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British Journal of Pharmacology Sep 2022HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency...
BACKGROUND AND PURPOSE
HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes.
EXPERIMENTAL APPROACH
Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model.
KEY RESULTS
Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias.
CONCLUSION AND IMPLICATIONS
This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.
Topics: Animals; Arrhythmias, Cardiac; Dogs; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Ether-A-Go-Go Potassium Channels; Heart Rate; Long QT Syndrome; Moxifloxacin; Quinidine; Reflex; Torsades de Pointes
PubMed: 35751378
DOI: 10.1111/bph.15905 -
Cureus Jun 2021Prophylactic doses of droperidol are effective in preventing postoperative nausea and vomiting (PONV). However, due to concerns of QT interval prolongation and...
Prophylactic doses of droperidol are effective in preventing postoperative nausea and vomiting (PONV). However, due to concerns of QT interval prolongation and ventricular arrhythmias, the safety of droperidol for PONV prophylaxis has been debated. A 70-year-old woman was scheduled for total knee arthroplasty. She had a history of aortic valve replacement. Oral aprindine (40 mg/day) was prescribed. Preoperative electrocardiogram showed mild QT interval prolongation (QTc = 475 ms). Anesthesia was induced using propofol, remifentanil, and rocuronium, and maintained using desflurane, remifentanil, and a bolus dose of rocuronium. The surgery was uneventful. At the time of skin closure, droperidol (1.25 mg) was administered intravenously for PONV prophylaxis. Twenty-three minutes after administration of droperidol, a sudden onset of premature cardiac contraction was observed, which progressed directly to ventricular tachycardia and atrioventricular block. Arrhythmia due to droperidol-induced QT interval prolongation was strongly suspected. Intravenous magnesium sulfate (2 g) and atropine (0.5 mg) were administered immediately. The ventricular tachycardia resolved quickly after the magnesium injection. Following the resolution of the arrhythmia, the patient was extubated. The patient experienced ventricular tachycardia after a prophylactic dose of droperidol that resulted from QT interval prolongation due to the preoperative medication. It may be prudent to avoid even low-dose droperidol in the background of already present QT prolongation, especially when multiple putative QT-prolonging drugs are used.
PubMed: 34277183
DOI: 10.7759/cureus.15560 -
Swiss Medical Weekly Aug 2019Drug-drug interaction (DDI) screening programmes aim to increase the safety of medication by issuing alerts based on the severity of DDIs, since an increased risk of...
AIMS OF THE STUDY
Drug-drug interaction (DDI) screening programmes aim to increase the safety of medication by issuing alerts based on the severity of DDIs, since an increased risk of adverse drug events has been reported for some DDIs (clinically relevant alerts). However, not all DDI alerts may be clinically relevant, depending on the clinical decision support system (CDSS) interaction tool used and the target population. There are few data about the frequency and relevance of DDIs in the paediatric population. The objective of this study was to evaluate the prevalence and appropriateness of high-risk DDI alerts (drug combinations that are rated as “contraindicated” or “contraindicated by precaution” according to the Swiss CDSS interaction tool Pharmavista® (HCI Solutions AG, Bern, Switzerland)) in paediatric inpatients.
METHODS
We carried out a retrospective, single-centre study examining a cohort of paediatric cases hospitalised between January and May 2017 on the surgery/orthopaedic and oncology wards at the University of Basel Children’s Hospital (UKBB), Switzerland. Drugs administered to the patients concomitantly were obtained from the medical records. DDI screening was performed using Pharmavista®. All DDIs detected were documented with their severity grading for each hospital day per case. The clinical relevance of DDI alerts for drug combinations rated as contraindicated or contraindicated by precaution was critically evaluated by a literature review.
RESULTS
A total of 300 patient cases were assessed for “contraindicated” or “contraindicated by precaution” DDI alerts. Of these, none had “contraindicated” and five had DDI alerts rated as “contraindicated by precaution” (1.7%, 95% CI 0.6–4.1%). The corresponding drug combinations were tramadol/fentanyl/morphine-nalbuphine (n = 3), droperidol-ondansetron (n = 1) and methotrexate-metamizole (n = 1), given for a duration of 1–2 days. Adverse drug events (ADEs) due to these three combinations (QT prolongation with the combination droperidol-ondansetron, reduced effect of opioid agonists with nalbuphine and increased haematotoxicity with methotrexate-metamizole) were not documented in the patients’ medical records.
CONCLUSIONS
The low prevalence of contraindicated DDIs suggests that Pharmavista® has a low risk of over-alerting when used in a Swiss paediatric hospital. However, the current literature suggests that the severity rating of established contraindicated DDIs could be partially downgraded, and that patient/population-specific evaluations of DDI alerts are needed.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Decision Support Systems, Clinical; Drug Interactions; Female; Hospitalization; Hospitals, Pediatric; Humans; Male; Medication Systems, Hospital; Prevalence; Retrospective Studies; Switzerland
PubMed: 31422575
DOI: 10.4414/smw.2019.20103 -
Emergency Medicine Australasia : EMA Oct 2021Administration of a sedative agent is required for safe transport of prehospital patients with severe agitation to EDs. Ambulance services in Australasia use ketamine,...
OBJECTIVE
Administration of a sedative agent is required for safe transport of prehospital patients with severe agitation to EDs. Ambulance services in Australasia use ketamine, droperidol or midazolam as first line agent but the optimal agent is uncertain. In Victoria, intramuscular (IM) ketamine is used. The present study aimed to examine the prehospital characteristics and ED outcomes of patients with severe agitation after IM ketamine administration.
METHODS
A retrospective review was conducted for patients who received IM ketamine for severe agitation over a 2-year period. Data were sourced from Ambulance Victoria and linked to hospital data. The primary outcome was time to sedation. Data collected included baseline characteristics, adverse events and ED outcomes.
RESULTS
Three hundred and fifty-eight prehospital cases transported to 32 hospitals were included. Outcome data were available for 305 patients (21 hospitals). Median age was 31 years (IQR 23-40). 71.2% were male. Adequate sedation was achieved in 96.9% of cases in a median time of 5.0 min (IQR 3.0-7.0; range 1-31 min). Adverse events were transient hypoxia (5.0%), hyper-salivation (4.2%) and emergence reactions (0.8%). A total of 45 (14.8%) patients were intubated; two prehospital.
CONCLUSION
Intramuscular ketamine is effective with a low rate of prehospital complications in severely agitated patients in the prehospital setting. Given the variation in ambulance practice in Australasia, prospective, randomised trials in the prehospital setting comparing ketamine to other sedating agents such as droperidol in patients with severe agitation are required.
Topics: Adult; Allied Health Personnel; Female; Humans; Ketamine; Male; Prospective Studies; Psychomotor Agitation; Retrospective Studies; Young Adult
PubMed: 33763938
DOI: 10.1111/1742-6723.13755 -
The Journal of Veterinary Medical... Aug 2019The present study used data from anesthetic records to analyze variables of intracranial pressure (ICP) during brain tumor surgery or in the early postoperative period...
The present study used data from anesthetic records to analyze variables of intracranial pressure (ICP) during brain tumor surgery or in the early postoperative period as prognostic indicators in dogs. Data from 17 dogs which were scheduled to undergo elective craniotomy for brain tumor surgery from 2009 to 2012 were included. Of these, five (29.4%) died during 14 days after the surgery because of respiratory failure following pneumonia (n=2), euthanasia due to difficulty in treatment of status epilepticus (n=1), tumor-bed hematoma (n=1), and unknown reason (n=1). In the 12 surviving dogs, neurological signs were improved or resolved at discharge. All dogs were administered midazolam and droperidol-fentanyl as premedication. General anesthesia was induced using propofol maintained on isoflurane and oxygen. Direct ICP was obtained via a Codman Microsensor strain gauge transducer. ICP hypertension (>13 mmHg) measured after 15 min of recovery from the moment after discontinuation of anesthesia by turning off the vaporizer dial was associated with poor prognosis (odds ratio, 20.00; 95% confidence interval, 1.39-287.60, P=0.028). This suggests that intracranial pressure influences the postoperative mortality rate in dogs undergoing brain tumor surgery.
Topics: Anesthesia, General; Animals; Brain Neoplasms; Craniotomy; Dog Diseases; Dogs; Intracranial Hypertension; Postoperative Period; Prognosis
PubMed: 30982789
DOI: 10.1292/jvms.18-0475 -
Federal Practitioner : For the Health... Apr 2024Acute agitation frequently occurs in the emergency department. Appropriate management is critical for the safety of all parties involved. Benzodiazepines and...
BACKGROUND
Acute agitation frequently occurs in the emergency department. Appropriate management is critical for the safety of all parties involved. Benzodiazepines and antipsychotics are commonly used for agitation, but safety concerns exist with these medications in older adults, even with acute use. The purpose of this study was to compare prescribing practices of anti-agitation medications between adults aged 18 to 64 years and those aged ≥ 65 years.
METHODS
This study was a retrospective chart review of patients who presented to the Veteran Affairs Southern Nevada Healthcare System emergency department and received haloperidol, droperidol, lorazepam, olanzapine, or ziprasidone from August 1, 2019, to July 31, 2022. Veterans were excluded if they had alcohol intoxication, alcohol withdrawal, benzodiazepine withdrawal, or medication administration unrelated to agitation. Safety outcomes included oxygen saturation < 95%, supplemental oxygen use, intubation, QTc prolongation, and new hypotension within 1 hour of medication administration.
RESULTS
For the 232 patients who met inclusion criteria, baseline characteristics differed significantly. When comparing patients aged 18 to 64 years and those aged ≥ 65 years, the younger cohort had higher rates of substance use disorder diagnosis (55.3% vs 27.5%, < .001), positive urine drug screen (69.7% vs 22.5%, < .001), and 72-hour legal hold (59.9% vs 32.5%, < .001), and lower rates of cognitive impairment or dementia (0.7% vs 48.8%, < .001), and altered mental status-related diagnosis (2.0% vs 18.8%, < .001). Anti-agitation medication selection significantly differed based on age ( = .02). Other than lorazepam ( = .007), no significant differences were noted in the dose ordered. No significant differences were observed for safety outcomes or additional anti-agitation doses.
CONCLUSIONS
Anti-agitation prescribing practices may differ between adults aged 18 to 64 years and those aged ≥ 65 years. The findings of this study also suggest that the most common agitation etiologies may differ based on patient age. Additional higher-quality studies are needed to further explore acute agitation in older adults.
PubMed: 38813266
DOI: 10.12788/fp.0456 -
Emergency Medicine Australasia : EMA Oct 2022Headache is a common presenting complaint to the ED. Using time from the first provider to discharge as a surrogate for effectiveness, we aimed to determine if... (Observational Study)
Observational Study
OBJECTIVE
Headache is a common presenting complaint to the ED. Using time from the first provider to discharge as a surrogate for effectiveness, we aimed to determine if intranasal (IN) droperidol is as beneficial as usual treatment for acute headache in the ED.
METHODS
There were 1213 consecutive presentations of adults with acute headache over a 42-month period. Electronic records for each event were interrogated, 406 events met pre-determined exclusion criteria. Of the remaining 805 eligible patient events, 139 received IN droperidol, whereas 666 were given usual therapy.
RESULTS
There was a 20 min reduction of mean and median ED length of stay (LOS) for the group that got treated with IN droperidol.
CONCLUSIONS
IN droperidol reduced LOS in the ED. There are potential cost savings of this effective treatment via this novel route. A prospective multi-centre study of the use of IN droperidol for the treatment of acute headache in the ED is recommended.
Topics: Adult; Droperidol; Emergency Service, Hospital; Headache; Humans; Prospective Studies; Retrospective Studies
PubMed: 35568501
DOI: 10.1111/1742-6723.14006 -
RSC Medicinal Chemistry Nov 2021Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced...
Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, ), was a potent Eis inhibitor with IC = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol () complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol (), eight analogues, some of which were smaller than , potently inhibited Eis (IC ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition.
PubMed: 34825186
DOI: 10.1039/d1md00239b -
Journal of Orthopaedic Surgery and... Aug 2022Insufficient pain control after lower limb arthroplasty results in delayed recovery and increased risk for pain chronicization. The ideal kind of analgesia is still...
Pain levels and patient comfort after lower limb arthroplasty comparing i.v. patient-controlled analgesia, continuous peripheral nerve block and neuraxial analgesia: a retrospective cohort analysis of clinical routine data.
BACKGROUND
Insufficient pain control after lower limb arthroplasty results in delayed recovery and increased risk for pain chronicization. The ideal kind of analgesia is still discussed controversially. We conducted a retrospective analysis of single-center routine data from a German university hospital, including patients receiving either total hip (THA) or knee arthroplasty (TKA).
METHODS
All patients received general anesthesia. Patients undergoing THA received either continuous epidural ropivacaine infusion (0.133%, Epi) or patient-controlled analgesia (PCA) with the Wurzburg Pain Drip (tramadol, metamizole and droperidol, WPD) or with piritramide (Pir). After TKA, patients received either continuous femoral nerve block (ropivacaine 0.2%, PNB) or Pir.
RESULTS
The analyzed cohort comprised 769 cases. Use of WPD after THA (n = 333) resulted in significantly reduced Numeric Rating Scale (NRS) values at rest, compared to Epi (n = 48) and Pir (n = 72) (.75 [IQR 1.14] vs. 1.17 [1.5], p = .02 vs. 1.47 [1.33], p < .0001) as well as maximum NRS scores (2.4 [1.7] vs. 3.29 [1.94], p < .001 vs. 3.32 [1.76], p < .0001). Positive feedback during follow-up visits was significantly increased in patients with a WPD PCA (p < .0001), while negative feedback (senso-motoric weakness/technical problems/nausea/dizziness/constipation) was particularly increased in Epi patients and lowest in those with WPD (p < .0001). After TKA, Pir (n = 131) resulted in significantly reduced NRS values at rest, compared to PNB (n = 185) (1.4 [1.4] vs. 1.6 [1.68], p = .02). Positive feedback was increased in patients with a Pir PCA in comparison with PNB (p = .04), while negative feedback was increased in PNB patients (p = .04). Overall, WPD presented with the lowest rate of any complications (8.7%), followed by Pir (20.2%), PNB (27.6%) and Epi (31.3%) (p < .001).
CONCLUSIONS
In the assessed population, the use of a WPD PCA after THA offered better pain control and patient comfort in comparison with continuous epidural or piritramide-based analgesia. After TKA, the use of a Pir PCA provided superior analgesia and a lower complication rate compared to continuous PNB.
Topics: Analgesia, Patient-Controlled; Anesthetics, Local; Arthroplasty, Replacement, Knee; Femoral Nerve; Humans; Lower Extremity; Nerve Block; Pain, Postoperative; Patient Comfort; Peripheral Nerves; Pirinitramide; Retrospective Studies; Ropivacaine
PubMed: 35962409
DOI: 10.1186/s13018-022-03277-0 -
Therapeutic Hypothermia and Temperature... Sep 2020Rapid induction and maintaining a target temperature of 32.0-36.0°C within a narrow range for <24 hours are essential, but those are very hard to perform in postcardiac...
Rapid induction and maintaining a target temperature of 32.0-36.0°C within a narrow range for <24 hours are essential, but those are very hard to perform in postcardiac arrest syndrome (PCAS) patients. We investigated the usability of an intravascular temperature management (IVTM) system with neurolept-anesthesia (NLA; droperidol and fentanyl). Single-arm, prospective multicenter trial was carried out in the seven university and the three affiliated hospitals. In the 24 comatose PCAS patients, the target temperature (33.0°C) was rapidly induced and maintained for 24 hours using an IVTM system with NLA. The rewarming speed was 0.1°C/h until 36.5°C and was maintained for 24 hours. The primary end point was the ability to achieve ≤34.0°C for <3 hours after starting cooling, and the secondary end points were the cooling rate, deviation from the target temperature, and adverse events. Cerebral Performance Category (CPC) score at 14 days was also evaluated. Statistical analyses were performed by SPSS software, using the intention-to-treat data sets. The target temperature of ≤34.0°C was reached by 45 minutes (35-73 minutes) and was within 3 hours in all patients. The cooling rate from 36.4°C to 33.0°C was 2.7°C/h (2.4-3.6°C/h). The temperature of 33.1°C (33.1-33.1°C) and 36.7°C (36.6-36.9°C) for 24 hours each was held during the maintenance and the after rewarming phases, respectively. Temperature deviations >0.2°C from 33.0°C in the maintenance phase occurred once each in two patients. The favorable neurological outcomes (CPC1, 2) were relatively good (50%). Five patients experienced serious adverse events; none was device related. We rapidly achieved therapeutic hypothermia within a narrow temperature range without major complications using the IVTM system with NLA in PCAS patients.
Topics: Body Temperature; Humans; Hypothermia, Induced; Post-Cardiac Arrest Syndrome; Prospective Studies; Rewarming; Temperature
PubMed: 32348714
DOI: 10.1089/ther.2019.0046