Cafedrine/theodrenaline in anaesthesia

Abstract

Hypotensive states that require fast stabilisation of blood pressure can occur during anaesthesia. In 1963, the 20:1 mixture of cafedrine/theodrenaline (Akrinor(®)) was introduced in Germany for use in anaesthesia and emergency medicine in the first-line management of hypotensive states. Though on the market for many years, few pharmacodynamic data are available on this combination net beta-mimetic agent.
This study aimed to examine the drug combination in real-life clinical practice and recorded time to 10 % mean arterial blood pressure (MAP) increase and heart rate. Furthermore, potential factors that influence drug effectiveness under anaesthesia were assessed.
Data were collected within a standardised anaesthesia protocol. A total of 353 consecutive patients (female/male = 149/204) who received cafedrine/theodrenaline after a drop in MAP ≥ 5 % were included in the study. The time to 10 % increase in MAP, dosage of cafedrine/theodrenaline, volume loading, blood pressure and heart rate were monitored over time.
Patients were a mean (standard deviation) of 64.4 ± 15.1 years old with a baseline MAP of 82 ± 14 mmHg, which dropped to a mean of 63 ± 10 mmHg during anaesthesia without gender differences. Cafedrine/theodrenaline (1.27 ± 1.0 mg/kg; 64 ± 50 µg/kg) significantly increased MAP (p < 0.001) by 11 ± 16 mmHg within 5 min, reaching peak values within 17.4 ± 9.0 min. Heart rate was not affected in a clinically significant manner. Cafedrine/theodrenaline induced a 10 % MAP increase after 7.2 ± 4.6 min (women) and after 8.6 ± 6.3 min (men) (p = 0.018). Independent of gender, the dose of cafedrine/theodrenaline required to achieve the observed MAP increase of 14 ± 16 mmHg at 15 min was significantly different in patients with heart failure [1.78 ± 1.67 mg/kg (cafedrine)/89.0 ± 83.5 µg/kg (theodrenaline)] compared with healthy patients [1.16 ± 0.77 mg/kg (cafedrine)/58.0 ± 38.5 µg/kg (theodrenaline)] (p = 0.005). Concomitant medication with beta-blocking agents significantly prolonged the time to 10 % MAP increase [9.0 ± 7.0 vs. 7.3 ± 4.3 min (p = 0.008)].
Cafedrine/theodrenaline quickly restores MAP during anaesthesia. Female gender is associated with higher effectiveness, while heart failure and beta-blocker administration lower the anti-hypotonic effect. Prospective studies in defined patient populations are warranted to further characterise the effect of cafedrine/theodrenaline.

Full text

Both general and regional anaesthe-
sia are associated with a high rate of
sympathicolysis-induced hypoten-
sion that requires fast-acting and re-
liable anti-hypotonic agents to stabi-
lise blood pressure. For decades hy-
potension was avoided by the provi-
sion of excessive fluid preload, how-
ever, this practice faces increasing
criticism [3]. In Germany, cafedrine/
theodrenaline (Akrinor®) is approved
as an anti-hypotensive agent along-
side a few other agents.
Background
Cafedrine/theodrenaline was introduced
in Germany in 1963, and pre-clinical da-
ta showed a beta-adrenergic and an alpha-
adrenergic component [22, 25, 26]. The net
effect is beta-adrenergic [25]. The combi-
nation preparation increases mean arte-
rial pressure (MAP), cardiac stroke vol-
ume and cardiac output [18, 25]. Com-
pared to alpha-adrenergic sympathomi-
metic agents, cafedrine/theodrenaline was
shown to cause less deterioration of renal,
cerebral and coronary perfusion [5]. In ad-
dition, clinical practice with alpha-adren-
ergic sympathomimetic agents requires
measures to control refectory critical bra-
dycardia, for example with atropine [7]. A
study in dogs demonstrated that increased
myocardial oxygen consumption caused
by positive inotropic cafedrine/theodren-
aline effects are compensated for by en-
hanced coronary perfusion, increasing the
myocardial oxygen supply [9]. The phar-
macologic properties of this drug combi-
nation may explain the distinctly favour-
able effects in patients with chronic isch-
aemic heart disease [11, 15]. In addition,
cafedrine/theodrenaline combination
seems to offer benefits from a metabolic
standpoint because of the lower lipolytic
effect compared with catecholamines, par-
ticularly under hypoxic conditions in acute
myocardial infarction or shock [21].
Although cafedrine/theodrenaline is
widely accepted in the management of hy-
potensive states in anaesthesia, intensive
care and emergency medicine [1, 6, 16],
few pharmacodynamic data have been
published [13], and it is therefore impor-
tant to collect data under routine clinical
practice conditions. Cafedrine/theodren-
aline is routinely administered at our in-
stitution to patients in whom a quick and
sustained MAP increase for 15–20 min is
warranted and feasible with a single drug
administration and without the vasopres-
sor side effect of bradycardia; during these
15–20 min, fluid volume can be balanced.
Gender-related differences in the ED50 of
cafedrine/theodrenaline have previously
been reported by our group [13]. To con-
firm and expand on this observation un-
der routine anaesthesia conditions, the
time to 10 % increase in MAP after ad-
ministration of cafedrine/theodrenaline
was examined. We hypothesized that gen-
der, heart failure and use of beta-blockers
influence the effectiveness of cafedrine/
theodrenaline.
Methods
This study was approved by the Institu-
tional Review Board at the University
Hospital Carl Gustav Carus Medical Fac-
ulty, Fetscherstrasse 74, Dresden, Germa-
ny (EK255122004, 17.01.2005). The re-
cords from 353 consecutive anaesthe-
sia patients at our institution who re-
ceived cafedrine/theodrenaline were col-
lected and retrospectively evaluated. Pa-
tients were included in the study between
July and November 2007, irrespective of
the type of surgery, and received cafe-
drine/theodrenaline to manage hypoten-
sion during anaesthesia. To reflect a re-
al-life cross-section of patients in a Ger-
man hospital, patients from the following
departments were included: orthopae-
dics, trauma surgery, neurosurgery, vis-
ceral- thoracic and vascular surgery, gyn-
aecology, urology, oral and facial surgery
and eye surgery.
All patients fasted 2 h prior to induc-
tion and received 7.5 mg midazolam OD
(Dormicum, Roche, Grenzach-Wyhlen,
Germany) 45 min prior to arrival in the
operating theatre. Concomitant medica-
tion, including anti-hypertensives such as
beta-blockers, was continued as indicat-
ed by the standard operating procedures
of the department. A 5-lead electrocardio-
gram, including measurement of segmen-
tal ST depression (II, aVF, V5), and pulse
oximetry was recorded. Non-invasive os-
cillometric blood pressure was monitored
in 5 min intervals on the right upper arm
(IntelliVue, MP70, Philips, Böblingen,
Germany). Values were manually trans-
ferred to anaesthesia protocols. The fol-
lowing data were recorded: age, gender,
height, body weight, current beta-blocker
therapy, American Society of Anesthesiol-
ogists physical status and individual dosage
of cafedrine/theodrenaline per injection.
A.R.Heller · J.Heger · M.Gama de Abreu · M.P.Müller
Department of Anaesthesia and Intensive Care Medicine, Department of Anesthesiology and Critical Care
Medicine, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Cafedrine/theodrenaline
in anaesthesia
Influencing factors in restoring
arterial blood pressure
Anaesthesist2015 · 64:190–196
DOI 10.1007/s00101-015-0005-y
Received:8 August 2014
Revised:16 December 2014
Accepted:17 December 2014
Published online: 11 March 2015
© The Author(s) 2015. This article is published
with open access at Springerlink.com
190
|
Der Anaesthesist 3 · 2015
Originalien

General anaesthesia was induced with
1.5 mg/kg propofol (Propofol 1 %, Fre-
senius-Kabi, Bad Homburg, Germany)
and 0.5 µg/kg sufentanil (Sufenta Jans-
sen-Cilag, Neuss, Germany). Tracheal in-
tubation was facilitated by 0.5 mg/kg ro-
curonium (Esmeron, Organon, Ober-
schleißheim, Germany). General anaes-
thesia was maintained with desflurane
(Suprane, Baxter, Unterschleißheim,
Germany) in O2/N2O (35 %/60 %). Pa-
tients were mechanically ventilated with
a minute volume adequate to maintain
end-tidal pCO2 of 36–40 mmHg at a fresh
gas flow of 1 l/min (Primus, Dräger, Lü-
beck, Germany). Neuraxial anaesthesia
(spinal anaesthesia, epidural anaesthesia)
was performed with approved local an-
aesthetics in awake seated patients [19].
In patients with ≥ 5 % drop in MAP
cafedrine/theodrenaline was adminis-
tered to maintain MAP within a 20 %
drop from baseline. We chose the 5 %
drop in MAP as the inclusion criterion
to raise awareness that hypotension even
in this range may be associated with late
complications. Timing and doses were re-
corded in anaesthesia protocols. The ob-
servation period in this study was limited
to 30 min after the drop in MAP because
the variability of factors affecting MAP,
such as additional volume therapy, ongo-
ing blood loss and the use of other drugs
increases with time. Individual dosage
was defined in accordance with a previous
dose-finding study, in which the ED50 of
cafedrine to achieve a 10 % MAP increase
within 10 min was 0.53 mg/kg [13].
Administration of cafedrine/
theodrenaline
An ampoule of 2 ml cafedrine/theodren-
aline (Akrinor, AWD.pharma GmbH
& Co. KG, Dresden, Germany) contains
200 mg cafedrinhydrochloride, 10 mg
theodrenalinehydrochloride, 0.4 mg sodi-
umdisulfite, ethanol 96 %, glycerol 85 %,
sodium acetate 3 H2O, acetic acid 99 %
and water. To enable fairly precise dos-
ing, 2 ml of cafedrine/theodrenaline were
diluted in 8 ml of saline to a total of 10 ml,
as suggested in the prescribing informa-
tion. Throughout the manuscript doses
are given for the cafedrine component of
the mixture. Due to the fixed milligram
ratio of 1:20, the dosage of theodrenaline
can be calculated by dividing the respec-
tive cafedrine dose by 20.
Endpoints
The primary endpoint was time to 10 %
increase in MAP after administration of
cafedrine/theodrenaline. Other study
endpoints were stability of heart frequen-
cy and time to onset of effect dose rela-
tive to gender, beta-blocking agents and
the presence of heart failure (NYHA ≥ 1).
Statistical analysis
Mean arterial blood pressure was calcu-
lated as MAP = diastolic + (systolic-dia-
stolic)/3. All data were anonymised and
191Der Anaesthesist 3 · 2015
|
85
80
75
70
65
60
55
50
MAP [mmHg]
Baseline 0510 15 20 25 30
Time [min]
p=0.04 GLM
female male
Fig. 18Effects of cafedrine/theodrenaline on mean arterial pressure (MAP, mean ± SE) injected at
time point 0 (reference value) in male and female patients. Both MAP drop and increase were statis-
tically significant (p < 0.001, paired t-test), as was the between-group comparison with general linear
model (GLM) according to two-way analysis of variance (ANOVA) (p = 0.04)
85
80
90
75
70
65
60
55
50
45
40
Heart rate [bpm]
Baseline 0510 15 20 25 30
Time [min]
p=0.668 GLM
female male
Fig. 28Effects of cafedrine/theodrenaline on heart rate (mean ± SE) injected at time point 0 (ref-
erence value) in male and female patients. The difference between genders was not significant
(p = 0.668), while the heart rate difference over time was statistically significant (p < 0.001)

analysed using the Statistical Package for
Social Sciences for Windows, version 17.0
(SPSS, Inc., Chicago, IL, USA). The pri-
mary study hypothesis was tested using a
Kaplan–Meier analysis followed by a log-
rank test. General linear model statistics
according to a two-way analysis of vari-
ance were applied for repeated measure-
ment analyses, followed by Sidak alpha
adjustment for multiple comparisons. A
paired t-test served for analysing point to
point changes in haemodynamics. To en-
sure equal distribution of risk factors be-
tween the observed cohorts, categorical
variables were compared with χ2 statistics.
Data are expressed as mean ± SD. To
support readability and interpretation in
. Figs.1 and 2, data are presented as mean
± SE. A p-value of < 0.05 was considered
statistically significant.
Abstract · Zusammenfassung
Anaesthesist2015 · 64:190–196 DOI 10.1007/s00101-015-00 05-y
© The Author(s) 2015. This article is published with op en access at Springerlink.com
A.R.Heller· J.Heger· M.Gama de Abreu· M.P.Müller
Cafedrine/theodrenaline in anaesthesia. Influencing factors in restoring arterial blood pressure
Abstract
Background. Hypotensive states that re-
quire fast stabilisation of blood pressure can
occur during anaesthesia. In 1963, the 20:1
mixture of cafedrine/theodrenaline (Akri-
nor®) was introduced in Germany for use in
anaesthesia and emergency medicine in the
first-line management of hypotensive states.
Though on the market for many years, few
pharmacodynamic data are available on this
combination net beta-mimetic agent.
Aim. This study aimed to examine the drug
combination in real-life clinical practice and
recorded time to 10 % mean ar terial blood
pressure (MAP) increase and heart rate. Fur-
thermore, potential factors that influence
drug effectiveness under anaesthesia were
assessed.
Methods. Data were collected within a
standardised anaesthesia protocol. A to-
tal of 353 consecutive patients (female/
male = 149/204) who received cafedrine/
theodrenaline after a drop in MAP ≥ 5 % were
included in the study. The time to 10 % in-
crease in MAP, dosage of cafedrine/theodren-
aline, volume loading, blood pressure and
heart rate were monitored over time.
Results. Patients were a mean (standard de-
viation) of 64.4 ± 15.1 years old with a base-
line MAP of 82 ± 14mmHg, which dropped
to a mean of 63 ± 10mmHg during anaes-
thesia without gender differences. Cafedrine/
theodrenaline (1.27 ± 1.0mg/kg; 64 ± 50µg/
kg) significantly increased MAP (p < 0.001) by
11 ± 16mmHg within 5min, reaching peak
values within 17.4 ± 9.0min. Heart rate was
not affected in a clinically significant man-
ner. Cafedrine/theodrenaline induced a 10 %
MAP increase after 7.2 ± 4.6min (women)
and after 8.6 ± 6.3min (men) (p = 0.018). In-
dependent of gender, the dose of cafedrine/
theodrenaline required to achieve the ob-
served MAP increase of 14 ± 16mmHg at
15min was significantly different in pa-
tients with heart failure [1.78 ± 1.67mg/
kg (cafedrine)/89.0 ± 83.5µg/kg (theodren-
aline)] compared with healthy patients
[1.16 ± 0.77mg/kg (cafedrine)/58.0 ± 38.5µg/
kg (theodrenaline)] (p = 0.005). Concomitant
medication with beta-blocking agents signif-
icantly prolonged the time to 10 % MAP in-
crease [9.0 ± 7.0 vs. 7.3 ± 4.3min (p = 0.008)].
Conclusion. Cafedrine/theodrenaline quick-
ly restores MAP during anaesthesia. Female
gender is associated with higher effective-
ness, while heart failure and beta-blocker ad-
ministration lower the anti-hypotonic effect.
Prospective studies in defined patient popu-
lations are warranted to further characterise
the effect of cafedrine/theodrenaline.
Keywords
Cafedrine/theodrenaline drug combination·
Hypotension· Heart frequency· Beta-blocker
effects· Heart failure
Cafedrin/Theodrenalin in der Anästhesie. Faktoren, die die Wirksamkeit
bei der Wiederherstellung des Blutdrucks beeinflussen
Zusammenfassung
Hintergrund. Cafedrin/Theodrenalin (Akri-
nor®) wird in Deutschland für die Therapie
von Blutdruckabfällen in Anästhesie und Not-
fallmedizin verwendet.
Ziel der Arbeit (Fragestellung). Die Studie
untersucht potentielle Faktoren, die die Wirk-
samkeit des Arzneimittels beeinflussen.
Material und Methoden. Patientendaten
wurden mittels Anästhesie-Protokollen ge-
sammelt. 353 Patienten (weiblich/männlich
= 149/204), die Cafedrin/Theodrenalin nach
einem Abfall des mittleren arteriellen Blut-
drucks (MAP) ≥ 5 % erhielten, wurden einbe-
zogen.
Ergebnisse. Die Patienten waren 64,4 ± 15,1
Jahre alt und hatten einen Ausgangs-MAP
von 82 ± 14mmHg, der während der Anäs-
thesie unabhängig von Geschlecht auf einen
Mittelwert von 63 ± 10mmHg abfiel.
Cafedrin/Theodrenalin (1,27 ± 1,0mg/
kg/64 ± 50µg/kg) erhöhte den MAP inner-
halb von 5min um 11 ± 16mmHg (p < 0,001).
Der maximale MAP war nach 17,4 ± 9,0min
erreicht; die Herzfrequenz wurde nicht
im klinisch signifikanten Maß verändert.
Cafedrin/Theodrenalin induzierte einen
10 % MAP-Anstieg nach 7,2 ± 4,6min bei
Frauen und nach 8,6 ± 6,3min bei Männern
(p = 0,018). Unabhängig vom Geschlecht
waren die Dosen von Cafedrin/Theodren-
alin, die zu dem beobachteten MAP-An-
stieg um 14 ± 16mmHg nach 15min füh-
rten, signifikant unterschiedlich zwisch-
en Patienten mit und ohne Herzinsuffizienz
(1,78 ± 1,67mg/kg (Cafedrin)/89,0 ± 83,5µg/
kg (Theodrenalin) vs. 1,16 ± 0,77mg/kg
(Cafedrin)/58,0 ± 38,5µg/kg (Theodrenalin),
p = 0,005).
Gleichzeitige Medikation mit Betablock-
ern verlängerte die Zeit bis zum 10 % MAP-
Anstieg [9,0 ± 7,0 vs. 7,3 ± 4,3min (p = 0,008)].
Schlussfolgerung. Theodrenalin/Cafe-
drin stellt den MAP nach Blutdruckabfällen
schnell wieder her ohne die Herzfrequenz
klinisch relevant zu verändern. Das Medika-
ment zeigt eine höhere Wirksamkeit bei Frau-
en, während Herzinsuffizienz und Betablo-
cker den Effekt schwächen.
Schlüsselwörter
Cafedrin/Theodrenalin· Blutdruckabfall·
Herzinsuffizienz· Betablocker-Effekte·
Herzfrequenz
192
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Der Anaesthesist 3 · 2015

Results
Data were collected for 353 consec-
utive anaesthesia patients (mean age
64.4 ± 15.1) at a single institution who re-
ceived cafedrine/theodrenaline to treat
hypotensive states during surgery be-
tween July and November 2007. Demo-
graphic characteristics, baseline values
and treatment are presented in . Table1.
172 and 181 patients received general and
neuraxial anaesthesia, respectively.
The MAP dropped from a mean base-
line value of 82 ± 14 to 63 ± 10 mmHg
(equivalent to 78 ± 12 % of the baseline
level; p < 0.001). MAP increase after 5 min
was also statistically significant (p < 0.001),
however mean baseline MAP values and
the drop during surgery did not differ be-
tween genders (. Fig.1, . Table2). MAP
increased by 11 ± 16 mmHg (p < 0.001)
5 min after administration of cafedrine/
theodrenaline, while heart rates remained
at a mean of 66 ± 18 bpm over 20 min.
The highest MAP values were achieved
17.4 ± 9.0 min after the drop and admin-
istration of 1.27 ± 1.0 mg cafedrine/kg,
independent of gender. For ease of trans-
ferring applied cafedrine/theodrenaline
dosages into the reader’s clinical practice,
. Table3 gives the relevant standard dos-
es, dilutions and relations to body weight.
Heart rates before the drop in MAP were
a mean of 71 ± 18 and 67 ± 19 bpm after
the drop (p < 0.001).
Cafedrine/theodrenaline
effectiveness according to gender
Heart rates did not differ significantly be-
tween genders (. Fig.2). After the drop
in blood pressure cafedrine/theodrena-
line induced a 10 % increase in MAP sig-
nificantly earlier in women 7.2 ± 4.6 vs.
8.6 ± 6.3 min in men (p = 0.018) (. Table2,
. Fig.3), however, the duration of the
pressure-elevating effect as assessed by
the time to peak MAP did not differ in a
gender-related manner (. Table2).
Cafedrine/theodrenaline in
patients with heart failure
The time to highest MAP was lon-
ger for the 67 patients with heart fail-
ure than for patients without heart prob-
lems (p = 0.007) (. Fig.4). In addition,
the dose (mg/kg body weight) to achieve
MAP increase in a similar range at 15 min
(by 14 ± 16 mmHg in heart failure patients
and by 14 ± 14 mmHg in healthy patients)
were 1.78 ± 1.67 mg/kg in patients with
heart failure and 1.16 ± 0.77 mg/kg in the
healthy cohort (p = 0.005). This difference
was independent of gender.
Cafedrine/theodrenaline in
patients with beta-blocking agents
Concomitant medication with be-
ta-blocking agents significantly pro-
longed the time to 10 % increase in
MAP (n = 111, 9.0 ± 7.0 vs. 7.3 ± 4.3 min,
p = 0.008) (. Fig.5). Factors potentially
affecting the effectiveness of beta-stim-
ulants such as the extent of volume load
(492 ± 288 ml without beta-blocking
agents and 475 ± 289 ml with beta-block-
ing agents) prior to blood pressure drop
did not differ between the groups.
Discussion
Risks of hypotonia
during anaesthesia
Induction of anaesthesia induces sym-
pathicolysis, regardless of the type of an-
aesthesia, whether general or neuraxial,
and poses a risk of hypotension, in par-
ticular when the administration of in-
travenous fluids is restricted [12, 17, 27].
The dilation of resistance and capacitance
vessels in the blocked area, with a subse-
quent decrease of pressure in the system-
ic and pulmonary circulation, leads to a
reduction in cardiac preload and after-
load, posing a risk of cerebral or myocar-
dial ischaemia as well as acute renal failure
[10, 14]. The use of balanced anti-hypo-
tonic agents such as cafedrine/theodren-
aline may be beneficial when combined
with gentle volume loading, especially in
193Der Anaesthesist 3 · 2015
|
Table 1 Demographic baseline characteristics and treatment (mean ± SD)
Women (n = 149) Men (n = 204) p-value
Age (years) 65.6 ± 16.6 63.6 ± 13.8 n.s.
Weight (kg) 69.6 ± 18.4 81.3 ± 15.4 0.001
ASA class 2.4 ± 0.7 2.5 ± 0.6 n.s.
Heart failure NYHA ≥ 1 [n (%)] 35 (23.5 %) 32 (15.7 %) n.s.
Current beta-blocker therapy [n (%)] 50 (33.6 %) 61 (29.9 %) n.s.
Heart failure NYHA ≥ 1 and beta-blocker therapy
[n (%)]
18 (12.1 %) 18 (8.8 %) n.s.
Score by Canadian Cardiovascular Society 0.2 ± 0.5 0.1 ± 0.4 n.s.
Volume load with crystalloids (ml) 481 ± 293 493 ± 287 n.s.
Baseline MAP (mmHg) 81.8 ± 12.8 82.2 ± 14.5 n.s.
MAP after decrease (mmHg); reference 62.4 ± 8.9 63.8 ± 11.4 n.s.
Dosage Akrinor® (cafedrine mg/kg)a1.3 ± 1.0 1.2 ± 1.0 n.s.
ASA American Society of Anesthesiologists, NYHA New Yor k Heart Association, MAP mean arterial pressure
aCafedrine:theodrenaline fixed milligram ratio = 20:1
Table 2 Gender-related pharmacodynamic effects of cafedrine/theodrenaline (mean ± SD)
Women (n = 149) Men (n = 204) p-value
10 % MAP increase (min) 7.2 ± 4.6 8.6 ± 6.3 0.018
Time to maximum MAP effect (min) 17.0 ± 9.1 17.7 ± 9.0 n.s.
Table 3 Conversion table for cafedrine/theodrenaline dosages into ml of standard dilutions
Akrinor® ampoules 1 1/2 1/4
Cafedrine (mg) 200 100 50
Theodrenaline (mg) 10 52.5
Akrinor® solution undiluted (ml) 210.5
Akrinor® 1 ampoule diluted to 10ml (ml) 10 52.5
Mean study dosage Akrinor® per 75kg BW (amp)a0.48
aStudy mean dosage used was 1.3 ± 1.0mg/kg(Cafedrine), 64 ± 50µg/kg ( Theodrenaline)

elderly patients [4, 28] and during more
extensive surgical interventions [20]. A
pilot study [13] suggested that male gen-
der, heart failure and beta-blocking agents
are factors that negatively influence the
effectiveness of cafedrine/theodrenaline.
Here we performed more in-depth analy-
ses (Kaplan–Meier analyses) using an in-
dependent patient population to further
elucidate the influences. We aimed to in-
clude a broad range of patients that had a
≥ 5 % blood pressure drop to represent a
real-life population, regardless of under-
lying conditions. The range of the drop in
blood pressure may vary in relation to the
underlying disease; this study focuses on
the therapy of the hypotensive states.
Blood pressure restoration with
pure alpha- or beta-adrenergic
agents vs. cafedrine/theodrenaline
Due to the limited half-life, bolus admin-
istration of catecholamines has only a
short-term circulatory effect [7]. More-
over, bolus injection of pure alpha-ago-
nists cause an undesirable direct increase
in peripheral resistance, resulting in ad-
ditional energy-consuming wall tension
in the myocardium [5] and bradycardia,
necessitating additional pharmacologic
treatment with atropine [7]. Alternative-
ly, pure beta-mimetic drugs induce a de-
layed increase in blood pressure, due to
initial vascular beta2-stimulation and the
dependency on vascular filling; as a con-
sequence, undesirable increases in heart
rate are observed [18].
Here we show that the administration
of cafedrine/theodrenaline significantly
increased MAP in both genders without
affecting the heart rate in a clinically sig-
nificant manner. These observations are
in line with experimental investigations
[9, 11] and small clinical studies [13, 24].
Affecting the effectiveness:
gender, beta-blocking
agents and heart failure
The time to 10 % MAP increase in this
cohort was longer in men and in patients
who had previously received beta-block-
ing agents. The more rapid increase in
MAP in women may be attributable to
the lower cafedrine/theodrenaline ED50
[13] and/or the higher intravascular flu-
id volume is observed in women [23] due
to the higher level of endogenous oestro-
gen and resulting increase in preload. The
downregulation of beta-receptors in old-
er men [8] and oestrogen receptor-de-
pendent effect that protects women from
left ventricular hypertrophy and conges-
tive heart failure [2] might represent con-
tributing factors as well. Although poten-
194
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Der Anaesthesist 3 · 2015
Originalien
female
male
p=0.018 log rank test
1,0
0,8
0,6
0,4
0,2
0,0
10% MAP increase reached
Time to 10% MAP increase [min]
0510 15 20 25 30
Fig. 38Kaplan–Meier analysis of the time to 10 % mean arterial pressure (MAP) increase in male
(dotted line) and female (solid line) patients after cafedrine/theodrenaline injection at time point 0
(p = 0.018, log-rank test)
p=0.007 log rank test
1,0
0,8
0,6
0,4
0,2
0,0
highest MAP increase reached
Time to highest MAP increase [min]
0510 15 20 25 30
healthy
heart
insuciency
Fig. 48Kaplan–Meier analysis of the time to highest mean arterial pressure (MAP) after cafedrine/
theodrenaline injection at time point 0 in patients with heart failure (NYHA ≥ 1, dotted line) and
healthy patients (solid line) (p = 0.007, log-rank test). Cases not reaching a MAP increase of 20 % with-
in 30min were censored

tially not relevant under day-to-day cir-
cumstances, during acute sympathicoly-
sis-dependent hypotension these factors
[2, 8] could have a clinical effect and at
least partially explain the gender-related
difference in the time to effect after cafe-
drine/theodrenaline administration. The
effect of concomitant beta-blocker thera-
py on the effectiveness of cafedrine/theo-
drenaline is not surprising, given the pre-
dominantly beta-mimetic effects of this
drug combination [24, 25] Patients with
heart failure required longer to reach the
maximum MAP and required higher dos-
es of cafedrine/theodrenaline. Apparently
patients with heart failure are not able to
respond to stimulation by alpha- and be-
ta-adrenergic agents [13].
Limitations
This study has a number of limitations.
The association between heart failure and
the use of beta-blockers and the influence
of health status and gender on the type
of anaesthesia (general vs. regional) ad-
ministered may have introduced sourc-
es of selection bias, especially in patients
with heart failure receiving beta-blockers.
Larger prospective and controlled stud-
ies with a more strictly defined and strati-
fied patient populations are certainly war-
ranted.
Conclusion for clinical practice
5 Cafedrine/theodrenaline results in a
rapid haemodynamic effect on blood
pressure without affecting heart rate
to a clinically significant extent.
5 Male gender, heart failure and the
previous administration of beta-
blocking agents negatively affect the
effectiveness of cafedrine/theodren-
aline.
5 Prospective studies to characterise
the effect of cafedrine/theodrenaline
in defined patient populations are
warranted.
Corresponding address
Prof. Dr. A. R. Heller
Department of Anaesthesia
and Intensive Care Medicine
Department of Anesthesiology
and Critical Care Medicine
Medizinische Fakultät Carl
Gustav Carus
Technische Universität Dresden
Fetscherstr. 74, 01307 Dresden
axel.heller@uniklinkum-dres-
den.de
Acknowledgements. This study was funded
solely from institutional sources. Author Axel R.
Heller received project funding (REF 13) from AWD.
pharma GmbH & Co. KG, Dresden, Germany. Editorial
assistance for manuscript preparation was provided
by Physicians World Europe GmbH, Mannheim,
Germany, with nancial support from Teva GmbH,
Ulm, Germany.
Compliance withethical
guidelines
Disclaimers. This work represents part of author
Julia Heger’s doctoral thesis.
Open Access. This article is distributed under the
terms of the Creative Commons Attribution License
which permits any use, distribution, and reproduc-
tion in any medium, provided the original author(s)
and the source are credited.
Conflict of interest. Julia Heger, Marcelo Gama
de Abreu, Michael P. Müller declare no conict of
interest.
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