Tag Archives: pharmacy friday pearls

High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema

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

Pharmacy Friday Pearl – Pharmacy & Acute Care University

Download PDF

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.

The Use of Norepinephrine vs Epinephrine in Post Cardiac Arrest Shock

The Use of Norepinephrine vs Epinephrine in Post Cardiac Arrest Shock

Pharmacy Friday Pearl – Pharmacy & Acute Care University

Download PDF

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.

Procainamide for Wide Complex Tachycardia

Procainamide for Wide Complex Tachycardia

Pharmacy Friday Pearl – Pharmacy & Acute Care University

Download PDF

Introduction

  • Ventricular tachycardia (VT) is an uncommon but dangerous medical condition with an extremely variable clinical presentation.
  • Intravenous procainamide is guideline recommended and is the drug of choice for hemodynamically stable VT with a class IIa recommendation.
  • Procainamide is an old drug with new evidence supporting its use, but dosing strategies and administration techniques make it difficult to use at the bedside.

Procainamide

Parameter Details
Bolus Dose 10–17 mg/kg over 20–60 minutes (Max dose 1g, max rate 20–50 mg/min) OR 100 mg every 5 minutes (max rate 50 mg/min) up to 1g
Renal Adjustments eCrCl 10–50 ml/min: reduce dose by 25–50%
eCrCl <10 ml/min: reduce dose by 50–75%
Maintenance Infusion 1–6 mg/min
Mechanism Class 1A anti-arrhythmic; blocks fast sodium channels, prolongs action potential, reduces impulse conduction speed
PK/PD IV Onset: <2 min; IM: 10–30 min
IV Peak: 25–60 min; IM: 15–60 min
Duration: 3–4 hrs
Metabolism: Hepatic to active NAPA
Half-life: 2.5–4.7 hrs (NAPA: 7 hrs)
Excretion: 40–70% renally unchanged
Adverse Effects Hypotension, hepatotoxicity, lupus-like syndrome, positive ANA, anaphylaxis (sulfite), MG exacerbation, angioedema
Drug Interactions Interacts with diazepam, diltiazem, milrinone, phenytoin, hydralazine
Compatibility Compatible: 0.9% NaCl, 0.45% NaCl
Incompatible: D5 (variable), LR, D5NS

Clinical Pearl: Define institutional dosing and administration policies due to variable strategies in the literature and risk of adverse events.

Overview of Key Evidence

Author/Year Design (n) Key Findings
Ortiz, 2017 RCT (n=62) Procainamide: 67% VT termination; 9% major cardiac adverse
Amiodarone: 38% VT termination; 41% adverse
Marill, 2010 Multicenter cohort (n=187) VT termination: Amio 25%, Procainamide 30%
Komura, 2010 Retrospective (n=90) Procainamide terminated 75.7% VT vs. Lidocaine 35%
Marill, 2006 Case series (n=33) Amio VT termination: 29%; 6% needed cardioversion
Gorgels, 1996 Randomized (n=79) Procainamide terminated 79% VT vs. Lidocaine 19% (p<0.001)
Callans, 1992 Observational (n=15) VT termination rate 93% with median 600 mg procainamide

Clinical Conclusions

  • Procainamide is guideline-supported for stable VT (Class IIa).
  • Use empiric 10–17 mg/kg bolus dosing up to 1g.
  • Consider renal function for bolus dose reductions.
  • Initiate maintenance infusion at 1–6 mg/min after bolus.
  • Clearly define hospital protocols to avoid variability.

Full Reference List

  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.
  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.
  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.
  6. Marill KA, deSouza IS, Nishijima DK, et al. Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Ann Emerg Med. 2006;47(3):217-224.
  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.
  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.
  9. Wellens HJ, Bär FW, Lie KI, et al. 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.
```

Statins for STEMI in the Emergency Department

Download Handout

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.

Corticosteroids in Sepsis by Marissa Marks, PharmD

Download PDF

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.

Alteplase for Acute Ischemic Stroke

Download Handout

Introduction  

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

Pharmacology

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

Overview of the Evidence  

Trials that showed no benefit

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

Trials that showed benefit

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

Trials that showed harm

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

Revisiting the NINDS Study

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

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

 Original Report (1995)  Re-analysis (2000)   
      
 Rt-PAPlacebo0-90 min 91-180 min 
   Rt-PAPlaceboRt-PAPlacebo
NIHSS, mean (SD); median 141415.2 (7.2); 1515.0 (6.7); 1413.5 (7.7); 1215.4 (6.9); 15
NIHSS, groups, percent       
0-5   8.36.2194.2
10-Jun  19.125.524.227.5
15-Nov  24.821.41721
16-20   25.525.521.619.8
>20   2230%21.418.327.5
The higher median NIHSS baseline scores in the placebo at 91-180 min group resulted in an overestimation of rt-PA’s efficacy in the original NINDS trial that even the original authors had to announce in their conclusions of their 2000 reanalysis.  

ECASS III Re-analysis 

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

 Conclusions  

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

References  

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

Hypertonic Saline Versus Mannitol for ICP Reduction  

Download PDF

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

Management of Hypertensive Emergency

Download PDF

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

ConditionBP GoalPreferred Agents
Acute aortic dissection  SBP < 120 mmHg within 20 minEsmolol Labetalol Nicardipine Nitroprusside
Eclampsia or Preeclampsia  SBP < 140 mmHg  within 1 hourNicardipine Labetalol Hydralazine
Pheochromocytoma (catecholamine excess)  SBP < 140 mmHg  within 1 hourNicardipine Phentolamine*
Intracranial hemorrhageSBP < 160 mmHg within 6 hoursNicardipine Labetalol
Acute ischemic strokePre-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 
MedicationClassOnsetDurationDosingClinical Pearls
Nicardipine    Ca channel blocker IV: 5-10 minIV: 2-6 hoursInitial: 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 minIV: 10-20 minBolus: 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 antagonistIV: 2-5 min Peak: 5-15 minIV: 2-6 hours Peak: 18 hoursBolus: 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 antagonistIV: SecondsIV: 15 min  Initial: 5 mg IV push  May repeat every 10 min PRN  Useful in catecholamine excess and clonidine withdrawal 
  Nitroglycerin        NOdependent vasodilatorIV: 2-5 minIV: 5-10 minACS: 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/minIndicated in ACS or pulmonary edema  Use caution in volume-depleted patients 
Sodium nitroprusside    NOdependent vasodilatorIV: SecondsIV: 1-2 minInitial: 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 vasodilatorIV: 10 min IM: 20 minIV: 1-4 hours IM: 2-6 hoursInitial: 10-20 mg IV push  Repeat every 4-6 hours PRN Not available as an IV infusion 
Enalaprilat        ACE inhibitorIV: 15-30 minIV: 12-24 hoursInitial: 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 DesignPurposeOutcome
Anderson (INTERACT), 2008RCT (N=404)Comparison of BP goals  (SBP < 140 vs SBP < 180)  in patients with acute ICHMean 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), 2016RCT (N=1,000)Comparison of BP goals  (SBP 110-139 vs SBP 179-140)  in patients with acute ICHAll 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), 2011RCT (N=226)Nicardipine IV infusion versus labetalol IV bolus for management of hypertensive emergencyPatients 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, 2004Prospective cohort (N=40)Nitroprusside IV versus nicardipine IV for hypertensive emergency with pulmonary edemaNo 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.