Reversal Of Sedation Research Articles

Pharmacokinetics and pharmacodynamics of intranasal and intramuscular administration of naloxone in working dogs administered fentanyl.

Working dogs exposed to narcotics might require reversal in the field. To explore the pharmacokinetic and pharmacodynamic effects of naloxone administered intramuscularly (IM) or intranasally (IN) to reverse fentanyl sedation in working dogs. Ten healthy, working dogs aged 1.7 ± 1 year and weighing 26 ± 3 kg. In this randomized, controlled cross-over study dogs received either 4 mg of naloxone IN or IM 10 minutes after fentanyl (0.3 mg IV) administration. Sedation was assessed at baseline and 5 minutes after fentanyl administration, then at 5, 10, 15, 20, 25, 30, 60 and 120 minutes after reversal with naloxone. Blood samples for naloxone detection were obtained at 0, 5, 10, 30, 60 and 120 minutes. Pharmacokinetic parameters and sedation scores were compared between IM and IN naloxone groups. There was a significant increase in sedation score from baseline (0.25 [-4 to 1] IM; 0 [-2 to 1] IN) after fentanyl administration (11 [5-12] IM; 9.25 [4-11] IN), followed by a significant reduction at 5 (0.5 [-0.5 to 1.5] IM; 1.25 [-1.5 to 4.5] IN) through 120 minutes (-0.5 [-2 to 1] IM; 0 [-4.5 to 1] IN) after reversal with naloxone. Route of administration had no significant effect on sedation score. Maximum plasma concentration was significantly lower after IN administration (11.7 [2.8-18.8] ng/mL IN, 36.7 [22.1-56.4] ng/mL IM, P < .001) but time to reach maximum plasma concentration was not significantly different from IM administration. Although IM administration resulted in higher naloxone plasma concentrations compared to IN, reversal of sedation was achieved via both routes after administration of therapeutic doses of fentanyl.

Safety and feasibility of oesophageal ultrasound for the work-up of thoracic malignancy in patients with respiratory impairment.

Biopsying lung tumours with endobronchial access in patients with respiratory impairment is challenging. However, fine needle aspiration with the endobronchial ultrasound-endoscope via the oesophagus (EUS-B-FNA) makes it possible to obtain tissue samples without entering the airways. Safety of EUS-B-FNA in these patients has not earlier been investigated prospectively. Therefore, this study aimed at assessing feasibility and safety of EUS-B-FNA from centrally located tumours suspected of thoracic malignancy in patients with respiratory insufficiency. The study is a prospective observational study. Patients with indication of EUS-B-FNA of centrally located tumours and respiratory impairment defined as modified Medical Research Council (mMRC) dyspnoea scale score of ≥3, saturation ≤90% or need of continuous oxygen supply were included prospectively in three centres. Any adverse events (AEs) were recorded during procedure and 1-hour recovery. AEs were defined as hypoxemia (saturation <90% or need for increased oxygen supply) or any kind of events needing intervention. Late procedure-related events were recorded during 30-day follow-up. Between April 1, 2020 and January 30, 2021, 16 patients were included. No severe AEs (SAEs) occurred, but AEs were seen in 50% (n=8) and 13% (n=2) of the patients during procedure and recovery respectively. AEs included hypoxemia corrected with increased oxygen supply and in two cases reversal of sedation. Late procedure-related events were seen in 13% (n=2) and included prolonged need of oxygen and one infection treated with oral antibiotics. In this cohort, EUS-B-FNA of centrally located tumours was safe and feasible in patients with respiratory impairment, when examined in the bronchoscopy suite. A variety of mostly mild and manageable complications may occur, a few even up to 30 days post-procedure.

Letter to the Editor Regarding “Perioperative Risk Factors Associated with Unplanned Neurological Intensive Care Unit Events Following Elective Infratentorial Brain Tumor Resection”

Awake craniotomy (AC) is the preferred option for the resection of tumors adjacent to eloquent cortical areas and in cases of intractable epilepsy. It is mostly used to maintain the integrity of the brain during intracranial neurosurgical procedures. Awake craniotomy requires the use of ideal anesthetics, hypnotics, and analgesics to balance sedation, prompt the reversal of sedation, and prevent respiratory depression while maintaining communication between patient and medical team. Although a wide variety of anesthetics and hypnotics have been used for awake craniotomy over the past several decades, the optimal drug for the procedure has yet to be determined. The purpose of this meta-analysis was to compare dexmedetomidine and propofol in terms of intraoperative adverse events (i.e., hypertension, hypotension, nausea, vomiting, respiratory depression), patient and surgeon satisfaction, and procedure duration.We searched PubMed, Google Scholar, and the Cochrane Library for relevant articles published between the inception of these databases and April of 2022. The systematic search yielded 781 articles. After screening, we excluded 778 articles. The remaining three articles reporting 138 patients were selected for meta-analysis.This meta-analysis showed no statistically significant difference between propofol and dexmedetomidine related to intraoperative adverse events, patient satisfaction, or procedure duration. The only statistically significant result was surgeon satisfaction, which appeared to be higher in the dexmedetomidine group.Further high-quality randomized and controlled trials are needed to find a preferred agent for intraoperative sedation in awake craniotomy.

Hyperbaric oxygen therapy positively interferes with oxidative metabolism in female cats undergoing vídeo-assisted elective ovariohysterectomy

This study aimed to determine whether hyperbaric oxygen therapy (HBOT) alters oxidative biomarkers after elective ovariohysterectomy (OHE). For this purpose, 45 healthy female cats were randomized into three groups: the hyperbaric group (HG): 15 animals pretreated with HBOT and submitted to OHE; the hyperbaric control group (HCG): 15 animals pretreated with HBOT without surgery; and the sham group (SHAM): 15 female cats submitted to OHE without pretreatment. The following biomarkers were evaluated: superoxide dismutase (SOD) and catalase (CAT), reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The collection times were: T1 = before the surgery for the operated groups and after sedation in the HCG; T2 = 30 min after reversal of sedation (HCG) or at the time of extubation in the other groups; T3 = 24 hr after T2. There was no difference regarding serum dosage of ROS, AChE, or BChE. There was an increase in TBARS in the T3 SHAM compared to the T3 HG (p=0.043). Moreover, CAT activity decreased in T2 SHAM and T3 SHAM compared to T1 SHAM (p=0.012 and p&lt;0.001mauric); T2 SHAM had lower CAT activity than T2 HCG (p=0.05). Additionally, the T3 SHAM was lower than the T3 HG (p=0.030) and T3 HCG (p=0.050). There was reduced SOD in the T2 SHAM compared to the T2 HG (p=0.033) and T2 HCG (p=0.027). Similarly, the T3 SHAM decreased compared to the T3 HG (p=0.039) and T3 HCG (p=0.019).

État des lieux de la sédation en situations palliatives

The right to deep and continuous sedation maintained until death was introduced by the law known as the Claeys-Leonetti law. It is no longer a question of reversible sedation, but of maintaining the patient in a deep sleep, without waking, until death. It can be put into care in specific cases. The borderline between euthanasia and this sedation implemented at the end of life lies in the intentionality of the medical act.

Evaluation of dexmedetomidine-midazolam sedation in budgerigars (Melopsittacus undulatus).

To evaluate the sedative effects of IM administration of a high or low dose of dexmedetomidine in combination with midazolam in budgerigars (Melopsittacus undulatus). 20 healthy adult budgerigars. In a prospective, randomized, blinded study, birds were sedated with a high dose (HD; 0.04 mg/kg, IM; n = 10) or low dose (LD; 0.01 mg/kg, IM; 10) of dexmedetomidine in combination with midazolam (3 mg/kg, IM). Twenty minutes later, atipamezole (0.4 mg/kg [HD group] or 0.1 mg/kg [LD group], IM) and flumazenil (0.1 mg/kg, IM) were administered for reversal of sedation. Times to first effect and to sternal recumbency after administration of the sedatives and times to standing and eating after administration of the antagonists did not differ between groups. Most birds (9/10 in the HD group and 7/10 in the LD group) lost the righting response by 10 minutes after sedative administration, and the peak effect for radiographic positioning was by 15 minutes. Although it was not clinically relevant, most birds showed mild resedation by 60 minutes after administration of the reversal agents. There was no significant cardiorespiratory compromise detected with either protocol. Dexmedetomidine-midazolam can safely and effectively provide a dose-dependent level of sedation in healthy budgerigars. The HD protocol is recommended for radiographic positioning, as it allows for a more reliable, deeper plane of sedation.

Audit of flumazenil use in special care and oral surgery sedation services.

Background The National Patient Safety Agency (2008) has advised against routine reliance on flumazenil for reversal of sedation and encourages regular audit to help identify issues with excessive dosing of midazolam. This multi-centre audit of flumazenil use across both community-based special care and dental hospital oral surgery specialist services was conducted to compare practice against that reported from other UK sedation services.Methods A six-year retrospective audit was conducted using controlled drug records and patient case notes.Results Both services used flumazenil at very infrequent levels and far below the agreed standard. The dose of flumazenil and justification for its use was recorded in all records. There was variability in the nature of the justifications between the two services, which likely relates to the differing patient groups seen by the specialties. The majority of cases related to supporting the patient's escort for their journey home; however, this was not always pre-planned.Conclusions There was a low level of flumazenil use over an extended period of time, supporting the concept of a culture of safe sedation provision in both services. The audit highlighted variation in record-keeping and need for improved communication with patients about escort requirements.

S2089 Massive Ischemic Stroke Due to Multiples Air Embolisms Following a Surveillance Esophagogastroduodenoscopy

INTRODUCTION: Cerebral air embolism is extremely rare, but serious complication of Esophagogastroduodenoscopy (EGD). There were only 21 reported cases in the literature by 2016. Most documented cases are iatrogenic in nature. We will present the first documented case of Cerebral air embolism following an EGD in Puerto Rico. CASE DESCRIPTION/METHODS: A 72 years old male with Chronic Liver Disease secondary to alcohol abuse, complicated with UGIB due to Esophageal Varices in the past, presented to our unit for a surveillance EGD. During procedure he developed severe retching, with distal esophageal tear accompanied by profuse bleeding, requiring endoscopic therapy with local epinephrine injection and placement of 2 clips to achieve hemostasis. After 30 minutes of standard recovery care and reversal of sedation, the patient failed to be aroused. There was only response to painful stimuli by withdrawal and the presence of Babinski reflex bilaterally. He was promptly transferred to the hospital ICU. Vital signs remained stable but with neurological deficit with GCS of 4/15. He was placed on mechanical ventilation. Initial laboratory tests were unremarkable. Head CT revealed multiple air globules within the territory of the right MCA (Figure 1) and Subsequent MRI was pertinent for extensive acute embolic hypoxic-ischemic brain injury (Figure 2). Given institution limitations, 32 hours after the precipitating event, the patient was transported and received hyperbaric oxygen therapy (HBOT) without significant neurologic improvement. Unfortunately, after prolonged hospitalization patient was discharge to hospice care in a persistent vegetative state. DISCUSSION: Cerebral air embolism is a rare, but devastating complication of endoscopic procedures. To occur it is necessary a communication between an air source and the vasculature, and the presence of a pressure gradient favoring passage of air into the circulation. Early recognition by endoscopists is essential requiring a high index of suspicion, especially since signs and symptoms may be confused as effects of persistent sedation. There are no standard treatments, but the most significant intervention appears to be HBOT, which accelerating the reabsorption and decreasing the size of the air bubbles in the vascular compartment, the maximum beneficial effects have been shown if administered during the first 4 to 6 hours after symptom onset. Unfortunately, due to severe neurological ischemic injury, our patient survived but with significant morbidity and disability.Figure 1.: MDCT axial images of the Head without Contrast: Scattered diffuse hypodense lesions throughout the right centrum semiovale and corona radiata which given the history of a recent procedure, findings are in favor of multiples cerebral air embolism within the territory of the right Middle Cerebral Artery (MCA).Figure 2.: Multiplanar multisequence MRI of the brain without Contrast: There is gyriform cortical restricted diffusion (A) with corresponding FLAIR hyperintensity (B) throughout the right cerebral hemisphere as well as to a lesser extent throughout the left frontal, parietal and occipital lobes; consistent with acute embolic (secondary to air emboli) hypoxic-ischemic brain injury and brain edema.

EVALUATION OF THE EFFECTS OF MIDAZOLAM AND FLUMAZENIL IN THE BALL PYTHON (PYTHON REGIUS).

The study objective was to evaluate the sedative, muscle relaxant, and cardiorespiratory effects of midazolam and flumazenil in the ball python (Python regius). Ten healthy adult female ball pythons were used in a randomized and blinded crossover trial evaluating the effects of two dosages (1 and 2 mg/kg intramuscular [i.m.] in the cranial third of the body). In a subsequent open trial, nine ball pythons received 1 mg/kg i.m. of midazolam followed by 0.08 mg/kg i.m. of flumazenil 60 min later. Heart rate, respiratory rate, temperature, and the level of sedation and muscle relaxation (using a semiobjective scoring system) were evaluated. There were no significant differences between midazolam dosages for any of the parameters evaluated. Sedation scores were significantly increased compared with baseline from 15 min (1 mg/kg) and 10 min (2 mg/kg) postinjection up until 56 hr (1 mg/kg) and 72 hr (2 mg/kg) postinjection. Peak effect was reached 60 min postinjection, with 60% of snakes (6/10) being unable to right themselves. One snake developed paradoxical excitation with the 2 mg/kg dosage. Heart rates were significantly lower than baseline from 30 min to 128 hr postinjection with both midazolam dosages. Respiratory rates were significantly lower than baseline at four time points, with the highest dosage only: 15, 45, 60 min, and 8 hr postinjection. Flumazenil resulted in reversal of sedation and muscle relaxation in all snakes within 10 min of administration. However, resedation was evident in all snakes 3 hr after reversal. Midazolam administered at 1 and 2 mg/kg i.m. provides a moderate to profound, although prolonged, sedation and muscle relaxation in ball pythons. Flumazenil reverses the effects of midazolam in ball pythons, but its duration of action at the evaluated dosage is much shorter than midazolam, leading to resedation.

Effect of three doses of nalbuphine on reversal of sedation and cardiopulmonary effects of morphine–acepromazine in healthy dogs

ObjectiveTo evaluate the efficacy of three doses of nalbuphine in reversing sedative and cardiopulmonary effects of morphine–acepromazine in dogs. Study designProspective, randomized experimental trial. AnimalsA group of eight healthy Beagle dogs, aged 5–6 years and weighing 12.5 ± 2.1 kg. MethodsDogs were administered morphine (0.5 mg kg–1) and acepromazine (0.05 mg kg–1) intravenously (IV). After 20 minutes, dogs were administered one of four treatments IV: saline (control); or nalbuphine (0.3 mg kg–1; treatment N0.3), (0.6 mg kg–1; treatment N0.6) or (1.0 mg kg–1; treatment N1.0), in random order separated by 1 week. Sedation was scored using a numeric descriptive scale (NDS) and simple numerical scale (SNS). Heart rate, systolic arterial pressure (SAP), respiratory rate (fR) and rectal temperature (RT) were recorded before (BL), 20 minutes after morphine–acepromazine (T0), then 10 (T10), 30, 60 and 90 minutes after saline or nalbuphine. Arterial blood gases were measured at BL, T0 and T10. Values were compared with BL, T0 and among treatments using anova (p < 0.05) and the Bonferroni correction (p < 0.008). ResultsNDS for N0.6 and SNS for N0.6 and N1.0 at T30, and both scores for all nalbuphine treatments at T60–T90 were lower compared with T0 (p < 0.05). Sedation scores were not different among nalbuphine treatments. SNS scores were lower than control at T10 for N0.3 and N0.6 (p < 0.05). SAP and fR were lower than BL for all treatments at some time points (p < 0.05). RT was higher than control at T60 in the nalbuphine treatments (p < 0.001). PaO2 was lower in N0.3 at T0 compared with BL (p = 0.036). Conclusions and clinical relevanceAll nalbuphine doses decreased the degree of sedation, without differences among them. Administration of nalbuphine resulted in minimal changes in measured cardiopulmonary variables.

Abstract 17022: Pericardial Decompression Syndrome: Incidence in a Large Consecutive Series of Echocardiographic-Guided Pericardiocentesis Procedures

Introduction: Pericardial decompression syndrome (PDS) has been reported as a spectrum of cardiac decompensation following pericardiocentesis including ventricular failure, cardiogenic shock and pulmonary edema. PDS has been reported in patients undergoing drainage ≥450 mL of pericardial fluid. Hence judicious drainage of large volume effusions to avoid complication has been recommended Hypothesis: PDS complicating undergoing transthoracic echocardiography (TTE) guided pericardiocentesis is uncommen Methods: Consecutive patients undergoing TTE guided pericardiocentesis at our center from 1/2007 to 12/2016 were reviewed. Procedures were performed in a standard fashion under moderate conscious sedation with TTE determining the location of aspiration and determining adequate resolution of pericardial fluid post procedure. All fluid was removed at time of centesis regardless of the size of effusion, except for patients with severe pulmonary hypertension (n=9), who had staged removal of 100cc every 10 minutes. Post procedure, a pigtail catheter was left in the pericardial space for ongoing intermittent drainage and removed after the total net output was &lt;50 mL/24 hours. Patients were monitored in an intermediate level care unit. All patients underwent repeat TTE at the time of catheter removal. Large volume was defined as ≥450 mL of fluid. Patients in whom pericardiocentesis was technically unsuccessful were excluded Results: Over a 10-year period a total of 1067 patients (57% male, mean age 62±16 years) underwent 1164 technically successful pericardiocentesis procedures. Of these, 561 patients had large volume (≥450 mL) aspirated (mean 750±345 mL aspirated, range 450 - 4300 mL). Patients had a pericardial catheter in place for a mean 2.9±2 days. One patient with pre-existing severe biventricular dysfunction after aspiration of 400cc developed hypotension that improved with reversal of sedation, but proceeded to have PEA arrest and die. No other patient developed clinical events of acute left or right heart failure, ventricular dysfunction, unexplained hypotension, cardiogenic shock or other clinical events that could relate to PDS Conclusions: At most one episode of PDS was observed after technically successful percutaneous pericardiocentesis in 1164 cases (561 were large volume), although whether this case was PDS is unclear. PDS appears to be very rare, and staging pericardial decompression over time may be unnecessary, other than, perhaps, in patients with severe ventricular dysfunction or severe pulmonary hypertension

Efficacy and safety of flumazenil injection for the reversal of midazolam sedation after elective outpatient endoscopy.

Midazolam sedation during elective endoscopy is widely performed and flumazenil is frequently administered after endoscopy to reverse sedation in clinical practice. This study aimed to investigate the safety and efficacy of flumazenil injections after elective endoscopy under midazolam sedation. Participants who underwent an upper endoscopy under midazolam sedation were randomly divided into two groups. In group I, flumazenil was administered i.v. 10 min after the patient's transfer to the recovery room, and no antidote was injected in group II. The time of stay in the recovery room and adverse events were reviewed through the nursing records. We asked the patients about their pain and degree of satisfaction according to a visual analogue scale (VAS), their memory of the procedure, mental status and the presence of uncomfortable symptoms on the day of the procedure and the day afterwards. The length of stay in recovery was significantly shorter in group I than in group II. No significant differences were found in the number of patients with pain (VAS ≥1), adverse events and discomfort between the two groups. Additionally, there were no differences in the patients' memory of the procedure, satisfaction with sedation, willingness to repeat the endoscopy and mental status. The time in the recovery room after flumazenil administration was significantly shortened, and the use of the drug did not increase the risk of adverse events or discomfort. The use of flumazenil for reversing midazolam sedation seems to be safe and effective.

Brain antioxidant effect of mirtazapine and reversal of sedation by its combination with alpha-lipoic acid in a model of depression induced by corticosterone

BackgroundDepression is accompanied by activated neuro-oxidative and neuro-nitrosative pathways, while targeting these pathways has clinical efficacy in depression. This study aimed to investigate the effects of mirtazapine (MIRT) alone and combined with alpha-lipoic acid (ALA) against corticosterone (CORT) induced behavioral and oxidative alterations. MethodsMale mice received vehicle or CORT 20mg/kg during 14 days. From the 15th to 21st days they were divided in groups administered: vehicle, MIRT 3mg/kg or the combinations MIRT+ALA100 or MIRT+ALA200. On the 21st day of treatment, the animals were subjected to behavioral tests. Twenty-four hours after the last drug administration hippocampus (HC) and striatum (ST) were dissected for the determination reduced glutathione (GSH), lipid peroxidation (LP) and nitrite levels. ResultsCORT induced anxiety- and depressive-like behaviors as observed by increased immobility time in the tail suspension test and decreased sucrose consumption. MIRT or MIRT+ALA are effective in reversing anxiety- and depressive-like behaviors induced by CORT. CORT and MIRT alone prolonged sleeping time and this effect was reversed by MIRT+ALA. CORT significantly increased LP, which was reversed by MIRT or MIRT+ALA. Nitrite levels were increased in CORT-treated animals and reversed by MIRT+ALA200 (HC), MIRT or MIRT+ALA (ST). LimitationA relative small sample size and lack of a washout period between drug administration and behavioral testing. ConclusionsMIRT or MIRT+ALA reverse CORT-induced anxiety- and depressive-like behaviors probably via their central antioxidant effects. Augmentation of MIRT with ALA may reverse sedation, an important side effect of MIRT. Randomized controlled studies are needed to examine the clinical efficacy of this combination in human depression.

Moderate sedation in cardiac electrophysiology laboratory: a retrospective safety analysis

ObjectiveCardiac electrophysiology (EP) procedures can be performed under moderate sedation without the direct involvement of an anaesthetist. However, concerns have been raised over the safety of this approach. This study...

Patterns of naloxone use in hospitalized patients

ABSTRACTObjectives: Naloxone is indicated for reversal of opioid-induced respiratory depression. The objective of this study is to evaluate patterns of naloxone use in hospitalized patients.Methods: Retrospective chart review at the University of California, San Diego Health. Subjects included adults ≥18 years old who were admitted to and received naloxone in the medical-surgical, telemetry, intermediate care, or obstetrics/gynecology units from May 1st, 2014 to April 30th, 2015. The primary endpoint was to determine the percentage of naloxone administrations that resulted in an improvement in sedation. Secondary endpoints included the percentage of naloxone administrations that reversed respiratory depression and any association of naloxone use with opioid routes of administration, other concomitant central nervous system depressants, or disease states. Data were analyzed using descriptive and contingency statistics.Results: 124 episodes of naloxone were identified during the study period. 62% of naloxone administrations resulted in an improved level of consciousness. In contrast to this, only 30 (24.2%) episodes of naloxone administration met the criteria for respiratory depression. Of these 30 episodes, naloxone reversed respiratory depression in 25 (83.3%) of them. The most frequent opioid routes of administration were short-acting oral (53.2%) and IV opioids (44.4%). Of the concomitant medications, gabapentin (28.2%) was the most frequently associated sedating medication.Conclusion: In our study, naloxone was more often used for reversal of sedation than for respiratory depression. Gabapentin may pose a risk factor for oversedation when combined with opioids, leading to increased naloxone use. Further studies are needed to explore these patterns.

Risk Factors and Outcomes of Reversal Agent Use in Moderate Sedation During Endoscopy and Colonoscopy.

Moderate sedation has been standard for noninvasive gastrointestinal procedures for decades yet there are limited data on reversal agent use and outcomes associated with need for reversal of sedation. To determine prevalence and clinical significance of reversal agent use during endoscopies and colonoscopies. Individuals with adverse events requiring naloxone and/or flumazenil during endoscopy or colonoscopy from 2008 to 2013 were identified. A control group was obtained by random selection of patients matched by procedure type and date. Prevalence of reversal agent use and statistical comparison of patient demographics and risk factors against controls were determined. Prevalence of reversal agent use was 0.03% [95% confidence interval (CI), 0.02-0.04]. Events triggering reversal use were oxygen desaturation (64.4%), respiration changes (24.4%), hypotension (8.9%), and bradycardia (6.7%). Two patients required escalation of care and the majority of patients were stabilized and discharged home. Compared with the control group, the reversal group was older (61±1.8 vs. 55±1.6, P=0.01), mostly female (82% vs. 50%, P<0.01), and had lower body mass index (24±0.8 vs. 27±0.7, P=0.03) but received similar dosages of sedation. When adjusted for age, race, sex, and body mass index, the odds of reversal agent patients having a higher ASA score than controls was 4.7 (95% CI, 1.7-13.1), and the odds of having a higher Mallampati score than controls was 5.0 (95% CI, 2.1-11.7) with P<0.01. Prevalence of reversal agent use during moderate sedation is low and outcomes are generally good. Several clinically relevant risk factors for reversal agent use were found suggesting that certain groups may benefit from closer monitoring.

The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males.

It is unknown whether flumazenil antagonizes the decrease in cerebral blood flow or the alteration in dynamic cerebral autoregulation induced by midazolam. We, therefore, investigated the effects on cerebral circulation of flumazenil administered after midazolam, to test our hypothesis that, along with complete reversal of sedation, flumazenil antagonizes the alterations in cerebral circulation induced by midazolam. Sixteen healthy young male subjects received midazolam followed by flumazenil. The modified Observer's Assessment of Alertness/Sedation (OAA/S) scale and bispectral index (BIS) were used to assess levels of sedation/awareness. For evaluation of cerebral circulation, steady-state mean cerebral blood flow velocity (MCBFV) was measured by transcranial Doppler ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability. During midazolam sedation, defined by an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly), BIS, steady-state MAP, steady-state CBFV, and transfer function gain decreased significantly compared with baseline. After flumazenil administration, an OAA/S score of 5 (responds readily to name spoken in a normal tone) was confirmed. Then, BIS and MAP returned to the same level as baseline. However, steady-state MCBFV showed a further significant decrease compared with that under midazolam sedation, and the decreased transfer function gain persisted. Contrary to our hypothesis, the present results suggest that despite complete antagonism of the sedative effects of midazolam, flumazenil would not reverse the alterations in cerebral circulation induced by midazolam.

Effect of flumazenil on diaphragm electrical activation during weaning from mechanical ventilation after acute respiratory distress syndrome

Diaphragm electrical activation (EAdi) and the ratio of tidal volume to EAdi (VT/EAdi) may provide clinical information on neuroventilatory efficiency (NVE) in patients being weaned from mechanical ventilation. We tested the hypothesis that residual sedation could interfere with respiratory recovery, by assessing the effects of flumazenil on EAdi and VT/EAdi ratio. This observational study included 13 patients breathing with pressure-support ventilation (PSV) after a long period of controlled mechanical ventilation (i.e. >4 days) plus midazolam-based sedation for acute respiratory distress syndrome. EAdi and respiratory patterns were compared before and after a bolus of flumazenil, which was given because neurological status needed to be evaluated. Flumazenil induced a significant increase in EAdi [+71 (41-123)%, P=0.0002] and VT [+17 (8-32)%, P=0.0005], resulting in significantly decreased NVE [-34 (15-43)%]. The increased VT was significantly correlated with the increased EAdi (ρ=0.70, P=0.009). During weaning from mechanical ventilation, the diaphragmatic contribution to the breathing process may be reduced by residual midazolam-induced ventilatory depression. The increased EAdi with reversal of residual sedation was associated with a proportional increase in VT. These findings should be considered by the attending physician when interpreting daily EAdi and VT changes during weaning from mechanical ventilation.

5-HT1A receptor agonist Befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats.

There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT1A receptor agonist without anesthesia. Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively. Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and "behavioral syndrome" in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem-spinal cord and medullary slice preparations. The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior.

Antagonism of Detomidine-Induced Sedation, Analgesia, Clinicophysiological, and Hematobiochemical Effects in Donkeys Using IV Tolazoline or Atipamezole

The present study aimed to investigate and evaluate the reversal of sedation, analgesia, ataxia, clinicophysiological findings, and hematobiochemical effects of detomidine by subsequent IV administration of tolazoline or atipamezole to improve safety and utility of detomidine in donkeys. Six mature donkeys weighing 250–300 kg and aged 4–6 years were used on three separate occasions. Each donkey received the following three treatments at the rate of one treatment per week in a randomized crossover study. The first group received 0.04 mg/kg bwt detomidine. The second group received 0.04 mg/kg bwt detomidine followed by 4.0 mg/kg bwt tolazoline. The third group received 0.04 mg/kg bwt detomidine followed by 0.4 mg/kg bwt atipamezole. Sedation, analgesia, ataxia, pulse rate, respiratory rate, and rectal temperature were recorded at 5 minutes before, then at 5, 15, 30, 60, and 90 minutes after injections. Red blood cell and white blood cell counts, Packed cell volume (%), hemoglobin, total protein, cholesterol, glucose, urea, aspartate amino transferase, alanine amino transferase, and gamma glutamyl transferase values were determined. Detomidine induced deep sedation, complete analgesia, and significant ataxia. Pulse and respiratory rates were decreased from the base line values, although rectal temperature was within the baseline value. The alterations in hematological and hematobiochemical parameters were mild and transient.