D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

Kato, Risako; Zhang, Edlyn R.; Mallari, Olivia G.; Moody, Olivia A.; Vincent, Kathleen; Melonakos, Eric D.; Siegmann, Morgan J.; Nehs, Christa J; Houle, Timothy T.; Akeju, Oluwaseun; Solt, Ken

doi:10.3389/fphar.2021.668285

Cited by 11 publications

(12 citation statements)

References 58 publications

(68 reference statements)

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“…The strategy used in this study may work for these other stimulants. Strong stimulants by themselves reverse deep dexmedetomidine sedation [ 36 ]. A different strategy would require a modest dosage of atipamezole and the stimulant.…”

Section: Discussionmentioning

confidence: 99%

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Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an α2-adrenergic receptor competitive antagonist in combination with caffeine

Xie

Fox

2023

BMC Anesthesiol

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Background The α2 adrenergic receptor agonist dexmedetomidine is an important intravenous sedative with analgesic properties. Currently available dexmedetomidine reversal agents, like the α2-receptor antagonist atipamezole, cause serious adverse effects at the large dosages required for effective reversal; they are not used clinically. Without reversal agents, emergence times from dexmedetomidine sedation are slow. In this study we tested the ability of low-dose atipamezole, in combination with caffeine, to reverse dexmedetomidine sedation. The low dose of atipamezole employed should not be associated with unwanted effects. Methods Two different sedation protocols were employed. In the first protocol, a bolus of dexmedetomidine was rapidly applied and the drug was allowed to equilibrate for 10 min before rats received either saline (as control) or low-dose atipamezole with caffeine. Following this procedure, rats were placed on their backs. Emergence from sedation was the time for rats to recover their righting reflex and stand with 4 paws on the floor. A second sedation protocol simulated a pediatric magnetic resonance imaging (MRI) scan. Adult rats were sedated with dexmedetomidine for one hour followed by 30 min with both dexmedetomidine and propofol. At the end of 90 min, rats received either saline (control) or a combination of low-dose atipamezole, and caffeine. Recovery of the righting reflex was used as a proxy for emergence from sedation. Results Emergence from sedation, the time for rats to recover their righting reflex, decreased by ~ 90% when using an atipamezole dose ~ 20 fold lower than manufacturer’s recommendation, supplemented with caffeine. Using an atipamezole dose ~ tenfold lower than recommended, with caffeine, emergence times decreased by ~ 97%. A different stimulant, forskolin, when tested, was as effective as caffeine. For the MRI simulation, emergence times were decreased by ~ 93% by low-dose atipamezole with caffeine. Conclusions Low dose atipamezole with caffeine was effective at reversing dexmedetomidine sedation. Emergence was rapid and the rats regained not only their righting reflex but also their balance and their ability to carry out complex behaviors. These findings suggest that the combination of low dose atipamezole with caffeine may permit rapid clinical reversal of dexmedetomidine without unwanted effects.

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Section: Discussionmentioning

confidence: 99%

“…A recent study showed that dexmedetomidine produced a more profound sedative effect in female than male rats [ 36 ]. In our study, the sedative effects produced by dexmedetomidine was not significantly different between male and female rats, although a larger group size may be needed to uncover a difference.…”

Section: Discussionmentioning

confidence: 99%

Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an α2-adrenergic receptor competitive antagonist in combination with caffeine

Xie

Fox

2023

BMC Anesthesiol

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“…Previous studies have reported the effects of dexmedetomidine on sedation, mild analgesia, inhibition of gland secretion and reduction of postoperative delirium ( Subramaniam et al, 2019 ; Pereira et al, 2020 ; Qiu et al, 2020 ). In addition, dexmedetomidine is known to lower the dose of opioids and reduce the incidence of complications of general anesthesia, and recent research has revealed that sedation with dexmedetomidine might be reversed by d-amphetamine ( Kato et al, 2021 ). Higher concentrations of dexmedetomidine are associated with greater sedation and analgesia, while decreasing HR and cardiac output ( Ebert et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

Perioperative Low Dose Dexmedetomidine and Its Effect on the Visibility of the Surgical Field for Middle Ear Microsurgery: A Randomised Controlled Trial

Han

et al. 2022

Front. Pharmacol.

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Background and Purpose: There are many benefits of administering dexmedetomidine perioperatively. The pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous, intranasal and oral dexmedetomidine that was administered before anesthesia were compared in this study, and the effects of dexmedetomidine on the surgical field visibility in tympanoplasty was evaluated.Methods: A single-blind, randomized controlled trial was conducted in a university-affiliated hospital where 45 patients who underwent tympanoplasty under general anesthesia were randomly allocated into three groups. Dexmedetomidine was administered by intravenous infusion at 0.8 μg.kg−1 for 10 min, intranasal instillation at a drop rate of 1 μg.kg−1 and oral intake at 4 μg.kg−1 ten minutes before the induction of anesthesia. The PK and PD of dexmedetomidine after a single low dose administration and its effect on the surgical field in tympanoplasty were analysed.Results: A plasma concentration of dexmedetomidine of 220 pg/ml was achieved immediately after intravenous infusion and at 13.2 and 70.3 min for intranasal and oral administration, respectively. Dexmedetomidine decreased the heart rate (HR) and mean arterial pressure (MAP) in all three groups, although these values remained higher in the oral dexmedetomidine group at all eight time points. Intravenous dexmedetomidine provided the best visualization of the surgical field for opening of the tympanic sinus, 30 min after the start of the infusion (p < 0.05). Intranasal dexmedetomidine provided a significantly better visual field than oral dexmedetomidine for the repair of a tympanic membrane perforation using the fascia temporal muscle (p < 0.05).Conclusion: A single low dose of dexmedetomidine administered intravenously or intranasally could decrease HR and MAP, improve surgical field visibility and be appropriate for deliberate hypotension for surgical procedures of 1–2 h in length.Trial registration: Clinicaltrials.gov identifier: NCT03800641.

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“…Dexmedetomidine was administered as an infusion rather than a bolus to avoid transient hypertension, which can result from rapid infusions (Weerink et al, 2017). We have previously observed that 50 µg/kg of dexmedetomidine reliably produces a deeply sedated state with full loss of righting in rats (Kato et al, 2021). However, RORR latency at this dose can exceed 3 h in females.…”

Section: Intravenous Anestheticsmentioning

confidence: 99%

“…Ketamine hydrochloride (Covetrus) was infused over 10 min to a total dose of 50 mg/kg. We have previously observed that infusions at this dose are sufficient to produce a reliable loss of righting in all rats without causing significant respiratory depression (Kato et al, 2021). Immediately following anesthetic infusion, tail vein catheters were quickly removed, the blood was staunched, and the rats were placed supine in the testing chambers.…”

Section: Intravenous Anestheticsmentioning

confidence: 99%

Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats

Vincent

Zhang

Kato

et al. 2021

Front. Syst. Neurosci.

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As the number of individuals undergoing general anesthesia rises globally, it becomes increasingly important to understand how consciousness and cognition are restored after anesthesia. In rodents, levels of consciousness are traditionally captured by physiological responses such as the return of righting reflex (RORR). However, tracking the recovery of cognitive function is comparatively difficult. Here we use an operant conditioning task, the 5-choice serial reaction time task (5-CSRTT), to measure sustained attention, working memory, and inhibitory control in male and female rats as they recover from the effects of several different clinical anesthetics. In the 5-CSRTT, rats learn to attend to a five-windowed touchscreen for the presentation of a stimulus. Rats are rewarded with food pellets for selecting the correct window within the time limit. During each session we tracked both the proportion of correct (accuracy) and missed (omissions) responses over time. Cognitive recovery trajectories were assessed after isoflurane (2% for 1 h), sevoflurane (3% for 20 min), propofol (10 mg/kg I.V. bolus), ketamine (50 mg/kg I.V. infusion over 10 min), and dexmedetomidine (20 and 35 μg/kg I.V. infusions over 10 min) for up to 3 h following RORR. Rats were classified as having recovered accuracy performance when four of their last five responses were correct, and as having recovered low omission performance when they missed one or fewer of their last five trials. Following isoflurane, sevoflurane, and propofol anesthesia, the majority (63–88%) of rats recovered both accuracy and low omission performance within an hour of RORR. Following ketamine, accuracy performance recovers within 2 h in most (63%) rats, but low omission performance recovers in only a minority (32%) of rats within 3 h. Finally, following either high or low doses of dexmedetomidine, few rats (25–32%) recover accuracy performance, and even fewer (0–13%) recover low omission performance within 3 h. Regardless of the anesthetic, RORR latency is not correlated with 5-CSRTT performance, which suggests that recovery of neurocognitive function cannot be inferred from changes in levels of consciousness. These results demonstrate how operant conditioning tasks can be used to assess real-time recovery of neurocognitive function following different anesthetic regimens.

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D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

Cited by 11 publications

References 58 publications

Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an α2-adrenergic receptor competitive antagonist in combination with caffeine

Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an α2-adrenergic receptor competitive antagonist in combination with caffeine

Perioperative Low Dose Dexmedetomidine and Its Effect on the Visibility of the Surgical Field for Middle Ear Microsurgery: A Randomised Controlled Trial

Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats

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