Population kinetic/pharmacodynamic modelling of the haemodynamic effects of cafedrine/theodrenaline (Akrinor) under general anaesthesia.

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.

Intraoperative haemodynamic monitoring and management of adults having non-cardiac surgery: Guidelines of the German Society of Anaesthesiology and Intensive Care Medicine in collaboration with the German Association of the Scientific Medical Societies.

Haemodynamic monitoring and management are cornerstones of perioperative care. The goal of haemodynamic management is to maintain organ function by ensuring adequate perfusion pressure, blood flow, and oxygen delivery. We here present guidelines on "Intraoperative haemodynamic monitoring and management of adults having non-cardiac surgery" that were prepared by 18 experts on behalf of the German Society of Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin; DGAI).

A randomized open label, parallel-group study to evaluate the hemodynamic effects of Cafedrine/Theodrenaline vs Noradrenaline in the treatment of intraoperative hypotension after induction of general anesthesia: the "HERO" study design and rationale.

OBJECTIVE: Intraoperative arterial hypotension (IOH) is associated with poor patient outcome. This study aims to compare the hemodynamic effects of Cafedrine/Theodrenaline (C/T) and Noradrenaline (NA) for the treatment of hypotension in patients who develop IOH after anesthesia induction. RESEARCH DESIGN AND METHODS: This is a national, randomized, parallel-group, multicenter, and open-label study. Adult patients (≥50 years, ASA-classification III-IV) who undergo elective surgery will be included. When IOH (MAP <70 mmHg) develops, C/T or NA will be given as a bolus injection ("bolus phase", 0-20 min after initial application) and subsequently as continuous infusion ("infusion phase", 21-40 min after initial application) to achieve MAP = 90 mmHg. Hemodynamic data are captured in real time by advanced hemodynamic monitoring. RESULTS: Primary endpoints, i.e. the treatment-related difference in average mean arterial pressure (MAP) during the "infusion phase" and the treatment-related difference in average cardiac index during the "bolus phase" are assessed (fixed-sequence method). Non-inferiority of C/T compared to NA in achieving 90 mmHg (MAP) when applied as continuous infusion is hypothesized. In addition, superiority of C/T over NA, applied as bolus injection, in increasing cardiac index is postulated. It is estimated that 172 patients are required to establish statistical significance with a power of 90%. After adjusting for ineligibility and dropout rate, 220 patients will be screened. CONCLUSION: This clinical trial will yield evidence for marketing authorization of C/T applied as continuous infusion. Additionally, the effects of C/T compared to NA on cardiac index will be assessed. First results of the "HERO"-study are expected in 2024. DRKS identifier: DRKS00028589. EudraCT identifier: 2021-001954-76.

Quantification of exhaled propofol is not feasible during single-lung ventilation using double-lumen tubes: A multicenter prospective observational trial.

BACKGROUND: Volatile propofol can be measured in exhaled air and correlates to plasma concentrations with a time delay. However, the effect of single-lung ventilation on exhaled propofol is unclear. Therefore, our goal was to evaluate exhaled propofol concentrations during single-lung compared to double-lung ventilation using double-lumen tubes. METHODS: In a first step, we quantified adhesion of volatile propofol to the inner surface of double-lumen tubes during double- and single-lumen ventilation in vitro. In a second step, we enrolled 30 patients scheduled for lung surgery in two study centers. Anesthesia was provided with propofol and remifentanil. We utilized left-sided double-lumen tubes to separately ventilate each lung. Exhaled propofol concentrations were measured at 1-min intervals and plasma for propofol analyses was sampled every 20 min. To eliminate the influence of dosing on volatile propofol concentration, exhalation rate was normalized to plasma concentration. RESULTS: In-vitro ventilation of double-lumen tubes resulted in increasing propofol concentrations at the distal end of the tube over time. In vitro clamping the bronchial lumen led to an even more pronounced increase (Δ AUC +62%) in propofol gas concentration over time. Normalized propofol exhalation during lung surgery was 31% higher during single-lung compared to double-lung ventilation. CONCLUSION: During single-lung ventilation, propofol concentration in exhaled air, in contrast to our expectations, increased by approximately one third. However, this observation might not be affected by change in perfusion-ventilation during single-lung ventilation but rather arises from reduced propofol absorption on the inner surface area of the double-lumen tube. Thus, it is only possible to utilize exhaled propofol concentration to a limited extent during single-lung ventilation. REGISTRATION OF CLINICAL TRIAL: DRKS-ID DRKS00014788 (www.drks.de).

Treatment of spinal anaesthesia-induced hypotension with cafedrine/theodrenaline versus ephedrine during caesarean section: Results from HYPOTENS, a national, multicentre, prospective, noninterventional study.

BACKGROUND: In Germany, hypotension induced by spinal anaesthesia is commonly treated with a combination of cafedrine hydrochloride (C, 200 mg) and theodrenaline hydrochloride (T, 10 mg) in 2 ml. We compared the effectiveness of C/T with ephedrine. OBJECTIVES: The primary objectives were to assess the speed of onset and the ability to restore blood pressure without an increase in heart rate. Secondary objectives were to evaluate maternal/foetal outcomes and the number of required additional boluses or other additional measures. DESIGN: HYPOTENS was a national, multicentre, prospective, open-label, two-armed, noninterventional study comparing C/T with ephedrine in two prospectively defined cohorts. This study relates to the cohort of patients receiving spinal anaesthesia for caesarean section. SETTING: German hospitals using either C/T or ephedrine in their routine clinical practice. PATIENTS: Women aged at least 18 years receiving spinal anaesthesia for caesarean section. INTERVENTIONS: Bolus administration of C/T or ephedrine at the discretion of the attending anaesthesiologist. MAIN OUTCOME MEASURES: Endpoints within 15 min after initial administration of C/T or ephedrine were area under the curve between the observed SBP and the minimum target SBP; and incidence of newly occurring heart rate of at least 100 beats min-1. RESULTS: Although effective blood pressure stabilisation was achieved with both treatments, this effect was faster and more pronounced with C/T (P < 0.0001). The incidence of tachycardia and changes in heart rate were higher with ephedrine (P < 0.01). Fewer additional boluses (P < 0.01) were required with C/T. Although favourable neonatal outcomes were reported in both groups, base deficit and lactate values were greater with ephedrine (P < 0.01). Physician satisfaction was higher with C/T. CONCLUSIONS: After C/T, tachycardia was not a problem, providing an advantage over ephedrine. Fewer additional boluses were required with C/T, suggesting greater effectiveness. An increased base deficit with ephedrine suggests reduced oxygen supply or increased demands in foetal circulation. TRIALS REGISTRATION: Clinicaltrials.gov: NCT02893241, German Clinical Trials Register: DRKS00010740.

An overview of intravenous amisulpride as a new therapeutic option for the prophylaxis and treatment of postoperative nausea and vomiting.

Introduction: Current therapies of postoperative nausea and vomiting (PONV) are based on a combination of antiemetics from different pharmacological classes. Dopamine receptor antagonists are one of the cornerstones of such multimodal antiemetic approach, with droperidol being the best studied representative of this group. Droperidol's use has significantly declined after the FDA's black-box warning in 2001 due to its QT-prolonging properties. Amisulpride is a promising antiemetic agent which could fill this gap.Areas covered: In this review, the authors discuss the pharmacological profile as well as clinical safety and efficacy of intravenous amisulpride and its relevance in the management of PONV. The article is based on a Medline, ClinicalTrials.gov, and Cochrane Library search for studies on amisulpride conducted so far.Expert opinion: Promising clinical results on Barhemsys®, an intravenous formulation of amisulpride, make it a potential future drug of choice from the dopamine receptor antagonist group, replacing droperidol after its safety concerns. Amisulpride's success on the market will mostly be determined by its cost-effectiveness and it will likely find a brighter use on the US-market, where the black-box warning led to droperidol's withdrawal, while in many European countries, droperidol is still being used as an antiemetic.

[Patient-controlled Analgesia (PCA): an Overview About Methods, Handling and New Modalities]. / Patientenkontrollierte Analgesie: Methoden, Handhabung und Ausbaufähigkeit.

Patient-controlled analgesia (PCA) is one of the well established methods for the treatment of postoperative pain. A cochrane-review concluded that PCA is associated with better postoperative pain ratings and improved patient-satifaction compared to traditional way of administering opioids. Some prerequisites concerning patient selection, education of the patient and the medical staff, and supervision during PCA therapy are mandatory for a safe use of PCA. Current PCA modalities (intravenous and epidural routes of application) are expanded by newer, less invasive routes of drug administration, e.g. by the iontophoretic transdermal and the sublingual route. Their role in improving safety and the quality of pain therapy on the one hand side, and costs on the other hand side are discussion.

A non-interventional comparative study of the 20:1 combination of cafedrine/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the 'HYPOTENS' study design and rationale.

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 post-operative outcomes in patients with intra-operative arterial hypotension of any origin under standard clinical practice conditions. METHODS AND RESULTS: 'HYPOTENS' is a national, multi-center, 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 Cesarean section under spinal anesthesia. Participating surgical departments will be assigned to a treatment arm by routinely used anti-hypotensive agent. To minimize bias, matched department pairs will be compared in a stratified selection process. The composite primary end-point is the lower absolute deviation from individually determined target blood pressure (IDTBP) and the incidence of heart rate ≥100 beats/min in the first 15 min. Secondary end-points include incidence and degree of early post-operative 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 intra-operative 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.

Pain During Venous Cannulation.

BACKGROUND: The pain of venous puncture for the cannulation of peripheral veins is disturbing to many patients. This is the first clinical trial of the efficacy of local anesthesia in comparison to placebo (no pretreatment) in a control group, as a function of the size of the cannula. METHODS: A randomized, controlled trial of fully factorial design was performed to study pain during venipuncture after local anesthesia either with intra - dermally injected lidocaine or with a vapocoolant spray, in comparison to placebo. A standardized protocol was used for structured communication with the patient to provide the greatest feasible degree of patient blinding (trial registration number DRKS00010155). The primary endpoints were the subjective discomfort of the patient during preparation and puncture of a vein of the dorsum of the hand, assessed on a numerical rating scale (NRS) from 0 (no discomfort) to 10 (unbearable discomfort), and the rate of unsuccessful puncture. RESULTS: The intention-to-treat analysis of all 450 patients revealed that the reported degree of pain during venipuncture depended to a large extent on the caliber of the chosen venous cannula. For a 17-gauge (17G) cannula, both the vapocoolant spray (NRS = 2.6 ± 1.3) and lidocaine (NRS = 3.5 ± 2.2) lessened the discomfort due to venipuncture compared to control treatment (5.0 ± 1.5). The effect of vapocoolant spray compared to the control was both clinically relevant and statistically significant (p < 0.0001). When a smaller 20G cannula was used, however, vapocoolant spray improved discomfort by only 0.8 NRS points, which, though still statistically significant (p = 0.0056), was no longer clinically relevant. The rate of unsuccessful puncture was higher after lidocaine pretreatment (12.7%) than after either vapocoolant spray (4.7%; p = 0.0066) or no pretreatment (4.0%; p = 0.0014). CONCLUSION: Local anesthesia can be recommended before venipuncture only if a large cannula is used (e.g., ≥ 17G). Vapocoolant spray may be at least as useful as lidocaine injection; it prevents pain to a similar extent and is associated with a lower rate of unsuccessful puncture.

Vapocoolant Spray Versus Lidocaine Infiltration for Radial Artery Cannulation: A Prospective, Randomized, Controlled Clinical Trial.

OBJECTIVES: Local infiltration with lidocaine is a frequently used measure to prevent pain during arterial cannulation. Its administration is associated with pain. Vapocoolants like ethyl chloride or alkanes also affect rapid-onset anesthesia. However, their administration causes less discomfort compared with administration of lidocaine. The effectiveness of vapocoolants in mitigating discomfort associated with arterial cannulation never has been studied. The authors therefore compared vapocoolant with lidocaine for reducing discomfort caused by arterial cannulation. DESIGN: Prospective, randomized, controlled study. SETTING: University hospital, single center. PARTICIPANTS: One hundred sixty adult patients requiring arterial cannulation before induction of general anesthesia for cardiac surgery or carotid endarterectomy. INTERVENTIONS: Patients received either lidocaine infiltration or vapocoolant spray prior to arterial cannulation. Overall discomfort resulting from the whole procedure (applying local/topical anesthesia followed by arterial puncture) was rated on a 0 to 10 numerical rating scale. Puncture failure rate and time required for the intervention also were recorded. MEASUREMENTS AND MAIN RESULTS: One hundred forty-three patients were included in the per-protocol analysis. Mean pain scores in the vapocoolant group were 3.4 (±1.58) compared with 4.5 (±2.29) in the lidocaine group (difference 1.1±0.33; p = 0.032; Mann-Whitney U-test). The higher puncture failure rate in the lidocaine group (n = 11 v 4) was not significant (p = 0.06; Fisher's exact test). The time required for the intervention was longer in the lidocaine group (138±44 s v 128±44 s; p = 0.019; Mann-Whitney U-test). CONCLUSIONS: Vapocoolant spray is an alternative to lidocaine infiltration to mitigate discomfort associated with arterial cannulation.

Use of Fentanyl Iontophoretic Transdermal System (ITS) (IONSYS®) in the Management of Patients with Acute Postoperative Pain: A Case Series.

Fentanyl iontophoretic transdermal system (ITS) [IONSYS®, The Medicines Company, Parsippany, NJ, USA] is a needle-free, patient-controlled, postoperative opioid pain management treatment. It is indicated for the short-term management of acute postoperative pain in adults requiring opioid analgesia in the hospital. The safety and effectiveness of fentanyl ITS for acute postoperative pain management has been demonstrated in a range of surgery and patient types studied in seven phase 3 trials (three placebo-controlled trials and four active-comparator trials). The majority of the patients in the phase 3 trials had undergone either abdominal/pelvic, orthopedic, or thoracic surgery. Consistent with the prescribing information, physicians in clinical practice may treat patients with this system following any type of surgery including those that may not have been included in the phase 3 trials. The purpose of this case series is to illustrate how fentanyl ITS is being utilized for postoperative pain management in real-world clinical practice following a variety of surgeries and in current pain management protocols that may have evolved since the completion of the phase 3 program. There are seven cases from three clinical centers described within this case series, each using fentanyl ITS according to the prescribing information. The surgery types included are bariatric (N = 3), prostate (N = 2), colorectal (N = 1), and perirectal abscess drainage (N = 1). A systematic review of each patient chart was conducted via a standardized retrospective assessment by the clinicians who managed each patient. Additionally, each healthcare professional was interviewed regarding their overall experience and key learnings using fentanyl ITS. Overall, fentanyl ITS was effective and well tolerated in these case reports in current-day clinical practice settings. These case studies are informative about fentanyl ITS use shortly after product approval and set the stage for additional clinical research.

Activity-based cost analysis of opioid-related nausea and vomiting among inpatients.

OBJECTIVE: Nausea and/or vomiting (N/V) are frequent side effects of opioid drugs. These are of major concerns to patients and caregivers and only few studies have focused on their economical costs. DESIGN: This is a prospective, nonproduct-related, activity-based evaluation of personnel and material costs of opioid-related N/V among inpatients. SETTING: Data were obtained from surgical, general medicine, and palliative care wards at 16 German hospitals of different size, healthcare mandate, and ownership. PATIENTS, PARTICIPANTS: According to predefined criteria, of 462 documented N/V events, 340 were diagnosed as opioid related. INTERVENTIONS: Elicited activities and pharmacological interventions for N/V episodes followed local standards. MAIN OUTCOME MEASURE: Both materials used and the time engaged to treat patients with N/V were documented on an "ad hoc" activity recording form. The total cost of an opioid-related N/V episode was calculated based on standard wages of the involved personnel and standard costs of the inherent materials used. RESULTS: Mean staff tenure time for handling an episode of N/V was 26.2 ± 19.8 minutes (nausea 16.9 ± 28.7 minutes; nausea + vomiting: 33.4 ± 26.8 minutes). In the German context, this corresponds to average personnel costs of €18.06 ± 13.64. Material cost contributes to another €13.49 ±13.38 of costs mainly depending on acquisition costs of antiemetic drugs. CONCLUSIONS: N/V showed to have impact on workload of nurses and (to lesser extent) physicians and economic burden of €31 ± 22 for each N/V episode. In view of these results, the potential costs of strategies to minimize the incidence of N/V (use of antiemetics and/or the use of new analgesics) should be outweighed against the incurred costs of N/V.

Does femoral nerve catheter placement with stimulating catheters improve effective placement? A randomized, controlled, and observer-blinded trial.

Continuous peripheral nerve blocks offer the benefit of extended postoperative analgesia and accelerated functional recovery after major knee surgery. Conventional nerve localization is performed over a stimulating needle followed by blind insertion of the peripheral catheter. Correct catheter placement is confirmed by testing for satisfactory analgesia. Stimulating catheters offer the advantage of verifying correct placement close to the nerve during catheter placement. The aim of this randomized trial was to determine whether accurate catheter positioning under continuous stimulation accelerates the onset of sensory and motor block, improves the quality of postoperative analgesia, and enhances functional recovery. We compared femoral nerve catheters inserted under continuous stimulation with catheters that were placed using the conventional technique of blind advancement in 81 patients undergoing major knee surgery. Time of catheter placement was similar in both groups with 4 min (3/7.3; median, 25th/75th percentile) in the conventional group and 5 min (4/8.8) in the stimulating catheter group. In both groups, 42% of the catheters could be correctly placed (motor response of the patella with a current < or =0.5 mA) at first attempt. In 22 patients (58%) of the stimulating catheter group, the catheter had to be redirected 1-20 times, including 2 that could not be correctly placed within 20 min. The onset time of sensory and motor block was almost similar in both groups. There were no differences in the postoperative IV opioid consumption, and visual analog scale pain scores at rest and movement, or maximal bending and stretching of the knee joint during the 5 days after surgery. We conclude that with continuous femoral nerve blocks, blind catheter advancement is as effective as the stimulating catheter technique with respect to onset time of sensory and motor block as well as for postoperative pain reduction and functional outcome.