(Summary version, updated August 2021)

Acute Coronary Syndrome with ST elevation (<12 hours)

FDA approved.
Adult Dose:

• ≤67kg: 15mg bolus + 0.75mg/kg in next 30 min

• >67kg: 15 mg bolus + 50 mg in 30 min + 35 mg in 60 min

Acute Isquemic Stroke (<4.5 hours)

FDA approved for <3 hours after symptom onset (1996), Universally accepted use in <4.5 hours.

Adult dose:

• <100kg: 0.09mg/kg bolus + 0.81mg/kg 60min

• >100kg: 9mg bolus + 81mg 60min

Pulmonary Embolism

FDA approved.

Adult dose:

• Intermediate risk: 50mg in 2 hrs

• High risk: 100mg in 2 hrs

• Cardiac arrest: 50mg bolus + 50mg if no ROSC in 15 min

______________________________________________

Emergency Medicine Executive Summary

Fibrin-specific Tissue Plasminogen Activator (fibrinolytic) widely accepted for emergency revascularization in acute myocardial infarction (MI), high risk acute pulmonary embolism (PE), and acute ischemic stroke (AIS)(1, 2, 3). In emergency medicine it is also used in intermediate-high risk PE and cardiac arrest when there is a high suspicion of MI or PE as the cause, in both scenarios the decision should be taken cautiously and in very selected cases (2, 4, 10).

Always seriously consider the contraindications and balance the risk of intracranial and other major bleeding events versus the benefit of the therapy. Fibrinolysis is an intervention that should be decided -or at least supported- by a specialist (emergency medicine, neurologist, cardiologist, intensivist).

Contraindications to systemic fibrinolytic therapy

There isn't a definite and universally accepted list of contraindications, and it seems to be a tendency to become simpler over the years. Beware that references differ in some issues.

Absolute contraindications (1, 2, 3, 9)

• Previous intracranial haemorrhage or stroke of unknown origin at any time

• Ischemic stroke in the preceding 6 months

• Central nervous system damage or neoplasms or arteriovenous malformation

• Recent major trauma / surgery / head injury (within the preceding month)

• Gastrointestinal bleeding within the past month

• Known bleeding disorder (excluding menses)

• Aortic dissection

• Non-compressible punctures in the past 24 hours (e.g. liver biopsy, lumbar puncture)

• Active internal bleeding

Relative contraindications (1, 2, 3, 9)

• Transient ischemic attack in the preceding 6 months

• Oral anticoagulant therapy

• Pregnancy or within 1 week postpartum

• Refractory hypertension (SBP >180mmHg and/or DBP >110 mmHg)

• Advanced liver disease

• Infective endocarditis

• Active peptic ulcer

• Prolonged or traumatic resuscitation

Adult dose

• Acute Coronary Syndrome with ST elevation (<12 hours)

FDA approval in 1987.

Relevant studies: GUSTO trial, 1993 (5).

Dose (6):

• ≤67kg: 15mg bolus + 0.75mg/kg in first 30 min + 0.5mg/kg in next 60min

• >67kg: 15 mg bolus + 50 mg in first 30 min + 35 mg in next 60 min

• Acute Ischemic Stroke (<4.5 hours)
  FDA approval for <3 hours after symptom onset in 1996 (15). Universally accepted use for <4.5 hours (3, 7).
  Relevant studies: NINDS trial, 1995 (8). ECASS III trial, 2008 (9).

Dose (6):

• <100kg: 0.09mg/kg bolus + 0.81mg/kg in 60min

• >100kg: 9mg bolus + 81mg in 60min

• Pulmonary Embolism

FDA approval in 2002 for high risk PE, but also for “PE obstructing blood flow to a lobe or multiple lung segments” which is controversial if not causing hemodynamic deterioration. Usage in intermediate-high risk PE has been questioned, studied schemes do not support fibrinolysis as an standard intervention; if considered, always decide under the supervision of a specialist, in this scenario Pulmonary Embolism Response Teams (PERTs) are recommended (2, 11, 12). For cardiac arrest it can be used in selected cases, with very limited available data (10).
Recommended review: European Society of Cardiology PE Guidelines, 2019 (2).
Dose (6, 2, 10)

• PE-High risk: 100mg in 2 hrs

• PE-Cardiac arrest: 50mg bolus + 50mg if no ROSC in 15 min

Pediatric dose

Very limited data. Not approved by the FDA. No dosing established by manufacturer (6).

• Acute ischemic stroke (13)

  • 0.09mg/kg bolus + 0.81mg/kg in 60min

• Pulmonary embolism (14)

  • High Risk PE: 0.5 mg/kg/hour IV in 6 hours

References

1. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018.
   https://pubmed.ncbi.nlm.nih.gov/28886621/

2. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020.
   https://pubmed.ncbi.nlm.nih.gov/31504429/

3. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2018 Mar;49(3):e138]. Stroke. 2018.
   https://pubmed.ncbi.nlm.nih.gov/29367334/

4. Busse LW, Vourlekis JS. Submassive pulmonary embolism. Crit Care Clin. 2014.
   https://pubmed.ncbi.nlm.nih.gov/24996605/

5. GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993.
   https://pubmed.ncbi.nlm.nih.gov/8204123/

6. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Activase - alteplase kit. Updated in October 2020. Visited in July 2021.
   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c669f77c-fa48-478b-a14b-80b20a0139c2#S1.2

7. Powers WJ. Acute Ischemic Stroke. N Engl J Med. 2020.
   https://www.nejm.org/doi/full/10.1056/NEJMcp1917030

8. NINDS - National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995.
   https://pubmed.ncbi.nlm.nih.gov/7477192/

9. ECASS III - 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.
   https://pubmed.ncbi.nlm.nih.gov/18815396/

10. Lavonas EJ, Drennan IR, Gabrielli A, et al. Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [published correction appears in Circulation. Circulation. 2016.
    https://pubmed.ncbi.nlm.nih.gov/30409433/

11. MOPETT - Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013.
    https://pubmed.ncbi.nlm.nih.gov/23102885/

12. Kiser TH, Burnham EL, Clark B, et al. Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism. Crit Care Med. 2018.
    https://pubmed.ncbi.nlm.nih.gov/29979222/

13. Roach ES, Golomb MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young [published correction appears in Stroke. 2009 Jan 1;40(1):e8-10]. Stroke. 2008.
    https://pubmed.ncbi.nlm.nih.gov/18635845/

14. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [published correction appears in Chest. 2014 Dec;146(6):1694. Dosage error in article text] [published correction appears in Chest. Chest. 2014.
    https://pubmed.ncbi.nlm.nih.gov/22315277/

15. US-FDA (United States Food and Drug Administration). Drug Approval Package: Alteplase. Company: Genentech. Application No.: 103172-Supplement 1055. Approval Date: 6/18/1996. Indication for Use: Management of acute ischemic stroke in adults, for improving neurological recovery, and reducing the incidence of disability. Visited in July 2021.
    https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/alteplase_toc.cfm

(Extended version, updated April 2021)

Emergency Medicine Executive Summary

Norepinephrine (NE) is used for hemodynamic support frequently as first line vasopressor with the exception of anaphylaxis and post cardiac arrest care (epinephrine). Consider using norepinephrine in combination with inodilator drugs in cardiogenic shock.

• Adult dose: 0.01-0.3 ug/kg/min IV (actual body weight), usually started at 0.05ug/kg/min IV.

Mechanism of Action and Usage

NE is an endogenous sympathomimetic catecholamine (acts as a hormone and neurotransmitter). It has alpha-1 and beta-1 adrenergic activity, causing arterial vasoconstriction (alpha-1), increase in heart rate (beta-1) and contractility (beta-1), thereby increasing systemic blood pressure and coronary blood flow. Clinically alpha effects are greater than beta effects. In short, it has inoconstrictor effects, and it also mobilizes unstressed venous blood volume.

The following clinical scenarios include NE for hemodynamic support:

• Shock: predominantly distributive shock (eg. septic and neurogenic shock).

  • Septic shock: universally accepted as first line vasopressor (1,3,5), its early administration is associated with improved survival (3), and is less arrhythmogenic than dopamine (4).

  • Cardiogenic shock: NE is commonly used in combination of inodilators (eg. dobutamine + NE, milrinone + NE). Primarily to mitigate the Beta-2 vasodilatory effect of those medications. NE is associated with improved survival at 28 days compared with dopamine in cardiogenic shock(4).

  • Anaphylactic shock: norepinephrine or vasopressin are frequently used in combination with epinephrine infusion in refractory hypotension secondary to anaphylaxis (1).

• Post-cardiac arrest care: usually used as second line vasopressor with epinephrine infusion.

• Profound sedation: usually used to increase vascular resistance attenuated by sympatholytic and parasympathomimetic effects of sedative and opioids agents.

Indications

• FDA - Labeled

• Severe hypotension unresponsive to volume replacement.

*FDA approved in 1982 (6).

• Non FDA - Labeled
  Consider that the only FDA approved labeled indication is not specific, it could include all the following conditions, but is not stated officially by the manufacturer or other health authority (7).

• Septic shock and other vasodilatory shock states.

• Cardiogenic shock.

• Post-cardiac arrest care.

Adult dose

0.01-3 ug/kg/min IV.

Starting dose in shock 0.05-0.1ug/kg/min IV.

In refractory shock, high doses of 1-3ug/kg/min are generally combined with other vasoactive or inotropic drugs.

Preparation:

• Peripheral access: 4mg in 500ml NaCl 0.9% or D5%.

• Central access: 8mg in 250ml NaCl 0.9% or D5%.

Pediatric dose

0.05-2ug/kg/min IV, in refractory shock higher doses may be needed. Usually similar dosing than adults.

Renal, Hepatic, and other adjustments

No adjustments needed.

Dosage Forms and Brand Names:

• Levophed™ (US, Canada, Australia, UK, Chile) 4mg/4ml, IV use.

• Adine™ (Chile) 4mg/4ml, IV use.

• Pridam™ (Latin-America) 4mg/4ml, IV use.

• Others: Arterenol™, Tartrato™, Norages™, Noradrenaline™ (Europe), etc.

⚠ Contraindications, Adverse Effects, Warnings and Major Drug Interactions

• Contraindications

Not contraindications determined.

• Adverse Effects

• Cardiovascular: reflex bradyarrhythmia. Hypertension and subsequent hypertensive emergencies may occur if supraoptimal dosing is used.

• Extravasation complications: peripheral gangrene can occur, but is rare in <1%. In case of extravasation local infiltration with phentolamine is indicated.

Central venous access is preferred for infusion, but peripheral use is reasonably safe when taken appropriate precautions (1, 2). Consider large veins particularly antecubital vein, and using peripheral catheters of at least 20G in caliber.

Emergency Treatment of Extravasation (7)

• To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with 5 to 10 mg of phentolamine mesylate in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults.

• Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.
  

• Warnings and Pathophysiological concerns

• Hypovolemia: address volemia before initiating therapy; hypovolemic patients may experience severe peripheral and visceral vasoconstriction, decreased renal, splanchnic and extremity perfusion.

• Hypoxia/hypercarbia: individuals with severe hypoxia or hypercarbia are in increased risk of ventricular tachycardia or fibrillation when norepinephrine is used.

• Abrupt discontinuation: gradually reduce infusion rate before discontinuation, otherwise severe hypotension may occur. During the reduction of infusion rate assess the intravascular volume.
  

• Major drug interactions
  The following content includes the most relevant interactions in the emergency department, check for other specific interactions if needed.

• May enhance the sympathomimetic effect:

• Sympathomimetics (vasopressin, adrenaline, ergotamines, amphetamine-like drugs, etc)

• Monoamine Oxidase Inhibitors

• Serotonin/Norepinephrine Reuptake Inhibitors

• Tricyclic Antidepressants

• Cannabinoid-containing products

• May enhance the arrhythmogenic effect of norepinephrine

• Inhalational anesthetics (isoflurane, sevoflurane, desflurane, etc)

• May diminish the vasoconstricting effect

• Alpha-1 blockers

• Clozapine

• Spironolactone

Pregnancy and Lactation

Pregnancy Risk Category: not classified as norepinephrine is an endogenous hormone and neurotransmitter. It crosses the placenta and can affect the fetus. For shock management there is not a preference of vasopressor drugs based on pregnancy and fetal risk.

Lactation: infant risk cannot be ruled out, weight risk/benefit in keeping breastfeeding during critical care when other drugs are being administered.

Pharmacology

• Onset of action: very rapid acting, usually less than a minute from infusion start.

• Time to peak, serum: steady state in 5 minutes.

• Duration: 1-2 minutes.

• Half-life elimination: mean 2.4 minutes.

• Protein binding: 25% mainly albumin.

• Metabolism: via catechol-o-methyltransferase and monoamine oxidase.

• Excretion: urine as inactive metabolites, small amounts as unchanged drug)

References

1. Ellender TJ, Skinner JC. The use of vasopressors and inotropes in the emergency medical treatment of shock. Emerg Med Clin North Am 2008.
   https://pubmed.ncbi.nlm.nih.gov/18655944/

2. Tian DH et al. Safety of Peripheral Administration of Vasopressor Medications: A Systematic Review. Emergency Medicine of Australasia 2019.
   https://pubmed.ncbi.nlm.nih.gov/31698544/

3. Bai X, Yu W, Ji W. Early versus delayed administration of norepinephrine in patients with septic shock. Critical Care 2014.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194405/

4. De Backer D, et al. Comparison of dopamine and norepinephrine in the treatment of shock. SOAP II Trial, The New England Journal of Medicine 2010.
   https://pubmed.ncbi.nlm.nih.gov/20200382/

5. Stratton L, Berlin DA, Arbo JE. Vasopressors and Inotropes in Sepsis. Emerg Med Clin North Am 2017.
   https://www.sciencedirect.com/science/article/abs/pii/S073386271630075X?via%3Dihub

6. US-FDA (US Food and Drug Administration), Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, Product Details for NDA 007513, Levophed; Norepinephrine Bitartrate. Visited in June 2021.
   https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=007513#18738

7. NIH-NLM (National Institues of Health National Library of Medicine). DailyMed. Label: Levophed - norepinephrine bitartrate injection, solution, concentrate. Updated in novembre 2020. Visited in June 2021.
   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c4de72a8-2a75-4984-ce90-e4870226dc12

(Summary version, updated September 2021)

Emergency Medicine Executive Summary

Olanzapine is a second generation (atypical) antipsychotic with a potent antagonism of serotonin 5-HT2A, 5-HT2C, dopamine D1-4, histamine H1 and alpha1-adrenergic receptors. It also has a moderate antagonism of muscarinic M1-5 receptors, as well as a weak agonism to GABA-A, BZD and beta-adrenergic receptors.

In the ED, olanzapine is frequently indicated as a first-line antipsychotic for acute agitation associated with psychiatric disorders (US-FDA and EMA approved for agitation in individuals with schizophrenia and bipolar disorder)(7, 9). Agitation in the ED is a very complex situation that includes a variety of dissimilar scenarios with a wide range of therapeutic options. Many clinical guidelines have been proposed with substantial differences between them; as emergency physicians, it is of great importance to be familiarized with the available therapeutic arsenal for agitation, such as haloperidol, droperidol, benzodiazepines, propofol, ketamine, etc.

• Adult dose for severe agitation: 5 to 10mg IM, repeated every 20 min if necessary, with a maximum of 30mg/day for intramuscular administration.

There are significant differences among first and second generation antipsychotics, and there is an abundant amount of literature available that compare olanzapine with haloperidol as well as other therapies to treat agitation. Clinically relevant data is summarized below:

Olanzapine vs haloperidol; extrapyramidal effects: olanzapine had a reduced risk of nearterm side effects such as dystonia or akathisia, with rates being less than 1%; 10 times less than haloperidol. (1, 2).

Olanzapine vs haloperidol; adequate sedation within 15 min: olanzapine showed better results (61% vs 42%)(6).

Olanzapine vs haloperidol; need of rescue medication: olanzapine needed less rescue medication (21% vs 33% in the entire encounter)(6).

Olanzapine vs haloperidol + benzodiazepine; sedation in 2 hours: either intervention showed similar results (3).

Olanzapine vs droperidol; time to sedation: no significant difference (16 min vs 17.5 min)(10).

Olanzapine vs droperidol; need of rescue medication: olanzapine needed more rescue medication (24% vs 17%)(10).

Olanzapine vs droperidol; extrapyramidal effects: olanzapine had a significantly lower risk (0.1% vs 6.1%)(10).

Therefore, olanzapine is currently recommended as the first-line antipsychotic for an agitated psychiatric adult patient (2). In the pediatric population it is considered to be safe and effective (8), but is not yet US-FDA nor EMA approved for agitation (7, 9).

⚠ Cautions

• When olanzapine is administered by oral formulation, it can be combined with a benzodiazepine; nonetheless, parenteral administration with a benzodiazepine is not recommended due to the risk of respiratory depression (2, 6, 7).

• In eldery patients, the half-life of olanzapine is 1.5 times longer compared to young adults, consequently, consider a starting dose of 5mg im for agitation (7).

• There is an association between antipsychotics (1st and 2nd generation) and an increased mortality risk when used to treat dementia-related psychosis at long term (4, 7). Haloperidol has an NNH of 26 and olanzapine an NNH 40 (4).

• Olanzapine is associated with an increased risk of hypotension (4.5% for 5-10mg im) (1, 7), orthostatism, and the potential consequence of syncope (6). Use with caution when other factors of cardiocirculatory depression are present.

• Avoid olanzapine in suspected or confirmed intoxications with anticholinergic medications. Other agents should be used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal.

Adult dose (2, 7)

Acute agitation associated with psychiatric disorders:

• Severe agitation (aggressive/threatening, non-cooperative):
  IM: 5-10mg; may repeat in 20 min if needed, max 30 mg/day for intramuscular route.
  Consider 5mg im as a starting dose in eldery patients (50% increase in half life in elder population).

• Mild or moderate agitation (cooperative or disruptive):
  Sublingual: 5-10mg, may repeat every 2 hours if needed; max 20mg/day for oral/sublingual route.
  Consider 5mg sublingual as a starting dose in eldery patients (50% increase in half life in elder population).

Pediatric dose (5)

• Severe agitation (aggressive/threatening, non-cooperative):
  IM: 0.1mg/kg, max 30mg/day for intramuscular route.

Usual dosing:

• Child: 2.5mg IM, may repeat every 20-30min if needed

• Adolescent: 5-10mg IM, may repeat every 20-30min if needed

• Mild or moderate agitation (cooperative):
  Sublingual: 0.1mg/kg, max 20mg/day for oral/sublingual route.

Usual dosing:

• Child: 2.5mg sublingual, may repeat every 30-45min if needed

• Adolescent: 5-10mg sublingual, may repeat every 30-45min if needed

References

1. Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002.
   https://pubmed.ncbi.nlm.nih.gov/11982448/

2. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med. 2012.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298219/

3. Huang CL, Hwang TJ, Chen YH, et al. Intramuscular olanzapine versus intramuscular haloperidol plus lorazepam for the treatment of acute schizophrenia with agitation: An open-label, randomized controlled trial. J Formos Med Assoc. 2015.
   https://pubmed.ncbi.nlm.nih.gov/25791540/

4. Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439579/

5. Chun TH, Mace SE, Katz ER; American Academy Of Pediatrics; Committee On Pediatric Emergency Medicine, And American College Of Emergency Physicians; Pediatric Emergency Medicine Committee. Evaluation and Management of Children and Adolescents With Acute Mental Health or Behavioral Problems. Part I: Common Clinical Challenges of Patients With Mental Health and/or Behavioral Emergencies. Pediatrics. 2016.
   https://pubmed.ncbi.nlm.nih.gov/27550977/

6. Klein LR, Driver BE, Miner JR, et al. Intramuscular Midazolam, Olanzapine, Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency Department. Ann Emerg Med. 2018.
   https://pubmed.ncbi.nlm.nih.gov/29885904/

7. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Zyprexa- olanzapine tablet, Zyprexa Zydis- olanzapine tablet, orally disintegrating, Zyprexa Intramuscular- olanzapine injection, powder, for solution. Updated in April 2020. Visited in September 2021.
   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5051fbc-846b-4946-82df-341fb1216341&audience=consumer

8. Cole JB, Klein LR, Strobel AM, Blanchard SR, Nahum R, Martel ML. The Use, Safety, and Efficacy of Olanzapine in a Level I Pediatric Trauma Center Emergency Department Over a 10-Year Period. Pediatr Emerg Care. 2020.
   https://pubmed.ncbi.nlm.nih.gov/28697164/

9. EMA (European Medicines Agency), Zyprexa, olanzapine: EPAR (European Public Assessment Report) - Product Information. Date of issue of marketing authorisation valid throughout the European Union: 1996. Last updated March 2020. Visited in September 2021.
   https://www.ema.europa.eu/en/documents/product-information/zyprexa-epar-product-information_en.pdf

10. Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages. Ann Emerg Med. 2021.
    https://pubmed.ncbi.nlm.nih.gov/33846015/

(Extended version, updated July 2021)

Emergency Medicine Executive Summary

Phentolamine is a vasodilator used to prevent tissue necrosis caused by extravasated catecholamine infusions (epinephrine, norepinephrine, dopamine, etc). Available in the US. Limited stock in Canada. Unavailable in Chile.

• Adult dose: 5-10mg diluted in 10-20ml of NaCl 0.9% subcutaneous immediately after extravasation (use within 12 hours).

Mechanism of Action and Usage

Potent and short-acting non-selective alpha blocker (alpha-1 and alpha-2). Alpha-1 blockade reduces peripheral resistance, and alpha-2 blockade causes cardiac stimulation due to an enhanced release of norepinephrine from sympathetic nerves, with subsequent inotropic and chronotropic effects.

It is used to prevent tissue ischemia caused by extravasation of norepinephrine and other alpha agonists (1, 3), obtaining the FDA approval in 1998 (2). From the safety patient perspective it is recommended to have an extravasation protocol in the hospital services where vasopressors are used (3), and in retrospective studies phentolamine use is associated with favorable outcomes (4, 5). It is also indicated to diagnose pheochromocytoma disease and to prevent and treat pheochromocytoma-related hypertensive crises (1).

Adult dose

Injection site vasopressor extravasation

Phentolamine 5 to 10mg in 10mL of normal saline, subcutaneous within 12 hours into the area of extravasation. Visible hyperemia and increased tissue warmth at the site of extravasation are signs of effective treatment.

Pediatric dose

Injection site vasopressor extravasation

• • Infants, children and adolescents: Infiltrate the area with 1 to 5 mL (in 5 divided doses) of a 0.5 to 1 mg/mL solution (made by diluting 5 to 10 mg in 10 mL 0.9% Sodium Chloride injection). Inject into the affected area within 12 hours of extravasation. Do not exceed 0.1 to 0.2 mg/kg or 5 mg total.

  • Neonates: Infiltrate the area with 1 mL of solution made by diluting 2.5 to 5 mg in 10 mL of 0.9% Sodium Chloride injection. Give 5 divided doses subcutaneously around the site. Inject into the affected area within 12 hours of extravasation. Do not exceed 0.1 mg/kg or 2.5 mg total.

Renal, hepatic, or other adjustments

No adjustments required.

Dosage Forms and brand names:

• Phentolamine mesylate (US): 5mg lyophilized powder

• Rogitine^® (Canada): 10mg/1ml ampules

Contraindications, Adverse effects, Warnings, and Major drug interactions

The following issues of concern are related mostly in endovenous administration of phentolamine. Consider that subcutaneous use in extravasation is intended to cause local effects rather than systemic effects. The following issues of concern are related to IV administration.

• Contraindications: hypersensitivity to drug or related compounds, acute or chronic coronary artery disease.

• Adverse effects: hypotension, tachycardia, dysrhythmias.

• Warnings: myocardial infarction and cerebrovascular spasms usually in association with marked hypotensive episodes have been reported.

• Major drug interactions: enhance effect with other alpha blockers (urapidil), and diminish effect with alpha agonists. Caution when combined with other antihypertensive or vasodilator medications.

Pregnancy and Lactation

Consider that subcutaneous use in extravasation is intended to cause local effects rather than systemic effects, with an hypothetical low risk for the fetus or infant.

Pregnancy Risk Factor Category (FDA): C.

Lactation: not known if excreted in milk.

Pharmacology

Alpha-adrenergic block of relatively short duration. Also direct but less marked positive inotropic and chronotropic effects. The pharmacokinetics of phentolamine are largely unknown.

Following specifications are not applicable to subdermic administration:

Onset of action: 1-2 min IV, 15-20 min IM.

Half-life elimination: 19 minutes IV.

Time to peak, plasma: unknown.

References

1. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Phentolamine mesylate injection, powder, for solution. Updated in december 2018. Visited in July 2021.
   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed6c506c-5535-4b7c-ae1a-d63f09d796c9

2. FDA (United States Food and Drug Administration), CDER (Center for Drug Evaluation and Research), Application Number 40235, Phentolamine Mesylate for Injection USP 5mg/vial, Bedford Laboratories, march 1998. Visited in July 2021.
   https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/40235ap.pdf

3. Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the Peripheral Administration of Vasopressor Agents. J Intensive Care Med 2019.
   https://pubmed.ncbi.nlm.nih.gov/28073314/

4. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med 2015.
   https://pubmed.ncbi.nlm.nih.gov/26014852/

5. Pancaro C, Shah N, Pasma W, et al. Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study. Anesth Analg 2020.
   https://pubmed.ncbi.nlm.nih.gov/32925324/

(Summary version, updated August 2021)

Acute Myocardial Infarction with ST elevation (STEMI <12hrs)

FDA approved, 2000. Indicated when anticipated STEMI diagnosis to Percutaneous Coronary Intervention-mediated reperfusion time is >120min.

Adult dose (IV ,bolus):

• <60 kg 30mg

• 60 - 69 kg 35mg

• 70 - 79 kg 40mg

• 80 - 89 kg 45mg

• ≥90 kg 50mg

Acute Ischemic Stroke (AIS <4.5hrs)

Not FDA approved.

Adult dose (IV ,bolus):

• AIS eligible for mechanical thrombectomy

  • 0.25mg/kg bolus (max 25mg)

• AIS with minor neurological impairment uneligible for a mechanical thrombectomy

  • 0.4mg/kg bolus

Pulmonary Embolism (PE)

Not FDA approved. Prefer alteplase for PE fibrinolytic therapy. If unavailable, consider tenecteplase.

Adult dose (IV, bolus):

• <60 kg 30mg

• 60 - 69 kg 35mg

• 70 - 79 kg 40mg

• 80 - 89 kg 45mg

• ≥90 kg 50mg

__________________________________________________

Emergency Medicine Executive Summary

Tenecteplase (TNK) is a modified form of the Tissue Plasminogen Activator alteplase, with enhanced fibrin affinity, diminished fibrinogenolysis (greater fibrin-specificity) and Plasminogen Activator Inhibitor-1 (PAI-1) resistance (1). These properties prolong its half-life permitting administration as a single bolus which is remarkably useful in emergency medicine.

FDA and EMA approved its use only for emergency reperfusion in Acute Myocardial Infarction with ST elevation (STEMI)(1, 2). Compared to alteplase, it is safer due to a lower risk of non-cerebral hemorrhage and blood transfusion (13), and is easier to administer. Those advantages led TNK as the fibrinolytic of choice in STEMI (3).

In the past decade tenecteplase has been studied to treat Acute Ischemic Stroke (AIS) with promising results (5, 7, 8, 17). Although this drug has not yet been universally adopted for the treatment of AIS, there are relevant data that favor it:

• Several randomized controlled trials (eg. 7, 17) and systematic reviews with meta-analyzes (eg. 8) show no-inferiority between tenecteplase and alteplase, as well as no differences in intracranial bleeding rates.

• Based on these studies and other important literature, the latest guidelines from the American Stroke Association recommend its use as an alternative to alteplase (3).

Therefore, the use of TNK for AIS is steadily increasing among clinicians beyond research purposes; for example in 2016 tenecteplase was approved to treat AIS by the Indian health authorities (9).

EMDrugs do not encourage its use for Pulmonary Embolism because there are no solid comparative studies of tenecteplase vs alteplase in high-risk PE (hemodynamic instability). Interestingly, when tenecteplase is compared with alteplase for PE, TNK is associated with an increased risk of major bleeding, but in myocardial infarction, the data show a reduced risk of major bleeding (10, 13). This increased risk is known to be related to the older population (significantly higher risk in patients >65 years)(11), and is probably associated with concomitant heparin administration (eg. PEITHO trial protocol)(16).

Always consider the contraindications seriously and balance the risk of tenecteplase fibrinolysis of intracranial hemorrhage and other major bleeding events versus the benefit of the therapy. This intervention must be decided -or at least supported- by a specialist (eg. emergency medicine, neurologist, cardiologist, intensivist).

Contraindications to systemic fibrinolytic therapy

There isn't a definite and universally accepted list of contraindications, and it seems to be a tendency to become simpler over the years. Beware that references differ on some issues.

Absolute contraindications (3, 4)

• Previous intracranial haemorrhage or stroke of unknown origin at any time

• Ischemic stroke in the preceding 6 months (except in AIS <4,5h indication)

• Central nervous system damage or neoplasms or arteriovenous malformation

• Recent major trauma / surgery / head injury (within the preceding month)

• Gastrointestinal bleeding within the past month

• Known bleeding disorder (excluding menses)

• Aortic dissection

• Non-compressible punctures in the past 24 hours (e.g. liver biopsy, lumbar puncture)

• Active internal bleeding

Relative contraindications (3, 4)

• Transient ischemic attack in the preceding 6 months

• Oral anticoagulant therapy

• Pregnancy or within 1 week postpartum

• Refractory hypertension (SBP >180mmHg and/or DBP >110 mmHg)

• Advanced liver disease

• Infective endocarditis

• Active peptic ulcer

• Prolonged or traumatic resuscitation

Adult dose

• Acute Myocardial Infarction with ST elevation (STEMI <12 hours)

FDA approval in 2000. EMA approval in 2001. Indicated when anticipated STEMI diagnosis to Percutaneous Coronary Intervention-mediated reperfusion time is >120min (3).

Relevant studies: ASSENT trial, 1999 (13).

Adult dose (IV ,bolus):

• <60 kg 30mg

• 60 - 69 kg 35mg

• 70 - 79 kg 40mg

• 80 - 89 kg 45mg

• ≥90 kg 50mg

• Acute Ischemic Stroke (AIS <4.5 hours)

Not FDA approved. Recent guidelines support usage as an alternative to alteplase (4).

Studied schemes in AIS have been conducted with 0.1, 0.25 and 0.4mg/kg, possibly 0.25mg/kg is the safer and equally effective dose, but more data is needed to reassure this (15).

Adult dose based on latest AHA/ASA Guidelines For the Early Management of Acute Ischemic Stroke 2018/2019 (4):

• AIS in patients eligible to undergo mechanical thrombectomy (7):

• 0.25mg/kg IV bolus (max 25mg)

• AIS with minor neurological impairment and no major intracranial occlusion (17):

  • 0.4mg/kg IV bolus

• Pulmonary Embolism

Not FDA approved. Prefer alteplase If alteplase is unavailable, consider same tenecteplase dose used for myocardial infarction:

Adult dose (IV, bolus):

• <60 kg 30mg

• 60 - 69 kg 35mg

• 70 - 79 kg 40mg

• 80 - 89 kg 45mg

• ≥90 kg 50mg

Pediatric dose

Efficacy and safety not established. Pediatric tenecteplase usage data derives mostly from case reports limited to dysfunctional central venous catheters (12).

Prefer alteplase for fibrinolytic therapy.

References

1. EMA (European Medicines Agency), Metalyse: EPAR (European Public Assessment Report) - Product Information. First published 2009, Last updated March 2021. Visited in August 2021.
   https://www.ema.europa.eu/en/documents/product-information/metalyse-epar-product-information_en.pdf

2. US FDA (United States Food and Drug Administration) CDER (Center for Drug Evaluation and Research), Tenecteplase Product Approval Information - Licencing Action, Department of Health and Human Services, June 2, 2000.
   https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/tenegen060200L.htm

3. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018.
   https://pubmed.ncbi.nlm.nih.gov/28886621/

4. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2018 Mar;49(3):e138]. Stroke. 2018.
   https://pubmed.ncbi.nlm.nih.gov/29367334/

5. Powers WJ. Acute Ischemic Stroke. N Engl J Med. 2020.
   https://www.nejm.org/doi/full/10.1056/NEJMcp1917030

6. Kheiri B, Osman M, Abdalla A, et al. Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. J Thromb Thrombolysis. 2018.
   https://pubmed.ncbi.nlm.nih.gov/30117036/

7. NOR-TEST - Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017.
   https://pubmed.ncbi.nlm.nih.gov/28780236/

8. Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke: Meta-Analysis of 5 Randomized Trials. Stroke. 2019.
   https://pubmed.ncbi.nlm.nih.gov/31318627/

9. National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases & Stroke (NPCDCS) Guidelines for Prevention and Management of Stroke Directorate General of Health Services Ministry of Health and Family Welfare Government of India. 2019.
   https://main.mohfw.gov.in/sites/default/files/Guidelines%20for%20Prevention%20and%20Managment%20of%20Stroke.pdf

10. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015.
    https://pubmed.ncbi.nlm.nih.gov/24917641/

11. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014.
    https://pubmed.ncbi.nlm.nih.gov/24938564/

12. Tebbi C, Costanzi J, Shulman R, et al. A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters. J Vasc Interv Radiol. 2011.
    https://pubmed.ncbi.nlm.nih.gov/21570873/

13. ASSENT-2 - Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999.
    https://pubmed.ncbi.nlm.nih.gov/10475182/

14. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: TNKASE tenecteplase kit. Updated in December 2019. Visited in August 2021.
    https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66a1e273-ab59-4e7a-a223-a96b86501f51

15. Zitek T, Ataya R, Brea I. Using Tenecteplase for Acute Ischemic Stroke: What Is the Hold Up?. West J Emerg Med. 2020.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081848/

16. PEITHO - Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014.
    https://pubmed.ncbi.nlm.nih.gov/24716681/

17. EXTEND-IA TNK Part 2 - Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA. 2020.
    https://pubmed.ncbi.nlm.nih.gov/32078683/

(Extended version, updated June 2021)

Emergency Medicine Executive Summary

Tetanus Immune Globulin (TIG) is indicated for tetanus disease treatment and prophylaxis (the latter in individuals with outdated or unknown tetanus immunization who suffered a contaminated or tetanus-prone wound).

Adult dose:

• Tetanus treatment: 500 units IM with part of the dose infiltrated close to the source wound. Up to 6000 units can be used.

• Tetanus prophylaxis: 250 units IM once.

Mechanism of Action and Usage

TIG consists of human antibodies derived from healthy donors used for the treatment of tetanus disease and tetanus prophylaxis. Provides passive immunity towards tetanus by neutralizing unbound toxins produced by Clostridium tetani (tetanus toxin or tetanospasmin). It improves survival and is considered to be standard treatment.

Tetanus Prophylaxis Scheme (1):

• Unknown or <3 previous doses

  • Dirty, tetanus-prone wound*:

    • Give Tetanus and diphtheria (Td) toxoids adsorbed

    • Give Tetanus immune globulin

  • Clean, not tetanus-prone wound:

    • Give Tetanus and diphtheria (Td) toxoids adsorbed, no TIG.

• 3 or more previous doses

  • Dirty, tetanus-prone wound*:

    • Give Td only if >5 years since last booster, no TIG

  • Clean, not tetanus-prone wound:

    • Give Td only if >10 years since last booster, no TIG
      

*Tetanus-prone wounds: >6 hours, >1cm depth, high risk of contamination mechanism of injury (missile, crush, burn, frostbite, agriculture-related injuries), presence of devitalized tissue, presence of contaminants (dirt, saliva, etc)

Adult dose

• Tetanus treatment: 500 units IM.
  The actual recommended dose is 500 units IM with part of the dose infiltrated around the source wound (1; CDC 2020). Classically the suggested dose of 3000-6000 Units IM, with part of the dose infiltrated around the wound, derived from limited data from 1960-1980s studies (3; Nation 1965). HyperTET^® 2020 label for active tetanus refers that the “dosage should be adjusted according to the severity of the infection” (4; NIH-NLM 2020).

• Tetanus prophylaxis: 250 Units IM*.

*FDA Approved in 1957 (7).

Pediatric dose

• Tetanus Prophylaxis:

<7 years: 4 IU/kg IM.

>7 years: 250 IU IM.

• Tetanus Treatment: 500 IU IM recommended (1; CDC 2020). Very limited data.

Renal, hepatic, geriatric or other adjustments

No adjustments needed.

Dosage Forms:

• USA - HyperTET^®: 250 units/mL (1ml), injectable, only intramuscular administration.

• Chile - Ingantet^®: 250 units/mL (1ml), injectable, only intramuscular administration.

Contraindications, Adverse Effects, Warnings, and Major Interactions:

• Contraindications
  Use with caution in individuals who have experienced allergic or other adverse effects secondary to other immunoglobulin-containing products.

• Adverse Effects
  Frequency not defined:
  Increased body temperature.
  Local soreness at injection site, pain at injection site, tenderness at injection site

<1%, postmarketing, and/or case reports:
Anaphylactic shock, angioedema, nephrotic syndrome.

• Warnings
  Product of human plasma, may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk.

• Major drug interactions
  Monitor closely the administration of live vaccines: adenovirus type 4 and 7, BCG, measles (rubeola), measles-mumps-rubella, measles-mumps-rubella-varicella, varicella virus, rubella, smallpox. As tetanus immune globulin decreases their effect. Separate any by 3 months (NIH 2020).

Pregnancy Risk Factor and Lactation

• Pregnancy Risk Factor Category C.

Animal reproduction and human pregnancy studies have not been conducted. The CDC recommends Tetanus Immune Globulin

and tetanus toxoid containing vaccine as part of the standard wound management to prevent tetanus in pregnant women.

• Lactation: very low risk, safe. Minimal risk for breastfeeding and infant. The secretion of immunoglobulin into breast milk may help to transfer passive immunization to the child.

Pharmacology

• Half-life elimination: individuals with normal IgG concentration: ~23 days

• Time to peak, plasma: IgG concentration: IM: ~2 days

References

1. CDC (Centers for Disease Control and Prevention), Epidemiology and Prevention of Vaccine-Preventable Diseases. Tejpratap S.P. Tiwari, MD; Pedro L. Moro, MD, MPH; and Anna M. Acosta, MD. Chapter 21: Tetanus. Updated December 2020. Visited in June 2021.
   https://www.cdc.gov/vaccines/pubs/pinkbook/tetanus.html#medical

2. Yen LMM, Thwaites CLU. Tetanus. Lancet. 2019 Apr 20;393(10181):1657-68. doi:10.1016/S0140-6736(18)33131-3.
   https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33131-3/fulltext#articleInformation

3. Nation NS, Pierce NF, Adler SJ, Chinnock RF, Wehrle PF: Tetanus: the use of human hyperimmune globulin in treatment. Calif Med 1963; 98: pp. 305-307.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575749/

4. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: HyperTET^® (Tetanus Immune Globuline - human injection), updated December 2020.
   https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=393fa198-7e07-4162-bd0a-9d873f1544a9&version=17

5. WHO/UNICEF. Breastfeeding and Maternal Medication Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs. Department of Child and Adolescent Health and Development, 2002.
   http://apps.who.int/iris/bitstream/handle/10665/62435/55732.pdf;jsessionid=6A78FBE9088BBFA2D9F8B66066747332?sequence=1

6. American College of Emergency Physicians, ED Vaccinations, Tetanus. Visited in August 2021.
   https://www.acep.org/patient-care/ed-vaccinations/tetanus/

7. US-FDA (United States Food and Drug Administration). Purple Book Database of Licenced Biological Products. Baytet, Hypertet. Visited in September 2021.
   https://purplebooksearch.fda.gov/results?query=Tetanus%20Immune%20Globulin%20(Human)&title=Baytet,%20Hypertet

• WHO - Model List of Essential Medicines 2019
  https://www.who.int/(...)

• US FDA - Approved Drugs Orange Book 2021
  https://www.accessdata.fda.gov/(...)

• EMA - European Medicines Agency - Covid-19 Updates 2021
  https://www.ema.europa.eu/(...)

• ACEP - American College of Emergency Physicians - Clinical Policies
  https://www.acep.org/(...)

• EUSEM - European Society for Emergency Medicine - Guidelines for the management of acute pain in emergency situations 2020
  https://eusem.org/(...)

• RCEM - The Royal College of Emergency Medicine - Clinical Guidance
  https://www.rcem.ac.uk/(...)