Br. J. Anaesth. 2002 Ngan Kee 556 61

7/28/2019 Br. J. Anaesth. 2002 Ngan Kee 556 61

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Randomized, double-blind comparison of different inspiredoxygen fractions during general anaesthesia for Caesarean

section

W. D. Ngan Kee1*, K. S. Khaw1, K. C. Ma2, A. S. Y. Wong1 and B. B. Lee1

1Department of Anaesthesia and Intensive Care, 2Department of Paediatrics, The Chinese University of

Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

*Corresponding author

Background. The optimal inspired oxygen fraction FIO2

for fetal oxygenation during general

anaesthesia for Caesarean section is not known.

Methods. We randomized patients having elective Caesarean section to receive one of the

following: FIO2

0.3, FIN2O 0.7 and end-tidal sevourane 0.6% (Group 30, n=20); FIO

20.5, FIN

2O

0.5 and end-tidal sevourane 1.0% (Group 50, n=20), or FIO2

1.0 and end-tidal sevourane 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


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We set out to compare the effect ofFIO2 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 concen-

trations. Because light anaesthesia can increase maternal

circulating catecholamines and cause uteroplacental vaso-

constriction,4 5

we measured maternal arterial plasma con-centrations 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).

Methods

After obtaining approval from the Clinical Research Ethics

Committee of the Chinese University of Hong Kong, we

consecutively recruited 60 ASA I and II women with term

singleton pregnancies having elective Caesarean sectionunder general anaesthesia. All patients gave written

informed consent. Patients with pre-existing or pregnancy-

induced hypertension, cardiovascular or cerebrovascular

disease or known fetal abnormalities were excluded.

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 Ringer's solution was

started. Patients were then randomly allocated to one of

three groups by drawing of sequentially numbered sealedenvelopes that each contained a computer-generated

randomization code. Each group received a different

inspired oxygen fraction during the period from immedi-

ately 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 succinylcho-

line 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 sevourane9 as the volatile agent

because of its low bloodgas partition coefcient.

Concentrations of oxygen, nitrous oxide and sevourane

were adjusted according to group allocation: Group 30

received FIO2 0.3, FIN2O 0.7 and sevourane adjusted to

maintain end-tidal concentration of 0.6%; Group 50

received FIO2 0.5, FIN2O 0.5 and end-tidal sevourane

1.0%; and Group 100 received FIO2 1.0 and end-tidal

sevourane 2.0%. These inspired fractions were chosen to

provide approximately equivalent MAC values. A circle

circuit with a fresh gas ow of 6 litre min 1 was used and for

all patients the sevourane vaporizer was initially set at 6%

for the rst 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 Drager, 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 investiga-

tors 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, andfor any patient who developed hypotension was to increase

the rate of i.v. uid 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 0.7and end-tidal sevourane 0.6% in all patients.

After delivery, the neonate was assessed by a paedia-

trician (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 oor.

Each patient was visited on the rst 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

FIO2 in general anaesthesia for Caesarean section

557


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analyser (Ciba-Corning, Medeld, 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 4C

and the plasma was separated and stored at 70C pendingbatch 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 coef-

cients of variation for norepinephrine and epinephrine were

7.06% and 8.48%, respectively, and the between-day

coefcients of variation were 10.69% and 12.69%, respect-

ively. The assay was linear to the lower limit of detection,

which was 25 pg ml1

for both norepinephrine andepinephrine.

Statistics

Prospective power analysis was based on data from our

previously published work.10 The primary outcome was

dened 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 difculties 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 Scheffe's procedure.

Single-variable intragroup comparisons were made using

the paired t-test. Nominal data were analysed using the chi

square test and Fisher's exact test. Analyses were performed

using Statview for Windows 4.53 (Abacus Concepts Inc.,

Berkeley, CA, USA). P


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greater in Group 100 than in Group 30 (10.8 (3.5) vs 7.0

(3.0) ml dl1, P


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These ndings 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 oxygenafnity of fetal haemoglobin, this should correspond to a

signicant increase in oxygen content. We have conrmed

this by measuring oxygen content using co-oximetry. Bogod,

Piggott and colleagues also emphasized the importance of

adjusting the concentration of volatile anaesthetic to com-

pensate for loss of the anaesthetic contribution from nitrous

oxide. This was not done in previous studies 6 7 and it was

suggested that light anaesthesia could have increased

plasma catecholamines and caused placental vasoconstric-

tion.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 cordblood 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

sevourane, because its low bloodgas partition coefcient

results in rapid changes of alveolar concentration. In

retrospect, we might have been further able to conrm

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 ndings, 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

isourane 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 aware-ness. 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, signicant differences would be difcult 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

Table 4 Clinical neonatal outcome. Values for neurologic and adaptive

capacity score (NACS) are mean (SD)

Group 30 Group 50 Group 100 P

(n=20) (n=20) (n=20)

Apgar score at 1 min

46 (n) 7 3 5 0.3

>7 (n) 13 17 15 0.3

Apgar score at 5 min

46 (n) 0 0 0

>7 (n) 20 20 20Assisted ventilation required at

birth (n)

8 3 5 0.2

Admitted to neonatal intensive

care (n)

1 0 2 0.3

NACS at 15 min 31.5 (4.7) 32.8 (3.6) 31.7 (4.8) 0.7

NACS at 2 h 35.8 (3.3) 36.9 (1.9) 36.0 (3.3) 0.5

Table 5 Maternal arterial plasma catecholamine concentrations. Values are

mean (SD)

Group 30 Group 50 Group 100 P

(n=20) (n=20) (n=20)

Baseline

Epinephrine (pg ml1) 142 (63) 154 (85) 122 (76) 0.4

Norepinephrine (pg ml1) 275 (103) 362 (223) 307 (131) 0.2

Delivery

Epinephrine (pg ml1

) 203 (92) 292 (279) 223 (143) 0.3

Norepinephrine (pg ml1

) 451 (150) 501 (281) 483 (277) 0.8

Ngan Kee et al.

560


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high concentrations of sevourane 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 effectsof oxygen should be considered. Maternal hyperoxia could

provoke vasoconstriction in the fetoplacental unit.14

However, our nding that fetal oxygenation improved in

the group that received the highest FIO2 suggests that this is

not a signicant 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 generalanaesthesia for Caesarean section.

AcknowledgementsThe authors thank the midwives of the Labour Ward, Prince of WalesHospital, Shatin, Hong Kong, China and research nurses Justina Liu, FloriaNg and Mabel Wong for their assistance with this study. This work wassupported by a Direct Grant for Research from the Chinese University ofHong Kong.

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FIO2 in general anaesthesia for Caesarean section

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