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Holzer M, et al. “Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”. The New England Journal of Medicine. 2002. 346(8):549-556.





Clinical Content
14 min read
January 28, 2025

Holzer M, et al. “Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”. The New England Journal of Medicine. 2002. 346(8):549-556.

J

Jimmy Pruitt

PharmD






PACULit Summary: Mild Therapeutic Hypothermia to Improve Neurologic Outcome After Cardiac Arrest


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Contents

Article Identification

  • Article Title: Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest
  • Citation: Bernard, S. A., Greyson, D., Bhanji, F., et al. (2002). Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest. New England Journal of Medicine, 346(8), 549-556.
  • DOI: 10.1056/NEJMoa012685

Quick Reference Summary

  • Primary Findings: Therapeutic mild hypothermia (32°C to 34°C) significantly increased the rate of favorable neurologic outcomes at six months (55% vs. 39%; risk ratio, 1.40; 95% CI: 1.08–1.81, p < 0.05) compared to normothermia.
  • Secondary Results: Mortality at six months was reduced in the hypothermia group (41%) versus the normothermia group (55%; risk ratio, 0.74; 95% CI: 0.58–0.95, p < 0.05), with no significant difference in complication rates.

Core Clinical Question

Does therapeutic mild hypothermia (32°C to 34°C) after resuscitation from ventricular fibrillation-related cardiac arrest improve six-month neurologic outcomes and reduce mortality compared to standard normothermia care?

Background

  • Disease Overview: Cardiac arrest leading to ventricular fibrillation causes widespread cerebral ischemia, often resulting in severe neurological impairment or death.
  • Prior Data:
    • Animal Studies: Moderate (30°C) or mild hypothermia (34°C) reduced brain damage post-cardiac arrest in canine models.
    • Preliminary Clinical Studies: Early studies suggested improved neurologic outcomes with mild hypothermia, though comparisons were often against historical controls.
  • Current Standard of Care: Prior to this study, no therapy had conclusively demonstrated efficacy in preventing brain damage post-cardiac arrest.
  • Knowledge Gaps Addressed:
    • Efficacy of mild hypothermia in improving long-term neurologic outcomes.
    • Impact of hypothermia on mortality rates post-cardiac arrest.
    • Safety profile of mild hypothermia in the acute post-resuscitation phase.
  • Study Rationale: To provide robust, randomized controlled evidence on the benefits and safety of therapeutic mild hypothermia in patients resuscitated from ventricular fibrillation-induced cardiac arrest.

Methods Summary

  • Study Design: Multicenter, randomized, controlled trial with blinded outcome assessment.
  • Setting and Time Period: Conducted in nine centers across five European countries between March 1996 and January 2001.
  • Population Characteristics: Adults aged 18-75 who were resuscitated after witnessed cardiac arrest due to ventricular fibrillation or nonperfusing ventricular tachycardia.
  • Inclusion Criteria:
    • Witnessed cardiac arrest.
    • Initial shockable rhythm (ventricular fibrillation or nonperfusing ventricular tachycardia).
    • Presumed cardiac origin of arrest.
    • Resuscitation initiated within 5-15 minutes of collapse.
    • Restoration of spontaneous circulation within 60 minutes.
  • Exclusion Criteria:
    • Tympanic temperature <30°C on admission.
    • Pre-arrest coma due to CNS depressants.
    • Pregnancy.
    • Responsive to verbal commands before randomization.
    • Prolonged hypotension or hypoxemia post-resuscitation.
    • Terminal illness or other factors precluding follow-up.
  • Intervention Details: Induction of hypothermia to a target bladder temperature of 32°C to 34°C for 24 hours using an external cooling device, followed by passive rewarming over approximately 8 hours.
  • Control Group Details: Maintenance of normothermia using conventional hospital care.
  • Primary Outcomes: Favorable neurologic outcome within six months, defined as cerebral-performance category 1 or 2.
  • Secondary Outcomes: Six-month mortality and incidence of complications within seven days.
  • Statistical Analysis Approach: Chi-square or Fisher’s exact test for categorical outcomes, multivariate logistic regression for confounder adjustment, intention-to-treat analysis.
  • Sample Size Calculations: Not specified; study was terminated early due to lower enrollment rates and funding cessation.
  • Ethics and Funding: Approved by institutional review boards; informed consent waived per ethical standards. No conflicts of interest reported.

Detailed Results

  • Participant Flow and Demographics:
    • Assessed for Eligibility: 3,551 patients.
    • Excluded: 3,246 did not meet inclusion criteria; 30 excluded due to logistic issues.
    • Enrolled: 275 patients (137 hypothermia, 138 normothermia).
    • Lost to Follow-Up: 1 patient in each group for neurologic status.
  • Primary Outcome:
    • Hypothermia Group: 75/136 (55%) favorable neurologic outcomes.
    • Normothermia Group: 54/137 (39%) favorable neurologic outcomes.
    • Risk Ratio: 1.40 (95% CI: 1.08–1.81, p = 0.01).
    • Number Needed to Treat (NNT): 6 (95% CI: 4–25).
  • Secondary Outcomes:
    • Mortality at Six Months:
      • Hypothermia Group: 56/137 (41%).
      • Normothermia Group: 76/138 (55%).
      • Risk Ratio: 0.74 (95% CI: 0.58–0.95, p = 0.02).
      • Number Needed to Treat (NNT): 7 (95% CI: 4–33).
    • Subgroup Analyses: Adjusted risk ratios slightly increased post-adjustment for baseline differences.
    • Adverse Events/Safety Data:
      • Complication Rates: Hypothermia (73%) vs. Normothermia (70%), p = 0.70.
      • Specific Complications: Non-significant trend towards increased sepsis in hypothermia group.
Outcome Intervention Group Control Group Difference (95% CI) P-value
Favorable Neurologic Outcome 75/136 (55%) 54/137 (39%) +16% (8-25%) <0.05
Mortality at Six Months 56/137 (41%) 76/138 (55%) -14% (4-38%) <0.05
Any Complication 98/135 (73%) 93/132 (70%) +3% (−5-12%) 0.70
Sepsis Higher in Hypothermia – Not significant –

Authors’ Conclusions

  • Primary Conclusions: Therapeutic mild hypothermia significantly increased the rate of favorable neurologic outcomes and reduced six-month mortality in patients resuscitated from ventricular fibrillation-induced cardiac arrest.
  • Clinical Implications: Mild hypothermia should be considered as a standard post-resuscitation intervention to improve neurologic and survival outcomes.
  • Future Research Recommendations: Further studies are needed to assess the applicability of hypothermia in broader patient populations, including those with different initial rhythms and lower risks of brain damage.

Critical Analysis

A. Strengths

  • Randomized Controlled Design: Minimizes selection bias and allows for causal inferences.
  • Blinded Outcome Assessment: Reduces detection bias in assessing neurologic outcomes.
  • Multicenter Approach: Enhances generalizability across different clinical settings and populations.
  • Clear Inclusion/Exclusion Criteria: Ensures a well-defined study population at high risk for poor outcomes.
  • Intention-to-Treat Analysis: Preserves the benefits of randomization and provides a conservative estimate of treatment effect.

B. Limitations

  • Early Termination: Enrollment was halted prematurely due to lower recruitment rates and funding issues, potentially affecting the study’s power and the precision of effect estimates.
  • Blinding Challenges: Personnel managing patients during the first 48 hours were not blinded, which could introduce performance bias, although outcome assessors remained blinded.
  • Generalizability: The study focused exclusively on patients with ventricular fibrillation, limiting applicability to individuals with non-shockable rhythms or different etiologies of cardiac arrest.
  • Implementation Barriers: The need for specialized cooling equipment and protocols may limit the feasibility of widespread adoption in all clinical settings.
  • Potential for Residual Confounding: Despite multivariate adjustments, unmeasured confounders may still influence outcomes.
  • Limited Data on Long-Term Complications: Adverse events were monitored only for seven days, providing an incomplete safety profile.

Literature Review

Positioning the Current Study in Existing Evidence

The study by Bernard et al. (2002) was pivotal in establishing therapeutic mild hypothermia as a beneficial intervention for improving neurologic and survival outcomes post-cardiac arrest. This multicenter, randomized controlled trial provided robust evidence that cooling patients to 32°C-34°C for 24 hours after resuscitation from ventricular fibrillation significantly enhanced favorable neurologic recovery and reduced mortality rates.

Prior to Bernard et al., the concept of hypothermia as a neuroprotective strategy was supported mainly by animal studies. For instance, Holzer et al. (2002) demonstrated similar benefits in canine models, showing that both moderate and mild hypothermia mitigated brain damage following induced cardiac arrest. These foundational studies underscored the potential mechanisms through which hypothermia could confer neuroprotection, such as reducing cerebral metabolism and inhibiting harmful enzymatic processes during reperfusion.

Comparison with ERC-ESICM Guidelines

Following the publication of Bernard et al., the European Resuscitation Council and European Society of Intensive Care Medicine (ERC-ESICM) incorporated therapeutic hypothermia into their guidelines. Initially, these guidelines strongly endorsed hypothermia for comatose survivors of out-of-hospital cardiac arrest (OHCA) with shockable rhythms, reflecting the positive outcomes reported in Bernard’s trial.

However, the 2022 ERC-ESICM guidelines represent an evolution informed by subsequent research. The guidelines now emphasize continuous core temperature monitoring and fever prevention for at least 72 hours post-resuscitation, rather than strictly adhering to hypothermia at 32°C-34°C. This shift acknowledges the findings from later studies, such as the Targeted Temperature Management (TTM) trial and the TTM2 trial, which questioned the optimal temperature targets and highlighted the benefits of controlled temperature management over aggressive cooling.

Comparison with Supporting Trials: TTM and TTM2

  • TTM Trial (Nielsen et al., 2013): This large-scale trial compared targeted temperatures of 33°C versus 36°C in 950 unconscious OHCA survivors. The TTM trial found no significant difference in all-cause mortality or neurologic outcomes between the two temperature targets. These results challenged the notion that deeper hypothermia (33°C) offers superior benefits over milder temperature control (36°C).
  • TTM2 Trial (Dankiewicz et al., 2021): Extending the discourse, the TTM2 trial evaluated targeted hypothermia at 33°C against targeted normothermia with early fever management in 1,900 comatose OHCA patients. The trial concluded that hypothermia did not provide a mortality benefit over normothermia and was associated with a higher incidence of arrhythmias. These findings further questioned the universal application of therapeutic hypothermia, suggesting that less aggressive temperature management may be equally effective and safer.

In-Depth Analysis of Similarities, Differences, and Key Findings

While all three trials—Bernard et al. (2002), TTM (Nielsen et al., 2013), and TTM2 (Dankiewicz et al., 2021)—employed randomized controlled designs to evaluate the impact of temperature management on outcomes post-cardiac arrest, key differences emerged:

  • Patient Populations: Bernard et al. focused exclusively on ventricular fibrillation-induced cardiac arrests, which are shockable rhythms, whereas TTM and TTM2 included a broader range of rhythms, including non-shockable ones. This inclusivity affects generalizability, as non-shockable rhythms are associated with different prognoses.
  • Temperature Targets: Bernard et al. set a target of 32°C-34°C, TTM compared 33°C to 36°C, and TTM2 compared 33°C to normothermia (≥37.8°C). The lack of significant differences in TTM and TTM2 suggests that milder temperature reductions may achieve similar benefits as deeper cooling.
  • Outcomes: Bernard et al. reported substantial benefits in both neurologic outcomes and mortality rates with hypothermia. In contrast, TTM found no difference between 33°C and 36°C, and TTM2 found no mortality benefit of hypothermia over normothermia, raising questions about the optimal temperature strategy.
  • Adverse Events: The TTM2 trial highlighted an increased incidence of arrhythmias with hypothermia, a concern less prominent in Bernard et al.’s study due to the lower sample size and earlier cessation.

Integration with Additional Studies

  • Implementation in Clinical Practice (Krawczyk et al., 2013): Despite evidence supporting hypothermia, its implementation in Polish ICUs was limited (21.7%) due to barriers like lack of knowledge, protocols, equipment, and economic constraints. This underscores the translational gap between research findings and clinical practice.
  • Seizure Prognosis (Lybeck et al., 2017): Clinical seizures post-cardiac arrest, common during TTM, were associated with poor outcomes, but target temperature did not influence seizure prevalence or prognostic significance. This indicates that while hypothermia may improve outcomes, seizures remain a critical prognostic marker irrespective of temperature management.
  • Biomarkers for Outcome Prediction (Broessner et al., 2015): Biomarkers like MR-proANP and Copeptin showed significant predictive value for neurological outcomes independent of temperature management, highlighting the multifaceted approach needed for prognosis post-cardiac arrest.
  • Predictive Modeling (Chiu et al., 2022): Artificial neural networks effectively predicted survival and neurologic outcomes post-TTM, suggesting that integrating predictive analytics could enhance decision-making in therapeutic hypothermia applications.
  • Ultrafast Hypothermia (Boissady et al., 2020): Rapid cooling via total liquid ventilation mitigated early inflammatory responses, such as interleukin-6, correlating with improved neurological recovery. This points to the potential benefits of not just temperature targets but also the speed of hypothermia induction.

Systematic Reviews and Meta-Analyses

A meta-analysis by Chen et al. (2020) consolidated data from multiple trials, reaffirming that therapeutic hypothermia improves neurologic outcomes but with variable effects on mortality. However, the analysis also noted heterogeneity in study designs, patient populations, and hypothermia protocols, suggesting that personalized temperature management strategies may be more effective.

Cost-Effectiveness and Resource Utilization

Implementing therapeutic hypothermia requires specialized equipment and trained personnel, potentially increasing healthcare costs. Studies like Krawczyk et al. (2013) highlight economic barriers to implementation, necessitating cost-benefit analyses to justify widespread adoption, especially in resource-limited settings.

Ongoing Trials

Emerging research continues to explore optimal temperature targets, duration, and methods of induction. Trials investigating combined therapies (e.g., hypothermia with cytokine modulation) and leveraging advanced predictive analytics are underway, aiming to refine and enhance the efficacy of temperature management post-cardiac arrest.

Gaps and Future Directions

  • Optimal Temperature and Duration: Determining the precise temperature targets and cooling durations that maximize benefits while minimizing risks.
  • Population Specificity: Assessing efficacy in diverse populations, including those with non-shockable rhythms, varying etiologies of cardiac arrest, and differing comorbidities.
  • Implementation Strategies: Developing standardized protocols and addressing barriers to ensure widespread, effective adoption of therapeutic hypothermia.
  • Long-Term Outcomes: Evaluating the impact of hypothermia on long-term quality of life and cognitive function beyond six months.
  • Combination Therapies: Exploring synergistic interventions that could enhance the neuroprotective effects of hypothermia.

Clinical Application

  • The findings from Bernard et al. (2002) initially revolutionized post-resuscitation care by endorsing mild hypothermia to improve neurologic and survival outcomes. Subsequent trials like TTM and TTM2 have nuanced these recommendations, suggesting that while temperature management remains crucial, the exact hypothermia protocols may need customization based on patient-specific factors and evolving evidence.
  • Clinicians should implement continuous temperature monitoring and prioritize fever prevention, aligning with the latest ERC-ESICM guidelines that emphasize individualized care over rigid temperature targets.
  • Specific patient populations, particularly those with ventricular fibrillation-induced cardiac arrest, may derive the most benefit from therapeutic hypothermia, while also considering potential risks such as arrhythmias.

How To Use This Info In Practice

Practitioners should integrate therapeutic mild hypothermia into post-cardiac arrest care for eligible patients, adhering to current guidelines that advocate for controlled temperature management and individualized treatment protocols, while staying informed on emerging evidence to optimize neurologic and survival outcomes.



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BICAR-ICU

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Featured

Statins for STEMI in the Emergency Department





Clinical Content
4 min read
August 2, 2024

Statins for STEMI in the Emergency Department

J

Jimmy

PharmD

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Introduction

  1. STEMI (ST-Elevation Myocardial Infarction) represents a critical emergency where timely intervention is crucial. Atorvastatin, a statin, has been investigated for its potential benefits when administered early during a STEMI.
  2. Early administration of atorvastatin may have pleiotropic effects beyond cholesterol lowering. Potential benefits include stabilization of atherosclerotic plaques, reduction of inflammation, and improved endothelial function.
  3. Guidelines recommend initiating high-intensity statin therapy as soon as possible in STEMI patients.
  4. This pharmacy pearl summarizes the pharmacology and evidence supporting the use of atorvastatin in this setting.

Pharmacology

  Atorvastatin  Rosuvastatin 
Dose 80 mg orally once daily 40 mg orally once daily
Administration Oral Oral
PK/PD Onset: 3-5 days for LDL reduction; Peak effect: 2-4 weeks Onset: 3-5 days for LDL reduction; Peak effect: 2-4 weeks
Adverse Effects Myopathy, elevated liver enzymes, gastrointestinal symptoms Myopathy, elevated liver enzymes, gastrointestinal symptoms
Drug Interactions and warnings CYP3A4 inhibitors/inducers can affect levels; avoid in active liver disease Minimal CYP interactions; avoid in active liver disease
Compatibility Compatible with most cardiovascular drugs, monitor for interactions with CYP3A4 inhibitors Compatible with most cardiovascular drugs, minimal interactions
Comments High-intensity statin recommended post-STEMI to reduce recurrence risk High-intensity statin alternative to atorvastatin

Overview of Evidence

Author, Year Design/Sample Size Intervention & Comparison Outcome
Schwartz, 2001 Randomized Controlled Trial (n=3086) Atorvastatin (80 mg/day) vs. placebo initiated 2496 hours after acute coronary syndrome Atorvastatin reduced recurrent symptomatic ischemia requiring rehospitalization (6.2% vs 8.4%; RR, 0.74; P=0.02)
Li, 2012 Randomized Controlled Trial (n=161) High-dose atorvastatin (80 mg) vs. placebo in patients with STEMI undergoing PCI High-dose atorvastatin significantly reduced the incidence of contrast-induced nephropathy (2.6% vs 15.7%; P=0.01)
Liu, 2013 Randomized Controlled Trial (n=102) Loading dose of atorvastatin (80 mg) before PCI vs. no loading dose Loading dose of atorvastatin reduced high-sensitivity C-reactive protein, B-type natriuretic peptide, and matrix metalloproteinase type 9, indicating reduced inflammation and improved cardiac function (P<0.05)
Xu, 2016 Randomized Controlled Trial (n=120) Intensive atorvastatin (40 mg) vs. standard atorvastatin (20 mg) in STEMI patients undergoing PCI Intensive atorvastatin significantly reduced serum endothelin-1 levels and ADP-induced platelet clot strength, improving endothelial function and platelet inhibition (P<0.05)
Kim, 2015 Randomized Controlled Trial (n=67) High-dose atorvastatin (80 mg) before PCI vs. low-dose atorvastatin (10 mg) No significant reduction in myocardial damage; however, high-dose pretreatment is generally considered safe and well-tolerated
Gavazzoni, 2017 Randomized Controlled Trial (n=52) High-dose atorvastatin (80 mg) vs. moderate dose (20 mg) in STEMI patients High-dose atorvastatin showed significant improvement in endothelial function (RH-PAT index 1.96±0.16 vs 1.72±0.19; P=0.002) and reduced levels of high-sensitivity CRP and IL6 (P<0.05)
Liu, 2013 Randomized Controlled Trial (n=102) Loading dose of atorvastatin (80 mg) before PCI vs. no loading dose Loading dose of atorvastatin significantly lowered inflammatory markers and improved left ventricular ejection fraction compared to no loading dose (P<0.05)
Adel, 2022 Randomized Controlled Trial (n=99) High-dose rosuvastatin (40 mg) vs. high-dose atorvastatin (80 mg) before PCI in STEMI patients Atorvastatin group had lower CTFC and better TIMI flow grade compared to control, and both statins improved microvascular myocardial perfusion (P<0.01)
Chen, 2022 Randomized Controlled Trial (n=98) Enhanced-dose atorvastatin (40 mg before PCI, 40 mg/day post-PCI, 20 mg/day after 1 week) vs. standarddose atorvastatin (20 mg/day) Enhanced-dose atorvastatin improved cardiac output, LVEF, TIMI blood flow classification, and reduced incidence of major adverse cardiac events (P<0.05)

Conclusions

  • Efficacy: High-intensity atorvastatin (80 mg) initiated early in the ED for STEMI patients reduces the risk of subsequent cardiovascular events and mortality. 
  • Safety: Generally well-tolerated with a similar side effect profile to other statins, though monitoring for myopathy and liver enzyme elevations is necessary.
  • Recommendation: Incorporating early administration of atorvastatin 80 mg for STEMI patients in the ED aligns with current guidelines and improves patient outcomes.

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved July 1 2024, from http://www.micromedexsolutions.com/
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. Liu H, Yang Y, Yang SL, et al. Administration of a loading dose of atorvastatin before emergency PCI reduces myocardial damage in patients with STEMI. Clin Ther. 2013;35(1):22-30. 
  4. Li W, Fu X, Wang Y, et al. Beneficial effects of high-dose atorvastatin pretreatment on microvascular obstruction and left ventricular function in STEMI patients undergoing primary PCI. Cardiology. 2012;123(4):212-220. 
  5. Kim EK, Hahn J, Song Y, et al. Effects of high-dose atorvastatin pretreatment on microvascular obstruction in STEMI patients undergoing primary PCI. J Korean Med Sci. 2015;30(4):435-441. 
  6. Xu X, Liu Y, Li K, et al. Intensive atorvastatin improves endothelial function and reduces inflammation in STEMI patients undergoing primary PCI. Int J Cardiol. 2016;220:616-621.
  7. Gavazzoni M, Lombardi CM, Vizzardi E, et al. Role of early high-dose atorvastatin loading in STsegment elevation myocardial infarction: real-life experience. J Cardiovasc Med (Hagerstown). 2017;18(6):406-411.
  8. Adel EM, Elberry A, Abdel Aziz A, Ibrahim MA, Abdelaal FA. Comparison of the treatment efficacy of rosuvastatin versus atorvastatin in preventing microvascular obstruction in patients undergoing primary PCI for STEMI. J Clin Med. 2022;11(17):5142.
  9. Chen Y, Zhang J, Huo Y, et al. Effects of atorvastatin on coronary microvascular function in STEMI patients undergoing primary PCI: a randomized controlled trial. J Am Coll Cardiol. 2022;79(9):901911.

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Tranexamic Acid in Trauma by Jordan Spurling





Clinical Content
6 min read
June 7, 2024

Tranexamic Acid in Trauma by Jordan Spurling

J

Jimmy

PharmD





Clinical Content
5 min read
June 7, 2024

Tranexamic Acid in Trauma by Jordan Spurling

J

Jimmy

PharmD

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Introduction

  1. Trauma is the leading cause of death in individuals up to 45 years old and the fourth leading cause of death overall for all ages.1
  2. Uncontrolled hemorrhage is the leading cause of early mortality in major trauma.2
  3. Trauma-associated hemorrhagic death occurs as an effect of uncontrolled bleeding and trauma-induced coagulopathy.3
  4. Tranexamic acid is an antifibrinolytic medication that works by forming a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis.4
  5. Tranexamic acid is readily available, simple to administer, relatively inexpensive, with minimal side effects.

Pharmacology

  Tranexamic Acid
Dose Loading dose: 1 g over 10 minutes started within 3 hours of injury2 gram via slow IV Push*   Maintenance: 1 g over the next 8 hours as a continuous infusion
Administration Loading dose:  administer undiluted   Max rate:100 mg/minute   For continuous IV infusions: dilute with compatible solutions and administer at a rate not to exceed 100 mg/minute
PK/PD Distribution: Vd: IV: 9 to 12 L   Protein binding: ~3%, primarily to plasminogen   Half-life elimination: ~2 hours   Excretion: Urine (>95% as unchanged drug)
Adverse Effects Hypersensitivity reactions, ocular effects, seizures and myoclonus, thromboembolic effects, abdominal pain, headache, back pain
*Emerging data from prehospital and military data use

Overview of Evidence

Author, year Design/ sample size Intervention & Comparison Outcome
Morrison, 2012 ○ Observational (n=896) ○ TXA 1g bolus + repeat prn vs placebo. All-cause mortality overall within 48 hours and in hospital mortality significantly reduced with TXA
Roberts, 2013 ○ Randomized placebo-controlled (n = 20,2011) ○ TXA 1g bolus + 1g over 8 hours vs placebo ○ All-cause mortality at 28 days was significantly reduced by TXA ○ Treatment within 1 hour and 1-3 hours from injury significantly reduced the risk of death due to bleeding
Sprigg, 2018 ○ Randomized placebo-controlled (n= 2325) ○ TXA 1 g bolus + 1g over 8 h infusion vs placebo ○ Patients in the tranexamic acid group experienced a reduction in early deaths and serious adverse events, but not long term functional status
Roberts, 2019 ○ Randomized, placebo-controlled (n=12737) ○ TXA 1 g bolus + 1g over 8 hours vs placebo ○ Treatment within 3 h of injury reduced head injury-related death.
Rowell, 2020 ○ Double-blinded, randomized ( n= 966) ● TXA 1 g bolus + 1 g 8-hour infusion vs 2 g bolus bolus + placebo infusion vs placebo bolus + placebo infusion ○ No statistically significant difference in 28-day mortality, favorable neurologic function, 6 month disability rating score, or progression of intracranial hemorrhage
Roberts, 2020 ○ Randomized placebo-controlled (n = 12,009) ○ TXA 1 g + 3g infusion vs placebo ○ No significant difference in death due to bleeding within 5 days
Bossers, 2021 ● Prospective observational cohort (n = 1827) ○ Pre-hospital TXA vs no TXA patients with TBI ○ No association between TXA and mortality was found at 30 days ○ TXA was associated with increased mortality in patients with isolated TBI
Guyette, 2021 ○ Double-blind, placebo-controlled, randomized ( n= 927) ○ TXA 1 g bolus only vs TXA 1g  + 1 g infusion vs TXA 1g bolus + 1g bolus + 1g infusion vs placebo bolus + placebo infusion ○ Prehospital administration of tranexamic acid compared with placebo did not result in a lower rate of 30-day mortality in this population. ○ No differences were found in 24-hour mortality or in-hospital mortality
Mahmood, 2021 ○ Randomized placebo-controlled (n = 1767) ○ TXA 1 g bolus + 1 vs placebo ○ No evidence that TXA prevents IPH expansion
Gruen, 2023 ○ Double-blind, randomized, placebo-controlled  (n = 1310) ○ TXA 1 g bolus prior + infusion vs matched placebo ○              No difference in survival with a favorable functional outcome at 6 months ○              No difference in 6 months mortality

Conclusions

  • Tranexamic acid has been studied in pre-hospital, hospital, and combat setting in patients who have sustained a traumatic injury
  • Efficacy of tranexamic acid was demonstrated in some studies above, while other studies failed to show a significant difference in outcomes
  • Dosing of tranexamic acid varied significantly in the above studies, however one dosing regimen has been widely adopted
  • Tranexamic acid has minimal adverse effects, is relatively inexpensive, and readily available in many settings

References

  1. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg. 2014;260(1):13-21. doi:10.1097/SLA.0000000000000600
  2. Callcut RA, Kornblith LZ, Conroy AS, et al. The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg. 2019;86(5):864-870. doi:10.1097/TA.0000000000002205
  3. Latif RK, Clifford SP, Baker JA, et al. Traumatic hemorrhage and chain of survival. Scand J Trauma Resusc Emerg Med. 2023;31(1):25. Published 2023 May 24. doi:10.1186/s13049-023-01088-8
  4. Hijazi N, Abu Fanne R, Abramovitch R, et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood. 2015;125(16):2558-2567. doi:10.1182/blood-2014-08-588442
  5. Cai J, Ribkoff J, Olson S, et al. The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients. Eur J Haematol. 2020;104(2):79-87. doi:10.1111/ejh.13348
  6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119. doi:10.1001/archsurg.2011.287
  7. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17(10):1-79. doi:10.3310/hta17100
  8. Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107-2115. doi:10.1016/S0140-6736(18)31033-X
  9. CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury
  10. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved January 17, 2021, from http://www.micromedexsolutions.com/

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How to Fail the BCEMP Exam





Board Prep
10 min read
March 14, 2024

How to Fail the BCEMP Exam

J

Jimmy

PharmD

The Board Certified Emergency Medicine Pharmacotherapy (BCEMP) exam, offered by the Board of Pharmacy Specialties, represents a significant milestone for healthcare professionals specializing in emergency medicine pharmacotherapy. This rigorous certification process is designed to validate a practitioner’s knowledge and skills, ensuring their capability to provide optimal medication therapy in emergency situations. While aiming for success is the natural course, today, we adopt a contrarian approach by highlighting the pitfalls that could lead to failure. This reverse-psychology method aims to illuminate the path towards effective preparation by understanding the common mistakes to avoid.

1. Misunderstanding the Exam’s Scope and Requirements

Understanding the full scope and requirements of the BCEMP exam is crucial for candidates aspiring to certify their expertise in emergency medicine pharmacotherapy. The Board of Pharmacy Specialties offers a detailed overview, including eligibility criteria, content areas, and a candidate’s guide on bpsweb.org, which serves as an essential resource for aligning preparation efforts with the exam’s demands. The exam encompasses a wide range of topics, from pharmacotherapy interventions to toxicological emergencies, requiring not just memorization but the ability to apply knowledge in complex clinical scenarios. Familiarity with these details ensures a targeted and effective study plan, addressing the depth of knowledge and breadth of topics expected.

Underestimating the breadth of topics covered in the BCEMP exam can lead to significant preparation gaps, potentially impacting exam performance. A narrow focus on certain areas while neglecting others can leave candidates ill-equipped to handle the diverse and complex questions posed. The comprehensive nature of the exam, designed to reflect the real-world challenges of emergency medicine, necessitates a thorough and well-rounded approach to study. By leveraging resources like the candidate’s guide from the Board of Pharmacy Specialties, candidates can avoid the pitfalls of underestimation and ensure a holistic preparation strategy that covers all necessary content areas.

2. Relying on Ineffective Study Techniques

Relying solely on ineffective study techniques such as cramming and passive reading can be a major pitfall in preparing for the BCEMP exam. These methods are particularly unsuitable for mastering the complex and detailed information required in emergency medicine pharmacotherapy. Cramming, or the intense absorption of material shortly before the exam, fails to facilitate the deep learning necessary for long-term retention of intricate concepts. Passive reading, without active engagement, doesn’t reinforce the material in a meaningful way, making it difficult to recall under exam pressure. recall under exam pressure. The “Eight Recommendations to Promote Effective Study Habits for Biology Students Enrolled in Online Courses” emphasize the value of active learning, even in online

settings, suggesting that techniques fostering active engagement lead to more effective study habits. On the other hand, the benefits of spaced repetition, a study technique that involves reviewing material over increasing intervals, cannot be overstated. This method is grounded in the psychological principle of the spacing effect, which suggests that information is more easily recalled if learning sessions are spaced out over time. The Medium article “Importance of Spaced-Repetitions” highlights that spaced repetition significantly enhances long-term retention compared to massed practice (cramming), making it a superior strategy for complex subjects like pharmacotherapy. Additionally, the concept of the Ebbinghaus Forgetting Curve, detailed in “Ebbinghaus Forgetting Curve (Definition + Examples),” illustrates the natural decline of memory retention over time and how spaced repetition can counteract this effect. By incorporating these evidenced-based strategies into their study plan, candidates can greatly improve their grasp and retention of the extensive material covered in the BCEMP exam.

The effect of flipped learning on academic performance as an innovative method for overcoming ebbinghaus’ forgetting curve (researchgate.net)

3. Overlooking Practice Exams and Question Banks

Overlooking the value of practice exams and question banks can be a critical misstep in preparing for the BCEMP exam. These tools are essential for familiarizing oneself with the exam’s structure and the variety of questions that may be encountered. A lack of exposure to the exam format and question types can lead to difficulties in navigating the actual test, potentially impacting performance. Incorporating practice materials into one’s study routine not only aids in understanding the exam’s layout but also helps in identifying weak areas that require additional focus.

Integrating practice exams and questions into the study schedule early and consistently is key to building confidence and competence. Engaging with a variety of questions, similar to those found in well-curated resources like PACUPrep’s Q-Bank, allows candidates to simulate the exam experience, enhancing their ability to manage time and approach questions effectively. This regular practice helps in cementing knowledge and honing test-taking strategies, making the actual exam environment more familiar and less intimidating. Through this disciplined approach, candidates can significantly improve their preparedness, paving the way for success in the BCEMP exam.

4. Poor Time Management

Poor time management in the context of BCEMP exam preparation can create significant barriers to success, primarily through the development of gaps in knowledge. Without a structured approach to studying, candidates risk spending too much time on certain topics while neglecting others, leading to an uneven grasp of the required material. This imbalance can be detrimental on exam day, where a comprehensive understanding across all areas is essential. Effective allocation of study time is crucial, ensuring that each topic is given due attention based on its complexity and the candidate’s familiarity with it.

To counteract this, adopting time management strategies can greatly enhance study efficiency. For instance, the Pomodoro Technique can be particularly effective in maintaining focus and preventing burnout. By dividing study sessions into 25-minute focused intervals followed by short breaks, candidates can improve retention and sustain longer periods of productive study. Additionally, the use of calendar apps to schedule study sessions and track important deadlines ensures a structured approach, covering all necessary topics systematically. During the exam, strategies such as quickly scanning all questions to allocate time effectively and keeping track of time to pace oneself can further optimize performance, ensuring that all questions are addressed within the allotted time.

5. Neglecting Mental and Physical Health

Neglecting mental and physical health during the preparation for the BCEMP exam can significantly undermine a candidate’s cognitive function and overall performance. The intense demands of studying for such a rigorous exam can lead to stress and sleep deprivation, which are known to impair memory, concentration, and decision-making abilities. Maintaining a healthy lifestyle, therefore, becomes not just a matter of personal well-being but a strategic component of exam preparation.

Adequate sleep is fundamental to cognitive processes, including the consolidation of memory, which is crucial when absorbing vast amounts of information. Similarly, effective stress management techniques such as regular exercise, mindfulness practices, or engaging in hobbies can mitigate the adverse effects of prolonged study sessions. These practices not only help in maintaining mental clarity and focus but also contribute to a more resilient and adaptable mindset, enabling candidates to tackle the challenges of the exam with greater composure and confidence. By prioritizing health and well-being, candidates can optimize their cognitive function, enhancing their ability to learn, retain, and apply knowledge effectively.

6. Studying in Isolation

Studying in isolation for the BCEMP exam can limit a candidate’s perspective and understanding, as it restricts the exchange of ideas, knowledge, and experiences that are vital for a comprehensive learning process. Engaging solely with the material without external input or discussion can lead to a narrow interpretation of complex topics and potentially overlook areas that might be crucial for the exam. The collaborative learning that occurs in group settings can expose candidates to diverse problem-solving approaches, clarify doubts through discussion, and reinforce learning through teaching others. To counteract the drawbacks of solitary study, candidates are encouraged to participate in study groups, professional forums, and seek mentorship.

7. Not Staying Updated with Current Practices

The field of emergency medicine pharmacotherapy is dynamic, with continuous advancements in treatment protocols, medication management, and clinical guidelines. Not incorporating the latest research findings, guidelines, and best practices into study materials for the BCEMP exam can lead to a knowledge base that is outdated and not reflective of current standards of care. This gap can be particularly detrimental in an exam setting that evaluates a candidate’s ability to apply contemporary, evidence-based practices in emergency medicine scenarios.

To ensure that study materials are current and comprehensive, candidates should regularly consult reputable medical journals in the field of emergency medicine and pharmacotherapy. These journals often publish the latest research, reviews, and consensus guidelines that can inform and update a candidate’s knowledge. Additionally, engaging in continuing education courses and participating in professional networks and associations can provide insights into emerging trends and consensus opinions in the field. These resources not only aid in preparing for the BCEMP exam but also contribute to a practitioner’s ongoing professional development, ensuring that their practice remains aligned with the highest standards of patient care in emergency medicine pharmacotherapy.

Conclusion: Embracing a Proactive and Balanced Approach to Exam Preparation

In preparing for the BCEMP exam, it’s crucial to avoid common pitfalls that can hinder success. Understanding the exam’s scope, avoiding ineffective study techniques, utilizing practice exams, managing time effectively, maintaining health, engaging with peers and mentors, and staying updated with current practices are all key to a well-rounded preparation strategy. Neglecting any of these areas can lead to gaps in knowledge, unnecessary stress, and ultimately, underperformance in the exam.

Embracing a proactive and balanced approach to studying is essential. This means not only covering all the necessary material but doing so in a way that promotes deep understanding and long-term retention. Active learning, effective time management, collaboration, and continuous learning are all part of a holistic study plan. The goal is not just to pass the BCEMP exam but to excel in the field of emergency medicine pharmacotherapy, ensuring that you are well-equipped to provide the highest level of care to patients in critical situations. By avoiding these common pitfalls and adopting a disciplined approach to preparation, candidates can position themselves for success, both in the exam and in their professional practice.

References

  • American Board of Pharmacy Specialties. Pharmacotherapy: Specialty Certification Examination Content Outline. https://www.bpsweb.org/wp-content/uploads/bps-specialties/pharmacotherapy/PT_contentoutline.pdf. Accessed September 28, 2021.
  • Dunlosky J, Rawson KA, Marsh EJ, Nathan MJ, Willingham DT. Improving students’ learning with effective learning techniques: promising directions from cognitive and educational psychology. Psychol Sci Public Interest. 2013;14(1):4-58. doi:10.1177/1529100612453266
  • Brown PC, Roediger HL 3rd, McDaniel MA. Make It Stick: The Science of Successful Learning. Cambridge, MA: Belknap Press of Harvard University Press; 2014.
  • Johnson M, Taubenheim A, Samar H, et al. Examining the impact of practice testing on learning and retention of medical information. Curr Pharm Teach Learn. 2020;12(9):1037-1045. doi:10.1016/j.cptl.2020.06.005
  • Hartwig MK, Dunlosky J. Study strategies of college students: are self-testing and scheduling related to achievement? Psychon Bull Rev. 2012;19(1):126-134. doi:10.3758/s13423-011-0181-y
  • McDaniel MA, Agarwal PK, Huelser BJ, McDermott KB, Roediger HL 3rd. Test-enhanced learning in a middle school science classroom: the effects of quiz frequency and placement. J Educ Psychol. 2011;103(2):399-414. doi:10.1037/a0021782
  • Kornell N, Bjork RA. The promise and perils of self-regulated study. Psychon Bull Rev. 2007;14(2):219-224. doi:10.3758/bf03194055
  • Chew SL. How to Get the Most Out of Studying Video Series. http://www.samford.edu/how-to-study/. Published 2011. Accessed September 28, 2021.
  • Tuckman BW, Rapport MD. A 16-session time management intervention for college students with attention deficit hyperactivity disorder. Behav Modif. 2019;43(4):527-559. doi:10.1177/0145445518777735
  • Dyrbye LN, Shanafelt TD, Sinsky CA, et al. Burnout among health care professionals: a call to explore and address this underrecognized threat to safe, high-quality care. NAM Perspectives. 2017;7(7). doi:10.31478/201707b
  • Pagnini F, Bercovitz KE, Phillips D. Calm education: meta-analysis of mindfulness and emotion regulation strategies for teachers and students. Int J Stress Manag. 2018;25(4):364-376. doi>10.1037/str0000104
  • Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298(14):1685-1687. doi:10.1001/jama.298.14.1685
  • Krupat E, Richards JB, Sullivan AM, Fleenor TJ Jr, Schwartzstein RM. Assessing the effectiveness of case-based collaborative learning via randomized controlled trial. Acad Med. 2016;91(5):723-729. doi:10.1097/ACM.0000000000001044
  • Karpicke JD, Blunt JR. Retrieval practice produces more learning than elaborative studying with concept mapping. Science. 2011;331(6018):772-775. doi:10.1126/science.1199327
  • Singh N. Habituation, Memory, Spaced-Repetitions, Massed-Repetition. LeMe’24 Blog Post 4. March 7, 2024. Available from: https://medium.com/@nishchay.singh.23510074/habituation-memory-spaced-repetitions-massed-repetition-7640d4595429
  • Ewell SN, Cotner S, Drake AG, Fagbodun S, Google A, Robinson L, Soneral P, Ballen CJ. 2022. Eight Recommendations to Promote Effective Study Habits for Biology Students Enrolled in Online Courses. J Microbiol Biol Educ. 23:e00260-21.

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Featured

PROPHY-VAP Trial





PACULit Review
4 min read
January 22, 2024

PROPHY-VAP Trial

J

Jimmy

PharmD

Study To Review

PROPHY-VAP: Prophylactic Antibiotic Use in Brain-Injured Patients to Prevent Ventilator-Associated Pneumonia – A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial

One Sentence Summary

The PROPHY-VAP trial showed that a single dose of ceftriaxone can significantly reduce early-onset VAP in mechanically ventilated brain-injured patients, offering a potential change in clinical practice for VAP prevention.

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Ventilator-associated pneumonia (VAP) is a significant concern in intensive care units (ICU), especially prevalent among brain-injured patients who are mechanically ventilated. With VAP incidence rates ranging from 22% to 71%, depending on the study, and brain injury being a notable independent risk factor, the prevention of this infection is paramount. Current standard of care includes a set of measures aiming to reduce the incidence of VAP; however, the challenge of early versus late onset VAP and the associated risk of multi-drug resistant organisms necessitate ongoing research and innovation in prophylactic strategies. The PROPHY-VAP trial is a pivotal study that explores the use of prophylactic antibiotics, specifically ceftriaxone, to prevent early-onset VAP in brain-injured patients. By addressing the controversial cut-off for early VAP onset in this population and considering the unique susceptibility profile of their infections, this trial holds significant importance for enhancing patient outcomes and refining ICU protocols.

PROPHY-VAP was a multicentre, randomized, double-blind, placebo-controlled trial conducted in nine French ICUs. The study enrolled comatose adult patients (Glasgow Coma Scale score ≤12) requiring mechanical ventilation post-acute brain injury. Patients were randomly assigned to receive either intravenous ceftriaxone 2 g or a placebo within 12 hours of tracheal intubation. The primary outcome was the incidence of early VAP (2nd to 7th day of mechanical ventilation). The study excluded patients with high death risk within 48 hours, previous hospitalizations for coma, contraindications to beta-lactams, and those receiving antibiotics for pre-existing infections.

  • The PROPHY-VAP trial was conducted over a period spanning from October 14, 2015, to May 27, 2020, during which 345 patients were randomized in a 1:1 ratio to receive either ceftriaxone (171 patients) or placebo (174 patients). The study observed a marked reduction in the incidence of early VAP in the ceftriaxone group, with only 14% (23 patients) developing the infection compared to 32% (51 patients) in the placebo group, translating to a hazard ratio of 0.60. This significant decrease in early-onset VAP incidence, demonstrated in a double-blind, placebo-controlled setting, suggests that a single dose of ceftriaxone can be an effective prophylactic intervention in brain-injured patients requiring mechanical ventilation.

A detailed analysis of the patient demographics within the trial revealed that out of the 319 patients included in the analysis, 166 were men and 153 were women. Adjudication confirmed a total of 93 cases of VAP, of which 74 were early infections. Importantly, the study reported no increase in multi-drug resistant organisms or adverse effects attributable to the administration of ceftriaxone. These results indicate that the intervention was not only efficacious in reducing the incidence of early VAP but also safe for the patients, with no additional risk of fostering antibiotic resistance. The authors report that these findings provide a strong argument for the inclusion of a single dose of ceftriaxone in VAP prevention bundles for this patient population.

Conclusion

The study demonstrates that a single dose of ceftriaxone significantly reduces the risk of early VAP in brain-injured patients requiring mechanical ventilation, without adverse microbiological consequences. This finding supports the inclusion of an early ceftriaxone dose in VAP prevention protocols for brain-injured patients.

Impression

The PROPHY-VAP trial’s findings have sparked debate within the medical community, with practitioners expressing both interest in the potential benefits of ceftriaxone prophylaxis and concern regarding the broader implications of antibiotic use, such as the risk of over-diagnosis of VAP and the absence of data on late-onset VAP and resistant pathogens. These discussions underscore the necessity for further research and careful consideration before integrating these results into standard practice.

Further Readings

AMIKINHAL trial
Pulm Crit Review of AMIKINHAL trial

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Piperacillin-tazobactam plus Vancomycin and Acute Kidney Injury by Caroline Rosario





Clinical Content
10 min read
January 5, 2024

Piperacillin-tazobactam plus Vancomycin and Acute Kidney Injury by Caroline Rosario

J

Jimmy

PharmD

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Introduction

  1. Vancomycin and piperacillin-tazobactam are combined for broad-spectrum antibiotic coverage including MRSA and Pseudomonas in hospitalized patients.
  2. AKI, often as acute tubular necrosis, is a known complication of vancomycin, especially with higher doses and co-administration of nephrotoxic drugs.
  3. Piperacillin-tazobactam alone has minimal nephrotoxicity (<1%); its nephrotoxicity is usually due to acute interstitial nephritis.
  4. Reported AKI rates vary in literature based on AKI definition and target population.
  5. Both drugs affect OAT1/3 transporters in the kidney, which are crucial for creatinine clearance and are especially significant in patients with CKD.

Pharmacology

  Vancomycin Piperacillin-tazobactam4
Dose Depends on infection and PK/PD target General dosing for systemic infections: IV 15-20 mg/kg IV Q8-12H for systemic infections Standard infusion: 3.375 g IV Q6H over 30 minAntipseudomonal: 4.5 g IV Q6-8H over 30 minExtended infusion: 4.5 g IV then 3.375-4.5 g over 4 hours Q8H
Administration Administer IV over ≥60 minutes at concentrations ≤5 mg/mL to reduce the risk of vancomycin infusion reaction Standard infusion: Infuse over 30 min Extended infusion: Infuse loading dose over 30 min, start maintenance dose four hours later infused over 4 hours
PK/PD Negligible oral bioavailability T1/2 = 4-6 hours Renally eliminated (40-100% unchanged) AUC:MIC dependent kinetics, PK/PD target AUC/MIC ≥400 µg/mL; surrogate serum trough concentrations often used T1/2 = 0.7-1.2 hours Renally eliminated (80% unchanged) Dose adjust at CrCl<40 T>MIC dependent kinetics, prolonged infusions enhance efficacy
Adverse Effects Nephrotoxicity Ototoxicity Vancomycin-infusion reaction (flushing, hypotension, tachycardia) GI upset (diarrhea, nausea, constipation) Headache Rash, pruritis
Drug Interactions and warnings Substrate of OAT1/3 +/- Inducer of OAT1/3 ↑ nephrotoxicity: aminoglycosides, aspirin   Piperacillin: substrate and inhibitor of OAT1/3∆, Tazobactam: substrate of OAT1/3 Interactions: Probenecid (↑ piperacillin-tazobactam), Methotrexate (↑ methotrexate)
Compatibility Compatible with dextrose, NS, LR Incompatible with lipid emulsion LR: only the formulation containing EDTA is compatible for Y-site administration Not chemically stable in solutions containing sodium bicarbonate or solutions that significantly alter pH Cannot be added to blood products or albumin hydrolysates
Comments Serum troughs are a poor proxy of 24-hour AUC, trough-guided regimens have been shown to exceed the target AUC in 60% of adults10 Useful in the ED for anaerobic coverage in Grade III open fractures, pneumonia with lung abscess or empyema, and empiric antipseudomonal coverage in patients with risk factors
∆ = meropenem is also a substrate of OAT1/3 but not an inhibitor

Overview of Evidence

Author, year Design/ sample size Intervention & Comparison AKI definition Outcome
Sanz et al., 2002 Prospective, multi-center (n = 969) Amikacin+cefepime vs. amikacin+piperacillin-tazobactam ↑ SCr ≥50% from baseline No difference in severe nephrotoxicity between amikacin+piperacillin-tazobactam vs. amikacin+cefepime
Karino et al., 2016 Retrospective cohort and nested case-control studies (n = 320) Vancomycin+piperacillin-tazobactam standard infusion vs. Vancomycin+piperacillin-tazobactam extended-infusion RIFILE criteriaAKIN criteriaVancomycin consensus guideline definition AKI occurred in 33% of patients receiving vancomycin+piperacillin-tazobactamUse of extended infusion piperacillin-tazobactam did not increase risk of AKI Highest daily incidence of AKI occurred on day 5 of combination therapy
Hammond et al., 2017 Meta-analysis of 14 observational studies (n = 3549) Vancomycin+piperacillin-tazobactam vs. vancomycin+any β-lactam or vancomycin alone All included studies used one of the following: RIFLE criteriaAKIN criteria↑ SCr ≥100% or >0.5 mg/dL Vancomycin+piperacillin-tazobactam greater association with AKI (aOR, 3.11; 95% CI, 1.77–5.47) Highest incidence of AKI in patients admitted to the ICU (OR 3.83 95% CI, 1.67-8.78)
Rutter et al., 2017 Retrospective matched cohort (n = 4103) Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime RIFLE criteria Vancomycin+piperacillin-tazobactam 2.18 times more likely to cause AKI vs. vancomycin+cefepime (95% CI, 1.64–2.94) Vancomycin doses between 3 and 4 g daily used,
Peyko et al., 2017 Prospective observational cohort (n = 85) Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime or vancomycin+meropenem KDIGO Incidence of AKI was higher in with  vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime or meropenem (37.3% vs. 7.7% P = .005) 
Rutter and Burgess et al., 2017 Retrospective matched cohort (n = 2448) Vancomycin+piperacillin-tazobactam vs. Vancomycin+ampicillin-sulbactam RIFLE criteria Increased risk of AKI with vancomycin+piperacillin-tazobactam (aOR, 1.77; 95% CI, 1.26–2.46), no increased rate of AKI with vancomycin+ampicillin-sulbactamRates of AKI similar for piperacillin-tazobactam and ampicillin-sulbactam without vancomycin
Jeon et al., 2017 Retrospective matched cohort (n = 5335) Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime ↑ SCr ≥0.3 mg/dL or ≥50% from baseline Vancomycin+piperacillin-tazobactam associated with a higher risk of AKI vs. vancomycin-cefepime (aHR, 1.25; 95% CI, 1.11–1.42.)
Mousavi et al., 2017 Retrospective matched cohort (n = 280) Vancomycin+piperacillin-tazobactam standard infusion vs. Vancomycin+piperacillin-tazobactam extended-infusion   RIFLE criteriaAKIN criteria Similar rate of AKI between vancomycin+piperacillin-tazobactam standard infusion vs. vancomycin+piperacillin-tazobactam extended-infusionHigher vancomycin troughs were observed in the extended infusion group
Miano et al., 2022 Prospective, observational Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime for ≥48 hours ↑ SCr vs. ↑ Cystatin C vs. ↑ BUN Vancomycin + piperacillin-tazobactam ➡️ ↑ serum creatinine-defined AKI, but no change in cystatin C, BUN, or AKI outcomes (dialysis/mortality).Indicates vancomycin + piperacillin-tazobactam AKI may be pseudotoxicity.
Qian et al, 2023 (ACORN Trial) Randomized controlled Trial N=2511 Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime KDIGO  ↑ SCr ≥0.3 mg/dL or ≥50% from baseline The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam groupThe incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillintazobactam group~77% of each concurrently received vancomycin

RIFLE, AKIN and KDIGO definitions of AKI are based upon ↑ in serum creatinine or ↓ in urine output

Conclusions

  • Since 2011, evidence indicates combined vancomycin+ piperacillin-tazobactam may be nephrotoxic.
    • Most studies were retrospective, defining nephrotoxicity by creatinine-based AKI.
  • Recent data show this AKI definition doesn’t align with severe AKI outcomes (hemodialysis/mortality).
  • Non-tubular secretion biomarkers (Cystatin C, BUN) didn’t show the same AKI increase.
  • Despite >50 studies linking the drug combo with AKI, some expert report true renal risk is likely minimal.
  • In emergencies, timely antibiotic use is vital; nephrotoxicity concerns shouldn’t delay this combo, especially for short use.

References

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  14. Watkins RR, Deresinski S. Increasing Evidence of the Nephrotoxicity of Piperacillin/Tazobactam and Vancomycin Combination Therapy-What Is the Clinician to Do? Clin Infect Dis. 2017 Nov 29;65(12):2137-2143. doi: 10.1093/cid/cix675.
  15. Karino S, Kaye KS, Navalkele B, Nishan B, Salim M, Solanki S, Pervaiz A, Tashtoush N, Shaikh H, Koppula S, Martin ET, Mynatt RP, Murray KP, Rybak MJ, Pogue JM. Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother. 2016 May 23;60(6):3743-50. doi: 10.1128/AAC.03011-15.
  16. Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam. Clin Infect Dis. 2017 Mar 1;64(5):666-674. doi: 10.1093/cid/ciw811. Epub 2016 Dec 10. PMID: 27940946.
  17. Rutter WC, Cox JN, Martin CA, Burgess DR, Burgess DS. Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime. Antimicrob Agents Chemother. 2017 Jan 24;61(2):e02089-16. doi: 10.1128/AAC.02089-16. Erratum in: Antimicrob Agents Chemother. 2017 Mar 24;61(4): PMID: 27895019; PMCID: PMC5278703.
  18. Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. 2017 Apr;30(2):209-213. doi: 10.1177/0897190016628960.
  19. Rutter WC, Burgess DS. Acute Kidney Injury in Patients Treated with IV Beta-Lactam/Beta-Lactamase Inhibitor Combinations. Pharmacotherapy. 2017 May;37(5):593-598. doi: 10.1002/phar.1918.
  20. Jeon N, Staley B, Klinker KP, Hincapie Castillo J, Winterstein AG. Acute kidney injury risk associated with piperacillin/tazobactam compared with cefepime during vancomycin therapy in hospitalised patients: a cohort study stratified by baseline kidney function. Int J Antimicrob Agents. 2017 Jul;50(1):63-67. doi: 10.1016/j.ijantimicag.2017.02.023.
  21. Mousavi M, Zapolskaya T, Scipione MR, Louie E, Papadopoulos J, Dubrovskaya Y. Comparison of Rates of Nephrotoxicity Associated with Vancomycin in Combination with Piperacillin-Tazobactam Administered as an Extended versus Standard Infusion. Pharmacotherapy. 2017 Mar;37(3):379-385. doi: 10.1002/phar.1901. E
  22. Miano TA, Hennessy S, Yang W, Dunn TG, Weisman AR, Oniyide O, Agyekum RS, Turner AP, Ittner CAG, Anderson BJ, Wilson FP, Townsend R, Reilly JP, Giannini HM, Cosgriff CV, Jones TK, Meyer NJ, Shashaty MGS. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Intensive Care Med. 2022 Sep;48(9):1144-1155. doi: 10.1007/s00134-022-06811-0.
  23. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Møller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y.
  24. Qian ET, Casey JD, Wright A, Wang L, Shotwell MS, Siemann JK, Dear ML, Stollings JL, Lloyd BD, Marvi TK, Seitz KP, Nelson GE, Wright PW, Siew ED, Dennis BM, Wrenn JO, Andereck JW, Han JH, Self WH, Semler MW, Rice TW; Vanderbilt Center for Learning Healthcare and the Pragmatic Critical Care Research Group. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial. JAMA. 2023 Oct 24;330(16):1557-1567. doi: 10.1001/jama.2023.20583. PMID: 37837651; PMCID: PMC10576861.

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Seizure Prophylaxis in Traumatic Brain Injury by Jordan Spurling





Clinical Content
9 min read
November 17, 2023

Seizure Prophylaxis in Traumatic Brain Injury by Jordan Spurling

J

Jimmy

PharmD

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Introduction

  1. Traumatic brain injury (TBI) is a leading cause of death and disability in the United States.
  2. 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.
  3. The incidence of early post-traumatic seizures may be as high as 30 percent in patients with severe TBI
  4. 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
  5. Prevention of early seizures is beneficial in order to prevent status epilepticus, further aggravating systemic injury.
  6. 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

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October  17, 2023, from http://www.micromedexsolutions.com/
  2. 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
  3. 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
  4. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 13, 2023, from http://www.micromedexsolutions.com/
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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.
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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.
  15. 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

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Penicillin Allergy Cross Reactivity





Clinical Content
6 min read
October 6, 2023

Penicillin Allergy Cross Reactivity

J

Jimmy

PharmD

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Introduction

  1. 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.
  2. True IgE-mediated penicillin allergies that cause anaphylaxis are rare.
  3. An IgE-mediated penicillin allergy can diminish over time, as 80% of patients become tolerant after a decade.
  4. Patients with a documented penicillin allergy may be inappropriately exposed to alternative antibiotics, resulting in increased treatment failures, adverse effects, and antimicrobial resistance.
  5. 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

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

References

  1. Apter AJ, Kinman JL, Bilker WB, et al. Is There Cross-Reactivity Between Penicillins and Cephalosporins? Am J Med. 2006;119(4):354e11-19.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Chaudry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and Beta-Lactam Cross-Reactivity. Pharmacy. 2019;7:1-16.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-199.
  15. 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.
  16. 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.

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Corticosteroids in Sepsis by Marissa Marks, PharmD





Clinical Content
7 min read
September 14, 2023

Corticosteroids in Sepsis by Marissa Marks, PharmD

J

Jimmy

PharmD

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Introduction

  1. Sepsis is a systemic inflammatory response (SIRS) with associated organ dysfunction as a result of an infection.
  2. 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
  3. 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.
  4. 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

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Hydrocortisone (2023) UpToDate. Available at: https://www.uptodate.com (Accessed: 13 August 2023).
  7. Hydrocortisone Sodium Succinate (2023) Micromedex. Available at: https://www.micromedexsolutions.com (Accessed: 13 August 2023).
  8. 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.
  9.  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.
  10. 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.
  11. 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.
  12. 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.

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Ketamine for Treatment of Acute Agitation





Clinical Content
3 min read
April 28, 2023

Ketamine for Treatment of Acute Agitation

J

Jimmy

PharmD

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Introduction

  1. Ketamine is a sedative used for patients with extreme/refractory undifferentiated agitation
  2. 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

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

References

  1. Ketamine. Micromedex [Electronic version].              
  2. Barbic D, et al. Trials. 2018;19(1):651. Published 2018 Nov 26.
  3. 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.
  4. Mankowitz WL, et al. J Emerg Med. 2018;55(5):670-81.
  5. Cole JB, et al. Clin Toxicol (Phila). 2016;54(7):556–562.
  6. Isbister GK, et al. Ann Emerg Med. 2016;67(5):581–587.
  7. Riddell J, et al. Am J Emerg Med. 2017. http://dx.doi.org/10.1016/j.ajem.2017.02.026
  8. Scheppke KA, et al. WestJEM. 2014;15(7);736-41.

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PPIs for the Management of Upper GI Bleed





Clinical Content
7 min read
April 21, 2023

PPIs for the Management of Upper GI Bleed

J

Jimmy

PharmD

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Introduction

  1. Upper GI bleed (UGIB) is a common reason for ED visits with a major cause of morbidity, mortality and medical care costs.
  2. Peptic ulcer accounts for at least 50% of UGIB cases.
  3. Patients with UGIB usually present with hematemesis, melena and/or hematochezia.
  4. Upon presentation, hemodynamic status should be evaluated and resuscitation provided if necessary. Resuscitation can include blood transfusion for target hemoglobin of ≥7 g/dl.
  5. Patients can be risk stratified to low or high-risk using the Rockall score (range 0-7) and Blatchford score (range 0-23).
  6. 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

  1. 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.
  2. Compared to placebo, PPIs reduced the signs of upper gastrointestinal bleeding observed during endoscopy and reduced the need for endoscopic treatment. 
  3. 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

  1. Clinical Pharmacology [Electronic version]. Elsevier, 302 Knights Run Ave., Suite 800, Tampa, FL 33602. Retrieved February 17, 2021, from http://www.clinicalpharmacology-ip.com/
  2. Uptodate [Electronic version]. Retrieved February 15, 2021, from http://www.uptodate.com/
  3. 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 
  4. 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.  
  5. 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.  
  6. 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.  
  7. 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.  
  8. 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.  
  9. 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.
  10. 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.

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Hypertonic Saline Versus Mannitol for ICP Reduction  





Clinical Content
4 min read
March 17, 2023

Hypertonic Saline Versus Mannitol for ICP Reduction  

J

Jimmy

PharmD

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Introduction  

  1. Elevated intracranial pressure (ICP) is caused by excess volume in the cerebral spaces, which causes a reduction in the cerebral perfusion pressure and affects blood flow and oxygenation to the brain.   
  2. Hyperosmolar agents (hypertonic saline and mannitol) are utilized to form a gradient across the blood-brain barrier to draw fluid from the cerebral space into the vasculature, thus reducing ICP  
  3. Mannitol was previously considered the gold standard of osmotic therapy, but hypertonic saline has proven to be at least as effective as mannitol at reducing ICP  

Pharmacology  

   Hypertonic Saline    Mannitol  
   Mechanism    Increases serum sodium levels, making it more hypertonic. Giving a bolus causes a gradient for   water to follow sodium extracellularly and move out   of the cerebral spaces into the vasculature, while a   continuous infusion aids in resuscitation    Osmotic diuretic by increasing the osmolality of the glomerular filtrate, thus blocking reabsorption of water and excretion of sodium. This leads to   movement of water to extracellular and vascular   spaces and reducing the ICP  
Dose   3 – 23.4% available      3%: optimal dose is unclear, reasonable to start with   300-500mL bolus or continuous infusion at 100mL/hr and titrate per response      23.4% : 0.43-0.5 mL/kg IV bolus, max 30mL/dose   5 – 25% solutions available (20% most common)      0.25 – 1g/kg/dose IV bolus q 6-8 hours (Usually 25-100g per dose)  
Administration   3% intermittent bolus or continuous infusion   *strong osmotic gradient not retained with continuous infusions      23.4% intermittent bolus over 15 minutes   Intermittent IV infusion over 30 minutes   
Adverse Effects   Hypervolemia,  respiratory distress, electrolyte imbalances (hypernatremia)   Hypotension, hypovolemia, AKI, electrolyte disturbances (specifically K+), extravasation  
Cautions/Pearls      Solutions > 3-5% require a central line       Requires in-line filter due to risk of crystallization Avoid in hypovolemia and anuria  
Patient population to consider use in   Hypovolemic, hypotensive, traumatic resuscitation    Euvolemia, hypertensive, fluid restrictions   
Monitoring   Serum sodium 145-155mEq/dL    Serum osmolality 300-320 mOsm/L Titrate based on ICP   Serum osmolality 300-320 mOsm/L  Titrated based on ICP  
Where to find in GHS   3% Sodium chloride – 500mL   EDZONE2, EDZONE3, ALL TRAUMA STATIONS   20% Mannitol – 500ML   EDZONE2, EDZONE3, TRAUMA-M, EDETENTION  

Considerations for Administration     

   3% Sodium Chloride   23.4% Sodium Chloride   20% Mannitol  
Vascular Access   Peripheral or central   Central ONLY   Peripheral or central  
Volume (per dose)   500mL +    ~30 mL   125 – 500 mL(20%)  
Equipment   Bolus: Infusion by gravity Continuous: IV infusion pump   Syringe pump preferred    IV infusion pump  

Overview of Evidence  

Author, year    Design/ sample   size   Intervention & Comparison   Outcome  
A. Kerwin, 2009   Retrospective analysis,  (22 patients)   HTS vs mannitol   mean ICP reduction in patients with TBI   HTS is as efficacious as mannitol, if not more so, and adds to the growing literature suggesting that HTS is an effective modality for the control of elevated ICP in patients with severe TBI  
M. Li, 2015   Meta-Analysis,    7 studies    (169 patients)   HTS vs mannitol in mean ICP reduction in patients with TBI   HTS reduces ICP more effectively than mannitol in the setting of TBI  
S. Burgess, 2016   Meta-Analysis,    7 trials    (191 patients)   HTS vs mannitol in mean ICP reduction, risk of ICP treatment  failure, mortality rates, and neurological outcomes   No statistical difference in mortality and neurological outcomes. No difference in mean reduced ICP; decreased risk of ICP treatment failure with HTS  
E. Berger- Pelleiter, 2016   Meta-Analysis,   11 studies   (1,820 patients)   HTS vs mannitol in reduction of mortality, ICP, and increasing functional outcomes   No significant reduction in mortality, no significant reduction in mean ICP, no significant difference in functional outcomes  
C.  Pasarikovski,  2017   Systematic   Review,   5 studies    (175 patients)   HTS vs mannitol in ICP reduction in aneurysmal subarachnoid hemorrhage   No difference between mannitol and 3% HTS in reducing ICP in patients with aneurysmal subarachnoid hemorrhage  
J. Gu, 2018   Mata-Analysis,   12 RCTs,    (438 patients)   HTS vs mannitol in ICP reduction, ICP control, changes in serum sodium and   osmolality, mortality,   neurological function  outcome   No difference in mean ICP reduction, neurological function, and mortality. HTS may be preferred in TBI patients with refractory intracranial hypertension  
It is essential to consider the adverse effects of each agent and the comorbidities for an individual patient rather than making a simple comparison in efficacy of hypertonic saline versus mannitol  

References

  • Burgess S, et al. Annals of pharmacotherapy. 2016;50(4):291-300.  
  • Li M, et al. Y, 2015. Medicine. 2015;9(4):17.  
  • Dastur C, et al. Stroke and vascular neurology. 2017;2:21-29.  
  • Kerwin A, et al. J Trauma. 2009;67:277-282.  
  • Pasarikovski C, et al. World Neurosurg. 2017;105:1-6.  
  • Gu J, et al. Neurosurg Rev. 2018;42:499.  
  • Berger-Pelleiter E, et al. CJEM. 2016;18:112–120.  
  • Farrokh S, et al. Curr opin crit care. 20119; 25:105-109.  
  • Witherspoon B, et al. Nurs Clin N Am. 2017;52:249-60.   
  • Micromedex [Electronic].Greenwood Village, CO: Truven Health Analytics. Retrieved August 12, 2019 from http://www.micromedexsolutions.com

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10 Things You Can Do If You Don’t Match for a Pharmacy Residency Program





Clinical Content
3 min read
March 15, 2023

10 Things You Can Do If You Don’t Match for a Pharmacy Residency Program

J

Jimmy

PharmD





Clinical Content
2 min read
March 15, 2023

10 Things You Can Do If You Don’t Match for a Pharmacy Residency Program

J

Jimmy

PharmD

As pharmacy residency application season comes to a close, it’s time to take a deep breath and reflect on the experience. Regardless of the outcome, it’s important to remember that you’ve put in a tremendous amount of effort and dedication to get to this point.

Things didn’t go as planned but here’s 10 things you can do now to try to focus on what you can versus what you cannot.

10 Things to Do

  1. Do not panic or lose hope. Not matching is not the end of your career and there are still opportunities to pursue your goals
  2. Review your application materials and identify areas of improvement. Seek feedback from mentors, preceptors, faculty members, or peers who can help you improve your CV, letter of intent, interview skills, etc
  3. Consider participating in Phase II of the Match or the Post-Match Scramble. Phase II is another round of matching for programs that still have unfilled positions after Phase I. The Post-Match Scramble is an informal process where applicants can contact programs directly after Phase II to inquire about any remaining vacancies
  4. Be flexible and open-minded about your options. You may need to expand your geographic preferences, consider different types of programs or settings, or apply for non-traditional residencies such as fellowships or industry positions
  5. Network and stay connected with potential employers, mentors, preceptors, faculty members, alumni, or colleagues who can offer you advice, support, referrals, or opportunities.
  6. Update your online profiles and portfolios such as LinkedIn, ePortfolio, ASHP Connect etc., to showcase your achievements, skills, and interests.
  7. Seek out additional learning opportunities such as continuing education courses, certificate programs, webinars, podcasts, journals, etc., to enhance your knowledge and skills and demonstrate your commitment to professional development
  8. Explore alternative career paths or transitional roles that can help you gain valuable experience and exposure to different aspects of pharmacy practice such as clinical pharmacist, staff pharmacist, adjunct faculty member, consultant pharmacist, etc
  9. Maintain a positive attitude and a growth mindset. Do not let rejection or failure define you or discourage you from pursuing your goals. Learn from your mistakes and challenges and use them as opportunities to improve yourself
  10. Seek professional help or support if needed. Not matching can be a stressful and emotional experience that can affect your mental health and well-being. Do not hesitate to reach out to counselors, therapists, coaches, mentors, friends, family members, or other sources of support who can help you cope with your feelings and provide you with guidance and encouragement.

Good Luck with the next phase of your life

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Beyond Residency Applications: How to Focus on Self-Improvement and Growth





Clinical Content
3 min read
March 3, 2023

Beyond Residency Applications: How to Focus on Self-Improvement and Growth

J

Jimmy

PharmD





Clinical Content
2 min read
March 3, 2023

Beyond Residency Applications: How to Focus on Self-Improvement and Growth

J

Jimmy

PharmD

As pharmacy residency application season comes to a close, it’s time to take a deep breath and reflect on the experience. Regardless of the outcome, it’s important to remember that you’ve put in a tremendous amount of effort and dedication to get to this point. Now, it’s time to shift your focus to other areas of your life.

One of the most important things you can do during this time is to focus on yourself. This means taking the time to catch up on any projects, research, or top discussions that were put on hold due to residency application season. It also means making time for things outside of pharmacy, such as exercising, reading, or even binge-watching a new Netflix series.

By focusing on something outside of pharmacy, you can clear your mind and approach your work with a fresh perspective. People who are flexible, open-minded, and hard-working will make the best out of every situation and get more from a residency program than other candidates simply due to the fact that they have an open mindset compared to having a fixed mindset.

Residency training has gotten larger and more structured, which means that there will be a great program for you no matter where you end up. Trust that you got it right with your rank list, and that you will end up in the best scenario. Be open to learning and growing, and you will make the most out of your residency program.

And if you don’t match, that’s okay too. There are other routes you can take to get to the ultimate goal of using your pharmacy degree to the maximum and getting the job you desire. Don’t be discouraged – keep pushing forward and pursuing your dreams.

Remember, it’s important to take care of yourself and your well-being during this time. If you have any thoughts or comments, please feel free to share them with us in the comments section below. We’d love to hear from you.

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Management of Hypertensive Emergency





Clinical Content
7 min read
February 23, 2023

Management of Hypertensive Emergency

J

Jimmy

PharmD





Clinical Content
5 min read
February 23, 2023

Management of Hypertensive Emergency

J

Jimmy

PharmD

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Introduction

  1. Hypertensive emergency is characterized by systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 120 mmHg with evidence of target organ damage. 
  2. Rapid blood pressure lowering with intravenous antihypertensives is warranted to prevent further organ damage. 
  3. Patients presenting with intracranial hemorrhage, aortic dissection, preeclampsia, or pheochromocytoma crisis should achieve target blood pressure within one hour of presentation. 
  4. Current literature lacks evidence of mortality benefit with any one antihypertensive drug. Selection of a medication should consider target organ(s) affected, underlying disease states, and time to target blood pressure. 

Treatment in Selected Co-Morbidities

Condition BP Goal Preferred Agents
Acute aortic dissection   SBP < 120 mmHg within 20 min Esmolol Labetalol Nicardipine Nitroprusside
Eclampsia or Preeclampsia   SBP < 140 mmHg  within 1 hour Nicardipine Labetalol Hydralazine
Pheochromocytoma (catecholamine excess)   SBP < 140 mmHg  within 1 hour Nicardipine Phentolamine*
Intracranial hemorrhage SBP < 160 mmHg within 6 hours Nicardipine Labetalol
Acute ischemic stroke Pre-alteplase: < 185/110 mmHg Post-alteplase: < 180/105 for 24 hours No thrombolytic: SBP reduced 15% in 24 hours**                                                                        Nicardipine Labetalol
*Phentolamine currently unavailable due to nationwide shortage
**Permissive hypertension may be reasonable; maintain SBP < 220 mmHg or DBP < 120 mmHg

Pharmacology: Intravenous Antihypertensives

 First-line Agents  
Medication Class Onset Duration Dosing Clinical Pearls
Nicardipine     Ca channel blocker  IV: 5-10 min IV: 2-6 hours Initial: 5 mg/hr  Titration: 2.5 mg/hr every 15 min  Maximum: 15 mg/hr  No dose adjustments in elderly patients 
Esmolol             Beta-blocker  IV: 1-2 min IV: 10-20 min Bolus: 500-1,000 mcg/kg Initial: 50 mcg/kg/min  Titration: repeat bolus dose, then increase by 50 mcg/kg/ min every 10 min Maximum: 200 mcg/kg/min  Contraindications:  Bradycardia Decompensated HF 
Labetalol     Beta-blocker  Alpha-1 antagonist IV: 2-5 min Peak: 5-15 min IV: 2-6 hours Peak: 18 hours Bolus: 10-20 mg IV push every 10 min IV infusion: 0.5 – 10 mg/min titrated 1-2 mg/min every 2 hours Maximum: 300 mg total  Precaution: Second-/thirddegree heart block Bradycardia Heart failure
 
Second-line Agents		  
Phentolamine* Non-selective alpha antagonist IV: Seconds IV: 15 min   Initial: 5 mg IV push  May repeat every 10 min PRN   Useful in catecholamine excess and clonidine withdrawal 
  Nitroglycerin         NOdependent vasodilator IV: 2-5 min IV: 5-10 min ACS: Initial: 5 mcg/min  Titration: 5 mcg/ min every 3-5 min Maximum: 20 mcg/min  Pulmonary edema: Initial: 100-200 mcg/min Titration: 50 mcg/min every 3-5 min Maximum: 400 mcg/min Indicated in ACS or pulmonary edema  Use caution in volume-depleted patients 
Sodium nitroprusside     NOdependent vasodilator IV: Seconds IV: 1-2 min Initial: 0.3-0.5 mcg/kg/min  Titration: 0.5 mcg/kg/min every 1 min Maximum: 10 mcg/kg/min  Requires intra-arterial BP monitoring   Tachyphylaxis and cyanide toxicity with prolonged use – Limit treatment duration
Hydralazine   Direct vasodilator IV: 10 min IM: 20 min IV: 1-4 hours IM: 2-6 hours Initial: 10-20 mg IV push  Repeat every 4-6 hours PRN  Not available as an IV infusion 
Enalaprilat         ACE inhibitor IV: 15-30 min IV: 12-24 hours Initial: 1.25 mg IV over 5 min  Titration: increase by 5 mg every 6 hours as needed  Slow onset (~15 min)  Contraindications:  Pregnancy MI Bilateral renal stenosis 
*Phentolamine currently unavailable due to nationwide shortage

Overview of Evidence

Author (Title), Year  Design Purpose Outcome
Anderson (INTERACT), 2008 RCT (N=404) Comparison of BP goals  (SBP < 140 vs SBP < 180)  in patients with acute ICH Mean hematoma expansion was smaller in the intensive group (13.7% vs 36.3%) No difference in death or disability at 3 months (48% vs 49%) Limitation: included patients with SBP > 150 mmHg, over 30% of patients were treated with oral antihypertensive therapy
Quereshi (ATACH-2), 2016 RCT (N=1,000) Comparison of BP goals  (SBP 110-139 vs SBP 179-140)  in patients with acute ICH All patients received nicardipine infusion No difference between death or disability at 3 months (38.7% vs 37.7%) Increased renal adverse events within 24 hours in the intensive group (9.0% vs 4.0%) Limitation: mean SBP differed by only 10 mmHg between groups 2 hours post-randomization (129 mmHg vs 141 mmHg)
Peacock (CLUE), 2011 RCT (N=226) Nicardipine IV infusion versus labetalol IV bolus for management of hypertensive emergency Patients receiving nicardipine were more likely to reach target BP within 30 min (91.7% vs 82.5%) Rescue antihypertensive use did not differ significantly between groups within first 6 hours Limitation: only 63.3% of patients had evidence of target organ damage at randomization
Yang, 2004 Prospective cohort (N=40) Nitroprusside IV versus nicardipine IV for hypertensive emergency with pulmonary edema No significant difference between blood pressure readings across groups at any time point No adverse events reported in either group Limitation: nicardipine dosing started at 3 mcg/kg/min (12.5 mg/hr in a 70 kg patient)

Conclusions

  1. Selection of a first-line antihypertensive should consider compelling indications and acute blood pressure goals, as robust literature comparing long-term outcomes across drug classes is lacking for most indications.
  2. Nicardipine may provide more consistent blood pressure control than labetalol. This is particularly important in patients with acute stroke, as large fluctuations in blood pressure are believed to negatively impact cerebral perfusion.
  3. Aggressive lowering of SBP less than 140 mmHg in patients with acute ICH has not been shown to improve long-term outcomes and may negatively impact renal perfusion. 
  4. Nicardipine has been shown to provide similar blood pressure control to nitroprusside. In patients with acute ICH, nitroprusside use within 24-hours of presentation was associated with higher in-hospital mortality. 

References

  1. Whelton, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Amer Heart Assoc 2018;71(6):e13-e115. 
  2. Benken ST. Hypertensive emergencies. CCSAP 2018;1:7-30.
  3. Anderson, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-9. 
  4. Quereshi, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. New Engl J Med 2016;375(11):1033-43. 
  5. Peacock WF, et al. CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department. Critical Care 2011;15(R157):1-8. 
  6. Yang HJ, Kim JG, Lim YS, et al. Nicardipine versus nitroprusside infusion as antihypertensive therapy in hypertensive emergencies. J Int Med Res 2004;32:118-23. 

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Featured

Fibrinolytics for STEMI





Clinical Content
6 min read
February 16, 2023

Fibrinolytics for STEMI

J

Jimmy

PharmD


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Introduction

  1. Percutaneous coronary intervention (PCI) is the preferred reperfusion strategy during a cardiac arrest; thrombolytic therapy is an option without PCI capability, followed by transfer to a PCI capable center.
  2. Thrombolytic therapy is most effective when administered within 30 minutes of first medical contact, however, may be considered within 12–24 hours of symptom onset and ongoing ischemia or extensive ST elevation.
  3. During ACS-Induced Cardiac Arrest, the goal for fibrinolysis is 30 minutes and reperfusion with PCI is preferred, however, if PCI is delayed, fibrinolytics therapy could be considered.

Pharmacology

Alteplase Tenecteplase
MOA Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin. Promotes initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin; similar to alteplase but more fibrin specific.
Dose Weight based:
>67kg: infuse 15mg IV bolus over 1–2 min, followed by 50mg infusion over 30 min, then 35mg over 1 hour (max 100mg)
≤67kg: infuse 15mg IV bolus over 1–2 min, followed by 0.75mg/kg infusion over 30 min, then 0.5mg/kg over 1 hour (max 100mg) 		Weight based:
<60kg: 30mg
≥60 to <70kg: 35mg
≥70 to <80kg: 40mg
≥80 to <90kg: 45mg
≥90kg: 50mg
Administration Bolus administered over 1 minute followed by infusion. Single bolus over 5 seconds.
PK/PD Duration: 1 hour after infusion terminated
Distribution: approximates plasma volume
Half-life elimination: 5 minutes
Excretion: hepatic and plasma clearance 		Distribution: weight related
Metabolism: hepatic
Half-life elimination: biphasic; initial 20–24 min, terminal 90–130 min
Excretion: plasma clearance
Adverse Effects Intracranial hemorrhage, ecchymosis, GI/GU hemorrhage, sepsis, cerebrovascular accident. Hemorrhage and hematoma, cerebrovascular accident.
Drug Interactions & Warnings Tranexamic acid — avoid combination. Internal bleeding, thromboembolic events, cholesterol embolization. Tranexamic acid — avoid combination. Internal bleeding, thromboembolic events, arrhythmias.
Contraindications Active internal bleeding; ischemic stroke within 3 months (except when within 4.5 hours); severe uncontrolled hypertension. Active internal bleeding; severe uncontrolled hypertension; recent intracranial/intraspinal surgery; ischemic stroke within 3 months.
Compatibility May be diluted in equal volume with 0.9% sodium chloride or D5W. Incompatible with dextrose.

Overview of Evidence

Author, Year Design / Sample Size Intervention & Comparison Outcome
Guillermin 2016a Meta-analysis of RCT (n=18,208) Tenecteplase 30–50mg vs alteplase 80–100mg Bleeding 4.8% in tenecteplase vs 5.8% alteplase (p=0.0002). No difference in mortality at 30 days.
Llevadot 2001 Retrospective review (38 studies) Reteplase, anoteplase, tenecteplase Tenecteplase and reteplase associated with accelerated infusion and more convenient bolus administration. Less fibrin-specific agents may cause greater systemic coagulopathy with potential for more bleeding.
Boersma 1996 Retrospective review (n=50,246) Fibrinolytic therapy vs placebo Mortality reduction in patients treated within 2 hours compared to later (p=0.001).
GUSTO 1993 Randomized, controlled trial (n=41,021) Streptokinase + SQ heparin; streptokinase + IV heparin; alteplase + IV heparin; alteplase + streptokinase + IV heparin Alteplase administered over 1.5 hours with IV heparin provided survival benefit over standard therapy. Thrombolytic therapy administered within 24–48 hours of admission.
Armstrong 2013b Randomized controlled trial (n=1,892) PCI vs bolus tenecteplase, clopidogrel, and enoxaparin Tenecteplase prehospital resulted in effective reperfusion when PCI was not completed within 1 hour. Fibrinolytic therapy associated with increased risk of intracranial bleeding.
Cardiac Arrest Data
Bottiger 2001 Prospective cohort (n=40) Alteplase 50mg bolus, repeat 50mg in 30 min vs placebo Increase in ROSC (68% vs 44%) and ICU admission compared to placebo.
Schreiber 2002 Retrospective chart review (n=157) Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min Thrombolytic therapy achieved better functional neurological recovery more frequently (p=0.03).
Lederer 2004 Retrospective chart review (n=108) Alteplase 100mg (15mg followed by 85mg over 90 min) 81% of patients discharged without neurological deficit. 67% of patients still alive 5–10 years after the event.
Li 2006 Meta-analysis Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min Thrombolytic therapy improved the rate of ROSC (p<0.01). 48% of patients had acute coronary artery obstruction.
Bottiger 2008 Randomized, double-blind, multicenter trial (n=1,050) Tenecteplase 30mg if <60kg
Tenecteplase 35mg if 60–69kg
Tenecteplase 40mg if 70–79kg
Tenecteplase 45mg if 80–89kg
Tenecteplase 50mg if >90kg
vs placebo 		No difference between tenecteplase and placebo in 30-day survival, ROSC, or neurologic outcomes. Increased intracranial hemorrhages in tenecteplase patients.
RuizBailen 2001 Retrospective cohort (n=303) Streptokinase; alteplase accelerated regimen; alteplase double bolus Systemic thrombolysis patients had lower mortality, less mechanical ventilation, fewer CPR attempts (p<0.0001). No fatal hemorrhagic complications.

a Administered as tenecteplase 30–50mg bolus and alteplase 15mg bolus followed by 0.75mg/kg infusion over 30 min.
b Half-dose tenecteplase administered in patients ≥75 years old.
c Reteplase administered as two boluses of 10 million units given 30 minutes apart.

Conclusions

  1. Evidence supports PCI is the first-line option for management of patients requiring reperfusion during cardiac arrest when a STEMI is suspected.
  2. Available evidence suggests tenecteplase and alteplase are appropriate fibrinolytic therapies when PCI is unavailable.
  3. Tenecteplase is an alternative fibrinolytic therapy and has been evaluated as safe and efficacious as a bolus dose of 30–50mg.
  4. When alteplase is the only fibrinolytic therapy available, there is data to support bolus therapy +/- a weight-based infusion during cardiac arrest.
  5. Thrombolytic agents administered during CPR can improve the rate of survival but are associated with a risk of severe bleeding.

References

  1. Lexicomp [Electronic version]. Macedonia, OH: Truven Wolters Kluwer Health. Retrieved January 26, 2021, from https://online.lexi.com/lco/action/login.
  2. Guillermin A, Yan D, Perrier A, Marti C. Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: a systematic review and meta-analysis of randomized trials. Arch Med Sci 2016; 12(6):1181–1187.
  3. Llevadot J, Giugliano R, Antman E. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA. 2001;286(4):442–449.
  4. Boersma E, Maas A, Deckers J, Simoons M. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348:771–775.
  5. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. NEJM. 1993;329(10):673–682.
  6. Armstrong P, Gershlick A, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. NEJM. 2013;268(15):1379–1387.
  7. Wilcox R. Randomized, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT). Lancet. 1995;346(8971):329–336.
  8. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J. 1999;137(5):786–791.
  9. Lederer W, Lichtenberger C, Pechlaner C, et al. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation. 2001;50(1):71–76.
  10. Schreiber W, Gabriel D, Sterz F, et al. Thrombolytic therapy after cardiac arrest and its effect on neurological outcome. Resuscitation. 2002;52(1):63–69.
  11. Lederer W, Lichtenberger C, Pechlaner C, et al. Long-term survival and neurological outcome of patients who received recombinant tissue plasminogen activator during out-of-hospital cardiac arrest. Resuscitation. 2004;61(2):123–129.
  12. Li X, Fu QL, Jing XL, et al. A meta-analysis of cardiopulmonary resuscitation with and without the administration of thrombolytic agents. Resuscitation. 2006;70(1):31–36.
  13. Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. NEJM. 2008;359(25):2651–2662.
  14. Kurkciyan I, Meron G, Sterz F, et al. Major bleeding complications after cardiopulmonary resuscitation: impact of thrombolytic treatment. J Intern Med. 2003;253(2):128–135.
  15. Ruiz-Bailén M, Aguayo de Hoyos E, Serrano-Córcoles M, et al. Efficacy of thrombolysis in patients with acute myocardial infarction requiring cardiopulmonary resuscitation. Intensive Care Med. 2001;27(6):1050–1057.
  16. Richling N, Herkner H, Holzer M, et al. Thrombolytic therapy vs primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction. Am J Emerg Med. 2007;25(5):545–550.
  17. Böttiger B, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet. 2001;357(9268):1583–1585.

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Featured

Procainamide for Wide Complex Tachycardia





Clinical Content
5 min read
February 9, 2023

Procainamide for Wide Complex Tachycardia

J

Jimmy

PharmD





Clinical Content
4 min read
February 9, 2023

Procainamide for Wide Complex Tachycardia

J

Jimmy

PharmD

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Introduction

  1. Ventricular tachycardia (VT) is an uncommon but dangerous medical condition, with an extremely variable clinical presentation.
  2. Intravenous procainamide is guideline recommended and is the drug of choice for the treatment of hemodynamically stable VT with a class IIa recommendation.
  3. Procainamide is an old drug with new evidence that supports it’s use but dosing strategies and administration techniques makes it difficult to use at the bedside.

Pharmacology

  Procainamide
Dose and administration
  • Bolus Dosing
    • 10-17 mg/kg over 20-60 minutes (Max dose suggest 1g and max rate of 20-50 mg/min)                   
    • alternative Dosing: 100 mg every 5 minutes at max rate of 50 mg/min to max dose 1g 
  • Renal Adjustments
    • eCrCl 10-50 ml/min: Reduce initial dosing by 25-50 %
    • eCrCL < 10 ml/min: Reduce initial dosing by 50-75%  
  • Maintenance Infusion Dosing 1-6 mg/min 
Mechanism of Action  •      Class 1A anti-arrhythmic that binds to fast sodium channels inhibiting recovery after repolarization. It also prolongs the action potential and reduces the speed of impulse conduction
PK/PD
  • Onset: IV <2 minutes; IM 10-30 minutes
  • Time to Peak: IV 25-60 minute; IM 15-60 minutes
  • Duration: IV/IM: 3-4 hours
  • Metabolism: Converted by the liver to N-acetylprocainamide (NAPA), an active compound
  • Half-life: 2.5– 4.7 hr (NAPA— 7 hr); increased in renal impairment
  • Excretion: 40– 70% excreted unchanged by the kidneys
Adverse Effects Hypotension Hepatotoxicity Positive ANA titer Lupus-like syndrome Anaphylaxis caused by sulfite salt Myasthenia gravis exacerbation  Angioedema
Drug Interactions and warnings         •      Interacts with diazepam, diltiazem, milrinone, phenytoin, and hydralazine
Compatibility Compatible in  o                0.9 % Sodium Chloride and 0.45% sodium chloride,  Incompatible with  o        D5 (depending on procainamide concentration), LR, and D5NS 
Comments •      Define hospital’s dosing and administration policy as there is a risk for adverse event’s due to multiple dosing strategies in the literature

Overview of Evidence

Author, year  Design/ sample size Intervention & Comparison Outcome
Ortiz,2017 Randomized controlled trial   n= 62 IV procainamide 10 mg/kg over 20 min IV amiodarone 5mg/kg over 20 min Major cardiac adverse occurred in 3 of 33 (9%) procainamide and 12 of 29 (41%) amiodarone patients.   Tachycardia terminated within 40 min in 22 (67%) procainamide and 11 (38%) amiodarone patients. 
Maril,2010 Multicenter cohort study    n= 187 IV Amiodarone 2 mg/kg infusion at a rate of at least 10 mg⁄ min   IV Procainamide 10 mg/kg infusion at a rate of at least 15 mg⁄ min •      The rates of VT termination were 25% (13 ⁄ 53) and 30% (9 ⁄ 30) for amiodarone and procainamide, respectively.
Komura,2010 Retrospective analysis   n= 90 IV Procainamide 100 mg over 1–2 min   IV Lidocaine bolus of 50 mg •      Procainamide and lidocaine terminated VTs in 53/70 (75.7%) and in 7/20 (35.0%) respectively.
Maril,2006 Retrospective case series   n= 33 IV Amiodarone 150 mg over 15 minutes Amiodarone rate of successful ventricular tachycardia termination was 8 of 28 (29%).   Two of 33 patients (6%) required direct current cardioversion for presyncope or hypotension temporally associated with amiodarone treatment.
Gorgels,1996 Randomized parallel study   n= 79 IV Procainamide 10 mg/kg   IV Lidocaine 1.5 mg/kg Lidocaine terminated 6 of 31 VTs and procainamide 38 of 48 (p <0.001).    A comparison of the QRS width and QT interval before and at the end of the injection revealed significant lengthening of these values after procainamide but no change after lidocaine.
Callans,1992 Observational study   n= 15 IV Procainamide rate of 50 mg/min until the arrhythmia terminated or a total dose of 15 mg/kg  •      Procainamide was well tolerated and resulted in termination of ventricular tachycardia in 93% of patients after administration of 100 to 1,080 mg (median dose 600 mg).

References

  1. Procainamide. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved July 6, 2020, from http://www.micromedexsolutions.com/
  2. Long B, Koyfman A. Best Clinical Practice: Emergency Medicine Management of Stable Monomorphic Ventricular Tachycardia. J Emerg Med 2017;52:484-492.
  3. Ortiz M, Martín A, Arribas F, et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J. 2017;38(17):1329-1335. doi:10.1093/eurheartj/ehw230
  4. Marill KA, deSouza IS, Nishijima DK, et al. Amiodarone or procainamide for the termination of sustained stable ventricular tachycardia: an historical multicenter comparison. Acad Emerg Med. 2010;17(3):297-306. doi:10.1111/j.1553-2712.2010.00680.x
  5. Komura S, Chinushi M, Furushima H, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010;74(5):864-869. doi:10.1253/circj.cj-09-0932
  6. Marill KA, deSouza IS, Nishijima DK, Stair TO, Setnik GS, Ruskin JN. Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Ann Emerg Med. 2006;47(3):217-224. doi:10.1016/j.annemergmed.2005.08.022
  7. Gorgels AP, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol. 1996;78(1):43-46. doi:10.1016/s0002-9149(96)00224-x
  8. Callans DJ, Marchlinski FE. Dissociation of termination and prevention of inducibility of sustained ventricular tachycardia with infusion of procainamide: evidence for distinct mechanisms. J Am Coll Cardiol. 1992;19(1):111-117. doi:10.1016/0735-1097(92)90060-z
  9. Wellens HJ, Bär FW, Lie KI, Düren DR, Dohmen HJ. Effect of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol. 1977;40(4):579-585. doi:10.1016/0002-9149(77)90074-1

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Featured

Digoxin Poisoning Management





Clinical Content
4 min read
February 3, 2023

Digoxin Poisoning Management

J

Jimmy

PharmD





Clinical Content
2 min read
February 3, 2023

Digoxin Poisoning Management

J

Jimmy

PharmD

Digoxin Poisoning Management

Pharmacy Friday Pearl – Pharmacy & Acute Care University



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Introduction

  • Digoxin treats atrial flutter, atrial fibrillation, and heart failure.
  • Toxicity occurs when Na+/K+-ATPase inhibition raises intracellular Na+/Ca2+, triggering dysrhythmias.
  • EKG red flags: PVCs, biphasic T waves, shortened QT interval, variable AV block.
  • Therapeutic range 0.8 – 2.0 ng/mL; toxicity often begins > 2 ng/mL.

Digoxin Immune Fab (DigiFab / DigiBind)

Parameter Key Details
Dose 1 vial = 40 mg (binds 0.5 mg digoxin).
Unknown ingestion → 10-vial empiric dose.
Alternative: vials = 2 × total body load (mg).
Chronic unknown: adults 3 – 6 vials; children 1 – 2 vials.
Administration IV infusion over 30 min (rapid bolus if arrest imminent).
Onset / Duration Onset 20 – 90 min • Duration 15 – 20 h.
Adverse Effects Orthostatic hypotension, ventricular tachycardia, hypokalemia.
Mechanism Fab fragments swiftly bind circulating digoxin, neutralising toxicity.
Compatibility Compatible only with 0.9 % sodium chloride.

Clinical pearl: monitor serum K+ closely—intracellular shifts often trigger hypokalemia post-Fab.

Overview of Key Evidence

Author / Year Design (n) Key Findings
Wei 2021 Case series (121) FAERS: DigiBind serious AEs 87 % vs DigiFab 63 %; hypotension, cardiac arrest, death most frequent.
Ward 2000 Observational (16) Both Fab products reduced free digoxin below assay limits; total digoxin ↑ ≈10-fold (binding confirmed).
Renard 1997 Observational (16) Fab clearance declined linearly with renal impairment & age; t½ 11 – 34 h; all patients recovered without AEs.
Antman 1990 Open-label (150) 90 % toxicity resolved/improved; median dose 5 vials (200 mg); maximum 40 vials.
Roberts 2016 Systematic review Fab therapy remains first-line; hyperkalemia & ventricular arrhythmias are key toxicity predictors.
Ujhelyi 1995 PK review Fab exhibits two-compartment kinetics; repeat dosing may be needed in large body-load poisonings.

Clinical Conclusions

  • Digoxin toxicity is life-threatening but rapidly reversible with Digoxin Immune Fab.
  • If the ingested amount is unknown, administer an empiric 10-vial dose.
  • Do not delay Fab therapy for age- or renal-based calculations.

Full Reference List

  1. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning. Clin Toxicol. 1973;6(2):153-162.
  2. David MNV, Shetty M. Digoxin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
  3. Lexicomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc. January 2023.
  4. Antman EM et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab fragments. Circulation. 1990;81(6):1744-1752.
  5. Renard C et al. Pharmacokinetics of digoxin-specific Fab: effects of renal function & age. Br J Clin Pharmacol. 1997;44(2):135-138.
  6. Roberts DM et al. Pharmacological treatment of cardiac glycoside poisoning. Br J Clin Pharmacol. 2016;81(3):488-495.
  7. Ujhelyi MR, Robert S. Pharmacokinetic aspects of digoxin-specific Fab therapy. Clin Pharmacokinet. 1995;28(6):483-493.
  8. Wei S et al. Adverse events with digoxin Immune Fab in FAERS 1986-2019. Drugs – Real World Outcomes. 2021;8:253-262.
  9. Ward SB et al. Pharmacokinetics & bioaffinity of DigiTAb vs Digibind. Ther Drug Monit. 2000;22(5):599-607.

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Push Dose Vasopressors





Clinical Content
5 min read
January 27, 2023

Push Dose Vasopressors

J

Jimmy

PharmD





Clinical Content
4 min read
January 27, 2023

Push Dose Vasopressors

J

Jimmy

PharmD

Download PDF

Patient Case  

  • The team gets a call that there is a 75 year old male that triggered a sepsis alert in route with EMS and is currently desaturating on 15 L of oxygen with decision made to intubate this patient  
  • Prior to intubation, the patient hasn’t responded to  a NS bolus infusion these are the patient’s vitals: 
  • Knowing that pre-intubation hypotension has been associated with peri-intubation cardiac arrest, which agent do you order? If it is not commercially available, how do you make it?  

Pharmacology  

  Phenylephrine (PE)   Epinephrine (EPI)  
Properties   A1 ++++   ↑ BP   B1  ±        ↔HR   B2  ±      A1 +++      ↑ BP   B1 +++++   ↑ HR   B2 +++++  
Dose   100-200 mcg PRN Q 1-5 minute   10- 20 mcg PRN Q 1-5 minute  
Formulation   Premixed Syringe- 1000 mcg/10 ml   Not commercially available  
PK/PD   Onset: 1 minute   Duration: ~10-20 minutes   Onset: 1 minute   Duration: ~5-10 minutes  
Adverse Effects   Reflex bradycardia Hypertension   Tachycardia   Hypertension  
 Precautions   Bradycardia, heart block, heart failure, angina, acute MI   Tachycardia  
Compatibility   Compatible with NS, LR, D5   Compatible with NS, LR, D5  
Location in GHS   CPR, Trauma, Zone 2+3 Pyxis   1 mg/ml: CPR, Trauma, Zone 2+3 Pyxis  
Comments   Administer through a large bore peripheral IV; Low extravasation risk   Administer through a large bore peripheral IV; Low extravasation risk   
Making Epinephrine and Phenylephrine the “EASY WAY” Supplies: 10 ml of NS, Insulin syringe, epinephrine or phenylephrine vial, tape, pen Instructions:    Take an insulin syringe and draw up 0.1 ml of epinephrine 1 mg/ml or phenylephrine 10 mg/ml, dilute in 10 ml of NS, label epinephrine 10 mcg/ml (100 mcg total) or phenylephrine 100 mcg/ml (1000 mcg total) 
Making Epinephrine and Phenylephrine the Alternative Way   Epinephrine    Draw up 9 mL of normal saline into a 10 mL syringe (DO NOT use 10ml IV line “flush” syringes)  Into this syringe, draw up 1 mL of EPINEPHphrine 0.1 mg/mL (1 mg/10ml) from a cardiac syringe   Label syringe epinephrine 10 mcg/ml      Phenylephrine o Draw up 1 mL of phenylephrine from a 10 mg/mL vial into a 3 mL syringe o Inject this into a 100 mL bag of normal saline. Label bag; safely discard when finished  o Draw up 10 mL into a 10 mL syringe o Label syringe phenylephrine 100 mcg/ml         

Overview of Evidence  

Author, year    Design/ sample size   Intervention & Comparison   Outcome  
Rotando, 2019   Observational   ED/ICU   N=146   PE 100 mcg/ mL   or   Ephedrine 50 mg/10 mL   Most common indication = peri-intubation hypotension   Both agents associated with:   ↑ SBP by 26 mmHg   ↑ SBP by 26 mmHg   ↓ HR by 6 beats per minute   
Schwartz, 2016   Observational   ED   N=76   PE 100 mcg/ mL     (pre-filled syringe)      46.5%  patients were initiated on vasopressor drip ≤ 30 minutes;   mean MAP ↑ from 56.5 to 79.3 mmHg most common dose 100 mcg most common indication = peri-intubation hypotension  
Panchal, 2015   Observational   ED   N=119   PE 100 mcg/1 mL     PE given during the peri-intubation period: ↑ SBP by 20 mmHg, ↑ DBP by 10 mmHg, HR unchanged  
Doherty, 2012   RCT   OR   N=60   PE  IV push 120 mcg    (pre-filled syringe)   Vs    PE infusion @ 120 mcg/min   The infusion used more drug ( 1740 v 964  mcg)      Push dose pressor  had favorable impact of MAP compared to infusion   

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved March 18, 2019, from http://www.micromedexsolutions.com/ 
  2. Scott Weingart. EMCrit Podcast 205 – Push-Dose Pressors Update. EMCrit Blog. Published on August 7, 2017. Accessed on March 19th 2019. Available at [https://emcrit.org/emcrit/push-dose-pressor-update/ ] 
  3. Holden D. Ann Emerg Med. 2018 Jan;71(1):83-92. 
  4. Panchal AR. J Emerg Med. 2015 Oct;49(4):488-94. 
  5. Rotando A. Am J Emerg Med. 2019 Mar;37(3):494-498. 
  6. Doherty A. Anesth Analg. 2012 Dec;115(6):1343-50. 
  7. Schwartz MB. Am J Emerg Med. 2016 Dec;34(12):2419-2422 

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Sodium Bicarbonate in Cardiac Arrest





Clinical Content
5 min read
January 26, 2023

Sodium Bicarbonate in Cardiac Arrest

J

Jimmy

PharmD





Clinical Content
3 min read
January 26, 2023

Sodium Bicarbonate in Cardiac Arrest

J

Jimmy

PharmD

Download PDF

Introduction

  1. Out-of-hospital cardiac arrest (OHCA) remains a leading cause of mortality and a substantial issue of public health concern worldwide.
  2. Sodium bicarbonate (SB) administration has been considered an important part of treatment for severe metabolic acidosis in cardiac arrest, because based on pathophysiologic considerations, normalization of extracellular and intracellular pH was considered a meaningful endpoint of resuscitation.
  3. Correction of metabolic acidosis with SB was recommended by early advanced cardiac life support (ACLS) guidelines published in 1973, and SB was the medication most frequently used during cardiac arrest until mid-1980s
  4. The 2010 ACLS Guidelines for adults published by the American Heart Association (AHA) state that “Routine use of sodium bicarbonate is not recommended for patients in cardiac arrest” (class lll recommendation, based on level of evidence (LOE) B)

Pharmacology

Dose   0.5-1 meq/kg/dose •     Repeat doses should be guided by arterial blood gases
Administration   IV injection during cardiac arrest
PK/PD   Onset Iv: Rapid Duration IV: 8-10mins Excretion: Urine (<1%)
Adverse Effects   Hypocalcemia Intracellular acidosis (without adequate ventilation) HYPERNATREMIA Hyperosmosis Shift O2 release by hemoglobin
Compatibility   Sodium bicarbonate solution may inactivate catecholamines such as epinephrine
  • May decrease of the biological effect of epinephrine to 77- 82 % of nonalkaline solution  
  • not powered

Overview of Evidence

Author, Year   Design/ sample size   NaHCO3 regimen    Outcome  
Chen YC, 2018   Observational/ n=5589    Not reported   Sodium bicarbonate during ED resuscitation was significantly associated with an increased rate of survival to hospital admission.  
Kawano T, 2017   Prospective observational/ n=13,865   Not reported    In OHCA patients, prehospital SB administration was associated with worse survival rate and neurological outcomes to hospital discharge.  
Ahn S, 2017   RCT/ n=50   50 mEq/L vs Placebo   No difference in sustained ROSC  (4% vs 16%) or good neurological outcome (0% vs 4% , p=.1)      SB had significant effect on pH (6.99 vs.   6.90, P=0.038) and bicarbonate levels   (21.0 vs. 8.0 mEq/L)  
Wang CH, 2016   Retrospective observational study/ n=109   Not Reported   SB was positively associated with sustained ROSC when serum potassium   level was <7.9 mEq in IHCA      Calcium and SB was positively associated with sustained ROSC when serum potassium level <9.4 mEq/L IHCA  
Vukmir RB, 2005   RCT/ n=792   1 mEq/kg NaHCO3   Overall survival rate was 13.9%      No difference in survival in those who   received bicarbonate      2-fold increase in survival in arrest >15 min (32.8 vs 15.4)*  
Bishop RL, 1976   Animal+human   case studies/ n=6   1 mEq/kg of 7.5% sodium bicarbonate in dogs      0.5-0.9 mEg/kg in humans   Animal 1 mEq/Kg   SB resulted in increases in the Pco2 (27→49),  pH (7.38 →7.56) and   the serum osmolality (309→349)      Man 0.5-0.9 mEq/Kg    SB resulted in increases in the Pco2 (24.5→38.8),  pH (7.23 →7.48) and the serum osmolality (308→343)  

References

  1. Sodium bicarbonate. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 11, 2018, from http://www.micromedexsolutions.com/ 
  2. Bishop RL, et al. Sodium bicarbonate administration during cardiac arrest. Effect on arterial pH PCO2, and osmolality. JAMA. 1976 Feb 2;235(5):506-9.
  3. Vukmir RB, et al. Sodium bicarbonate in cardiac arrest: a reappraisal. Am J Emerg Med. 1996 Mar;14(2):192206. 
  4. Vukmir RB, et al. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006 Mar;24(2):156-61. 
  5. Wang CH,et al. The effects of calcium and sodium bicarbonate on severe hyperkalaemia during cardiopulmonary resuscitation: A retrospective cohort study of adult in-hospital cardiac arrest. Resuscitation. 2016 Jan;98:105-11. 
  6. Ahn S, et al. Sodium bicarbonate on severe metabolic acidosis during prolonged cardiopulmonary resuscitation: a double-blind, randomized, placebo-controlled pilot study. J Thorac Dis. 2018 Apr;10(4):22952302 
  7. Kawano T, et al. Prehospital sodium bicarbonate use could worsen long term survival with favorable neurological recovery among patients with out-of-hospital cardiac arrest. Resuscitation. 2017 Oct;119:63-69. 
  8. Chen YC, et al. The association of emergency department administration of sodium bicarbonate after out of hospital cardiac arrest with outcomes.  Am J Emerg Med. 2018 Mar 5. pii: S0735-6757(18)30187-6. 

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How Space Learning helps you pass board certification exams





Board Prep
5 min read
January 3, 2023

How Space Learning helps you pass board certification exams

J

Jimmy

PharmD





Board Prep
4 min read
January 3, 2023

How Space Learning helps you pass board certification exams

J

Jimmy

PharmD

Unleash the Power of Spaced Repetition for Pharmacist Board Certification Exams

Outline

Introduction

A. What is Spaced Repetition?

B. Benefits of Spaced Repetition for Pharmacist Board Certification Exams

II. How to Implement Spaced Repetition Strategies

A. Create a Study Plan and Set Regular Review Points

B. Tailor the Study Plan to Your Learning Style

C. Focus on Strengthening Weak Areas

III. Conclusion

A. Maximizing Exam Scores with Spaced Repetition Strategies

B. Final Thoughts on Using Spaced Repetition for Board Certification Exams

Introduction

Are you preparing for your Pharmacist Board Certification Exam? If so, you need to study effectively so you can make the most of your time and maximize your exam score. One way to do this is by using spaced repetition – an evidence-based learning technique proven to increase the rate of learning. In this blog post, we will discuss the benefits of spaced repetition for Pharmacist Board Certification Exams, how to implement it, and some tips on maximizing your exam score with space repetition strategies. So let’s dive in!

What is Spaced Repetition?

Spaced repetition is an evidence-based learning technique that is usually performed with flashcards or questions. It involves deliberately spacing out the time spent studying a specific topic or material in order to better retain the knowledge. Newly introduced and more difficult questions are shown more frequently, while older and less difficult flashcards are shown less frequently in order to exploit the psychological spacing effect. The use of space repetition has been proven to increase the rate of learning by helping students to better retain information over time. It can be used effectively in many contexts, including for pharmacist board certification exams. By using space repetition, pharmacists can ensure that they are consistently revisiting the material they need to know and strengthening their understanding of the topics. This can ultimately lead to improved exam performance and a successful board certification.

Benefits of Spaced Repetition for Pharmacist Board Certification Exams

Spaced repetition is an excellent tool for pharmacist board certification exams, as it can help to increase the rate of learning and improve performance on the exam. It can also be used to reinforce knowledge and strengthen understanding of concepts. By utilizing space repetition strategies, pharmacists can ensure that they are reviewing material in a way that is tailored to their individual needs and learning styles. By scheduling regular review sessions, pharmacists can ensure that all of the material has been thoroughly understood. This will ultimately lead to improved exam scores and better overall performance in the board certification process. Additionally, space repetition is a great way to focus on weaker areas of knowledge, allowing pharmacists to spend their studying time on topics that need more work. In this way, space repetition can be used to maximize the effectiveness of studying for board certification exams.

How to Implement Spaced Repetition Strategies

In order to effectively use space repetition strategies for pharmacist board certification exams, it is important to create a comprehensive study plan that incorporates space repetition. First, pharmacists should break down the material into smaller, more manageable chunks and create a timeline for studying each section. This timeline should be tailored to the individual’s learning style and include regular review points for space repetition. It is important to space out those reviews in order to maximize their effectiveness, as this will allow pharmacists to fully understand and retain the material. Additionally, space repetition should be used to focus on weaker areas of knowledge and ensure that those topics are being thoroughly reviewed. By creating a comprehensive space repetition strategy and sticking to it, pharmacists can ensure that they are fully prepared for their board certification exam.

Conclusion

Spaced repetition is an evidence-based learning technique that can be used effectively to maximize exam scores for pharmacist board certification exams. By utilizing space repetition strategies, pharmacists can ensure that they are consistently revisiting material and reinforcing their understanding of the topic. This will ultimately lead to improved performance on the exam and better overall outcome in the board certification process. Additionally, space repetition is a great way to focus on weaker areas of knowledge and ensure that those topics are being thoroughly reviewed. In this way, space repetition can be used to maximize the effectiveness of studying for board certification exams.

Repeated retrieval with long intervals between each test produced a 200% improvement in long-term retention relative to repeated retrieval with no spacing between tests

Reference: How To Remember What You Learn For Longer With Spaced Repetition. https://blog.alexanderfyoung.com/how-to-remember-what-you-learn-for-longer-with-spaced-repetition/

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How the BCEMP Test is Administered and What Is On It?





Board Prep
7 min read
January 3, 2023

How the BCEMP Test is Administered and What Is On It?

J

Jimmy

PharmD





Board Prep
6 min read
January 3, 2023

How the BCEMP Test is Administered and What Is On It?

J

Jimmy

PharmD

Preparing for the BCEMP Exam: What You Need to Know about the Exam

1. Introduction

2. Overview of the BCEMP Exam

3. Over of Domains of BCEMP EXAM

4. Conclusion

Introduction

The Board Certified Emergency Medicine Pharmacist (BCEMP) exam is a rigorous assessment of emergency medicine knowledge and understanding. As an essential component for those seeking professional success within the field, this 4-hour and 23 minutes, computer-based test covers topics such as pharmacology, patient assessment, disease state management, and emergency department protocols. Knowing what to expect on the exam and how to properly prepare for it is key to passing with flying colors. This article provides an overview of the BCEMP exam and offers strategies for success. From understanding the domains covered, to reviewing relevant material, this guide will equip you with the knowledge necessary for approaching the BCEMP exam with confidence. Read on to learn more about this essential test and take the first step towards professional advancement.

BCEMP Exam Overview

The BCEMP exam is divided into three domains. Domain 1: Patient Care and Management covers topics such as patient assessment, diseases state management, pharmacology, medications, and other related issues. Domain 2: Practice Management focuses on the delivery of emergency care services including review adverse drug events and medication errors, quality assurance activities,  drug shortages, drug shortages, emergency/disaster preparedness planning, and practice advancement and growth. Domain 3: Education and Research looks into the delivery of patient education and research skills in emergency medicine. A successful completion of the BCEMP exam can be used to demonstrate mastery in emergency medicine topics and may lead to increased professional opportunities. It is important to properly prepare for the BCEMP exam by studying resources provided by the Board of Specialty Pharmacy. The exam is 175 questions , multiple-choice and is based on the content outline released by the Board. The length of the exam is 4 hours and 23 minutes. Taking the time to study for this exam adequately can ensure candidates are positioned for success on their certification journey.

Domains of BCEMP EXAM

Domain 1: Patient Care and Management covers patient assessment, disease state management, pharmacology, medications, and other related issues. This is 75% of the exam or 131 questions on the certification exam and is mostly pharmacotherapy. This included your disease state management, drug information, and preparation and procurement activities. The subdomain items are listed below

  • Participate in the bedside management of medical emergencies (e.g., trauma, stroke, psychiatric, toxicological) and resuscitations to optimize the medication use process. 
    • Identify and prioritize (triage) Emergency Department patients by analyzing the relevant acuity indices and opportunities for optimization of pharmacotherapy.
    • Collect essential patient information (including patient history, medication use) by utilizing available resources (e.g., pre-hospital providers).
    • Identify and evaluate medication-related problems based on clinical presentation, available history, or laboratory data.
    • Contribute to the formulation of a differential diagnosis in the setting of limited information. 1.06 Design pharmaceutical care plan utilizing available patient-specific information and best available evidence to provide patient and family-centered care.
    • Recommend and support implementation of the pharmaceutical care plan in the Emergency Department.
    • Expedite the preparation/procurement and administration of time-sensitive therapeutic regimens.
    • Make evidence-based recommendations for alternative routes of administration.
    • Monitor and evaluate patient response to initial therapy and re-design treatment plan as necessary.
    • Serve as the primary source of drug information for all practitioners and patients within the Emergency Department. 
    • Ensure continuity of care during healthcare transition and across levels of care.
    • Identify and seek appropriate outside resources available to assist in the management of the Emergency Department patient. 

Domain 2: Practice Management focuses on the delivery of emergency care services including review adverse drug events and medication errors, quality assurance activities, drug shortages, drug shortages, emergency/disaster preparedness planning, and practice advancement and growth. we can think of this as part of your day when you’re replying to emails, making protocols, reviewing medication safety events, and dealing with stocking your automatic dispense cabinets with medications that may or may not be on shortage. Domain 2 represents 15% of the exam or 26 questions on the certification exam. The subdomain items for domain 2 is below.

  • 2.01 Anticipate, monitor, detect, report, and review adverse drug events and medication errors. 2.02 Recognize trends, system failures, and gaps in the medication use process, and perform quality assurance activities (e.g., MUE) that promote safe and effective medication use.
  • 2.03 Ensure a process to maintain and optimize inventory and availability of medications essential to provide timely care in the Emergency Department.
  • 2.04 Ensure an appropriate process exists for medication order review in the Emergency Department.
  • 2.05 Assist the organization in achieving compliance with accreditation, legal, regulatory, and safety requirements related to the medication use process.
  • 2.06 Contribute to contingency planning that addresses limited availability of critical drugs that affect patients in the Emergency Department (e.g., drug shortages, emergency preparedness). 2.07 Participate in emergency/disaster preparedness planning or response activities.
  • 2.08 Develop, maintain, monitor, and support evidence-based medication use guidelines and pathways to assure safe and cost-effective medication use.
  • 2.09 Identify and implement opportunities for practice advancement and growth within the Emergency Department (e.g., collaborative practice agreements, public health initiatives, expanded coverage).
  • 2.10 Advocate for and justify emergency medicine pharmacy services. 

Domain 3: Education and Research look into the delivery of patient education and research skills in emergency medicine. This is probably the code name for some biostatistics and research designs here. Most of this will need a little touching on if you’re not actively involved in research. Domain 3 represents 10% of the exam or 18 questions on the certification exam. The subdomain items are listed below

  • 3.01 Provide emergency medicine professionals and trainees. — focused education, training, or mentoring for healthcare
  • 3.02 Educate patients and caregivers using appropriate techniques tailored to the audience, with a focus on high risk medications or where the visit resulted from an adverse drug event.
  • 3.03 Participate in continuous professional development related to emergency pharmacy practice (e.g., professional organizations, continuing education, clinical pharmacy networks).
  • 3.04 Retrieve and critically evaluate biomedical literature and other sources regarding study design methodology, statistical analysis, and applicability of study results to emergency medicine. 3.05 Contribute to the body of knowledge in the field of emergency medicine

Conclusion

In conclusion, the BCEMP exam is a comprehensive test that covers all aspects of emergency medicine, from patient care to practice management and education and research. Preparing for the test requires an understanding of the content domains and subdomains, as well as a thorough review of related materials. With proper preparation and dedication, individuals can successfully pass the BCEMP exam and become certified in emergency medicine. Good luck!

The BCEMP exam is a challenging test, but with the right preparation, anyone can become certified in emergency medicine.

Good luck!

Jimmy L. Pruitt III, PharmD, BCPS, BCCP
Emergency Medicine Clinical Pharmacy SPeacialist

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The Best Practices for Passing the Pharmacy Board Certification Exam





Board Prep
5 min read
January 3, 2023

The Best Practices for Passing the Pharmacy Board Certification Exam

J

Jimmy

PharmD





Board Prep
3 min read
January 3, 2023

The Best Practices for Passing the Pharmacy Board Certification Exam

J

Jimmy

PharmD

I. Introduction

II. Review the Topics Covered by the Exam

III. Decide Which Study Materials to Use

IV. Create a Study Plan or Schedule

V. Stay Motivated and Track Your Progress

VI.Conclusion  

Introduction

Are you looking to take the pharmacy board exam? Becoming certified is an important step towards a successful career as a pharmacist and requires proper preparation. This guide will provide you with all the information you need to know about studying for the pharmacy board certification exam, from which materials to use to creating an effective study plan. With these tips and strategies, you can be well on your way to passing the pharmacy board exam!

Review the topics covered by your chosen board examination

When studying for the pharmacy board certification exam, it is important to review the topics covered by your chosen board examination. This will help you determine what material will be tested on the exam so you can focus your study efforts and make sure that you are adequately prepared. Generally, these exams cover a variety of topics such as pharmacology, drug therapy, pharmacy law and ethics, compounding, and pharmacokinetics. It is also important to be aware of any prerequisites or continuing education credits that may need to be completed before taking the exam.

Additionally, you should make sure to access relevant study materials that are specific for your board certification examination. Doing so will help ensure that you have all the information you need to successfully pass the exam.

Decide which study materials are best for you

When deciding which study materials are best for you, it is important to choose materials that are approved by your chosen board examination. This will help ensure that the material you are studying is accurate and up to date with the latest information. You can find these materials on websites such as the ASHP, ACCP, Pharmacy & Acute Care University or through continuing education classes.

Additionally, consider utilizing study guides, practice tests, and other resources such as online discussion forums to help you stay on track. The material you choose should be tailored to your specific board exam so that you can focus your studying for optimal results.

Create a study plan or schedule

Creating a study plan or schedule is an essential part of preparing for the pharmacy board certification exam. Start by selecting a realistic completion date and setting smaller goals along the way. Breaking up your studying into manageable chunks can help make it easier to stay on track and motivated.

Additionally, consider utilizing online tools such as a calendar or task list to keep you organized and accountable. Make sure to set aside plenty of time for practice questions and review material. This will help you become familiar with what to expect on the exam and ensure that you have mastered all the material before taking it.

Stick with your plan and stay motivated

Once you have created your study plan, it is important to stick with it and stay motivated. This can be challenging, especially if you have a busy schedule or other commitments. However, consistency is key when it comes to studying for the pharmacy board certification exam. Make sure to set aside ample time each day to focus on your studies and give yourself breaks when needed. Additionally, consider finding a study partner or forming a study group to help keep you accountable and motivated. Finally, don’t forget to reward yourself when you reach your goal so that you have something to look forward to while studying.

Conclusion

Passing the pharmacy board certification exam can be a challenging but rewarding experience. Seeking advice and support from other pharmacists can help make the process easier. Connecting with other pharmacists, whether it’s through online discussion forums or in person, can provide valuable insight and guidance that can help you succeed. Don’t be afraid to ask questions and take advantage of the wisdom of other pharmacists who have been through the process before you. With their help and support, you can feel confident as you prepare for your pharmacy board certification exam.

Good luck!

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Featured

What are the Pass rates for BPS Exams?





Board Prep
4 min read
January 3, 2023

What are the Pass rates for BPS Exams?

J

Jimmy

PharmD





Board Prep
3 min read
January 3, 2023

What are the Pass rates for BPS Exams?

J

Jimmy

PharmD

Uncovering the Success Rates of Board Certification Exams for Specialty Pharmacists

Are you considering a career in specialty pharmacy? If so, it is important to understand the pass rates of board certification exams for this field. Board-certified specialty pharmacy certifications offer pharmacists additional training and expertise in specific areas of practice. In this article, we will explore the overall and first time pass rates for Board-Certified Critical Care Pharmacist (BCCCP) and Board-Certified Pharmacotherapy Specialist (BCPS). We will also provide useful information to help you understand the importance of obtaining specialty pharmacy certification.

Pass Rates

In this administration window, a total of 2,757 out of 4,272 examinees were successful in one of thirteen certification examinations or nine recertification examinations.

  • Board-Certified Critical Care Pharmacist (BCCCP) has a pass rate of 73% and a first-time pass rate of 82% in the most recent examination period.
  • Board-Certified Pharmacotherapy Specialist (BCPS) has a pass rate of 63% and a first-time pass rate of 72% in the most recent examination period.

These results demonstrate that pharmacists who take the relevant exams are generally successful, though they may require additional preparation depending on their field.

The statistics indicate that the exams are not easy and require a significant amount of preparation. Pharmacists should consider taking additional courses or engaging in self-study to ensure they pass the certification examinations with flying colors. Additionally, pharmacists should have experience working in their respective field before taking any board certification exam in order to better prepare themselves for the exams. It is recommended that pharmacists research the requirements for their respective certifications and begin preparing at least 3-6 months before the examination date.

The Benefits of Obtaining Board-Certified Specialty Pharmacy Certification

Becoming board-certified in a specialty field of pharmacy has many advantages. For example, pharmacists who are certified may receive higher salaries and better job opportunities. They can also help patients manage their medications more effectively and provide improved care. Furthermore, being certified is an important step to advancing one’s career and becoming a leader in the field.

Other Pass Rates

Board-Certified Critical Care Pharmacist (BCCCP) 73%

Board-Certified Cardiology Pharmacist (BCCP)     54%

Board-Certified Infectious Diseases Pharmacist (BCIDP)  73%

Board-Certified Nutrition Support Pharmacist (BCNSP)    93%

Board-Certified Oncology Pharmacist (BCOP)       57%       

Board-Certified Pediatric Pharmacy Specialist (BCPPS)     66%       

Board-Certified Pharmacotherapy Specialist (BCPS)          63%       

Board-Certified Psychiatric Pharmacist (BCPP)     52%                       

Board-Certified Transplant Pharmacist (BCTXP)  43%

In conclusion, specialty pharmacy certifications open up new opportunities to those who have the dedication and commitment to pursue them. With a pass rate of 73% for Board-Certified Critical Care Pharmacists (BCCCP) and 63% for Board-Certified Pharmacotherapy Specialists (BCPS), pharmacists who take the relevant exams are generally successful. Becoming certified provides numerous benefits such as higher salaries, better job opportunities, and improved patient care. Pharmacists should take the time to research the requirements for their respective certifications and begin preparing at least 3-6 months before the examination date in order to maximize their chances of success. With dedication, any pharmacists can achieve board certification status in a specialty field of pharmacy.

References:

https://www.bpsweb.org/2022/12/06/september-october-2022-bps-certification-and-recertification-examination-results/

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Big Changes in Blood Pressure: A Simple Guide to the 2025 Hypertension Guidelines





Clinical Content
5 min read
August 20, 2025

Big Changes in Blood Pressure: A Simple Guide to the 2025 Hypertension Guidelines

J

Jimmy

PharmD





Clinical Content
3 min read
August 20, 2025

Big Changes in Blood Pressure: A Simple Guide to the 2025 Hypertension Guidelines

J

Jimmy

PharmD

The way doctors and pharmacists manage high blood pressure is about to change. The new 2025 AHA/ACC Hypertension Guidelines have been released, introducing significant, evidence-based updates designed to improve patient safety and provide more effective care.

Whether you are a patient or a healthcare provider, it’s important to understand these key shifts. Here’s a simple breakdown of what you need to know.

1. “Hypertensive Urgency” Gets a New Name and a Safer Approach

One of the biggest changes is the terminology. The term “hypertensive urgency” is now being replaced with

“severe hypertension”. This refers to a blood pressure reading higher than 180/120 mm Hg in a patient

without symptoms of acute target organ damage.

Why the change? The old term often led to unnecessary emergency department visits and the use of potent IV medications that could lower blood pressure too quickly, causing harm. The new approach for patients with asymptomatic severe hypertension is to:

  • Avoid IV medications in the hospital or ED.
  • Start well-tolerated oral medications.
  • Arrange for a follow-up appointment with a primary care provider or cardiologist within a few days.

2. A Smarter Way to Decide Who Needs Medication: The PREVENT Calculator

The new guidelines integrate the

PREVENT risk calculator, a more accurate and inclusive tool for predicting a person’s 10-year risk of heart attack or stroke. This calculator includes factors like kidney disease and social determinants of health to better guide treatment decisions.

The new rules are:

  • High-Risk Patients: If you have established cardiovascular disease, diabetes, chronic kidney disease, or a PREVENT risk score of 7.5% or higher, medication is now recommended if your blood pressure is 130/80 mm Hg or higher.
  • Lower-Risk Patients: If your blood pressure is between 130-139/80-89 mm Hg and your risk score is less than 7.5%, the first step is a 3-6 month trial of lifestyle changes. Medication is only recommended if blood pressure remains high after that period.

3. New Rules for Stroke and Brain Bleeds

The guidelines provide critical updates for managing blood pressure during neurological emergencies:

  • After an Ischemic Stroke (Post-Reperfusion): The guidelines now state that lowering systolic blood pressure below 140 mm Hg in the first 24-72 hours can be harmful and should be avoided. The goal is to maintain pressure between 140-180 mm Hg to ensure the brain gets enough blood flow to recover.
  • For a Brain Bleed (ICH): If the systolic pressure is between 150-220 mm Hg, the new target is to lower it to 130-140 mm Hg within the first 7 days. For extremely high pressures (>220 mm Hg), a continuous IV infusion is recommended over single “bolus” injections to prevent dangerous blood pressure swings.

4. Critical Updates for Managing Hypertension in Pregnancy

The 2025 guidelines emphasize safer and more proactive care for pregnant patients:

  • Treat Urgently: Severe hypertension (BP ≥160/110 mm Hg) during pregnancy is a medical emergency. Treatment must be started within 30-60 minutes to prevent a maternal stroke.
  • Treat Earlier: For chronic hypertension in pregnancy, treatment should now begin when blood pressure is 140-159/90-109 mm Hg to a target of <140/90 mm Hg.
  • Preeclampsia Prevention: Low-dose aspirin (81 mg daily) is strongly recommended for pregnant patients with chronic hypertension, starting at 12 weeks of gestation, to reduce the risk of preeclampsia.
  • Medication Safety: The list of contraindicated medications has been expanded. Common drugs like ACE inhibitors (e.g., lisinopril), ARBs (e.g., losartan), and the beta-blocker atenolol should be avoided during pregnancy due to risks to the fetus.

Guideline Resources

These updates represent a major step forward in hypertension management. For healthcare professionals seeking more information, the following resources are available:

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 PubMed Search Guide for Pharmacists





Clinical Content
9 min read
August 20, 2025

 PubMed Search Guide for Pharmacists

J

Jimmy

PharmD






PubMed Search Guide for Pharmacists


🔬 PubMed Search Guide for Pharmacists

Master evidence-based drug therapy research with advanced search strategies

🎯 Core Concepts You’ll Use Every Time

A. MeSH (Medical Subject Headings)

What: PubMed’s controlled vocabulary for indexing citations (e.g., Septic Shock[MeSH], Drug Interactions[MeSH]). Searching with MeSH enhances precision and recall by unifying synonyms under a single concept.

Pharmacy-Relevant MeSH Hierarchy Example:
Pharmaceutical Preparations [MeSH]
├── Dosage Forms [MeSH]
├── Drug Combinations [MeSH]
└── Pharmaceutical Solutions [MeSH]
💡 Pro Tip: Always check the MeSH Database first! Look up your concept, review the Scope Note and Entry Terms (synonyms), and consider using Major Topic or No Exp restrictions.

B. Essential Field Tags for Pharmacists

[ti]
Title only
High precision
[tiab]
Title OR Abstract
Balanced approach
[MeSH]
MeSH heading
Controlled vocabulary
[au]
Author
Find specific researchers

C. Boolean Logic & Critical Behavior

✅ Good Practice

vasopressin[tiab] OR argipressin[tiab]

Uses OR to combine synonyms within a concept

❌ Poor Practice

vasopressin argipressin

Missing Boolean operator – unpredictable results

⚠️ Important: Always capitalize AND/OR/NOT in PubMed. Quoting phrases disables Automatic Term Mapping – use quotes only when necessary for exact phrases.

💊 Essential Pharmacy MeSH Terms

Core Pharmaceutical Concepts

Drug Interactions[MeSH]
Main term for DDIs
Pharmacokinetics[MeSH]
ADME processes
Pharmacodynamics[MeSH]
Drug effects
Cytochrome P-450[MeSH]
Metabolism enzymes
Pharmaceutical Care[MeSH]
Clinical pharmacy practice
Medication Errors[MeSH]
Patient safety
Drug Monitoring[MeSH]
Therapeutic monitoring
Polypharmacy[MeSH]
Multiple medications

Clinical Conditions Pharmacists Encounter

Septic Shock[MeSH]
ICU pharmacy
Diabetes Mellitus[MeSH]
Ambulatory care
Hypertension[MeSH]
Community pharmacy
Heart Failure[MeSH]
Cardiology pharmacy
Renal Insufficiency[MeSH]
Dose adjustments
Liver Diseases[MeSH]
Hepatic impairment

🔍 Advanced Search Strategies

Study Design Filters

Cochrane Highly Sensitive RCT Filter
(randomized controlled trial[pt] OR controlled clinical trial[pt]
OR randomized[tiab] OR placebo[tiab] OR randomly[tiab]
OR trial[tiab] OR groups[tiab])
NOT (animals[mh] NOT humans[mh])

This is the gold standard for finding RCTs in PubMed, validated by Cochrane.

Pragmatic Observational Filter
(cohort[tiab] OR “cohort studies”[MeSH] OR case-control[tiab]
OR “case-control studies”[MeSH] OR cross-sectional[tiab]
OR “Cross-Sectional Studies”[MeSH] OR observational[tiab]
OR retrospective[tiab] OR prospective[tiab])

Use for real-world evidence and outcomes research.

High-Quality Evidence Filter
(systematic review[ti] OR meta-analysis[pt] OR meta-analysis[ti]
OR “systematic review”[ti] OR “meta analysis”[ti])

Perfect for evidence-based guidelines and protocols.

Date Limiting Strategies

Two Approaches to Date Limiting:

1UI Method: Use sidebar → Publication Dates → Custom range (e.g., 2019-2025)

2Query Method: Include in your search string:

AND (“2019/01/01″[Date – Publication] : “2025/12/31″[Date – Publication])

📝 Comprehensive Worked Examples

Example 1: Vasopressin in Septic Shock

Clinical Context:

Norepinephrine is first-line; vasopressin is second-line. The 2025 OVISS study suggests earlier vasopressin initiation.

1Broad Seed Search (MeSH + tiab):

(“Septic Shock”[MeSH] OR septic shock[tiab])
AND
(“Vasopressins”[MeSH] OR vasopressin[tiab] OR argipressin[tiab])
NOT (animals[mh] NOT humans[mh])

2RCT-Focused Version:

(“Septic Shock”[MeSH] OR septic shock[tiab])
AND
(“Vasopressins”[MeSH] OR vasopressin[tiab] OR argipressin[tiab])
AND
(randomized controlled trial[pt] OR controlled clinical trial[pt]
OR randomized[tiab] OR placebo[tiab] OR randomly[tiab]
OR trial[tiab] OR groups[tiab])
NOT (animals[mh] NOT humans[mh])

Example 2: Drug-Drug Interactions with Warfarin

Clinical Scenario:

Community pharmacist needs evidence on clinically significant warfarin interactions.

(“Warfarin”[MeSH] OR warfarin[tiab] OR coumadin[tiab])
AND
(“Drug Interactions”[MeSH] OR “drug interaction”[tiab] OR “drug interactions”[tiab])
AND
(“Cytochrome P-450 CYP2C9″[MeSH] OR CYP2C9[tiab] OR “vitamin K”[tiab])
AND (“2018/01/01″[Date – Publication] : “2025/12/31″[Date – Publication])
NOT (animals[mh] NOT humans[mh])

Example 3: Medication Adherence in Diabetes

Clinical Question:

What interventions improve medication adherence in diabetic patients?

(“Diabetes Mellitus”[MeSH] OR diabetes[tiab])
AND
(“Medication Adherence”[MeSH] OR “medication adherence”[tiab]
OR “medication compliance”[tiab] OR “treatment adherence”[tiab])
AND
(“Pharmaceutical Care”[MeSH] OR “pharmacist intervention”[tiab]
OR “clinical pharmacist”[tiab])
AND (randomized controlled trial[pt] OR controlled clinical trial[pt]
OR randomized[tiab] OR trial[tiab])
AND (“2015/01/01″[Date – Publication] : “2025/12/31″[Date – Publication])

⚠️ Drug Interaction Research Strategies

Key MeSH Terms for Drug Interactions

Drug Interactions[MeSH]
Primary term
Drug Synergism[MeSH]
Additive effects
Drug Antagonism[MeSH]
Opposing effects
Cytochrome P-450 Enzyme System[MeSH]
Metabolism interactions
P-Glycoprotein[MeSH]
Transport interactions
Food-Drug Interactions[MeSH]
Nutrition interactions

Common CYP450 Interaction Searches

(“Cytochrome P-450 CYP3A”[MeSH] OR CYP3A4[tiab] OR CYP3A[tiab])
AND
(“Drug Interactions”[MeSH] OR “drug interaction”[tiab])
AND
(inhibitor[tiab] OR inducer[tiab] OR substrate[tiab])

(“P-Glycoprotein”[MeSH] OR “p-glycoprotein”[tiab] OR “pgp”[tiab] OR “MDR1″[tiab])
AND
(“Drug Interactions”[MeSH] OR “drug transport”[tiab])
AND
(substrate[tiab] OR inhibitor[tiab] OR inducer[tiab])

Specific Interaction Examples

Grapefruit-Drug Interactions:

(“Grapefruit”[MeSH] OR grapefruit[tiab])
AND
(“Drug Interactions”[MeSH] OR “food-drug interaction”[tiab])
AND
(“Cytochrome P-450 CYP3A”[MeSH] OR CYP3A4[tiab])

📋 Copy-Paste Templates

A. Therapy/RCT Template

(<POPULATION MeSH/tiab block>) AND (<INTERVENTION MeSH/tiab block>)
AND (randomized controlled trial[pt] OR controlled clinical trial[pt]
OR randomized[tiab] OR placebo[tiab] OR randomly[tiab]
OR trial[tiab] OR groups[tiab])
NOT (animals[mh] NOT humans[mh])
AND (“YYYY/MM/DD”[Date – Publication] : “YYYY/MM/DD”[Date – Publication])

B. Observational Template

(<POPULATION MeSH/tiab block>) AND (<EXPOSURE/INTERVENTION MeSH/tiab block>)
AND (cohort[tiab] OR “cohort studies”[MeSH] OR case-control[tiab]
OR “case-control studies”[MeSH] OR cross-sectional[tiab]
OR “Cross-Sectional Studies”[MeSH] OR observational[tiab]
OR retrospective[tiab] OR prospective[tiab])
NOT (animals[mh] NOT humans[mh])
AND (“YYYY/MM/DD”[Date – Publication] : “YYYY/MM/DD”[Date – Publication])

C. Drug Interaction Template

(“<DRUG 1 NAME>”[MeSH] OR <drug1>[tiab] OR <synonym>[tiab])
AND
(“<DRUG 2 NAME>”[MeSH] OR <drug2>[tiab] OR <synonym>[tiab])
AND
(“Drug Interactions”[MeSH] OR “drug interaction”[tiab] OR “drug interactions”[tiab])
NOT (animals[mh] NOT humans[mh])

D. Pharmacokinetics Template

(“<DRUG NAME>”[MeSH] OR <drug>[tiab])
AND
(“Pharmacokinetics”[MeSH] OR pharmacokinetic*[tiab] OR bioavailability[tiab]
OR “area under curve”[tiab] OR AUC[tiab] OR clearance[tiab])
AND
(“<POPULATION>”[MeSH] OR <population>[tiab])
NOT (animals[mh] NOT humans[mh])

🔧 Troubleshooting & Pro Tips

Common Issues & Solutions

🔍 Too Many Results?
• Add field tags ([ti] for key terms)
• Include MeSH subheadings
• Apply Article Type, Humans, and Date filters
• Use Narrow option in Clinical Queries
📊 Too Few Results?
• Remove quotes to re-enable ATM
• Use OR to include more synonyms
• Combine MeSH with [tiab]
• Check spelling and try broader terms
🎯 Phrase Issues?
• Try proximity: “term A term B”[tiab:~0]
• Drop quotes and use field tags
• Check Search Details for interpretation
📝 Reproducibility?
• Use Advanced → History to combine sets
• Save final strategy for future use
• Document your search approach
• Share search strings with colleagues

📚 Key Resources & Training

Essential Training Links

📋 PubMed Search Guide for Pharmacists |
Master evidence-based practice with precision searching |
🔬 Last updated: August 2025



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High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema





Clinical Content
3 min read
July 9, 2025

High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema

R

Riszel

PharmD

High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema (SCAPE)

Pharmacy Friday Pearl – Pharmacy & Acute Care University

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Introduction

  • SCAPE is a form of hypertensive heart failure triggered by a surge in catecholamines.
  • The result is pulmonary capillary leakage and alveolar flooding.
  • Management includes non-invasive ventilation and pharmacologic agents such as nitroglycerin.
  • Dose-dependent afterload reduction with nitroglycerin requires doses >50–150 mcg/min.

Pharmacology of Nitroglycerin (NTG)

Parameter Details
Mechanism of Action Organic nitrate vasodilator that reduces tension on vascular smooth muscle and dilates peripheral veins and arteries (at higher doses).
Dose • Chest pain: 5–400 mcg/min (starting at 5 mcg/min)
• Pulmonary edema/afterload reduction: 50–400 mcg/min
• Titrate to symptom improvement and tolerated blood pressure
Administration • IV infusion: 50–400 mcg/min until symptom resolution
• IV bolus: 400–2000 mcg over 2–5 min (check hospital policy)
• Sublingual: 400 mcg tab, 2–4 tablets (≈160–320 mcg/min IV)
• Ointment: slow onset 30–60 min
PK/PD • Onset: IV 1–5 min; SL 1–3 min
• Peak: 3–15 min
• Duration: IV 5–10 min; SL 10–60 min
• Elimination: 22% renal
Adverse Effects Headache, hypotension, syncope, rebound hypertension, tolerance with prolonged use (~24 hrs)
Warnings/Interactions • PDE inhibitors
• Aortic stenosis, preload-dependent cardiomyopathy, hypertrophic obstructive cardiomyopathy, hypotension at any time
Compatibility Incompatible with levofloxacin, SMX-TMP, daptomycin, and phenytoin

Clinical pearl: Higher doses of IV or bolus nitroglycerin may reduce ICU admissions and intubation risk in SCAPE.

Overview of Key Evidence

Author/Year Design (n) Intervention & Comparison Key Findings
Patrick, 2020 Observational (n=48) IV NTG 1 mg bolus by EMS ↓SBP by 31 mmHg, ↓HR by 10 bpm, ↑O2 from 86% to 98%; 2% symptomatic hypotension
Hsieh, 2018 Case Report (n=3) SL NTG 0.6 mg x 3, IV NTG bolus 1 mg Q2 min, then infusion 40 mcg/min Normalized respiratory status, avoided intubation & ICU admission
Paone, 2018 Case Report (n=1) IV NTG 400 mcg/min titrated Symptom resolution at 6 minutes
Wilson, 2016 Observational (n=395) IV NTG bolus (500–2000 mcg) Q3–5 min vs infusion vs both ↓ICU admissions, shorter LOS, no increase in intubations
Levy, 2007 Observational (n=29) IV NTG bolus 2 mg IV Q3 min ↓Intubation, ↓BiPAP/ICU admission
Sharon, 2000 RCT (n=40) IV isosorbide bolus 4 mg Q4 min vs infusion + BiPAP ↓Intubation, MI, mortality; ↑PaO₂
Cotter, 1998 RCT (n=104) IV isosorbide bolus 3 mg Q5 min + furosemide vs infusion titration ↓MV & MI, ↑PaO₂, fewer adverse effects

Clinical Conclusions

  • High-dose nitroglycerin (bolus and/or infusion) is effective in rapidly reducing preload and afterload in SCAPE.
  • Doses of ≥400 mcg/min (or equivalent bolus) are supported by case reports and observational studies.
  • High-dose IV or sublingual NTG has been associated with improved respiratory status, fewer ICU admissions, and reduced need for intubation.
  • Symptomatic hypotension is rare but monitoring is necessary, especially with bolus regimens.
  • Bolus dosing strategies may outperform continuous infusions in acute SCAPE decompensation.

Full Reference List

  1. Nitroglycerin. Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved March 5, 2020, from http://www.micromedexsolutions.com/
  2. Kramer K. Am Heart J. 2000;140:451–5.
  3. Agrawal N. Crit Care Med. 2016;20:39–43.
  4. Mebazaa A. Eur J Heart Fail. 2015;17:544–58.
  5. Viau DM. Heart. 2015;101:1861–7.
  6. McMurray JJ. Eur J Heart Fail. 2012;14:803–69.
  7. López-Rivera F. Am J Case Rep. 2019 Jan 21;20:83–90.
  8. Clemency BM. Prehosp Disaster Med. 2013 Oct;28(5):477–81.
  9. Yancy CW. J Am Coll Cardiol. 2013;62:e147–239.
  10. Hsieh Y. Turk J Emerg Med. 2018;18(1):34–36.
  11. Wilson SS. Am J Emerg Med. 2017;35(1):126–31.
  12. Levy P. Ann Emerg Med. 2007;50:144–52.
  13. Sharon A. J Am Coll Cardiol. 2000;36(3):832–7.
  14. Cotter G. Lancet. 1998;351(9100):389–93.
  15. Paone S. Am J Emerg Med. 2018;36(8):1526.e5–1526.e7.
  16. Patrick C. Prehosp Emerg Care. 2020 Jan 27:1–7.

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The Use of Norepinephrine vs Epinephrine in Post Cardiac Arrest Shock





Clinical Content
2 min read
July 9, 2025

The Use of Norepinephrine vs Epinephrine in Post Cardiac Arrest Shock

R

Riszel

PharmD

The Use of Norepinephrine vs Epinephrine in Post Cardiac Arrest Shock

Pharmacy Friday Pearl – Pharmacy & Acute Care University

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Introduction

  • The effects of epinephrine on animal hemodynamics have been studied since the late 1800s with recent concern regarding deleterious complications with cerebral and myocardial oxygen supply.
  • Recently, norepinephrine has been considered post cardiac arrest to minimize complications associated with epinephrine.

Pharmacology of Epinephrine and Norepinephrine

Category Epinephrine Norepinephrine
Dose Weight-based: 0.01–1 mcg/kg/min
Non-weight-based: 1–80 mcg/min
Institutional infusion rates may vary		 Weight-based: 0.05–1 mcg/kg/min (initiate at 0.05–0.15)
Non-weight-based: 5–80 mcg/min (initiate at 5–15)
Institutional infusion rates may vary
Pharmacokinetics Onset: Immediate
Distribution: 1–2 min to peak
Metabolism: hepatic
Elimination: urine (inactive metabolites)
Half-life: <5 min		 Onset: Immediate
Distribution: 1–2 min to peak
Metabolism: hepatic
Elimination: urine (inactive metabolites)
Half-life: <5 min
Adverse Effects Tachyarrhythmias, myocardial ischemia, extravasation leading to necrosis
Mechanism of Action α agonist → Peripheral vasoconstriction → ↑ myocardial & cerebral blood flow
β agonist → ↑ heart rate & contractility → ↑ myocardial oxygen demand
Compatibility Refer to institutional policies for line compatibility and Y-site administration.

Clinical pearl: Norepinephrine may offer a hemodynamic advantage over epinephrine in certain post-arrest scenarios.

Overview of Key Evidence

Author/Year Design (n) Key Findings
Bougouin, 2022 Retrospective (N=766) Epinephrine group had higher all-cause hospital mortality (OR 2.6; 95% CI 1.4–4.7; P=0.002) and more CPC 3–5 at discharge.
Weiss, 2021 Retrospective (N=93) EPI group had more refractory hypotension, rearrest, or death in ED (50% vs 22.2%; P=0.008); adjusted odds of adverse events 3.94 times higher (P=0.013).
Mion, 2014 Case report (N=1) After recurrent VF with epinephrine, transition to norepinephrine led to ROSC and full recovery post ICU stay.
Kim, 2012 Retrospective (N=90) Survivors were more likely to have received norepinephrine (34.8% vs 22.6%); even more pronounced in prolonged arrest group (42.85% vs 25%).

Clinical Conclusions

  • It remains controversial whether epinephrine is the preferred vasopressor post-cardiac arrest.
  • Norepinephrine is a reasonable alternative post-arrest, particularly when adverse effects from epinephrine are of concern.

Full Reference List

  1. Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Accessed 2022, March 15. http://www.micromedexsolutions.com/
  2. Callaway C. Epinephrine for cardiac arrest. Current Opinion in Cardiology. 2013;28(1):36-42.
  3. Epinephrine [package insert] Lake Forest, IL: Hospira, Inc.; 2019.
  4. Kim et al. THE BENEFIT OF NOREPINEPHRINE INFUSION FOR HEMODYNAMIC SUPPORT FOLLOWING CARDIOPULMONARY ARREST AND RESUSCITATION. Critical Care Medicine. 2012;40(12):1-328.
  5. Mion G, et al. Cardiac arrest: should we consider norepinephrine instead of epinephrine? Am J Emerg Med. 2014;32(12):1560.e1-2. PMID: 24997106.
  6. Weiss A, et al. Comparison of Clinical Outcomes with Initial Norepinephrine or Epinephrine for Hemodynamic Support After Return of Spontaneous Circulation. Shock. 2021;56(6):988-993. PMID: 34172611.
  7. Bougouin W, et al. Epinephrine versus norepinephrine in cardiac arrest patients with post-resuscitation shock. Intensive Care Med. 2022;48(3):300-310. PMID: 35129643.

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PACULit Newsletter July 2025 (3 of 4)





PACULit Review
6 min read
June 20, 2025

PACULit Newsletter July 2025 (3 of 4)

R

Riszel

PharmD






PACULit Newsletter – July 2025


High-Impact Studies Review — July 2025 (3/4)

Stay updated with breakthrough research in emergency medicine, critical care, and advanced therapeutics.

Featured Educational Video

In this clinical dive from PACUPod, we explore three timely studies changing how we approach critical care, sepsis, and cardiac arrest. First up, we examine a bold randomized trial testing whether ultra-high doses of esomeprazole can reduce inflammation in septic patients. Despite the pharmacologic promise, the results show no reduction in organ dysfunction or inflammatory markers—reminding us that more isn’t always better.

Next, we break down the hemodynamic physiology of out-of-hospital cardiac arrest from the AMCPR trial. This study reveals that diastolic blood pressure, more than ETCO₂, strongly predicts return of spontaneous circulation—spotlighting real-time metrics that may guide resuscitation strategies in the field.

Finally, we look at whether adding lactate to the qSOFA score (LqSOFA) enhances risk stratification for septic patients in the ED. The answer? A solid yes, with better sensitivity for identifying patients who will need ICU care, vasopressors, or who are at risk of death—though specificity takes a small hit.

These are insights you can use on your next shift—evidence-based, fast-paced, and practice-changing.

1. A Multinational Randomized Trial of Mega-Dose Esomeprazole As Anti-Inflammatory Agent in Sepsis
Critical Care Medicine | 2025

This double-blind trial enrolled 307 adults with sepsis/septic shock across 17 ICUs/EDs, comparing 72 h of high-dose esomeprazole (1024 mg) versus placebo on organ-dysfunction outcomes.

Key Findings

  • No SOFA Improvement: Median mean daily SOFA to day 10 was identical (5; IQR 3-9 vs 3-8; p>0.99).
  • Neutral Secondary Outcomes: ICU-free days, antibiotic-free days, and 28-day mortality were unchanged.
  • Mechanistic Sub-Study: Ex vivo monocyte cytokine responses were unaffected, disputing an anti-inflammatory benefit.

Clinical Pharmacist’s Perspective

High-dose PPI therapy should not be pursued for immunomodulation in sepsis; prioritize proven bundle elements (early antibiotics, source control) and reserve PPIs for GI bleeding prophylaxis.

Full Article

2. Diastolic Blood Pressure & End-Tidal CO₂ During CPR and Outcomes: Secondary Analysis of the AMCPR Trial
Resuscitation | 2025

Among 264 adult out-of-hospital cardiac arrest patients, investigators correlated early CPR hemodynamics with sustained return of spontaneous circulation (ROSC).

Key Findings

  • DBP Predicts Success: Follow-up DBP >26.5 mmHg (≈10 min) yielded aOR 10.0 for sustained ROSC.
  • Delta DBP Matters: Raising DBP by >6.5 mmHg doubled ROSC likelihood (aOR 4.8).
  • ETCO₂ Less Informative: ETCO₂ values were largely similar between groups except at follow-up, indicating DBP is the stronger physiologic target.

Clinical Pharmacist’s Perspective

Encourage teams to monitor DBP (e.g., arterial line or Doppler) and titrate compression quality/vasopressors to maintain >26 mmHg; stock ready-to-push epinephrine/norepinephrine to achieve perfusion pressures.

Full Article

3. Initial Lactate-Augmented qSOFA (LqSOFA) in Emergency Department Sepsis
American Journal of Emergency Medicine | 2025

This retrospective cohort of 1,274 suspected sepsis patients compared LqSOFA (qSOFA+ initial lactate) against standard qSOFA for predicting ICU admission, vasopressor need, and 72-h mortality.

Key Findings

  • Higher Sensitivity: LqSOFA better identified patients needing ICU (48 % vs 30 %), pressors (68 % vs 50 %), and those who died (76 % vs 71 %).
  • Trade-Off in Specificity: Specificities were lower for LqSOFA (e.g., mortality 67 % vs 80 %).
  • Superior AUROC for Mortality: LqSOFA showed a statistically greater AUC for death prediction (p<0.05).

Clinical Pharmacist’s Perspective

Advocate point-of-care lactate testing with triage; LqSOFA can flag high-risk patients sooner, but balance earlier escalation against false positives and resource strain.

Full Article

🔎 Final Takeaways:
  • No Benefit from Mega-Dose Esomeprazole: High-dose PPI therapy failed to improve organ dysfunction in sepsis—stick to guideline-directed care.
  • Target DBP >26 mmHg During CPR: Diastolic pressure outperforms ETCO₂ as a hemodynamic goal for ROSC in OHCA.
  • LqSOFA Beats qSOFA for Early Sepsis Risk: Adding lactate boosts sensitivity and AUROC, aiding rapid triage—accepting some loss of specificity.

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PACULit Newsletter July 2025 (1 of 4)





PACULit Review
6 min read
June 5, 2025

PACULit Newsletter July 2025 (1 of 4)

R

Riszel

PharmD






PACULit Newsletter – June 2025


High-Impact Studies Review — June 2025 (1/4)

Stay updated with breakthrough research in emergency medicine, critical care, and advanced therapeutics.

Featured Educational Video

In this episode of PACUPod, we explore three fresh studies with immediate implications for acute care practice. First, we unpack a prospective trial comparing oxymetazoline, tranexamic acid, and an epinephrine–lidocaine mix for treating nosebleeds. Oxymetazoline emerges as the clear winner, demonstrating rapid, effective bleeding control—crucial for emergency settings.

Next, we delve into a phase II trial investigating whether IV salbutamol can alleviate renal colic pain. Despite its theoretical promise, the study found no significant benefit, adding nuance to the debate over non-traditional analgesics.

Finally, we tackle the perennial challenge of IV insertion pain. A head-to-head comparison of vapocoolant spray and lidocaine–prilocaine cream reveals comparable pain relief, but the spray’s immediacy and fewer side effects may give it the upper hand.

Tune in for these evidence-based updates, each ready to reshape your practice at the bedside.

1. Comparison of the Efficacy of Oxymetazoline, Tranexamic Acid, and Epinephrine-Lidocaine Combination in the Treatment of Epistaxis
American Journal of Emergency Medicine | 2025

This prospective ED study compared three topical agents—oxymetazoline, tranexamic acid, and an epinephrine-lidocaine mix—to determine which achieves the fastest and most durable hemostasis for non-traumatic epistaxis.

Key Findings

  • Highest Hemostasis Success: Oxymetazoline controlled bleeding in 71% of cases, outperforming tranexamic acid (55%) and epinephrine-lidocaine (49%).
  • Statistically Significant Advantage: Oxymetazoline’s superiority reached significance (p=0.007).
  • Practical Implications: Rapid action and easy availability make oxymetazoline a pragmatic first-line choice in EDs.

Clinical Pharmacist’s Perspective

Stock oxymetazoline and integrate it into epistaxis protocols; provide team education on correct dosing to optimize bleeding control and reduce returns.

Full Article

2. Salbutamol for Analgesia in Renal Colic: A Prospective, Randomised, Placebo-Controlled Phase II Trial
Emergency Medicine Journal | 2025

Investigated whether a single 250 µg IV dose of salbutamol, given alongside standard therapy, provides superior pain relief for ED patients with confirmed renal colic.

Key Findings

  • No Additional Analgesic Benefit: Median pain-score reduction at 30 min was similar between salbutamol (-18 mm) and placebo (-13 mm); difference 5 mm, p=0.575.
  • Higher Adverse-Event Burden: 65 AEs in the salbutamol arm vs 42 with placebo (p=0.02).
  • Clinical Implication: Routine IV salbutamol is not justified for renal-colic pain control.

Clinical Pharmacist’s Perspective

Focus on established multimodal analgesia (NSAIDs ± opioids); reserve salbutamol for bronchospasm rather than ureteric spasm until larger efficacy data emerge.

Full Article

3. Vapocoolant Spray vs Lidocaine-Prilocaine Cream for Reducing Pain of Intravenous Cannulation: A Randomised Controlled Trial
Emergency Medicine Journal | 2025

Compared a rapid-acting vapocoolant spray (applied 30 s pre-cannulation) with lidocaine-prilocaine cream (45 min pre-cannulation) in adult ED patients requiring peripheral IV access.

Key Findings

  • Comparable Pain Scores: Median NRS pain 2 with spray vs 3 with cream (p=0.09).
  • Fewer Adverse Effects: Transient paleness occurred in 31% overall—predominantly in the cream group (p=0.03).
  • Greater Patient Preference: 43% opted to reuse the spray vs 27% for the cream (p=0.02).

Clinical Pharmacist’s Perspective

Vapocoolant offers a fast, low-cost option when time constraints preclude topical-cream dwell times; monitor skin reactions and document patient preferences for future procedures.

Full Article

🔎 Final Takeaways:
  • Oxymetazoline for Epistaxis: Achieves the highest and fastest hemostasis success, supporting its adoption as first-line topical therapy in the ED.
  • IV Salbutamol in Renal Colic: Fails to improve pain relief and increases adverse events—avoid routine use for ureteric pain control.
  • Vapocoolant Spray for IV Access: Offers comparable analgesia to lidocaine-prilocaine cream with near-instant application, ideal when rapid cannulation is required.

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PACULit Newsletter May 2025





PACULit Review
7 min read
May 19, 2025

PACULit Newsletter May 2025

R

Riszel

PharmD






PACULit Newsletter – March 14, 2025


High-Impact Studies Review — May 2025

Stay updated with breakthrough research in emergency medicine, critical care, and advanced therapeutics.

Featured Educational Video

In this high-impact episode of PACUPod, we break down five critical studies reshaping emergency and critical care. From the ripple effects of the 2024 IV fluid shortage on ED operations to the potential of Nirsevimab in reducing pediatric ICU admissions, we dive deep into how the latest data is influencing frontline practice. We also explore compelling evidence for rescue ketamine in prehospital status epilepticus, the role of prothrombin complex concentrate for anticoagulated patients with mild TBI, and new insights into arginine vasopressin’s hemodynamic effects in septic shock. Whether you’re on shift or between cases, this is your evidence-based update—fast, focused, and clinically relevant.

1.
The Impact of the 2024 Intravenous Fluid Shortage on Emergency Department Length of Stay and 72-Hour Return Rate
Critical Care Medicine | 2025

This study examines the consequences of the 2024 intravenous (IV) fluid shortage on emergency department (ED) operations, focusing on patient length of stay and 72-hour return rates.

Key Findings

  • Increased ED Length of Stay: Patients experienced longer stays due to fluid shortages.
  • Higher 72-Hour Return Rates: More patients returned to the ED within 72 hours, indicating unresolved symptoms.
  • Critical Impact on Supply Chain Management: Highlights the need for robust inventory management strategies.

Clinical Pharmacist’s Perspective

Support proactive supply chain management and optimize fluid therapy to prevent adverse patient outcomes during shortages.

Full Article

2.
Nirsevimab Prophylaxis on Pediatric Intensive Care Hospitalization for Severe Acute Bronchiolitis
Annals of Intensive Care | 2025

This study evaluates the impact of administering Nirsevimab, a monoclonal antibody targeting the respiratory syncytial virus (RSV), as a prophylactic treatment in neonates.

Key Findings

  • Reduced PICU Admissions: Nirsevimab significantly lowered the rate of PICU admissions for severe bronchiolitis.
  • Cost-Effective Prophylaxis: Reduced healthcare costs due to lower PICU utilization.
  • Safe Administration: Minimal adverse effects observed, making it a safe option for prophylaxis.

Clinical Pharmacist’s Perspective

Ensure appropriate use of Nirsevimab, monitor for adverse effects, and educate caregivers on RSV prevention to optimize outcomes.

Full Article

3.
Evidence Mounts Backing Rescue Ketamine for Prehospital Status Epilepticus
ACEP Now | 2025

This article highlights the use of ketamine as a rescue therapy for midazolam-resistant status epilepticus in prehospital settings.

Key Findings

  • Effective Seizure Control: Ketamine provided rapid seizure control when midazolam failed.
  • Multiple Administration Routes: Ketamine was effective via IV, IO, IM, or IN routes.

Clinical Pharmacist’s Perspective

Ketamine is considered an essential option for rescue therapy in benzodiazepine-resistant status epilepticus, offering rapid seizure control.

Full Article

4.
Systematic Vitamin K Antagonist Reversal with Prothrombin Complex Concentrate in Mild Traumatic Brain Injury
European Journal of Emergency Medicine | 2025

This study examines the impact of using 4F-PCC for rapid reversal of VKAs in patients with mild TBI, reducing hemorrhage progression.

Key Findings

  • Reduced Hemorrhage Progression: 4F-PCC minimized intracranial bleeding risks.
  • Improved Recovery: Patients showed better outcomes with rapid VKA reversal.

Clinical Pharmacist’s Perspective

4F-PCC is crucial for rapid VKA reversal in TBI patients, ensuring effective hemostasis and better recovery.

Full Article

5.
Hemodynamic Effects of Adjunct Arginine Vasopressin to Norepinephrine in Septic Shock
Annals of Intensive Care | 2025

This study investigates the hemodynamic effects of adjunctive arginine vasopressin to norepinephrine in septic shock, identifying factors associated with patient response.

Key Findings

  • 79% Response Rate: Patients showed significant hemodynamic improvement with AVP.
  • Negative Predictors: Obesity and hyperlactatemia were linked to reduced response.
  • Positive Predictors: Higher norepinephrine infusion rates correlated with better response.

Clinical Pharmacist’s Perspective

AVP is a valuable adjunct in septic shock, but response may vary. Pharmacists should evaluate patient factors to optimize therapy.

Full Article

🔎 Final Takeaways:
  • IV Fluid Shortage: Highlights the need for proactive inventory management to prevent care disruptions in emergencies.
  • Nirsevimab Prophylaxis: Demonstrates reduced PICU admissions and cost-effectiveness for severe bronchiolitis prevention.
  • Rescue Ketamine: Provides effective seizure control for midazolam-resistant status epilepticus in prehospital settings.
  • VKA Reversal with 4F-PCC: Ensures rapid reversal of anticoagulation in mild TBI, reducing hemorrhage risks.
  • AVP in Septic Shock: Effective in improving hemodynamics, but patient response varies based on specific factors.

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🎥
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PACULit Newsletter March 14 –





PACULit Review
9 min read
March 14, 2025

PACULit Newsletter March 14 –

J

Jimmy

PharmD






PACULit Newsletter – March 14, 2025


High-Impact Studies Review — March 2025

Stay updated with breakthrough research in emergency medicine, critical care, and advanced therapeutics.

Featured Educational Video

In this episode, experts review key updates from the 2025 ACS guidelines, examine the emerging role of short‐acting beta-blockers and dexmedetomidine in septic shock, compare novel analgesic strategies using nebulized versus intravenous ketamine, and discuss the impact of tranexamic acid in pediatric traumatic brain injury.


1.
2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Acute Coronary Syndromes
JACC & Circulation | February 2025

The 2025 update to the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines for Acute Coronary Syndrome (ACS) introduces important changes based on the latest clinical evidence. The new recommendations focus on optimizing early risk stratification, refining antithrombotic therapy, and tailoring invasive management strategies to improve patient outcomes.

Key Updates and Findings

  • Dual Antiplatelet Therapy (DAPT):
    Used to be: Clopidogrel was often an equivalent option.
    Now: Ticagrelor or prasugrel is now the preferred P2Y12 inhibitor over clopidogrel in all patients undergoing PCI unless contraindicated.
  • ECG Timing and Risk Assessment: All patients with suspected ACS should have an ECG performed within 10 minutes of arrival to facilitate rapid classification and treatment initiation.
  • Radial vs. Femoral PCI Access: Radial artery access is strongly recommended over femoral access due to lower bleeding risks, fewer vascular complications, and reduced mortality.
  • Complete Revascularization Strategy: Routine PCI of non-culprit lesions in STEMI patients is not recommended during the initial procedure, except in cases of cardiogenic shock.
  • High-Intensity Statins and Lipid Management: High-intensity statins should be initiated in all ACS patients. If LDL remains ≥70 mg/dL, additional lipid-lowering agents (ezetimibe or PCSK9 inhibitors) should be considered.
  • Beta-Blocker Therapy:
    Used to be: For all, regardless of risk factors.
    Now: Early beta-blocker use is no longer required for all ACS patients. Therapy should be reserved for those with ongoing ischemia, hypertension, or left ventricular dysfunction.
  • Anticoagulation Strategy: Selection of unfractionated heparin (UFH), enoxaparin, or bivalirudin should be individualized based on renal function, prior anticoagulation, and bleeding risk.
  • Early Discharge for Low-Risk NSTEMI: Selected low-risk patients with negative troponins and normal ECG findings may be safely discharged within 24 hours with close outpatient follow-up.
  • Cardiogenic Shock Management: Emergency PCI should target the culprit vessel only. Non-culprit PCI at the time of intervention is discouraged unless clinically indicated.

Clinical Implications

These updates emphasize a more individualized approach to ACS management, balancing ischemic protection with bleeding risk. The move toward radial PCI access, a shift in beta-blocker recommendations, and an intensified focus on lipid-lowering strategies mark significant changes in clinical practice.

Clinical Pharmacist’s Perspective

Pharmacists play a key role in ensuring appropriate DAPT selection, optimizing statin therapy adherence, and managing anticoagulation. The inclusion of PCSK9 inhibitors highlights the need for careful assessment of cost-effectiveness in high-risk patients. Close monitoring of potential drug interactions is also essential to ensure safe therapy implementation.

Full Article


2.
Impact of Short-Acting Beta-Blockers in Septic Shock
Critical Care Medicine | 2025

This systematic review and meta-analysis of 12 randomized controlled trials (RCTs) involving 1,170 patients examined the effects of short-acting beta-blockers in septic shock. The findings suggest potential benefits in mortality reduction and heart rate control, but also raise concerns about prolonged vasopressor use.

Key Findings
  • Reduction in 28-Day Mortality: Short-acting beta-blockers were associated with a 24% relative reduction in 28-day mortality (RR 0.76, 95% CI 0.62–0.93).
  • New-Onset Tachyarrhythmia Prevention: Significant reduction in tachyarrhythmias (RR 0.37, 95% CI 0.18–0.78), suggesting improved heart rate control.
  • Impact on Hemodynamics: Beta-blockers stabilized heart rate but prolonged vasopressor requirements by an average of 1.04 days (95% CI 0.37–1.72).
  • No Clear Benefit on Long-Term Outcomes: No significant impact was observed on 90-day mortality, ICU length of stay, or mechanical ventilation duration.
Mechanism of Action

Beta-blockers such as esmolol and landiolol counteract excessive catecholamine stimulation, which can cause myocardial stress, endothelial injury, and metabolic dysfunction in septic shock. By reducing sympathetic overdrive, they may improve cardiac efficiency and tissue oxygenation while preventing secondary organ dysfunction.

Clinical Implications

The potential mortality benefit makes beta-blockers a promising adjunctive therapy in septic shock, particularly for patients with persistent tachycardia despite adequate fluid resuscitation and vasopressor therapy. However, the prolonged vasopressor requirements suggest that beta-blockers should be used selectively and with careful monitoring.

Clinical Pharmacist’s Perspective

The use of beta-blockers in septic shock remains controversial and should be limited to patients who demonstrate clear benefit. Pharmacists should focus on:

  • Dosing and titration: Adjust doses carefully to prevent excessive bradycardia and hypotension.
  • Monitoring interactions: Watch for interactions with vasopressors and inotropes that could impact hemodynamics.
  • Assessing patient eligibility: Ensure beta-blockers are used in clinically stable individuals with controlled shock parameters.

As further studies emerge, pharmacists can help refine treatment protocols to integrate beta-blockers safely in select patients.


Full Article

3.
Nebulized Ketamine vs IV Subdissociative Dose Ketamine for Acute Pain
Annals of Emergency Medicine | October 2024

In a randomized, double-blind trial of 150 adults, both nebulized (0.75 mg/kg) and IV (0.3 mg/kg) ketamine provided substantial pain relief at 30 minutes with comparable safety profiles.

Key Findings:
  • Both regimens significantly reduced pain scores.
  • No clinically significant differences in adverse effects.
  • Noninvasive nebulized administration may benefit patients without IV access.
Clinical Pharmacist’s Perspective:

Ketamine offers an effective alternative for acute pain management; route selection can be tailored to clinical settings and patient needs.

Full Article

4.
Dexmedetomidine in Refractory Septic Shock (ADRESS Trial)
Critical Care Medicine | 2025

This pilot trial evaluated dexmedetomidine (1 µg/kg/hr) for enhancing vasopressor sensitivity in refractory septic shock. The trial was halted early due to a lower phenylephrine response and higher early mortality in the dexmedetomidine group.

Key Findings:
  • Significantly lower MAP response to phenylephrine in the dexmedetomidine group.
  • Higher early mortality noted, raising safety concerns.
  • No significant improvements in vasopressor dose requirements.
Clinical Pharmacist’s Perspective:

Given the safety signals, cautious use of dexmedetomidine is advised in septic shock until larger trials clarify its role.

Full Article

5.
Tranexamic Acid in Pediatric Traumatic Brain Injury
Annals of Emergency Medicine | February 2025

A multicenter retrospective study of 368 pediatric severe TBI patients found that TXA administration was not associated with a reduction in inhospital mortality or poor neurologic outcomes.

Key Findings:
  • Inhospital mortality: 14% overall with no significant difference between TXA and non-TXA groups.
  • Poor neurologic outcomes were similar regardless of TXA use.
  • Results do not support routine TXA administration for severe pediatric TBI.
Clinical Pharmacist’s Perspective:

TXA remains valuable in hemorrhagic trauma; however, its role in pediatric TBI is unproven and should be applied cautiously.

Full Article

🔎 Final Takeaways:
  • ACS Guidelines: Updated recommendations favor aggressive dual antiplatelet and radial access strategies.
  • Beta-Blockers: May lower short-term mortality in septic shock, but further research is needed to balance benefits with prolonged vasopressor use.
  • Ketamine: Both IV and nebulized routes offer effective, safe analgesia for acute pain.
  • Dexmedetomidine: Its use in refractory septic shock is not supported by current evidence due to safety concerns.
  • TXA in Pediatric TBI: No clear benefit was demonstrated, underscoring the need for prospective trials.

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PACULit Newsletter March 3





PACULit Review
10 min read
February 16, 2025

PACULit Newsletter March 3

J

Jimmy

PharmD






PACULit Newsletter – March 3 2025


High-Impact Studies Review — March 2025

Stay updated with the latest breakthrough research in emergency medicine, critical care, and advanced therapeutics.

Featured Educational Video

This month’s featured educational video provides an in-depth discussion on emerging treatments in emergency medicine and critical care. Our medical experts review the key research findings presented in this newsletter, with practical applications for your clinical practice.

1. Magnesium Sulfate vs. Lidocaine as an Adjunct for Renal Colic
Annals of Emergency Medicine | December 2024

This randomized, double-blind controlled trial compared the effectiveness of intravenous MgSO4 and lidocaine as adjuncts to diclofenac for managing acute renal colic in the emergency department setting.

Patients Achieving ≥50% Pain Reduction at 30 Minutes
81.7%
MgSO4

72.9%
Lidocaine

71.8%
Control

Statistically significant differences: MgSO4 vs. Lidocaine (p=0.013) and MgSO4 vs. Control (p=0.004)

Key Findings:
  • MgSO4 showed statistically superior pain relief compared to lidocaine and placebo
  • The magnitude of differences was below the accepted threshold for clinical importance
  • MgSO4 group required less rescue analgesia
  • More adverse events in the MgSO4 group, primarily facial flushing (48.2%)
Clinical Implications:
  • Use MgSO4 cautiously, balancing marginal benefits with adverse event risks
  • Lidocaine showed no major benefit over diclofenac alone
Clinical Pharmacist’s Perspective

The modest analgesic benefit of IV magnesium must be weighed against the high incidence of facial flushing (48.2%). When administering IV MgSO4, ensure patients are warned about this common side effect to prevent unnecessary anxiety. From a cost perspective, MgSO4 is an inexpensive adjunct that may reduce the need for opioid rescue medication. Consider it in patients with contraindications to opioids or those with prior inadequate response to NSAIDs alone. The 1g dose used in this study is well below the threshold for serious toxicity, making it relatively safe even in patients with mild renal impairment.

Full Article

2. Intranasal Ketamine as an Adjunct to Fentanyl for Prehospital Trauma Pain
Annals of Emergency Medicine | October 2024 (Epub January 12, 2024)

This randomized, placebo-controlled trial evaluated whether adding intranasal ketamine to fentanyl improves early pain control after traumatic injury in the out-of-hospital setting.

Patients Achieving ≥2-Point Pain Reduction at 30 Minutes
44.7%
Ketamine

36.0%
Placebo

Difference not statistically significant (8.7%, 95% CI [5.1% to 22.5%], P=0.22)

Key Findings:
  • No statistically significant difference in pain reduction between ketamine (44.7%) and placebo (36.0%)
  • The observed difference of 8.7% suggests a trend that might warrant further investigation
  • No differences in pain scores at any time point through 3 hours
  • No difference in need for additional pain medications
  • Side effects were similar between groups with no concerning safety signals
Clinical Implications:
  • A single 50 mg intranasal dose of ketamine appears safe but current evidence doesn’t support a significant analgesic benefit
  • Higher doses might be worth exploring in future studies
Clinical Pharmacist’s Perspective

The bioavailability of intranasal ketamine is approximately 40%, meaning the 50mg dose used in this study translates to roughly 20mg of systemic exposure. This is likely at the lower end of effective analgesic dosing for adults. While the observed 8.7% improvement didn’t reach statistical significance, this trend suggests that higher doses might be more effective. For EMS protocols, intranasal administration remains attractive for its ease of use and avoidance of vascular access, but based on this study, higher intranasal doses (75-100mg) may be worth investigating. Remember that absorption of intranasal medications can be compromised by nasal congestion, bleeding, or prior intranasal medication administration, which may have affected the results here.

Full Article

3. Transfusion Practices in Traumatic Brain Injury (TBI): A Systematic Review & Meta-Analysis
Critical Care Medicine | February 2025

This comprehensive review examined whether liberal blood transfusion strategies improve neurologic outcomes in TBI patients compared to restrictive strategies across five randomized controlled trials involving 1,533 patients.

Neurologic Outcomes (Favorable Glasgow Outcome Scale)
1.16
Liberal

1.00
Restrictive

Risk Ratio: 1.16 (95% CI 1.00-1.34)

Acute Respiratory Distress Syndrome (ARDS) Risk
1.78
Liberal

1.00
Restrictive

Risk Ratio: 1.78 (95% CI 1.06-2.98)

Key Findings:
  • Trend toward better neurologic outcomes with liberal transfusion that approaches statistical significance (RR, 1.16; 95% CI, 1.00-1.34)
  • No significant differences in mortality rates between groups at any time point
  • Liberal strategy was associated with significantly higher prevalence of ARDS (RR, 1.78; 95% CI, 1.06-2.98)
  • Liberal strategy group received significantly more blood units per patient
Clinical Implications:
  • Current guidelines recommending restrictive transfusion protocols (Hb < 7 g/dL) should be reconsidered for TBI patients
  • The 9 g/dL threshold may represent an optimal balance between brain oxygenation and transfusion risks
  • Despite increased ARDS risk, the potential neurologic benefits should be considered when making transfusion decisions
  • Future research should explore the ideal hemoglobin threshold specifically for TBI patients
Clinical Pharmacist’s Perspective

While pharmacists don’t directly administer blood products, understanding transfusion thresholds is essential for comprehensive patient care in critical care settings. This meta-analysis suggests a potential paradigm shift for TBI patients that differs from general critical care guidelines. As part of the multidisciplinary team, pharmacists should be aware that TBI patients may benefit from higher hemoglobin targets due to the brain’s high oxygen demands and vulnerability to hypoxic injury. When managing patients receiving liberal transfusion strategies, be vigilant for signs of ARDS and consider how medication therapies might interact with fluid status and oxygen delivery. Pharmacists can play a role in ensuring appropriate venous thromboembolism prophylaxis is prescribed alongside transfusion strategies, as both hypercoagulable and bleeding risk considerations must be balanced in TBI care.

Full Article

🔎 Final Takeaways:
  • Magnesium Sulfate for Renal Colic: Provides statistically significant but clinically modest improvement in pain when added to diclofenac. Consider in patients who need enhanced analgesia, but be mindful of facial flushing as a common side effect.
  • Intranasal Ketamine for Trauma Pain: The addition of 50 mg intranasal ketamine to fentanyl showed a trend toward improved pain control (8.7% difference) that didn’t reach statistical significance. Further research with larger sample sizes or higher doses may be warranted.
  • Liberal Transfusion in TBI: Evidence suggests that maintaining hemoglobin levels ≥9 g/dL may improve neurologic outcomes in TBI patients, but also increases ARDS risk. This challenges the standard restrictive approach and warrants further investigation.
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