Brit. J. Anaesth. (1973), 45,493
HASTENING OF AROUSAL AFTER GENERAL ANAESTHESIA
WITH DOXAPRAM HYDROCHLORIDE
P. K. GUPTA AND J. W. DUNDEE
SUMMARY
A double-blind study was undertaken to determine the effect of doxapram hydrochloride on arousal after short general anaesthesia. Of a total of forty patients, twenty
were given doxapram hydrochloride at the end of anaesthesia. Doxapram injection
was associated with a significantly shorter mean arousal time than was placebo. No
differences in mean blood pressure or pulse rate occurred but the change in respiratory
minute volume in the group given doxapram was significantly higher. No complication
was observed in either group as a result of treatment.
In a review of central nervous stimulants, Adriani bodies (Kato and Buckley, 1964). Its effect in
(1960) commented that emphasis was being placed shortening the recovery time after general anaesthesia
upon the termination of narcosis following thiopen- has been intensively studied in America. Siker,
tone and similar drugs by means of an injection Mustafa and Wolfson (1964) reported that doxapram
of an analeptic at the conclusion of anaesthesia. lightened the level of consciousness and increased the
Various papers had been published about the arousal respiratory minute volume after thiopentone but that
effect of different analeptics after barbiturate anaes- there was no effect on blood pressure and pulse rate.
thesia (Gale, 1958; Waine and Dinmore, 1958; Wolfson, Siker and Gccarelli (1965), in a doubleRomagnoli and Diamond, 1961; Dobkin, Keil and blind study with three analeptics, found that methylAlbano, 1962). These include nikethamide, ethamivan phenidate had a marked pressor effect, vanillic acid
(vanillic acid diethylamide), methylphenidate, beme- and diethylamide had a marked arousal effect and
gride and Micoren (a combination of equal parts of doxapram had a marked respiratory stimulant effect.
ciopropamide and crotethamide). Recently attention Noe, Borrillo and Greifenstein (1965) observed some
has been focused on the use of doxapram for this degree of arousal and respiratory stimulation after
administration of doxapram in a group of 20 patients
purpose.
Doxapram hydrochloride (Dopram; Robins) is an anaesthetized with pentobarbitone or thiamylal folanaleptic with a marked arousal effect (Ward and lowed by nitrous oxide-oxygen-halothane. On the
Franko, 1962). Its chemical name is l-ethyl-4-(2- other hand, Evers and Dobkin (1967) described the
morpholinoethyl)-3,3 diphenyl-2-pyrrolidone. Figure stimulating effect of doxapram on blood pressure and
1 shows the structural formula. Doxapram is pre- respiration after thiopentone anaesthesia but found
pared as a dear colourless 2% aqueous solution with no arousal effect. They were, however, of the opinion
a pH of 3.5-5.0 and is stable at room temperature. that once the patient was awake, doxapram sustained
An infusion of 500 ml of 5% dextrose containing arousal and prevented return of sleep. Po, Watson
doxapram hydrochloride 2 mg/ml is available in this and Hansen (1968) also observed that doxapram 1.5
country. The drug acts mainly by direct stimulation mg/kg hastened the recovery after thiopentoneof the chemoreceptors of the carotid and aortic nitrous oxide-oxygen anaesthesia.
From the above reports it is evident that opinions
differ
in respect of the ability of doxapram to shorten
C6H5
the time of arousal after general anaesthesia but that
per. H2O none of the workers found any untoward reactions
after its administration. This paper reports a doubleblind study carried out to clarify these contradictory
C2H5
FIG. 1. Formula of doxapram hydrochloride.
P. K. GUPTA, MJ>., D.A.; J. W. DUNDEE, MJX, PH.D.,
F.F.A.R.C.S.; Department of Anaesthetics, Tht Queen's
University of Belfast, Northern Ireland.
BRITISH JOURNAL OF ANAESTHESIA
494
reports about the arousal effect of doxapram. The
standard clinical situation was a short general anaesthetic. Light premedication was followed by induction with a single dose of barbiturate followed by
nitrous oxide-oxygen-halothane with spontaneous
ventilation. The objective was to find whether doxapram shortened the period of depression from the
combined effect of premedication and barbiturate
induction and whether it hastened elimination of
halothane by stimulating the breathing, thereby producing a more rapid and sustained return of consciousness.
METHOD
The study was carried out in fit healthy females
coming for minor gynaecological operations. Following premedication with pethidine 50 mg and atropine
0.6 mg anaesthesia was induced with thiopentone
5 mg/kg, and maintained widi 75% nitrous oxide in
oxygen mixture with 2% halothane throughout the
surgical procedure. Adequate anaesthesia was present
when the patient tolerated swabbing of the vulval
region with the usual antiseptic solutions. At the end
of the operation the patient breathed oxygen for 1
minute. Blood pressure, and pulse rate were recorded
and respiratory minute volume measured by a Wright
respirometer. The patient's level of consciousness was
assessed as follows:
Level 0: awake and able to answer questions;
Level 1: asleep but rousable; Level 2: unconscious,
responding to painful stimuli and maintaining airway; Level 3: unconscious wih no reaction to stimuli
and requiring airway maintenance.
Forty patients whose level of consciousness was
graded as 3 at the 2nd minute after anaesthesia were
included in the study. Half were given doxapram
1 mg/kg intravenously and the remainder were
given saline. Medicaments were prepared by a nurse
who did not disclose their identity to the observer
until the end of the complete observation period.
Each treatment was given over a period of 1 min..
Immediately after completion of injection the
patient's level of consciousness was assessed and at
1-min intervals until consciousness returned. The
total time period required to reach level 0 was called
"recovery time". Blood pressure, pulse rate and
respiratory minute volume were noted before and
twice during the 5-min period after treatment. The
average of the two later readings of each parameter
was used for comparison with preinjection values.
Mean arterial blood pressure was calculated at each
observation time.
All patients were seen 1 hour after the end of
anaesthesia and the level of consciousness was
assessed again.
RESULTS
The mean age, weight and duration of anaesthesia
(table 1) show no statistical significant differences
between the two treatment groups. The same table
shows that the groups were comparable with respect
to pulse rate, blood pressure and respiratory minute
volume prior to injection of the test drug.
Table II shows that recovery times of the two
groups differed significantly. The average effects of
doxapram and saline on mean blood pressure and
heart rate were similar. However, the mean increase
in respiratory minute volume was significandy
higher in the patients given doxapram.
Figure 2 shows die minute-to-minute distribution
of die level of consciousness. It is evident diat die
recovery time after saline is spead over a period
of 2-17 min whereas after doxapram it is distributed
over a period of 2-10 min. At die 2nd minute after
treatment only 1 patient in the saline group had
recovered consciousness compared to 3 patients in
die doxapram group.
One hour after the end of anaesthesia 17 cases
TABLE I. Mean of the parameters recorded and number of patients in each treatment group.
Group
Anaesthesia followed
by saline
Anaesthesia followed
by doxapram
Difference between
groups 1 and 2
Number of
cases
20
20
t= 0.030
P>0.95
Age
(yr)
33.60
±2.23
33.70
±2.44
r=1.283
P>0.20
Weight
(kg)
64.55
±2.82
60.30
±2.00
I =0.20
P>0.98
Recorded before injecting the trial
drug after anaesthesia
Respiratory
Duration of
Mean blood
minute
pressure
anaesthesia Pulse rate
volume
(mm Hg)
(min)
(beats/min)
0./min)
9.40
77.30
89.30
±0.85
±1.73
80.20
±2.82
±2.64
87.55
±3.00
9.20
±0.75
t=0.020
P>0.40
t=0.876
P>0.40
r=0.452
P>0.70
6.300
±2.23
6.750
±2.33
r=0.150
P>0.90
HASTENING OF AROUSAL AFTER GENERAL ANAESTHESIA
495
TABLE II. Mean of recovery time and changes in mean blood pressure, pulse rate and respiratory minute volume in each group
during the 5 minutes after the injection of saline or doxapram (±SE).
Treatment
(1) Anaesthesia followed by saline
(2) Anaesthesia followed by doxapram
Difference between 1 and 2
Time taken to
recover after
treatment
(min)
7.20
±0.82
4.65
±0.58
r=2.34
P<0.025
Change in
mean blood
pressure
(mm Hg)
+ 1.70
±1.73
+2.15
±1.00
r=0.22
P>0.70
Change
in
pulse rate
(beats/min)
+3.75
±1.41
+0.70
±1.00
f = 1.70
P>0.10
Change in
respiratory
minute volume
(l./min)
+ 1.00
±0.024
+5.250
±0.95
t=4.4
P<0.0005
were drowsy. No patient in either group showed
any complication such as twitching, coughing or
sickness after treatment.
DISCUSSION
Dundee (1969) has noted that an important objective
of the study of new barbiturates is to seek a drug
characterized by a more rapid recovery from a comparable degree of anaesthesia than is thiopentone.
An alternative approach is to employ stimulant drugs
to hasten recovery from anaesthesia in which currently available barbiturates have been employed.
Reviewing the published work on the shortening of
thiopentone recovery time by analeptics, he noted
that methylphenidate 0.2-0.4 mg/kg appears to have
no toxic effect but bemegride causes tremors of the
jaws and extremities. Although ethamivan is a potenr
awakening agent after barbiturate anaesthesia, it produces sneezing, coughing, itching and laryngospasm
and patients tend to fall asleep again. In contrast,
doxapram 0.5 mg/kg hastens recovery from anaesthesia and increases the rate and depth of respiration
IO II
12 13 14 IS 16
with no reported side effects.
MINUTES
AJTER
INJECTION
In the present work it was found that doxapram
FIG. 2. Incidence of various grades of recovery in the
doxapram and saline groups.
given in the dose of 1 mg/kg body weight reduced
Solid area
= Level 3
the time of awakening to a significant extent. It
Stippled area = Level 2
produced little change in pulse rate and mean blood
Hatched area =Level 1
Clear area
= Level 0
pressure. This is in agreement with the work of
Siker, Mustafa and Wolfson (1964). It has also been
TABLE III. Distribution of patients in each treatment group shown here that once the patients are awake they do
according to the level of consciousness 1 hour after termination
not go back to sleep again, which is in agreement
of anaesthesia.
with the views of Evers and Dobkin (1967). The
Level of consciousness
0
1 2
3
most important observation was the marked increase
(1) Patients having saline
in respiratory minute volume after doxapram treatafter anaesthesia
17
3
0
0
ment which is in agreement with the findings of
(2) Patients having doxapram
after anaesthesia
18
2
0
0
all previous observers.
These findings should not be interpreted as a
of the saline group and 18 cases of the doxapram recommendation for the use of analeptic drugs at
group had maintained consciousness (table IH) while the end of general anaesthesia to hasten recovery.
3 in the saline group and 2 in the doxapram group Analeptic drugs neither accelerate destruction nor
I
BRITISH JOURNAL OF ANAESTHESIA
496
facilitate elimination of depressant drugs, and furthermore Eckenhoff and Dam (1958) have pointed out
that the administration of an analeptic necessitates
the elimination of two drugs. Stimulation of respiration at the end of a general anaesthetic may be
useful to speed up elimination of volatile agents
but the coughing and straining that often occur
are not conducive to smooth awakening. These side
effects were not observed after doxapram treatment
in the present study. The respiratory stimulation
by doxapram was consistent in this study but Siker,
Mustafa and Wolfson (1964) have shown that it is
transient after a single injection. Where required,
doxapram could be safely used to lighten narcosis
in a patient who is depressed after long administration of volatile anaesthetics or with a combination
of many depressant agents during anaesthesia. In
view of its safety it is worthy of further study as
a continuous infusion.
ACKNOWLEDGEMENTS
Doxapram (Dopram) was supplied by A. H. Robins and
Co. Ltd and we are grateful to this company and to Mr
F. S. Walker for their encouragement and support in this
study.
REFERENCES
Adriani, J. (1960). Editorial: Respiratory stimulants.
Anesthesiology, 21, 214.
Dobkin, A. B., Keil, A. M., and Albano, P. C. (1962).
Effect of Micoren, ethamivan and nikethamide on
thiopental recovery. Anesth. Analg. Curr. Res., 41, 58.
Dundee, J. W. (1969). Current views of the clinical
pharmacology of the barbiturates; in Newer Intravenous
Anesthetics (ed. R. S. J. Clarke). International Anesthesiology Clinics, 7, 3.
Eckenhoff, J. W., and Dam, W. (1958). The treatment
of barbiturate poisoning with or without analiptics.
Anesth. Analg. Curr. Res., 37, 174.
Evers, W., and Dobkin, A. B. (1967). Influence of doxapram hvdrochloride on recovery from thiopental anesthesia. N.Y. med. J., 67, 3236.
Gale, A. S. (1958). The effect of methylphenidate (Ritalin)
on thiopintal recovery. Amsthesiology, 19, 521.
Kato, H., and Buckley, J. P. (1964). Possible sites of action
of the resoirarory stimulant effect of doxapram hydrochloride. J. Pharmacol, exp. Ther., 144, 260.
Noe, F. W., Borrillo, N., and Greifenstein. F. E. (1965).
Use of a new analeptic doxapram hydrochloride during
general anesthesia and recovery. Anesth. Analg. Curr.
Res., 44, 206.
Po, B. T., Watson, R. L., and Hansen, H. R. (1968).
Arousal time following intravenous anesthetic agents
methohexital and thiopental: effect of doxaoram hydrochloride. Anesth. Analg. Curr. Res., 47, 446.
Romagnoli, A., and Diamond, M. J. (1961). Some trials
with vanillic diethylamide: a new analeptic. Canad.
Anaesth. Soc. J., 8, 551.
Siker, E. S., Mustafa, K., and Wolfson. B. (1964). The
analeptic effects of doxapram hydrochloride on thiopentone-induced depression. Brit. J. Anaesth., 36, 216.
Waine, T. E., and Dinmore, P. (1958). Thiopentone
anaesthesia terminated by bemegride. Anaesthesia, 13,
324.
Ward; J. W., and Franko, B. V. (1962). A new centrally
acting agent (AHR 619) with marked respiratory
•stimulating pressure and awakening effects. Fed. Proc.,
22, 325.
Wolfson, B., Siker, E. S., and Ciccarelli, H. E. (1965).
A double blind comparison of doxapram, ethamivan
and methylphenidate. Amer. J. med. Sci., 249, 391.
ACCELERATION DE L'EVEIL PAR LE
CHLORHYDRATE DE DOXAPRAM A LA SUITE
D"UNE ANESTHESIE GENERALE
SOMMAIRE
Une £tude en double-aveugle a 6tt entreprise en vue de
determiner quel est l'effet du chlorhydrate de doxapram
sur 1'eVeil, a la suite d'une anesthesie genirale de courte
duree. Sur un total de quarante malades, vingt de ceux-ci
ont recu du chlorhydrate de doxapram en fin d'anesthesie.
Par rapport au placebo, 1'injection de doxapram a entraini
un racourcissement de la moyenne du temps ecoul4 jusqu'a
l'iveil des malades. Aucune difference n'a iti notee en ce
qui concerne la pression arterielle moyenne ou la frequence
cardiaque; cependant, les modifications affectant la ventilation minute ont iti significativement plus cievees dans la
sirie traitfc par le doxapram. Que ce soit dans Tune ou
l'autre serie, aucune complication imputable au traitement
n'a 6t£ enregistree.
BESCHLEUNIGUNG DER AUFWACHZEIT NACH
ALLGEMEINNARKOSE MIT DOXAPRAM
HYDROCHLORID
ZUSAMMENFASSUNG
Es wurde ein doppelter Blindversuch untemommen, urn
die Wirkung von Doxapram-hydrochlorid auf die Aufwachzeit nach kurzen Allgemeinnarkosen zu bestimmen.
Von einer Gesamtzahl von 40 Patienten erhielten 20 am
Ende der Narkose Doxapramhydrochlorid. Die Doxapraminiektion ging mit einer wesentlich kiirzeren durchschnittlichen Aufwachzeit einher, als dies bei dem Placebo
der Fall war. Die durchschnittliclwn Blutdruckwerte und
die Pulsfrequenz wiesen keine Unterschiede auf. Die
Veranderungen des respiratorischen Minutenvolumens
waren iedoch bei der Grupp:, welche Doxapram erhielt,
eindeurig hoher. Es wurden in keiner der beiden Gruppen
Komplikationen als Folgen der Behandlung beobachtet.
ACTIVACION DEL DESPERTAR DESPUES DE
ANESTESIA GENERAL CON CLORURO DE
DOXAPRAM
RESUMEN
Se Uev6 a cabo un doble estudio ciego para determinar el
efecto del cloruro de doxapram sobre el despertar despues
de una anestesia general corta. De un total de cuarenta
enfennos, a veinte se les administro cloruro de doxapram
al final de la anestesia. La inyeccion de doxapram se
asociaba con un tiempo de despertar medio significativamente mas corto que con placebo. No se produjeron
diferencias de la presi6n arterial media o frecuencia del
pulso, pero en el grupo al que se aplico doxapram la
variaci6n del volumen minuto respiratono era considerablemente mayor. No se observaron complicaciones a causa
del tratamiento en ninguno de los grupos.