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pearl
1
A single pediatric general anesthetic exposure is associated with increased parental-reported behavioural changes though no difference in general intelligence.
Ing C, Jackson WM, Zaccariello MJ et al. Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis. Br J Anaesth. 2021 Feb 1; 126 (2): 433-444.
  Daniel Jolley
pearl
1
Subcutaneous GTN may assist paediatric radial artery cannulation and improve first pass success.
Jang YE, Ji SH, Kim EH et al. Subcutaneous Nitroglycerin for Radial Arterial Catheterization in Pediatric Patients: A Randomized Controlled Trial. Anesthesiology. 2020 Jul 1; 133 (1): 53-63.
  Daniel Jolley
pearl
1
Videolaryngoscopy may improve first-pass success in the ICU and among less experienced practitioners outside the operating theatre.
Arulkumaran N, Lowe J, Ions R et al. Videolaryngoscopy versus direct laryngoscopy for emergency orotracheal intubation outside the operating room: a systematic review and meta-analysis. Br J Anaesth. 2018 Apr 1; 120 (4): 712-724.
  Daniel Jolley
pearl
1
Videolaryngoscopy in children and neonates reduced intubation trauma & improved indirect glottic view, although demonstrated no other benefits.
Hu X, Jin Y, Li J et al. Efficacy and safety of videolaryngoscopy versus direct laryngoscopy in paediatric intubation: A meta-analysis of 27 randomized controlled trials. J Clin Anesth. 2020 Nov 1; 66: 109968.
  Daniel Jolley
pearl
1
GlideScope-Titanium videolaryngoscopy improved glottic visualisation but prolonged intubation time for placement of double lumen tubes.
Risse J, Schubert AK, Wiesmann T et al. Videolaryngoscopy versus direct laryngoscopy for double-lumen endotracheal tube intubation in thoracic surgery - a randomised controlled clinical trial. BMC Anesthesiol. 2020 Jun 16; 20 (1): 150.
  Daniel Jolley
reference
1
Collection: Morphine
Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.
A. Physiochemistry
• Natural phenathrene opioid - plant, animal and even human synthesis identified.
  • Synthesized by mammalian cells from dopamine, although exact role unclear.
• pKa - 7.9 (20% nonionised @ 7.4)
• Octanol water coefficient - 1.4 (relatively low lipid solubility compared with other opioids)
• 3 rings attached to piperidine ring with a tertiary amine.
B. Pharmacokinetics
1. Dose - 50 mcg/kg IV
   • analgesia @ [plasma] 0.05 mcg/mL
   • epidural: 10-20 mcg/mL
   • PCA adult: 50 mg in 50 mL; 1 mL (1 mg) bolus 5 min lockout, commonly used.
   • PCA paeds: 1 mg/kg in 50 mL; 1 mL (20 mcg/kg) bolus; background 0.5-1 mL/h (10-20 mcg/kg/h).
2. Absorption - IV, IM, s/c, po (3x dose as HER 0.69)
3. Distribution - Vdcc 0.3, Vdss 3.5 L/kg
4. Protein binding - 30% (albumin)
5. Onset: peak onset at 20 min when given parenteral, 60 min orally; Offset 4 h
6. Metabolism - t½α 10-20 min, t½ß 2-4 h
   • 75% metabolised by conjugation → 90% morphine-3-glucuronide (no activity)
   • 10% morphine-6-gluc (13x potency of morphine). MAOIs inhibit glucuronidation.
7. Clearance - 15 mL/kg/min
C. Pharmacodynamics
1. Mech - mu, kappa, delta agonist. (GI linked). Effective against visceral, skeletal & joint pain.
2. CNS - little CNS penetration (cf. heroin, which readily crosses BBB), although alkalisation (⇣pCO2) ⇡ non-ionised fraction, and ⇡pCO2 ⇡CBF. Both ⇡ cerebral morphine concentration.
   • 'Ceiling effect' on EEG reaching high voltage, slow frequency (delta 2-4 Hz) waves.
   • ⇣ CMRO2 & ⇣ ICP.
   • ⇡ cortical stimulation of Edinger-Westphal nucleus → miosis.
3. CVS - ⇣ SNS & ⇡ PNS tone. Bradycardia, venodilation, histamine release (causes ⇣ MAP). Orthostatic hypotension due to depression of SNS responses. Direct depressant effect on SA node, slowing conduction (⇡ VF risk).
   • Administration with N₂O results in CVS depression.
4. Resp - Respiratory depression & response to CO₂ & hypoxia (shift pCO₂/VA curve to right).
   • Bronchoconstriction due to histamine release (similar with pethidine). Depresses airway reflexes & ciliary reflexes.
5. Renal - diuresis (kappa receptors → ADH release)
6. GIT - Nausea & vomiting due to stimulation of CTZ (30-40% of subjets); ileus; constipation; sphincter of Oddi spasm.
7. Pruritus
  Daniel Jolley
pearl
1
Red-haired patients show no greater risk of intraoperative awareness than other phenotypes.
Gradwohl SC, Aranake A, Abdallah AB et al. Intraoperative awareness risk, anesthetic sensitivity, and anesthetic management for patients with natural red hair: a matched cohort study. Can J Anaesth. 2015 Apr 1;62(4):345-55.
  Daniel Jolley
pearl
1
Patients with a history of intraoperative awareness are five-times more likely to experience awareness than those without.
Aranake A, Gradwohl S, Ben-Abdallah A et al. Increased Risk of Intraoperative Awareness in Patients with a History of Awareness. Anesthesiology. 2013 Dec 1;119(6):1275-83.
  Daniel Jolley
reference
1
Collection: Tapentadol
Tapentadol (Paliex™, Nucynta™) is a synthetic opioid agonist and noradrenaline-reuptake inhibitor. Similar to and based upon tramadol, although with much weaker inhibition (by design) of serotonin reuptake.
A. Physiochemistry
• Synthetic analgesic of 'amino-cyclo-hexanol' group.
• Unlike tramadol, prepared as only the (R,R) stereoisomer (weakest opioid activity).
• Oral: 50, 75 & 100 mg immediate release, and 50,100,150 & 200 mg extended release preparations.
• No parenteral preparation is approved for use.
B. Pharmacokinetics
1. Dose: 50-200 mg bd/qid for immediate release preparations, 50-200mg bd for extended release.
   • approximately double potency of tramadol, similar to oxycodone and between tramadol and morphine.
2. Absorption - po (only 32% biov)
   • increasing doses have a non-linear effect on increasing peak plasma concentration, thus higher doses result in disproportionately higher Cmax.
3. Distribution - ~8 L/kg (higher than tramadol).
4. Protein binding - 20% (low!)
5. Onset 30 min; Offset 4-6 h
6. Metabolism - t½ 4h
   • hepatic conjugation with glucuronic acid → glucuronides is main pathway (tapentadol-O-glucuronide); p450 metabolism to N-desmethyl tapentadol and hydroxyl tapentadol.
   • No known active metabolites
   • 99% excreted in urine, 1% in faecies.
7. Clearance - 22 mL/kg/min
C. Pharmacodynamics
1. Mech - weak mu agonists (30% of action / 18x less affinity than morphine) ; inhibits NAd reuptake (through indirect activation of post-synaptic alpha-2 adrenoreceptors), activating descending NAd (70%) modulating pain pathways.
2. CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating, ⇡ ICP.
3. CVS - few CVS effects. Some tachycardia and flushing.
4. Resp - little respiratory depression.
5. Renal - possible caution in renal failure, although no active metabolites even if 99% renal excreted.
6. GIT - Nausea & vomiting (less than tramadol), minimal constipation, more biliary spasm than tramadol.
7. SEs - interacts with MAOI (adrenergic storm), SSRIs (serotonin syndrome).
• Although thought to have less abuse potential than other common opioids, it is still classed as a Schedule 2 drug in the US, Schedule 1 in Canada, Class A controlled drug in the UK and S8 in Australia.
• Safety of tapentadol in pregnant, lactating women, and pediatric patients is not yet established. 
  Daniel Jolley
reference
1
Collection: Tramadol
Tramadol is a synthetic opioid agonist and neurotransmitter-modulating analgesic.
A. Physiochemistry
• Synthetic analgesic of 'amino-cyclo-hexanol' group.
• Racemic mixture of two enantiomers + and -:
  • (-) Inhibits NAd reuptake
  • (+) Enhances 5HT release, inhibits 5HT reuptake, weak mu (& less kapaa/delta) agonist.
• Oral (50 mg capsules, 100 mg tablets) & parenteral (100 mg/2mL) preparations.
• pKa 9.4
B. Pharmacokinetics
1. Dose - 5-10x less potent than morphine: 50-100 mg q6h, max 400-600 mg/day.
   • 2-3 mg/kg loading, then 1-2 mg/kg q6h.
   • PCA IV tramadol: 20 mg/mL then step down to oral (Prof Schug, Perth: 25-50 mg q1h PCA, using up to 1500 mg/24h).
   • analgesic efficacy and potency comparable to pethidine
   • Caudal: 2 mg/kg
2. Absorption - IV, IM, po (80% biov)
3. Distribution - 3 L/kg (80% crosses placenta).
4. Protein binding - 20%
5. Onset 30 min; Offset 6 h
   • peak [plasma] after po: 2h
6. Metabolism - t½ 6h (12h in renal impairment);
   • 85% p450 (CYP-2D6 - also converts codeine → morphine & metabolises ondansetron!)
   • Demethylation to 'O-demethyl-tramadol' (M1) t½ 9h - has some activity as it has 6x greater mu affinity than tramadol. Some consider tramadol a prodrug because of this.
   • 90% excreted in urine, 10% in faecies.
   • metabolism inhibited by quinidine
7. Clearance - 9 mL/kg/min
C. Pharmacodynamics
1. Mech - weak mu agonists (30% of action) (very weak kappa & delta); inhibits NAd reuptake (through indirect activation of post-synaptic alpha-2 adrenoreceptors) and stimulates 5HT release, so activates desc NAd and 5HT pathways (70%), modulating pain pathways.
   • Naloxone antagonises only 30% tramadol analgesic effect. Ondansetron antagonises a further 30% of tramadol analgesic effect.
2. CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating.
   • stops shivering?
3. CVS - few CVS effects. Some tachycardia and flushing.
4. Resp - little respiratory depression.
5. Renal - caution in renal failure.
6. GIT - Nausea & vomiting (30-40%, like morphine), minimal constipation, minimal biliary spasm.
7. SEs - interacts with MAOI, SSRIs.
• Quinidine may decrease efficacy of tramadol by inhibiting CYP-2D6, thus decreasing production of M1. Codeine my compete for the same enzyme with a similar result.
• Carbamazepine induces CYP-2D6 decreasing effect by increasing metabolism.
  Daniel Jolley