This episode we take a dive into physiology. We talk about cocaine and wide complex tachycardia, CPR on television, which medications end up in breast milk, and practical tips for using ketamine in procedural sedation.
Wide complex tachycardia
Hoffman RS. “Treatment of patients with cocaine-induced arrhythmias: bringing the bench to the bedside.” Br J Clin Pharmacol. 2010. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856045/
- Cocaine increases concentrations of circulating catecholamines (which typically increase heart rate).
- Since sodium channel blockade follows use-dependent kinetics, increases in heart rate exacerbate sodium channel blockade.
- Tachycardia alone may be sufficient to trigger a re-entrant rhythm in a susceptible host.
- Cocaine can cause ischemia and infarction
- Blockade of both sodium and potassium channels (+vasospasm) creates a substrate for arrhythmia
- QRS widening from sodium channel blockade.
- QT prolongation from K+ channel blockade as well as QRS being widened.
- In the setting of sodium channel blockade QRS duration continually narrows as pH increases.
CPR on TV and in ‘real life’
Cardiopulmonary Resuscitation on Television — Miracles and Misinformation → https://www.nejm.org/doi/full/10.1056/nejm199606133342406
Results. There were 60 occurrences of CPR in the 97 television episodes — 31 on ER, 11 on Chicago Hope, and 18 on Rescue 911. In the majority of cases, cardiac arrest was caused by trauma; only 28 percent were due to primary cardiac causes. Sixty-five percent of the cardiac arrests occurred in children, teenagers, or young adults. Seventy-five percent of the patients survived the immediate arrest, and 67 percent appeared to have survived to hospital discharge.
Conclusions. The survival rates in our study are significantly higher than the most optimistic survival rates in the medical literature, and the portrayal of CPR on television may lead the viewing public to have an unrealistic impression of CPR and its chances for success. Physicians discussing the use of CPR with patients and families should be aware of the images of CPR depicted on television and the misperceptions these images may foster. (N Engl J Med 1996;334:1578-82.)
“Regional Variation in Out-Of-Hospital Cardiac Arrest Incidence and Outcome” → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187919/
|REGION||ARREST SURVIVAL (%)||VFIB SURVIVAL (%)|
- Used for induction of anesthesia. Sometimes used in conjunction with propofol (“ketofol” to be covered on a future episode)
- Inhibits NMDA receptor complex
- “Dissociative anesthesia”: eyes remain open with slow nystagmic gaze
- “Unpleasant” emergence reactions: vivid colorful dreams, hallucinations, out of body experience
- CV/sympathetic stimulation → Increased BP, HR, and CO
Ketamine now approved by FDA for intranasal treatment of depression → https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
“What is the nature of the emergence phenomenon when using intravenous or intramuscular ketamine for paediatric procedural sedation?” Emerg Med Australas. 2009. → https://www.ncbi.nlm.nih.gov/pubmed/19682018
Premedicating with midazolam to avoid emergence phenomenon → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418142/
“Premedication With Midazolam or Haloperidol to Prevent Recovery Agitation in Adults Undergoing Procedural Sedation With Ketamine: A Randomized Double-Blind Clinical Trial.” Ann Emerg Med. 2019. https://www.ncbi.nlm.nih.gov/pubmed/30611640
We evaluate the effect of midazolam and haloperidol premedication for reducing ketamine-induced recovery agitation in adult patients undergoing procedural sedation. We also compare physician satisfaction and recovery time. We enrolled 185 subjects. The maximum Pittsburgh Agitation Scale score was significantly less with midazolam compared with placebo (difference 3; 95% confidence interval 1.27 to 4.72) and with haloperidol compared with placebo (difference 3; 95% confidence interval 1.25 to 4.75), and Richmond Agitation-Sedation Scale scores at 5, 15, and 30 minutes trended lower with the active agents. Midazolam and haloperidol significantly delayed recovery but did not alter overall clinician satisfaction.
Xigris, “surviving sepsis” campaign, and bioethicists
- “Surviving Sepsis — Practice Guidelines, Marketing Campaigns, and Eli Lilly” → https://www.nejm.org/doi/full/10.1056/NEJMp068197
Breast milk and medications (general overview)
Models of drug passage into breastmilk → https://www.fda.gov/downloads/Drugs/NewsEvents/UCM496951.pdf
- M/P ratio and Relative Infant Dose
- RID classification:
- Acceptable: < 10% of maternal dosage
- Caution: 10% to 25% of maternal dosage
- Unacceptable >25% of maternal dosage
- RID classification:
Anderson PO, et al. “A Review of Adverse Reactions in Infants From Medications in Breastmilk.” Clinical Pediatrics. 2015. https://www.ncbi.nlm.nih.gov/pubmed/26170275
- “The age distribution of case reports in the current study is similar to results in our previous article, which found that 63% of adverse reactions occurred in the first month and 15% in the second month of life.”
Maternal plasma protein binding
Transfer into breast milk is also influenced by the extent to which the drug is bound by maternal plasma proteins. Free unbound drug diffuses readily while highly protein-bound drugs like ibuprofen or warfarin (both 99% protein bound) are unable to diffuse in significant amounts. Sertraline is highly protein bound (98%) so overall it will be minimally transferred to the breastfed baby. By comparison, venlafaxine has much lower protein binding and so more of the drug will be present in milk.
Size of the drug molecule
Most drug molecules, including alcohol, nicotine and caffeine, are small enough to enter milk. Exceptions are drugs with high molecular weights such as heparins and insulin.
Degree of ionization
Drugs cross membranes in an un-ionized form. Milk is generally slightly more acidic (pH 7.2) than the mother’s plasma (pH 7.4) so it attracts weak organic bases such as oxycodone and codeine. Such drugs become ionized and ‘trapped’ in the milk. Conversely, weak organic acids such as penicillin tend to be ionized and held in maternal plasma.
In addition to the passive diffusion into the aqueous phase, lipid-soluble drugs such as citalopram may have co-secretion by dissolution in the fat droplets of milk. In practical terms, this may not be of concern. It would not be an indication to change therapy if citalopram has been effective, but infant drowsiness should be monitored. Although the fat content of the milk varies according to infant age and phase of the feed, this is unlikely to impact on the choice of drug therapy.
(Source for 4 headings above: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657301/ )
Breast milk and some common medication categories:
- Avoid: meperidine, hydrocodone, codeine
- Careful: buprenorphine, oxycodone
- Okay: morphine, hydromorphone (dilaudid), fentanyl, acetaminophen, ibuprofen
- “Morphine is still considered an ideal analgesic for breastfeeding mothers due to its limited transport to milk and its poor oral bioavailability in infants.” https://www.guidelinecentral.com/summaries/analgesia-and-anesthesia-for-the-breastfeeding-mother-revised-2012/#section-society
- Avoid: erythromycin; sulfas with jaundice (plus sulfa always in G6PD)
- “Erythromycin appears in higher amounts in the milk than in the plasma; if provided intravenously to the mother, then the levels in milk are 10 times higher. After 1 month of age, administering erythromycin directly to the infant is usually safe. Another concern with erythromycin is the risk of cross-reaction with other drugs, such as carbimazole, cyclosporin, digoxin, triazolam, theophylline, and anticoagulants”
- Careful: tetracyclines
- Okay: generally any antibiotic you would give to infant at that same dosage
General → “Concerns exist for amiodarone, chemotherapeutic/antineoplastic agents, chloramphenicol, ergotamine, gold salts, phenindione, radioactive pharmaceuticals, retinoids, tetracyclines (chronic > 3 weeks) and certain psychotropic medications (lithium now can be taken with careful monitoring of blood levels in mother and baby).” -AAP https://www.aap.org/en-us/Pages/Breastfeeding-and-Medication.aspx
Breast milk medication resource → Lactmed (web search + smartphone app from NIH → NLM TOXMED database) → https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
Forme fruste & akathisia
Akathisia. A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, 134–168. Owens, D. G. C. (n.d.). doi:10.1017/cbo9781139149112.006
“Kenneth Kendler, who has subsequently gone on to a distinguished career in psychiatric research, began his professional authorship with a lucid and compelling account of his own experiences of akathisia, which he developed as a medical student after volunteering for a research project. Kendler ( 1976 ) wrote:
At 9.00 pm I received 1 mg of haloperidol intramuscularly. I felt drowsy by 9.20. By 9.30 the drowsiness had dissipated and was replaced by a diffuse, slowly increasing anxiety. My uneasiness soon began to focus on the idea that I could not possibly sit still for the rest of the experiment. I imagined walking outside: the idea of walking was particularly attractive. I could not concentrate on what I had been reading … As soon as I could move, I found myself pacing up and down the lab, shaking and wringing my hands. Whenever I stopped moving the anxiety increased … the reaction peaked at 10.30 pm … At home, I walked rapidly several times around the apartment complex … I did a little jig, moving my arms and legs quickly. By midnight the intensity of the reaction was decreasing … the intensity of the dysphoria was striking … (and) the sense of a foreign influence forcing me to move was dramatic.”
Akathisia in haloperidol review paper → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516628/
— Episode credits —
Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Show notes written by Addie. Theme music (Too Cool, and Laserpack) by Kevin MacLeod of incompetech.com, licensed under Creative Commons: By Attribution 3.0 License.