A 46-year-old male with a past medical history of COPD and uncontrolled diabetes is intubated and sedated in the ICU requiring inotropic and vasopressor support for septic shock due to pneumonia. Several days into his admission he develops bradycardia that is refractory to treatment, necessitating the placement of a transvenous catheter. Urinalysis is positive for myoglobin and his CK levels approach 50 000 U/L. You obtain a blood gas that reveals a:
Propofol infusion syndrome (PRIS) is suspected.
Which of the following is NOT a known triggering factor for this condition?
Correct Answer: A
PRIS is characterized by acute bradycardia (which may be refractory to treatment and that may progress to asystole, hypertriglyceridemia, hepatomegaly, metabolic acidosis, rhabdomyolysis, and myoglobinuria and is associated with propofol infusions >48 hours. Usually, doses at or exceeding 4 mg/kg/h are causative; however, there are case reports with smaller doses. Steroid use, vasopressors, low carbohydrate intake, poor tissue perfusion, sepsis, and cerebral injury have been shown to be associated PRIS; all of which may be seen in critical illness. The onset of PRIS is typically rapid and seen within 4 days of initiation. The mechanism of PRIS is poorly understood but may be related to direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism and blockage of beta-adrenoreceptors and cardiac calcium channels.
The best treatment is prevention and first-line therapy is immediate discontinuation of the infusion of propofol. Renal replacement therapy may become necessary because of metabolic acidosis, hyperkalemia, and rhabdomyolysis. Bradyarrhythmias can be managed with transthoracic or transvenous pacing and shock managed with the support of vasopressors and inotropes. Extracorporeal membrane oxygenation should be considered in cases of refractory PRIS. Ensuring adequate carbohydrate intake may also help to prevent PRIS development.
References:
A 62-year-old Cantonese woman with no significant past medical history is admitted to the ICU with intense nausea, vomiting, and diarrhea 24 hours after ingestion of an unknown mushroom. Laboratory studies are negative for Epstein-Barr, all forms of hepatitis, and antinuclear antibody. ALT and AST are elevated. On day 3 of admission, she goes into acute hepatic failure. Mushroom poisoning is suspected.
Which of the following drugs is amatoxin uptake inhibitor?
Correct Answer: C
Patients ingesting mushrooms, such as Amanita phalloides, typically do so incidentally when foraging for mushrooms and mistake its identity for an edible mushroom. Patients usually suffer intoxication from the amatoxin of the mushroom (most commonly alpha-amanitin, which is heat stable and insoluble in water) and endure four clinical stages. The first stage is usually observed during the first 6 to 12 hours after mushroom ingestion and is known as the latent stage, where patients usually will not experience any symptoms. Severe muscarinic symptoms might be evident during the second stage, typically with severe gastritis, nausea, vomiting, abdominal pain, and severe diarrhea, which may be bloody or contain mucus. This second stage usually lasts between 12 to 24 hours. The third stage has been classified as a pseudo-remission period where the patient may begin to feel better, but unfortunately patients will rapidly progress to the fourth stage, which is characterized by acute liver failure with massive hepatocyte death. If not treated early, patients may go on to suffer multiorgan failure and death, which can be seen as early as 5 to 8 days after ingestion of the mushroom.
Silibinin, which is a water-soluble silymarin (a flavonolignan from milk thistle), inhibits the amatoxin uptake and penetration into hepatocytes and improves cellular survival in human hepatocytes exposed to alphaamanitin. Silibinin is most effective when given within 24 to 48 hours of ingestion and is administered as an initial intravenous loading dose of 5 mg/kg followed by continuous infusion of 20 to 50 mg/kg/d for 6 to 8 days. Increased mortality or need for transplantation is seen when silibinin is administered >48 hours after ingestion. Other therapies that have been tried and abandoned include antibiotics, thioctic acids, steroids, hormones, and other antioxidants.
Which of the following statements is most appropriate when considering the risk of arrhythmias between typical and atypical antipsychotics?
Correct Answer: D
Typical antipsychotics exert their action by postsynaptic blockade of D2 dopamine receptors in the brain with extensive metabolism via the cytochrome P450 system, which makes this class quite dependent on adequate hepatic clearance to reduce systemic accumulation or drug-drug interactions. This class carries an increased risk for extrapyramidal side effects and tardive dyskinesia.
Atypical antipsychotics also have postsynaptic blockade of brain dopamine D2 receptors but they tend to have more serotonin 5HT-2 affinity than their dopamine affinity. This primarily separates them from typical antipsychotics. This serotonin receptor affinity is also what is suggested as the mechanism behind the lower incidence of extrapyramidal side effects seen in this class. This class is metabolized through the cytochrome P450 system, but there is individual drug variability that alters the risk for accumulation and drug-drug interactions (which is beyond the specific scope of this question).
Although there are clear differences in the extent of QTc prolongation between the two classes (haloperidol averages approximately 4.7 ms, quetiapine averages 14.5 ms), there does not seem to be a difference in the risk of arrhythmias, including Torsades de Pointes (TdP) between them. Patients taking either of these classes are approximately at a twofold increased risk of arrhythmias and TdP compared with patients not receiving these medications. Within the two classes, thioridazine (typical) and ziprasidone (atypical) have the highest risk of QTc prolongation and risk of TdP. Haloperidol does have a clinically significant risk; however, this is usually seen with doses of >35 mg/d. Of additional importance, QTc prolongation and TdP tend to occur when additional risk factors are present. These include age >65, preexisting cardiovascular disease, conduction disorders, brady or tachyarrythmias, female sex, electrolyte disturbances (hypokalemia, hypomagnesemia), supratherapeutic or toxic levels of accumulation, or concomitant administration of other drugs that interfere with cardiac conduction or drug metabolism.