Brit. J. Anaesth.

(1971), 43, 1066

THE EFFECTS OF ATROPINE AND NEOSTIGMINE ON

HEART RATE AND RHYTHM
Recommendation for their use to reverse Residual Neuromuscular Block
BY
V. ROSNER, E. R. KEPES AND F. F. FOLDES

SUMMARY
Fifty patients anaesthetized with nitrous oxide-oxygen, supplemented by thiopentone
and pethidine, thiopentone and halothane, or droperidol and fentanyl, who received
tubocurarine for the maintenance of muscular relaxation were divided into five groups
each of ten. At the end of anaesthesia, the patients of groups A and B received intra-
venously atropine 6 /ig/kg and neostigmine 20 yug/kg, those in groups C and D atropine
12 /fg/kg and neostigmine 40 /ig/kg, and those in group E atropine 8 /ig/kg and
neostigmine 20 /ig/kg. In groups A and C atropine was injected in 60 seconds and was
followed 1 minute later by neostigmine also administered in 60 seconds. In groups B,
D, and E atropine and neostigmine were injected together in 60 seconds. Reversal of
residual neuromuscular block was achieved in all five groups without the development
of any serious arrhythmias. Statistically significant tachycardia developed only in those
groups (A and C) in which atropine was injected 2 minutes before the administration
of neostigmine. Of the different dosages and sequences of administration investigated,
the combined injection of atropine 6 /*g/kg and neostigmine 20 /tg/kg over 60 seconds
appears to be most suitable for the reversal of residual neuromuscular block.

Atropine sulphate and neostigmine methyl- Premedication consisted of 50-100 mg intra-

sulphate (Prostigmin) are frequently used at the
end of surgery for the reversal of a residual non-
depolarizing neuromuscular block. Considerable
differences of opinion exist concerning the
optimal dosage (Gray, 1950; Doughty and
Wylie, 1952) and time of administration
(Churchill-Davidson and Wise, I960) of these
agents. The aim of this study was to clarify the
effect of various combinations of atropine and
neostigmine on the heart rate and rhythm and to
recommend a safe method for their administra-
tion.
MATERIAL AND METHODS
Fifty surgical patients, 46 of whom underwent
intra-abdominal and 4 intra-thoracic operations,
were included in this study; of these, 21 were
males and 29 females. Their ages ranged from 19
to 78 years with an average of 49.4 + 2.1.* All
had normal circulatory systems; pre-operative
electrocardiographic tracings showed regular sinus
rhythm in all.
* Standard error of the mean.
muscular diphenhydramine hydrochloride (Ben-
adryl) or sodium pentobarbitone (Nembutal)
administered 90 minutes, and 50-100 mg pethi-
dine hydrochloride (pethidine) and 0.3-0.4 mg
atropine or hyoscine hydrobromide 45 minutes
before induction.
Thirty-nine patients were anaesthetized with
sodium thiopentone (Pentothal), nitrous oxide-
oxygen, and pethidine and 11 with droperidol
(Inapsine), fentanyl citrate (Sublimase), and
nitrous oxide-oxygen. All patients were intubated
after the intravenous administration of 40-60
mg of suxamethonium chloride (Anectine). After
skin incision muscular relaxation was induced by
the intravenous administration of 0.2 mg/kg
tubocurarine chloride and maintained with 0.06
mg/kg administered as required. The mean dose
was 28.6 + 2.1 (standard error) mg (range 9-51
V. ROSNER, M.D.; E. R. KEPES, M.D.; F. F. FOLDES,
M.D., F.F.A.R.A.C.S.; Departments of Anesthesiology of
the Montefiore Hospital and Medical Center and
Albert Einstein College of Medicine, Bronx, New
York, U.S.A.
EFFECTS OF ATROPINE AND NEOSTIGMINE ON HEART RATE
mg). The mean duration of surgery was 160 ±9.6
(range 70-300) min. Breathing was assisted or
controlled manually throughout the surgical pro-
cedure and during the reversal of the neuro-
muscular block.
After the neuromuscular effect of suxame-
thonium, used to facilitate endotracheal intuba-
tion, had worn off and before the administration
of tubocurarine, the needle electrode of a nerve
stimulator (Block-Aid Monitor, Burroughs Well-
come and Co.)f was inserted in the vicinity of
the ulnar nerve at the wrist. The response (inten-
sity of the contraction of the adductor pollicis
and the deep flexors of the fourth and fifth
fingers) to single (0.25/sec) and tetanic (30/sec)
supramaximal stimuli was observed. Before the
start of the reversal and at 10 minutes after the
start of neostigmine administration the response
to stimulation was again tested. At these times,
the effects of single stimuli were compared with
those obtained before the administration of
tubocurarine. The degree of neuromuscular block
was empirically graded between 0, no block, res-
ponse same as before administration of tubo-
curarine, and 3 no response, complete block. The
response to tetanic stimulation (Hutter, 1952;
Churchill-Davidson, 1959), intensity and main-
tenance of tetanic contracture and presence or
absence of post-tetanic facilitation, were also ob-
served. The criteria upon which the intensity of
the neuromuscular block were based are sum-
marized in table I. Reversal was considered to be
complete when the response to single stimuli was
the same as before the administration of tubo-
curarine, tetanus was maintained for at least 5
seconds, and there was no post-tetanic facilitation.
TABLE I
Criteria used for the assessment of the degree of
neuromuscular block.
Degree of neuromuscular block
0 1
Intensity of response to
single stimuli +++ + + + 0
Maintenance of tetanus
for 5 sec yes no no
Post-tetanic facilita-
tion 0 ++ + ++
t The duration of the stimulus supplied is approxi-
mately 0.2 msec, the maximum voltage is 30 mV, and
the current output with this voltage is 0.93 mA.
1067
Ten to fifteen minutes before the expected end
of surgery, an arterial blood sample was obtained
from the radial or brachial artery. pH, Pco2, base
excess and standard bicarbonate were determined
using Astrup's micro-method. Po, was deter-
mined with a Beckman macro-electrode. In two
patients base deficit of 8 m.equiv/1. was corrected
with 50 m.equiv of sodium bicarbonate admin-
istered intravenously before reversal.
At the end of surgery, with the endotracheal
tube in place and the patient inhaling a mixture
of nitrous oxide (2 l./min) and oxygen (2 l./min),
a control electrocardiographic tracing (e.c.g.) was
taken on a direct-writing Sanborn electrocardio-
graph. With the exception of one case of nodal
rhythm and one of sinus arrhythmia, all e.c.g.
tracings were normal.
The patients were divided into five equal
groups. Group A received atropine 6 ^tg/kg in
60 seconds; 1 minute after the completion of the
atropine administration, neostigmine 20 yUg/kg
was injected in 60 seconds. Group B received
atropine 6 ^g/kg mixed with neostigmine 20
^tig/kg in 60 seconds. Group C received atropine
12 ^g/kg in 60 seconds; 1 minute after the com-
pletion of the atropine administration neostigmine
40 jug/kg was injected in 60 seconds. Group D
received atropine 12 /ig/kg mixed with neostig-
mine 40 /tg/kg injected in 60 seconds. Group E
received atropine 8 ,ug/kg mixed with neostig-
mine 20 jttg/kg in 60 seconds.
The electrocardiographic tracings were ob-
served for at least 10 minutes from the start of
the neostigmine injections in all groups. In ten
patients, selected at random, the tracings were
recorded up to 25 minutes from the start of the
atropine injections. The tracings were examined
for alterations of rate, rhythm and other changes.
RESULTS
The mean heart rates in the five groups at various
times after the start of the atropine injection are
presented in figure 1 and table II. The maximum
increases in mean heart rates occurred at 2
minutes after the beginning of atropine injection
no
in groups A, B, D and E and at 3 minutes in
+ group C. The range of maximal increases of
individual heart rates were 6-26, 2-20, 10-56,
0-34 and 0-26 beats/min in groups A, B, C, D
and E respectively. The highest individual pulse
1068 BRITISH JOURNAL OF ANAESTHESIA

100

90

80
x

70

60

50
0
10 11 12

MINUTES FROM START OF ATROPINE INJECTION

1
FIG.
Mean heart rates after the combined administration of various doses of atropine and neostigmine;
"and" indicates that atropine was injected first, followed by neostigmine; "with" indicates that
they were injected simultaneously. Note that whatever their dose and sequence of administration
tachycardia ensues. Also note that the tachycardia is smaller when the same doses of atropine
and neostigmine are injected together than when atropine is injected before neostigmine.
A=atropine 6 /<g/kg over 60 sec followed after 1 min by neostigmine 20 jug/kg administered in
60 sec.
B=atropine 6 /<g/kg with neostigmine 20 /ig/kg injected together over 60 sec.
C=atropine 12 /»g/kg injected in 60 sec followed 1 min later by neostigmine 40 /ig/kg injected
in 60 sec.
D=atropine 12 Mg/kg with neostigmine 40 /»g/kg injected together in 60 sec.
E = atropine 8 /»g/kg with neostigmine 20 /ig/kg injected together in 60 sec.

TABLE II
Mean heart rates in each group of ten patients.
Groups
.^din after
atropine A B C D E
admin. (6 + 20) (6 + 20) (12+40) (12+40) (8 + 20)
Control 66.6 + 2.2* 66.0 + 3.4 72.2 + 3.5 75.5 + 6.3 77.6 ±3.7
1 72.8 + 2.6 66.6 + 4.8 80.8 + 3.5 78.4 + 6.9 81.0 + 3.4
2 86.4 + 3.2 71.8+4.2 98.8 + 4.8* 86.4 + 5.8 93.2 + 4.9f
3 86.0 + 3.5+. 69.8 + 4.5 101.2 + 4.9§ 86.0 + 1.8 87.0 + 5.1
4 80.4+ 3.3+. 65.8+3.9 91.4+4.81 78.0 ±4.9 82.0 + 5.4
5 74.2 + 3.7 62.2 + 4.8 80.6 + 2.9 73.0 + 5.1 78.2 + 4.7
6 67.4 + 1.6 59.8 + 3.2 72.4 + 3.0 78.3 + 5.3 74.2+4.2
7 62.4 + 1.3 57.2 + 3.0 69.8 + 3.3 66.5 + 5.4 71.0 + 4.2
8 59.8 + 1.2+ 52.6 + 3.7f 65.8 + 3.6 64.1 + 5.5 69.4+4.3
9 58.4 + 1.31 54.6 + 2.6+ 64.4 + 3.6 63.3 + 5.3 66.8 + 4.0
10 56.8 + 1.2* 52.5 + 2.4f 61.6 + 3.8 63.8 + 4.9 66.6 ±4.3
11 56.8 + 1.5* 60.0 + 3.7+
12 54.1+2.0+ 58.8 + 3.8
* Mean and standard error.
t Indicates statistically significant difference from control at P<0.05 level.
§P<0.001.
EFFECTS OF ATROPINE AND NEOSTIGMINE ON HEART RATE 1069

rate was 104 beats/min in group A, 108 in group TABLE III

B, 136 in group C, 118 in group D, and 118 in Arrhythmias observed during and after reversal.
group E. Number in group
The maximum mean decreases of heart rates
Types of arrhythmias AB C D E
•occurred at 12 minutes after the start of neostig-
mine injection in groups A and C, at 9 minutes Supraventricular pre-
in group D, and at 10 minutes in groups B and mature contractions 4
Wandering pacemaker 1 3 1*
E. The range of maximal decreases of individual
Sinus arrhythmia 1
heart rates were 2-26, 0-30, —4-36, —2-26 and
Nodal rhythm 1* 1
O-30 beats/min in groups A, B, C, D and E res-
pectively. The lowest individual heart rate was Occasional ventricular
premature contractions 1 1
46 in group A, 30 in group B 4 52 in group C, Multiple ventricular
42 in group D, and 48 in group E. premature contractions 1 1
In addition to the one case of nodal rhythm Bigeminy 1
and one case of sinus arrhythmia present before First degree heart
reversal, various arrhythmias developed in some block 1 1

i—1
patients in all five groups after the administration Second degree heart
block 1*
of atropine and/or neostigmine. In one patient
of group A, wandering pacemaker, and in one of * Indicates that two different types of arrhythmias
occurred in the same patient.
group C, nodal rhythm, was encountered after
the administration of atropine but before the TABLE IV
administration of neostigmine. In one patient of Measurement of intensity of neuromuscular block
group C who developed transient nodal rhythm before and after reversal.
about 30 seconds after the start of atropine Intensity of neuromuscular block
administration, wandering pacemaker was ob- Before neostigmine 10 minutes later
served just before the end of the observation
Group 0 1 2 3 0 1 2 3
period.
The types of arrhythmias encountered are A 0* 7 1 2 8 1 1 0
B 0 5 5 0 9 1 0 0
summarized in table III. The arrhythmias were C 0 4 5 1 9 1 0 0
usually transient, lasting 1-5 minutes. In none of D 0 3 6 1 10 0 0 0
the patients did they cause any significant change E 0 3 7 0 5 5 0 0

in blood pressure. * Number of patients.

Assessments of the intensity of neuromuscular
block before and 10 minutes after the start of
neostigmine administration are summarized in
table IV. It is evident from this table that before
the administration of neostigmine all patients had
neuromuscular block of variable intensity. Fol-
lowing the administration of neostigmine the
neuromuscular block was completely antagonized,
according to our criteria, in 41 of the 50 patients.
Reversal was incomplete in 8 of 30 patients who
received 20 jug/kg and in 1 of 20 patients who
received neostigmine 40 /zg/kg. The reversal was
complete following the administration of an addi-
i This was encountered in a patient with a control
heart rate of 60 beat/min who developed 2-1 block
at 8 minutes after the start of neostigmine administra-
tion. After 1 minute the 2-1 block disappeared, the
heart rate reverted to 58 beat/min. The P-R interval
was prolonged for 14 minutes.
tional 0.5 mg dose of neostigmine in these 8
patients. Clinical observations (e.g., ability to
take a deep breath, to lift the head from the
table, and to open the eyes) confirmed the find-
ings obtained with the electrical stimulation of
the ulnar nerve.
DISCUSSION
Soon after the introduction of neostigmine-
atropine combinations for the reversal of residual
neuromuscular block, there appeared several
reports of fatalities attributed to these agents
(Hill, 1949; Clutton-Brock, 1949; Macintosh,
1949; Johnstone, 1951). At first, it was generally
assumed that neostigmine was responsible for
the serious arrhythmias encountered (Macintosh,
1949; Clutton-Brock, 1949; Hill, 1949; Waquet,
1951). Because of this, it has been recommended
1070
that the administration of neostigmine should be
preceded by the intravenous injection of rela-
tively large doses (1.3 mg) of atropine. Subse-
quently, however, the possibility that atropine
might be the agent responsible for the develop-
ment of cardiac arrhythmias received considerable
attention (Bain and Broadbent, 1949; Johnstone,
1951; Pooler, 1957; Averill and Lamb, 1959;
Eger, 1962; Gottlieb and Sweet, 1963; Mclntyre
and Drummond, 1963).
It is well known that the primary cardio-
vascular effect of atropine is the production of
tachycardia, and that of neostigmine, brady-
cardia. Atropine exerts its effect by inhibiting the
muscarinic effect of acetylcholine at the post-
ganglionic parasympathetic receptor sites of the
heart. The neostigmine-induced bradycardia is
caused by its anticholinesterase effect which
results in accumulation of acetylcholine and
increased stimulation of the vagus receptors of
the heart.
It has been reported that moderate doses of
atropine administered subcutaneously or by very
slow intravenous infusion may cause, at first,
bradycardia (Harris, 1921; McGuigan, 1921;
Danielopolu, 1924; Orkin, Bergman and Nathan-
son, 1956; Morton and Thomas, 1958; Thomas,
1965; Fielder et al., 1969). It was stated, how-
ever, by Thomas (1965) that in anaesthetized
patients, premedicated with atropine or hyoscine,
the subsequent administration of atropine is not
followed by transient bradycardia. In agreement
with this, no transient bradycardia developed after
the slow intravenous administration of atropine
6 or 12 fig/kg in our series.
In all but one patient, with all five combina-
tions of atropine and neostigmine, at first there
was an increase in heart rate followed by a
gradual decrease below control levels. The
maximum increase was observed at 2-3 minutes
Mean changes in heart rate.
A B
Maximum increase 19.8 + 3.2*§
Maximum decrease 12.5 + 2.0$
Mean and standard error.
BRITISH JOURNAL OF ANAESTHESIA
after the start of injection of atropine, control
levels were reached at 5-6 minutes, and
maximum decreases were observed at 9-12
minutes. Continued electrocardiographic observa-
tion of 10 of the 50 subjects for additional 12-25
minute periods revealed further decrease of heart
rate in only two patients.
All subjects were observed in the recovery
room for 2-3 hours. No further decreases of
pulse rate were observed in any of the subjects.
To the contrary there was a gradual increase in
pulse rates in 39 of the 50 subjects. The
maximum mean increases were greater and
significantly different from control in groups A
(19.8 ±3.2) and C (29.0 + 4.9) in which atropine
preceded the administration of neostigmine, than
in groups B (11.6 ±5.7), D (10.9 ±5.8) and E
(12.2 ±3.3 beats/min) in which atropine and
neostigmine were administered together. The
mean decrease of heart rates was about the same,
11.2±4.0 to 14.4±3.1 beats/min when the
smaller or larger doses of atropine and neostig-
mine were administered separately or together
(table V).
These findings indicate that the effects of neo-
stigmine develop more slowly than those of atro-
pine. This was also observed by Kemp and Morton
(1962) who found that injecting atropine 1.28 m j
and neostigmine 2.5 mg together had no effect
on the time and magnitude (39 beats/min
increase) of the development of the maximum
effect of atropine. The more rapid onset and
greater magnitude of the maximum effect of
atropine in their studies may be explained by the
higher dose and more rapid rate of injection
(5 sec).
Similar observations were made recently by
Kjellberg and Tammisto (1970) who also recom-
mended that atropine 15 yug/kg and neostigmine
30 ,ag/kg should be administered simultaneously
TABLE V
Groups
C D E
11.6+5.7 29.0+ 4.9$ 10.9 + 5.8 12.2±3.3t
11.2 + 4.0 13.4 + 3.8t 12.2 + 5.3 14.4±3.1f
t P<0.05. P<0.01. § P<0.C01.
EFFECTS OF ATROPINE AND NEOSTIGMINE ON HEART RATE
for the reversal of residual neuromuscular block.
The ratio of atropine to neostigmine was higher
(1:2) in their than in our (1:3.3) studies. In
line with this the mean maximum increases of
heart rates in the various groups were somewhat
higher in their (16-35 beats/min) than in our
(U-29 beats/min) studies (see table V).
Interestingly the mean maximal decreases of pulse
rates were very similar in their (10-17 beats/min)
and in our (11—14 beats/min) groups. Salem and
associates (1970) also found a consistent increase
of heart rate following the administration of mix-
tures of atropine 20 /zg/kg and neostigmine 50
,wg/kg in neonates and paediatric patients with
congenital heart disease. No serious arrhythmias
were encountered after the concomitant adminis-
tration of atropine and neostigmine in these
patients, in whom the incidence and severity of
arrhythmias is known to be high.
The degree of bradycardia was the same after
the combined or separate administration of
atropine and neostigmine, but the combined
administration of the two drugs caused less
tachycardia than did their separate administra-
tion. Because of this, it is reasonable to postulate
that the two agents should be administered
together when used for the reversal of the
residual curarization.
Ovassapian (1969) found that when atropine
1.0 mg was injected first, followed in 3-4 min by
neostigmine 2.5 or 3.0 mg, the degree and dura-
tion of tachycardia was much greater than when
the two drugs were injected together. He also
observed that while the rapid or slow injection
of the atropine-neostigmine mixtures had the
same effect on the initial rise in pulse rate, the
subsequent bradycardia was greater after fast
than after slow injection.
It may be argued that the dose level of atropine
used by us in relation to the dose of neostigmine
was relatively low, since ultimately some brady-
cardia developed in most patients. We feel, how-
ever, that it is just as important to prevent exces-
sive tachycardia as to avoid bradycardia. For
example, in one patient of group C in whom the
administration of atropine 12 /4g/kg was followed
by a heart rate of 136 beats/min, there was
depression of the S-T segment which developed
when the heart rate reached its maximum and
lasted for 2 minutes, at which time the heart rate
1071
returned to 96 beats/min. We feel that it is much
safer to administer initially the small doses of
atropine recommended by us and to give addi-
tional increments of 0.1-0.3 mg atropine intra-
venously if at any time significant bradycardia
develops.
The neostigmine-induced arrhythmias were
attributed (Hoffman et al., 1945) to the intra-
cardiac release of adrenaline or noradrenaline
caused by the accumulated acetylcholine. In
agreement with this assumption, the first three
fatalities reported after the use of atropine and
neostigmine for the reversal of residual neuro-
muscular block occurred in patients, anaesthetized
with agents such as cyclopropane (Clutton-Brock,
1949; Macintosh, 1949) or ether (Hill, 1949) that
sensitize the heart to adrenaline.
It was recognized as early as 1915 by Wilson
that the administration of atropine may cause
atrioventricular rhythm in man. More recently
the role of atropine in the development of various
arrhythmias (including ventricular premature
beats, tachycardia and fibrillation) during reversal
of residual curarization has been emphasized by
several clinicians (Johnstone, 1951; Pooler, 1957;
Averill and Lamb, 1959; Eger, 1962; Gottlieb
and Sweet, 1963; Mclntyre and Drummond,
1963).
It was observed that respiratory acidosis
(Johnstone, 1951; Pooler, 1957) and inhalation
anaesthetic agents (e.g., cyclopropane, halothane)
that increase cardiac irritability predispose to
atropine-induced arrhythmias. The 19 arrhythmias
encountered in 82 patients by Gottlieb and
Sweet (1963) after the administration of atropine
1.2 mg followed by neostigmine 2.5 mg occurred
after the administration of atropine and before
the injection of neostigmine. In the present series,
2 of the 10 arrhythmias observed in groups A
and C developed after atropine alone.
The review of the literature indicates that both
atropine and neostigmine are potentially dan-
gerous drugs which must be used with extreme
caution for the reversal of residual neuromuscular
block in anaesthetized patients. In addition to
the absolute and relative doses of atropine and
neostigmine, the sequence and rate of their
administration, the patient's ventilatory status
(Baraka, 1968) and the inhalation anaesthetic
agent used must be carefully considered.
1072
Recommended technique.
Since respiratory acidosis and hypoxia increase
the sensitivity of the myocardium to the
arrhythmogenic effects of atropine and neostig-
mine, patients must be well ventilated before,
during and after the reversal. Similarly, metabolic
acidosis when suspected should be ruled out or
corrected before reversal. Whenever inhalation
anaesthetic agents capable of increasing myo-
cardial irritability (e.g., cyclopropane, halothane,
ether) have been used, their partial pressure in
the patient should be reduced, as much as
practicable, by ventilation with high flows of 50
per cent nitrous oxide/50 per cent oxygen for
5-10 minutes before the start of the reversal. If
the patient is apnoeic at the end of anaesthesia it
should be determined whether the apnoea is due
to complete block of the respiratory muscles, to
hyperventilation, or to central depression
(Churchill-Davidson, 1959; Churchill-Davidson
and Wise, 1960). The type and intensity of the
neuromuscular block can be determined with a
nerve stimulator. If the muscle responds to
indirect stimulation and there is reason to believe,
that the apnoea is due to narcotics, levallorphan
tartrate (Lorfan) 20 /*g/kg or naloxone hydro-
chloride (Narcan) 5-10 /ig/kg (Foldes, Duncalf
and Kuwabara, 1969) may be used. The start of
reversal as recommended by Gray and Wilson
(1959) should be delayed until there is some
indication of the spontaneous return of neuro-
muscular transmission. If the administration of
neostigmine is withheld until there is some spon-
taneous respiratory activity, the dose required
for the reversal will be reduced and it is less
likely that serious cardiovascular side effects will
develop. If a nerve stimulator is not available,
the patient should be carefully ventilated until
there is some spontaneous respiratory activity.
During proper ventilation with high flows of
nitrous oxide-oxygen, or oxygen, while waiting
for the return of neuromuscular activity, two other
possible causes of apnoea, namely central depres-
sion by inhalation anaesthetic agent or by hypo-
or hypercapnia, will also be corrected.
With the relatively small (4-8 /<g/kg/min)
doses of tubocurarine used in this study, there
was no significant difference in the degree of the
reversal after the smaller and larger neostigmine
doses employed. Our previous clinical experience
BRITISH JOURNAL OF ANAESTHESIA
(Foldes, 1966) also indicates that when non-
depolarizing muscle relaxants are used judiciously,
in the majority of cases this dose of neostigmine
provides satisfactory reversal of the residual
neuromuscular block. The data presented also
indicate that the combined administration of
atropine 6 /^g/kg and neostigmine 20 /<g/kg is
preferable to the separate administration of these
two agents.
With this method of administration, no early
bradycardia was observed; excessive acceleration
of the heart rate could be prevented; and no-
serious arrhythmias had been encountered.
Because of its more rapid onset of action, atropine
even when administered together with neostig-
mine will provide instantaneous protection against
the unwanted cardiac effects of the latter.
The initial dose of the atropine-neostigmine
combination should be injected over a 60-sec
period. Since the maximal effect of neostigmine
develops relatively slowly, at least 5 minutes
should be allowed to elapse before its efficacy is
evaluated. If this dose of neostigmine has no
effect on the patient's spontaneous ventilation, the
respiratory depression is either not due to neuro-
muscular blockade or the intensity of the block
is such that it is not suitable for reversal by safe
doses of anticholinesterases. If the first dose of
neostigmine is only partially effective, additional
increments of neostigmine 10 /^g/kg and atropine
3 /ig/kg should be administered 3-5 minutes
apart as long as each dose causes further improve-
ment of muscular activity. Additional doses of
atropine 0.1-0.3 mg are indicated if in the course
of the reversal, bradycardia develops.
Using larger initial doses of atropine and/or
neostigmine, especially if the two agents are
administered separately, exposes the patient to
the potentially serious cardiac effects of both of
the drugs. It should be emphasized that when-
ever atropine and neostigmine are used to reverse
residual curarization, patients should be closely
observed for 12-15 minutes after their adminis-
tration to detect and correct any late bradycardia.
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Averill, K. H., and Lamb, L. E. (1959). Less com-
monly recognized actions of atropine on cardiac
rhythm. Amer. J. med. Sci., 237, 304.
Bain, W. A., and Broadbent, J. L. (1949). Death fol-
lowing neostigmine. Brit. med. J., 1, 1137.
EFFECTS OF ATROPINE AND NEOSTIGMINE ON HEART RATE
Baraka, A. (1968). Safe reversal (1): atropine followed
by neostigmine; an electrocardiographic study.
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EFFETS DE L'ATROPINE ET DE LA
NEOSTIGMINE SUR LE RYTHME ET LA
FREQUENCE CARDIAQUES:
RECOMMANDATIONS CONCERNANT LEUR
EMPLOI EN VUE DE L'INVERSION D'UN
BLOCAGE NEUROMUSCULAIRE RESIDUEL
SOMMAIRE
Cinquante malades anesthesies par le melange pro-
toxyde d'azote-oxygene avec administration, en com-
plement, de thiopentone et de pethidine, de thiopentone
et d'halothane ou de droperidol et de fentanyl et qui
recurent de la tubocurarine en vue du maintien du
relachement musculaire, ont 6te repartis en 5 groupes
de 10 individus chacun. A la fin de Panesthesie, les
malades des groupes A et B ont fait l'objet d'une
injection intraveineuse de 6 jug/Kg d'atropine et de
20 /ig/Kg de neostigmine, ceux des groupes C et D,
d'une injection intraveineuse de 12 /xg/Kg d'atropine
et de 40 pg/Kg de neostigmine, alors que ceux du
groupe E recurent, egalement par voie intraveineuse,
8 /ig/Kg d'atropine et 20 /'g/Kg de neostigmine. Dans
les groupes A et C, l'atropine avait 6te injectee en 60
secondes, suivie, une minute plus tard, de 1'injection
de neostigmine, egalement en 60 secondes. Dans les
groupes B, D et E, l'atropine et la neostigmine avaient
ete injectees ensemble, en 60 secondes. Une inversion
du blocage neuromusclaire residuel a ete obtenue dans
les cinq groupes, sans apparition d'arythmie serieuse.
Une tachycardie statistiquement significative n'est sur-
venue que dans les groupes (A et C) dans lesquels
l'atropine avait et€ injectee 2 minutes avant Padmini-
stration de neostigmine. Parmi les differentes poso-
logies et modes d'administration etudies, 1'injection de
l'association atropine 6 /ig/Kg et neostigmine 20 /*g/Kg
en 60 secondes semble convenir le mieux en vue de
l'inversion d'un blocage neuromusculaire residuel.
1074 BRITISH JOURNAL OF ANAESTHESIA

DIE WIRKUNGEN VON ATROPIN UND EFECTOS DE LA ATROPINA Y NEOSTIGMINA

NEOSTIGMIN AUF HERZFREQUENZ UND
SCHLAGFOLGE: EMPFEHLUNGEN FOR IHRE
ANWENDUNG BEI DER DURCHBRECHUNG
EINES ANDAUERNDEN NEUROMUSKULAREN
BLOCKS
ZUSAMMENFASSUNG
Fiinfzig Patienten, die mit Lachgas-Sauerstoff, erganzt
durch Thiopental und Pethidin, Thiopental und Halo-
than, oder Droperidol und Fentanyl anasthesiert waren
und Tubocurarin zur Aufrechterhaltung der Muskeler-
schlaffung erhielten, wurden in 5 Gruppen zu je zehn
aufgeteilt. Bei Narkoseende erhielten die Patienten der
Gruppen A und B intravenos 6 Mg/kg Atropin und 20
Pg/kg Neostigmin, die der Gruppen C und D 12 Mg/kg
Atropin und 40 Mg/kg Neostigmin und die der Gruppe
E 8 /ig/kg Atropin und 20 /ig/kg Neostigmin. Bei den
Gruppen A und C wurde das Atropin in 60 Sekunden
injiziert und genau eine Minute danach das Neostigmin,
ebenfalls wahrend 60 Sekunden. Bei den Gruppen B,
D und E wurden Atropin und Neostigmin zusammen
in 60 Sekunden injiziert. Die Beseitigung des noch
bestehenden neuromuskularen Blocks wurde bei alien
fiinf Gruppen ohne Entwicklung ernsterer Rhythmus-
storungen erreicht. Eine statistisch signifikante Tachy-
kardie wurde nur bei den Gruppen (A und C) beob-
achtet, bei denen Atropin zwei Minuten vor der
Application von Neostigmin injiziert wurde. Unter den
verschiedenen Dosierungen und Administrationszeiten,
die getestet wurden, erscheint die kombinierte Injektion
von 6 yug/kg Atropin und 20 /^g/kg Neostigmin inner-
halb von 60 Sekunden die am meisten zu empfehlende
zur Umkehr eines noch bestehenden neuromuskularen
Blocks.
SOBRE LA FRECUENCIA Y RITMO DEL
CORAZON: RECOMENDACIONES PARA SU
USO CON OBJECTO DE INVERTIR EL
BLOQUEO NEUROMUSCULAR
RESUMEN
Cincuenta pacientes anestesiados con oxido nitroso-
oxigeno, suplementado por tiopentona y petidina, tio-
pentona y halotano o droperidol y fentanyl, quienes
recibieron tubocurarina para mantener el relajamiento
muscular, fueron divididos en 5 grupos de 10 cada uno.
Al final de la anestesia, los pacientes de los grupos A
y B recibieron intravenosamente 6 Mg/kg de atropina
y 20 Mg/kg de neostigmina, los de los grupos C y D, 12
Mg/kg de atropina y 40 Mg/kg de neostigmina, y los
del grupo E 8 Mg/kg de atropina y 20 jug/kg de neo-
stigmina. En los grupos A y C, la atropina fue
inyectada en 60 segundos y fue seguida un minuto
despues por la neostigmina que tambien fue admini-
strada en 60 segundos. En los grupos B, D y E la
atropina y neostigmina fueron inyectadas juntas en 60
segundos. La inversion del bloqueo neuromuscular
residual fue conseguida en los 5 grupos sin aparicion
de arritmias intensas. Se desarroll6 una taquicardia
estadisticamente significativa solamente en los grupos
(A y C) en los cuales la atropina fue inyectada 2
minutos antes de la administracion de neostigmina. De
las diversas dosis y secuncias de administracion que
fueron investigadas, la inyeccion combinada de 6 /ig/kg
de atropina y 20 /'g/kg de neostigmina durante 60
segundos parece ser la mas adecuada para la inversion
del bloqueo neuromuscular.

BASIC SCIENCE REVISION COURSE FOR ANAESTHETISTS

Day-release course for twenty-one weeks, all day every Monday, for Part I of the F.F.A.
Examination. The next course commences on February 14, 1972, and finishes on July
17, 1972.

LONDON HOSPITALS REFRESHER COURSE

Twenty-week day-release course held at ten different London Teaching Hospitals, to
help prepare for Part II of the F.F.A. Examination. Eighteen sessions will be held on a
Wednesday and the remaining two sessions will be held on a Tuesday. The next course
commences on February 16, 1972, and finishes on June 28, 1972.

Applications for the above courses should be addressed to the

COURSE SECRETARY, DEPARTMENT OF ANAESTHETICS,
ST THOMAS'S HOSPITAL, LONDON S.E.I