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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 % within 30 min were censored
Source publication
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...
Context in source publication
Context 1
... 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 ...
Citations
... The clinical effects of cafedrine/theodrenaline are mediated through β 1 -adrenoreceptor and α-adrenoreceptor stimulation, and nonspecific inhibition of phosphodiesterases (PDEs) is believed to enhance their response 14,17 . In contrast with synthetic vasopressors (e.g., ephedrine, phenylephrine), systemic vascular resistance and heart rate remain mostly unaffected, which makes cafedrine/theodrenaline especially appealing in obstetric surgery 14,16,19 . Although cafedrine/theodrenaline has been widely used for decades, little is known about its pharmacodynamics or pharmacokinetics in specific end organs 14,16 . ...
Mucociliary clearance is a pivotal physiological mechanism that protects the lung by cleaning the airways from pollution and colonization, thereby preventing infection. Ciliary function is influenced by various signal transduction cascades, and Ca²⁺ represents a key second messenger. A fixed 20:1 combination of cafedrine and theodrenaline has been widely used to treat perioperative hypotension and emergency hypotensive states since the 1960s; however, its effect on the intracellular Ca²⁺ concentration ([Ca²⁺]i) of respiratory epithelium remains unknown. Therefore, human tracheal epithelial cells were exposed to the clinically applied 20:1 mixture of cafedrine/theodrenaline and the individual substances separately. [Ca²⁺]i was assessed by FURA-2 340/380 fluorescence ratio. Pharmacological inhibitors were applied to elucidate relevant signal transduction cascades, and reverse transcription polymerase chain reaction (RT-PCR) was performed on murine tracheal epithelium to analyze ryanodine receptor (RyR) subtype expression. All three pharmacological preparations instantaneously induced a steep increase in [Ca²⁺]i that quickly returned to its baseline value despite the persistence of each substance. Peak [Ca²⁺]i following the administration of 20:1 cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone increased in a dose-dependent manner, with median effective concentrations of 0.35 mM (7.32 mM cafedrine and 0.35 mM theodrenaline), 3.14 mM, and 3.45 mM, respectively. When extracellular Ca²⁺ influx was inhibited using a Ca²⁺-free buffer solution, the peak [Ca²⁺]i following the administration of cafedrine alone and theodrenaline alone were reduced but not abolished. No alteration in [Ca²⁺]i compared with baseline [Ca²⁺]i was observed during β-adrenergic receptor inhibition. Depletion of caffeine-sensitive stores and inhibition of RyR, but not IP3 receptors, completely abolished any increase in [Ca²⁺]i. However, [Ca²⁺]i still increased following the depletion of mitochondrial Ca²⁺ stores using 2,4-dinitrophenol. RT-PCR revealed RyR-2 and RyR-3 expression on murine tracheal epithelium. Although our experiments showed that cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone release Ca²⁺ from intracellular stores through mechanisms that are exclusively triggered by β-adrenergic receptor stimulation, which most probably lead to RyR activation, clinical plasma concentrations are considerably lower than those used in our experiments to elicit an increase in [Ca²⁺]i; therefore, further studies are needed to evaluate the ability of cafedrine/theodrenaline to alter mucociliary clearance in clinical practice.
... However, the impact of drugs used to treat perioperative hypotension, which is a frequently observed condition in clinical practice, remains unclear. In Germany, a fixed 20:1 combination of cafedrine and theodrenaline (Akrinor ® , Ratiopharm GmbH, Ulm, Germany) has been the main drug used to treat intraoperative hypotension or hypotensive states due to emergency situations since the 1960s (Heller et al., 2015;Bein et al., 2017;Weitzel et al., 2018). Cafedrine is composed of covalently linked theophylline and norephedrine, and theodrenaline is formed from theophylline and noradrenaline in the same manner (Bein et al., 2017;Kloth et al., 2017). ...
... The clinical effects of cafedrine/theodrenaline are provided through β1-and αadrenoreceptor stimulation, while nonspecific inhibition of phosphodiesterases is thought to enhance their response (Bein et al., 2017;Kloth et al., 2017). In contrast with synthetic vasopressors (e.g., ephedrine, phenylephrine), systemic vascular resistance and heart rate remain mostly unaffected, which makes cafedrine/theodrenaline especially appealing in obstetric surgery (Heller et al., 2015;Bein et al., 2017;Kranke et al., 2021). Although cafedrine/theodrenaline has been widely used for decades, little is known about its pharmacodynamics and pharmacokinetics in specific end organs (Heller et al., 2015;Bein et al., 2017). ...
... In contrast with synthetic vasopressors (e.g., ephedrine, phenylephrine), systemic vascular resistance and heart rate remain mostly unaffected, which makes cafedrine/theodrenaline especially appealing in obstetric surgery (Heller et al., 2015;Bein et al., 2017;Kranke et al., 2021). Although cafedrine/theodrenaline has been widely used for decades, little is known about its pharmacodynamics and pharmacokinetics in specific end organs (Heller et al., 2015;Bein et al., 2017). This is rather surprising, as the unique combination of three single drugs (theophylline, norephedrine, noradrenaline) in a 20:1 mixture can produce various effects in vivo, which have recently been evaluated in human atrial myocardium (Kloth et al., 2017). ...
Background: Mucociliary clearance is a pivotal physiological mechanism that protects the lung by ridding the lower airways of pollution and colonization by pathogens, thereby preventing infections. The fixed 20:1 combination of cafedrine and theodrenaline has been used to treat perioperative hypotension or hypotensive states due to emergency situations since the 1960s. Because mucociliary clearance is impaired during mechanical ventilation and critical illness, the present study aimed to evaluate the influence of cafedrine/theodrenaline on mucociliary clearance.
Material and Methods: The particle transport velocity (PTV) of murine trachea preparations was measured as a surrogate for mucociliary clearance under the influence of cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone. Inhibitory substances were applied to elucidate relevant signal transduction cascades.
Results: All three applications of the combination of cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone induced a sharp increase in PTV in a concentration-dependent manner with median effective concentrations of 0.46 µM (consisting of 9.6 µM cafedrine and 0.46 µM theodrenaline), 408 and 4 μM, respectively. The signal transduction cascades were similar for the effects of both cafedrine and theodrenaline at the murine respiratory epithelium. While PTV remained at its baseline value after non-selective inhibition of β-adrenergic receptors and selective inhibition of β 1 receptors, cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone increased PTV despite the inhibition of the protein kinase A. However, IP 3 receptor activation was found to be the pivotal mechanism leading to the increase in murine PTV, which was abolished when IP 3 receptors were inhibited. Depleting intracellular calcium stores with caffeine confirmed calcium as another crucial messenger altering the PTV after the application of cafedrine/theodrenaline.
Discussion: Cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone exert their effects via IP 3 receptor-associated calcium release that is ultimately triggered by β 1 -adrenergic receptor stimulation. Synergistic effects at the β 1 -adrenergic receptor are highly relevant to alter the PTV of the respiratory epithelium at clinically relevant concentrations. Further investigations are needed to assess the value of cafedrine/theodrenaline-mediated alterations in mucociliary function in clinical practice.
... Tab. [8]. In älteren Untersuchungen konnte sowohl an gesunden Probanden als auch an Patienten unter verschiedenen Untersuchungsbedingungen regelhaft eine Zunahme des MAP gezeigt werden [15,16,20,22]. ...
Background
There is insufficient knowledge about the hemodynamic effects of cafedrine/theodrenaline (caf/theo), a commercially available drug combination, to treat hypotension.
Methods
This prospective observational study investigated the hemodynamic effects of caf/theo on anesthesia-induced hypotension in 20 patients scheduled for elective major abdominal surgery. After induction of total intravenous anesthesia (TIVA) with propofol and remifentanil, a decrease in mean arterial blood pressure (MAP) below 60 mm Hg (n = 12) was treated with 60 mg/3 mg caf/theo. The systemic vascular resistance index (SVRI), cardiac index (CI), global end-diastolic index (GEDI), maximum pressure increase in the aorta (dPmx) and global ejection fraction (GEF) were assessed by transpulmonary thermodilution (PiCCO2-Monitor).
Results
The MAP increased by approximately 60% 10 min after administration of caf/theo. The increase in MAP was a result of the simultaneous effects on various cardiovascular determinants. An increase in peripheral resistance (SVRI +42%) and CI (+17%) could be determined. Data further indicated that the increase in CI was a consequence of an increase in both dPmx (+31%) and GEDI (+9%) but the GEF remained constant.
Conclusion
In anesthesia-induced hypotension caf/theo effectively increased the mean arterial blood pressure by combined effects on preload, contractility, and afterload without altering cardiovascular efficiency.
... These results have direct relevance for the study of other poorly understood, yet clinically-applied covalent theophylline conjugates, such as cafedrine and theodrenaline. 29 Furthermore, our findings implicate the use of amphetamine and theophylline binding haptens, including FEN and 1-A 1 , as efficacious and potentially complementary vaccination strategies to blunt the pharmacodynamic effects of fenethylline, a synthetic drug whose abuse is undergoing conflict-driven global expansion. Perhaps most importantly, we expect that this 'dissection through vaccination' strategy can be broadly applied to numerous other complex chemical systems-including natural product extracts, SPD's, and post-metabolic tissue samples-in order to illuminate unexpected polypharmacologic interactions and identify the exact chemical origin for each component within a multi-faceted pharmacodynamic profile. ...
PARAGRAPH
Fenethylline, also known as Captagon, is a synthetic psychoactive stimulant that has recently been linked to substance use disorder and ‘pharmacoterrorism’ in the Middle East.1–4 Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it additionally incorporates a covalently-linked xanthine moiety into its parent structure.5,6 These independently-active pharmacophores are liberated during metabolism, resulting in a structurally-diverse chemical mixture being deployed to the central nervous system.7–9 Although fenethylline’s psychoactive properties have been reported to differ from other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects.10,11 Here we develop a ‘dissection through vaccination’ approach, called DISSECTIV, to mitigate fenethylline’s psychoactivity and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacologic activity. We anticipate that DISSECTIV will be employed to expose unidentified active chemical species and illuminate pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples, and natural product extracts.
Aims
The 20:1 combination of cafedrine and theodrenaline (C/T) is widely used in Germany for the treatment of arterial hypotension. Since there is little knowledge about the impact of covariates on the effect, the aim was to develop a kinetic/pharmacodynamic covariate model describing mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) for 30 min after the administration of C/T.
Methods
Data of patients receiving C/T from the HYPOTENS study (NCT02893241, DRKS00010740) were analysed using nonlinear mixed‐effects modelling techniques.
Results
Overall, 16 579 measurements from 315 patients were analysed. The combination of two kinetic compartments and a delayed effect model, coupled with distinct Emax models for HR, SBP and DBP, described the data best. The model included age, sex, body mass index (BMI), antihypertensive medication, American Society of Anaesthesiologists (ASA) physical status classification grade, baseline SBP at the time of hypotension and pre‐surgery HR as covariates (all P < .001). A higher baseline SBP led to a lower absolute increase in MAP. Patients with higher age, higher BMI and lower ASA grade showed smaller increases in MAP. The initial increase was similar for male and female patients. The long‐term effect was higher in women. Concomitant antihypertensive medication caused a delayed effect and a lower maximum MAP. The HR increased only slightly (median increase 2.6 bpm, P < .001).
Conclusions
Seven covariates with an impact on the effect of C/T could be identified. The results will enable physicians to optimize the dose with respect to individual patients.
Hundreds of thousands of pregnant women undergo surgery for nonobstetric reasons each year. Surgery and anaesthesia during pregnancy are critical since an intervention to the mother may also affect the baby. Anatomical, physiological and pharmacodynamics/pharmacokinetic changes in pregnancy, limited time for preoperative anaesthetic preparation due to the urgency of the intervention as well as dealing with two patients at the same time are challenging even for a senior anaesthesiologist. Thus, anaesthesiologists should remodify the standard anaesthetic protocols to achieve maternal and foetal safety. In this section, an overview of the physiological changes in pregnancy, anaesthetic drugs and their maternal and foetal effects, difficult airway management, and the principles of advanced cardiovascular life support in pregnant women is presented.KeywordsAnesthesiaAnestheticsOtolaryngologyPregnancyPostpartum period
Vasopressoren kommen besonders in kritischen, nicht selten lebensbedrohlichen Situationen der Anästhesie, Notfall- und Intensivmedizin zum Einsatz. Die Wahl der geeigneten Substanz sowie die Erkennung und Beherrschung möglicher Nebenwirkungen sind von großer Bedeutung. Im folgenden Beitrag sollen daher die klinisch wichtigsten Substanzen vorgestellt und deren pharmakologische Charakteristika beleuchtet werden.
Vasopressoren kommen besonders in kritischen, nicht selten lebensbedrohlichen Situationen der Anästhesie, Notfall- und Intensivmedizin zum Einsatz. Die Wahl der geeigneten Substanz sowie die Erkennung und Beherrschung möglicher Nebenwirkungen sind von großer Bedeutung. Im folgenden Beitrag sollen daher die klinisch wichtigsten Substanzen vorgestellt und deren pharmakologische Charakteristika beleuchtet werden.
Background
Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally.
Methods
HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures.
Results
A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E.
Conclusion
Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.
Background
Maternal hypotension is a common side effect of spinal anaesthesia for Caesarean section. The combination of colloid coloading and vasopressors was considered our standard for its prevention and treatment. As the safety of hydroxyethyl starch is under debate, we replaced colloid with crystalloid coloading.
Objective
We hypothesize that the mean blood pressure drop is greater when coloading with crystalloids.
Design
Prospective, observational clinical trial.
Setting
Two-centre study conducted in Berlin, Germany.
Patients
Parturients scheduled for a Caesarean section were screened for eligibility.
Intervention
The study protocol and patient monitoring were based on the standard operating procedure for Caesarean section in both centres. The data from the crystalloid group were prospectively collected between November 2014 and July 2015.
Main outcome measures
The primary endpoint was the median drop in mean blood pressure after induction of spinal anaesthesia. Secondary endpoints were incidence of hypotension (drop > 20% of baseline systolic pressure /drop < 100 mmHg), vasopressor and additional fluid requirements (mL), incidence of bradycardia (heart rate < 60 beats per minute), blood loss, Apgar score, and umbilical artery pH. In case of hypotension, patients received phenylephrine or cafedrine/theodrenaline according to their heart rate. A p < 0.05 was considered significant.
Results
345 prospectively enrolled patients (n = 193 crystalloid group vs. n = 152 colloid group) were analysed. The median drop in mean blood pressure was greater in the crystalloid group [34 mmHg (25; 42 mmHg) vs. 21 mmHg (13; 29 mmHg), p < 0.001]. Incidences of hypotension [93.3% vs. 83.6%, p: 0.004] and bradycardia [19.7% vs. 9.9%, p: 0.012] were also significantly greater in the crystalloid group. Vasopressor requirements, blood loss and neonatal outcome were not different between the groups.
Conclusions
Crystalloid coloading was associated with a greater drop in mean blood pressure and a higher incidence of hypotension when compared with colloid coloading. Neonatal outcome was, however, unaffected by the type of fluid.
Trial registration
DRKS00006783 (http://www.drks.de).
Objective: To compare the effectiveness of 20:1 cafedrine/theodrenaline approved for use in Germany to ephedrine in the restoration of arterial blood pressure and on postoperative outcomes in patients with intraoperative arterial hypotension of any origin under standard clinical practice conditions.
Methods and results: ‘HYPOTENS’ is a national, multicenter, prospective, open-label, two-armed, non-interventional study. Effectiveness and post-operative outcome following cafedrine/theodrenaline or ephedrine therapy will be evaluated in two cohorts of hypotensive patients. Cohort A includes patients aged ≥50 years with ASA-classification 2-4 undergoing non-emergency surgical procedures under general anesthesia. Cohort B comprises patients undergoing Caesarean section under spinal anesthesia. Participating surgical departments will be assigned to a treatment arm by routinely used antihypotensive agent. To minimize bias, matched department pairs will be compared in a stratified selection process. The composite primary endpoint is the lower absolute deviation from individually determined target blood pressure (IDTBP) and the incidence of heart rate ≥100 beats/minute in the first 15 min. Secondary endpoints include incidence and degree of early postoperative delirium (cohort A), severity of fetal acidosis in the newborn (cohort B), upper absolute deviation from IDTBP, percentage increase in systolic blood pressure, and time to IDTBP.
Conclusion: This open-label, non-interventional study design mirrors daily practice in the treatment of patients with intraoperative hypotension and ensures full treatment decision autonomy with respect to each patient’s individual condition. Selection of participating sites by a randomization process addresses bias without interfering with the non-interventional nature of the study. First results are expected in 2018. ClinicalTrials.gov identifier: NCT02893241; DRKS identifier: DRKS00010740.
