STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA V: PETHIDINE 100 MG ALONE AND WITH ATROPINE OR HYOSCINE

Brit. J. Anaesth. (1964), 36, 703

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA V: PETHIDINE 100 MG ALONE AND WITH ATROPINE OR HYOSCINE BY

JOHN W. DUNDEE, JAMES MOORE AND RICHARD S. J. CLARKE

Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland SUMMARY

In a well controlled study of the emetic effects of some premedicants Riding (1960) found that morphine 5-10 mg increased the incidence of postoperative vomiting, retching and nausea. His results, based on observations made with a standard anaesthetic technique employed for a constant operation, also showed the value of atropine and hyoscine in reducing this undesirable action of the opiate. When evaluating the effects of various premedicants, the authors were impressed with the very high incidence of pre-operative vomiting and nausea which occurred when pethidine 100 mg was given alone. This appeared to be contrary to the commonly held opinion of this popular premedication and in view of Riding's findings it was felt that the difference might be accounted for by the common practice of giving pethidine in conjunction with atropine or hyoscine. This paper reports the findings of a comparison of the effects of pethidine 100 mg, alone and in combination with atropine 0.6 mg and hyoscine 0.4 mg. The study includes most of the readily observable pre-operative effects of these drugs, their effect on the course of methohexitone anaesthesia and the emetic sequelae observed after their use. METHOD

random order for premedication. Patients were observed at 20-minute intervals for the first hour after giving the drugs and again at 90 minutes (detailed studies), or else they were seen once, 60-90 minutes after the injection. The preference for multiple observations depended on whether one of the authors could spare the time to remain in the ward. At each visit, the sedative and side effects were assessed and scored according to the scheme described by Dundee, Moore and Nicholl (1962a). This is summarized as follows: Drowsiness. If the patient had fallen asleep, or spontaneously complained of being very sleepy, this state was classed as "good". At the other end of the scale were those who, on questioning, failed to admit to any degree of sleepiness, and the state here was classed as "nil". Other degrees of drowsiness were graded as "fair" or "slight" on an arbitrary basis. Apprehension. Patients who spontaneously complained of being "scared" of the operation or anaesthesia were classed as having "marked" apprehension. In the absence of such a remark they were asked directly if they were "worried about the operation", and on the basis of an affirmative reply and a further question as to whether the injection had decreased this fear, the degree of apprehension was classed as "moderate" or "slight". Restlessness or excitement. This was easily classified as "absent", "slight" or "marked". Side effects. These consisted of "local effects", referring to persistent pain at injection site, "dizziness" and "emetic effects". Pulse rates were classified as under 100 beats/min, 100-120 beats/min, 121-140 beats/ min, and 141 + beats/min, while a fall in systolic arterial pressure in excess of 20 mm Hg was noted.

Fit female subjects, scheduled for minor gynaecological operations, were given the drugs in 703

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Pethidine 100 mg has been studied alone and in combination with atropine or hyoscine. Pre-operatively there was a very high incidence of nausea or vomiting after pethidine which was diminished when atropine was given in conjunction and even more when hyoscine was added. Dizziness was also a common toxic effect in all three groups. As judged by lack of excitatory phenomena and hypotension during anaesthesia, pethidine with atropine was the combination of choice. Recovery was delayed in the group given pethidine and hyoscine but these patients had much the lowest incidence of postoperative emetic sequelae.

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BRITISH JOURNAL OF ANAESTHESIA TABLE I

Details of patients. Average age (yr)

Average weight (kg)

100 100 50

32.7 29.8 34.6

58.5 57.6 59.6

— —

250 350 150

32.4 30.5 32.5

59.8 58.0 57.9

— —

200 300 100

32.3 318 31.5

60.8 58.5 56.9

7.3 ± 0.25 8.1 ± 0.24 7.7 ± 0.31

The detailed observations pertain to the condition of the patients at the times of the observations, while the single observations (referred -to as index readings) include all side effects noted by the observer up to the time of the observation. It will be appreciated that the final total of index readings will include the patients on whom detailed observations have been made. In order to permit a comparison of the overall effects of the premedicants, the desired effects have been scored on an arbitrary scale (efficacy score) varying from 5 (good sedation with no apprehension or excitement) to 1 (no sedation with marked apprehension), while side effects (toxic score) were graded from 1 (nil) to 5 (patient unmanageable or other severe side effects). More observations were made in the preoperative phase than were made of the effects of premedication on the course and sequelae of methohexitone anaesthesia (table I). This is because some patients were included in other studies (Dundee, 1963) and were given other intravenous agents. Anaesthesia was induced with methohexitone 1.6 mg/kg and maintained with 75 per cent nitrous oxide in oxygen. Further doses of the barbiturate were injected as required to maintain an even level of anaesthesia. The observations made during anaesthesia and a method of classifying these have been listed and described by Dundee, Moore and Nicholl (1962b). In this way a com-

parison could be made of the overall effects of the premedicant drugs. In order to validate comparisons of the incidence and severity of postoperative emetic symptoms, each series of patients contained an equal number having cervical dilatation and curettage and having uterine curettage or similar operation without preliminary dilatation of the cervix. Patients were interviewed at 1 hour and again 6 hours after anaesthesia and the presence or absence of emetic sequelae recorded according to the method of Dundee, Nicholl and Moore (1962). It can be seen from table I that each aspect of the action of the drugs was studied on groups of patients which were broadly comparable as regards age and weight. The average duration of anaesthesia was also similar in each series. RESULTS

Premedication. Table II demonstrates the superior action of the pethidine-hyoscine combination, both in producing drowsiness and in allaying apprehension, as compared with pethidine alone or with atropine. It was surprising to find a significantly higher incidence of marked drowsiness with pethidineatropine than when the antisialogogue was omitted; this was undoubtedly due to their sleep being disturbed by the high incidence of vomiting. Dizziness was frequent with all three forms of premedication, but, except with pethidine alone, it was usually so mild as not to upset the affected

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Pre-operative evaluation Detailed studies Pethidine Pethidine + atropine Pethidine + hyoscine Indices only Pethidine Pethidine + atropine Pethidine + hyoscine Anaesthetic and postoperative evaluation Pethidine Pethidine + atropine Pethidine + hyoscine

No. of patients

Average duration of anaesthesia (min)

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—V

705

TABLE II

Comparison of pethidine. petliidine + atropine, and pethidine + hyoscine (percentages) 60-90 minutes after intramuscular injection. Pethidine Pethidine

44 32 21

66 26 8

26 7 2

22 10 1

26 2 2

2

1

6

42 17

49 6

50 8

34 12

24 3

22 4

16 6 0 4

34 14 6 1

24 4 0 8

4 12 28 35 21 3.57

2 7 22 32 37 3.95

0 3 13 34 50 4.31

24 22 32 16 6 2.58 + 0.99

22 35 29 12 2 2.37 + 1.58

22 32 30 12 4 2.44 + 1.87

Dizziness Slight Marked Emetic symptoms Nausea Vomiting Tachycardia 100-120 121-140 141 + Hypotension (20 ram Hg) Efficacy score 1

2

3 4 5 Mean

4

5 Mean Net mian score

+

hyoscine

28 45 20

Pain at injection site

Toxicity score 1 2 3

atropine

Pethidine

patients who only noticed it when they lifted their heads. Atropine and hyoscine were equally effective in reducing the pre-operative emetic effects of pethidine, but vomiting was reduced more than nausea. Atropine, and to a much lesser degree hyoscine, increased the tachycardia following the injection of pethidine. Pre-operative hypotension was infrequent with all combinations studied and only with pethidine-hyoscine was its incidence of clinical importance. Although the overall desired effect of the combination of pethidine with atropine, as judged by

the average score, was slightly better than that of pethidine alone, the difference in distribution of scores is not quite statistically significant (x* = 7.16; df = 3; 0.10>P>0.05). On the same basis pethidine-hyoscine was better than pethidine alone (xJ = 24.16; d f = 3 ; P<0.0005), but not significantly different from pethidine atropine (x* = 7.26; df = 3; 0.10>P>0.05). There is no significant difference between the average or the distribution of the scores with the three premedicants. On the basis of the net scores (efficacy less toxic) the overall effects of the drugs have been

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Drowsiness Good Fair Slight Apprehension Slight Marked Excitement or restlessness

+

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PETHIDINE

EFFECT %

PETHIDINE-ATROPINE PETHIDINE-HYOSCINE

ICKh

DROWSINESS

50-

APPREHENSION DIZZINESS • EMETIC EFFECTS

HEART RATE

40-

(H

MINUTES AFTER INJECTION

20

40 60 90

20

40 60 90

20 40 60 90

FIG. 1 Comparison of pcthidine, pethidine-atropine and pethidine-hyoscine at 20, 40, 60, and 90 minutes after injection. Solid column : Hatched column : Drowsiness Good or fair Slight Apprehension Moderate or marked Slight Dizziness Marked Slight Emetic effects Vomiting Nausea Heart rate 120+ 100-120

GO

55

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—V grouped in table HI. The distribution of net scores showed pethidine to be significantly worse than pethidine-atropine (x2 = 21.45; df = 6; P<0.005) or pethidine-hyoscine (,Y2 = 31.57; df=6; P < 0.0005), but the combinations of pethidine with either antisialogogue do not differ (x2 = 3.02; df = 5; 0.7>P>0.6).

707

cardia was apparent 20 minutes after injection and the peak effect occurred after 40 minutes, and persisted for over an hour.

TABLE IV

Dosage and complications of anaesthesia with methohexitone after pethidine, pethidine + atropine, and pethidine + hyoscine. Pethidine Pethidine + hyoscine + atropine Pethidine Average dosage (mg/kg) Induction

1.56 2.14 ±0.045

1.56 2.02 + 0.044

1.58 2.19 ±0.065

Course of anaesthesia % excitatory phenomena Respiratory upset Hypotension 20 mm Hg +

6 42 14

7 24 16

17 18 24

Grade of anaesthesia 1 2a 2b 3

49 37 12 2

64 26 8 2

61 16 14 9

43 . 44 13

60 32 8

28 53 19

Total

Condition at end Awake Safe Unsafe

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Course of anaesthesia. The important findings with the three premedicants are listed in table IV. The addition of hyoscine (but not atropine) significantly increases the incidence of excitatory phenomena with methoTABLE III hexitone. Either antisialogogue, particularly hyosPercentage incidence of overall effects of the three premedications as judged by net scores (efficacy score cine, decreases the incidence of hiccough to a significant degree. less toxic score). Arterial hypotension was much more frequent Overall Pethidine Pethidine Net Pethieffect scores dine + atropine + hyoscine with pethidine-hyoscine than with either of the two premedicants. The hypotensive index (DunGood + 4& +3 16 29 35 dee, 1963) (which takes into account both the Fair + 2& +1 47 49 49 severity and duration of the blood pressure fall) Poor 19 0& - 1 31 15 is very much greater with pethidine-hyoscine Undesirable - 2 + 6 1 3 (32.1) than with pethidine-atropine (19.1) or pethidine alone (18.0). Figure 1 summarizes the findings of the detailed The overall course of anaesthesia, as judged by studies. When combined with pethidine the super- the distribution of grades, was significantly better iority of hyoscine, as compared with atropine, in after pethidine-atropine than after pethidine producing drowsiness was not obvious until 40 alone (x 2 = 12.95; df = 2; P<0.005) or pethidineminutes after injection. Both dizziness and nausea hyoscine (x 2 = 13.16; df = 2; P<0.005). Although and/or vomiting were early side effects of pethi- pethidine-hyoscine showed a significantly better dine and there was little to choose between the distribution of grades of anaesthesia (determined ability of either antisialogogue to decrease the by x2 or ridit analysis) than pethidine alone, the incidence. As in the previous study with atropine high incidence of grade 3 anaesthesia (defined as alone (Clarke, Dundee and Moore, 1964), tachy- serious difficulties which, if untreated, make sur-

708

BRITISH JOURNAL OF ANAESTHESIA hour after operation in patients premedicated with pethidine (table V). There was no significant difference in the sequelae from the three premedicants during the 1-6 hours period after anaesthesia. Pethidine-hyoscine, but not pethidineatropine, was followed by a significantly lower incidence (P<0.05) of vomiting during the first 6 hours after anaesthesia as compared with pethidine alone, but the overall incidence of nausea was the same for all drugs studied. Both antisialogogues, but especially hyoscine, reduced the severity of emetic symptoms in sick patients during the period of this study.

TABLE V

Percentage incidence of emetic sequelae and average emetic scores following methohexitone anaesthesia and different premedications. Time after the end of the operation First hour

1-6 hrs.

N Pethidine Pethidine + atropine Pethidine + hyoscine

23 16

12 14

5

9

First 6 hours

N

23 21 19

20 18 17

34 30 20

N

Nil

Average score

Average score sick patients only

21 19 20

45 51 60

2.56 2.18 1.22

4.70 4.17 3.05

V=vomiting (including retching); N = nausea alone.

TABLE VI

Summary of the effects of the three premedicants studied. Pethidine alone Pre-operative Sedation Dizziness Emetic symptoms Tachycardia Anaesthesia Excitatory phenomena Hiccough Hypotension Delay in recovery Emetic Sequelae Vomiting Nausea

Pethidine + atropine

Pethidine + hyoscine

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gery impossible or place the patient's life in jeopardy) after this premedication should be noted. There seems little doubt that the use of hyoscine delayed recovery from methohexitone anaesthesia. The lower incidence of cases awake 2 minutes after the end of anaesthesia following pethidine as compared with pethidine-atropine was probably due to the larger doses of methohexitone given in the former series in an attempt to control the high incidence of hiccough. Sequelae. Hyoscine, and to a much lesser extent atropine, reduced the incidence of vomiting during the first

STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA—V DISCUSSION

there are other reasons why it should not be given. It should also be remembered that there are factors other than premedication which will influence postoperative vomiting, and these are not likely to be affected by the choice of antisialogogue. It must not be assumed that the present findings can be applied directly to other narcotic premedicants, although the reported tendencies may persist with drugs other than pethidine. To carry out similar investigations with the many analgesics which are currently available, and also with doses of pethidine different from those in the present study, would entail many years of work, which the findings are not likely to justify. The authors are currently investigating the use of atropine and hyoscine with an analgesic (morphine) which has been found to cause emetic symptoms of much later onset than pethidine. These findings, when available, combined with those of the present study should provide sufficient information to cover most of the analgesic drugs likely to be used in premedication. It is important to bear the present findings in mind when assessing the relative merits of new premedicants. In critically surveying the claims for such drugs, it is essential to note whether these were given alone or with atropine or hyoscine. Unfortunately such information is not always recorded in publications, and its omission may give misleading impression of the drug. ACKNOWLEDGMENTS

Our thanks are due to the nursing, theatre and gynaecological staff of Musgrave Park Hospital, Balmoral, without whose co-operation this study would not have been possible. REFERENCES

Clarke, R. S. J., Dundee, J. W., and Moore, J. (1964). Studies of drugs given before anaesthesia. IV: Atropine and hyoscine. Brit. J. Anaeslh., 36, 648. Dundee, J. W. (1963). Clinical studies of induction agents. VII: A comparison of eight intravenous anaesthetics as main agents for a standard operation. Brit. J. Anaesth., 35, 784. Armstrong, C. A. G., and Alexander, J. P. (1964). Clinical studies of induction agents. VIII: A comparison of the effects of atropine and hyoscine on the course and sequelae of thiopentone anaesthesia Brit. J. Anaesth., 36, 39. Moore, J., and Nicholl, R. M. (1962a). Studies of drugs given before anaesthesia. I: A method of pre-operative assessment Brit. J. Anaesth.. 34, 458.

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For the sake of clarity, the findings concerning the various aspects of the actions of the three forms of premedication have been summarized in table VL From the pre-operative view, the most important finding was the unexpectedly high incidence of dizziness, nausea and vomiting with pethidine alone and the evidence of the anti-emetic action of atropine and hyoscine. This is worthy of note in view of the current feeling against the use of atropine. For choice of premedicant before an anaesthetic technique which does not involve intermittent intravenous anaesthesia, pethidinehyoscine would seem to be the combination of choice. A disadvantage of this mixture which would not be shown in this study is the danger of severe bradycardia after repeated suxamethonium. There is also the reputed undesirable effect of hyoscine in elderly patients (Wylie and ChurchillDavidson, 1960) although Pedersen (1963) found this was not very severe and consisted of confusion rather than restlessness. In both this and a previous paper comparing atropine, hyoscine and a placebo (Clarke, Dundee and Moore, 1964), the highest incidence of hypotension before and during anaesthesia occurred when hyoscine was used. The observations made during anaesthesia might not appear to have much relevance to routine clinical practice but similar techniques are often used in outpatient surgical procedures. The high incidence of hiccough if atropine is omitted, and of excitatory phenomena if hyoscine is given, would be of clinical significance if the drugs were given before an intravenous-inhalation sequence. Under these circumstances pethidine-atropine is the most satisfactory of the three premedications. The finding that hyoscine is a comparatively short acting anti-emetic in the circumstances of this investigation, and that its effect is mostly in evidence during the first hour after anaesthesia is in keeping with the observations of Dundee, Armstrong and Alexander (1964) using thiopentone. They found that this applied when the antisialogogue was combined with pethidine or papaveretum and that vomiting was more affected than nausea. Thus the postoperative anti-emetic effect of hyoscine was not found to be a sufficiently strong reason for the authors to recommend the use of this drug in preference to atropine, when

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710 Dundee, J. W., Moore, J., and Nicholl, R. M. (1962b). Studies of drugs given before anaesthesia. II: A method for the assessment of their influence on the course of anaesthesia. Brit. J. Anaesth., 34, 523. Nicholl, R. M., and Moore, J. (1962). Studies of drugs given before anaesthesia. Ill: A method for the studying of their effects on postoperative vomiting and nausea. Brit. J. Anaesth., 34, 527. Pedersen, J. E. P. (1963). Scopolamine as sole preanaesthetic medication. Ada anaesth. scand., 7, 121. Riding, J. E. (1960). Postoperative vomiting. Proc. roy. Soc. Med., 53, 671. Wylie, W. D., and Churchill-Davidson, H. C. (1960). A Practice of Anaesthesia. London: Churchill.

SOMMAIRE

La dose de pe'thidine de 100 mg a 6li e'tudie'e seule et en association avec l'atropine ou l'hyoscine. Avant Pope'ration il y avait frequemment des nause'es et des vomissements apres administration de pe'thidine qui diminuaient si l'atropine et plus encore si l'hyoscine dtait associe'e. Des troubles de la conscience repre'sentaient d'autre part un effet toxique commun dans

UNTERSUCHUNG VON DROGEN FUR DIE PRAM EDUCATION. V: PETHIDIN 100 MO ALLEIN UND ZUSAMMEN MIT ATROPIN ODER SKOPOLAMIN ZUSAMMENFASSUNO

Es wurden Untersuchungen tiber Pethidin 100 mg allein und in {Combination mit Atropin oder Skopolamin vorgenommen. Nach Pethidin kam es pra'operativ sehr hSufig zu Ubelkeit oder Erbrechen, nach Zugabe von Atropin wurde die Hflufigkeit verringert und nach Zugabe von Skopolamin in noch hoherem MaCe. Bei alien drei Gruppen war Benommenheit eine haufige toxische Nebenwirkung. Wegen des Mangels an Exzitationszeichen und Hypotension wShrend der AnSsthesie ist Pethidin mit Atropin die Kombination der Wahl. Bei den Gruppen, die Pethidin und Skopolamin erhielten, war das Erwachen verzSgert, aber bei diesen Patienten kam es nur sehr selten zu postoperativen Erbrechen.

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ETUDE DES DROGUES ADMINISTREES AVANT L'ANESTHESIE. V: 100 MO DE PETHIDINE SEULE ET AVEC L'ATROPINE OU L'HYOSCINE

les trois groupes. II ressort de l'absence des phe'nome'nes d'excitation et d'hypotension au cours de l'anesthe'sie que la pe'thidine constitue avec l'atropine l'association de choix. La remission e'tait retardde dans les groupes ayant recu de la p^thidine avec hyoscine, mais ces mfimes malades pre'sentaient de loin le moins de vomissements postope'ratoires.