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

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:

 PubMed Search Guide for Pharmacists

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

Statins for STEMI in the Emergency Department

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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 
Dose80 mg orally once daily40 mg orally once daily
AdministrationOralOral
PK/PDOnset: 3-5 days for LDL reduction; Peak effect: 2-4 weeksOnset: 3-5 days for LDL reduction; Peak effect: 2-4 weeks
Adverse EffectsMyopathy, elevated liver enzymes, gastrointestinal symptomsMyopathy, elevated liver enzymes, gastrointestinal symptoms
Drug Interactions and warningsCYP3A4 inhibitors/inducers can affect levels; avoid in active liver diseaseMinimal CYP interactions; avoid in active liver disease
CompatibilityCompatible with most cardiovascular drugs, monitor for interactions with CYP3A4 inhibitorsCompatible with most cardiovascular drugs, minimal interactions
CommentsHigh-intensity statin recommended post-STEMI to reduce recurrence riskHigh-intensity statin alternative to atorvastatin

Overview of Evidence

Author, YearDesign/Sample SizeIntervention & ComparisonOutcome
Schwartz, 2001Randomized Controlled Trial (n=3086)Atorvastatin (80 mg/day) vs. placebo initiated 2496 hours after acute coronary syndromeAtorvastatin reduced recurrent symptomatic ischemia requiring rehospitalization (6.2% vs 8.4%; RR, 0.74; P=0.02)
Li, 2012Randomized Controlled Trial (n=161)High-dose atorvastatin (80 mg) vs. placebo in patients with STEMI undergoing PCIHigh-dose atorvastatin significantly reduced the incidence of contrast-induced nephropathy (2.6% vs 15.7%; P=0.01)
Liu, 2013Randomized Controlled Trial (n=102)Loading dose of atorvastatin (80 mg) before PCI vs. no loading doseLoading 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, 2016Randomized Controlled Trial (n=120)Intensive atorvastatin (40 mg) vs. standard atorvastatin (20 mg) in STEMI patients undergoing PCIIntensive atorvastatin significantly reduced serum endothelin-1 levels and ADP-induced platelet clot strength, improving endothelial function and platelet inhibition (P<0.05)
Kim, 2015Randomized 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, 2017Randomized Controlled Trial (n=52)High-dose atorvastatin (80 mg) vs. moderate dose (20 mg) in STEMI patientsHigh-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, 2013Randomized Controlled Trial (n=102)Loading dose of atorvastatin (80 mg) before PCI vs. no loading doseLoading dose of atorvastatin significantly lowered inflammatory markers and improved left ventricular ejection fraction compared to no loading dose (P<0.05)
Adel, 2022Randomized Controlled Trial (n=99)High-dose rosuvastatin (40 mg) vs. high-dose atorvastatin (80 mg) before PCI in STEMI patientsAtorvastatin group had lower CTFC and better TIMI flow grade compared to control, and both statins improved microvascular myocardial perfusion (P<0.01)
Chen, 2022Randomized 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.

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

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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

 VancomycinPiperacillin-tazobactam4
DoseDepends on infection and PK/PD target General dosing for systemic infections: IV 15-20 mg/kg IV Q8-12H for systemic infectionsStandard 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
AdministrationAdminister IV over ≥60 minutes at concentrations ≤5 mg/mL to reduce the risk of vancomycin infusion reactionStandard infusion: Infuse over 30 min Extended infusion: Infuse loading dose over 30 min, start maintenance dose four hours later infused over 4 hours
PK/PDNegligible 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 usedT1/2 = 0.7-1.2 hours Renally eliminated (80% unchanged) Dose adjust at CrCl<40 T>MIC dependent kinetics, prolonged infusions enhance efficacy
Adverse EffectsNephrotoxicity Ototoxicity Vancomycin-infusion reaction (flushing, hypotension, tachycardia)GI upset (diarrhea, nausea, constipation) Headache Rash, pruritis
Drug Interactions and warningsSubstrate 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)
CompatibilityCompatible with dextrose, NS, LR Incompatible with lipid emulsionLR: 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
CommentsSerum troughs are a poor proxy of 24-hour AUC, trough-guided regimens have been shown to exceed the target AUC in 60% of adults10Useful 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, yearDesign/ sample sizeIntervention & ComparisonAKI definitionOutcome
Sanz et al., 2002Prospective, multi-center (n = 969)Amikacin+cefepime vs. amikacin+piperacillin-tazobactam↑ SCr ≥50% from baselineNo difference in severe nephrotoxicity between amikacin+piperacillin-tazobactam vs. amikacin+cefepime
Karino et al., 2016Retrospective cohort and nested case-control studies (n = 320)Vancomycin+piperacillin-tazobactam standard infusion vs. Vancomycin+piperacillin-tazobactam extended-infusionRIFILE criteriaAKIN criteriaVancomycin consensus guideline definitionAKI 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., 2017Meta-analysis of 14 observational studies (n = 3549)Vancomycin+piperacillin-tazobactam vs. vancomycin+any β-lactam or vancomycin aloneAll included studies used one of the following: RIFLE criteriaAKIN criteria↑ SCr ≥100% or >0.5 mg/dLVancomycin+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., 2017Retrospective matched cohort (n = 4103)Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepimeRIFLE criteriaVancomycin+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., 2017Prospective observational cohort (n = 85)Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime or vancomycin+meropenemKDIGOIncidence 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., 2017Retrospective matched cohort (n = 2448)Vancomycin+piperacillin-tazobactam vs. Vancomycin+ampicillin-sulbactamRIFLE criteriaIncreased 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., 2017Retrospective matched cohort (n = 5335)Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepime↑ SCr ≥0.3 mg/dL or ≥50% from baselineVancomycin+piperacillin-tazobactam associated with a higher risk of AKI vs. vancomycin-cefepime (aHR, 1.25; 95% CI, 1.11–1.42.)
Mousavi et al., 2017Retrospective matched cohort (n = 280)Vancomycin+piperacillin-tazobactam standard infusion vs. Vancomycin+piperacillin-tazobactam extended-infusion  RIFLE criteriaAKIN criteriaSimilar 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., 2022Prospective, observationalVancomycin+piperacillin-tazobactam vs. vancomycin+cefepime for ≥48 hours↑ SCr vs. ↑ Cystatin C vs. ↑ BUNVancomycin + 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=2511Vancomycin+piperacillin-tazobactam vs. vancomycin+cefepimeKDIGO  ↑ SCr ≥0.3 mg/dL or ≥50% from baselineThe 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

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 4, 2023, from http://www.micromedexsolutions.com/
  2. VANCOMYCIN HYDROCHLORIDE [package insert]. Rockford, IL: Mylan Institutional LLC; Jul, 2018.
  3. Blair M, Côté JM, Cotter A, Lynch B, Redahan L, Murray PT. Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review. Am J Nephrol. 2021;52(2):85-97. doi: 10.1159/000513742.
  4. Pill MW, O’Neill CV, Chapman MM, Singh AK. Suspected acute interstitial nephritis induced by piperacillin-tazobactam. Pharmacotherapy. 1997 Jan-Feb;17(1):166-9..
  5. Li H, Yang Q, Gui M, Ding L, Yang L, Sun H, Li Z. Changes of renal transporters in the kinetic process of VCM-induced nephrotoxicity in mice. Toxicol Res (Camb). 2021 Jun 9;10(4):687-695. doi: 10.1093/toxres/tfab048. PMID: 34484661; PMCID: PMC8403606.
  6. Giuliano CA, Patel CR, Kale-Pradhan PB. Is the Combination of Piperacillin-Tazobactam and Vancomycin Associated with Development of Acute Kidney Injury? A Meta-analysis. Pharmacotherapy. 2016 Dec;36(12):1217-1228. doi: 10.1002/phar.1851.
  7. Boucher, H. (2023) Piperacillin-tazobactam, Sanford Guide Web Edition. Available at: https://webedition.sanfordguide.com/en/drug-information/antibacterial-agents/penicillins/anti-pseudomonal-penicillins/piperacillin-tazobactam (Accessed: 12 October 2023).
  8. Yang S, Liu Z, Wang C, Wen S, Meng Q, Huo X, Sun H, Ma X, Peng J, He Z, Liu K. Piperacillin enhances the inhibitory effect of tazobactam on β-lactamase through inhibition of organic anion transporter 1/3 in rats. Asian J Pharm Sci. 2019 Nov;14(6):677-686. doi: 10.1016/j.ajps.2018.11.003.
  9. Landersdorfer CB, Kirkpatrick CM, Kinzig M, Bulitta JB, Holzgrabe U, Sörgel F. Inhibition of flucloxacillin tubular renal secretion by piperacillin. Br J Clin Pharmacol. 2008 Nov;66(5):648-59. doi: 10.1111/j.1365-2125.2008.03266.x.
  10. Neely MN, Youn G, Jones B, Jelliffe RW, Drusano GL, Rodvold KA, Lodise TP. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1):309-16. doi: 10.1128/AAC.01653-13.
  11. Alvarez-Arango S, Ogunwole SM, Sequist TD, Burk CM, Blumenthal KG. Vancomycin Infusion Reaction – Moving beyond “Red Man Syndrome”. N Engl J Med. 2021 Apr 8;384(14):1283-1286. doi: 10.1056/NEJMp2031891. Epub 2021 Apr 3.
  12. Vallon V, Eraly SA, Rao SR, Gerasimova M, Rose M, Nagle M, Anzai N, Smith T, Sharma K, Nigam SK, Rieg T. A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am J Physiol Renal Physiol. 2012 May 15;302(10):F1293-9. doi: 10.1152/ajprenal.00013.2012. Epub 2012 Feb 15. PMID: 22338083; PMCID: PMC3362066.
  13. Sanz MA, López J, Lahuerta JJ, Rovira M, Batlle M, Pérez C, Vázquez L, Julià A, Palau J, Gutiérrez M, Capote FJ, Ramos F, Benlloch L, Larrea L, Jarque I; Spanish PETHEMA Group. Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob Chemother. 2002 Jul;50(1):79-88. doi: 10.1093/jac/dkf087. PMID: 12096010.
  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.

Corticosteroids in Sepsis by Marissa Marks, 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
DoseIV: 50 mg Q6H or 100 mg Q8H x 5-7 daysIV (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
AdministrationIV: over ≥30 secondsIV: over several minutes or over 15 to 60 minutes as an infusionAdminister 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
CompatibilityDrug in Solution: None tested  Drug in Solution:    -Compatible: D5W- ½ NS, NS    -Incompatible: D5W, D5NS, LRN/A

Overview of Evidence

Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
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, 2016RCT (n = 1400)  Vasopressin vs. norepinephrine plus hydrocortisone vs. placeboNo 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, 2018RCT (n = 380)  Infusion of hydrocortisone 200 mg daily for five days followed by tapering until day 11  vs placeboThe 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.

Ketamine for Treatment of Acute Agitation

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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

PropertiesRapid 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 
Dose2-5 mg/kg IM to a max single dose of 500mg
1-2 mg/kg IV  
AdministrationIM: Inject deep IM into large muscle (glute or vastus lateralis muscle)
IV: Administer over at least 60 seconds
Formulation10 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 EffectsHypertension
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 ConsiderationsRapid 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, yearDesign (sample size)Intervention & ComparisonOutcome
Lin et al., 2020Prospective, 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/IVKetamine achieved greater sedation within 5 and 15 minutes (22% vs 0% at 5 mins; 66% vs 7% at 15 mins)
Mankowitz et al., 2018Systematic review (n=650)Ketamine IV or IMMean 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., 2016Prehospital prospective, observational (n=146)  Haloperidol 10 mg IM   Ketamine 5 mg/kg IMMedian 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., 2016Subgroup analysis from DORM II study; prospective, observational  (n=49)Ketamine as rescue treatment after Droperidol alone   Droperidol + DZP or MDZ   Midazolam aloneMedian 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., 2016Prospective, 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., 2014Retrospective chart review (n=52)Ketamine ~4mg/kg IM   *Recommended midazolam 2-2.5 mg IM or IV following ketamine for emergence reaction96% 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 pendingParallel, prospective, randomized, controlledKetamine 5mg/kg IM   Midazolam 5mg IM + haloperidol 5mg IMPrimary: 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.

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

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

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

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.