Anaesthesia, 1976, Volume 31, pages 873-882

The cardiovascular effects of ketamine in man

MICHAEL JOHNSTONE

Ketamine stimulates the cardiovascular system of man and of some species of experi-
mental animal. It raises the cardiac output, the pulse rate, the arterial and central
venous pressures and has little effect on the total peripheral resistance.'.' The stimu-
lation is maximal after the first dose and persists for about 20 minutes. The effect has
been variously ascribed to activation of the central sympathetic nervous ~ y s t e m , ~
blockade of the cardiac vagus nerves," increased levels of circulating cat echo la mine^,^
activation of the adrenocortical system,6 and constriction of the alpha adrenoceptor
blood vessels with increased venous return to the heart.' Propranolol has little influence
on the cardiac effects of ketamine which indicates that adrenergic overactivity is not
the main cause of the cardiac reaction to ketamine.'~~
The possibility that ketamine may act directly on the myocardial cells was con-
sidered by Hamilton and Bryson." They showed that the drug has a dual action on the
transmembrane potentials of the PurkinjC fibres of the isolated perfused pig heart.
The primary or main effect seems to be a veratrinic facilitation of ionic movements
across the cell membranes. The drug also increases the response of the preparation to
small doses of adrenaline. Drugs with a veratrine-like action increase the permeability
of cell membranes and make the cells more excitable and responsive to physiological
stimuli.'
The similarity between the cardiac effects of ketamine and those of ionic calcium
prompted a clinical study of ketamine which is reported under the following headings:
first the effect of verapamil,' ' * I 3 a calcium ion antagonist, on ketamine hypertension,
second the effect of ketamine on vagal bradycardia, third the effect of ketamine on
reflex surgical vasoconstriction, and last the effect of ketamine on ergometrine
vasoconstriction,

Method
Forty-five relatively fit patients were selected, 35 of whom were female and the rest
male. Their ages ranged from 19 to 36 years and they were admitted to hospital to
Michael Johnstone, M D, FFARCS, Consultant, Department of Anaesthetics, The Royal Infirmary,
Manchester.

873
874 M . Johnstone

have either elective gynaecological or orthopaedic operations of varying degrees of

severity. Each patient had clinically normal cardiovascular, respiratory and other
systems and all were normotensive, normovolaemic, afebrile and free from pain.
Each was sedated with lorazepam 4 mg given intravenously about 2 hours before the
induction of anaesthesia. Lorazepam provides good sedation, abolishes the digital
vasoconstriction of fear and has no effect on the reflex vasoconstrictor reactions to
other adrenergic stimuli such as pain, cold or trauma.I4 It also seems t o prevent the
undesirable psychomotor reactions to ketamine. Cardiovascular behaviour in each
patient was assessed by electrocardiography, finger and fore-arm muscle volume-pulse
plethysmography,' and sphygmomanometry (Riva-Rocci). The initial plethysmograms
in each case were recorded during the insertion of an intravenous cannula to confirm
the presence of normal sympathetic reflex activity prior to the induction of anaesthesia.

Calcium ion antagonism

Twenty patients were studied. Anaesthesia was induced in each patient with ketamine
3 mg/kg intravenously. Verapamil was given intravenously when a systolic pressure
rise of at least 30 mmHg had been recorded in each patient. The dose of verapamil
was 5 mg every 30 seconds until an effect was observed on the arterial pressure. The
maximum dose given was 20 mg. Adequate spontaneous or assisted respiration was
maintained with oxygen whilst the various measurements were made. The electro-
cardiogram, finger and muscle plethysmograms, and the systolic pressures were re-
corded frequently before, during and after the injection of each drug. Anaesthesia
was then maintained with a nitrous oxide, oxygen and halothane 0.5% mixture with
pancuronium relaxation and controlled respiration (Blease Pulmoflator) as required.

Vagal bradycardia
Ten patients were studied. Anaesthesia was induced in each by the inhalation of nitrous
oxide, oxygen and halothane 1% in a high-flow non-return system. Ketamine 3 mg/kg
was given intravenously when consciousness was lost and a moderate bradycardia of
sinus or atrio-ventricular nodal origin had appeared on the electrocardiogram.
Atropine 0.5 mg was given intravenously to each patient about 5 minutes after the
injection of ketamine. The systolic arterial pressure, the electrocardiogram and the
finger and muscle plethysmograms were recorded at appropriate intervals. Anaes-
thesia was maintained with nitrous oxide, oxygen and halothane 0.5%.

Surgical vasoconstriction
Ten patients were studied, each of whom required an abdominal hysterectomy. The
procedure was similar to that of a previous study of the effects of other anaesthetic
agents on reflex surgical vasoconstriction. l6 After lorazepam sedation anaesthesia
was induced with propanidid 200 mg mixed with atropine 0.5 mg intravenously in
each patient, followed by pancuronium 5 mg, endotracheal intubation and ventilation
with nitrous oxide-oxygen from a Blease Pulmoflator. Ketamine 100 mg was given
intravenously to each patient when persistent reflex digital vasoconstriction was
provoked by the surgery. The arterial pressure, finger and muscle plethysmograms were
recorded at appropriate intervals throughout the procedures.
 Cardiovascular effects of ketamine 875

Ergometrine vasoconstriction
Five patients were studied, each of whom required uterine curettage for incomplete
abortion. Ergometrine 0.5 mg was given intravenously shortly after sedation with
lorazepam. Blood loss was not excessive in any of the patients. The vasoconstrictor
effect of the ergometrine was confirmed plethysmographically and the arterial pres-
sures recorded in the usual manner. Anaesthesia was then induced in each patient with
ketamine 3 mglkg and the effect of the drug on the peripheral vasculature was re-
corded plethysmographically. Anaesthesia was maintained with a nitrous oxide-
oxygen mixture.

Results

Calcium ion antagonism

Before the induction of anaesthesia the range of pulse rates was 50-98 beats a minute
(mean 73) and that of the systolic pressures was 80-140 mmHg (mean 106). The
amplitudes of the finger pulse waves were between 2 and 4 mm and those of the muscle
pulse waves between 15 and 30 mm (mean 23).
Five minutes after ketamine the range of pulse rates was 75-125 beats a minute
(mean 93) and the systolic pressures 120-180 mmHg (mean 149). The finger plethys-
mograms showed vasodilatation with an amplitude range of 17-28 mm (mean 19)
and those of the muscle vessels showed vasoconstriction with a range of 6-11 mm
(mean 8).
The verapamil caused immediate falls in the systolic blood pressures of all patients
to levels similar to or slightly lower than those recorded before the ketamine was given.
Two minutes after verapamil the range of systolic pressures was 85-140 mmHg
(mean 107). Most of the pulse rates were moderately increased after verapamil, the
range being 85-130 beats a minute (mean 106). The amplitudes of the pulse waves
of the finger and the muscle plethysmograms were moderately decreased in all patients,
presumably as the result of diminished cardiac stroke-volume and contractility. The

Fig. 1. Female, 32 years. Uterine curettage. Blood pressure 120/70 mmHg. Premedication : lorazepam
4 mg. Recorder speed 25 mm/sec. All Lead 4.
A. Immediately before induction; B. 5 minutes later, after ketamine 150 mg iv; C. 1 minute after
verapamil 10 mg iv.
876 M . Johnstone

Fig. 2. Robust male, 29 years. Menisectomy. Blood pressure 125/80 mmHg. Premedication: lorazepam
4 mg. Recorder speed 25 mmlsec; sensitivity 5 mm/mV.
A. Before induction, during insertion of intravenous cannula; B. 5 minutes later, after ketamine
200 mg iv.; C. 1 minute after verapamil 20 mg iv.

electrocardiograms showed increased sinus rates in most patients. The typical sequence
of cardiovascular responses to ketamine and verapamil are illustrated in Figs 1
and 2. Cardiovascular behaviour remained stable throughout the subsequent opera-
tions and the recoveries were smooth and uneventful in all patients.

Vagal bradycardia
The range of pulse rates before the induction of anaesthesia was 75-100 beats a
minute (mean 78) and that of the systolic pressures was 80-115 mmHg (mean 103).
The initial plethysmograms which were recorded during the insertion of intravenous
cannulae showed constriction of the finger vessels and dilatation of the muscle vessels
in all patients.
After the induction of anaesthesia with the halothane-nitrous oxide mixture the
range of pulse rates was 60-80 beats a minute (mean 66) and the systolic pressures
60-105 mmHg (mean 86). The bradycardia was of atrio-ventricular nodal origin
in 4 patients and of sinus origin in the remainder. The plethysmograms showed vaso-
dilatation of the finger vessels and constriction of the muscle vessels.
Ketamine caused no significant changes in the pulse rates, systolic pressures or
plethysmograms of any patient, the range of pulse rates being 50-95 beats a minute
(mean 65) and the systolic pressures 65-105 mmHg (mean 83).
Atropine caused immediate increases in the pulse rate and systolic pressure of every
patient and sinus rhythm was present in all patients 1 minute after the injection.
Isolated ventricular ectopic beats were seen in 4 patients and disappeared spontane-
ously in about I minute. The range of pulse rates after the atropine was 85-125 beats
a minute (mean 109) and the systolic pressures 120-140 mmHg (mean 126). The typical
sequence of changes in the electrocardiograms and the plethysmograms are illustrated
in Figs 3 and 4. The recovery from anaesthesia was smooth and uneventful in all
patients.
 Cardiovascular effects of ketamine 877

Fig. 3. Female, 34 years. Abdominal hysterectomy. Blood pressure 130/70 mmHg. Prernedication :
lorazepam 4 mg. Recorder speed 25 mmlsec. All Lead 4.
A. Before induction; B. 5 minutes later, under light nitrous oxide-halothane anaesthesia; C. 5
minutes after ketamine 150 mg iv; D. 30 seconds after atropine 0.5 mg iv; E. 1 minute later.

FINGER MUSCLE

Fig. 4. Robust male, 20 years. Tendon suture. Blood pressure 120/70 mmHg. Premedication: loraze-
pam 4 mg. Recorder speed 25 mmisec, sensitivity 5 mm/mV.
A. Before induction, during insertion of intravenous cannula; B. 5 minutes later, during light
halothane-nitrous oxide anaesthesia; C. 3 minutes after ketamine 200 mg iv; D. 1 minute after
atropine 0.5 mg iv.
878 M.Johnstone
SYSTOLIC B P
ALPHA (mmHg) BETA

Fig. 5. Female, 36 years. Abdominal hysterectomy. Blood pressure 135/80 mmHg. Premedication:
lorazepam 4 mg. Finger (alpha) and muscle (beta) plethysmograms. Recorder speed 25 mmlsec,
sensitivity 5 mm/mV.
1. Before surgery, under nitrous oxide-oxygen-pancuronium; 2. 15 minutes later, during surgery;
3. 1 minute later, after ketamine 100 mg iv.

Surgical vasoconstriction
After the induction of anaesthesia with propanidid and nitrous oxide and pancuronium
and before surgery the finger plethysmograms showed vasodilatation and the muscle
plethysmograms vasoconstriction. The finger vessels constricted during surgery. The
intravenous injection of ketamine caused the immediate return of digital vaso-
dilatation and moderate increases in the systolic pressures of all patients. The muscle
plethysmograms remained unaltered. The typical sequence of plethysmographic
FINGER MUSCLE

Fig. 6. Female, 19 years. Uterine curettage. Blood pressure 100/70 mmHg. Premedication: lorazepam
4 mg. Recorder speed 25 mmlsec, sensitivity 5 mm/mV.
A. During lorazepam sedation; B. 5 minutes later, after ergometrine 0-5 mg iv; C. 5 minutes after
ketamine 150 mg iv; D. 15 minutes later, during nitrous oxide-oxygen anaesthesia.
 Cardiovascular efects of ketamine 879

changes is illustrated in Fig. 5. The recovery from anaesthesia was smooth and un-
eventful in all patients.

Ergometrine vasoconstriction
Shortly after the injection of lorazepam each patient was well sedated and both the
finger and the muscle plethysmograms showed vasodilatation. The range of amplitude
of the finger waves was 16-26 mm (mean 18) and the muscle waves 15-23 mm
(mean 19). The systolic pressures ranged between 85 and 1 15 mmHg (mean 96).
Ten minutes after the injection of ergometrine the finger and the muscle plethysmo-
grams showed persistent vasoconstriction with pulse wave amplitudes ranging from
2 to 5 mm. The ranges of systolic pressures was 105-125 mmHg (mean 117).
The injection of ketamine had no effect on either the finger or the muscle vaso-
constriction and caused moderate increases in the systolic pressures, the range of
pressures being 125-145 mmHg (mean 132). Subsequent anaesthesia with nitrous
oxide-oxygen was associated with moderate decreases in the systolic pressure and in
the severity of the vasoconstriction in each patient. The typical sequence of plethysmo-
graphic changes is illustrated in Fig. 6. The recovery from anaesthesia was smooth
and uneventful in all patients.

Discussion
The arterial hypertension of ketamine is reversed by verapamil. Verapamil is a calcium
ion antagonist acting by impeding calcium transfer across cell membranes thereby
reducing the excitability, contractility and oxygen requirements of the myocardial and
the Purkinjt cells.'3 The mutual antagonism of ketamine and verapamil on cardiac
activity implies that ketamine is a direct myocardial stimulant acting through a
veratrine-like facilitation of calcium transfer across the cell membranes of the myo-
cardial and PurkinjC tissues thereby increasing their excitability, contractility and
oxygen requirements. This mode of action explains the ineffectiveness of propranolol
in preventing the arterial hypertension of ketamine. It also suggests that the mechanism
of the positiveinotropicaction of ketamine may be basically similar to that of digitalis."
The action of verapamil is not related to sympathetic blockade at any level and
although the drug has some effects similar to those of a beta blocker-negative ino-
tropic and antidysrhythmic-it does not modify the effect of sympathetic stimulation
on either cardiac function or oxygen uptake in relatively intact animals." This may
explain its failure to modify the sinus tachycardias of ketamine. The injection of
verapamil in patients under ketamine anaesthesia was often followed by further
increases in the sinus rates. This is probably a baroreceptor response to the falls in
arterial pressure caused by the verapamil and may be amenable to treatment with a
beta blocker if such treatment were considered safe. The combination of verapamil
and a beta blocker is thought to be dangerous as it may produce intense depression of
cellular activity in the myocardial and Purkinjt tissue^.'^
The use of a beta blocker in the control of the cardiac reactions to ketamine may
have to be considered in certain circumstances. It has been shown that ketamine sensi-
tizes the heart to adrenaline." Ketamine may therefore, be expected to precipitate
adrenergic dysrhythmias in frightened patients, in patients with untreated thyrotoxi-
cosis or phaeochromocytoma or when adrenaline is used for haemostasis. In these
circumstances a beta blocker may be the drug of choice for the control of the situation.
880 M.Johnstone
Kaplan and C o ~ p e r r n a n ’have
~ reported dramatic improvements after propranolol
1 mg intravenously in two patients with thyrotoxic heart disease in whom ketamine
precipitated very rapid supraventricular tachycardia and severe hypertension. When
confronted with an undesirable cardiac reaction to ketamine the anaesthetist should
consider the relative roles of adrenergic activity and calcium facilitation before
choosing the appropriate remedy. It remains to be seen whether verapamil and a
beta blocker can be used simultaneously with safety in anaesthetized patients.
Halothane prevents completely the increases in the sinus rate and the arterial pres-
sure caused by ketamine and has at least two actions operating simultaneously. One
is increased vagal activity and the other may be a direct verapamil-like depression of
calcium activity.
Stimulation of the cardiac vagal reflexes inhibits cardiac dysrhythmias of adrener-
gic origin.20 Excessive vagal stimulation may suppress all cardiac activity to produce
arrest in asystole.21The effect of vagal stimulation is mediated by acetylcholine which
inhibits the function of cell membranes by producing a state of hyperpolarization.
This reduces the excitability of the myocardial and the Purkinjt cells and may com-
pletely suppress their rhythmic self-excitation property.22 Atropine blocks the action
of acetylcholine and exposes the heart to the full effects of ketamine and of catechola-
mines. Ketamine is not vagolytic and its cardiac effects are increased by atropine.
Halothane in doses larger than those used in this study rapidly reverses the arterial
hypertension of ketamine in atropinized patients and the withdrawal of the halothane
is followed by the equally prompt return of the hypertension which means that halo-
thane, in addition to its vagotonic action, has a directly depressant effect on the myo-
cardium. It has been reported that the negative inotropic action of halothane on the
intact human heart is prevented by the intravenous injection of calcium chloride
solutions.23 This suggests that halothane, like verapamil, reduces the availability of
calcium at cell membrane level and lowers the excitability, contractility and the oxygen
requirements of the myocardial cells. This effect is consistent with Ferguson’s defini-
tion of an anaesthetic agent: ‘a drug which inhibits reversibly any biological function’.24
The cardiovascular effects of ketamine are not confined to the heart. The drug
dilates the finger vessels (alpha adrenoceptor) and constricts the somatic muscle blood
vessels (beta adrenoceptor). The respective vasodilatation and vasoconstriction persist
in the face of the most severe surgical stimuli, e.g. traction on abdominal viscera. This
indicates a block of the reflex sympathetic nervous reaction to adrenergic stimuli.
Pharmacological studies have not yet identified the level at which the block occurs
within the sympathetic reflex arc. It may be in the efferent pathways at either gang-
lionic or preganglionic level, or it may be in the afferent sensory pathways. It is not an
alpha adrenoceptor blockade because the drug has no effect on the vasoconstriction
of ergometrine which, like noradrenaline, is an alpha adrenoceptor agonist2’ the
vasoconstrictor effect of which is prevented by alpha blockers such as chlorpromazine
(Johnstone, unpublished work). Ketamine is not a directly acting vasodilator substance
as such a property would influence both the alpha and the beta adrenoceptor vascular
beds.” The use of ergometrine during ketamine anaesthesia may be potentially
dangerous in obstetric patients. The widespread vasoconstriction of ergometrine
coupled with the myocardial stimulation of ketamine and the hypervolaemia of late
pregnancy may overload the relatively passive pulmonary and cerebral circulations
and predispose to pulmmary or cerebral oedema. Oxytocin is preferable to ergome-
trine as its vasodilator action will tend to diminish the hypertension of ketamine.
The possibility that ketamine may produce sympathetic blockade by sensory de-
 Cardiovascular efects of ketamine 88 1

afferentiation may be considered. Self-experiments26 have shown that ketamine

causes a brief period of unconsciousness which is followed by the return of the ability
to think, to see and to hear. Skin and muscle-joint sensations do not return for a
further 40 minutes or more after a single anaesthetic dose. Smaller doses abolish skin
and muscle-joint sensations without seriously impairing consciousness. The subjective
feeling associated with the selective sensory deprivation of ketamine is not unlike
that experienced during the inhalation of sub-anaesthetic doses of nitrous oxide.
Barbara C ~ l l i e r , ~in’ her commentary on human consciousness, may be correct when
she suggests that the subjective feelings of ketamine, phencyclidine or lysergic acid
may be the result of the inability to feel gravity because of the loss of skin and muscle-
joint sensations: one becomes a disembodied mind floating in space when one is in a
silent darkened room.
The selective sensory deprivation of ketamine is an unpleasant and possibly
frightening experience especially in subjects without pharmacological insight in
whom it may provoke, like sensory deprivation by physical means,” hallucinations
and noisy delirium. It is for this reason that adequate sedation should be provided
throughout the period of ketamine action. Lorazepam promises to be the best drug
for this purpose, a single dose providing sedation, sleep and anterograde amnesia for
up to 12 hours in all patients except those who have become tolerant to any one of the
other benzodiazepines. Lorazepam, and perhaps other forms of sedation, has the
additional benefit of preventing the adrenergic reaction to fear and should therefore
diminish the arterial hypertension of ketamine.
Ketamine has an unusual combination of attractive features for use in surgical
anaesthesia and especially as an intravenous induction agent. It causes a brief period
of unconsciousness which is followed by a relatively long period of selective sensory
deprivation; it is a direct myocardial stimulant by what appears to be a digitalis-like
action; it prevents the reflex peripheral vascular reaction to the severest surgical
stimuli; and, in contrast to the natural and the synthetic opiates, it has comparatively
little effect on respiration. This is not to say that it is the perfect anaesthetic agent.
Its safe use requires a reasonable appreciation of its overall effects, especially the
cardiovascular effects and their control in patients whose coronary circulations may
not be sufficient to meet the increased metabolic demands imposed by ketamine on
their hearts.’ The least that may be said of ketamine at the present time is that it is
probably the most important advance in the symptomatic treatment of pain since the
discovery of opium.

Summary
The arterial hypertension of ketamine is prevented by verapamil, a calcium ion
antagonist. This indicates that ketamine is a direct myocardial stimulant acting by
increasing the availability of calcium across the cell membranes of the myocardial
and the Purkinjt systems. The positive chronotropic action of ketamine is not reversed
by verapamil. Both the chronotropic and the inotropic effects of ketamine are pre-
vented by halothane which acts partly by increased vagal tone and partly by what
appears to be a verapamil-like depression of calcium availability.
Ketamine blocks the reflex sympathetic response of the peripheral blood vessels to
surgical stimuli. Thr; site of the block within the sympathetic reflex arc has not been
identified. It is not at the alpha adrenoceptor level. The clinical implications of the
findings have been discussed.
882 M. Johnstone

Acknowledgments
Lorazepam (Ativan) was provided by John Wyeth and Brother Ltd. ;pharmacological
data on verapamil (Cordilox) by Abbott Laboratories Ltd. ; and the illustrations by
courtesy of the University of Manchester, Department of Medical Illustration.

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