Effects of Butorphanol on Respiration in White Rhinoceros

(Ceratotherium simum ) Immobilized with Etorphine-Azaperone

Peter Buss,1,2,3,7 Michele Miller,4 Andrea Fuller,2,3 Anna Haw,2 Emily Thulson,5

Francisco Olea-Popelka,6 and Leith Meyer2,3

1 Veterinary Wildlife Services, South African National Parks, Kruger National Park, Private Bag X402, Skukuza 1350,
South Africa
2 Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 29
Princess of Wales Terrace, Private Bag 3, 2050, Parktown, South Africa
3 Department of Paraclinical Sciences and Centre for Veterinary Wildlife Research, Faculty of Veterinary Science, Uni-
versity of Pretoria, Soutpan Road, Wildlife Hub Building, Private Bag X04, Onderstepoort 0110, South Africa
4 Department of Science and Innovation, National Research Foundation Centre of Excellence for Biomedical Tuberculo-
sis Research, South African Medical Research Council Centre for TB Research, Division of Molecular Biology and
Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000,
South Africa
5 Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Science, Colorado State University,
300 W. Drake Road, Fort Collins, Colorado 80523, USA
6 Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Dental Sciences Building
Room 4044, Western University, 1151 Richmond Street, London, Ontario N6A5C1, Canada
7Corresponding author (email: peter.buss@sanparks.org)

ABSTRACT: This article reports on respiratory function in white rhinoceros (Ceratotherium simum)
immobilized with etorphine-azaperone and the changes induced by butorphanol administration as part
of a multifaceted crossover study that also investigated the effects of etorphine or etorphine-butorphanol
treatments. Six male white rhinoceros underwent two immobilizations by using 1) etorphine-azaperone
and 2) etorphine-azaperone-butorphanol. Starting 10 min after recumbency, arterial blood gases, limb
muscle tremors, expired minute ventilation, and respiratory rate were evaluated at 5-min intervals for 25
min. Alveolar to arterial oxygen gradient, expected respiratory minute volume, oxygen consumption, and
carbon dioxide production were calculated. Etorphine-azaperone administration resulted in hypoxemia
and hypercapnia, with increases in alveolar to arterial oxygen gradient, oxygen consumption, and carbon
dioxide production, and a decrease in expired minute ventilation. Muscle tremors were also
observed. Intravenous butorphanol administration in etorphine-azaperone–immobilized white
rhinoceros resulted in less hypoxemia and hypercapnia; a decrease in oxygen consumption, carbon
dioxide production, and expired minute ventilation; and no change in the alveolar to arterial
oxygen gradient and rate of breathing. We show that the immobilization of white rhinoceros with
etorphine-azaperone results in hypoxemia and hypercapnia and that the subsequent intravenous
administration of butorphanol improves both arterial blood oxygen and carbon dioxide partial pressures.
Key words: Azaperone, butorphanol, etorphine, metabolism, white rhinoceros.

INTRODUCTION

Etorphine-azaperone is preferentially used in
the immobilization of free-ranging white rhinoc-
eros (Ceratotherium simum) for management
purposes (La Grange et al. 2016). Etorphine, a
high-potency opioid, enables a sufficient dose
for the immobilization of a rhinoceros to be
delivered intramuscularly (IM) by dart; however,
a major side effect is depression of ventilation,
resulting in hypoxemia, hypercapnia, and acide-
mia (Buss et al. 2018). Alternative potent opioids
including thiafentanil or carfentanil are not
routinely used in the immobilization of free-
ranging white rhinoceros. Etorphine is seldom

administered on its own and is usually com-
bined with azaperone, a butyrophenone tran-
quilizer, to shorten induction time from drug
administration to the animal becoming immobi-
lized (Buss et al. 2022). Azaperone modifies ani-
mal behavior, primarily by dopamine receptor
blockade (Leysen and Gommeren 2008), and
may influence breathing modulation through
central and peripheral receptors (Hsiao et al.
1989). Although etorphine-azaperone is com-
monly used to immobilize rhinoceros, ventila-
tory perturbations pose significant mortality
risks, especially in already compromised indi-
viduals. Therefore, it is essential to investigate
the pathophysiology of these negative physiologic

388

DOI: 10.7589/JWD-D-23-00034 Journal of Wildlife Diseases, 60(2), 2024, pp. 388–400
� Wildlife Disease Association 2024

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mailto:peter.buss@sanparks.org


consequences to facilitate the development
of improved chemical capture procedures
(Miller et al. 2013; Boardman et al. 2014; Haw
et al. 2014).
In the past 10 yr, butorphanol has been com-

monly administered to immobilized rhinoceros
in the belief that it antagonizes depression of
ventilation caused by various anaesthetic agents
(Haw et al. 2014; Wenger et al. 2007). As part
of a larger study, Buss et al. (2018) showed that
administration of butorphanol intravenously
(IV) in etorphine-immobilized rhinoceros, at a
ratio of 10 mg of butorphanol to 1 mg of etor-
phine, lessened the marked opioid-induced
hypoxia and hypercapnia; this effect was medi-
ated by decreased oxygen consumption and car-
bon dioxide production associated with reduced
muscle tremoring.
The aim of this study was to investigate the

effects of butorphanol in white rhinoceros immo-
bilized with etorphine-azaperone, the effects
of which had not been investigated previously.
It was hypothesized that the administration of
butorphanol to etorphine-azaperone–immobi-
lized white rhinoceros would decrease meta-
bolic rate, resulting in decreased hypoxemia
and hypercapnia.

MATERIALS AND METHODS

Study design

The study had ethical approval from the South
African National Parks (SANParks) Animal Use
and Care Committee (reference 14-2) and the
University of the Witwatersrand Animal Research
Ethics Committee (reference 2014/15/C). Man-
agement of the white rhinoceros was conducted
according to the SANParks standard operating
procedures for the capture, transportation, and
maintenance in holding facilities of wildlife.

Six subadult (5- to 6-yr-old) male white rhinoc-
eros were captured in the Kruger National Park,
South Africa, in June 2014 and habituated to cap-
tivity in holding pens over a period of 4 mo. The
number of study animals was limited by welfare
considerations and logistical challenges associated
with adapting and managing wild-caught rhinoc-
eros in captivity. White rhinoceros were adminis-
tered the following two treatments from October

2014 to February 2015: 1) etorphine (9.8 mg/mL,
M99, Elanco, Gauteng, South Africa)-azaperone
(40 mg/mL, Janssen Pharmaceutical Ltd., Half-
way House, South Africa) IM and 2) etorphine-
azaperone IM followed by butorphanol (50 mg/mL,
Kyron Laboratories, Gauteng, South Africa) IV. Both
treatments included hyaluronidase (5,000 IU, Kyron
Laboratories). Doses were 2.5 mg of etorphine, 37.5
mg of azaperone, and 25 mg of butorphanol for
1,000- to 1,250-kg white rhinoceros and 3.0 mg of
etorphine, 45 mg of azaperone, and 30 mg of butor-
phanol for 1,250- to 1,500-kg white rhinoceros (Haw
et al. 2014; Buss et al. 2016). An additional two treat-
ments, etorphine alone and etorphine-butorphanol,
were part of a larger study in the same white rhinoc-
eros (Buss et al. 2018).

A multifaceted crossover study design was used
in which a study white rhinoceros was randomly
allocated one of the two treatments and 2 wk later
it was administered the second treatment. Food
and water were removed from the white rhinoc-
eros in the late afternoon, and it was immobilized
in an outdoor holding facility early the next morn-
ing when environmental temperatures were cool.

Drug administration and sample collection

Etorphine-azaperone was administered using a
3.0-mL plastic dart with a 60-mm uncollared nee-
dle propelled from a compressed air rifle (DAN-
INJECT, Skukuza, International S.A., South Africa).
Induction time was measured as the time from dart
placement to the animal becoming recumbent with
its body on the ground either in a sternal or lateral
position. The immobilized rhinoceros was blind-
folded and initially placed in sternal recumbency for
1 min and then subsequently rolled randomly into
right or left lateral recumbency to facilitate instru-
mentation. The influence of variable induction times
on physiologic measurements was reduced by con-
ducting a trial only if the rhinoceros became recum-
bent and could be safely handled within 15 min
after darting (Buss et al. 2018). As part of the
larger study, each rhinoceros was immobilized
four times; however, two rhinoceros did not
become immobilized within this time limit and
the interventions were repeated after a 2-wk
washout period. These two animals were immobi-
lized five times. Recumbency was used as an indica-
tor of immobilization level equivalency between
trials. Data collection started 10 min after initial
recumbency (t ¼ 0) and was repeated at 5-min

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intervals over a 25-min study period. Butorphanol
was administered IV into an auricular vein by using
a 1-mL syringe and 20-gauge needle (Thermo Fisher
Scientific, Randburg, South Africa) at 2 min (t ¼ 2)
because this allowed for initial data collection at t ¼
0 and most closely approximated the time at which
butorphanol is administered in field-immobilized rhi-
noceros. In rhinoceros not receiving butorphanol,
sterile saline was administered IV at t ¼ 2. At the
end of each trial, all rhinoceros were weighed,
administered naltrexone (40 mg/mL, Kyron laborato-
ries) IV at 20 times the etorphine dose (in milli-
grams), and observed until standing without any
residual etorphine-induced clinical effects. The rhi-
noceros were monitored for a further 2 wk as
described by Miller et al. (2016) to ensure sufficient
food intake; appropriate fecal volume, color, and
consistency; and normal demeanor.

Once a rhinoceros was instrumented, respiratory
functions, oxygen consumption, arterial blood gases,
and muscle tremor scores were evaluated. Respira-
tory physiologic values were calculated as described
previously (Buss et al. 2018). Expired minute venti-
lation corrected for body temperature and saturated

pressure ( _VEBTPS in liters per minute) was measured
by redirecting expired air through a PowerLab exer-
cise physiology system (ADInstruments, Castle Hill,
New South Wales, Australia) by using modified
equine endotracheal (ET) tubes (Jørgen Kruuse A/S,
Langeskov, Denmark) inserted into each nostril with
the cuffs inflated to create an airtight seal; a 1,000-L/
min capacity respiratory flow head linked to a spi-
rometer (ML140); and a 4.7-L capacity gas mixing
chamber (all from ADInstruments). A two-way Y-
shape nonrebreathing valve (2730 Series; Hans
Rudolph, Inc., Shawnee, Kansas, USA) was attached
to the end of each ET tube to allow inspiration of
fresh air and expiration through the PowerLab sys-
tem. Expired air temperature was recorded by a
thermistor pod (ADInstruments) in the mixing cham-
ber. The respiratory flow head was calibrated daily
according to manufacturer’s instructions.

Expired air was collected in a Douglas bag
(Harvard Apparatus, Holliston, UK) for 1 min
during each sampling interval and analyzed using
a multiparameter monitor (Cardiocap/5, Datex-
Ohmeda, GE Healthcare, Helsinki, Finland) for
mixed-expired carbon dioxide pressure (PECO2,
in millimeters of mercury) and mixed-expired
oxygen percentage (FEO2 in percent). Expired
air from one of the ET tubes was analyzed using
the same monitor to determine end-tidal carbon

dioxide pressure (in millimeters of mercury), oxy-
gen fraction (in percent), and respiratory rate
(fR). Body temperature (T in Celsius) was mea-
sured using a rectal digital thermometer (BAT-12,
Physitemp Instruments, Clifton, New Jersey,
USA).

Arterial blood samples were collected into 1-mL
heparinized syringes from a 22-gauge IV catheter
placed into an auricular artery, and immediately ana-
lyzed using a portable blood gas analyser (i-STAT 1
handheld clinical analyzer, Heska Corporation,
Loveland, Colorado, USA) and CG4þcartridge
(i-STAT CG4þcartridges, Heska Corporation).
Alveolar to arterial oxygen gradient [P(A-a)O2 in
millimeters of mercury] was calculated using the for-
mula FIO2(PB�PH2O)–(PaCO2/RQ)�PaO2, where
PaO2 is arterial partial pressure of oxygen, PaCO2 is
arterial partial pressure of carbon dioxide, and RQ is
respiratory quotient. Inspired fraction for oxygen
was assumed to be FIO2 ¼ 20.9% and barometric
pressure (PB in millimeters of mercury) was mea-
sured by the portable blood gas analyzer before
each immobilization. The RQ is unknown for white
rhinoceros and was assumed to be 1. Alveolar vapor
pressure of saturated air (PH2O in millimeters of
mercury), at a specific T, was determined using the
formula 4.58 exp [(17.27 T)/(237.3þT) according to
Meyer et al. (2010) and expected respiratory minute

ventilation ( _VEXP in liters per minute) before
immobilization was estimated using the formula
0.518 (body mass0.802; Bide et al. 1997). Actual
respiratory minute ventilation was equivalent to
_VEBTPS, which was divided by fR to calculate tidal
volume (VT in liters per breath).

The Enghoff modified Bohr’s equation ((PaCO2�
PECO2/PaCO2)3VT was used to determine physio-

logic dead space ( _VDPHYS in liters per breath;

Tusman et al. 2012). The calculated _VDPHYS

was corrected by 300 mL/breath for the volume of
the two ET tubes extending beyond the rhinoc-
eros’ nostrils.

Oxygen consumption ( _VO2 in liters per minute)
was calculated as describe previously (McArdle et al.

1986) as _VO2 ¼ (FIO2�FEO2)/1003ð _VESTPD),
_VESTPD is expired minute ventilation at standard

temperature and dry pressure. The _VEBTPS was
multiplied by (273/310)((PB�47)/760) to convert
from BTPS to standard temperature and pressure
and dry (STPD; West 2008). The Haldane transfor-
mation was used to correct the inspired oxygen

volume, that is, _VO2 ¼ _VESTPD(FIO2((1�(FEO2þ

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FECO2)/1�(FIO2þFICO2))�FEO2) according to
McArdle et al. (1986), because inspired and
expired minute ventilations were not equivalent

(depending on the RQ), and _VESTPD was used to
determine both FIO2 and FEO2. The inspired
fraction for carbon dioxide (FICO2) was assumed
to be 0.03% and FECO2 was calculated as PECO2

as a percent of PB. Carbon dioxide production

( _VCO2 in liters per minute) was calculated as

the product of _VESTPD and the difference
between expired and inspired carbon dioxide

fractions [ _VESTPD(FECO2�FICO2)] according
to McArdle et al. (1986).

Muscle tremor scores, especially of the limbs,
head, and shoulder, were subjectively evaluated
by a single observer at each time point by using
set criteria (Table 1). Scores ranged from 1 (no
visible tremors) to 5 (severe tremors). Total mus-
cle tremor scores were calculated as the sum of
all scores per time point for that treatment.

Interpretation of the physiologic parameters
resulting from etorphine-azaperone and etor-
phine-azaperone-butorphanol was facilitated by
comparing results with those from the same rhi-
noceros administered etorphine alone or etor-
phine-butorphanol as part of the multifaceted
crossover study (Buss et al. 2018). Equivalent drug
doses were administered to all study animals under
the same conditions, and the resulting physiologic
effects were evaluated using identical methods
(Buss et al. 2018).

Data analyses

We used STATA 14 (StatCorp, College Station,
Texas, USA) for statistical analyses. Descriptive
statistics were calculated to assess data distribution

for each treatment at different sampling points.
Because of the small sample size (n ¼ 6), nonpara-
metric statistical tests were used to compare median
blood gas and respiratory values at specific sampling
points within each treatment. For an initial and
exploratory phase, the Kruskal-Wallis test was used
to assess whether median values for blood gases and
respiratory variables differed over sampling points.
Median values were then compared between t ¼ 0
and t ¼ 10 as well as t ¼ 0 and t ¼ 25, and t ¼ 10
and t ¼ 25 by using the Wilcoxon signed rank test.
To confirm that no further changes occurred
after 10 min, linear regression (using ranks) was
used to assess changes in blood gases and respira-
tory parameters after 10 min by using t ¼ 10 as the
reference value. Correlations between blood gases,
respiratory parameters, and muscle tremor scores
were evaluated using linear regression while con-
trolling for time and repeated measures. Statistical
significance was set at P,0.05 for all statistical tests.

RESULTS

All rhinoceros except two became recumbent
within 15 min of etorphine-azaperone adminis-
tration by dart. Prolonged inductions in the two
animals were because of inaccurate dart place-
ment resulting in slow drug absorption. These
rhinoceros were reimmobilized without further
complications after a 2-wk washout period.
Immobilized rhinoceros were instrumented
within 10 min of becoming recumbent and
remained immobilized for the study period;
no addition doses of drugs were necessary.

Treatment: etorphine-azaperone

Etorphine-azaperone administration resulted in
an initial median PaO2 ¼ 24.0 mmHg, PaCO2 ¼
65 mmHg, P(A-a)O2 ¼ 53 mmHg, _VEBTPS ¼ 70

L/min, _VO2 ¼ 4.4 L/min, and _VCO2 ¼ 3.2 L/
min, along with muscle tremors. There were no
significant changes in median PaO2, PaCO2,

P(A-a)O2, and _VDPHYS over time (t ¼ 0 to t ¼
25; Fig. 1); however, declines in median _VO2,
_VCO2, VT, and _VEBTPS between t ¼ 0 and t ¼
25 were significant (P ¼ 0.028; Figs. 2 and 3).
Median fR increased significantly (P ¼ 0.030)
from t ¼ 10 to t ¼ 25 (Table 2).

TABLE 1. Muscle tremor scores: criteria for subjec-
tively scoring muscle tremors in chemically immobi-
lized white rhinoceros (Ceratotherium simum).

Score Degree of muscle tremors

5 Severe, resulting in whole-body and head

movement

4 Moderate, resulting in severe shoulder, chest, leg

and foot movement

3 Slight, resulting in minor shoulder and chest, and

severe leg and foot movement

2 Mild, resulting in minor leg and foot movement

1 No visible tremors

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FIGURE 1. Median and interquartile range of arterial partial pressures of (a) oxygen (PaO2) and (b) carbon
dioxide (PaCO2) at sampling periods 0, 5, 10, 15, 20, and 25 min in six 5- to 6-yr-old captive male white rhinoc-
eros (Ceratotherium simum) for treatment etorphine-azaperone intramuscularly (IM) or treatment etorphine-
azaperone IM plus butorphanol intravenously (IV). Arterial blood samples collected anaerobically from the
auricular artery. The study was conducted at Skukuza, Kruger National Park, South Africa (elevation, 281 m;
atmospheric pressure, 734–737 mmHg; environmental temperature, 23.4–29 C); rhinoceros rectal body tem-
perature, 35.8–37.5 C. The dashed line indicates the time at which butorphanol was administered. The asterisk
(*) indicates a significant (P,0.05) difference within treatment between t ¼ 0 and t ¼ 10. The pound symbol (#)
indicates a significant (P,0.05) difference within treatment between t ¼ 10 and t ¼ 25. The infinity symbol (1)
indicates a significant (P, 0.05) difference with treatment between t ¼ 0 and t ¼ 25.

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There was a positive association between
_VO2 and _VCO2, with muscle tremor scores
(P,0.0001, r2 ¼ 0.56 and P ¼ 0.0001, r2 ¼

0.54, respectively) that decreased over the trial
period (Fig. 4). There was an inverse associ-

ation between PaO2 and _VO2 (P ¼ 0.002, r2 ¼
0.25) and no significant association between

PaCO2 and _VCO2 (P¼ 0.370, r2¼ 0.02).

Treatment: etorphine-azaperone-butorphanol

The administration of butorphanol IV at t ¼
2 in etorphine-azaperone–immobilized rhinoc-
eros was associated with a significant increase
in median PaO2 (P ¼ 0.027) and decrease in
median PaCO2 (P ¼ 0.028) between t ¼ 0 and

t ¼ 10. Between t ¼ 10 and t ¼ 25, PaO2

decreased (P ¼ 0.027) and there was no signifi-
cant change in PaCO2 (Fig. 1). The median
_VO2 and the _VCO2 decreased between t ¼ 0
and t ¼ 10 (P ¼ 0.028 and P ¼ 0.028, respec-
tively), with no further statistically significant
changes from t ¼ 10 to t ¼ 25 (Fig. 3). There
was a rapid but short-lived increase in median
_VEBTPS from t ¼ 2 to t ¼ 5, but changes
between t ¼ 0 to t ¼ 25 were not statistically
different (Fig. 2). Median P(A-a)O2, VT, fR,

and _VDPHYS did not change significantly over
time (Table 2).

The _VO2 and _VCO2 were positively associated
with muscle tremor scores (P ¼ 0.001, r2 ¼ 0.39

FIGURE 2. Median and interquartile range of expired minute ventilation ( _VEBTPS) measured at sampling peri-
ods 0, 5, 10, 15, 20, and 25 min in six 5- to 6-yr-old captive male white rhinoceros (Ceratotherium simum) for
treatment etorphine plus azaperone intramuscularly (IM) or treatment etorphine plus azaperone IM and butor-
phanol intravenously (IV). Expired minute ventilation was measured by directing expired air through a PowerLab
exercise physiology system by using modified equine endotracheal tubes place in each nostril. The study was con-
ducted at Skukuza, Kruger National Park, South Africa (elevation, 281 m; atmospheric pressure, 734–737 mmHg;
environmental temperature, 23.4–29 C); rhinoceros rectal body temperature, 35.8–37.5 C. The dashed line indi-
cates the time at which butorphanol was administered. The asterisk (*) indicates a significant (P,0.05) difference
within treatment between t ¼ 0 and t ¼ 10. The pound symbol (#) indicates a significant (P,0.05) difference within
treatment between t ¼ 10 and t ¼ 25. The infinity symbol (1) indicates a significant (P,0.05) difference with treat-
ment between t ¼ 0 and t ¼ 25.

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FIGURE 3. Median and interquartile range of (a) oxygen consumption ( _VO2) and (b) carbondioxide produc-
tion ( _VCO2) calculated at sampling periods 0, 5, 10, 15, 20, and 25 min in six 5- to 6-yr-old captive male white
rhinoceros (Ceratotherium simum) for treatment etorphine plus azaperone intramuscularly (IM) or treatment
etorphine plus azaperone IM and butorphanol intravenously (IV). Oxygen consumption was calculated using
the inspired oxygen fraction, mixed-expired oxygen percentage of expired air collected in a Douglas bag and
analyzed using a Cardiocap/5 monitor, and expired minute ventilation was measured by directing expired air

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and P ¼ 0.024, r2 ¼ 0.25, respectively), which
decreased rapidly between t ¼ 0 and t ¼ 5 and
remained low for the rest of the immobilization
period (Fig. 4). There was an inverse association

between PaO2 and _VO2 (P ¼ 0.008, r2 ¼ 0.19)
and no significant association between PaCO2

and _VCO2 (P¼ 0.928, r2¼ 0.0002).
Table 3 shows the overall distribution of blood

gas and respiratory values (from t ¼ 5 to t ¼ 25)
for etorphine-azaperone and etorphine-azaper-
one-butorphanol treatments. The median PaO2

was higher (P,0.001) and the median PaCO2

was lower (P,0.001) in etorphine-azaperone-
butorphanol–immobilized rhinoceros than in
etorphine-azaperone–immobilized rhinoceros.
Median fR was significantly higher (P,0.001)
and VT was statistically lower (P ¼ 0.002) in ani-
mals given butorphanol. There was no significant

difference in overall median P(A-a)O2, _VO2, and
_VCO2 between treatments.
The rhinoceros in this study made uneventful

recoveries and were standing within 2 min after
naltrexone administration. Food consumption;
quantity, consistency, and color of feces; and
demeanor were not changed in any rhinoceros
as the result of either of the treatments.

DISCUSSION

Hypoxemia and hypercapnia were of clinical
concern in white rhinoceros immobilized with
etorphine-azaperone, as reported previously in
white rhinoceros immobilized with etorphine
(Buss et al. 2018; Table 2); however, butorpha-
nol administration provided clinically beneficial
improvements in hypoxemia and hypercapnia in
etorphine-azaperone–immobilized rhinoceros,
similar to the effects of butorphanol in rhinoc-
eros immobilized with etorphine alone (Buss

et al. 2018). The improvements in PaO2 and
PaCO2 after butorphanol administration did not
appear to be a result of increased minute venti-
lation, because an initial increase was short
lived. Positive associations between muscle

tremor scores and _VO2 and _VCO2, which both
decreased after butorphanol IV, indicate that
these improvements in blood gases probably
resulted from a decrease in metabolic activity.

An unexpected finding was that _VEBTPS did
not change significantly after butorphanol admin-
istration in our etorphine-azaperone–immobi-
lized rhinoceros compared with an increase in
ventilation after butorphanol administration
to the same rhinoceros immobilized with
etorphine (Buss et al. 2018). The different
outcome for the two interventions appeared

to be associated with a lower _VEBTPS at t ¼ 0
in etorphine-azaperone–immobilized rhinoc-
eros. In the rhinoceros immobilized with etor-
phine-azaperone, there was an initial short-lived

increase in _VEBTPS after butorphanol adminis-
tration; however, the ventilation trends and val-
ues were similar to those in rhinoceros not
receiving butorphanol for the remainder of the
immobilization period.
Butorphanol administration in etorphine-

azaperone–immobilized rhinoceros resulted
in PaO2 values that were inversely associated with
_VO2 and muscle tremor scores, supporting the
theory that butorphanol-induced reduction in
metabolic activity led to improvements in blood
gas values (Buss et al. 2018). It has been previ-
ously shown that butorphanol administration
decreased muscle tremor scores in etorphine-
immobilized white rhinoceros, resulting in a
rapid and significant decrease in both hypox-
emia and hypercapnia (Buss et al. 2018); how-
ever, unlike etorphine-immobilized rhinoceros

 
through a PowerLab exercise physiology system by using modified equine endotracheal tubes place in each
nostril. The study conducted at Skukuza, Kruger National Park, South Africa (elevation, 281 m; atmospheric
pressure, 734–737 mmHg; environmental temperature, 23.4–29 C); rhinoceros rectal body temperature, 35.8–
37.5 C. The dashed line indicates the time at which butorphanol was administered. The asterisk (*) indicates a
significant (P, 0.05) difference within treatment between t ¼ 0 and t ¼ 10. The pound symbol (#) indicates a sig-
nificant (P ,0.05) difference within treatment between t ¼ 10 and t ¼ 25. The infinity symbol (1) indicates a sig-
nificant (P,0.05) difference with treatment between t ¼ 0 and t ¼ 25.

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TABLE 2. Distribution of arterial blood gases collected from the auricular artery and respiratory parameters,a

with median and interquartile range (25th–75th percentile), at sampling periods 0, 5, 10, and 25 min in six 5-
to 6-yr-old captive male white rhinoceros (Ceratotherium simum) for two treatments: etorphine-azaperone
(EA) intramuscularly (IM) and etorphine-azaperone IM plus butorphanol intravenously (EAB IV). The study
was conducted at Skukuza, Kruger National Park, South Africa (elevation, 281 m; atmospheric pressure, 734–
737 mmHg; environmental temperature, 23.4–29 C); rhinoceros rectal body temperature, 35.8–37.5 C. The
table includes two additional treatments, etorphine IM (E) and etorphine IM plus butorphanol IV (EB),
administered as part of the same multivariant crossover study, as reported previously (Buss et al. 2018).

Treatment 0 min 5 min 10 min 25 min

PaO2 (mmHg)

EA 24 (21–27) 26 (24–28) 27 (25–29) 26 (23–2.8)

EAB 24 (20–26) 49 (43–49) 46 (45–48) 39 (36–40)

E 25 (23–28) 25 (23–28) 28 (23–29) 26 (25–29)

EB 26 (22–26) 48 (42–50) 49 (42–51) 44 (38–46)

P(A-a)O2 (mmHg)

EA 53 (47–61) 45 (44–47) 46 (42–49) 41 (36–49)

EAB 44 (42–48) 39 (34–50) 40 (38–43) 46 (44–47)

E 42 (37–45) 49 (39–53) 44 (34–47) 39 (34–44)

EB 37 (33–42) 39 (33–43) 37 (31–39) 36 (35–39)

PaCO2 (mmHg)

EA 65 (62–72) 74 (72–78) 72 (67–75) 74 (70–81)

EAB 79 (77–80) 59 (54–62) 59 (52–61) 60 (57–65)

E 76 (67–81) 71 (61–80) 72 (67–82) 79 (71–82)

EB 81 (76–89) 58 (55–68) 63 (58–75) 64 (63–65)
_VEBTPS (L/min)

EA 70 (68–79) 65 (61–69) 61 (51–71) 62 (55–67)

EAB 95 (94–105) 135 (109–140) 83 (73–87) 82 (76–89)

E 164 (127–182) 137 (103–154) 118 (89–131) 96 (67–101)

EB 151 (139–172) 153 (126–161) 90 (85–99) 83 (77–87)

fR (breaths/min)

EA 4 (4–5) 4 (4–4) 4 (4–4) 6 (5–6)

EAB 5 (4–7) 10 (9–11) 6 (5–6) 7 (5–8)

E 10 (9–10) 9 (8–9) 7 (6–7) 6 (5–8)

EB 10 (8–10) 11 (10–13) 8 (6–8) 6.0 (6–7)

VT (L/breath)

EA 15 (13–20) 14 (12–16) 16 (14–17) 11 (10–11)

EAB 17 (9–23) 12 (10–13) 12 (10–13) 11 (10–12)

E 18 (14–22) 16 (14–17) 18 (18–19) 14 (13–16)

EB 17 (15–20) 12 (12–16) 12 (11–17) 13 (12–14)
_VDPHYS (L/min)

EA 23 (19–34) 26 (22–29) 23 (22–28) 24 (21–35)

EAB 33 (26–38) 40 (28–50) 29 (19–34) 24 (18–44)

E 60 (36–70) 42 (19–61) 40 (24–44) 36 (26–48)

EB 48 (47–51) 36 (18–52) 31 (22–41) 29 (26–35)
_VO2 (L/min)

EA 4 (4–5) 4 (4–5) 4 (4–5) 3 (3–4)

EAB 6 (6–7) 5 (5–6) 3 (3–4) 4 (3–4)

E 11 (10–12) 9 (8–10) 8 (6–9) 7 (4–7)

EB 11 (9–12) 7 (6–8) 4 (4–5) 4 (4–5)

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receiving butorphanol (Buss et al. 2018), in our
study, changes in PaO2 and PaCO2 after butor-
phanol administration appeared to also be influ-
enced by differences in oxygen and carbon
dioxide solubility. Median PaCO2 was not corre-
lated with changes in _VCO2 after butorphanol
administration. This result implies that PaCO2

was not only influenced by metabolic activity

and carbon dioxide production but also by
elimination in the lungs. Although pulmo-
nary exchange of oxygen and carbon dioxide
are similarly affected by ventilation and perfu-
sion perturbations, the increased water solubil-
ity of carbon dioxide compared with that of
oxygen supports a hypothesis that the difference
in elimination of the two gases resulted in a loss

FIGURE 4. Muscle tremor scores at sampling periods 0, 5, 10, 15, 20, and 25 min were the sum of all the
scores (1–5) at each time point in six 5- to 6-yr-old captive male white rhinoceros (Ceratotherium simum) for
treatment etorphine plus azaperone (intramuscularly [IM]) or treatment etorphine plus azaperone (IM) and
butorphanol intravenously (IV). Muscle tremor scores were subjectively evaluated by a single observer, with 1
indicating no visible tremors and 5 indicating severe tremors. The study was conducted at Skukuza, Kruger
National Park, South Africa (elevation, 281 m; atmospheric pressure, 734–737 mmHg; environmental tempera-
ture, 23.4–29 C); rhinoceros rectal body temperature, 35.8–37.5 C.

TABLE 2. Continued.

Treatment 0 min 5 min 10 min 25 min

_VCO2 (L/min)

EA 3 (3–4) 3 (3–3) 3 (2–4) 2 (2–3)

EAB 4 (4–5) 5 (4–5) 3 (3–3) 3 (3–3)

E 8 (8–11) 7 (6–8) 6 (5–7) 4 (4–5)

EB 9 (7–10) 7 (6–8) 4 (4–4) 4 (3–4)

a PaO2 ¼ arterial partial pressure of oxygen; P(A-a)O2 ¼ alveolar to arterial oxygen gradient; PaCO2 ¼ arterial partial pressure of carbon
dioxide; _VEBTPS ¼ expired minute ventilation; _VDPHYS ¼ physiologic dead space; fR ¼ respiratory rate; VT ¼ tidal volume; _VO2 ¼
oxygen consumption; _VCO2 ¼ carbon dioxide production.

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of association between _VCO2 and PaCO2 (Pow-
ers and Dhamoon 2020). Because the association

between _VCO2 and PaCO2 persisted in
etorphine-butorphanol rhinoceros, these find-
ings suggest that the different outcome in our
study is related to concurrent administration of
azaperone with etorphine (Buss et al. 2018).

The addition of azaperone to etorphine in
this study resulted in initial reduced muscle
trembling and limb movement, which was asso-

ciated with lower _VO2 and _VCO2 than those of
animals receiving etorphine alone (Buss et al.
2018). Etorphine-immobilized white rhinoceros
are reported to have increased metabolic activity

(measured by _VO2 and _VCO2) that was associ-
ated with the degree of limb movements and
muscle trembling (Buss et al. 2018). The
decreased tremor scores suggest azaperone
may reduce metabolic activity, thereby impacting
oxygen consumption and carbon dioxide produc-
tion. Because azaperone is a dopamine receptor
antagonist, it may influence the activity of

dopamine, which plays a role in a variety of cen-
tral and peripheral metabolic processes (Leysen
and Gommeren 2008; Rubı́ and Maechler 2010).
The findings of our study at t¼ 0 also suggest

that etorphine-azaperone–immobilized rhinoc-
eros had reduced ventilation compared with
that of etorphine-immobilized rhinoceros. In
etorphine-azaperone–immobilized rhinoceros,

median _VEBTPS at the start of data recording

was lower than that of _VEXP and _VEBTPS

reported for rhinoceros receiving etorphine

(Buss et al. 2018). The overall median _VEBTPS

was also lower in the study rhinoceros adminis-
tered etorphine-azaperone compared with etor-
phine alone (Buss et al. 2018). Because there
were limited differences in blood gas values
between etorphine-azaperone– versus etor-
phine-immobilized rhinoceros, ventilation may
have been reduced in response to the decreased
metabolic oxygen requirements and carbon
dioxide produced (Buss et al. 2018).

The reduced _VEBTPS in etorphine-azaperone–
treated rhinoceros was probably related to the

decreased _VCO2, compared with etorphine
alone (Buss et al. 2018); however, a direct sup-
pression of ventilation by azaperone cannot be
excluded. The suppression of respiratory
central and peripheral chemoreceptors and
inhibition of ventilation by opioids are well
documented (McDonald and Lambert 2005;
Pattinson 2008); however, the contribution
of azaperone to etorphine-associated venti-
latory depression is unknown and requires
further investigation (Kolesnikova and Serebrov-
skaya 1998). Azaperone may influence ventilation
through its antagonistic action at multiple recep-
tors that are believed to influence breathing,
including dopamine-, alpha1-, histamine1-,
5-hydroxytyptamine-, and muscarinic3-recep-
tors (Lemke 2007; Leysen and Gommeren
2008; Burroughs et al. 2012).
Our results suggest that etorphine-azaperone

causes an elevated P(A-a)O2 (median, 53 mmHg).
The normal gradient in white rhinoceros at rest is
unknown; however, when comparing results in
etorphine-azaperone–immobilized rhinoceros
with those in horses at rest (10 mmHg; Doherty

TABLE 3. Overall distribution of blood gases collected
from the auricular artery and respiratory parameters,a

with median and interquartile range (25th–75th percen-
tile), at sampling periods 0, 5, 10, and 25 min in six 5- to
6-yr-old captive male white rhinoceros (Ceratotherium
simum) for two treatments: etorphine-azaperone intra-
muscularly (EA) and etorphine-azaperone intramuscu-
larly plus butorphanol intravenously (EAB). The study
was conducted at Skukuza, Kruger National Park, South
Africa (elevation, 281 m; atmospheric pressure, 734–737
mmHg; environmental temperature, 23.4–29 C); rhinoc-
eros rectal body temperature, 35.8–37.5 C.

EA EAB

PaO2 (mmHg) 25 (23–28) 42 (40–46)

P(A-a)O2 (mmHg) 45 (38–50) 42 (38–47)

PaCO2 (mmHg) 73 (68–8) 60 (55–62)
_VEBTPS (L/min) 66 (56–70) 78 (73–90)

ƒR (breaths/min) 4 (4–5) 6 (5–8)

VT (L/breath) 14 (11–17) 11 (9–13)

DPHYS (L/min) 25 (21–33) 27 (19–38)
_VO2 (L/min) 3.7 (3.1–4) 3.5 (3–3.9)

_VCO2 (L/min) 2.7 (2.2–3.3) 2.9 (2.4–3.2)

a PaO2 ¼ arterial partial pressure oxygen; P(A-a)O2 ¼ alveolar to
arterial oxygen gradient; PaCO2 ¼ partial pressure of carbon
dioxide; _VEBTPS ¼ expired minute ventilation; _VDPHYS ¼ physio-
logic dead space; fR ¼ respiratory rate; VT ¼ tidal volume; _VO2 ¼
oxygen consumption; _VCO2 ¼ carbon dioxide production.

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and Valverdis 2008), it suggests an increase of
clinical significance in rhinoceros. Similar
increases in P(A-a)O2 have been reported
for rhinoceros immobilized with etorphine only
(Buss et al. 2018). These results suggest that
azaperone has limited effect on the A-a gradient
changes induced by etorphine. Etorphine mark-
edly increased pulmonary arterial pressure in
immobilized white rhinoceros, and gas exchange
across alveolar-capillary membranes may be
reduced by pulmonary congestion, intersti-
tial oedema, increased speed of blood flow
through pulmonary vasculature, or ventila-
tion-perfusion mismatching (Meyer et al. 2015;
Boesch et al. 2018; Mosing et al. 2020). The
inclusion of azaperone probably reduces etor-
phine-associated systemic arterial hypertension
by blocking alpha1-receptors at peripheral
arterioles (Buss et al. 2016); however, the
effects of azaperone on pulmonary vasculature
and blood pressure within the lungs are
unknown. Studies on how azaperone might
influence lung perfusion, ventilation, or both are
still required (Lemke 2007).
In this study, the small sample size (six rhinoc-

eros) may have reduced statistical power and
masked additional physiologic changes of clini-
cal importance. In addition, a more complete
understanding of the physiologic mechanisms
influencing blood gases was limited by an inabil-
ity to assess alveolar ventilation, cardiac output,
pulmonary artery pressures, shunt fractions,
and ventilation:perfusion ratios. Differences in
physiologic responses may exist between captive
and free-ranging rhinoceros, and further studies
should compare these conditions.
Overall, our study demonstrated a clinical

benefit of butorphanol administration in etor-
phine-azaperone–immobilized white rhinoceros,
with decreases in both hypoxia and hypercap-
nia. This effect appeared to be associated with
reduced metabolic activity. Although the arte-
rial partial pressures of oxygen and carbon diox-
ide measured in white rhinoceros immobilized
with etorphine-azaperone were not clinically
different from values in white rhinoceros that
received only etorphine, based on the metabolic-
sparing effects of azaperone, we recommend

that azaperone should be included with
etorphine in the chemical immobilization of
white rhinoceros.

ACKNOWLEDGMENTS

The authors thank the Veterinary and Opera-
tions teams of Veterinary Wildlife Services, Kruger
National Park. The assistance of members of the
Brain Function Research Group, University of Wit-
watersrand Medical School, and staff and students
of the Faculty of Veterinary Science, University of
Pretoria, is also acknowledged. Financial and in-
kind support was provided by SANParks. The pro-
ject was supported by funding grants from the South
African Veterinary Foundation and University of
Witwatersrand. Financial support for Michele Miller
was provided by the South African Medical Research
Council and National Research Foundation South
African Research Chair Initiative (grant 86949).

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Accepted 10 October 2023.

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https://www.ncbi.nlm.nih.gov/books/NBK539907/
https://www.ncbi.nlm.nih.gov/books/NBK539907/