Journal of Applied Physiology
Vol. 83, No. 4,
pp. 1110-1115,
October 1997
CONTROL OF BREATHING, CIRCULATION, AND TEMPERATURE
Effects of haloperidol on ventilation during isocapnic hypoxia
in humans
Michala E. F.
Pedersen,
Keith L.
Dorrington, and
Peter A.
Robbins
University Laboratory of Physiology, University of Oxford, Oxford
OX1 3PT, United Kingdom
ABSTRACT
- INTRODUCTION
- METHODS
- RESULTS
- DISCUSSION
- ACKNOWLEDGEMENTS
- FOOTNOTES
- REFERENCES
ABSTRACT 
Pedersen, Michala E. F., Keith L. Dorrington, and Peter A. Robbins. Effects of haloperidol on ventilation during isocapnic hypoxia in humans. J. Appl. Physiol.
83(4): 1110-1115, 1997.
Exposure to isocapnic hypoxia produces an
abrupt increase in ventilation [acute hypoxic ventilatory
response (AHVR)], which is followed by a subsequent decline
[hypoxic ventilatory depression or decline (HVD)]. In cats, both anesthetized and awake,
haloperidol has been reported to increase AHVR and almost entirely
abolish HVD. To investigate whether this occurs in humans, the
ventilatory responses of 15 healthy young volunteers to 20 min of
isocapnic hypoxia (end-tidal PO2 = 50 Torr) were assessed at 1, 2, and 4.5 h after placebo (control) and
after oral haloperidol (Seranace, 0.05 mg/kg) on different days. Three
subjects were unable to complete the study because of akathisia. AHVR
was significantly greater with haloperidol compared with control
(P < 0.01, analysis of variance).
However, no significant change in HVD was found [control HVD = 9.3 ± 1.6 (SD) l/min, haloperidol HVD = 9.9 ± 2.1 l/min;
P = not significant, analysis of
variance]. We conclude that combined central and peripheral
dopamine-receptor antagonism in humans with haloperidol produces a
similar pattern of change to that reported previously with the
peripheral antagonist domperidone. We have been unable to show in
humans a decrease in HVD by the centrally acting drug as observed in
cats.
dopamine; acute hypoxic ventilatory response; hypoxic ventilatory
decline
INTRODUCTION
THE HUMAN VENTILATORY RESPONSE to isocapnic hypoxia is
biphasic; there is an initial abrupt increase in ventilation at the onset of hypoxia [known as the acute hypoxic ventilatory response (AHVR)], which is then followed by a subsequent slower decline in
ventilation [known as hypoxic ventilatory depression or decline (HVD)] (7). The AHVR arises as a reflex response to the increase in chemoreceptor discharge from the carotid body, but the origins of
HVD remain a matter for debate (14, 17). One substance that affects the
ventilatory response to hypoxia is dopamine, which occurs naturally as
a neurotransmitter in the carotid body (15, 20). In humans, infusion of
low-dose dopamine (1-5
µg · kg
1 · min1)
causes a reduction in the AHVR (1, 2, 5, 19, 24-26). Whether
dopamine affects the subsequent HVD in humans if a period of isocapnic
hypoxia is sustained is controversial. Two studies have found that
dopamine reduces the magnitude of HVD (5, 25), and another found that
dopamine does not affect HVD (2). However, in the former two studies,
ventilation would have to have fallen below baseline values if the
magnitude of HVD were to have remained unaltered. In humans,
administration of domperidone, a peripheral dopamine antagonist, causes
an elevation of the AHVR (2, 6, 8, 11, 23) but does not affect the
magnitude of the following HVD (2, 8).
Recently, Tatsumi et al. (21) have reported, in both awake and
anesthetized cats, that haloperidol, a dopamine antagonist that crosses
the blood-brain barrier, abolishes HVD. They conclude that central
dopaminergic pathways are involved in the genesis of HVD. The purpose
of the present study was to administer haloperidol to human subjects to
see whether a similar abolition of HVD can be obtained.
METHODS
Subjects.
Fifteen healthy adults were studied (aged 19-51 yr, 7 men and 8 women). Their individual characteristics are listed in Table 1. Three of the subjects did not complete the study
because of the side effects of haloperidol. All subjects received
written and verbal descriptions of the experiment before they gave
their consent. The study was approved by the Central Oxford Research Ethics Committee.
|
Table 1.
Physical characteristics of subjects
|
| Subject No. |
Gender |
Age, yr |
Body Weight, kg |
|
| 973
|
F |
28 |
55 |
| 981 |
M |
51 |
85 |
| 985 *
|
F |
20 |
61 |
| 989 |
F |
20 |
50 |
| 1003 |
F |
23
|
62 |
| 1004 |
M |
19 |
60 |
| 1005 |
F |
20 |
61
|
| 1006 |
M |
20 |
75 |
| 1007 * |
M |
21
|
60 |
| 1008 |
F |
23 |
68 |
| 1010* |
M |
21
|
89 |
| 1015 |
F |
21 |
52 |
| 1023 |
M |
24 |
77
|
| 1025 |
M |
20 |
62 |
| 1026 |
F |
22 |
62 |
|
|
F, female; M, male.
*
Subjects who did not complete the study
because of side effects of haloperidol.
|
|
Protocols.
Before the experiment, subjects came into the laboratory for
familiarization with the procedures. The subjects then returned on two
different occasions, separated by at least 1 wk, for the actual study.
On one day a single dose of haloperidol (Seranace, 0.05 mg/kg) was
administered; on the other day a placebo tablet was given. The order of
the two experiments was chosen randomly. To evaluate the effects of the
drug on ventilation during isocapnic hypoxia, the following hypoxic
exposure was employed: end-tidal PO2
(PETO2) was held at 100 Torr
for the first 5 min, then abruptly lowered to 50 Torr for 20 min, and
finally returned to 100 Torr for the last 5 min. End-tidal
PCO2 (PETCO2) was held at
1-2 Torr above its normal value throughout the experimental
period. The hypoxic exposure was repeated three times for each subject
under both pharmacological conditions, at 1, 2, and 4.5 h after
placebo/haloperidol administration. Ten minutes before each exposure, a
venous blood sample (10 ml) was taken for measurement of haloperidol
concentration as described below.
An anticholinergic drug (procyclidine, single dose of 5 mg po) was
available to reverse the side effects of haloperidol, either during the
course of an experiment, in which case the experiment was abandoned, or
after the experiment if the subject felt uncomfortable.
To assess the level of side effects, we used a brief questionnaire that
was sent to the subjects a few days after the experiment.
Measurement of plasma haloperidol concentrations.
The plasma samples were analyzed by Cozart Bioscience (Abingdon, Oxon,
UK). A haloperidol microplate enzyme immunoassay, which is
a solid-phase immunoassay designed to work with a sample of urine,
serum, and whole blood, was used. The test was performed in microwells
coated with a high-affinity antibody. A sample was added to the wells
followed by an enzyme conjugate. During the following incubation
period, the enzyme conjugate competed with the drug in the sample for
binding sites on the antibody-coated well. After a wash step to remove
any unbound material, substrate was added for the final
color-development process. The color intensity is inversely
proportional to the amount of drug present in the sample. Therefore,
those samples that contain the drug would inhibit the binding of the
enzyme conjugate to the capture antibody, resulting in less color than
in the negative control. Haloperidol concentration in the samples was
then obtained by reading the absorbance of the wells with a microplate
reader and comparing the color intensity with known controls. The
minimum level of detection of the assay was 0.4 mg/ml. Control samples
were run with the assay, with a maximum variation of ±10% being
taken as acceptable.
Respiratory measurements.
Subjects were seated comfortably and breathed through a mouthpiece with
the nose occluded. A pulse oximeter was attached to a finger to monitor
oxygen saturation, and electrodes were placed on the chest to obtain
the electrocardiogram. The mouthpiece was connected in series with a
turbine volume-measuring device (10) and a pneumotachograph to measure
respiratory volumes and flows. Gas was sampled at the mouth
continuously and analyzed for PCO2 and PO2 by mass spectrometry. All
experimental data were recorded in real time at a sampling frequency of
50 Hz by computer, which also determined
PETO2 and
PETCO2 together with the
inspiratory and expiratory volumes and durations. The end-tidal gas
values were then passed, breath by breath, to a second computer, which
controlled a fast-responding gas-mixing system. The computer that
controlled the gas-mixing system compared the actual end-tidal values
with the desired values and, to obtain the desired end-tidal profile,
made appropriate adjustments to the inspired gas. The details of the
forcing procedure and the gas-mixing system are described in greater
detail elsewhere (10, 18).
Data analysis.
The experiment resulted in three sets of data for each subject in each
pharmacological condition. Data from each trial were time averaged over
60-s intervals. From these, four 1-min periods were used to calculate
the magnitude of the rapid component of the ventilatory responses at
the onset (on-response) and relief (off-response) of hypoxia and the
magnitude of HVD. The four periods (Fig. 1)
were 1) the last minute of the first
euoxic period (prehypoxic ventilation),
2) the second minute of the hypoxic
period (peak ventilation), 3) the
last minute of the hypoxic period (depressed ventilation), and
4) the second minute of the euoxic
recovery period (posthypoxic ventilation). The on-response
was calculated as the difference between peak and prehypoxic
ventilation. The magnitude of HVD was obtained as the difference
between peak and depressed ventilation. The magnitude of the
off-response was calculated as the difference between depressed and
posthypoxic ventilation.
Fig. 1.
A: four 1-min periods used to
calculate magnitude of on-response, hypoxic ventilatory depression or
decline (HVD), and off-response. 
E,
ventilation. B and
C: associated end-tidal
PO2
(PETO2) and end-tidal
PCO2
(PETCO2), respectively
.
[View Larger Version of this Image (15K GIF file)]
Statistical differences between the various measures of the ventilatory
response to the end-tidal gas profile in the two conditions were
assessed by using analysis of variance (ANOVA) with subjects as a
random factor and drug (placebo or haloperidol) and time (1, 2, 4.5 h)
as fixed factors, together with the interactive terms. A probability of
<0.05 was taken as statistically significant. Analysis was undertaken
by using the SPSS statistical software package.
RESULTS
Side effects of haloperidol.
Ten of the 15 subjects that took part reported side effects from the
administration of haloperidol. Three did not wish to finish the study
and were treated with procyclidine before completion. These three
subjects reported unpleasant agitation, uncomfortable restlessness, a
feeling of tenseness, and an inability to sit still (akathisia). Their
data are not included in the results. The other seven who felt side
effects reported agitation, restlessness, and akathisia to varying
degrees but always only beginning 2 h or more after drug
administration. No subject felt side effects from the placebo.
Measured concentrations of drug.
The haloperidol concentrations for the three blood samples (1, 2, and
4.5 h after drug administration) from each subject are listed in Table 2. The concentration
increased over time, consistent with reported times to peak plasma
concentration of 1.7-3.2 h (9) and 4.5 h (12), although the
pharmacokinetics for haloperidol are known to show wide intersubject
variation. This increase in concentration is consistent with the
intensification of side effects observed over time.
|
Table 2.
Initial dose and measured concentrations of haloperidol in plasma
samples taken 1, 2, and 4.5 h after drug administration
|
| Subject No. |
Dose, mg
|
Haloperidol in Plasma, ng/ml
|
| 1 h |
2 h |
4.5
h |
|
| 973 |
2.75 |
<0.04 |
1.74 |
1.66 |
| 981 |
4.1
|
<0.04 |
1.74 |
3.41 |
| 985 * |
3.0 |
1.32
|
1.75 |
| 989 |
2.25 |
<0.04 |
1.97 |
| 1003 |
3.0
|
<0.04 |
<0.04 |
1.89 |
| 1004 |
3.0 |
<0.04 |
1.59
|
2.78 |
| 1005 |
3.0 |
<0.04 |
1.80 |
2.38 |
| 1006
|
3.75 |
<0.04 |
1.65 |
3.10 |
| 1007 * |
3.0
|
<0.04 |
<0.04 |
1.74 |
| 1008 |
3.4 |
<0.04 |
1.33
|
2.26 |
| 1010* |
4.5 |
<0.04 |
1.40 |
2.76
|
| 1015 |
3.0 |
<0.04 |
0.74 |
3.02 |
| 1023 |
3.8
|
<0.04 |
0.61 |
3.01 |
| 1025 |
3.0 |
0.69 |
0.73
|
2.55 |
| 1026 |
3.0 |
<0.04 |
1.06 |
3.62 |
|
|
*
Subjects who did not complete the study because of side
effects of haloperidol.
|
|
Quality of gas control.
The quality of the gas control obtained is illustrated for one subject
on a breath-by-breath basis in Fig. 2.
Averages for individual subjects are shown in Fig.
3.
PETCO2 values were held
constant throughout most of the exposure but did vary slightly in a few
subjects during transitions into and out of hypoxia.
PETO2 was lowered and raised
abruptly at the onset and relief of hypoxia.
Fig. 2.
Breath-by-breath gas control and breath-by-breath ventilatory responses
from subject 1023 1 h after
administration of placebo (A) and
haloperidol (B).
[View Larger Version of this Image (16K GIF file)]
Fig. 3.
Top panels: ventilatory responses to
hypoxia (1-min averages, mean of 3 exposures for each subject) for
placebo (A) and haloperidol (B).
Middle and bottom
panels: associated
PETO2 and
PETCO2, respectively.
[View Larger Version of this Image (21K GIF file)]
Ventilatory responses.
Figure 3 and Table 3 show the ventilatory
responses for each individual subject (average of 3 repeats for each
protocol). The general form of response to the hypoxic
exposure seems similar in all subjects. Of particular note is that
haloperidol does not appear to have suppressed HVD (it increased HVD in
7 subjects and reduced it in 5 subjects). However, both the on-response
(all subjects) and the off-response (all but 2 subjects) appear greater after administration of haloperidol than during control conditions. The
overall means for all subjects in each pharmacological condition are
illustrated in Fig. 4 and appear consistent
with the above observations.
|
Table 3.
On-response, off-response, and HVD for each subject
|
| Subject No. |
Control
|
Haloperidol
|
| On-response |
Off-response |
HVD
|
On-response |
Off-response |
HVD |
|
| 973 |
11.7 |
1.9
|
5.1 |
14.8 |
13.2 |
4.9 |
| 981 |
10.2 |
2.9 |
9.0
|
11.2 |
 0.6 |
8.8 |
| 989 |
16.3 |
7.1 |
13.1 |
18.1
|
6.1 |
15.2 |
| 1003 |
6.4 |
3.0 |
3.0 |
10.0 |
7.8
|
3.3 |
| 1004 |
14.1 |
11.1 |
2.9 |
18.1 |
16.3 |
3.3
|
| 1005 |
13.2 |
7.1 |
7.8 |
18.8 |
9.1 |
10.7 |
| 1006
|
15.3 |
7.2 |
12.0 |
19.7 |
10.1 |
12.3 |
| 1008 |
10.9
|
8.9 |
4.0 |
13.7 |
10.2 |
3.5 |
| 1015 |
14.7 |
6.6
|
6.9 |
18.2 |
9.4 |
9.1 |
| 1023 |
11.5 |
3.4 |
11.2
|
16.5 |
7.0 |
10.3 |
| 1025 |
20.7 |
4.8 |
21.0 |
35.2
|
12.9 |
33.6 |
| 1026 |
19.7 |
6.6 |
15.7 |
21.4 |
13.0
|
11.5 |
|
| Mean ± SE
|
13.7 ± 1.2 |
5.9 ± 0.8 |
9.3 ± 1.6 |
17.9 ± 1.9 |
9.5 ± 1.3 |
9.9 ± 2.1 |
|
|
Values are for 12 subjects given in l/min. For explanation of
on-response, off-response, and hypoxic ventilatory depression or
decline (HVD), see Fig. 1.
|
|
Fig. 4.
A: average across all subjects for
ventilatory response to 20 min of hypoxia after placebo (
) and
haloperidol (
). B and C: associated
PETO2 and
PETCO2, respectively. Error
bars, SE.
[View Larger Version of this Image (17K GIF file)]
In view of the rising concentration of haloperidol over the repeats of
the protocol at 1, 2, and 4.5 h, it is possible that taking the mean of
the three repeats is obscuring a dose-dependent effect. This
possibility is examined in Fig. 5, where
the ventilatory responses have been averaged across all subjects but
where the three averages for the repeats have been kept separate. No
differential effects over time are apparent from Fig. 5.
Fig. 5.
Average ventilatory responses to isocapnic hypoxia across all subjects
at 1 (A), 2 (B), and 4.5 h
(C) after administration of placebo
() and haloperidol ().
[View Larger Version of this Image (15K GIF file)]
The above impressions were tested statistically by using ANOVA. There
was no significant effect of time in either protocol. The on-response
was significantly greater after pretreatment with haloperidol compared
with the control condition (P < 0.001), as was the off-response (P < 0.001). There was, however, no significant difference
(P = not significant) in the magnitude
of HVD between the two pharmacological conditions.
DISCUSSION
Effect of haloperidol on the AHVR to hypoxia.
Our results demonstrate that the ventilatory sensitivity
to hypoxia is increased after pretreatment with haloperidol, a
peripherally and centrally acting dopamine antagonist. This appears
inconsistent with the results of Bainbridge and Heistad (1), who found
that haloperidol, in a dose similar to that used in the present study, did not have any significant effect on the ventilatory response to
hypoxia. One important difference between the two studies was that the
exposures to hypoxia used by Bainbridge and Heistad were poikilocapnic
rather than isocapnic, and this resulted in rather small increases in
ventilation of only 1.4 l/min in control experiments and 1.7 l/min in
experiments with haloperidol. This might have masked an effect of
haloperidol on AHVR. Other differences between the two sets of
experiments include the route of administration of the drug and the
time at which the measurements were made. Bainbridge and Heistad
administered the haloperidol by intramuscular injections and began
their measurements 10 min later. Measurements were always complete by
70 min.
Other studies in humans that have used different dopamine antagonists,
droperidol (22) and prochlorperazine (16), have, as in the present
study, found an augmented hypoxic ventilatory response. Both these
antagonists, like haloperidol, cross the blood-brain barrier and are
both centrally and peripherally acting.
The effects of haloperidol on AHVR are very similar to those obtained
with domperidone, a peripheral dopamine antagonist that does not cross
the blood-brain barrier. In the present study the mean increase in AHVR
with haloperidol was 31%. Bascom et al. (2) obtained an average
increase in AHVR with domperidone of 39%. Foo et al. (8) found an
increase in AHVR of 19.6% with domperidone. In the study by Bainbridge
and Heistad (1), the actual change in AHVR with haloperidol was 21%;
however, possibly because of the very low ventilatory responses to
poikilocapnic hypoxia (1.4 and 1.7 l/min, respectively), the changes
did not reach statistical significance. The similarity between the
results for domperidone and those for haloperidol suggests that the
effect of haloperidol on AHVR is mostly peripheral, with little central modification.
The effect of haloperidol on the AHVR was constant throughout the
experiment, despite the fact that the concentration of haloperidol in
the blood increased substantially between repeats of the hypoxic exposure. This suggests that the effect was already fully developed after 1 h at the very lowest concentration. This result is consistent with the finding that other peripheral effects of haloperidol can be
obtained at low dose; in particular the antiemetic effect of
haloperidol is obtained with a postoperative dose of 0.5-1.0 mg.
Chow et al. (4) reported dose-response curves for haloperidol (0.1-1,000 µg/kg) in the anesthetized cat. They found that
haloperidol produced a dose-related progressive increase in ventilation
over the range of very low-dose haloperidol (0.1-10 µg/kg), an
increased but steady response at low dose (10-100 µg/kg), and a
tendency for depression of ventilation at any higher dose. These
findings are consistent with our finding that the full effect of
haloperidol on AHVR is reached at very low dose. With use of a standard
volume of distribution in the midrange of estimates of 15 l/kg (9), our
blood concentrations would correspond to intravenous doses of 1, 19, and 40 µg/kg at 1, 2, and 4.5 h. With the exception of the first
measurement, these correlate well with the first part of the
dose-response curve of Chow et al., where there is no further increase
in ventilation with increasing dose of haloperidol.
Effect of haloperidol on HVD.
Haloperidol at the dose used in this study did not have any significant
effect on HVD in humans. We are unaware of any other results from human
studies with which to compare this finding, but it appears to differ
from the finding of Tatsumi et al. (21) that haloperidol abolished HVD
in the cat. Two possible explanations for this difference are
1) a species difference and
2) a difference in the dose of
haloperidol used. With respect to a species difference, one possibility
is that HVD in the cat is a poor model of HVD in humans. Indeed, early
work in the cat suggested that HVD occurred in the absence of a
peripheral chemoreceptor input, whereas in humans the peripheral
chemoreceptor input was required (17). However, more recent work
suggests that this difference may be related to anesthesia and that in
awake cats a peripheral chemoreflex is required for HVD to occur (13,
17). In the experiment of Tatsumi et al., the cats were studied awake
as well as anesthetized, and an abolition of HVD was found in both
cases.
Turning to the second possibility of a difference in dose of
haloperidol, Tatsumi et al. administered a dose of haloperidol of 0.1 mg/kg iv to their cats. They found, in a preliminary study, that a dose
of haloperidol of 0.3 mg/kg iv completely blocked the inhibitory effect
of intravenous dopamine (10 mg) on carotid sinus nerve activity. They
used the lower dose of 0.1 mg/kg in the main study to avoid the
behavioral effects of the drug. However, even at this dose, they
reported a transient hypoactivity and sedation that largely disappeared
within 10 min. Similar hypoactivity and sedation in cats has been
reported by Bonora and Gautier (3), who used a dose of 0.1 mg/kg iv.
Bonora and Gautier also observed that this dose was sufficient to
reverse the inhibitory effect of apomorphine, a centrally acting
dopamine agonist.
In a pilot study we tried an oral dose of 0.1 mg/kg on three subjects
to match the intravenous dose employed in the cat, but all subjects
suffered intolerable side effects (akathisia, tenseness, etc.) after
~2 h. For this reason, for the study reported here, the postoperative
dose was halved to 0.05 mg/kg. Even at this dose, side effects were
seen in 10 of 15 subjects, with 3 subjects withdrawing from the study
before completion. Thus our dose was chosen on the same criteria as
used by Tatsumi et al. (21): as high as possible without provoking
excessive side effects.
In a comparison of the intravenous dose in the cats to the oral dose in
humans, absorption is another factor that has to be considered.
Bioavailability has been reported as in the range 60-65% (9). The
mean level of the drug at 4.5 h was 2.6 ng/ml. By using a standard
volume of distribution of 15 l/kg (9) and assuming equilibration, this
corresponds to a dose of 0.04 mg/kg, giving a bioavailability of 80%.
These factors suggest that the majority of the drug was absorbed, and
thus the route of administration is relatively unimportant.
In summary, both the cats used by Tatsumi et al. (21) and our human
subjects exhibited some features associated with the central effects of
haloperidol, and the difference between the actual doses employed is
probably only a factor of about three. Hence, it seems unlikely that
the different results between the two studies, in the one case complete
abolition of HVD and in the other case no effect, can be attributed
purely to differences in the dose of haloperidol employed.
Conclusion.
We determined the following. 1)
Combined peripheral and central dopamine-receptor antagonism in humans
with haloperidol produces a similar pattern of change in the
ventilatory response to sustained hypoxia to that seen with peripheral
receptor antagonism with domperidone alone.
2) We have been unable to show in
humans a decrease in HVD by the centrally acting drug as observed in
cats.
ACKNOWLEDGEMENTS
We thank D. F. O'Conner for skilled technical assistance.
FOOTNOTES
This study was supported by the Wellcome Trust. M. E. F. Pedersen holds
a Medical Research Council fees-only studentship and a scholarship from
the Danish Research Academy.
Address for reprint requests: P. A. Robbins, Univ. Laboratory of
Physiology, Parks Rd., Oxford OX1 3PT, United Kingdom (E-mail:
peter.robbins{at}physiol.ox.ac.uk).
Received 12 March 1997; accepted in final form 22 May 1997.
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