1. No difference in outcome when compared to holding statin therapy or delaying resumption.
   
2. An equivalent benefit when compared with resuming a lower dose statin.
   
3. A significant worsening of patient outcomes.
   
4. Strong association with increased post‐stroke survival, even compared to low‐dose therapy.
   
5. No significant effect on clinical outcomes.

A large retrospective study of 17 hospitals (Flint et al.) found that those patients who underwent statin withdrawal in the hospital had a substantially greater risk of death. Although the use of low‐dose statins appears to be beneficial, those taking high‐dose statins (>60 mg/day) compared to low‐dose (<60 mg/day) have been shown to have a greater survival benefit. Multiple trials have demonstrated statin therapy is associated with a marked improvement in patient outcomes in ischemic stroke.

Answer: D

Flint AC, Kamel H, Navi BB, Rao VA, Faigeles BS, Conell C, Klingman JG, Sidney S, Hills NK, Sorel M, Cullen SP, Johnston SC . Statin use during ischemic stroke hospitalization is strongly associated with improved poststroke survival. Stroke 2012; 43(1):147–154. 10.1161/STROKEAHA.111.627729.

Flint AC, Kamel H, Navi BB, Rao VA, Faigeles BS, Conell C, Klingman JG, Hills NK, Nguyen‐Huynh M, Cullen SP, Sidney S, Johnston SC . Inpatient statin use predicts improved ischemic stroke discharge disposition. Neurology 2012; 78(21):1678–1683. 10.1212/WNL.0b013e3182575142

1. Higher rates of respiratory compromise
   
2. Lower rates of respiratory compromise
   
3. Higher rate of resulting neurologic deficit at hospital discharge
   
4. Lower rate of resulting neurologic deficit at hospital discharge
   
5. Unchanged duration of status epilepticus

Out‐of‐hospital use of benzodiazepines in the treatment of status epilepticus is associated with a trend toward lower out‐of‐hospital complications than placebo, as demonstrated in a randomized, double‐blind by Alldredge BK et al. The rates of respiratory or circulatory complications after the study treatment were 10.6% for the lorazepam group, 10.3% for the diazepam group, and 22.5% for the placebo group. Though the use of out‐of‐hospital benzodiazepines resulted in a statistically significant decreased duration of out‐of‐hospital status epilepticus, it did not ultimately affect the rate of resulting neurologic deficit at hospital discharge. Additionally, a more recent study examined pre‐enrollment data from the Established Status Epilepticus Treatment Trial (ESETT) and found that many of those patients with status epilepticus who were considered to “fail” benzodiazepine receive lower than guideline recommended dosages. This trial found that approximately 76% of patients received lower than recommended first doses of benzodiazepine treatment for status epilepticus, suggesting this delay may place patients at high risk for longer seizures and poor outcomes.

Answer: B

Alldredge BK . A comparison of lorazepam, diazepam, and placebo for the treatment of out‐of‐hospital status epilepticus. New England Journal of Medicine 2001; 345(9):631–637.

Sathe AG, Underwood E, Coles LD, Elm JJ, Silbergleit R, Chamberlain JM, Kapur J, Cock HR, Fountain NB, Shinnar S, Lowenstein DH, Rosenthal ES, Conwit RA, Bleck TP, Cloyd JC . Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial. Epilepsia 2021; 62(3):795–806. 10.1111/epi.16825.

1. IV lorazepam
   
2. IV midazolam
   
3. IV phenobarbital
   
4. IV phenytoin
   
5. IV magnesium

A double‐blind study at 16 VA medical centers and 6 affiliated university hospitals over 5 years randomly assigned patients with generalized convulsive status‐epilepticus to receive intravenous lorazepam, phenobarbital, phenytoin, or diazepam followed by phenytoin. Treatment was considered successful if all clinical and electrical evidence of seizure activity halted within 20 minutes of infusion and did not recur within 60 minutes. Lorazepam was demonstrated to have the highest rate of treatment success. More recently, a systematic review by the Japan Resuscitation Council Task Force in 2020 performed a meta‐analysis and found that IV lorazepam had a statistically significant superior effect for seizure cessation when compared with diazepam.

Answer: A

Kobata H, Hifumi T, Hoshiyama E, Yamakawa K, Nakamura K, Soh M, Kondo Y, Yokobori S ; Japan Resuscitation Council (JRC) Neuroresuscitation Task Force and the Guidelines Editorial Committee. Comparison of diazepam and lorazepam for the emergency treatment of adult status epilepticus: a systemic review and meta‐analysis. Acute Medicine & Surgery. 2020; 7(1):e582. 10.1002/ams2.582.

Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans affairs status epilepticus cooperative study group. New England Journal of Medicine 1998; 339(12):792–798.

1. Respiratory depression
   
2. Hypoventilation
   
3. Sedative effects
   
4. Cardiac depression/hemodynamic instability
   
5. Benzodiazepine‐induced amnesia

Although flumazenil has been shown to reverse the effects of benzodiazepine‐induced ventilatory depression, it appears to be inconsistent particularly in pediatric use, those with liver disease or those who have concurrently received an opioid. While flumazenil has been shown to reliably reverse the sedative effect of benzodiazepines, the duration of flumazenil tends to be shorter than that of the most commonly used benzodiazepines. Flumazenil has no significant effect on cardiovascular parameters when administered to patients with stable ischemic heart disease and does not completely and consistently reverse benzodiazepine‐induced amnesia.

Answer: C

Marraffa J, Cohen V, Howland MA . Antidotes for toxicological emergencies: a practical review. American Journal of Health‐System Pharmacy 2012; 69(3):199–212.

Roche Pharmaceuticals. Flumazenil (Romazicon) data sheet. Revised April 2010.

1. Anticholinergic effect
   
2. QTc prolongation
   
3. Hyperprolactinemia
   
4. Akathisia
   
5. Weight gain

All the listed side effects are associated with atypical antipsychotic agent use. Anticholinergic symptoms include constipation, urinary retention, blurred vision, or dry mouth. All antipsychotics, including atypical, cause prolongation of ventricular repolarization, which can lead to torsades and sudden cardiac death. Antipsychotics block the normal inhibition of dopamine production on pituitary mammotropic cells in the hypothalamus, leading to higher levels of prolactin. This may be asymptomatic or may be associated with gynecomastia, galactorrhea, acne, infertility, or loss of bone density. Akathisia can subjectively be described as a feeling of inner restlessness and inability to remain still for long. Second‐generation antipsychotics have often been distinguished from first‐generation antipsychotics by the decreased risk of extrapyramidal side effects such as akathisia. Despite a relative decreased risk compared to first‐generation antipsychotics, a review of the literature demonstrated that second‐generation drugs still lead to akathisia with rates ranging from 2.9 to 13.0%. Weight gain is more common in the second‐generation antipsychotics than in some first generation.

Answer: D

Chow CL, Kadouh NK, Bostwick JR, VandenBerg AM . Akathisia and newer second‐generation antipsychotic drugs: a review of current evidence. Pharmacotherapy 2020; 40(6):565–574. 10.1002/phar.2404.

Muench J, Hamer AM . Adverse effects of antipsychotic medications. American Family Physician 2010; 81(5):617–622.

Solmi M, Murru A, Pacchiarotti I . Safety, tolerability, and risks associated with first‐ and second‐generation antipsychotics: a state‐of‐the‐art clinical review. Therapeutics and Clinical Risk Management 2017; 13:757–777.

1. Hypertension
   
2. Tachycardia
   
3. Polycythemia vera
   
4. Hypokalemia
   
5. Increased vascular tone

Hypotension is a common side effect of barbiturate due to medullary depression, peripheral vasodilation, and myocardial depression. Inadvertent intra‐arterial administration of barbiturates has resulted in ischemia and gangrene of the extremity. Rather than leading to excessive RBC production, phenobarbital has been implicated in drug‐induced megaloblastic anemia, thought to be induced by decreased absorption of folic acid. Multiple case reports have identified the development of persistent hypokalemia in certain patients undergoing barbiturate infusion, particularly those patients with severe traumatic brain injury. Multiple various mechanisms have been suggested for this effect, including inhibition of voltage‐dependent potassium channels, inhibition of ATP‐dependent potassium channels of the B‐cells of the pancreas leading to excessive insulin secretion or excess mineralocorticoid secretion and catecholamine surge leading to hypokalemia. One recent study examined the incidence of dyskalemia in patients with traumatic brain injuries treated with barbiturate therapy. This study found that 62% of patients treated with barbiturate therapy developed mild‐to‐moderate hyperkalemia (2.6–3.5 mEq/L); 16.2% of patients developed severe hypokalemia (<2.5 mEq/L). It was noted that 66% of patients with severe hypokalemia who had received aggressive potassium supplementation went on to develop severe hyperkalemia after cessation of barbiturate therapy. This suggests that the barbiturate‐induced redistributive hypokalemia reverses quickly with cessation of therapy, placing those who undergo aggressive supplementation at higher risk for developing rebound hyperkalemia.

Answer: D

Aytuluk HG, Topcu H . Severe hypokalemia and rebound hyperkalemia during barbiturate coma in patients with severe traumatic brain injury. Neurocirugía (Asturias, Spain). 2020; 31(5):216–222. 10.1016/j.neucir.2019.12.003.

Mintzer DM, Billet SN, Chmielewski L . Drug‐induced hematologic syndromes. Advances in Hematology. 2009; 2009:495863. 10.1155/2009/495863.

Neil MJ, Dale MC . Hypokalaemia with severe rebound hyperkalaemia after therapeutic barbiturate coma. Anesthesia & Analgesia 2009; 108(6):1867–1868. 10.1213/ane.0b013e3181a16418

Vangerven M, Delrue G, Brugman E, Cosaert P . A new therapeutic approach to accidental intra‐arterial injection of thiopentone. British Journal of Anaesthesia 1989; 62(1):98–100.

1. Hyperkalemia
   
2. Cardiac dysrhythmia
   
3. Decreased urine output
   
4. Hepatic failure
   
5. Hypoglycemia

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