial PaO2 at delivery and umbilical venous organic hydroperoxides. Data from air and oxygen groups are presented. r=0.611, P<0.001.
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Fig 5 Scatter plot of maternal arterial PaO2 at delivery and umbilical venous malondialdehyde. Data from air and oxygen groups are presented. r=0.556, P<0.001.
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Discussion
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The rationale for providing supplementary oxygen to the mother during Caesarean section is to optimize neonatal outcome.25 Although several previous studies have shown benefits, such as improved UA PaO2, UV PaO2, acidbase status and enhanced fetal adaptation, most of these studies were based on general anaesthesia. Therefore, it may not be valid to extrapolate their findings to spinal anaesthesia. Nonetheless, giving oxygen supplementation to patients undergoing Caesarean section under regional anaesthesia is commonly advocated.12 Ramanathan and colleagues reported that UV PaO2 was improved when parturients receiving epidural anaesthesia breathed increased FIO2 (47100% FIO2).5 However, in a more recent study, Kelly and colleagues reported that parturients who received spinal anaesthesia had no maternal oxyhaemoglobin desaturation despite deterioration in respiratory mechanics, and that administration of 35% oxygen did not improve UV PaO2.1 In our study, we found that administration of 60% FIO2to parturients undergoing spinal anaesthesia resulted in a modest increase in UV PaO2. However, because the magnitude of this increase was relatively small and because there was no difference in neonatal outcome, the clinical advantage of administering a high FIO2 compared with air routinely to elective cases is questionable, provided that continuous monitoring with pulse oximetry is available. Moreover, administration of a high FIO2 was associated with increased free radical activity in both the mother and fetus.
Direct detection of free radicals is extremely difficult because of their brief lifespan. Thus, in our study we measured lipid hydroperoxides, the products of attack by free radicals on polyunsaturated fatty acids, as footprints of free radical activity.13 14 Isoprostanes, formed by non-enzymatic oxygenation of arachidonic acid in membrane phospholipids, are highly specific as markers for in vivo oxidative stress.15 The best-characterized isoprostane is 8-isoprostaglandin F2
(8-isoprostane), which is abundant in plasma and urine. MDA and OHP concentrations are less specific, and can be influenced by the extent of prostaglandin metabolism as well as by free radical activity.
Pathological generation of free radicals commonly involves one of several possible pathways. We have shown previously an association between increased concentrations of lipid peroxides and prolonged labour, fetal distress, oligohydramnios and tight nuchal cord entanglement.1621 In these conditions, free radicals are generated via the pathways involving hypoxic stress and ischaemiareperfusion injury. During hypoxia, xanthine dehydrogenase is converted into xanthine oxidase. After reperfusion, xanthine oxidase catalyses the formation of hydroxyl free radicals from the breakdown of purine metabolites, xanthine and hypoxanthine.22 Thus, an accompanying increase in purine metabolites is a co-marker of ischaemiareperfusion injury. Hyperoxia per se generates free radicals via an alternative pathway involving direct mitochondrial electron transfer, with no concurrent formation of purine metabolites. Thus, in our study, because there was no increase in purine metabolites, the most likely mechanism for the generation of free radicals was maternal hyperoxia.23 24
Lipid peroxide concentrations were much greater in UV than in UA blood, suggesting that the main site of free radical activity was the placenta, the interface where hyperoxia occurs. Concentrations of 8-isoprostane were greater in umbilical than in maternal blood, implying generation in the fetoplacental unit. Concentrations of MDA were greater in maternal than in umbilical blood, but were unlikely to be the result of placental transfer because of the weak correlation between the maternal and umbilical concentrations.11 In the maternal blood, the increase in lipid peroxides results from the net effect of lipid peroxidation and free radical scavenging throughout the body, whereas the increase in the umbilical vein reflects the origin more specifically at the placenta. A positive correlation between maternal arterial PaO2 and the umbilical lipid peroxide concentration suggests a direct relationship between the oxygen partial pressure and the extent of free radical activity in the fetoplacental unit.
The clinical relevance of the increase in free radical activity we found in the oxygen group is uncertain. Although clinical effects were not apparent in our study, free radicals cause depletion of intrinsic antioxidant systems and could weaken the infants ability to withstand any subsequent neonatal insult. MDA, a product of lipid peroxidation, is toxic because of its ability to form disulphide bridges across nucleotide or amino acid chains,25 and also causes immunosuppression by inhibiting lymphocytic activity.26 Our study was confined to healthy, elective cases with uncomplicated pregnancies. Although we found no difference in neonatal outcome between groups, Apgar scores can only demonstrate very gross changes, and in elective low-risk cases maternal hyperoxygenation would not be expected to have a significant effect on an outcome that is already likely to be favourable.
Conversely, the relative benefit of administration of a high FIO2 where there is fetal compromise is unknown. It has been shown that hyperoxia increases the formation of free radicals, which may exacerbate tissue damage in ischaemia reperfusion injury.23 24 27 28 Hyperoxia mediates tissue injury in bronchopulmonary dysplasia, retinopathy of prematurity, persistent ductus arteriosus, necrotizing enterocolitis and intracranial haemorrhage.2931 Furthermore, when oxygen was compared with air during neonatal resuscitation, a poorer outcome resulted because of the generation of free radicals.32 33 Therefore, further investigation is required to clarify the relative advantages and disadvantages of high FIO2 in emergency Caesarean section when there is fetal distress, as high FIO2 may increase fetal oxygenation, but may also exacerbate ischaemia reperfusion injury in the fetus.
Patient comfort is also an issue. This has led to the investigation of different methods of oxygen delivery during Caesarean section.34 In our experience, parturients sometimes complain of discomfort from wearing oxygen facemasks, which may be unnecessary given the questionable benefit of supplementary oxygen.
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Acknowledgement
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We thank Mr Raymond Chung (statistician) for advice and help with analysis.
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References
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