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PREGNANCY DELAYS PARACETAMOL ABSORPTION AND GASTRIC EMPTYING IN PATIENTS UNDERGOING SURGERY
Br. J. Anaesth. (1988), 60, 24-27
PREGNANCY DELAYS PARACETAMOL ABSORPTION AND GASTRIC EMPTYING IN PATIENTS UNDERGOING SURGERY K. H. SIMPSON, A. F. STAKES AND M. MILLER Nausea, vomiting and heartburn occur during early pregnancy, and may indicate abnormal SUMMARY gastrointestinal function at this time. An increase in the release of progesterone from the corpus Gastric emptying may be delayed during pregluteum and placenta causes relaxation of gastro- nancy by hormonally mediated relaxation of the intestinal smooth muscle and this may result in a musculature of the stomach and by mechanical decrease in the motility of the stomach [1]. Gastric effects. In the present study, the rate of paraemptying may also be impeded mechanically cetamol absorption was used to measure gastric during pregnancy if the stomach is pushed into a emptying in 14 non-pregnant women undermore horizontal position and the pylorus is going minor gynaecological surgery, and in 28 women undergoing termination of pregnancy. displaced upwards and posteriorly [2]. Previous studies of gastric emptying during Of the pregnant patients 16 were of 8-11 weeks pregnancy have produced conflicting results. In gestation and 12 were of 12-14 weeks gestation. 1937, Hansen [3] found that the emptying time of Paracetamol absorption was delayed in those a radio-opaque test meal was increased by who were 12-14 weeks pregnant compared with 30-90 min during pregancy. However Boy den non-pregnant controls. Paracetamol absorption and Rigler [4], using fluoroscopic examination, in the 8-11 weeks pregnant group was between found little alteration in gastric emptying during the other two groups, but was not significantly the second and third trimester of pregnancy, but different from either. suggested that peristalsis may have been slower. Hunt and Murray [5] used dye dilution to measure aspiration methods correct for the volume of the rate of emptying of 750 ml of fluid in five gastric secretion during the study period, but only pregnant women and showed that it did not differ allow one single measurement of emptying. from that found in the same patients 40 weeks Solute absorption has been used widely to after delivery. In 1970, Davison, Davison and measure stomach emptying before surgery, as it is Hay [6] measured gastric emptying using a double non-invasive and does not require the ingestion of sampling dye-dilution technique in 11 non- large amounts of fluid [7]. In the present study the pregnant women and 11 women of at least 34 rate of paracetamol absorption was used to weeks gestation. The mean total emptying time of measure gastric emptying rate during pregnancy a water test meal was increased in pregnant and in non-pregnant control subjects. patients, but there was no difference in the volume of the stomach contents after 30 min. PATIENTS AND METHODS These conflicting results may reflect differences in the measurement techniques. It is difficult to Twenty-eight women undergoing termination of quantitate gastric emptying radiologically. Gastric pregnancy and 14 non-pregnant women having minor gynaecological surgery were studied. All K. H. SIMPSON, M.B., CH.B., F.F.A.R.C.S. ; A. F. STAKES, M.B., patients were healthy and none was taking any B.S., F.F.A.R.C.S.; M. MILLER, M.B., CH.B., F.F.A.R.C.S.; drugs, including oral contraceptives, which might University Department of Anaesthesia, Clinical Sciences alter gastric motility. Before surgery the gestation Building, St James's University Hospital, Leeds LS9 7TF. of the pregnant patients was assessed by a Accepted for Publication: August 4, 1987. consultant gynaecologist, and they were grouped Correspondence to K.H. S.
PREGNANCY AND GASTRIC EMPTYING
25
TABLE I. Age and weight of patients and duration of fasting (mean (SD))
Gestation
Age (yr)
Weight (kg)
Starved (h)
Control (n = 14) 8-11 weeks (n = 16) 12-14 weeks (» =12)
31.8(7.5)
59.6 (9.6)
8.0 (4.5)
25.6 (8.0)
60.3 (11.5)
6.8 (4.1)
24.8 (8.6)
57.8 (7.3)
5.7 (2.9)
30-
e CD C
uc 20o u •5 nj
—• Controls
10-
o8-11 weeks pregnant 12-14 weeks pregnant
15
30
45
60
75
90
120
Time (min) FIG. 1. Mean plasma paracetamol concentrations ( + SEM) after paracetamol 1.5 g by mouth with 150 ml of water. Women 12-14 weeks pregnant had significantly lower concentrations at 30, 45 (P < 0.05), 60 (P < 0.01) and 75 (P < 0.05) min compared with controls.
according to the size of the uterus as 8-11 weeks (n = 16) or 12-14 weeks (n = 12). Gastric emptying was measured using a paracetamol absorption technique similar to that described by Heading and colleagues [8]. After a fast of at least 4 h each patient took paracetamol tablets 1.5 g (Winthrop Laboratories) with 150 ml of water. Patients remained supine for 2 h whilst blood was sampled at intervals, through an i.v. cannula; blood sampling was completed before the induction of anaesthesia. Plasma samples were frozen at —20 °C and paracetamol concentrations were measured using an enzymatic assay method, specific for the parent compound, which did not detect paracetamol metabolites (Cambridge Life Sciences). The enzyme aryl acylamide amidohydrolase was used to split the amide bond of
paracetamol, producing acetate and p-aminophenol. The latter reacted with o-cresol to form a stable blue compound which was measured using a spectrophotometer capable of reading at 615 nm. The procedure was automated to improve the performance of the assay at the low concentrations of paracetamol expected. The system used was a hybrid Technicon AAII/Fisons Vitatron with a Hook and Tucker sampler adapted for the procedure. The external quality control was a commercial kit (American Hospital Supplies), used routinely for measuring therapeutic concentrations of paracetamol in plasma. The coefficients of variation were 0.96% (within batch) and 2.24% (between batch). The assays of 72 patients were reanalysed on a different day and gave a coefficient of varation of 2.35%.
BRITISH JOURNAL OF ANAESTHESIA
26 40-1 D Control E3 8-11 weeks pregnant 19 12-14 weeks pregnant
£ 30E
\\ \ \\ \\
< 20o CD
ft \\\ \\
00 O to
10-
0-1
0-2 Time (h)
FIG. 2. Mean area under the plasma paracetamol concentration-time curve (AUC) ( + SEM) at 1 and 2 h after paracetamol 1.5 g by mouth with 150 ml of water. *Significantly less in women 12-14 weeks pregnant than in controls at both times (P < 0.05). TABLE II. Peak paracetamol concentrations and time to peak significantly different from either of, the other two (mean (SEM)) after paracetamol 1.5 g by mouth with 150 ml groups (fig. 1). The 12-14 weeks pregnant group of water. *P < 0.05 compared with controls; fP < 0.05 had lower peak paracetamol concentrations comcompared with controls and 8-11 weeks pregnant patients Gestation
Peak concn (ug ml"1)
Time (min)
Control (« = 14) 8-11 weeks (n = 16) 12-14 weeks (n = 12)
34.4 (4.3) 26.8 (2.7) 21.4* (2.2)
45.0 (5.9) 46.4 (8.1) 71.9+ (9.2)
The area under the plasma paracetamol concentration-time curve was calculated using the trapezoidal rule. Data were analysed using oneway analysis of variance for independent samples, followed by Scheffes test where appropriate. RESULTS
There was no significant difference in age, weight or duration of fasting between the pregnant and control groups (table I). Plasma paracetamol concentrations were significantly lower at 30,45 (P < 0.05), 60 (P < 0.01) and 75 (P < 0.05) min in patients who were 12-14 weeks pregnant compared with control subjects. Paracetamol concentrations in the 8-11 weeks pregnant group were between, but were not
pared with controls (P < 0.05), and showed a delay in the time taken to reach a peak compared with controls and 8-11 weeks pregnant women (P < 0.05) (table II). The areas under the plasma paracetamol concentration-time curve (AUC) at 1 and 2 h were less in 12-14 weeks pregnant patients compared with controls (P < 0.05). The AUC in the 8-11 weeks pregnant group were not significantly different from either of the other groups (fig. 2). DISCUSSION
As paracetamol is not absorbed in the stomach, but is readily absorbed in the upper small bowel, the rate of absorption depends on the rate of gastric emptying. Heading and colleagues [8] demonstrated a significant correlation between the half-time of gastric emptying, measured by sequential gamma scintiscanning of the stomach, and plasma paracetamol concentrations. Therefore, the reduction in mean plasma paracetamol concentrations in the 12-14 weeks pregnant patients, in the present study, represented a delay in gastric emptying. The smaller area under the
PREGNANCY AND GASTRIC EMPTYING
27
plasma paracetamol concentration-time curve in We are grateful to Professor W. S. Nimmo (University these subjects reflected a reduction in paracetamol Department of Anaesthesia, Sheffield) for his advice on the absorption [9]. Although no statistically signi- preparation of this paper. ficant difference was demonstrated between the control and the 8-11 weeks pregnant patients, the REFERENCES values for the latter group were between the 12-14 1. Hytten FE. The alimentary system. In: Hytten FE, weeks and the non-pregnant values. Chamberlain GC, eds. Clinical Physiology in Obstetrics. Oxford: Blackwell Scientific Publications, 1980; 147-162. Inhalation of gastric contents remains an im2. Williams NH. The variable significance of heartburn. portant cause of anaesthetic mortality and morAmerican Journal of Obstetrics and Gynaecology 1941; 42: bidity [10]. Many studies have demonstrated 814-820. large volumes of acid stomach contents in patients 3. Hansen R. Zur physiologie des magens in der schwangerprepared for surgery. Hester and Heath [11] schaft. Zentralblatt fur Gynakologie 1937; 61: 2306-2309. 4. Boyden EA, Rigler LG. Initial emptying time of stomach reported that, after prolonged fasting, more than in primagravidae as related to evacuation of biliary tract. 40 ml of fluid was recovered from the stomach of Proceedings of the Society for Experimental Biology and one in eight patients presenting for elective Medicine 1944; 56: 200-201. surgery, and over half the patients had gastric 5. Hunt JN, Murray FA. Gastric function in pregnancy. contents with a pH of less than 2.5. More than Journal of Obstetrics and Gynaecology of the British Commonwealth 1958; 65: 78-83. 25 ml of acidic stomach fluid was aspirated from 6. Davison JS, Davison MC, Hay DM. Gastric emptying 66% of patients presenting for minor outpatient time in late pregnancy and labour. Journal ofOstetrics and operations [12]. As many patients undergo surgery Gynaecology of the British Commonwealth 1970; 77: during early pregnancy, it may be important to 37-41. determine whether significant gastric stasis is 7. Nimmo WS. Effect of anaesthesia on gastric motility and emptying. British Journal of Anaesthesia 1984; 56: present at this time. Although the present study 29-36. demonstrated delayed stomach emptying during 8. Heading RC, Nimmo J, Prescott LF, Tothill P. The pregnancy, it did not show whether this increased dependence of paracetamol absorption on the rate of the risk of aspiration of gastric contents. gastric emptying. British Journal of Pharmacology 1973; ACKNOWLEDGEMENTS We are grateful to the staff of the Department of Chemical Pathology, St James's University Hospital, Leeds: Dr Evans (Top Grade Biochemist) and Mr Altren (Senior Chief MLSO) for advice and encouragement during the study, and Mr Smith (Chief MLSO) and Mr Mallinson (Chief MLSO) for excellent technical assistance and development of the automated paracetamol assay from the Cambridge Life Sciences kit. The authors thank Mr D. R. Bromham and Mr G. J. Jarvis (Consultant Gynaecologists) for access to patients during this study.
47: 415-421. 9. Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. British Journal of Clinical Pharmacology 1980; 10: 291S-298S. 10. Lunn JN, Mushin WW. Mortality Associated with Anaesthesia. London: Nuffield Provincial Hospitals Trust, 1982. 11. Hester JB, Heath ML. Pulmonary acid aspiration syndrome: should prophylaxis be routine? British Journal of Anaesthesia 1977; 49: 595-599. 12. Ong BY, Palahniuk RJ, dimming M. Gastric volume and pH in outpatients. Canadian Anaesthetists Society Journal 1978; 25: 36-39.
PREGNANCY DELAYS PARACETAMOL ABSORPTION AND GASTRIC EMPTYING IN PATIENTS UNDERGOING SURGERY K. H. SIMPSON, A. F. STAKES AND M. MILLER Nausea, vomiting and heartburn occur during early pregnancy, and may indicate abnormal SUMMARY gastrointestinal function at this time. An increase in the release of progesterone from the corpus Gastric emptying may be delayed during pregluteum and placenta causes relaxation of gastro- nancy by hormonally mediated relaxation of the intestinal smooth muscle and this may result in a musculature of the stomach and by mechanical decrease in the motility of the stomach [1]. Gastric effects. In the present study, the rate of paraemptying may also be impeded mechanically cetamol absorption was used to measure gastric during pregnancy if the stomach is pushed into a emptying in 14 non-pregnant women undermore horizontal position and the pylorus is going minor gynaecological surgery, and in 28 women undergoing termination of pregnancy. displaced upwards and posteriorly [2]. Previous studies of gastric emptying during Of the pregnant patients 16 were of 8-11 weeks pregnancy have produced conflicting results. In gestation and 12 were of 12-14 weeks gestation. 1937, Hansen [3] found that the emptying time of Paracetamol absorption was delayed in those a radio-opaque test meal was increased by who were 12-14 weeks pregnant compared with 30-90 min during pregancy. However Boy den non-pregnant controls. Paracetamol absorption and Rigler [4], using fluoroscopic examination, in the 8-11 weeks pregnant group was between found little alteration in gastric emptying during the other two groups, but was not significantly the second and third trimester of pregnancy, but different from either. suggested that peristalsis may have been slower. Hunt and Murray [5] used dye dilution to measure aspiration methods correct for the volume of the rate of emptying of 750 ml of fluid in five gastric secretion during the study period, but only pregnant women and showed that it did not differ allow one single measurement of emptying. from that found in the same patients 40 weeks Solute absorption has been used widely to after delivery. In 1970, Davison, Davison and measure stomach emptying before surgery, as it is Hay [6] measured gastric emptying using a double non-invasive and does not require the ingestion of sampling dye-dilution technique in 11 non- large amounts of fluid [7]. In the present study the pregnant women and 11 women of at least 34 rate of paracetamol absorption was used to weeks gestation. The mean total emptying time of measure gastric emptying rate during pregnancy a water test meal was increased in pregnant and in non-pregnant control subjects. patients, but there was no difference in the volume of the stomach contents after 30 min. PATIENTS AND METHODS These conflicting results may reflect differences in the measurement techniques. It is difficult to Twenty-eight women undergoing termination of quantitate gastric emptying radiologically. Gastric pregnancy and 14 non-pregnant women having minor gynaecological surgery were studied. All K. H. SIMPSON, M.B., CH.B., F.F.A.R.C.S. ; A. F. STAKES, M.B., patients were healthy and none was taking any B.S., F.F.A.R.C.S.; M. MILLER, M.B., CH.B., F.F.A.R.C.S.; drugs, including oral contraceptives, which might University Department of Anaesthesia, Clinical Sciences alter gastric motility. Before surgery the gestation Building, St James's University Hospital, Leeds LS9 7TF. of the pregnant patients was assessed by a Accepted for Publication: August 4, 1987. consultant gynaecologist, and they were grouped Correspondence to K.H. S.
PREGNANCY AND GASTRIC EMPTYING
25
TABLE I. Age and weight of patients and duration of fasting (mean (SD))
Gestation
Age (yr)
Weight (kg)
Starved (h)
Control (n = 14) 8-11 weeks (n = 16) 12-14 weeks (» =12)
31.8(7.5)
59.6 (9.6)
8.0 (4.5)
25.6 (8.0)
60.3 (11.5)
6.8 (4.1)
24.8 (8.6)
57.8 (7.3)
5.7 (2.9)
30-
e CD C
uc 20o u •5 nj
—• Controls
10-
o8-11 weeks pregnant 12-14 weeks pregnant
15
30
45
60
75
90
120
Time (min) FIG. 1. Mean plasma paracetamol concentrations ( + SEM) after paracetamol 1.5 g by mouth with 150 ml of water. Women 12-14 weeks pregnant had significantly lower concentrations at 30, 45 (P < 0.05), 60 (P < 0.01) and 75 (P < 0.05) min compared with controls.
according to the size of the uterus as 8-11 weeks (n = 16) or 12-14 weeks (n = 12). Gastric emptying was measured using a paracetamol absorption technique similar to that described by Heading and colleagues [8]. After a fast of at least 4 h each patient took paracetamol tablets 1.5 g (Winthrop Laboratories) with 150 ml of water. Patients remained supine for 2 h whilst blood was sampled at intervals, through an i.v. cannula; blood sampling was completed before the induction of anaesthesia. Plasma samples were frozen at —20 °C and paracetamol concentrations were measured using an enzymatic assay method, specific for the parent compound, which did not detect paracetamol metabolites (Cambridge Life Sciences). The enzyme aryl acylamide amidohydrolase was used to split the amide bond of
paracetamol, producing acetate and p-aminophenol. The latter reacted with o-cresol to form a stable blue compound which was measured using a spectrophotometer capable of reading at 615 nm. The procedure was automated to improve the performance of the assay at the low concentrations of paracetamol expected. The system used was a hybrid Technicon AAII/Fisons Vitatron with a Hook and Tucker sampler adapted for the procedure. The external quality control was a commercial kit (American Hospital Supplies), used routinely for measuring therapeutic concentrations of paracetamol in plasma. The coefficients of variation were 0.96% (within batch) and 2.24% (between batch). The assays of 72 patients were reanalysed on a different day and gave a coefficient of varation of 2.35%.
BRITISH JOURNAL OF ANAESTHESIA
26 40-1 D Control E3 8-11 weeks pregnant 19 12-14 weeks pregnant
£ 30E
\\ \ \\ \\
< 20o CD
ft \\\ \\
00 O to
10-
0-1
0-2 Time (h)
FIG. 2. Mean area under the plasma paracetamol concentration-time curve (AUC) ( + SEM) at 1 and 2 h after paracetamol 1.5 g by mouth with 150 ml of water. *Significantly less in women 12-14 weeks pregnant than in controls at both times (P < 0.05). TABLE II. Peak paracetamol concentrations and time to peak significantly different from either of, the other two (mean (SEM)) after paracetamol 1.5 g by mouth with 150 ml groups (fig. 1). The 12-14 weeks pregnant group of water. *P < 0.05 compared with controls; fP < 0.05 had lower peak paracetamol concentrations comcompared with controls and 8-11 weeks pregnant patients Gestation
Peak concn (ug ml"1)
Time (min)
Control (« = 14) 8-11 weeks (n = 16) 12-14 weeks (n = 12)
34.4 (4.3) 26.8 (2.7) 21.4* (2.2)
45.0 (5.9) 46.4 (8.1) 71.9+ (9.2)
The area under the plasma paracetamol concentration-time curve was calculated using the trapezoidal rule. Data were analysed using oneway analysis of variance for independent samples, followed by Scheffes test where appropriate. RESULTS
There was no significant difference in age, weight or duration of fasting between the pregnant and control groups (table I). Plasma paracetamol concentrations were significantly lower at 30,45 (P < 0.05), 60 (P < 0.01) and 75 (P < 0.05) min in patients who were 12-14 weeks pregnant compared with control subjects. Paracetamol concentrations in the 8-11 weeks pregnant group were between, but were not
pared with controls (P < 0.05), and showed a delay in the time taken to reach a peak compared with controls and 8-11 weeks pregnant women (P < 0.05) (table II). The areas under the plasma paracetamol concentration-time curve (AUC) at 1 and 2 h were less in 12-14 weeks pregnant patients compared with controls (P < 0.05). The AUC in the 8-11 weeks pregnant group were not significantly different from either of the other groups (fig. 2). DISCUSSION
As paracetamol is not absorbed in the stomach, but is readily absorbed in the upper small bowel, the rate of absorption depends on the rate of gastric emptying. Heading and colleagues [8] demonstrated a significant correlation between the half-time of gastric emptying, measured by sequential gamma scintiscanning of the stomach, and plasma paracetamol concentrations. Therefore, the reduction in mean plasma paracetamol concentrations in the 12-14 weeks pregnant patients, in the present study, represented a delay in gastric emptying. The smaller area under the
PREGNANCY AND GASTRIC EMPTYING
27
plasma paracetamol concentration-time curve in We are grateful to Professor W. S. Nimmo (University these subjects reflected a reduction in paracetamol Department of Anaesthesia, Sheffield) for his advice on the absorption [9]. Although no statistically signi- preparation of this paper. ficant difference was demonstrated between the control and the 8-11 weeks pregnant patients, the REFERENCES values for the latter group were between the 12-14 1. Hytten FE. The alimentary system. In: Hytten FE, weeks and the non-pregnant values. Chamberlain GC, eds. Clinical Physiology in Obstetrics. Oxford: Blackwell Scientific Publications, 1980; 147-162. Inhalation of gastric contents remains an im2. Williams NH. The variable significance of heartburn. portant cause of anaesthetic mortality and morAmerican Journal of Obstetrics and Gynaecology 1941; 42: bidity [10]. Many studies have demonstrated 814-820. large volumes of acid stomach contents in patients 3. Hansen R. Zur physiologie des magens in der schwangerprepared for surgery. Hester and Heath [11] schaft. Zentralblatt fur Gynakologie 1937; 61: 2306-2309. 4. Boyden EA, Rigler LG. Initial emptying time of stomach reported that, after prolonged fasting, more than in primagravidae as related to evacuation of biliary tract. 40 ml of fluid was recovered from the stomach of Proceedings of the Society for Experimental Biology and one in eight patients presenting for elective Medicine 1944; 56: 200-201. surgery, and over half the patients had gastric 5. Hunt JN, Murray FA. Gastric function in pregnancy. contents with a pH of less than 2.5. More than Journal of Obstetrics and Gynaecology of the British Commonwealth 1958; 65: 78-83. 25 ml of acidic stomach fluid was aspirated from 6. Davison JS, Davison MC, Hay DM. Gastric emptying 66% of patients presenting for minor outpatient time in late pregnancy and labour. Journal ofOstetrics and operations [12]. As many patients undergo surgery Gynaecology of the British Commonwealth 1970; 77: during early pregnancy, it may be important to 37-41. determine whether significant gastric stasis is 7. Nimmo WS. Effect of anaesthesia on gastric motility and emptying. British Journal of Anaesthesia 1984; 56: present at this time. Although the present study 29-36. demonstrated delayed stomach emptying during 8. Heading RC, Nimmo J, Prescott LF, Tothill P. The pregnancy, it did not show whether this increased dependence of paracetamol absorption on the rate of the risk of aspiration of gastric contents. gastric emptying. British Journal of Pharmacology 1973; ACKNOWLEDGEMENTS We are grateful to the staff of the Department of Chemical Pathology, St James's University Hospital, Leeds: Dr Evans (Top Grade Biochemist) and Mr Altren (Senior Chief MLSO) for advice and encouragement during the study, and Mr Smith (Chief MLSO) and Mr Mallinson (Chief MLSO) for excellent technical assistance and development of the automated paracetamol assay from the Cambridge Life Sciences kit. The authors thank Mr D. R. Bromham and Mr G. J. Jarvis (Consultant Gynaecologists) for access to patients during this study.
47: 415-421. 9. Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. British Journal of Clinical Pharmacology 1980; 10: 291S-298S. 10. Lunn JN, Mushin WW. Mortality Associated with Anaesthesia. London: Nuffield Provincial Hospitals Trust, 1982. 11. Hester JB, Heath ML. Pulmonary acid aspiration syndrome: should prophylaxis be routine? British Journal of Anaesthesia 1977; 49: 595-599. 12. Ong BY, Palahniuk RJ, dimming M. Gastric volume and pH in outpatients. Canadian Anaesthetists Society Journal 1978; 25: 36-39.