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Psychiatry Research May 2015Panic disorder (PD) is characterized by anticipatory anxiety and panic, both causing physiological arousal. We investigated the differential responses between... (Randomized Controlled Trial)
Randomized Controlled Trial
Panic disorder (PD) is characterized by anticipatory anxiety and panic, both causing physiological arousal. We investigated the differential responses between anticipatory anxiety and panic in PD and healthy controls (HC). Subjects (15 PD and 30 HC) received an injection of a respiratory stimulant, doxapram, with a high rate of producing panic attacks in PD patients, or an injection of saline. PD subjects had significantly higher scores in anxiety and panic symptoms during both conditions. Analysis of heart rate variability (HRV) indices showed higher sympathetic activity (LF) during anticipatory anxiety and panic states, an increase in the ratio of LF/HF during the anticipatory and panic states and a decrease in parasympathetic (HF) component in PD patients. During doxapram PD subjects increased their LF/HF ratio while HC had a reduction in LF/HF. Parasympathetic component of HRV was lower during anticipatory anxiety in PD. In general, PD showed greater sympathetic and psychological responses related to anxiety and sensations of dyspnea, reduced parasympathetic responses during anticipatory and panic states, but no differences in respiratory response. This confirms previous studies showing that PD patients do not have an intrinsic respiratory abnormality (either heightened or dysregulated) at the level of the brain stem but rather an exaggerated fear response.
Topics: Adult; Arousal; Cross-Over Studies; Doxapram; Female; Heart Rate; Humans; Male; Middle Aged; Panic Disorder; Respiratory Rate; Sympathetic Nervous System
PubMed: 25819170
DOI: 10.1016/j.psychres.2015.03.001 -
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 -
Experimental and Therapeutic Medicine Apr 2015Dexmedetomidine is a suitable sedative for awake fiberoptic intubation in patients with obstructive sleep apnea (OSA). However, previous studies have shown that...
Dexmedetomidine is a suitable sedative for awake fiberoptic intubation in patients with obstructive sleep apnea (OSA). However, previous studies have shown that dexmedetomidine delays recovery from propofol-remifentanil anesthesia. This study aimed to determine whether doxapram may hasten the recovery following dexmedotomidine-propofol-remifentanil anesthesia. Sixty patients scheduled for uvulopalatopharyngoplasty with total intravenous anesthesia were randomized to two groups according to the medicine given at the end of surgery. These were the doxapram (1 mg/kg) and control (normal saline) groups (n=30 per group). The primary outcome was the time to eye opening on verbal command. The time to return to spontaneous breathing, to hand squeezing in response to verbal command, to extubation of the trachea, and the heart rate (HR), bispectral index (BIS) values, respiratory rate (RR) and pulse oximetry values were also recorded and compared. The time to return to spontaneous breathing (5.2±2.9 vs. 11.7±3.4 min, P<0.001), eye opening (9.3±4.7 vs. 15.9±6.3 min, P<0.001), hand squeeze to command (11.8±6.5 vs. 17.6±7.7 min, P=0.0026) and extubation (14.2±7.8 vs. 19.2±9.6 min, P=0.0308) were significantly shorter in the doxapram group compared with the control group. BIS scores (at 3-14 min), RR (at 4-10 min) and HR (at 2-13 min) were significantly higher in the doxapram group compared with those in the control group (P<0.05). Doxapram hastens the recovery from dexmedetomidine-propofol-remifentanil anesthesia in patients undergoing uvulopalatopharyngoplasty, and may benefit patients with OSA.
PubMed: 25780462
DOI: 10.3892/etm.2015.2249 -
European Journal of Anaesthesiology Feb 2021
Topics: Airway Extubation; Bariatric Surgery; Delayed Emergence from Anesthesia; Doxapram; Humans; Neuromuscular Blockade; Obesity, Morbid
PubMed: 33394796
DOI: 10.1097/EJA.0000000000001338 -
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 -
Paediatric Drugs Aug 2020Caffeine is a common treatment for neonatal intensive care management of the developmental complication of apnea of prematurity in preterm infants. There are several...
BACKGROUND
Caffeine is a common treatment for neonatal intensive care management of the developmental complication of apnea of prematurity in preterm infants. There are several systematic reviews (SRs) on the performance of caffeine in the treatment of apnea. The evidence provided by those, however, is depressed by an information overload due to high heterogeneity in the characteristics as well as the quality of these SRs.
OBJECTIVE
The aim was to provide a systematic overview of SRs on the use of caffeine for the management of neonatal apnea. Such overviews are a recent method used to assess and filter top evidence among SRs, enabling enhanced access to targeted information of interest.
METHODS
A comprehensive literature search was conducted via EMBASE, Cochrane Database of Systematic Reviews (CDSR), and PubMed since inception to January 2020. Two reviewers independently conducted study selection and data extraction, and assessed the quality of methods and the risk of bias in included SRs based on A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) and Risk of Bias in Systematic Reviews (ROBIS) tools. Extracted data related to study type, characteristics, patients, intervention, comparator, regimen, and outcome measures.
RESULTS
Seven SRs with meta-analyses (SRMAs) were included in the current overview, involving a total of 63,315 neonates. SRMAs included randomized clinical and observational studies, with various types of patients, comparators, and outcomes. The quality of SRMAs ranged from critically low (n = 1), low (n = 1), moderate (n = 2), to high (n = 3), and the risk of bias was unclear (n = 2), low (n = 4), and high (n = 1). The effectiveness of caffeine with regard to treatment success and the rate of apnea was not significantly different from that of theophylline or doxapram in two SRMAs. Against control, in one SRMA, while caffeine reduced the rate of failure as well as the need for pressure ventilation, it did not significantly reduce mortality. This comparative effectiveness of caffeine was based on high-quality SRMAs with a low risk of bias. The effectiveness against apnea seems to be enhanced via the administration of early (0-2 days) or high doses of caffeine in one and three SRMAs, respectively. This, nevertheless, was based on lower-quality SRMAs with a higher risk of bias. Safety outcomes were mostly based on comparative SRMAs of different drug regimens, whereby, less tachycardia and lower risk for complications were reported with lower and earlier caffeine administrations, respectively. The evidence behind this, however, was limited in quantity and quality.
CONCLUSION
While limited in quantity, there is evidence of non-inferior effectiveness of caffeine against other methylxanthines or doxapram for the management of apnea in neonates. Owing to the limited quality, however, limited evidence exists in support of an optimal administration regimen for caffeine. Further controlled studies are, therefore, needed to confirm the comparative usefulness of caffeine as well as to assess its different potential regimens, including in relation to safety.
Topics: Apnea; Caffeine; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Randomized Controlled Trials as Topic; Theophylline; Treatment Outcome
PubMed: 32488731
DOI: 10.1007/s40272-020-00404-4 -
Surgical Endoscopy Dec 2020Endoscopic retrograde cholangiopancreatography (ERCP) requires moderate to deep sedation, usually with propofol. Adverse effects of propofol sedation are relatively... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Endoscopic retrograde cholangiopancreatography (ERCP) requires moderate to deep sedation, usually with propofol. Adverse effects of propofol sedation are relatively common, such as respiratory and cardiovascular depression. This study was conducted to determine if doxapram, a respiratory stimulant, could be used to reduce the incidence of respiratory depression.
METHODS
This is a single-center, prospective randomized double-blind study performed in the endoscopy unit of Helsinki University Central Hospital. 56 patients were randomized in a 1:1 ratio to either receive doxapram as an initial 1 mg/kg bolus and an infusion of 1 mg/kg/h (group DOX) or placebo (group P) during propofol sedation for ERCP. Main outcome measures were apneic episodes and hypoxemia (SpO < 90%). Mann-Whitney test for continuous variables and Fisher's exact test for discrete variables were used and mixed effects modeling to take into account repeated measurements on the same subject and comparing both changes within a group as a function of time and between the groups.
RESULTS
There were no statistically significant differences in apneic episodes (p = 0.18) or hypoxemia (p = 0.53) between the groups. There was a statistically significant rise in etCO levels in both groups, but the rise was smaller in group P. There was a statistically significant rise in Bispectral Index (p = 0.002) but not modified Observer's Assessment of Agitation/Sedation (p = 0.21) in group P. There were no statistically significant differences in any other measured parameters.
CONCLUSIONS
Doxapram was not effective in reducing respiratory depression caused by deep propofol sedation during ERCP. Further studies are warranted using different sedation protocols and dosing regimens. Clinical trial registration ClinicalTrials.gov ID NCT02171910.
Topics: Adult; Aged; Cholangiopancreatography, Endoscopic Retrograde; Double-Blind Method; Doxapram; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Propofol; Prospective Studies; Young Adult
PubMed: 31993819
DOI: 10.1007/s00464-019-07344-2 -
Veterinary Anaesthesia and Analgesia Jul 2019To compare the effect of chemical and mechanical stimulation on arytenoid cartilage motion during anaesthetic induction with alfaxalone, thiopentone or propofol.
OBJECTIVE
To compare the effect of chemical and mechanical stimulation on arytenoid cartilage motion during anaesthetic induction with alfaxalone, thiopentone or propofol.
STUDY DESIGN
Masked, randomized, crossover study.
ANIMALS
A group of eight adult Beagle dogs.
METHODS
Anaesthesia was induced with thiopentone (7.5 mg kg), propofol (3 mg kg) or alfaxalone (1.5 mg kg) intravenously (IV), which were concurrently paired with either chemical (doxapram at 2.5 mg kg IV) or mechanical (gentle pressure to the corniculate process of the right arytenoid cartilage using a cotton bud) stimulation for enhanced assessment of laryngeal motion, in random order, with a 1 week wash-out period between treatments. If deemed inadequately anaesthetized, supplemental boli of thiopentone (1.8 mg kg), propofol (0.75 mg kg) or alfaxalone (0.4 mg kg) were administered. Assessment of number of arytenoid motions and vital breaths, among others, was initiated immediately after induction. Chemical (doxapram) and mechanical stimulation were begun 2 minutes after anaesthetic induction. Data were collected at 2, 3 and 5 minutes after anaesthetic induction and the Friedman rank-sum or repeated-measures analysis of variance tests were used when applicable for statistical analysis.
RESULTS
The duration of examination time was shorter among treatments combined with chemical stimulation (p=0.001). Examination time during induction was longer for alfaxalone-chemical (8.9 minutes) and -mechanical (10.9 minutes) compared to both induction with thiopentone-chemical (3.8 minutes) and propofol-chemical (4.0 minutes). The median number of arytenoid motions for both thiopentone (67) and propofol (59) induction combined with chemical stimulation was significantly higher in comparison to that of alfaxalone (1), thiopentone (2) and propofol (2), when combined with mechanical stimulation at 3 minutes after induction.
CONCLUSION AND CLINICAL RELEVANCE
Among the regimens for assessing laryngeal motion assessed in the present study, combinations of thiopentone or propofol with doxapram are the most effective means of stimulating arytenoid motion and could improve the accuracy of diagnosis of laryngeal paralysis in dogs.
Topics: Anesthesia; Anesthetics; Anesthetics, Intravenous; Animals; Cross-Over Studies; Dog Diseases; Dogs; Larynx; Pregnanediones; Propofol; Random Allocation; Thiopental; Vocal Cord Paralysis
PubMed: 31202619
DOI: 10.1016/j.vaa.2018.12.010 -
Epilepsy & Behavior : E&B Apr 2015Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. DBA/1 mice are a relevant animal model for the study of SUDEP, as these mice exhibit...
Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. DBA/1 mice are a relevant animal model for the study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in patients with witnessed SUDEP. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using noninvasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram, and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air+7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice.
Topics: Animals; Death, Sudden; Disease Models, Animal; Epilepsy; Fluoxetine; Mice; Mice, Inbred DBA; Pulmonary Ventilation; Respiratory Insufficiency; Selective Serotonin Reuptake Inhibitors
PubMed: 25771493
DOI: 10.1016/j.yebeh.2015.02.013 -
BMC Anesthesiology Nov 2019Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of anxiety that propofol provides, low SpO may also result. Doxapram is a respiratory stimulant with a short half-life. The primary aim of this study was to investigate the effects of doxapram on alleviating low SpO induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy.
METHODS
In this prospective study, patients scheduled for painless gastrointestinal endoscopy were randomly assigned to group D or S with 55 patients per group. Initially, both groups received a combination of propofol and fentanyl. Patients in group D received 50 mg doxapram after propofol injection, while patients in group S received an equal volume of saline. Vital signs of the patients, propofol dose, examination duration, and incidences of low SpO were recorded.
RESULTS
There were no statistical differences in propofol consumption and examination duration between the two groups. Twenty-six patients in group S experienced low SpO versus 10 in group D (P = 0.001). Nineteen patients in group S underwent oxygenation with a face mask in contrast to 8 in group D (P = 0.015). Eighteen patients in group S were treated with jaw lifting compared to 5 in group D (P = 0.002). Four patients in group S underwent assisted respiration compared to 2 in group D (without statistical difference). The average oxygen saturation in group S was significantly lower than that in group D at 1, 2 and 3 min after propofol injection (P < 0.001, P = 0.001 and P = 0.020, respectively). There were no statistical differences in oxygen saturation at other time points. There were no statistical differences in MAP and HR (except for the time point of 1 min after the induction) between the two groups.
CONCLUSIONS
Low dose of doxapram can effectively alleviate low SpO in painless gastrointestinal endoscopy with intravenous propofol, without affecting propofol consumption, examination duration, MAP, or HR.
TRAIL REGISTRATION
The study was approved by the Institutional Ethics Committee of Clinical and New Technology of Wuxi People's Hospital on 20th July, 2018 (KYLLH2018029) and registered in the Chinese Clinical Trial Register on 16th August, 2018 (ChiCTR1800017832).
Topics: Adult; Anesthetics, Intravenous; Double-Blind Method; Doxapram; Endoscopy, Gastrointestinal; Female; Fentanyl; Humans; Male; Middle Aged; Oxygen; Propofol; Prospective Studies; Respiratory System Agents; Time Factors
PubMed: 31757206
DOI: 10.1186/s12871-019-0860-1