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AORTOCAVAL COMPRESSION AND PLASMA CONCENTRATIONS OF THIOPENTONE AT CAESAREAN SECTION
Br. J. Anaesth. (1984), 56, 349
AORTOCAVAL COMPRESSION AND PLASMA CONCENTRATIONS OF THIOPENTONE AT CAESAREAN SECTION D. J. MORGAN, J. D. PAULL, C. T. T O H AND G. L. BLACKMAN SUMMARY
The venous plasma concentration- time profiles of thiopentone were measured simultaneously over the first 30—40 min after induction of anaesthesia, in blood obtained from an arm vein and a vein in the foot, in nine healthy full-term women undergoing Caesarean section. Patients were tilted laterally to the left by from 8 to 18° during the procedure. In all but two of the patients, the profiles from the arm and foot were virtually identical, suggesting that aortocaval compression was absent or irmignifirfmt. Therefore, the large intersubject variability in volume of distribution of thiopentone at Caesarean section is unlikely to be the result of aortocaval compression.
Thiopentone is transferred rapidly to the fetus via the placenta following administration to the mother on induction of anaesthesia at Caesarean section. Previous studies have shown that, at delivery, there is wide intersubject variability in the fetal umbilical blood thiopentone concentration which cannot be accounted for by differences in the dose administered to the mother, or in the induction - delivery interval (McKechnie and Converse, 1955; Crawford and Kane, 1956; Finster et al., 1966; Schepens and Heyndrickx, 1975). Recently the umbilical plasma thiopentone concentration at delivery was shown to correlate closely with the initial volume of distribution (Vi) and the clearance of thiopentone in the mother (Morgan et al., 1981a). Therefore, it was concluded that the large intersubject variability in umbilical thiopentone plasma concentrations at delivery was largely a result of the correspondingly wide intersubject variability observed in the pharmacokinetics of the drug in the mother (Morgan et al., 1981a). The authors suggested that the large intersubject variability, particularly of volume of distribution, may be related to the effect of aortocaval compression by the gravid uterus during surgery (Morgan etal., 1981a). Aortocaval compression in the supine patient at Caesarean section causes an increase in venous pressure in the lower part of the body (Kerr, Scott and Samuel, 1964; Lees et al., 1967), a significant decrease in leg but not arm blood flow (Wright, OsDENIS J. MORGAN, PH.D. (Department of Pharmaceutics); CJENG
born and Edmonds, 1950; Drummond et al., 1974) and a decrease in the rate of mixing in, and apparent volume of, the plasma compartment (Chesley and Duffus, 1972). The better oxygenation and clinical status of infants whose mothers are tilted laterally by 10-15° to the left during surgery suggests that tilting the patient minimizes caval compression ( Ansari et al., 1970; Crawford, Burton and Davies, 1972; Downing et al., 1974). In the study by Morgan and colleagues (1981a) a 10-15° left lateral tilt was used, but they suggested that this may not have been sufficient to eliminate aortocaval compression since caval compression may be "concealed" and difficult to recognize clinically (Crawford, Burton and Davies, 1972). If aortocaval compression in the mother is a major cause of the large intersubject variability in the volume of distribution of thiopentone at Caesarean section, then the plasma concentration of thiopentone in the foot could be expected to lag behind that in the arm, at least until delivery. Aortocaval compression would be expected to result in a smaller initial volume of distribution ( Vi) of thiopentone in the mother and, consequently, in a higher umbilical venous plasma concentration of the drug at delivery. In this study, the possibility of delay in the return of venous blood from the lower half of the body, as a result of aortocaval compression at Caesarean section, was assessed by comparing the plasma thiopentone concentration-time profile in blood obtained from a foot vein with that obtained from a vein in the arm.
T. TOH.M.PHARM., GRAEME L. BLAOCMAN,PH.D.,(Department
of Pharmaceutical Chemistry); Victorian College of Pharmacy Ltd, 381 Royal Parade, Parkville, Victoria, 3052, Australia. JOHN D. PAUU., M.B., B.s. F.F.A.R.A.C.S., DIP. ED., Department of Anaesthetics, The Royal Women's Hospital, Carlton, Victoria, Australia.
PATIENTS AND MATERIALS Nine healthy women who gave birth to healthy infants (one patient gave birth to twins) by elective © The Macmillan Press Ltd 1984
350
BRITISH JOURNAL OF ANAESTHESIA
Caesarean section were studied. None of the infants showed any evidence of depression at delivery. All had Apgar scores of 7 or greater 1 min after delivery and of 9 or greater 5 min after delivery. All established regular respiration within 2 min of delivery. The mean age of the patients was 28 yr (range 21 -36 yr) and their mean weight was 71.6 kg (range 59.0-90.3 kg). The study was approved by the Research Committee of the Hospital and all patients gave written informed consent before the investigation. The technique of anaesthesia was the same as that used in our previous study (Morgan et al., 1981a). Following pre-medication with papaveretum i.m. 30 min before the induction of anaesthesia, the patients received thiopentone sodium by bolus injection i.v. over 30 s. Suxamethonium was used to facilitate tracheal intubation and general anaesthesia was maintained with nitrous oxide in oxygen. All patients received 1 litre of Compound Sodium Lactate Injection B.P. during the first 30 min of the operation. Patients lay supine with a left lateral tilt and with arms extended to either side for the duration of anaesthesia. The angle of tilt ranged from 8 to 18° among patients and was measured to within 1-2° using a geometric device. The patients also received routine drug therapy as required (for example oxytocin or ergometrine after delivery and morphine or pethidine for postoperative analgesia). A scalp vein needle was inserted to a vein in the right cubital fossa immediately before the induction of anaesthesia: a 5-ml control blood sample was
obtained. Immediately after the injection of thiopentone to a freely running i.v. infusion in the left arm, another scalp vein needle was inserted to a vein in the dorsum of the left foot. Blood samples (5 ml) were then taken simultaneously from the arm and the foot at 1-min intervals from the induction of anaesthesia until 5 min after delivery. Subsequently, samples were then taken at 2-min and later at 5-min intervals for the next 30 min. Umbilical cord venous blood samples were collected at delivery. The blood samples were collected in plastic tubes containing lithium heparin and chilled in ice. The plasma was separated by centrifugation and stored at - 20 °C until analysis. Thiopentone was assayed in plasma by reverse-phase high pressure liquid chromatography (Morgan et al., 1981b). RESULTS
Details of the patients, the administration of thiopentone and the plasma thiopentone concentrations at delivery are detailed in table I. The venous plasma thiopentone concentration-time profiles in the arm and the foot of the nine subjects are shown in figure 1. Apart from subjects 4 and 5, venous plasma thiopentone concentrations in the arm and foot were similar throughout. In subjects 4 and 5, the venous concentrations in the foot were less than those in the arm until shortly after delivery, suggesting that some degree of aortocaval compression had occurred in these two patients. There was a significant correlation between plasma thiopentone concentrations in arm blood and leg
TABUB I. Patient details and plasma thiopentone concentrations at delivery
Patient 1 2 3 4 5 6 (a) 6(b) 7 8 9 Mean SD
Body weight (kg)
Tilt angle
O
Dose (mg)
80.2 62.1 59.0 66.0 58.0 74.0
10 8 10 8 10 17
350 400 300 450 400 400
90.3 70.8 83.1
15 18 10
375 400 425
Interval admin, to delivery (min) 4.0 8.0 19.0 9.0 6.0 9.5 11.5 8.0 11.0 10.0
Plasma thiopentone concn (pgmT 1 ) Maternal venous Umbilical Arm Foot venous 8.% 11.1 6.83 12.2 11.9 8.02 7.39 8.61 9.68 7.87
7.89 11.4 5.94 9.10 8.48 7.90 7.79 7.66 9.26 7.56
7.15 5.03 5.81 8.92 5.64 7.04 5.47 5.25
9.26 1.9
8.30 1.4
6.33 1.2
6.68
THIOPENTONE AT CAESAREAN SECTION 24
351
Subject 1
Subject 2
Subject 3
Subject 4
Subject 5
Subject 6
20 16 12 8 4 0
E tion
a 24 20-
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CD U
16-
O
u
I
12-
c
-
o
8-
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CO U) CO Q.
40
±L
\
201 Subject 9
Subject 8
Subject 7 16
12 8 4 0
± 10
20
30
40
10
20
30
40
10
20
30
Time (min) FIG. 1. Venous plasma thiopentone concentration—time profiles in arm ( ) and foot (. . .) at and following Caesarean section. The arrow indicates delivery.
40
BRITISH JOURNAL OF ANAESTHESIA
352
blood at delivery (r= 0.73; P= 0.024), but not between maternal and umbilical venous plasma concentrations at delivery (r= 0.19). DISCUSSION
In the present study, the similarity of the profiles of venous plasma thiopentone concentration v. time in the arm and the foot show that there were no delays in the venous return from the foot and suggest strongly that caval compression was not present. Kosaka, Takahashi and Mark (1969), in a study in non-pregnant women, showed that arterial and antecubital venous blood thiopentone concentrations are similar within 3 or 4 min after i. v. injection. This suggests that, in the absence of delayed venous return, venous thiopentone concentrations in the foot and, presumably, elsewhere in the body may accurately represent the time profile of the drug in well-perfused vital organs within 3 - 4 min following injection. This study was prompted by the findings of our previous study (Morgan et ah, 1981a) in which it was noted there was a large variation in umbilical venous plasma thiopentone concentrations at delivery by Caesarean section. The umbilical concentration correlated inversely with the initial volume of distribution (Vi) of thiopentone in the mother. In that study the initial volume of distribution (mean 17.3 litre) was defined as the apparent volume in which the dose of thiopentone was diluted immediately following injection. It was calculated as the ratio of dose to peak plasma thiopentone concentration, the peak value being obtained by extrapolation of the plasma concentration—time profile back to zero time. It is important to differentiate between V| and the apparent volume of distribution after the attainment of distribution equilibrium of the drug among the body tissues (V*, mean 564 litre in the previous study). It was suggested that the large intersubject variation in VI may have resulted from the effect of concealed aortocaval compression by the gravid uterus during surgery. Similar variability in umbilical plasma thiopentone concentrations at delivery was also apparent in previous studies, for example those by Schepens and Heyndrickx (1975) and Kosaka, Takahashi and Mark (1969). On the basis of previous studies (Wright, Osborne and Edmonds, 1950; Chesley and EHiffus, 1972; Drummond et ah, 1974) it seemed reasonable to postulate that, if aortocaval compression occurred in these patients, plasma thiopentone concentra-
tions in the foot would lag behind those of the arm, at least until delivery. The plasma concentration-time profiles for subjects 4 and 5 are consistent with some degree of aortocaval compression in these subjects, as the difference in venous thiopentone concentrations in arm and foot, which was evident before delivery, disappeared shortly after delivery. Caval compression may also have occurred in subject 7, but the data are not conclusive. The fact that the plasma thiopentone concentration of the arm correlated with that of the leg at delivery in the seven subjects in whom there was no significant foot-arm difference suggests that aortocaval compression was minimal in these subjects. It has been noted that if subject 3, with the protracted injection-delivery interval, is omitted, there was a significant correlation between maternal plasma concentration of thiopentone at delivery and body weight (r= -0.80; P=0.016) in spite of the variable doses and injection-delivery intervals. The thiopentone concentration measured at 1 min (the peak value) also correlated with body weight (r = - 0.77; P=0.024) in these eight subjects. However, both correlations were probably artefactual because when the peak concentration for the ninth subject was included, the correlation was not significant (r= -0.48; P> 0.1). Furthermore, if body weight is one of the major factors determining the distribution characteristics of the drug shortly after injection, Vi would be expected to correlate with body weight. However, Vi (estimated as dose/plasma concentration at 1 min) did not correlate with body weight (r = — 0.47). Similarly, in our previous study, V but not Vi correlated with body weight. Whereas the plasma thiopentone concentration in umbilical vein correlated with the maternal venous concentration at delivery in our previous study (r = 0.88) (Morgan et ah, 1981a) no such correlation was observed in this investigation (r= 0.19), in spite of a similar technique of anaesthesia. The lack of a correlation is probably the result of the small ranges of maternal and umbilical plasma thiopentone concentrations (6.83-12.2 ngml"1 and 5.03-8.93ngml~', respectively) compared with 4.4-26.O^gml"1 and 2.9-33.9^gml" 1 , respectively in the previous study. The differences in the respective maternal and fetal ranges were significant (Ftest; P < 0.05). The only difference which we can identify between the two studies is that the angle to which patients were tilted during surgery may have been less in the previous study than in this one. In
THIOPENTONE AT CAESAREAN SECTION this study the tilt angle was measured with a geometric device to within 1-2°, whereas previously the angle was estimated by eye. We have since found that estimating the angle by eye is grossly inaccurate, the true angle being much smaller than the estimated angle. Thus, a lower tilt angle in the previous study could have resulted in significant aortocaval compression in some subjects, and high plasma thiopentone concentrations in the arm. In conclusion, the accurately measured left lateral tilt of 8-18° used in this study appears to have eliminated, in seven of the nine subjects, delays in venous return from the lower half of the body which could have been caused by aortocaval compression. In two patients differences in arm-foot thiopentone concentration before delivery may have been caused by aortocaval compression, and these disappeared immediately after delivery. These results suggest that free mixing of drugs in the intravascular compartment does not necessarily occur before delivery and much greater care is necessary in subsequent pharmacokinetic studies in pregnancy if the observations are to lead to valid conclusions. In those subjects in whom delays in intravascular mixing apparently did not occur, the variation in distribution of thiopentone among subjects must be related to other factors, such as weight and variation in age, as demonstrated recently in non-pregnant subjects (Jung et al., 1982; Christiansen, Andreasen and Jensen, 1981).
353 and Mahomedy, Y. H. (1974). Lateral table tilt for Caesarean section. Anaesthesia, 29,696. Drummond, G. B., Scott, S. E. M., Lees, M. M., and Scott, D. B. (1974). Effects of posture on limb blood flow in late pregnancy. Br. Med. J., 1, 587. Finster, M.,Mark, L. C , Morishima, H. C.Moya, F., James, L. S., Perel, J. M., and Dayton, P. G. (1966). Plasmathiopental concentration in the newborn following delivery under thiopental-nitrous oxide anesthesia. Am. J. Obsut. Gynecol., 95,621. Jung, D., Mayersohn, M.,Perrier, D., Calkin, J.,and Saunders, R. (1982). Thiopental disposition in <"•" and obese patients undergoing surgery. AnesthaMogy, 56,269. Kerr, M. G., Scott, D. B., and Samuel, E. (1964). Studies of the inferior vena cava in late pregnancy. Br. Med. J.,1, 532. Kosaka, Y., Takahashi, T., and Mark, L. C. (1969). Intravenous thiobarbiturate anesthesia for Cesarean section. Anesthesiology, 31,489. Lees, M. M., Taylor, S. H., Scott, D. B., and Kcrr, M. G. (1967). A study of cardiac output at rest throughout pregnancy. Br. J. Obsut. Gynaecol., 74, 319. McKechnie, F. B., and Converse, J. G. (1955). Placental transmission of thiopental. Am. J. Obsut. Gynecol., 70, 639. Morgan, D. J., Blackman, G. L., Paull, J. D., and Wolf, L. J. (1981a). Pharmacokinetics and plasma binding of thiopental.il: studies at Cesarean section. Anaihetiology, 54, 474. (1981b). Pharmacokinetics and plasma binding of thiopental. 1: studies in surgical patients. Antsthaiology, 54,468. Schcpens, P., and Heyndrickx, A. (1975). Placental transfer of thiopental. Eur. J. Toxicol., 8,87. Wright, H. P., Osborn, L. M., and Edmonds, D. G. (1950). Changes in the rate of flow of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg. Gynecol. Obstet.,
90,4%l.
ACKNOWLEDGEMENTS
We wish to thank Sister Sue Nolan for assistance in the collection of clinical samples and Ms Lynda Prest for typing the manuscript. The work was supported in part by the National Health and Medical Research Council. C. T. Toh was the recipient of a Pestin-Elmer Research Fellowship.
REFERENCES
Ansari, I., Wallace, G., Clemetson, C. A. B., Mallikarjunewara, V. R., and Clemetson, C. D. M. (1970). Tilt Caesarean section. / . Obsut. Gynaecol. Br. Commoma., 77,713. Chesley, L. C , and Duffus, G. M. (1972). Posture and apparent plasma volume in late pregnancy. / . Obsut. Gynaecol. Br. Commonw., 78,406. Christiansen, J. H., Andreasen, F., and J arisen, J. A. (1981). Influence of age and sex on the pharmacokinetics of thiopentone. Br. J. Anaesth., 53,1189. Crawford, J. S., Burton, M., and Davies, P. (1972). Time and lateral tilt at Caesarean section. Br. J. Anattth., 44,477. Kane, P. O. (1956). Some aspects of obstetric anm-nhi-.jjg Part 1: The use of thiopentone sodium. Br. J. Anaesth., 28, 146. Downing, J. W.,Coleman, A. J., Mahomedy, M.C., Jeal.D.E.,
COMPRESSION AORTOCAVE ET CONCENTRATIONS PLASMATIQUES DE THIOPENTAL LORS DE LA CESARIENNE RESUME
Nous avons mesure simultanement les concentrations plasmatiques de thiopental dans du sang obtenu a partir d'une veine du bras et d'une veine du pied au couredes 30-40 premieres minutes apres l'induction de l'anesthesie generate chez neuf femmes subissant une cesarienne. Les patientes etaient basculees sur le cote gauche de 8-18° au cours de 1'intervention. Chez toutes les patientes sauf deux, les courbes obtcnues avec le sang du bras et avec celui du pied etaient virtuellement identiques, ce qui suggcre que la compression aorto-cave etait absente ou insignifiante. Par consequent, la grande variabuite individuelle du volume de distribution du thiopental lors de la cesarienne n'est probablement pas due a une compression aorto-cave.
BRITISH JOURNAL OF ANAESTHESIA
354 AORTOCAVALE KOMPRESSION UND PLASMAKONZENTRATIONEN VON THIOPENTAL BEIM KAISERSCHNITT
COMPRESION DE LA AORTA Y DE LA VENA CAVA Y CONCENTRACIONES DE TIOPENTONA EN EL PLASMA DURANTE OPERACIONES CESAREAS
ZUSAMMENFASSUNG
SUMARIO
Bci neun Frauen wurde wfihrend termingemSBem Kaiserschnitt die PlasmakonzentrationB-Zeit-Kurve von Thiopental simultan wahrend der ersten 30 bis 40 Minuten nach Narkosceinleitung bestimmt. Die Blutprobe wurden aus einer Armvcnc und einer Fufivene entnommcn. Die Patientinnen waren wahrend des Eingriffs um 8 bis 18 Grad nach links scitlich gckippt. Bei alien aufier zwei Patientinnen waren die Profile aus den Arm- und Fuflvenen identisch, was auf fehlende oder unbedeutende aortocavale Kompression schliefien lafk. Die grofie individuelle Streubreite im Verteilungsvolumen von Thiopental beim Kaiserschnitt ist wahrscheinlich nicht auf aonocavale Kompression zuruckzufuhren.
En nueve mujeres sanas sometidas a una operacidn cesarea al termino del embarazo, se midieron simultiincamente durante los primcros 30—4Omin despues de la anestesia los perfiles del tiempo-concentracion en el plasma venoso de la tiopentona en sangre obtenida en una vena del brazo y de una vena del pie. Las pacientes estuvieron incUnadas lateralmente hacia la izquierda de 8 a 18° durante el procedimiento. En todas las mujeres, salvo unas dos de ellas, los perfiles del brazo y del pie eran virtualmente identicos, lo que hace pensar que la compresion de la aorta y de la vena cava era insignificante o nula. Por lo tan to, la enorme variacion entre las pacientes del volumen de distribution de la tiopentona en operaciones cesareas poco tiene que ver con la compresion de la aorta o de la vena cava.
AORTOCAVAL COMPRESSION AND PLASMA CONCENTRATIONS OF THIOPENTONE AT CAESAREAN SECTION D. J. MORGAN, J. D. PAULL, C. T. T O H AND G. L. BLACKMAN SUMMARY
The venous plasma concentration- time profiles of thiopentone were measured simultaneously over the first 30—40 min after induction of anaesthesia, in blood obtained from an arm vein and a vein in the foot, in nine healthy full-term women undergoing Caesarean section. Patients were tilted laterally to the left by from 8 to 18° during the procedure. In all but two of the patients, the profiles from the arm and foot were virtually identical, suggesting that aortocaval compression was absent or irmignifirfmt. Therefore, the large intersubject variability in volume of distribution of thiopentone at Caesarean section is unlikely to be the result of aortocaval compression.
Thiopentone is transferred rapidly to the fetus via the placenta following administration to the mother on induction of anaesthesia at Caesarean section. Previous studies have shown that, at delivery, there is wide intersubject variability in the fetal umbilical blood thiopentone concentration which cannot be accounted for by differences in the dose administered to the mother, or in the induction - delivery interval (McKechnie and Converse, 1955; Crawford and Kane, 1956; Finster et al., 1966; Schepens and Heyndrickx, 1975). Recently the umbilical plasma thiopentone concentration at delivery was shown to correlate closely with the initial volume of distribution (Vi) and the clearance of thiopentone in the mother (Morgan et al., 1981a). Therefore, it was concluded that the large intersubject variability in umbilical thiopentone plasma concentrations at delivery was largely a result of the correspondingly wide intersubject variability observed in the pharmacokinetics of the drug in the mother (Morgan et al., 1981a). The authors suggested that the large intersubject variability, particularly of volume of distribution, may be related to the effect of aortocaval compression by the gravid uterus during surgery (Morgan etal., 1981a). Aortocaval compression in the supine patient at Caesarean section causes an increase in venous pressure in the lower part of the body (Kerr, Scott and Samuel, 1964; Lees et al., 1967), a significant decrease in leg but not arm blood flow (Wright, OsDENIS J. MORGAN, PH.D. (Department of Pharmaceutics); CJENG
born and Edmonds, 1950; Drummond et al., 1974) and a decrease in the rate of mixing in, and apparent volume of, the plasma compartment (Chesley and Duffus, 1972). The better oxygenation and clinical status of infants whose mothers are tilted laterally by 10-15° to the left during surgery suggests that tilting the patient minimizes caval compression ( Ansari et al., 1970; Crawford, Burton and Davies, 1972; Downing et al., 1974). In the study by Morgan and colleagues (1981a) a 10-15° left lateral tilt was used, but they suggested that this may not have been sufficient to eliminate aortocaval compression since caval compression may be "concealed" and difficult to recognize clinically (Crawford, Burton and Davies, 1972). If aortocaval compression in the mother is a major cause of the large intersubject variability in the volume of distribution of thiopentone at Caesarean section, then the plasma concentration of thiopentone in the foot could be expected to lag behind that in the arm, at least until delivery. Aortocaval compression would be expected to result in a smaller initial volume of distribution ( Vi) of thiopentone in the mother and, consequently, in a higher umbilical venous plasma concentration of the drug at delivery. In this study, the possibility of delay in the return of venous blood from the lower half of the body, as a result of aortocaval compression at Caesarean section, was assessed by comparing the plasma thiopentone concentration-time profile in blood obtained from a foot vein with that obtained from a vein in the arm.
T. TOH.M.PHARM., GRAEME L. BLAOCMAN,PH.D.,(Department
of Pharmaceutical Chemistry); Victorian College of Pharmacy Ltd, 381 Royal Parade, Parkville, Victoria, 3052, Australia. JOHN D. PAUU., M.B., B.s. F.F.A.R.A.C.S., DIP. ED., Department of Anaesthetics, The Royal Women's Hospital, Carlton, Victoria, Australia.
PATIENTS AND MATERIALS Nine healthy women who gave birth to healthy infants (one patient gave birth to twins) by elective © The Macmillan Press Ltd 1984
350
BRITISH JOURNAL OF ANAESTHESIA
Caesarean section were studied. None of the infants showed any evidence of depression at delivery. All had Apgar scores of 7 or greater 1 min after delivery and of 9 or greater 5 min after delivery. All established regular respiration within 2 min of delivery. The mean age of the patients was 28 yr (range 21 -36 yr) and their mean weight was 71.6 kg (range 59.0-90.3 kg). The study was approved by the Research Committee of the Hospital and all patients gave written informed consent before the investigation. The technique of anaesthesia was the same as that used in our previous study (Morgan et al., 1981a). Following pre-medication with papaveretum i.m. 30 min before the induction of anaesthesia, the patients received thiopentone sodium by bolus injection i.v. over 30 s. Suxamethonium was used to facilitate tracheal intubation and general anaesthesia was maintained with nitrous oxide in oxygen. All patients received 1 litre of Compound Sodium Lactate Injection B.P. during the first 30 min of the operation. Patients lay supine with a left lateral tilt and with arms extended to either side for the duration of anaesthesia. The angle of tilt ranged from 8 to 18° among patients and was measured to within 1-2° using a geometric device. The patients also received routine drug therapy as required (for example oxytocin or ergometrine after delivery and morphine or pethidine for postoperative analgesia). A scalp vein needle was inserted to a vein in the right cubital fossa immediately before the induction of anaesthesia: a 5-ml control blood sample was
obtained. Immediately after the injection of thiopentone to a freely running i.v. infusion in the left arm, another scalp vein needle was inserted to a vein in the dorsum of the left foot. Blood samples (5 ml) were then taken simultaneously from the arm and the foot at 1-min intervals from the induction of anaesthesia until 5 min after delivery. Subsequently, samples were then taken at 2-min and later at 5-min intervals for the next 30 min. Umbilical cord venous blood samples were collected at delivery. The blood samples were collected in plastic tubes containing lithium heparin and chilled in ice. The plasma was separated by centrifugation and stored at - 20 °C until analysis. Thiopentone was assayed in plasma by reverse-phase high pressure liquid chromatography (Morgan et al., 1981b). RESULTS
Details of the patients, the administration of thiopentone and the plasma thiopentone concentrations at delivery are detailed in table I. The venous plasma thiopentone concentration-time profiles in the arm and the foot of the nine subjects are shown in figure 1. Apart from subjects 4 and 5, venous plasma thiopentone concentrations in the arm and foot were similar throughout. In subjects 4 and 5, the venous concentrations in the foot were less than those in the arm until shortly after delivery, suggesting that some degree of aortocaval compression had occurred in these two patients. There was a significant correlation between plasma thiopentone concentrations in arm blood and leg
TABUB I. Patient details and plasma thiopentone concentrations at delivery
Patient 1 2 3 4 5 6 (a) 6(b) 7 8 9 Mean SD
Body weight (kg)
Tilt angle
O
Dose (mg)
80.2 62.1 59.0 66.0 58.0 74.0
10 8 10 8 10 17
350 400 300 450 400 400
90.3 70.8 83.1
15 18 10
375 400 425
Interval admin, to delivery (min) 4.0 8.0 19.0 9.0 6.0 9.5 11.5 8.0 11.0 10.0
Plasma thiopentone concn (pgmT 1 ) Maternal venous Umbilical Arm Foot venous 8.% 11.1 6.83 12.2 11.9 8.02 7.39 8.61 9.68 7.87
7.89 11.4 5.94 9.10 8.48 7.90 7.79 7.66 9.26 7.56
7.15 5.03 5.81 8.92 5.64 7.04 5.47 5.25
9.26 1.9
8.30 1.4
6.33 1.2
6.68
THIOPENTONE AT CAESAREAN SECTION 24
351
Subject 1
Subject 2
Subject 3
Subject 4
Subject 5
Subject 6
20 16 12 8 4 0
E tion
a 24 20-
CO
CD U
16-
O
u
I
12-
c
-
o
8-
"A r vX /
CO U) CO Q.
40
±L
\
201 Subject 9
Subject 8
Subject 7 16
12 8 4 0
± 10
20
30
40
10
20
30
40
10
20
30
Time (min) FIG. 1. Venous plasma thiopentone concentration—time profiles in arm ( ) and foot (. . .) at and following Caesarean section. The arrow indicates delivery.
40
BRITISH JOURNAL OF ANAESTHESIA
352
blood at delivery (r= 0.73; P= 0.024), but not between maternal and umbilical venous plasma concentrations at delivery (r= 0.19). DISCUSSION
In the present study, the similarity of the profiles of venous plasma thiopentone concentration v. time in the arm and the foot show that there were no delays in the venous return from the foot and suggest strongly that caval compression was not present. Kosaka, Takahashi and Mark (1969), in a study in non-pregnant women, showed that arterial and antecubital venous blood thiopentone concentrations are similar within 3 or 4 min after i. v. injection. This suggests that, in the absence of delayed venous return, venous thiopentone concentrations in the foot and, presumably, elsewhere in the body may accurately represent the time profile of the drug in well-perfused vital organs within 3 - 4 min following injection. This study was prompted by the findings of our previous study (Morgan et ah, 1981a) in which it was noted there was a large variation in umbilical venous plasma thiopentone concentrations at delivery by Caesarean section. The umbilical concentration correlated inversely with the initial volume of distribution (Vi) of thiopentone in the mother. In that study the initial volume of distribution (mean 17.3 litre) was defined as the apparent volume in which the dose of thiopentone was diluted immediately following injection. It was calculated as the ratio of dose to peak plasma thiopentone concentration, the peak value being obtained by extrapolation of the plasma concentration—time profile back to zero time. It is important to differentiate between V| and the apparent volume of distribution after the attainment of distribution equilibrium of the drug among the body tissues (V*, mean 564 litre in the previous study). It was suggested that the large intersubject variation in VI may have resulted from the effect of concealed aortocaval compression by the gravid uterus during surgery. Similar variability in umbilical plasma thiopentone concentrations at delivery was also apparent in previous studies, for example those by Schepens and Heyndrickx (1975) and Kosaka, Takahashi and Mark (1969). On the basis of previous studies (Wright, Osborne and Edmonds, 1950; Chesley and EHiffus, 1972; Drummond et ah, 1974) it seemed reasonable to postulate that, if aortocaval compression occurred in these patients, plasma thiopentone concentra-
tions in the foot would lag behind those of the arm, at least until delivery. The plasma concentration-time profiles for subjects 4 and 5 are consistent with some degree of aortocaval compression in these subjects, as the difference in venous thiopentone concentrations in arm and foot, which was evident before delivery, disappeared shortly after delivery. Caval compression may also have occurred in subject 7, but the data are not conclusive. The fact that the plasma thiopentone concentration of the arm correlated with that of the leg at delivery in the seven subjects in whom there was no significant foot-arm difference suggests that aortocaval compression was minimal in these subjects. It has been noted that if subject 3, with the protracted injection-delivery interval, is omitted, there was a significant correlation between maternal plasma concentration of thiopentone at delivery and body weight (r= -0.80; P=0.016) in spite of the variable doses and injection-delivery intervals. The thiopentone concentration measured at 1 min (the peak value) also correlated with body weight (r = - 0.77; P=0.024) in these eight subjects. However, both correlations were probably artefactual because when the peak concentration for the ninth subject was included, the correlation was not significant (r= -0.48; P> 0.1). Furthermore, if body weight is one of the major factors determining the distribution characteristics of the drug shortly after injection, Vi would be expected to correlate with body weight. However, Vi (estimated as dose/plasma concentration at 1 min) did not correlate with body weight (r = — 0.47). Similarly, in our previous study, V but not Vi correlated with body weight. Whereas the plasma thiopentone concentration in umbilical vein correlated with the maternal venous concentration at delivery in our previous study (r = 0.88) (Morgan et ah, 1981a) no such correlation was observed in this investigation (r= 0.19), in spite of a similar technique of anaesthesia. The lack of a correlation is probably the result of the small ranges of maternal and umbilical plasma thiopentone concentrations (6.83-12.2 ngml"1 and 5.03-8.93ngml~', respectively) compared with 4.4-26.O^gml"1 and 2.9-33.9^gml" 1 , respectively in the previous study. The differences in the respective maternal and fetal ranges were significant (Ftest; P < 0.05). The only difference which we can identify between the two studies is that the angle to which patients were tilted during surgery may have been less in the previous study than in this one. In
THIOPENTONE AT CAESAREAN SECTION this study the tilt angle was measured with a geometric device to within 1-2°, whereas previously the angle was estimated by eye. We have since found that estimating the angle by eye is grossly inaccurate, the true angle being much smaller than the estimated angle. Thus, a lower tilt angle in the previous study could have resulted in significant aortocaval compression in some subjects, and high plasma thiopentone concentrations in the arm. In conclusion, the accurately measured left lateral tilt of 8-18° used in this study appears to have eliminated, in seven of the nine subjects, delays in venous return from the lower half of the body which could have been caused by aortocaval compression. In two patients differences in arm-foot thiopentone concentration before delivery may have been caused by aortocaval compression, and these disappeared immediately after delivery. These results suggest that free mixing of drugs in the intravascular compartment does not necessarily occur before delivery and much greater care is necessary in subsequent pharmacokinetic studies in pregnancy if the observations are to lead to valid conclusions. In those subjects in whom delays in intravascular mixing apparently did not occur, the variation in distribution of thiopentone among subjects must be related to other factors, such as weight and variation in age, as demonstrated recently in non-pregnant subjects (Jung et al., 1982; Christiansen, Andreasen and Jensen, 1981).
353 and Mahomedy, Y. H. (1974). Lateral table tilt for Caesarean section. Anaesthesia, 29,696. Drummond, G. B., Scott, S. E. M., Lees, M. M., and Scott, D. B. (1974). Effects of posture on limb blood flow in late pregnancy. Br. Med. J., 1, 587. Finster, M.,Mark, L. C , Morishima, H. C.Moya, F., James, L. S., Perel, J. M., and Dayton, P. G. (1966). Plasmathiopental concentration in the newborn following delivery under thiopental-nitrous oxide anesthesia. Am. J. Obsut. Gynecol., 95,621. Jung, D., Mayersohn, M.,Perrier, D., Calkin, J.,and Saunders, R. (1982). Thiopental disposition in <"•" and obese patients undergoing surgery. AnesthaMogy, 56,269. Kerr, M. G., Scott, D. B., and Samuel, E. (1964). Studies of the inferior vena cava in late pregnancy. Br. Med. J.,1, 532. Kosaka, Y., Takahashi, T., and Mark, L. C. (1969). Intravenous thiobarbiturate anesthesia for Cesarean section. Anesthesiology, 31,489. Lees, M. M., Taylor, S. H., Scott, D. B., and Kcrr, M. G. (1967). A study of cardiac output at rest throughout pregnancy. Br. J. Obsut. Gynaecol., 74, 319. McKechnie, F. B., and Converse, J. G. (1955). Placental transmission of thiopental. Am. J. Obsut. Gynecol., 70, 639. Morgan, D. J., Blackman, G. L., Paull, J. D., and Wolf, L. J. (1981a). Pharmacokinetics and plasma binding of thiopental.il: studies at Cesarean section. Anaihetiology, 54, 474. (1981b). Pharmacokinetics and plasma binding of thiopental. 1: studies in surgical patients. Antsthaiology, 54,468. Schcpens, P., and Heyndrickx, A. (1975). Placental transfer of thiopental. Eur. J. Toxicol., 8,87. Wright, H. P., Osborn, L. M., and Edmonds, D. G. (1950). Changes in the rate of flow of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg. Gynecol. Obstet.,
90,4%l.
ACKNOWLEDGEMENTS
We wish to thank Sister Sue Nolan for assistance in the collection of clinical samples and Ms Lynda Prest for typing the manuscript. The work was supported in part by the National Health and Medical Research Council. C. T. Toh was the recipient of a Pestin-Elmer Research Fellowship.
REFERENCES
Ansari, I., Wallace, G., Clemetson, C. A. B., Mallikarjunewara, V. R., and Clemetson, C. D. M. (1970). Tilt Caesarean section. / . Obsut. Gynaecol. Br. Commoma., 77,713. Chesley, L. C , and Duffus, G. M. (1972). Posture and apparent plasma volume in late pregnancy. / . Obsut. Gynaecol. Br. Commonw., 78,406. Christiansen, J. H., Andreasen, F., and J arisen, J. A. (1981). Influence of age and sex on the pharmacokinetics of thiopentone. Br. J. Anaesth., 53,1189. Crawford, J. S., Burton, M., and Davies, P. (1972). Time and lateral tilt at Caesarean section. Br. J. Anattth., 44,477. Kane, P. O. (1956). Some aspects of obstetric anm-nhi-.jjg Part 1: The use of thiopentone sodium. Br. J. Anaesth., 28, 146. Downing, J. W.,Coleman, A. J., Mahomedy, M.C., Jeal.D.E.,
COMPRESSION AORTOCAVE ET CONCENTRATIONS PLASMATIQUES DE THIOPENTAL LORS DE LA CESARIENNE RESUME
Nous avons mesure simultanement les concentrations plasmatiques de thiopental dans du sang obtenu a partir d'une veine du bras et d'une veine du pied au couredes 30-40 premieres minutes apres l'induction de l'anesthesie generate chez neuf femmes subissant une cesarienne. Les patientes etaient basculees sur le cote gauche de 8-18° au cours de 1'intervention. Chez toutes les patientes sauf deux, les courbes obtcnues avec le sang du bras et avec celui du pied etaient virtuellement identiques, ce qui suggcre que la compression aorto-cave etait absente ou insignifiante. Par consequent, la grande variabuite individuelle du volume de distribution du thiopental lors de la cesarienne n'est probablement pas due a une compression aorto-cave.
BRITISH JOURNAL OF ANAESTHESIA
354 AORTOCAVALE KOMPRESSION UND PLASMAKONZENTRATIONEN VON THIOPENTAL BEIM KAISERSCHNITT
COMPRESION DE LA AORTA Y DE LA VENA CAVA Y CONCENTRACIONES DE TIOPENTONA EN EL PLASMA DURANTE OPERACIONES CESAREAS
ZUSAMMENFASSUNG
SUMARIO
Bci neun Frauen wurde wfihrend termingemSBem Kaiserschnitt die PlasmakonzentrationB-Zeit-Kurve von Thiopental simultan wahrend der ersten 30 bis 40 Minuten nach Narkosceinleitung bestimmt. Die Blutprobe wurden aus einer Armvcnc und einer Fufivene entnommcn. Die Patientinnen waren wahrend des Eingriffs um 8 bis 18 Grad nach links scitlich gckippt. Bei alien aufier zwei Patientinnen waren die Profile aus den Arm- und Fuflvenen identisch, was auf fehlende oder unbedeutende aortocavale Kompression schliefien lafk. Die grofie individuelle Streubreite im Verteilungsvolumen von Thiopental beim Kaiserschnitt ist wahrscheinlich nicht auf aonocavale Kompression zuruckzufuhren.
En nueve mujeres sanas sometidas a una operacidn cesarea al termino del embarazo, se midieron simultiincamente durante los primcros 30—4Omin despues de la anestesia los perfiles del tiempo-concentracion en el plasma venoso de la tiopentona en sangre obtenida en una vena del brazo y de una vena del pie. Las pacientes estuvieron incUnadas lateralmente hacia la izquierda de 8 a 18° durante el procedimiento. En todas las mujeres, salvo unas dos de ellas, los perfiles del brazo y del pie eran virtualmente identicos, lo que hace pensar que la compresion de la aorta y de la vena cava era insignificante o nula. Por lo tan to, la enorme variacion entre las pacientes del volumen de distribution de la tiopentona en operaciones cesareas poco tiene que ver con la compresion de la aorta o de la vena cava.