12. CELLULAR MECHANISM Ca ++ Ca ++ Ca ++ – – + Decrease in influx of Ca ++ Decrease in action potential due to hyperpolarization 2 A 2 AR G o G k K + K + K +
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Hinweis der Redaktion
High concentrations of 2 adrenergic receptors in the brain (locus ceruleus), brain stem, and spinal cord. The locus ceruleus is primarily responsible for regulating stress/anxiety and consciousness. Therefore, activation of these receptors produces sedation and anxiolysis and general decrease in CNS sympathetic discharge. Activation in the spinal cord produces analgesic effect mediated by Substance P.
Locus Ceruleus Activates transmembrane 2 -adrenergic receptor of the noradrenergic neuron, dexmedetomidine. Via subsequent G-protein coupling, one of two effects observed – either inhibition of Ca ++ influx (voltage-sensitive calcium channels) or promotion of K + efflux (potassium channels). The net effect is cell membrane hyperpolarization, making it less likely to fire, thereby decreasing norepinephrine release. Result is an inhibition of histamine release and hypnotoc response in a pattern that resembles the natural sleep pathway.
Adult study - cardiorespiratory response to multiple, escalating doses. In highest dose group (2 u g/kg), saw small but statistically significant decreases in SpO 2 , PaCO 2 , minute ventilation, and an altered ventilatory response to hypercarbia. While not likely of great clinical importance, and of smaller magnitude than with other commonly used sedatives (at equi-sedating doses), the data DO suggest some small respiratory depressing effects of dexmedetomidine
Primary source of experience is adult literature Compared to propofol, dex use in the OR was associated with less significant hypotension though it persisted longer in the PACU, as well as an inconsistent decrease in immediate post-op analgesic (opioid) requirements. During procedures employing controlled hypotension, the degree of tachycardia response during hypotension is blunted Following vascular procedures, post-op dex use up to 48 hours was associated with less hypertension and decreased serum catecholamine levels, especially norepeniphrine Several operative studies now have described ongoing post-extubation sedation with dex with limited if any significant respiratory effects
Crossover study of midazolam vs low-dose (0.25) or higher dose (0.5) dex in 30 ventilated PICU pts – n=10 per group Morphine 0.1 mg/kg prn for agitation/pain Pts crossed over dex to/from midazolam at 24 hrs if still ventilated (no crossover between dex groups) Evaluation of sedation quality (Ramsay Sedation Score) and amount of adjunct morphine use Less morphine use in both dex groups (significant in 0.5 u g group) and fewer patients in dex groups had RSS scores of 1 (inadequate sedation) vs midazolam)
Most of the experience with dex in the ICU is also adult Has been described for use in both surgical and medical populations
2 notes about these trials: Few centers would use midazolam only for MRI - ? Clinical relevance
RSS = Ramsay Sedation Score
3 different protocolized dosing strategies (induction + maintenance infusion)
Sedation options especially limited for EEG exams due to EEG/seizure altering effects of most sedatives KCH = Kosair Children’s Hospital; Louisville, KY CECH = Chris Evert Children’s Hospital; Ft. Lauderdale, FL
Primary other sedatives inc chloral, ketamine, propofol, pentobarbital
Database does not enable us to differentiate inadequate sedation from agitation Failures uncommon, rarely related to complications Respiratory events extremely uncommon compared to being most common event with other sedatives Pts requiring increased level of care: Pt wheezed during nuc med study – sent to PICU – subsequently Dx aspiration pneumonia and UTI/sepsis Pt with 1 st degree ht block on EKG – briefly in PICU (4 hr) – 48 hr later readmitted with +ve monospot and recurrence of 1 st degree ht block
Dex administered transmucosally (slow drip into buccal cavity, not swallowed) Dose of dex relatively low Unclear what effects of altered timing schedule is on post-op effects While no difference in post-op anxiety, found decreased pain scores and signs of decreased sympathetic tone (dec HR, BP) on arrival to PACU in pts receiving either dex or clonidine
All premeds given with 20 mg/kg acetaminophen and given 60 min prior to anesthesia induction Rationale – circumvent taste, paradoxical agitation issues with po midaz Dex diluted in 0.9% saline to make final administered volume of 0.4 mL in all pts Benefits of dex in sedation, parental separation were also dose dependent * = sig diff comparing dex 1 u g/kg vs midaz groups
Increasing interest in co-administration with ketamine to blunt sympathetic effects of ketamine and still maintain respiratory benefits of both. Rescue anesthetic if needed with 1 mg/kg ketamine Due to increased ketamine boluses, authors concluded that dex/ketamine was feasible but not superior to propofol/ketamine
Initial maintenance dex at 2 u g/kg/hr, dec to 1 u g/kg/hr after 30 min