Jimmy – Page 3 – Pharmacy & Acute Care University

Seizure Prophylaxis in Traumatic Brain Injury by Jordan Spurling

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States.
The Brain Trauma Foundation updated its guidelines for the management of severe TBI in 2016; however, there remains a lack of randomized clinical trials addressing many aspects of care in TBI patient.
The incidence of early post-traumatic seizures may be as high as 30 percent in patients with severe TBI
Antiseizure medications in acute management of TBI has been shown to reduce incidence of early seizures but has not been shown to prevent later development of epilepsy
Prevention of early seizures is beneficial in order to prevent status epilepticus, further aggravating systemic injury.
The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury, however levetiracetam is commonly used in this setting.

Pharmacology

	Phenytoin	Valproic Acid		Levetiracetam	Lacosamide
Dose	Loading dose: 17 to 20 mg/kg IV (max dose 2 g) Maintenance dose: 100 mg every 8 hours or 5 mg/kg/day divided q8h (individual doses not to exceed 400 mg) Duration not to exceed 7 days		10 – 15 mg/kg/day	Loading dose: 20 mg/kg IV infused over 5-20 min Maintenance dose: 1 g IV over 15 min every 12 hours for 7 days (may be increased to 1.5 g q12)	50 – 100 mg IV twice daily May give loading dose of 200 mg
Administration	IV piggyback rate of ≤50 mg/minute	IV piggyback over 60 minutes at a rate ≤20 mg/minute		IV push or piggyback over 5-20 min	Bolus: May be administered undiluted at ≤80 mg/minute Infusion: over 30 to 60 minutes
PK/PD	Onset: 30 min – 1 hour Half-life:10 to 12 hours.	Peak: <1 hour Half-life:9 to 19 hours		Peak: 5-30 minutes Half-life: 6-8 hours	Peak: < 1 hour Half-life: ~13 hours
Adverse Effects	Hematologic effects, cardiovascular effects, CNS effects, gingival hyperplasia, hepatotoxicity	CNS effects, hematologic effects, hepatotoxicity, encephalopathy, pancreatitis		CNS depression, hypersensitivity reactions, psychiatric and behavioral abnormalities, increased blood pressure, asthenia	Cardiac arrhythmias including bradycardia, AV block, CNS effects
Warnings	Vesicant, acute toxicity	Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma		Caution in renal impairment.	Administer loading doses under medical supervision due to increased incidence of CNS adverse reactions

Guideline Recommendation

Journal	Recommendations
Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition – 2017	Phenytoin is recommended to decrease the incidence of early PTS (within 7 d of injury), when the overall benefit is thought to outweigh the complications associated with treatment. There is insufficient evidence to recommend levetiracetam compared with phenytoin regarding efficacy in preventing early post-traumatic seizures and toxicity.

Overview of Evidence

Author, year	Design/ sample size	Intervention & Comparison	Outcome
Temkin, 1990	A randomized, double-blind study N = 404	Phenytoin vs Placebo	Within the first week 3.6% of phenytoin patients experienced seizure compared to 14.2% (p<0.001) Between day 8-1 year 21.5% of patients in phenytoin group experienced seizure compared to 15.7% in placebo group Phenytoin is effective in reducing seizures within the first 7 days after severe head injury
Young, 2004	Randomized, Double-Blinded, Placebo- Controlled Trial in pediatric patients (age < 16 yo) N = 102	Phenytoin vs Placebo for prevention of early posttraumatic seizures	During the 48-hour observation period, 3 of 46 (7%) patients in the phenytoin group and 3 of 56 (5%) patients in the placebo group experienced a posttraumatic seizure. No significant difference in survival or neurologic outcome between the two groups. Phenytoin did not significantly reduce the rate of posttraumatic seizures at 48 hours, neurologic outcomes, or overall survival at 30 days.
Jones, 2008	Prospective, single-center trial N = 32	Phenytoin vs Levetiracetam in patients with severe TBI (GCS 3-8)	Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556) Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003). Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG
Temkin, 1990	A randomized, double-blind study N = 404	Phenytoin vs Placebo	Within the first week 3.6% of phenytoin patients experienced seizure compared to 14.2% (p<0.001) Between day 8-1 year 21.5% of patients in phenytoin group experienced seizure compared to 15.7% in placebo group Phenytoin is effective in reducing seizures within the first 7 days after severe head injury
Szaflarski, 2009	Prospective, single-center, randomized, single-blinded comparative trial N = 52	Levetiracetam vs Phenytoin in patients with severe traumatic brain injury (sTBI) or subarachnoid hemorrhage	Levetiracetam patients experienced better long-term outcomes than those on phenytoin. No differences between groups in seizure occurrence during cEEG (levetiracetam 5/34 vs. phenytoin 3/18; P = 1.0) or at 6 months (levetiracetam 1/20 vs. phenytoin 0/14; P = 1.0), or mortality (levetiracetam 14/34 vs. phenytoin 4/18; P = 0.227). Lower frequency of worsened neurological status (P = 0.024), and gastrointestinal problems (P = 0.043) in levetiracetam group Levetiracetam improved long-term outcomes of compared to phenytoin with less ADRs and may be an alternative.
Chi-yuan, 2010	Retrospective, cohort study N = 171	Sodium Valproate vs Placebo in early posttraumatic seizures in traumatic brain injury (TBI) patients.	No patients who received sodium valproate treatment experienced seizures; however, this was not statistically significant. Sodium valproate is effective in decreasing the risk of early posttraumatic seizures in severe TBI patients
Inaba, 2012	Prospective, comparative study N = 1,191	Levetiracetam vs Phenytoin for prevention of early post-traumatic seizures	No difference in seizure rate (1.5% vs.1.5%, p = 0.997) No difference between levetiracetam and phenytoin in the prevention of early post traumatic seizures, mortality or ADRs in patients following TBI.
Caballero, 2013	Multicenter retrospective analysis N = 90	Phenytoin vs Levetiracetam in TBI with at least one day of EEG monitoring	Prevalence of EEG-confirmed seizure activity was similar between the levetiracetam and phenytoin groups (28% vs 29%; p = .99). The median daily cost of levetiracetam therapy was $43 compared to $55 for phenytoin therapy and monitoring (p = .08). Levetiracetam may be an alternative treatment option for seizure prevention inTBI patients in the ICU while also providing lower costs for drug therapy and monitoring.
Kruer, 2013	Retrospective observational study N = 109	Phenytoin vs Levetiracetam in patients with a TBI and GCS < 8.	79 out of 81 (98%) patients admitted between 2000 and 2007 received PHT, whereas 18 of 28 (64%) patients admitted between 2008 and 2010 received LEV. 1 patient out of 89 receiving phenytoin had a posttraumatic seizure and 1 patient out of 20 recieving levetiracetam experiences a posttraumatic seizure Only 2 patients experienced posttraumatic seizure after receiving AED, indicating low incidence of posttraumatic seizures.
Gabriel, 2014	Single-center, prospective cohort analysis N = 19	Phenytoin vs Levetiracetam after severe TBI	No difference in Glasgow Outcome Scale–Extended score assessed ≥6 months after injury No difference in early seizures (p = 0.53) or late seizures (p = 0.53) Higher days with fever experienced in the hospital in the phenytoin group. Long-term functional outcome in patients who experienced a TBI was not affected by treatment with PHT or LEV.
Khan, 2016	Randomized controlled trial N = 154	Phenytoin vs Levetiracetam in patients with moderate to severe head trauma	Phenytoin was effective in preventing early post traumatic seizures in 73 of 77 patients (94.8%) Levetiracetam effectively controlled seizures in 70 of 77 patients (90.95%) cases No statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early post-traumatic seizures in moderate to severe traumatic brain injury.

Conclusions

The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury, however levetiracetam is commonly used in this setting.
In recent studies, lacosamide and levetiracetam showed no difference compared to phenytoin in prevention of early post-traumatic seizures following TBI
Less side effects were associated with levetiracetam and lacosamide compared to phenytoin when used in seizure prophylaxis in TBI.

References

Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 17, 2023, from http://www.micromedexsolutions.com/
Carney N, Totten AM, O’Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15. doi:10.1227/NEU.0000000000001432
Frey LC. Epidemiology of Posttraumatic Epilepsy: A critical review. Epilepsia. 2003;44(s10):11-17. doi:10.1046/j.1528-1157.44.s10.4.x
Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 13, 2023, from http://www.micromedexsolutions.com/
Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497-502. doi:10.1056/NEJM199008233230801
Young KD, Okada PJ, Sokolove PE, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Annals of Emergency Medicine. 2004;43(4):435-446. doi:10.1016/j.annemergmed.2003.09.016
Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25(4):E3. doi:10.3171/FOC.2008.25.10.E3
Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response. Epilepsy Behav. 2010;17(4):525-530. doi:10.1016/j.yebeh.2010.02.005
Ma CY, Xue YJ, Li M, Zhang Y, Li GZ. Sodium valproate for prevention of early posttraumatic seizures. Chin J Traumatol. 2010;13(5):293-296.
Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013;74(3):766-773. doi:10.1097/TA.0b013e3182826e84
Caballero GC, Hughes DW, Maxwell PR, Green K, Gamboa CD, Barthol CA. Retrospective analysis of levetiracetam compared to phenytoin for seizure prophylaxis in adults with traumatic brain injury. Hosp Pharm. 2013;48(9):757-761. doi:10.1310/hpj4809-757
Kruer RM, Harris LH, Goodwin H, et al. Changing trends in the use of seizure prophylaxis after traumatic brain injury: A shift from phenytoin to Levetiracetam. Journal of Critical Care. 2013;28(5). doi:10.1016/j.jcrc.2012.11.020
Gabriel WM, Rowe AS. Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after traumatic brain injury. Ann Pharmacother. 2014;48(11):1440-1444. doi:10.1177/1060028014549013
Khan SA, Bhatti SN, Khan AA, et al. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016;28(3):455-460.
Kwon YH, Wang H, Denou E, et al. Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis. Cell Mol Gastroenterol Hepatol. 2019;7(4):709-728. doi:10.1016/j.jcmgh.2019.01.004

Penicillin Allergy Cross Reactivity

Download Handout

Introduction

Only 0.5% to 2% of patients with a documented penicillin allergy that are administered a penicillin will exhibit a hypersensitivity reaction, usually presenting as a rash or hives.
True IgE-mediated penicillin allergies that cause anaphylaxis are rare.
An IgE-mediated penicillin allergy can diminish over time, as 80% of patients become tolerant after a decade.
Patients with a documented penicillin allergy may be inappropriately exposed to alternative antibiotics, resulting in increased treatment failures, adverse effects, and antimicrobial resistance.
Penicillins, cephalosporins, and carbapenems all share a beta-lactam core structure, thus raising the potential for cross-reactivity among these agents.

Pharmacology

The following drugs in each group may have cross-reactivity to each other due to similar side chains
Cross-reactivity between penicillins and cephalosporins is about 2%
Cefazolin is NOT likely to cross react with penicillin (side chains NOT similar)
Cross-reactivity with monobactams (i.e. aztreonam) is negligible
Cross-reactivity between penicillins and carbapenems is <1%

Group 1	Group 2	Group 3	Group 4
Penicillin Cefoxitin Cefuroxime	Amoxicillin Ampicillin Cefaclor Cephalexin Cefadroxil	Ceftriaxone Cefotaxime Cefuroxime Cefepime Cefpodoxime Ceftaroline	Aztreonam Ceftolazane Ceftazidime

Overview of Evidence

Author	Design	Intervention & Comparison		Outcome
Why Cross-Reactivity?
Nagakura, 1990 Mayorga, 1995	Animal study	-Studied antibodies formed when animals were immunized with protein-beta-lactam conjugates	-92% of the antibodies recognized an epitope in which the side chain was the main constituent -The side chain is the most important determinant in penicillin immunogenicity
Cephalosporins
Goodman, 2001	Retrospective review (n=2933)	-Orthopedic patients with penicillin allergy receiving cefazolin prior to a procedure	Only 1 patient may have had an allergic reaction to cefazolinCross-reactivity rate with cefazolin was 0.33%
Daulat, 2004	Retrospective review (n=606)	-Patients with penicillin allergy receiving cephalosporins -42% 1st gen., 21% 2nd gen., and 37% 3rd or 4th gen. cephalosporins	Only 1 patient had an allergic reaction that was documented as worsening of underlying eczema after being placed on cefazolinCross-reactivity was 0.17%
Apter, 2006	Retrospective review (n=3920)	-Patients with a prescription for penicillin followed by a prescription for a cephalosporin -Identified allergic-like events within 30 days after each prescription	Only 43 patients who experienced an allergic- like reaction after both penicillin and cephalosporinCross-reactivity rate was 1.1%70% of these patients just had urticariaThe risk of anaphylaxis to cephalosporins was only 0.001%
Romano, 2018	Prospective review (n=252)	Prospective study of 252 subjects with IgE-mediated hypersensitivity to penicillins – Serum specific IgE assays for cefaclor and skin tests for 10 cephalosporins -Oral challenges with cefuroxime axetil, ceftriaxone, cefaclor, and cefadroxil for subjects with negative skin tests	99 subjects (39.3%) had positive allergy tests for cephalosporins 95 subjects (37.7%) were positive to aminocephalosporins and/or cefamandole, which share side chains with penicillins All 244 subjects who underwent challenges with cefuroxime axetil and ceftriaxone tolerated them 7 subjects reacted to cefaclor or cefadroxil
Carbapenems
Romano, 2006	Prospective study (n=112)	-Skin tested to penicillins and then skin tested to imipenem -If skin test to imipenem was negative, then challenged with IM dose	Only 1 patient of the penicillin skin-test positive patients had a positive skin test to imipenemCross-reactivity rate was 0.9%None of the 110 patients with a negative imipenem skin test that underwent IM challenge had a reaction
Romano, 2007	Prospective study (n=104)	-Skin tested to penicillins and then skin tested to meropenem -If skin test to imipenem was negative, then challenged with IV dose	Only 1 patient of the penicillin skin-test positive patients had a positive skin test to meropenemCross-reactivity rate was 1%All 103 patients with a negative meropenem skin test tolerated the IV challenge
Atanaskovic- Markovic, 2008	Prospective study (n=108)	-Children with penicillin allergy were skin tested to penicillin and meropenem -If skin test to meropenem was negative, then challenged with IV dose	Only 1 patient with a positive penicillin test reacted to the meropenem skin testCross-reactivity rate was 0.9%All 107 patients with a negative meropenem skin test tolerated the IV challenge
Sánchez de Vicente, 2020	Prospective study (n=137)	Tolerance testing for cephalosporins and carbapenems in patients with confirmed penicillin allergy	0/46 patients showed positive skin tests for imipenem. 0.79% (1/137) patients showed a positive skin test for cefuroxime.0.79% (1/137) patients showed a positive skin test for ceftriaxone.

Conclusions

True penicillin allergies are less common than reported, and anaphylaxis is uncommon.
Cross-reactivity among penicillins and cephalosporins is attributed to similarity in side chains.
Cephalosporin cross-reactivity with penicillins is much lower than reported in early studies partly due to contamination of study drugs with penicillin.
Cross-reactivity between cephalosporins is about 2% and with carbapenems is <1%

References

Apter AJ, Kinman JL, Bilker WB, et al. Is There Cross-Reactivity Between Penicillins and Cephalosporins? Am J Med. 2006;119(4):354e11-19.
Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B, Romano A. Tolerability of Meropenem in Children with IgE-Mediated Hypersensitivity to Penicillins. Allergy. 2008;63:237-240.
Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing Inpatient Beta-Lactam Allergies: A Multihospital Implementation. J Allergy Clin Immunol Pract. 2017;5(3):616-625.
Blumenthal KG, Huebner EM, Fu X, et al. Risk-Based Pathway for Outpatient Penicillin Allergy Evaluations. J Allergy Clin Immunol Pract. 2019;7(7):2411-2414.
Campagna JD, Bond MC, Schabelman E, Hayes BD. The Use of Cephalosporins in Penicillin-Allergic Patients: A Literature Review. J Emerg Med. 2012;42(5):612-620.
Chaudry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and Beta-Lactam Cross-Reactivity. Pharmacy. 2019;7:1-16.
Daulat S, Solensky R, Earl HS, Casey W, Gruchalla RS. Safety of Cephalosporin Administration to Patients with Hstories of Penicillin Allergy. J Allergy Clin Immunol Pract. 2004;113(6):1220-1222.
DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin Use in Treatment of Patients with Penicillin Allergies. J Am Pharm Assoc. 2008;48:530-540.
Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be Given to Penicillin-Allergic Patients Who Do Not Exhibit an Anaphylactic Response. J Clin Anesth. 2001;13(8):561-564.
Mayorga C, Obispo T, Jimeno L, et al. Epitope Mapping of Beta-Lactam Antibiotics with the Use of Monoclonal Antibodies. Toxicology. 1995;97:225-234.
Nagakura N, Souma S, Shimizu T, Yanagihara Y. Anti-Ampicillin Monoclonal Antibodies and their Cross- Reactivities to Various Beta-Lactams. Br J Hosp Med. 1990;44:252-258.
Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Pettinato R, Gueant JL. Imipenem in Patients with Immediate Hypersensitivity to Penicillins. N Engl J Med. 2006;354:2835-2837.
Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Valluzzi R, Gueant JL. Brief Communication: Tolerability of Meropenem in Patients with IgE-Mediated Hypersensitivity to Penicillins. Ann Intern Med. 2007;146:266-269.
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-199.
Sánchez de Vicente J, Gamboa P, García-Lirio E, Irazabal B, Jáuregui I, Martínez MD, Segurola A, Seras Y, Galán C. Tolerance to Cephalosporins and Carbapenems in Penicillin-Allergic Patients. J Investig Allergol Clin Immunol. 2020;30(1):75-76. doi: 10.18176/jiaci.0463. Epub 2019 Nov 4. PMID: 31680067.
Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1662-1672. doi: 10.1016/j.jaip.2018.01.020. Epub 2018 Feb 3. PMID: 29408440.

Corticosteroids in Sepsis by Marissa Marks, PharmD

Download PDF

Introduction

Sepsis is a systemic inflammatory response (SIRS) with associated organ dysfunction as a result of an infection.
Sepsis is defined as ≥2 of the criteria:
1. Temperature >38 ºC or <36 ºC
1. Heart rate of >90 bpm
1. Respiratory rate of >20 breaths/minute or pCO2 of <32 mmHg
1. WBC >12,000 cells/mL or <4000 cells/mL
Initial management of sepsis includes:
1. Intravenous fluids (LR/NS) 30 mL/kg (based on total body weight) administered within the first 3 hours.
1. Empiric antibiotic therapy based on the common bacteria and site of infection initiated within the first hour.
Per the Surviving Sepsis guidelines, IV hydrocortisone is recommended for patients at least 4 hours after initiation of norepinephrine/epinephrine ≥0.25 mcg/kg/min to maintain a MAP of ≥65 mmHg.

Pharmacology

	Hydrocortisone	Methylprednisolone	Fludrocortisone
Dose	IV: 50 mg Q6H or 100 mg Q8H x 5-7 days	IV (succinate): 40 to 125 mg/day (maximum of 1 to 2 mg/kg/day)	PO (in addition to another glucocorticoid): 0.05 mg/day x 7 days
Administration	IV: over ≥30 seconds	IV: over several minutes or over 15 to 60 minutes as an infusion	Administer by NG tube
PK/PD	-Onset of action (IV): 1 hour -T ½ elimination (IV): 2 +/- 0.3 hours	-Onset of action (IV): 1 hour -T ½ elimination (IV): 0.25 +/- 0.1 hour	-Onset of action (PO): 1-2 hours -T ½ elimination (PO): ~3.5 hours
Mechanism of Action	-Anti-inflammatory (decreased synthesis and release of inflammatory mediators) -Immunosuppressive (decreased response to hypersensitivity reactions) -Antiproliferative: vasoconstriction and decreased permeability of WBC to the injury	-Same mechanism of action as hydrocortisone with a 4-5x greater potency	– Mineralocorticoid activity > hydrocortisone or methylprednisolone
Adverse Effects	-Cardiovascular: increased blood pressure -Endocrine: fluid retention, hyperglycemia, weight gain -Gastrointestinal: increased appetite -Psychiatric: altered behavior	-Similar adverse effects as hydrocortisone	-Higher risk of fluid retention, hypertension, and decreased electrolyte concentrations
Drug Interactions and warnings	–Warnings: adrenal suppression, immunosuppression (higher doses for increased duration of therapy), psychiatric changes -Drug Interactions: antacids (separate by 2 hours), live vaccinations, DDAVP (risk of hyponatremia), succinylcholine	-Warnings: adrenal suppression, acute hepatitis (rare) -Drug Interactions: similar to hydrocortisone and fludrocortisone	-Warnings: patients with underlying hepatic dysfunction, myasthenia gravis, systemic sclerosis, or thyroid disease -Drug Interactions: similar to hydrocortisone and methylprednisolone
Compatibility	Drug in Solution: None tested	Drug in Solution: -Compatible: D5W- ½ NS, NS -Incompatible: D5W, D5NS, LR	N/A

Overview of Evidence

Author, year	Design/ sample size	Intervention & Comparison	Outcome
French Trial Annane D, 2002.	RCT (n = 300)	hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.	7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.
Teng-Jen Yu, 2009.	RCT (n = 40)	Hydrocortisone 50 mg IV Q6H or methylprednisolone 20 mg Q12H x 7 days	-Higher survival rates with hydrocortisone vs methylprednisolone
VANISH Gordan, 2016	RCT (n = 1400)	Vasopressin vs. norepinephrine plus hydrocortisone vs. placebo	No significant difference in mortality at 28 days, but vasopressin plus hydrocortisone was associated with faster reversal of shock and reduced need for renal replacement therapy
Gibbison B, 2017.	Systematic review & meta-analysis (n = 33 clinical trials)	Systemic treatment with any corticosteroids	-Decreased septic shock reversal with methylprednisolone vs hydrocortisone -Increased 28-day mortality with methylprednisolone vs dexamethasone -Decreased risk of superinfections with methylprednisolone –Decreased ICU mortality and LOS with methylprednisolone
CORTICUS Sprung, 2018	RCT, (n=499)	Hydrocortisone 50 mg every 6 hours vs. placebo	The study found no significant difference between the two groups in 28-day mortality, but hydrocortisone was associated with a higher rate of shock reversal and a lower rate of progression to multiple organ dysfunction syndrome.
HYPRESS Key, 2018	RCT (n = 380)	Infusion of hydrocortisone 200 mg daily for five days followed by tapering until day 11 vs placebo	The study found no significant difference between the two groups in the primary outcome of time alive and free of vasopressor support by day 7 The study also found no significant difference between the two groups in secondary outcomes such as mortality at 28 days, ICU-free days, and hospital-free days
ADRENAL Venkatesh B, 2018.	RCT (n = 3800)	Hydrocortisone 200 mg IV daily	-No difference in 28 or 90-day mortality with hydrocortisone –Decreased time to resolution of septic shock and discharge from the ICU with hydrocortisone -Decreased number of patients received a blood transfusion with hydrocortisone -Higher number of adverse events with hydrocortisone
APROCCHHSAnnane D, 2018.	RCT (n = 1280)	-Hydrocortisone 50 mg IV Q6H + fludrocortisone 50 mcg PO daily in AM x 7 days -Drotrecogin alfa -Combination therapy of the three medications	–Decreased 90-day mortality with hydrocortisone + fludrocortisone -Decreased mortality with hydrocortisone + fludrocortisone at ICU and hospital discharge -Decreased time to discontinue vasopressor therapy and mechanical ventilation and achieve a SOFA score of <6 with hydrocortisone + fludrocortisone

Conclusions

Per the Surviving Sepsis guidelines, hydrocortisone is recommended first-line for the treatment of septic shock in patients that are refractory to fluid (volume) resuscitation.
Hydrocortisone portrayed greater efficacy in clinical trials than methylprednisolone.
There are no clinical trials for the comparison of hydrocortisone monotherapy versus hydrocortisone + fludrocortisone; however, it is hypothesized that hydrocortisone provides sufficient mineralocorticoid activity as monotherapy without the increased risks of adverse effects with the addition of fludrocortisone.
- Necessary to avoid fludrocortisone in specific patient populations (i.e. congestive heart failure, hepatic and renal disease, etc.)

References

Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, Lehmann B, Millul V, Maxime V, Bellissant E; APROCCHSS Investigators for the TRIGGERSEP Network. Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial. Ann Intensive Care. 2016 Dec;6(1):43.
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, François B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohé J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818.
Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247.
Gibbison B, López-López JA, Higgins JP, Miller T, Angelini GD, Lightman SL, Annane D. Corticosteroids in septic shock: a systematic review and network meta-analysis. Crit Care. 2017 Mar 28;21(1):78.
Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016 Jun 30;2:16045.
Hydrocortisone (2023) UpToDate. Available at: https://www.uptodate.com (Accessed: 13 August 2023).
Hydrocortisone Sodium Succinate (2023) Micromedex. Available at: https://www.micromedexsolutions.com (Accessed: 13 August 2023).
Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808.
Yu TJ, Liu YC, Yu CC, Tseng JC, Hua CC, Wu HP. Comparing hydrocortisone and methylprednisolone in patients with septic shock. Adv Ther. 2009 Jul;26(7):728-35.
Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn SO, Hüter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schädler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM; SepNet–Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. doi: 10.1001/jama.2016.14799. PMID: 27695824.
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. PMID: 18184957.
Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485. PMID: 27483065.

Etomidate for RSI: Seizure Considerations

Download PDF

Introduction

Rapid sequence intubation (RSI) is a process whereby an induction agent and a neuromuscular blocking agent are given in rapid succession to facilitate endotracheal intubation
The selection of a specific sedative depends on multiple factors: the clinical scenario, which includes patient factors (includes cardiorespiratory and neurologic status, allergies, comorbidity) and the clinician’s experience/training and institutional factors, as well as the characteristics of the sedative
Etomidate remains the most commonly used induction agent; however, it is not without its own pharmacologic considerations such the decrease in seizure threshold.

Pharmacology

Dose	0.3 mg/kg IV
Administration	IV push
Formulation*	20 mg/ 10 ml 40 mg/ 20ml
PK/PD	Onset: ~20 seconds Duration: 4-10 minutes Metabolism: Hydrolysis of the ethylester side Renal Excretion: 75%
Adverse Effects	Injection site pain, nausea, vomiting, myoclonus
Drug Interactions	No major reactions
Compatibility	Incompatible with vitamin c and vecuronium
Comments	There is hypothetical concerns about adrenal insufficiency with a single dose. Hemodynamically neutral

*Various formulations may appear, check you institution formulary

Drug	Hemodynamic Effect	Comments
Etomidate	↔ BP, ↔ CO, ↔ HR, ↓ cortisol , ↔ ICP	Prolonged inhibition of steroid synthesis in the critically ill; withdrawn from number of countries
Ketamine	↑BP, ↑ HR, ↑ CO, ↔ cortisol, ↑↓ ICP	↔ or ↑ CPP and ↔ ICP with standard anesthetic management
Propofol	↓ BP, ↔ HR,↓ CO, ↔ cortisol, ↓ ICP	Hemodynamic compromise marked in elderly, ASA 3 or more or hypovolemic patients with ‘standard’ induction dose

Overview of Evidence

Author, year	Design/ sample size	Intervention & Comparison	Outcome
Perier et al,2018	Retrospective N=97	Etomidate vs sodium thiopental for RSI in patients with convulsive status epilepticus	• Seizure and/or status epilepticus recurred in 13 (56%) patients in the etomidate group and 11 patients (44%) in the sodium thiopental group
Gabor,2006	Retrospective N=30	1 mg/kg of propofol or 0.2 mg/kg of etomidate for electroconvulsive therapy	• After etomidate induction, seizure durations registered either by EEG or by EMG were longer than propofol treated cases.
Zuckerbraun et al, 2006	Retrospective N=101	Etomidate for RSI in general population	• There was no relationship between seizures after etomidate administration and prior seizure history (p = 0.25).
Guldner,2003	Retrospective N=105	Etomidate for RSI in general population	• Complications included three patients who vomited within 10 minutes of etomidate administration. There were no cases of documented myoclonus, status epilepticus, or new-onset seizures.
Reddy,1993	Prospective randomized study N=68	Etomidate, thiopental, methohexital or propofol for anesthesia induction	Spontanous movement (myoclonic, dystonic or tremor): Etomidate 86%, thiopental 16.6%, methohexital 12.5%, propofol 5.5% EEG activity: 2 patients receiving etomidate, no generalized epileptiform activity noted
Ebrahim, 1986	Case reports N=12	etomidate for anesthesia induction in patient with intractable seizures	Electroencephalograms were recorded by means of subdural electrodes. Nine of the 12 patients showed an increase in epileptiform activity. In six of the nine patients, the activity was marked.
Krieger,1985	Letter to editor N=55	Etomidate for anesthesia induction or to activate seizure focus	25 patients had epilptiform activity associated with etomidate administration 6/30 patients had generalized epileptiform activity noted on EEG
Grant,1983	Case series N=4	Etomidate infusion for sedation in ICU	Generalized and focal seizures after variable periods of etomidate o EEGs were not evaluated at the time of suspected seizure activity. Patients were on infusion for 6-28 hours at onset of seizure activity.
Ghonrim,1977	Prospective randomized study N=120	Etomidate or thiopental for anesthesia induction	28% etomidate vs. 0% thiopental had myoclonic movements 11% etomidate vs. 1% thiopental had tonic movements No epileptiform discharges were noted in 10 patients who had EEG monitoring

Conclusion

Etomidate is a commonly used induction agent for RSI in emergency settings. Etomidate has been shown to elicit myoclonus in a significant number of patients. However, whether myoclonus is associated with EEG confirmed epileptiform activities remains uncertain. To make matters worse, depending on the origin and type of seizure, it may be challenging for EEG to differentiate between non-seizure and seizure activity during myoclonic events.
Due to the low level of evidence, the patients with a history of seizures should have the risk versus benefit assessment to determine the best induction agent.

References

Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 6, 2021, from http://www.micromedexsolutions.com/
Perier F. Seizure. 2018 Oct;61:170-176. PMID: 30176574.
Zuckerbraun NS. Acad Emerg Med. 2006 Jun;13(6):602-9. PMID: 16636355.
Grant IS, et al. Epileptiform seizures during prolonged etomidate sedation. Lancet 1983; 322(8348):511-2.
Guldner G, et al.. Acad Emerg Med 2003; 10:134—139.
Reddy RV, et al.. Anesth Analg 1993; 77:1008-11.
Ebrahim ZY, et al. . Anesth Analg 1986; 65:1004-6.
Krieger W, et al K. Seizures with etomidate anesthesia [letter]. Anesthesiol Analg. 1985; 64:1226–7.
Ghoneim MM, Anesth Analg 1977; 56:479-85.
Gabor G. Neuropsychopharmacol Hung 2007; 9(3):125-30.

Ketamine for Treatment of Acute Agitation

Download PDF

Introduction

Ketamine is a sedative used for patients with extreme/refractory undifferentiated agitation
Indications for utilizing ketamine for emergent sedation of agitated patients include
- Patient poses and immediate threat to patient and healthcare provider safety (RASS +4)
- Failure and/or futility of alternative non-pharmacologic de-escalation strategies
- Absence of IV access
- Not a candidate for intramuscular antipsychotics and/or benzodiazepines due to onset of action

Pharmacology

Properties	Rapid acting general anesthetic producing cataleptic-like state due to antagonism of N-methyl-Daspartate (NMDA) receptors in the central nervous system. • Ketamine also has significant analgesic/dissociative properties at lower doses
Dose	2-5 mg/kg IM to a max single dose of 500mg 1-2 mg/kg IV
Administration	IM: Inject deep IM into large muscle (glute or vastus lateralis muscle) IV: Administer over at least 60 seconds
Formulation	10 mg/mL, 50 mg/mL, 100 mg/mL *must use 100 mg/mL for IM administration to reduce volume
PK/PD (for amnestic effects)	Onset: 3-5 mins IM; <1 minutes IV Duration: 15-25 mins IM; 5-10 minutes IV Bioavailability: 93% IM Metabolism: Extensively through hematic N-demethylation Elimination: Greater than 90% urine, <5% feces
Adverse Effects	Hypertension Tachycardia Hypersalivation Nausea and vomiting Laryngospasm Emergence phenomenon during recovery phase Increased muscle function (hyperactivity, twitching, rigidity)
Contraindications	• Significant hypertension may be hazardous, ACS, ADHF, and unstable dysrhythmia
Warnings and Considerations	Rapid IV administration may increase risk of respiratory depression/apnea Verify concentration of formulation Caution in diagnosed schizophrenia Hypotension in catecholamine depleted states Pregnancy and lactation (crosses placenta)

Overview of Evidence

Author, year	Design (sample size)	Intervention & Comparison	Outcome
Lin et al., 2020	Prospective, randomized, pilot (n=93)	Ketamine 4 mg/kg IM or 1 mg/kg IV Haloperidol 5-10 mg IM/IV + lorazepam 1-2 mg IM/IV	Ketamine achieved greater sedation within 5 and 15 minutes (22% vs 0% at 5 mins; 66% vs 7% at 15 mins)
Mankowitz et al., 2018	Systematic review (n=650)	Ketamine IV or IM	Mean time to sedation was 7.21min and effective in 68.5% of patients 30.5% of patients required intubation, but not all secondary to ketamine administration
Cole et al., 2016	Prehospital prospective, observational (n=146)	Haloperidol 10 mg IM Ketamine 5 mg/kg IM	Median time to adequate sedation was faster with ketamine (5 min) vs haloperidol (17 min) • Intubation rates were higher with ketamine (39%) than haloperidol (4%), as well as more complications (49% vs 5%, respectively) 38% hypersalivation in ketamine group
Isbister et al., 2016	Subgroup analysis from DORM II study; prospective, observational (n=49)	Ketamine as rescue treatment after Droperidol alone Droperidol + DZP or MDZ Midazolam alone	Median time to sedation post-ketamine was 20 minutes (IQR 10-30) 3 patients had adverse reactions after ketamine (vomiting n=2; desaturation n=1)
Riddell et al., 2016	Prospective, observational (n=106)	Ketamine Lorazepam, midazolam, haloperidol, or benzodiazepine + haloperidol	Ketamine resulted in a greater number of patients with no agitation at 5 minutes than other medications
Scheppke et al., 2014	Retrospective chart review (n=52)	Ketamine ~4mg/kg IM *Recommended midazolam 2-2.5 mg IM or IV following ketamine for emergence reaction	96% of patients obtained sedation, mean time to sedation was 2 minutes 3 patients experienced significant respiratory depression About ½ of patients received midazolam

Trials in Progress

Barbic et al., Completed March 2020, results pending

Parallel, prospective, randomized, controlled

Ketamine 5mg/kg IM Midazolam 5mg IM + haloperidol 5mg IM

Primary: Time to adequate sedation Secondary: safety and tolerability, requirement of rescue medication

DZP= Diazepam; MDZ= Midazolam

Conclusions

Ketamine has been shown to be effective with a quick time to sedation but is not without risks, including respiratory depression
Used ketamine with caution in patients who have an underlying psychiatric disorder
Ketamine should be reserved for specific patient populations and as last line for patient/provider safety

References

Ketamine. Micromedex [Electronic version].
Barbic D, et al. Trials. 2018;19(1):651. Published 2018 Nov 26.
Lin M, et al. Am J Emerg Med. 2020. https://doi.org/10.1016/doi:10.1186/s13063-018-2992-x j.ajem.2020.04.013.
Mankowitz WL, et al. J Emerg Med. 2018;55(5):670-81.
Cole JB, et al. Clin Toxicol (Phila). 2016;54(7):556–562.
Isbister GK, et al. Ann Emerg Med. 2016;67(5):581–587.
Riddell J, et al. Am J Emerg Med. 2017. http://dx.doi.org/10.1016/j.ajem.2017.02.026
Scheppke KA, et al. WestJEM. 2014;15(7);736-41.

PPIs for the Management of Upper GI Bleed

Download PDF

Introduction

Upper GI bleed (UGIB) is a common reason for ED visits with a major cause of morbidity, mortality and medical care costs.
Peptic ulcer accounts for at least 50% of UGIB cases.
Patients with UGIB usually present with hematemesis, melena and/or hematochezia.
Upon presentation, hemodynamic status should be evaluated and resuscitation provided if necessary. Resuscitation can include blood transfusion for target hemoglobin of ≥7 g/dl.
Patients can be risk stratified to low or high-risk using the Rockall score (range 0-7) and Blatchford score (range 0-23).
Proton pump inhibitors (PPIs) remain one of the mainstays of pharmacological therapy for the management of UGIB. It can be initiated if endoscopy cannot be performed, will be delayed for >24 after presentation or following endoscopy.

	Pantoprazole	Esomeprazole	Omeprazole
Dose	Initial Infusion: 80mg bolus then 8mg/hr continuous infusion for a total of 72hours Intermittent: 80mg LD then 40mg IVP Q12H Maintenance High-risk: 40mg PO BID for 14days, then 40mg PO once daily Low-risk: 20mg PO once daily *Duration ranges from 4-12weeks	Initial Infusion: 80mg bolus then 8mg/hr continuous infusion for a total of 72hours Intermittent: 80mg LD then 40mg IVP Q12H Maintenance High-risk: 40mg PO BID for 14days, then 40mg PO once daily Low-risk: 20mg PO once daily *Duration ranges from 4-12weeks	Initial IV Omeprazole not available in the U.S, give IV Pantoprazole or Esomeprazole Maintenance High-risk: 40mg PO BID for 14days, then 40mg PO once daily Low-risk: 20mg PO once daily *Duration ranges from 4-12weeks
Administration	IVP: Give over at least 2 minutes Continuous Infusion: 8mg/hr PO: Swallow whole without crushing or splitting 30-60minutes before food	IVP: Give over at least 3 minutes for dose <80 mg; Loading dose over 30 minutes Continuous Infusion: 8mg/hr PO: Capsule can be given orally or opened and mixed with 50mL water for NG administration	PO: Swallow whole without crushing or splitting 30-60minutes before food
PK/PD	Onset: IV 15 to 30 minutes, PO 2.5hrs Absorption: Rapid, well absorbed Duration: 24hours (IV and PO) Distribution: 98% albumin bound Half-life elimination: 1hr, 3.5-10hrs in CYP2C19 deficiency Excretion: Urine (71%), feces (18%)	Distribution: 97% protein bound Metabolism: Hepatic primarily via CYP2C19 Half-life elimination: 1 to 1.5hrs in adults Excretion: Urine (80%), 20% feces	Onset: PO 1hr Absorption: Rapid Duration: Up to 72hours Distribution: 95% albumin bound Half-life elimination: 30min – 1hr, 3 hrs in hepatic impairment Excretion: Urine (77%)
Adverse Effects	Headache, nausea, abdominal pain, diarrhea, vomiting	Headache, flatulence, nausea, dyspepsia, abdominal pain, diarrhea	Headache, abdominal pain, nausea, diarrhea, vomiting, flatulence
Drug Interactions & Warnings	Contraindicated with Atazanavir, Rilpivirine and their combinations	Contraindicated with Atazanavir, Rilpivirine and their combinations, CYP2C19 Inducers	Contraindicated with Atazanavir, Rilpivirine and their combinations, CYP2C19 Inducers
Compatibility	Compatible with D5W, NS or LR	Compatible with D5W, NS or LR	Not Applicable

Comments: PPIs may increase the risk of Clostridium difficile associated diarrhea – use lowest dose and shortest duration where possible

Overview of Evidence

Author, year	Design & Sample Size	Intervention & Comparison	Outcomes
Daneshmend et al., 1992	Double-blind, placebo- controlled, parallel study (n=1147)	Omeprazole 80mg IV bolus followed by 40mg IV every 8hr x3, then 40mg PO twice daily vs placebo Treatment started within 12h of admission, continued for 4 days or until surgery, discharge or death	No significant differences between placebo and omeprazole for blood transfusions (53% v 52%), rebleeding (18% v 15%), surgery (11% v 11%) and death (5.3% v 6.9%) Significant reduction in signs of UGIB observed during endoscopy with omeprazole (33%) vs placebo (45%); p < 0.0001
Andriulli et al., 2008	Randomized, multicenter double-blind study (n=474)	PPI Continuous (80mg bolus followed by 8mg/hr infusion for 72hr) PPI Intermittent (40mg IV bolus daily for 72hr) Switched to oral PPI (20 mg twice daily) after 72hr and continued until discharge Used Pantoprazole and Omeprazole	Bleeding recurred in 11.8% continuous regimen vs 8.1% in the intermittent regimen; P = 0.18 7.6% vs 8.1% rebleeding during first 72hr in the continuous vs intermittent group; P = 0.32 Patients in the continuous group had a prolonged hospital stay > 5 days (P = 0.03)
Sung et al., 2009	Randomized, multicenter double-blind study (n=764)	Esomeprazole 80mg IV bolus followed by 8mg/hr Placebo, continued for 72hr after endoscopic hemostasis o Both groups received esomeprazole PO 40mg daily for 27days after infusion	Esomeprazole had less recurrent bleeding within 72hr compared to placebo (5.9% vs 10.3%). Findings remained significant at day 7 and day 30; p = 0.010 Esomeprazole decreased endoscopic re-treatment (6.4% vs 11.6%), need for surgery (2.7% vs 5.4%) and mortality (0.8% vs 2.1%)
Sreedharan et al., 2010	Systematic review and meta-analysis (6RCTs, n=2223)	Active treatment with a PPI (oral or IV) and control with either placebo, histamine-2 receptor antagonist or no treatment before endoscopy	PPI before endoscopy did not decrease mortality (OR 1.12 95% CI 0.72-1.73), rebleeding (OR 0.81, 95% CI 0.61- 1.09) or the need for surgery (OR 0.96, 95% CI 0.68-1.35) PPIs significantly decreased the number of patients with stigmata of recent hemorrhage at endoscopy PPIs compared to control significantly reduced endoscopic intervention
Chen et al., 2012	Prospective, randomized control trial (n=201)	Pantoprazole 80mg IV bolus then 8mg/hr Pantoprazole 40mg IV bolus once daily for 72hr o Both groups received pantoprazole 40mg daily PO for 27days after 72hr	No statistical differences in units of blood transfused, length of hospital stay, surgical/radiological interventions and mortality within 30 days High-dose PPI regimen was not superior in the reduction of recurrent bleeding at 30 days as compared with a standard-dose regimen
Sachar et al., 2014	Systematic review and meta-analysis (13RCTs)	Intermittent doses of PPIs (IV or PO) 80mg IV bolus followed by 8mg/hr for 72hours	Intermittent PPI regimens were comparable and are non-inferior to continuous PPI infusion regimens in patients with bleeding ulcers and high-risk endoscopic findings. There is no difference in recurrent bleeding with intermittent vs continuous PPI therapy
Rattanasupar et al., 2016	Prospective, randomized control trial (n=113)	Pantoprazole 80mg IV bolus then 8mg/hr Pantoprazole 40mg IV twice daily	No difference in average time of hospital stay (3.03 vs 2.89 days, p>0.05) and mean amount of blood transfused (1.79 vs 1.63 units, p>0.05) between continuous and intermittent pantoprazole No statistically significant difference in terms of recurrent bleeding and mortality between both groups (p>0.05) Blatchford score greater than 10, 11, and 12 showed high sensitivity of predicting high-risk peptic ulcer bleeding

Conclusions

Compared to placebo or other non-PPI treatment measures, evidence suggests PPI therapy did not reduce the need for blood transfusion, rebleeding rate, surgery or death.
Compared to placebo, PPIs reduced the signs of upper gastrointestinal bleeding observed during endoscopy and reduced the need for endoscopic treatment.
Administration of a PPI as continuous infusion did not impact patient outcomes and is not superior to intermittent therapy; however, high dose PPI may be considered in patients with Blatchford scores greater than 12.

References

Clinical Pharmacology [Electronic version]. Elsevier, 302 Knights Run Ave., Suite 800, Tampa, FL 33602. Retrieved February 17, 2021, from http://www.clinicalpharmacology-ip.com/
Uptodate [Electronic version]. Retrieved February 15, 2021, from http://www.uptodate.com/
Laine, Loren MD; Jensen, Dennis M MD. Management of Patients With Ulcer Bleeding, American Journal of Gastroenterology: March 2012 – Volume 107 – Issue 3 – p 345-360
Daneshmend, T. K., Hawkey, C. J., Langman, M. J., Logan, R. F., Long, R. G., & Walt, R. P. (1992). Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ (Clinical research ed.), 304(6820), 143–147.
Andriulli, A., Loperfido, S., Focareta, R., Leo, P., Fornari, F., Garripoli, A., Tonti, P., Peyre, S., Spadaccini, A., Marmo, R., Merla, A., Caroli, A., Forte, G. B., Belmonte, A., Aragona, G., Imperiali, G., Forte, F., Monica, F., Caruso, N., & Perri, F. (2008). High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. The American journal of gastroenterology, 103(12), 3011–3018.
Sung JJ, Barkun A, Kuipers EJ, et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2009; 150(7):455-464.
Sreedharan, A., Martin, J., Leontiadis, G. I., Dorward, S., Howden, C. W., Forman, D., & Moayyedi, P. (2010). Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. The Cochrane database of systematic reviews, 2010(7), CD005415.
Chen CC, Lee JY, Fang YJ, et al. Randomised clinical trial: high-dose vs. standard-dose proton pump inhibitors for the prevention of recurrent haemorrhage after combined endoscopic haemostasis of bleeding peptic ulcers. Aliment Pharmacol Ther. 2012; 35(8):894-903.
Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014; 174(11):1755-1762.
Rattanasupar A, Sengmanee S. Comparison of High Dose and Standard Dose Proton Pump Inhibitor before Endoscopy in Patients with Non-Portal Hypertension Bleeding. J Med Assoc Thai. 2016; 99(9):988-995.

Single-Dose Aminoglycosides for UTIs

Introduction

UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus spp., Klebsiella spp., etc.) and other Gram-negative organisms.
UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus spp., Klebsiella spp., etc.) and other Gram-negative organisms.

UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus spp., Klebsiella spp., etc.) and other Gram-negative organisms.
UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus spp., Klebsiella spp., etc.) and other Gram-negative organisms.
Barriers to traditional oral antibiotic therapy include increasing bacterial resistance, nonadherence rates approaching 60%, and medication access issues.

Pharmacology

Rationale: Excellent activity against most uropathogens, including drug-resistant EnterobacteriaceaeEliminated as active drug almost exclusively by the kidneys with concentrations 100-fold greater in the urine than plasma

✓Post-antibiotic effect of aminoglycosides may persist for up to 72 hoursToxicities may be limited with one-time administration

✓Prevents medication access & adherence concerns

Dosing

	Gentamicin	Amikacin	Tobramycin
Dosing	5 mg/kg IV/IM once	15 mg/kg IV/IM once	5 mg/kg IV/IM once

Underweight [TBW<IBW]: use TBW
Nonobese [TBW 1x to 1.25x IBW]: use IBW or TBW
Obese [TBW >1.25x IBW]: use adjusted body weight

Administration

Pharmacokinetics/ Pharmacodynamics

Adverse Effects

Nephrotoxicity
Ototoxicity

Considerations

Caution in renal impairment
Large volume for IM administration

*Definitions

Uncomplicated – non-pregnant women with no known anatomical and functional abnormalities of the urinary tract or comorbidities
Complicated – all men, pregnant women, anatomical or functional abnormalities of the urinary tract, indwelling urinary catheters, renal diseases, and/or other immunocompromising diseases such as diabetes
Cystitis – infection confined to the bladder; symptoms of increased urinary urgency, frequency & dysuria
Pyelonephritis – infection extends beyond the bladder; cystitis symptoms + fever, chills, flank & pelvic pain

Overview of Evidence

Study	Goodlet et al. 2018
Design	Systematic review (n=13,804 patients across 13 studies published from 1978 to 1991)
Included Studies	-Single-dose aminoglycoside with no concomitant antibiotic therapy -Average patient: pediatric female with acute uncomplicated cystitis secondary to E.coli with normal renal function treated in the outpatient setting -7 studies with a comparator arm: –Single dose oral fosfomycin –Oral trimethoprim-sulfamethoxazole, amoxicillin, or cephalosporin x 5-10 days *-72% of isolates were E. coli* -Netilmicin was the most commonly used aminoglycoside, followed by amikacin and gentamicin
Outcomes	*-Overall microbiologic cure rate of 94.5% ± 4.3%* No differences between pediatric- and adult-only studies No differences between aminoglycosides ad comparator arms Patients with anatomical abnormalities were less likely to have initial microbiologic cure *-Overall 19% (84/443) 30-day recurrence rate* in studies that had minimum 30-day follow-up *-Only 0.5% (64/13,804) reported adverse effects*, mainly due to vestibular toxicity (53 patients) and nephrotoxicity (7 patients)
Limitations	*-Majority of patients (13,258/13,804) were from one study* *-Generalizability is questionable* 8 studies (pediatric only) & 3 studies (adults only) Only 1 study included patients with moderate or severe renal impairment (10/44 patients) Only 2 studies included patients with pyelonephritis No cases of sepsis or bacteremia were reported -Older studies Did not study against modern uropathogens Did not compare to commonly used agents, such as nitrofurantoin or IV ceftriaxone -Did not assess for future uropathogen resistance -Symptom data was not reported Patients could have been treated for asymptomatic bacteriuria Lack of assessment of clinical cure rate for majority of studies -No studies were blinded -Unknown drug dosing of comparator arms

The

Bottom Line

Consider use in patients with:

· Lower urinary tract infection (cystitis),

· No systemic signs/symptoms,

· Normal renal function, and

· No urinary tract abnormalities

AND multiple of the following:

· Medication access issues

· Known medication nonadherence

· Multiple antibiotic allergies

· Known history of resistant organisms

· Unable to take oral medications

Conclusions

Single-dose aminoglycoside therapy may be a plausible treatment option in patients with cystitis.
Aminoglycosides can be administered either the IV or IM route, and therefore, does not necessarily require IV access. Gentamicin may be considered the preferred aminoglycoside based on frequency of use in studies.
The risk for adverse events with single-dose aminoglycosides is low, however, there are concerns for nephrotoxicity and ototoxicity.
Single-dose aminoglycoside should NOT be recommended as first-line therapy. It can be considered in patients with acute cystitis with normal renal function and multiple barriers to the standard of care.

References

Bonkat G, Bartoletti RR, Bruyere F et al. EAU Guidelines on Urological Infections. Urological Infections. 2019.
Uncomplicated Cystitis and Pyelonephritis (UTI). Clinical Infectious Diseases. 2011;52(5):e103-e120.
Clinical Practice Guideline for the management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2019;68(10):e83-75.
Goodlet KJ, Benhalima FZ, Nailor MD. A Systematic Review of Single-Dose Aminoglycoside Therapy for Urinary Tract Infection: Is It Time To Resurrect an Old Strategy? Antimicrob Agents Chemother. 2018 Dec 21;63(1):e02165-18.

Concomitant Parenteral Benzodiazepines and Olanzapine

Download Handout

Introduction

Intramuscular olanzapine and parenteral benzodiazepines are commonly used agents in the ED for acute agitation.
An FDA warning states that potentially fatal respiratory depression can occur when olanzapine and parenteral benzodiazepines are administered concomitantly stating “concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended.”
This warning initially stemmed from post-marketing adverse event monitoring data, but the clinical significance of this warning is questionable

Pharmacology

	Olanzapine	Lorazepam	Midazolam
Dose	5-10 mg w/ maximum of 30 mg/day	1-4 mg PRN until adequately sedated	2.5-5mg PRN until adequately sedated
Administration	IM: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution is ~5 mg/mL. Use within 1 hour following reconstitution	IM: administer undiluted IV: dilute IV dose prior to use with an equal volume of compatible diluent	IM: administer undiluted IV: can administered undiluted or dilute with compatible diluent
PK/PD	Onset: within 15 minutes Duration: at least 2 hours Metabolism: glucuronidation and CYP450 (1A2 and 2D6) Half-life: 30 hours in adults; ~1.5x greater in elderly Excretion: urine (57%) and feces (30%)	Onset: 15-30 minutes Duration: 6-8 hours Metabolism: hepatic Half-life: 13-18 hours Excretion: urine (88%) and feces (7%)	Onset: 15 minutes Duration: 2-6 hours Metabolism: hepatic CYP3A4 Half-life: 2-6 hours Excretion: urine (90%)
Adverse Effects	Orthostatic hypotension, dizziness, and drowsiness	Drowsiness and sedated state	Drowsiness and sedated state
Drug Interactions and warnings	Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled out	Have been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible.	Have been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible.
Compatibility	SWFI	D5W, NS, SWFI	D5W, NS

Overview of Evidence

Author, year	Design/ sample size	Intervention & Comparison	Outcome
Klein 2018	Prospective observational study (n=737)	Intramuscular haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg were administered for treatment of agitation in the ED.	At 15 minutes, participants having received midazolam were most likely to be adequately sedated (71% vs 40-61%).Olanzapine resulted in more participants being adequately sedated compared to haloperidol 5 mg, haloperidol 10 mg, or ziprasidone 20 mg (61% vs 40-52%).Adverse events were uncommon and were not statistically different between groups.
Marder 2010	Overview of Post-Marketing Adverse Event Case Reports (n=160)	539,000 patients received IM olanzapine in a period of 21 months: -Adverse events: 160 (0.03%) -Serious AEs: 83 (0.01%) -Fatalities: 29 (0.0053%)	Of the fatalities, olanzapine and benzodiazepines were given concomitantly 66% of the time while 76% also received other concomitant antipsychotics.Of the fatalities, 76% of the patients had comorbid conditions or clinically significant risk factors for the AE that occurred.12 cases of death occurred >24 hours up to 12 days following the injections.
Wilson 2010	Retrospective chart review (n=25)	Patients receiving IM olanzapine for agitation in the ED with vital signs documented both before and after (w/in 4 hours) administration	10/25 (40%) received concomitant olanzapine + benzo.Decreased oxygen saturations were seen in patients who had ingested significant amounts of alcohol (irrespective of benzo use).Of the patients that received olanzapine + benzo, only those with significant alcohol use had decreased oxygen saturations.
Chan 2012	Randomized placebo-controlled trial (n=336)	Agitated adult patients in the ED were randomized to saline, droperidol 5mg, or olanzapine 5mg. All patients then received midazolam 2.5-5mg until adequately sedated	Differences in time to sedation from placebo for droperidol and olanzapine were 4 and 5 mins, respectively.Patients receiving olanzapine or droperidol were 1.6x more likely to achieve adequate sedation.Low rates of AEs were seen and were comparable in all groups (e.g., O2 de-saturation: 7.8% control; 8% droperidol; 4.6% olanzapine.
Williams 2018	Medication use evaluation (n=91)	Patients receiving IM olanzapine and IM lorazepam within a 24-hour period	Concomitant administration within 60 mins occurred in 41 patients.No instances of hypotension, bradycardia, bradypnea, or oxygen desaturation occurred following administration.

Conclusions

1. The concomitant administration of IM olanzapine and IM/IV benzodiazepines is likely not as clinically risky as was initially thought.

2. Careful consideration should be used when recommending agents for the management of acute agitation to ensure the agent and dose is appropriate. Additionally, patient-specific factors, particularly the use/presence of additional CNS depressants (e.g., alcohol) should be considered.

References

Olanzapine. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
Lorazepam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
Midazolam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
Klein LR. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027
Chan EW, Ann Emerg Med. 2013;61(1):72-81. doi:10.1016/j.annemergmed.2012.07.118
Marder SR. J Clin Psychiatry. 2010;71(4):433-441. doi:10.4088/JCP.08m04411gry
Olanzapine. Package insert. Eli Lilly and Company; 2009
Williams AM. Ment Health Clin. 2018;8(5):208-213. Published 2018 Aug 30. doi:10.9740/mhc.2018.09.208
Wilson MP. J Emerg Med. 2012;43(5):889-896. doi:10.1016/j.jemermed.2010.04.012

Alteplase for Acute Ischemic Stroke

Download Handout

Introduction

Alteplase (rt-PA) has been used for acute ischemic stroke since its approval by the FDA in 1996 after publication of promising results of the NINDS trial
NINDS trial has been criticized for its strict inclusion criteria and all major clinical trials since have sought to show benefit in those patients excluded from the NINDS trial
Recent re-analysis of the ECASS III trial has been published using independent patient level data

Pharmacology

MOA	Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin
Dose	Patient weight <100 kg: 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes. Patient weight ≥100 kg: 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.
Administration	10% given as IV bolus over 1 minute; remainder infused over 1 hour
PK/PD	Duration: 1 hour after infusion terminated, bleeding risk can occur past 1 hour Distribution: approximates plasma volume Half-life elimination: 5 minutes Excretion: hepatic and plasma clearance
Adverse Effects	Intracranial hemorrhage Angioedema GI/GU hemorrhage
Drug Interactions and Warnings	Tranexamic acid, avoid combination Internal bleeding, thromboembolic events, cholesterol embolization
Contraindications	Active internal bleeding Ischemic stroke within 3 months except when within 4.5 hours Severe uncontrolled hypertension
Compatibility	May be diluted in equal volume with: 0.9% sodium chloride D5W NOT compatible with lactated ringers

Overview of the Evidence

Trials that showed no benefit

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
NINDS-1 (1995)	PRCT (n=291)	≤ 3 hours	• Mean 67 y • Median NIHSS 14 • TTT 0-90 m 47% • TTT 91-180 m 53%	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	No difference in NIHSS score at 24 hours
ECASS II (1998)	PRCT ( n=800)	≤ 6 hours	• Median 68 y • Median NIHSS 11 • TTT 0-3 h 19.8% • TTT 3-6 h 80.2%	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	No difference in functional outcomes at 90 days No significant difference in morbidity, despite 2.5 fold ↑ SICH in rtPA group
IST-3 (2012)	PRCT (n =3035)	≤ 6 hours	• 1407 patients >80 y • 201 patients >90 y • TTT 4.2 h	• 0.9 mg/kg t-PA (Max 90 mg) • Placebo	No difference in functional outcomes at 180 days ↑ 7-day mortality in rt-PA group (11% vs. 7%) ↑ SICH in rt-PA group (7% vs. 1%)

Trials that showed benefit

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
NINDS-2 (1995)	PRCT (n=333) ≤ 3 hours		• Mean 69 y • Median NIHSS 14 • TTT 0-90 m 49% • TTT 91-180 m 51%	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	• • 33% more patients treated with t-PA had mRS 0-1 at 90 days 2.9% ↑ fatal ICH in tPA group
ECASS III (2008)	PRCT (n =821)	3-4.5 hours	• Mean 65 y • Median NIHSS 9 • TTT 4 h	• 0.9 mg/kg t-PA (Max 90 mg) • Placebo	7% more patients treated with t-PA had mRS 0-1 at 90 days 2.2% ↑ SICH in rt-PA group
WAKE-UP (2018)	PRCT (n =503)	≥ 4.5 hours since LKN	• Mean 65 y • Median NIHSS 6 • TTT 10 h	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	11% more patients treated with t-PA had mRS 0-1 at 90 days 8% increase in SICH
EXTEND (2019)	PRCT (n =225)	4.5-9 hours	• Mean 73 y • Median NIHSS 12 • TTT 7.5 hours	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	Stopped early mRs 0-1 occurred in 35.4% of the tPa group and 29.5% of the placebo group (adjusted OR 1.44; 95%CI 1.01 – 2.06, p=0.04. o In unadjusted primary outcome not statistically significant (OR 1.2, 95% CI 0.82 – 1.76, p =0.35) More symptomatic intracranial hemorrhage in the tPa group (6.2% vs 0.9%)

Trials that showed harm

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
ECASS-1 (1995)	PRCT (n=620)	≤ 6 hours	• Median 69 y • Median NIHSS 12 • TTT 4.4 h	• 1.1 mg/kg rt-PA (Max 100 mg) • Placebo	• No difference in functional outcomes at 90 days • Significant ↑ 30-day mortality in T-PA group (22.4% vs. 15.8%)
ATLANTISB (1999)	PRCT ( n =613)	3-5 hours	• Mean 65 y • Median NIHSS 10 • TTT 4.5 h	• 0.9 mg/kg rt-PA (Max 90 mg) • Placebo	Stopped early Trend towards ↑ mortality in rt-PA group (11% vs. 7%)
ATLANTIS- A (2000)	PRCT (n =142)	≤ 6 hours	• Mean 67 y • Median NIHSS 10 • TTT 4.5 h	• 0.9 mg/kt t-PA (Max 90 mg) • Placebo	• Stopped early More • 4-point improvement at 30 days with placebo than alteplase (75% vs 60%) • Significant ↑ SICH w/in 10 days of rt-PA treatment (11% vs. 0%) • Significant ↑ 90-day mortality in rt-PA group(23% vs. 7%)
Epithet (2008)	PRCT (n =101)	3-6 hours	Mean 71 y Median NIHSS 13	0.9 mg/kg t-PA (Max 90 mg) Placebo	Non-significant difference in their primary outcome, which was a disease oriented imaging outcome Non-significant difference in mortality (26% with alteplase vs 12% with placebo in patients with perfusion mismatch

TTT: Time-to-treatment; ITT: Intention-to-treat; PRCT: Prospective Randomized Controlled Trial;

Revisiting the NINDS Study

Reason: the original authors of NINDS rt-PA stroke study (1995) performed further analysis after patients treated earlier did not seem to benefit compared to those treated later, contrary to an expected difference.

However when the baseline NIHSS scores were shown by time-to-treatment instead of treatment group, baseline differences between the rt-PA and placebo groups became apparent.

	Original Report (1995)		Re-analysis (2000)

	Rt-PA	Placebo	0-90 min		91-180 min
			Rt-PA	Placebo	Rt-PA	Placebo
NIHSS, mean (SD); median	14	14	15.2 (7.2); 15	15.0 (6.7); 14	13.5 (7.7); 12	15.4 (6.9); 15
NIHSS, groups, percent
0-5			8.3	6.2	19	4.2
10-Jun			19.1	25.5	24.2	27.5
15-Nov			24.8	21.4	17	21
16-20			25.5	25.5	21.6	19.8
>20			2230%	21.4	18.3	27.5

The higher median NIHSS baseline scores in the placebo at 91-180 min group resulted in an overestimation of rt-PA’s efficacy in the original NINDS trial that even the original authors had to announce in their conclusions of their 2000 reanalysis.

ECASS III Re-analysis

Previously reported unadjusted analyses were based on modified NIHSS score. The secondary efficacy outcome was no longer significant using the original NIHSS score.
In analyses adjusted for baseline imbalances, all efficacy outcomes were no longer significant. • Increases in symptomatic intracranial hemorrhage remained significant in 5/6 analyses.

Conclusions

Currently, the AHA recommends for eligible patients the benefit of alteplase therapy is time dependent, and treatment should be initiated as quickly as possible.
Baseline imbalances favoring rt-PA in the NINDS trial and the ECASS III trial could be considered controversial, considering these trials were instrumental for drug approval and time window expansion.
A re-analysis cannot overturn the original findings of a study, only increase or decrease the confidence in the findings it presented.
The decision to use rt-PA for an acute ischemic stroke should continue to consider potential benefits with consideration for upfront risk of fatal ICH.

References

Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke A. Stroke. 2019;50(12):E344-E418. doi:10.1161/STR.0000000000000211
NINDS rt-PA Stroke Study Group. TISSUE PLASMINOGEN ACTIVATOR FOR ACUTE ISCHEMIC STROKE. N Engl J Med. 1995;333:1581-1587.
Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251. doi:10.1016/S01406736(98)08020-9
Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): A randomised controlled trial. Lancet. 2012;379(9834):2352-2363. doi:10.1016/S0140-6736(12)60768-5
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med. 2008;359(13):1317-1329. doi:10.1056/nejmoa0804656
Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622. doi:10.1056/nejmoa1804355
Hacke W, kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA J Am Med Assoc. 1995;274(13):10171025. doi:10.1001/jama.274.13.1017
Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant Tissue-Type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 to 5 Hours After Symptom Onset The ATLANTIS Study: A Randomized Controlled Trial. JAMA. 1999;282(21):2019-2026.
Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (Alteplase) 0-to 6-Hour Acute Stroke Trial, Part A (A0276g) Results of a Double-Blind, Placebo-Controlled, Multicenter Study. Stroke. 2000;31:811-816.
Davis SM, Rey G, Donnan A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299-309. doi:10.1016/S1474
Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380(19):1795-1803. doi:10.1056/nejmoa1813046
Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: The NINDS rt-PA Stroke Study. Neurology. 2000;55(11):1649-1655. doi:10.1212/WNL.55.11.1649
Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: Trial reanalysis adjusted for baseline imbalances. BMJ Evidence-Based Med. 2020;0(0):172-179. doi:10.1136/bmjebm-2020-111386

Master the BCPS Exam: Effective Study Techniques for Pharmacists Using Spaced Repetition and Testing

Pharmacists play a crucial role in the healthcare industry, ensuring safe and effective drug therapy management. Pursuing board certification, such as the Board Certified Pharmacotherapy Specialist (BCPS) credential, not only validates your expertise but also enhances your career prospects. As the exam requires a deep understanding of complex concepts, it’s essential to employ the most effective learning techniques. In this SEO-optimized article, we’ll explore the science of studying, focusing on spaced repetition and testing, and introduce you to PACUPrep Q-Bank – an AI-driven learning platform tailored for healthcare professionals like you.

The Science Behind Spaced Repetition for BCPS Exam Preparation:

Spaced repetition is a learning technique that involves breaking down material into smaller, more manageable pieces and reviewing them at increasingly longer intervals. This method has been proven to be more effective than simply rereading material, as it reinforces the information in your long-term memory, making it easier to recall when needed.

For pharmacists preparing for the BCPS exam, spaced repetition can be a powerful tool to improve your understanding of complex drug interactions, side effects, pharmacokinetics, and other essential topics. By reviewing the material at strategic intervals, you’re more likely to retain crucial information for the exam.

Harness the Power of Testing for BCPS Exam Success:

Active testing is another proven technique to enhance retention and recall. By regularly testing yourself on the material you’ve learned, you engage in deeper cognitive processes, strengthening neural connections in your brain. This method, known as retrieval practice, has been shown to be more effective than rereading or passive learning.

Pharmacists studying for the BCPS exam can significantly benefit from incorporating testing into their study routine. By creating flashcards or engaging in practice quizzes, you can reinforce your understanding of drug classifications, dosage calculations, patient counseling techniques, and other essential BCPS exam topics.

Discover PACUPrep Q-Bank for BCPS Exam Preparation:

Recognizing the value of spaced repetition and testing, the PACUPrep team has developed a state-of-the-art Q-Bank platform specifically designed for healthcare professionals, including pharmacists pursuing the BCPS credential. PACUPrep Q-Bank is an AI-driven learning tool that uses spaced repetition and incorporates the latest findings in cognitive psychology.

PACUPrep Q-Bank offers the following advantages for BCPS exam preparation:

Customized Learning Path: The AI-driven platform analyzes your performance and tailors the learning path to your specific needs, ensuring you focus on areas where you need the most improvement.
Spaced Repetition: PACUPrep Q-Bank optimizes the spacing of questions to maximize long-term retention, making your BCPS exam study sessions more efficient and effective.
Team-Focused: Collaborate with your peers, share study resources, and track each other’s progress to foster a supportive learning environment for BCPS exam success.
Up-to-Date Content: The platform is continuously updated to reflect the latest advancements in pharmacology, ensuring you stay current with the most recent developments in the field and the BCPS exam requirements.

PACUPrep Q-Bank offers the following advantages for BCPS exam preparation:

Customized Learning Path: The AI-driven platform analyzes your performance and tailors the learning path to your specific needs, ensuring you focus on areas where you need the most improvement.
Spaced Repetition: PACUPrep Q-Bank optimizes the spacing of questions to maximize long-term retention, making your BCPS exam study sessions more efficient and effective.
Team-Focused: Collaborate with your peers, share study resources, and track each other’s progress to foster a supportive learning environment for BCPS exam success.
Up-to-Date Content: The platform is continuously updated to reflect the latest advancements in pharmacology, ensuring you stay current with the most recent developments in the field and the BCPS exam requirements.