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American Journal of Perinatology Oct 2014The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use...
OBJECTIVE
The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
STUDY DESIGN
We performed a retrospective review (2005-2010) of a large prospectively collected administrative database.
RESULT
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
CONCLUSION
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants.
Topics: Drug Therapy; Drug Utilization; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Intensive Care, Neonatal; Male; Retrospective Studies; United States
PubMed: 24347262
DOI: 10.1055/s-0033-1361933 -
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 -
Frontiers in Veterinary Science 2021Sepsis is a frequent life-threatening condition in young calves, requiring rapid broad spectrum and bactericidal therapy to maximize survival chances. Few studies have...
Sepsis is a frequent life-threatening condition in young calves, requiring rapid broad spectrum and bactericidal therapy to maximize survival chances. Few studies have identified and characterized bacteria involved in sepsis in calves. This report demonstrates the involvement of a multidrug resistant , an emerging pathogen in human medicine, in a calf with suspected sepsis. was identified by MALDI-TOF MS from blood cultures of a critically ill calf. Susceptibility testing showed phenotypic resistance against ampicillin, gentamicin, potentiated sulphonamides, streptomycin, tetracyclines and intermediate susceptibility for enrofloxacin. Whole genome sequencing confirmed identification as and the multidrug resistant character of the isolate. Antimicrobial resistance genes acting against aminoglycosides, beta-lactam antibiotics, fosfomycin, quinolones, sulphonamides, trimethoprim and tetracyclines were found. The calf recovered after empirical parenteral therapy with enrofloxacin and sodium penicillin for seven days. Ancillary therapy consisted of fluid therapy, ketoprofen and doxapram hydrochloride. To the authors' knowledge, this is the first report characterizing a multidrug resistant isolate from blood culture in cattle. It is currently unknown whether animals and farms may act as reservoirs for multidrug resistant strains.
PubMed: 33842574
DOI: 10.3389/fvets.2021.631716 -
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 -
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 -
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 -
Anesthesiology Sep 2014Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed.
METHODS
In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI).
RESULTS
Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent.
CONCLUSION
GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.
Topics: Adolescent; Adult; Alfentanil; Analgesia; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Doxapram; Healthy Volunteers; Hemodynamics; Humans; Large-Conductance Calcium-Activated Potassium Channels; Male; Middle Aged; Potassium Channel Blockers; Respiratory Insufficiency; Triazines
PubMed: 25222672
DOI: 10.1097/ALN.0000000000000367 -
Molecular Pharmacology Nov 2015Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899...
Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2''-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K2P) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118-128 and 228-248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded.
Topics: Amino Acid Sequence; Animals; Benzamides; Benzeneacetamides; Binding Sites; Cells, Cultured; Doxapram; Molecular Docking Simulation; Molecular Sequence Data; Mutagenesis; Potassium Channels, Tandem Pore Domain; Rats; Rats, Inbred F344; Respiratory System Agents; Structure-Activity Relationship
PubMed: 26268529
DOI: 10.1124/mol.115.100107