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Veterinary Anaesthesia and Analgesia May 2018To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs.
STUDY DESIGN
Randomized, crossover, blinded study.
ANIMALS
Ten female Beagle dogs, aged 11-13 months and weighing 7.2-8.6 kg.
METHODS
The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone+acepromazine and butorphanol (ALF-AB), propofol (PRO) and propofol+AB (PRO-AB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality.
RESULTS
A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PRO-AB and ALF-AB before doxapram. All dogs in PRO-AB and ALF-AB with <20% increase in RGSA before doxapram had ≥20% increase in RGSA after doxapram. Examination quality was significantly better in PRO-AB and ALF-AB.
CONCLUSIONS AND CLINICAL RELEVANCE
The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion.
Topics: Acepromazine; Anesthesia; Anesthetics; Anesthetics, Combined; Animals; Butorphanol; Cross-Over Studies; Dog Diseases; Dogs; Doxapram; Female; Laryngoscopy; Larynx; Physical Examination; Pregnanediones; Propofol; Vocal Cord Paralysis
PubMed: 29426677
DOI: 10.1016/j.vaa.2017.08.014 -
Antimicrobial Agents and Chemotherapy Jan 2018Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram...
Earlier, we reported that three Food and Drug Administration-approved drugs, trifluoperazine (TFP; an antipsychotic), amoxapine (AXPN; an antidepressant), and doxapram (DXP; a breathing stimulant), identified from an murine macrophage cytotoxicity screen, provided mice with 40 to 60% protection against pneumonic plague when administered at the time of infection for 1 to 3 days. In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with when it was administered at the time of infection or at 24 h postinfection. Using the same cytotoxicity assay, we identified an additional 76/780 nonantibiotic drugs effective against For , 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.
Topics: Acinetobacter baumannii; Amoxapine; Animals; Anti-Bacterial Agents; Cell Line; Disease Models, Animal; Doxapram; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Female; Klebsiella pneumoniae; Levofloxacin; Macrophages; Mice; Mice, Inbred C57BL; Plague; RAW 264.7 Cells; Trifluoperazine
PubMed: 29109161
DOI: 10.1128/AAC.01943-17 -
Zebrafish Dec 2017Considering the conserved nature of synaptic physiology among vertebrates, we tested the effects of three psychotropics (diazepam, doxapram, and nicotine) on...
Considering the conserved nature of synaptic physiology among vertebrates, we tested the effects of three psychotropics (diazepam, doxapram, and nicotine) on Microsternarchus cf. bilineatus, measuring 10 parameters associated to the electric organ discharges rhythm and waveform before and after the administration of each drug and a control group. There were statistically significant differences (p < 0.005) among all the experimental groups, F (70, 22619.25) = 77.7, between the two experimental phases within their respective drug treatment, F (80, 24604.51) = 16.0, and among the six experimental hours within their respective phases and groups, F (320, 37124.15) = 4.1. We observed a common general trend of reduction in the electric organ's (EO) firing rate, regardless of the expected stimulant or depressor effect of the drugs on the central nervous system (CNS). The intensity of the response changed with the treatment. The observed changes in the fishes' behavior may be a result of the drugs' direct action on the CNS or a combination of this with systemic effects of each substance tested, also in the EO.
Topics: Animals; Anticonvulsants; Behavior, Animal; Central Nervous System; Central Nervous System Stimulants; Diazepam; Doxapram; Electric Organ; Gymnotiformes; Nicotine; Nicotinic Agonists
PubMed: 28968184
DOI: 10.1089/zeb.2017.1459 -
Current Pharmaceutical Design 2017Drug effect evaluation is often based on subjective interpretation of a selection of patient data. Continuous analyses of high frequency patient monitor data are a...
BACKGROUND
Drug effect evaluation is often based on subjective interpretation of a selection of patient data. Continuous analyses of high frequency patient monitor data are a valuable source to measuring drug effects. However, these have not yet been fully explored in clinical care. We aim to evaluate the usefulness and applicability of high frequency physiological data for analyses of pharmacotherapy.
METHODS
As a proof of principle, the effects of doxapram, a respiratory stimulant, on the oxygenation in preterm infants were studied. Second-to-second physiological data were collected from 12 hours before until 36 hours after start of doxapram loading dose plus continuous maintenance dose in seven preterm infants. Besides physiological data, plasma concentrations of doxapram and keto-doxapram were measured.
RESULTS
Arterial oxygen saturation (SpO2) increased after the start of doxapram treatment alongside an increase in heart rate. The respiratory rate remained unaffected. The number of saturation dips and the time below a saturation of 80%, as well as the area under the 80%-saturation-time curve (AUC), were significantly lowered after the start of doxapram. The AUC under 90% saturation also significantly improved after start of doxapram. Plasma concentrations of doxapram and keto-doxapram were measured.
CONCLUSION
Using high-frequency monitoring data, we showed the detailed effects over time of pharmacotherapy. We could objectively determine the respiratory condition and the effects of doxapram treatment in preterm infants. This type of analysis might help to develop individualized drug treatments with tailored dose adjustments based on a closed-loop algorithm.
Topics: Big Data; Doxapram; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Off-Label Use; Oxygen Consumption; Proof of Concept Study; Respiratory Mechanics; Respiratory System Agents
PubMed: 28925893
DOI: 10.2174/1381612823666170918121556 -
Neonatology 2017Restrictive use of invasive mechanical ventilation (IMV) in preterm infants reduces the risk of bronchopulmonary dysplasia (BPD). Our objective was to determine its... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVE
Restrictive use of invasive mechanical ventilation (IMV) in preterm infants reduces the risk of bronchopulmonary dysplasia (BPD). Our objective was to determine its effect on neurodevelopmental impairment (NDI) at 24 months' corrected age (CA).
METHODS
This retrospective single-center cohort study included all patients with a gestational age <30 weeks born in 2004/2005 (epoch 1) and 2010/2011 (epoch 2). In epoch 2, we introduced a policy of restriction on IMV and liberalized the use of respiratory stimulants in the delivery room and neonatal intensive care. Data on patient characteristics, respiratory management, short-term outcomes, mortality, BPD, and NDI at 24 months' CA were collected.
RESULTS
Four hundred and four preterm infants were included. Compared to those in epoch 1, infants in epoch 2 were less likely to be intubated and the duration of IMV was shorter. Other noninvasive adjuvant therapies such as caffeine, doxapram, and nasal ventilation were more often used during epoch 2. There was a trend to less BPD in epoch 2 compared to epoch 1 (17 vs. 23%, adjusted OR = 0.75, 95% CI: 0.48, 1.16). Mortality did not change over time. The combined outcome death or NDI at 24 months' CA was significantly lower in epoch 2 compared to epoch 1 (24.7 vs. 33.9%, adjusted OR = 0.71, 95% CI: 0.53, 0.97).
CONCLUSIONS
Restricted use of IMV is feasible in preterm infants and might be associated with a reduced risk of the combined outcome death or NDI at 24 months' CA. Larger studies are needed to confirm these findings.
Topics: Age Factors; Bronchopulmonary Dysplasia; Child Development; Child, Preschool; Continuous Positive Airway Pressure; Delivery Rooms; Feasibility Studies; Female; Gestational Age; High-Frequency Ventilation; Humans; Infant; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Intubation, Intratracheal; Male; Nervous System; Netherlands; Neurodevelopmental Disorders; Noninvasive Ventilation; Pulmonary Surfactants; Respiration, Artificial; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 28601870
DOI: 10.1159/000471841 -
Journal of Zoo and Wildlife Medicine :... Mar 2017This report describes the anesthetic management of a 14-yr-old, 160-kg, female Indo-Pacific bottlenose dolphin ( Tursiops aduncus ) that underwent surgical debridement...
This report describes the anesthetic management of a 14-yr-old, 160-kg, female Indo-Pacific bottlenose dolphin ( Tursiops aduncus ) that underwent surgical debridement for a refractory subcutaneous abscess twice within a 6-mo interval. The animal was otherwise in good physical condition at each anesthetic procedure. Following premedication with intramuscular midazolam and butorphanol, anesthesia was induced with propofol and maintained with sevoflurane by intubation. During surgery ventilation was controlled. Blood pressure was indirectly estimated using either oscillometric or pulse oximetry. Presumed hypotension was managed by adjusting the sevoflurane concentration and infusion of dopamine. During recovery, the dolphin regained adequate spontaneous respiration following intravenous administration of flumazenil and doxapram. The dolphin was extubated at 85 min and 53 min after the first and second surgeries, respectively. Successful weaning from the ventilator and initiation of spontaneous respiration was the most important complication encountered. Establishment of a reliable blood pressure measurement technique is critical to success for anesthesia in this species.
Topics: Abscess; Adjuvants, Anesthesia; Analgesics, Opioid; Anesthesia; Anesthetics, Inhalation; Animals; Bottle-Nosed Dolphin; Butorphanol; Debridement; Female; Hypnotics and Sedatives; Methyl Ethers; Midazolam; Propofol; Sevoflurane; Staphylococcal Infections; Staphylococcus aureus; Tail
PubMed: 28363054
DOI: 10.1638/2016-0088.1 -
Bioanalysis Mar 2017Doxapram, a respiratory stimulant, is used to treat apnea. A reliable method of determining doxapram in blood is required for monitoring purposes.
AIM
Doxapram, a respiratory stimulant, is used to treat apnea. A reliable method of determining doxapram in blood is required for monitoring purposes.
RESULTS
Doxapram, keto-doxapram (active metabolite) and propranolol (internal standard) were extracted from human serum by protein precipitation and plate filtration. Molecular ions were generated by electrospray ionization in positive ion mode, and the ions were analyzed using a triple-quadrupole mass spectrometer. The calibration curves were linear from 20 to 5000 ng/ml. The method was validated and the selectivity, reproducibility and stability met the acceptance criteria.
CONCLUSION
An LC-MS/MS method was successfully developed for determining doxapram and keto-doxapram in human serum. The method can be used to monitor doxapram and keto-doxapram concentrations in blood.
Topics: Calibration; Chromatography, Liquid; Doxapram; Drug Monitoring; Drug Stability; Humans; Limit of Detection; Propranolol; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 28225296
DOI: 10.4155/bio-2016-0267 -
Acta Paediatrica (Oslo, Norway : 1992) May 2017Using doxapram to treat neonates with apnoea of prematurity might avoid the need for endotracheal intubation and invasive ventilation. We studied whether doxapram...
AIM
Using doxapram to treat neonates with apnoea of prematurity might avoid the need for endotracheal intubation and invasive ventilation. We studied whether doxapram prevented the need for intubation and identified the predictors of the success.
METHODS
This was a retrospective study of preterm infants born from January 2006 to August 2014 who received oral or intravenous doxapram. Success was defined as no need for endotracheal intubation, due to apnoea, during doxapram therapy. Univariable and multivariable logistic regression analyses identified predictors of success during the first 48 hours of doxapram therapy.
RESULTS
Data on 203 patients with a median gestational age of 26.1 (interquartile range 25.1-27.4) weeks were analysed. During the first 48 hours of doxapram therapy, 157 (77%) patients did not need endotracheal intubation and 127 (63%) patients were successfully treated over the entire treatment course. The median postnatal age at the start of doxapram therapy was 20 days (interquartile range 12-30). Postnatal age and a lower fraction of inspired oxygen at the start of doxapram therapy were significant predictors of success (odds ratio 0.964, 95% confidence interval 0.938-0.991, p = 0.001).
CONCLUSION
Oral and intravenous doxapram effectively treated most cases of apnoea in preterm infants, avoiding the need for intubation.
Topics: Apnea; Doxapram; Female; Humans; Infant, Newborn; Infant, Premature; Intubation, Intratracheal; Male; Respiratory System Agents; Retrospective Studies
PubMed: 28130789
DOI: 10.1111/apa.13761 -
Clinical Pharmacology and Therapeutics Jul 2017Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background... (Randomized Controlled Trial)
Randomized Controlled Trial
Doxapram-mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic-Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers.
Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.
Topics: Adult; Alfentanil; Analgesics; Analgesics, Opioid; Blood Pressure; Cardiac Output; Central Nervous System Stimulants; Doxapram; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Respiratory Insufficiency; Respiratory System Agents; Treatment Outcome
PubMed: 28001306
DOI: 10.1002/cpt.601 -
JAMA Pediatrics Feb 2017Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease or inadequate respiratory drive.
OBJECTIVE
To conduct a systematic review and meta-analysis of interventions to improve rates of successful extubation in preterm infants.
DATA SOURCES
Searches were undertaken in PubMed and The Cochrane Library.
STUDY SELECTION
The review was conducted using the methods of the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included if they were randomized clinical trials published in English, enrolled intubated preterm infants (born <37 weeks' gestation), and reported 1 or both of the primary outcomes.
DATA EXTRACTION AND SYNTHESIS
One thousand three hundred seventy-nine titles were screened independently by 2 investigators to assess need for full-text review. Disagreements were resolved via consensus of all authors. Where no Cochrane Review existed for an intervention, or not all identified studies were included, a new pooled analysis was performed.
MAIN OUTCOMES AND MEASURES
Primary outcomes were treatment failure or reintubation within 7 days of extubation.
RESULTS
Fifty studies were eligible for inclusion. Continuous positive airway pressure reduced extubation failure in comparison with head-box oxygen (risk ratio [RR], 0.59; 95% CI, 0.48-0.72; number needed to treat [NNT], 6; 95% CI, 3-9). Nasal intermittent positive pressure ventilation was superior to continuous positive airway pressure in preventing extubation failure (RR, 0.70; 95% CI, 0.60-0.81; NNT, 8; 95% CI, 5-13). High-flow nasal cannula therapy and continuous positive airway pressure had similar efficacy (RR, 1.11; 95% CI, 0.84-1.47). Methylxanthines reduced extubation failure (RR, 0.48; 95% CI, 0.32-0.71; NNT, 4; 95% CI, 2-7) compared with placebo or no treatment. Corticosteroids (RR, 0.18; 95% CI, 0.04-0.97; NNT, 12; 95% CI, 6-100) and chest physiotherapy (RR, 0.32; 95% CI, 0.13-0.82; NNT, 15; 95% CI, 7-50) both reduced extubation failure rates but were associated with significant adverse effects. Doxapram did not aid successful extubation (RR, 0.80; 95% CI, 0.22-2.97).
CONCLUSIONS AND RELEVANCE
Preterm infants should be extubated to noninvasive respiratory support. Caffeine should be used routinely, while corticosteroids should be used judiciously, weighing up the competing risks of bronchopulmonary dysplasia and neurodevelopmental harm.
Topics: Airway Extubation; Evidence-Based Medicine; Humans; Infant, Newborn; Infant, Premature; Quality Improvement
PubMed: 27918754
DOI: 10.1001/jamapediatrics.2016.3015