Article Notes
- Analysis of 927 confirmed symptomatic cases of COVID-19 demonstrates BNT162b2 is highly effective with 91.3% vaccine efficacy observed against COVID-19, measured seven days through up to six months after the second dose.
- Vaccine was 100% effective in preventing severe disease as defined by the U.S. Centers for Disease Control and Prevention and 95.3% effective in preventing severe disease as defined by the U.S. Food and Drug Administration.
- Vaccine was 100% effective in preventing COVID-19 cases in South Africa, where the B.1.351 lineage is prevalent.
- Vaccine safety now evaluated in more than 44,000 participants 16 years of age and older, with more than 12,000 vaccinated participants having at least six months follow-up after their second dose.
- pKa - 8.5 (9% nonionised @ 7.4)
- Octanol water coefficient - 39 (so 40x lipid solubility of morphine)
- phenylpiperidine opioid
- Dose - 25-100 mg (10% morphine potency). Limit 1000 mg 1st day, then 600 mg/day there after.
- Absorption - IV, IM, epidural, po (55% biov)
- Distribution - Vdss 4.5 L/kg. Crosses placenta - foetal 80% of maternal.
- Protein binding - 60%
- Onset 10 min ; Offset 2-3 h
- Metabolism - ß½ 3 h; N-demethylation to norpethidine and then hydrolysis to norpethidinic acid; also direct hydrolysis to pethidinic acid. Renal elimination.
- Norpethidine - ß½ 15 h; 50% analgesic properties, 2x convulsant effects.
- Clearance - 20 mL/kg/min (same as morph & fentanyl)
- Mech - mu and kappa agonist, causing potent spinal and supraspinal analgesia.
- CNS - more euphoria, less N/V than morphine. No miosis, but may cause mydriasis (pupil dilation -atropine-like kappa action). No EEG changes like morphine. ⇡ latency & amplitude of SSEPs.
- NB: has LA action, so can be used as sole agent for neuroaxial block.
- anti-shivering effect (kappa)
- CVS - ⇣ MAP (> than morphine) due to histamine release & alpha adrenergic blockade (vasodilation). Inc HR (atropine like effect). Large doses depress myocardial contractility. May cause hypertensive crisis in those on MAOIs.
- vasodilation
- tachycardia
- depress myocardial contractility
- Resp - potent resp depressant - greater effect on TV than RR. Histamine release. Chest wall rigidity.
- OWC 1800
- pKa 8.0
- Potency 5-10x fentanyl, 500x morphine.
- Vd 3 L/kg
- Protein binding 93%
- Clearance 12 mL/kg/min
- tß½ 3 hours
- CSHT(8h) 30 min (alfentanil ~60 m)
- mu agonist, also stimulates serotonin release and at high dose has local anaeshetic effect.
- Structurally different from fentanyl, with a methoxymethyl group on the piperidine ring (increases potency and reduces duration of action) and thiophene instead of phenyl ring.
- 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.
- 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).
- Absorption - IV, IM, s/c, po (3x dose as HER 0.69)
- Distribution - Vdcc 0.3, Vdss 3.5 L/kg
- Protein binding - 30% (albumin)
- Onset: peak onset at 20 min when given parenteral, 60 min orally; Offset 4 h
- 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.
- Clearance - 15 mL/kg/min
- Mech - mu, kappa, delta agonist. (GI linked). Effective against visceral, skeletal & joint pain.
- 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.
- 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.
- 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.
- Renal - diuresis (kappa receptors → ADH release)
- GIT - Nausea & vomiting due to stimulation of CTZ (30-40% of subjets); ileus; constipation; sphincter of Oddi spasm.
- Pruritus
Pfizer and BioNTech reported that phase 3 trials of their mRNA SARS-COV-2 vaccine showed:
Daniel Jolley
Although interesting and perhaps relevant to settings which require motor block resolution before discharge from PACU (or when there are bupivacaine shortages), the practical relevance of this study is questionable.
Notable in this French study is the extended duration of PACU stay after caesarean section: more than 2 hours in the prilocaine group, and 3 hours in the bupivcaine group! It is unclear whether this is routine post-CS care, or specific to the study design to allow for motor block assessment.
Also of note, the caesarean sections were "...performed using Misgav-Ladach technique with externalisation of the uterus" which may again make this study less relevant in settings where it is routinely accepted that avoiding uterine externalisation makes for better patient experience.
Daniel Jolley
Following their important 2020 study of the risk of surgery for COVID patients, the COVIDSurg Collaborative reports on their prospective cohort study aiming to determine the optimal delay for planned surgery after COVID infection.
Once again this was an international (116 countries), multicentre, prospective cohort study including all surgery types, over 140,000 patients, and 3,127 post-COVID. Once again the 30-day postoperative mortality was sobering: even in the 5-6 week post-COVID group, 30-day mortality was dramatically higher (OR 3.6, 2.0-5.2) compared to those without a COVID diagnosis. Worryingly the risk was consistent among both low-risk and high-risk surgical groups.
Although after the 7-week mark postoperative mortality was similar to non-post-COVID patients (OR 1.5, 0.9–2.1), those with persisting COVID symptoms still suffered a 6.0% 30-day mortality (3.2–8.7). (30-day mortality among non-COVID patients was 1.5% (1.4-1.5).
Post-COVID surgical timing takeaway:
Surgery should be delayed for at least 7 weeks after COVID, although those with persistent COVID symptoms will still have more than twice the 30-day mortality than those without.
Daniel Jolley
The most relevant takeaway from this meta-analysis is really just how poor a lot of the evidence around resuscitation and CPR is (not for lack of effort, but because of the obvious limitations of research around critical-event and end-of-life medicine). Not only was the analysed evidence of low certainty but notably all seven RCTs were manikin studies.
Manikins are designed for resuscitation education and training, not for physiological fidelity. Even if this study had shown an improvement in compression depth for different surfaces, it's relevance to CPR in flesh-and-blood humans would be no less questionable.
Daniel Jolley
Kataife et al. (2021) describe a cognitive aid for better managing perioperative haemorrhage, the Haemostasis Traffic Light algorithm. Using a simulation-based RCT across two centres (University Hospital Zurich & the Italian Hospital of Buenos Aires, N=84), they showed that using the HTL improved case solutions (OR 7.23, 3.82-13.68), quickened therapeutic decisions, (HR 1.97, 1.18-3.29), improved therapeutic confidence, (OR 4.31, 1.67-11.11) and reduced workload perception.
The aim of the HTL is to improve both situational awareness and decision making, by integrating clinical judgement and point-of-care testing (ROTEM) within an accessible, structured algorithm.
Haemostasis Traffic Light takeaway:
Kataife's study again shows the benefit of cognitive aids, particularly in critical, time-sensitive situations. The anaesthesia and critical care community's historical resistance to decision-support tools requires challenge.
Daniel Jolley
Interesting Cochrane meta-analysis looking at PONV prophylaxis from German (Weibel et al. 2021) that included almost 100,000 study participants across 585 trials. Interesting not so much because it confirms much of what we already new (or assumed, based on our common PONC prophylaxis drug choices), but because it reassures us that side-effects from commonly used PONV drugs are low to non-existent.
Takeaway: granisetron is probably the best single-agent or in combination with other agents because of it's efficacy (better than ondansetron), low-cost, long duration, and absent side-effects.
Daniel Jolley
Matthew Smith
Pethidine (Meperidine) is a phenylpiperidine synthetic opioid first synthesized in 1938. Although widely used in the 20th century, it has fallen out of favour over the past decade due to abuse potential, limited advantages over other opioids and the existence of toxic metabolites.
A. Physiochemistry
B. Pharmacokinetics
C. Pharmacodynamics
Daniel Jolley
Sulfentanil is a potent, short-acting synthetic opioid used in anesthesia and critical care. First synthesized by Janssen Pharmaceutica in 1974. It is the most potent opioid licensed for use in humans.
Daniel Jolley
Morphine is one of the most commonly used opioids worldwide. First isolated in 1803 and commercially marketed by Merck in 1827.
A. Physiochemistry
B. Pharmacokinetics
C. Pharmacodynamics
Daniel Jolley