pharmacy pearls – Pharmacy & Acute Care University

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

Introduction

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

Pharmacology

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

∆ = meropenem is also a substrate of OAT1/3 but not an inhibitor

Overview of Evidence

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

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

Conclusions

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

References

Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 4, 2023, from http://www.micromedexsolutions.com/
VANCOMYCIN HYDROCHLORIDE [package insert]. Rockford, IL: Mylan Institutional LLC; Jul, 2018.
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.
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..
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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

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

Pharmacology

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

Overview of Evidence

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

Conclusions

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

References

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

Alteplase for Acute Ischemic Stroke

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Introduction

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

Pharmacology

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

Overview of the Evidence

Trials that showed no benefit

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

Trials that showed benefit

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

Trials that showed harm

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

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

Revisiting the NINDS Study

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

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

	Original Report (1995)		Re-analysis (2000)

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

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

ECASS III Re-analysis

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

Conclusions

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

References

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

Management of Hypertensive Emergency

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Introduction

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

Treatment in Selected Co-Morbidities

Condition	BP Goal	Preferred Agents
Acute aortic dissection	SBP < 120 mmHg within 20 min	Esmolol Labetalol Nicardipine Nitroprusside
Eclampsia or Preeclampsia	SBP < 140 mmHg within 1 hour	Nicardipine Labetalol Hydralazine
Pheochromocytoma (catecholamine excess)	SBP < 140 mmHg within 1 hour	Nicardipine Phentolamine*
Intracranial hemorrhage	SBP < 160 mmHg within 6 hours	Nicardipine Labetalol
Acute ischemic stroke	Pre-alteplase: < 185/110 mmHg Post-alteplase: < 180/105 for 24 hours No thrombolytic: SBP reduced 15% in 24 hours**	Nicardipine Labetalol

*Phentolamine currently unavailable due to nationwide shortage
**Permissive hypertension may be reasonable; maintain SBP < 220 mmHg or DBP < 120 mmHg

Pharmacology: Intravenous Antihypertensives

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

*Phentolamine currently unavailable due to nationwide shortage

Overview of Evidence

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

Conclusions

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.
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.
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.
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

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.
Benken ST. Hypertensive emergencies. CCSAP 2018;1:7-30.
Anderson, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-9.
Quereshi, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. New Engl J Med 2016;375(11):1033-43.
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.
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.