Brit. J. Anaesth. (1970), 42, 286

THE EFFECT OF METHOXYFLURANE ON THE FOETUS BY

R. B. CLARK, J. O. COOPER, W. E. BROWN AND F. E. GREIFENSTEIN SUMMARY

Sixty-four patients received methoxyflurane analgesia and/or anaesthesia for labour and delivery. Analgesia with methoxyflurane-air produced satisfactory analgesia for labour and delivery in the multigravidae of Group I. Foetal and maternal blood levels did not increase with increased duration of inhaler use, apparently due to the absence of paininduced hyperventilation. Patients in Group II required t i e addition of light methoxyflurane, nitrous oxide and oxygen anaesthesia. This resulted in the highest foetal memoxyflurane levels of the three groups, and the highest rate of neonatal depression. Group HI patients arrived with delivery imminent, and were given light methoxyflurane, nitrous oxide and oxygen anaesthesia. Despite high maternal levels of methoxyflurane, foetal levels were no higher than in Group I, presumably because of the short duration of exposure. Methoxyflurane has little effect on the foetus if low concentrations are administered to the mother, or if the duration of higher concentrations is kept short. Methoxyflurane has achieved considerable popularity as an obstetrical analgesic and anaesthetic. Reports by Boisvert and Hudon (1962), Romagnoli and Konnan (1962), Hudon and colleagues (1963) and Major, Rosen and Mushin (1967) have attested to its safety and effectiveness. Siker and colleagues (1968) reported methoxyflurane levels in mother and newborn, and found little foetal depression, d a r k and colleagues (1968) and Cosmi and Marx (1968) studied acid-base relationships in newborn infants delivered under methoxyflurane anaesthesia and found the biochemical status of the foetus to be normal. There was, however, measurable foetal depression, which was considered to be the result of transplacental passage of methoxyflurane. The present study was undertaken to elucidate: (1) the relationship between foetal and maternal blood levels of methoxyflurane and the duration of analgesia and anaesthesia; (2) the relationship between blood levels of methoxyflurane and foetal depression; and (3) the acid-base status of the foetus following the use of methoxyflurane. METHOD

Sixty-four healthy women at term, in active labour, with no obstetrical or medical complications, were studied. All foetuses were normal, and all were in the vertex presentation. The mothers

were from the lower socio-economic strata, and had little rapport with their physicians. Analgesia and/or anaesthesia was obtained with methoxyflurane and air, or with a combination of methoxyflurane, nitrous oxide, and oxygen. None of the mothers received other anaesdietic or sedative drugs during labour or delivery. Analgesia (with Cyprane inhaler turned full on) was provided when the effective labour had begun. The patients were instructed to breathe through the inhaler during contractions, and to breathe room air between contractions. This has been shown to produce a methoxyflurane concentration of 0.35 to 1.15 per cent, depending on the minute volume and duration of use (Romagnoli and Konnan, RICHARD B. CLARK, MJJ.,- JAMES O. COOPER, MJ>.; WILLIS E. BROWN, MJJ.*; FERDINAND E. GREIFENSTEIN,

MJ>.; from the Departments of Anesthesiology, Obstetrics and Gynecology, and Pediatrics, of the University of Arkansas Medical Center, Little Rock, Arkansas 72205. Supported in part by a grant-in-aid from Abbott Laboratories, North Chicago, Illinois, and by General Research Support Grant 5501 FR 5350-5 from the National Institutes of Health, U.S. Public Health Service. Assistance was provided for this research by the University of Arkansas Medical Center Research Computation Laboratory, which is supported by Grant FR 00208-05, from the National Institutes of Health, U.S. Public Health Service. •Deceased.

THE EFFECT OF METHOXYFLURANE ON THE FOETUS 1962). Analgesia was graded as excellent, good, fair, or poor by the obstetrician and anaestheaiologist. The analgesia was considered to be "satisfactory" if it was graded excellent or good. Light anaesthesia, using a flow of nitrous oxide of 6 l./min and oxygen 2 L/min, and methoxyflurane delivered from a No. 8 Ohio vaporizer was administered for delivery. It has been shown that this flow rate delivers between 02 and 0.8 per cent methoxyflurane with dial settings of 2 to 6 (Boisvert and Hudon, 1962). Maternal venous blood samples for methoxyflurane analysis were obtained at delivery. The 1-minute Apgar score was assessed and a doubly clamped section of umbilical cord (Clark et al., 1969) obtained. Blood was aspirated from the umbilical artery and vein of the clamped section for acid-base analysis and methoxyflurane concentration. Technical difficulties made it impossible to obtain arterial cord blood samples in every case. Samples were obtained from the femoral vein of the newborn infant at 1 hour of age for acid-base and methoxyflurane measurements. The acid-base determination was performed immediately after sampling, or after a maximum storage on ice for 1 hour. Analysis was performed at 38 °C on a Model 27 Astrup Modular apparatus* and base deficit was calculated from Siggaard-Andersen nomogram (Siggaard-Andersen and Engel, 1960). Methoxyflurane concentrations were determined with an F&M Model 700 gas chromatograph utilizing a thermal conductivity detector. A tetrachlorethylene extraction technique (J. R. Miller, personal communication) was used to separate methoxyflurane from blood. Halothane was used as the internal standard. To obtain an estimate of laboratory variability, twenty samples of blood with a known concentration of methoxyflurane were analyzed. In these samples, recovery rates varied from 97.9 to 107 per cent, with a standard deviation (experimental error) of ±0.20 mg/100 ml blood RESULTS

The patients were divided into three groups. Seventeen patients (Group I) delivered only with the use of the Cyprane inhaler for analgesia. These patients were of advanced parity, and did * Radiometer Company, Copenhagen, Denmark,

287

not require surgical planes of anaesthesia with methoxyflurane, nitrous oxide and oxygen. They used the inhaler throughout each contraction, and breathed room air between contractions. Group II (29 patients) received analgesia during labour with the inhaler, and light surgical anaesthesia during delivery with methoxyflurane, nitrous oxide and oxygen. Group HI (18 patients) received methoxyflurane, nitrous oxide and oxygen anaesthesia for delivery, without previous exposure to methoxyflurane analgesia. These patients arrived in the obstetrical suite with delivery imminent. Group I: Intermittent methoxyflurane-mr analgesia for labour and delivery. The mean methoxyflurane level in maternal venous blood at delivery was 2.88 (±1.91)* mg/100 mL The use of the inhaler ranged from 10 minutes to 3 hours 20 minutes, with a mean of 68.1 minutes. The mean umbilical vein level was 2.00 (±1.42) mg/100 ml; umbilical artery level 0.91 (±0.06) mg/100 ml (12 determinations). The relation between duration of inhaler use and umbilical vein methoxyflurane concentration is given in figure 1. Twelve of the 17 patients were graded as exhibiting "satisfactory" analgesia with the inhaler. One of the infants was depressed (1minute Apgar scores of 6 or less) (table I). There were no primigravidae in this group. The relation between umbilical artery methoxyflurane level at birth, and duration of inhaler use, was also plotted. Again, no correlation existed, and the plot resembled figure 1, but with lower values of methoxyflurane. Group II: Intermittent methoxyflurane-air analgesia for labour and continuous methoxyflurane, nitrous oxide and oxygen anaesthesia for delivery. The mean methoxyflurane level in maternal venous blood at delivery was 5.45 (±3.00) mg/ 100 ml. This followed the use of methoxyfluraneair analgesia for a mean duration of 156.6 minutes (range 27 minutes to 7 hours 5 minutes) and methoxyflurane, nitrous oxide and oxygen anaesthesia for a mean duration of 5.1 minutes (range 1 to 15). The mean umbilical vein methoxyflurane level was 3.68 (±1.78) mg/100 ml; umbilical artery, 1.69 (±1.19) mg/100 ml (21 determinations). Sixteen of the 29 patients showed evidence of "satisfactory" analgesia with the inhaler. Five of the infants were depressed, with 1-minute * ± 1 standard deviation in parentheses.

TABLE I eight depressed infants.

Maternal methoxy-

Umbilical artery

9ur£Lnc

Duration Duration (venous) Methoxyanalgesia anaesthesiat at del. flurane P t Group Gravida Apgar (hi min) (min) I[mg/lOOml) (mg/lOOml) PH 1 1 — — 2 3 3° 20' 3.5 7.15 2 2 3 5 6' 16' 9.3 4.4 7.11 5°

Po, — 8.8

Pco, — 99

21.0 15.5

84 64 44

3 4 5

2 2 2

2 6 1

5 6 6

5° 43' 45' 44'

12' 4' 8'

5.2 3.4 10.1

1.1 1.9

7.13 7.19 7.21

6 7

2 3

1 6

3 6

4° 7' —

3' 91

8.8 —

— 0

— 7.21

— 23.0

— 57

8

3

11

4

—

13'

8.6

3.3

7.22

—

—

Umbilical vein MethoxyBase flurane deficit (mg/100 ml) PH Comments — — 7.34 2.7 Tight nuchal -5.0 8.6 7.18 cord Long labour 7.31 -6.9 3.8 Long labour 7.34 -4.2 2.0 Shoulder -9.8 6.3 7.22 dystocia — — 7.34 6.5 Tight nuchal -6.2 0 7.26 cord — 6.3 7.33 Stormy induction with hyperventilatkm td

C/5

TABLE II

B

Blood acid-base and methoxyflurane mean values for the sixty-four infants. One standard deviation indicated by figures in parentheses. Femoral vein at Umbilical artery Umbilical vein 1 hour of age 7.19 7.29 7.28 pH (±0.07) (±0.06) (±0.06) 40.9 49.5 24.5 Po, (mm Hg) (±8.0) (±10.5) (±17.2) 60.6 44.6 45.8 Pco, (mm Hg) 60.6 44.6 45.8 (±13.0) (±6.5) r±8.5) ( -5.0 13) ( -4.6 65) -5.05) (±2.9) (±2.8) (±2.9) Base deficit (m.equiv/1.) 1.21 2.75 (±1.17) (±1.88) Methoxyflurane (mg/100 ml.)

"p* 2 3 ? ^

£ g

289

THE EFFECT OF METHOXYFLURANE ON THE FOETUS 5.0-1

3.0-

FIG. 1 Relation of methoxyflurane concentration in umbilical vein at birth in Group I infants, to total duration of inhaler use. There is no significant correlation.

o o o

2.0-

I 0-

00 0

30

TIME

8* 18 5

I

60

90

IN MINUTES

120

150

180

210

(INITIAL USE OF INHALER TO DELIVERY)

6.0-

A

5JOFIG. 2 Concentration of methoxyflurane in umbilical vein at birth in Group III infants, compared to duration of anaesthesia. Correlation coefficient r =0.65, P =