ANESTH A N A L C 58:3%-4W, 1979
Lomparison of Domperidone, Droperidol, and Metoclopramide in the Prevention and Treatment of Nausea and Vomiting after Balanced General Anesthesia K. Korttila, MD,* A. Kauste, MD,? and J. Auvinen, M Pharm$ KORTTILA,K., KAUSTE,A., AND AUVINEN, J: Comparison of domperidone, droperidol, and metoclopramide in the prevention and treatment of nausea and vomiting after balanced general anesthesia. Anesth Analg 58:396-400, 1979. Women (185) undergoing elective orthopedic surgery under balanced general anesthesia were given 5 or 10 mg of domperidone, 1.25 mg of droperidol, 10 rng of metoclopramide, or a saline placebo intravenously in a double-blind random fashion 5 minutes before the end of anesthesia to prevent postoperative vomiting. Administration of the same antiemetic was repeated intramuscularly during the first 24 hours postoperatively if the patient complained of nausea or retched or vomited. Significantly ( p c 0.05 to p < 0.001), fewer of the patients given droperidol were nauseated (25%) or vomited (1 7%) in comparison with patients given saline (incidence of nausea was 55% and vomiting 40%). Incidences of nausea and vomiting were similar in patients given domperidone, metoclopramide, or saline. Furthermore, 39 to 45% of the patients given domperidone, metoclopramide, or saline needed additional doses of the same drug, whereas only 22% of the patient given droperidol required a second dose. It is concluded that droperidol is effective in the prevention and treatment of postoperative nausea and vomiting after balanced general anesthesia but that domperidone or metocloprarnide are not. Key Words: VOMITING: antiemetics.
P
OSTOPERATIVE nausea and vomiting are quite
Domperidone is a new benzimidazole antiemetic.
common after general anesthesia,'"l and the prophylactic administration of antiemetics has been suggested for those patients most prone to ~ o m i t i n g . ~
It is assumed to prevent and treat nausea and vomiting
Associate Professor of Experimental Anesthesiology, Department of Anesthesia, Helsinki University Central Hospital. t Anesthetist, Department of Anesthesia, Surgical Hospital, Helsinki University Central Hospital. $ Orion Pharmaceutical Company, Helsinki. Received from the Department of Anesthesia, Helsinki University Central Hospital, Helsinki 29, Finland; and Orion Pharmaceutical Company, Helsinki 51,Finland. Accepted for publication June 9, 1979. Reprint requests to Dr. Korttila, Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242.
396
ANESTHESIA AND ANALGESIA VOI 58, NO 5. Sept-Oct 1979
by increasing the motility of the upper gastrointestinal tract and by having a direct antiemetic effect on the chemoreceptor trigger zone 5*6 It has been reported to be effective in the treatment of chronic dyspepsia7 and in the prevention of postoperative nausea and vomiting.6 In this study, we have compared the antiemetic efficacy of domperidone in the prevention and treatment of postoperative nausea and vomiting to that of droperidol and metoclopramide, both of which have previously been reported to decrease the incidence of postoperative nausea and
KORTTILA, KAUSTE, AND AUVINEN Materials and Methods Patients and Anesthesia We studied 185 women undergoing elective orthopedic surgery (Table 1). All of the patients belonged to A.S.A. class 1-11 and during the 2 weeks prior to the operation none had taken any drugs with an antiemetic action. Informed consent was obtained from each patient. For premedication, all patients received 0.15 mg/kg of oxycodone chloride intramuscularly for 40 to 60 minutes and 0.01 mg/kg of atropine intravenously for 5 minutes before the induction of anesthesia. Anesthesia was induced with a sleep dose of thiopental and maintained by supplementation of nitrous oxide-oxygen (33%)with fentanyl and alcuronium chloride to provide adequate analgesia and muscle relaxation. Endotracheal intubation was facilitated by 1.5mg/kg of succinylcholine after a small “precurarizing dose” of alcuronium. At the end of anesthesia, 0.03 mg/kg of neostigmine chloride was given with atropine, 0.015 mg/kg, to reverse the muscle relaxation. For moderate to severe postoperative pain, oxycodone chloride, 0.15 mg/kg was given intramuscularly. Administration of Antiemetics Five minutes before the end of anesthesia, the patients were given intravenously a 2-ml solution which consisted of 5 or 10 mg of domperidone (R 33 812,Janssen, Beerse), 1.25 mg of droperidol, 10 mg of metoclopramide (Emperal, Neofarma, Seinajoki), or a saline placebo in a double-blind randomized fashion. In addition to the prophylactic administration of the antiemetics, the same antiemetic, in the same amount, was given intramuscularly if the patient complained of nausea or retched or vomited during the first 24 postoperative hours. If the test drug did not allevaite emesis even though the dose had been repeated once, the patients were TABLE 1 Characteristicsof the Test Groups (meens f Treatment
No. of patients
Domperidone, 5 mg Domperidone, 10 mg Droperidd, 1.25mg Metoc~amide,lOmg Saline
36 36 36 37 40
p
given 1.25 mg of droperidol 30 minutes after the second intramuscular dose of the test drug. To determine the effects of the three antiemetics studied on emergence from anesthesia, we measured the time elapsed after the cessation of nitrous oxide administration until the patients opened their eyes after repeated commands. Side effects were registered during the first 2 postoperative hours in the recovery room by monitoring the patients’ consciousness, muscle activity, respiration, circulation, and color every 15 minutes.” During the subsequent 22 hours in the ward, these functions were monitored every 2 hours and every 30 minutes for the 2 hours following a possible administration of additional doses of antiemetics. Assessment of Emetic Sequelae The incidence of nausea and vomiting was determined for the first 24 hours after operation at different intervals: 0 to 3, 3 to 6,6 to 12, 12 to 18,and 18 to 24 hours. At the end of each interval, a trained nurse registered whether retching or vomiting had occurred and asked the patients whether they felt nauseated. The results were scored in a manner similar to that of Bellville et all2 (0 = none, 1 = nausea, 2 = retching, 3 = vomiting). Statistics Student’s t-test was used for the comparisons made between the characteristics of the patients and anesthesia. The chi-square test was used to compare the efficacy of the antiemetics because of the nonparametric nature of the data.
The principal result was that only droperidol decreased the incidence of nausea and vomiting when compared to the saline placebo; domperidone or metoclopramide did not.
SD) Weight
Height
Duration of anesthesia
Yr
kg
cm
min
40f13 42f13 43f14 41 f14 41 f 1 3
61 f 10 64f10 64f12 61 f 1 0 62f10
162f5 161 f 6 163f7 162f6 162f6
94 f30 76f28 107f42’ 85*28 95f51
Thiopentel mg
347f68 347f56 350-+75 339f71 334f51
Akuronium mg
19f4 18f3 21 f 5 17f3 l9f4
Fentanyl mg
0.29f0.10 0.27f0.16 0.33f0.11 0.25f0.08 0.31 f0.17
c 0.05vs domperidone, 10 mg,and vs metoclopramide. ANESTHESIA AND ANALGESIA V O l 5 8 . NO 5. Sept-Oa 1979
397
POSTOPERATIVE ANTIEMETICS
The amount of thiopental needed for induction was similar in each group, as were the amounts of alcuronium required for muscle relaxation and the doses of fentanyl and oxycodone administered for operative and postoperative pain, respectively (Tables 1and 2). The duration of anesthesia and the time elapsed until the patients opened their eyes at the end of anesthesia were longest in patients given droperidol (Tables 1 and 2). No clinically significant side effects were observed in any patient after the administration of any of the antiemetics, either in the recovery room or in the ward. Fig 1 shows the incidence of emetic sequelae during the 24-hour follow-up period in the different test groups. Significantly fewer of the patients given droperidol felt nauseated (25%) or vomited (1Wo) in comparison with control patients given saline (inciTABLE 2 Postopemtive Awakening and Amount of Postoperative Analgesia (Oxycodone) Needed in Flrst 24 Hours (means f SO) Treatment
Oxycodone
Eyes open
min
Domperidone, 5 mg Domperidone. 10 mg Droperidoi, 1.25 mg Metoclopramide, 10 mg Saline
mg
2.03 f 1.95 f 2.48 f 1.49 f 1.45 f
1.87 1.43 1.70' 0.59 0.75
23 f 10 24 f 9 22 f 15 24 f 10 2 0 f 10
10
50
60
1
I
1
< 0.05 vs saline.
p
10
I
20 I
30
'10 ,
l=NAUSEA 2=RETCHING (meansf SE )
0 0
DOMPERIDONE 5rng DOMPERIDONE lOmg DROPERIDOL 1.25rng METOCLOPRAMIDE 10m! SALINE
v)
u' I-
W
I
W
0
TIME (h) FIG 2. Postoperative emetic score as a function of time after balanced general anesthesia in patients undergoing elective orthopedic surgery.
dence of nausea was 55% and of vomiting 40%). The incidences of nausea and vomiting in patients given domperidone or metoclopramide were similar to those in control patients. As shown in Fig 2, nausea and vomiting were most common between 3 and 12 hours after anesthesia. As shown in Fig 3, 39 to 45% of the patients given domperidone, metoclopramide, or saline needed additional doses of the same drug, while only 22% of the patients given droperidol needed a repeated dose. None of the patients receiving droperidol as a blind drug needed to be given additional droperidol as a known antiemetic because of failure of the blind drug to prevent or treat emetic symptoms; however, 8 to 14%of the patients given domperidone, metoclopramide, or saline as the blind drug were also given an additional dose of droperidol (Fig 3).
Discussion In our present investigation, only droperidol significantly decreased the incidence of postoperative nausea and vomiting in comparison to the corresponding incidence after a saline placebo. Nausea and vomiting were not reduced by either domperidone or metoclopramide.
Trial Design m N o u s e o
* ** ***
Pe0.05 P
Lomparison of Domperidone, Droperidol, and Metoclopramide in the Prevention and Treatment of Nausea and Vomiting after Balanced General Anesthesia K. Korttila, MD,* A. Kauste, MD,? and J. Auvinen, M Pharm$ KORTTILA,K., KAUSTE,A., AND AUVINEN, J: Comparison of domperidone, droperidol, and metoclopramide in the prevention and treatment of nausea and vomiting after balanced general anesthesia. Anesth Analg 58:396-400, 1979. Women (185) undergoing elective orthopedic surgery under balanced general anesthesia were given 5 or 10 mg of domperidone, 1.25 mg of droperidol, 10 rng of metoclopramide, or a saline placebo intravenously in a double-blind random fashion 5 minutes before the end of anesthesia to prevent postoperative vomiting. Administration of the same antiemetic was repeated intramuscularly during the first 24 hours postoperatively if the patient complained of nausea or retched or vomited. Significantly ( p c 0.05 to p < 0.001), fewer of the patients given droperidol were nauseated (25%) or vomited (1 7%) in comparison with patients given saline (incidence of nausea was 55% and vomiting 40%). Incidences of nausea and vomiting were similar in patients given domperidone, metoclopramide, or saline. Furthermore, 39 to 45% of the patients given domperidone, metoclopramide, or saline needed additional doses of the same drug, whereas only 22% of the patient given droperidol required a second dose. It is concluded that droperidol is effective in the prevention and treatment of postoperative nausea and vomiting after balanced general anesthesia but that domperidone or metocloprarnide are not. Key Words: VOMITING: antiemetics.
P
OSTOPERATIVE nausea and vomiting are quite
Domperidone is a new benzimidazole antiemetic.
common after general anesthesia,'"l and the prophylactic administration of antiemetics has been suggested for those patients most prone to ~ o m i t i n g . ~
It is assumed to prevent and treat nausea and vomiting
Associate Professor of Experimental Anesthesiology, Department of Anesthesia, Helsinki University Central Hospital. t Anesthetist, Department of Anesthesia, Surgical Hospital, Helsinki University Central Hospital. $ Orion Pharmaceutical Company, Helsinki. Received from the Department of Anesthesia, Helsinki University Central Hospital, Helsinki 29, Finland; and Orion Pharmaceutical Company, Helsinki 51,Finland. Accepted for publication June 9, 1979. Reprint requests to Dr. Korttila, Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242.
396
ANESTHESIA AND ANALGESIA VOI 58, NO 5. Sept-Oct 1979
by increasing the motility of the upper gastrointestinal tract and by having a direct antiemetic effect on the chemoreceptor trigger zone 5*6 It has been reported to be effective in the treatment of chronic dyspepsia7 and in the prevention of postoperative nausea and vomiting.6 In this study, we have compared the antiemetic efficacy of domperidone in the prevention and treatment of postoperative nausea and vomiting to that of droperidol and metoclopramide, both of which have previously been reported to decrease the incidence of postoperative nausea and
KORTTILA, KAUSTE, AND AUVINEN Materials and Methods Patients and Anesthesia We studied 185 women undergoing elective orthopedic surgery (Table 1). All of the patients belonged to A.S.A. class 1-11 and during the 2 weeks prior to the operation none had taken any drugs with an antiemetic action. Informed consent was obtained from each patient. For premedication, all patients received 0.15 mg/kg of oxycodone chloride intramuscularly for 40 to 60 minutes and 0.01 mg/kg of atropine intravenously for 5 minutes before the induction of anesthesia. Anesthesia was induced with a sleep dose of thiopental and maintained by supplementation of nitrous oxide-oxygen (33%)with fentanyl and alcuronium chloride to provide adequate analgesia and muscle relaxation. Endotracheal intubation was facilitated by 1.5mg/kg of succinylcholine after a small “precurarizing dose” of alcuronium. At the end of anesthesia, 0.03 mg/kg of neostigmine chloride was given with atropine, 0.015 mg/kg, to reverse the muscle relaxation. For moderate to severe postoperative pain, oxycodone chloride, 0.15 mg/kg was given intramuscularly. Administration of Antiemetics Five minutes before the end of anesthesia, the patients were given intravenously a 2-ml solution which consisted of 5 or 10 mg of domperidone (R 33 812,Janssen, Beerse), 1.25 mg of droperidol, 10 mg of metoclopramide (Emperal, Neofarma, Seinajoki), or a saline placebo in a double-blind randomized fashion. In addition to the prophylactic administration of the antiemetics, the same antiemetic, in the same amount, was given intramuscularly if the patient complained of nausea or retched or vomited during the first 24 postoperative hours. If the test drug did not allevaite emesis even though the dose had been repeated once, the patients were TABLE 1 Characteristicsof the Test Groups (meens f Treatment
No. of patients
Domperidone, 5 mg Domperidone, 10 mg Droperidd, 1.25mg Metoc~amide,lOmg Saline
36 36 36 37 40
p
given 1.25 mg of droperidol 30 minutes after the second intramuscular dose of the test drug. To determine the effects of the three antiemetics studied on emergence from anesthesia, we measured the time elapsed after the cessation of nitrous oxide administration until the patients opened their eyes after repeated commands. Side effects were registered during the first 2 postoperative hours in the recovery room by monitoring the patients’ consciousness, muscle activity, respiration, circulation, and color every 15 minutes.” During the subsequent 22 hours in the ward, these functions were monitored every 2 hours and every 30 minutes for the 2 hours following a possible administration of additional doses of antiemetics. Assessment of Emetic Sequelae The incidence of nausea and vomiting was determined for the first 24 hours after operation at different intervals: 0 to 3, 3 to 6,6 to 12, 12 to 18,and 18 to 24 hours. At the end of each interval, a trained nurse registered whether retching or vomiting had occurred and asked the patients whether they felt nauseated. The results were scored in a manner similar to that of Bellville et all2 (0 = none, 1 = nausea, 2 = retching, 3 = vomiting). Statistics Student’s t-test was used for the comparisons made between the characteristics of the patients and anesthesia. The chi-square test was used to compare the efficacy of the antiemetics because of the nonparametric nature of the data.
The principal result was that only droperidol decreased the incidence of nausea and vomiting when compared to the saline placebo; domperidone or metoclopramide did not.
SD) Weight
Height
Duration of anesthesia
Yr
kg
cm
min
40f13 42f13 43f14 41 f14 41 f 1 3
61 f 10 64f10 64f12 61 f 1 0 62f10
162f5 161 f 6 163f7 162f6 162f6
94 f30 76f28 107f42’ 85*28 95f51
Thiopentel mg
347f68 347f56 350-+75 339f71 334f51
Akuronium mg
19f4 18f3 21 f 5 17f3 l9f4
Fentanyl mg
0.29f0.10 0.27f0.16 0.33f0.11 0.25f0.08 0.31 f0.17
c 0.05vs domperidone, 10 mg,and vs metoclopramide. ANESTHESIA AND ANALGESIA V O l 5 8 . NO 5. Sept-Oa 1979
397
POSTOPERATIVE ANTIEMETICS
The amount of thiopental needed for induction was similar in each group, as were the amounts of alcuronium required for muscle relaxation and the doses of fentanyl and oxycodone administered for operative and postoperative pain, respectively (Tables 1and 2). The duration of anesthesia and the time elapsed until the patients opened their eyes at the end of anesthesia were longest in patients given droperidol (Tables 1 and 2). No clinically significant side effects were observed in any patient after the administration of any of the antiemetics, either in the recovery room or in the ward. Fig 1 shows the incidence of emetic sequelae during the 24-hour follow-up period in the different test groups. Significantly fewer of the patients given droperidol felt nauseated (25%) or vomited (1Wo) in comparison with control patients given saline (inciTABLE 2 Postopemtive Awakening and Amount of Postoperative Analgesia (Oxycodone) Needed in Flrst 24 Hours (means f SO) Treatment
Oxycodone
Eyes open
min
Domperidone, 5 mg Domperidone. 10 mg Droperidoi, 1.25 mg Metoclopramide, 10 mg Saline
mg
2.03 f 1.95 f 2.48 f 1.49 f 1.45 f
1.87 1.43 1.70' 0.59 0.75
23 f 10 24 f 9 22 f 15 24 f 10 2 0 f 10
10
50
60
1
I
1
< 0.05 vs saline.
p
10
I
20 I
30
'10 ,
l=NAUSEA 2=RETCHING (meansf SE )
0 0
DOMPERIDONE 5rng DOMPERIDONE lOmg DROPERIDOL 1.25rng METOCLOPRAMIDE 10m! SALINE
v)
u' I-
W
I
W
0
TIME (h) FIG 2. Postoperative emetic score as a function of time after balanced general anesthesia in patients undergoing elective orthopedic surgery.
dence of nausea was 55% and of vomiting 40%). The incidences of nausea and vomiting in patients given domperidone or metoclopramide were similar to those in control patients. As shown in Fig 2, nausea and vomiting were most common between 3 and 12 hours after anesthesia. As shown in Fig 3, 39 to 45% of the patients given domperidone, metoclopramide, or saline needed additional doses of the same drug, while only 22% of the patients given droperidol needed a repeated dose. None of the patients receiving droperidol as a blind drug needed to be given additional droperidol as a known antiemetic because of failure of the blind drug to prevent or treat emetic symptoms; however, 8 to 14%of the patients given domperidone, metoclopramide, or saline as the blind drug were also given an additional dose of droperidol (Fig 3).
Discussion In our present investigation, only droperidol significantly decreased the incidence of postoperative nausea and vomiting in comparison to the corresponding incidence after a saline placebo. Nausea and vomiting were not reduced by either domperidone or metoclopramide.
Trial Design m N o u s e o
* ** ***
Pe0.05 P
