EM·DRUGS

Emergency Medicine Executive Summary

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

Dosing 0.01-0.3 ug/kg/min (actual body weight). Usually started at 0.05ug/kg/min.

Mechanism of Action and Usage

Norepinephrine (NE) is an endogenous sympathomimetic catecholamine (acts as 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.

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

Refractory shock 1-3ug/kg/min is generally combined with other vasoactive or inotropic drugs.

Pediatric dose

0.05-2ug/kg/min, 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

Emergency Medicine Executive Summary

Vasodilator used to prevent tissue necrosis caused by extravasated catecholamine infusions (epinephrine, norepinephrine, dopamine, etc).

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

Available in the US. Limited stock in Canada. Not available in Chile.

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). It is recommended to have an extravasation protocol (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).

Indications

FDA-labeled

• Prevention and treatment of dermal necrosis due to extravasation of norepinephrine*

*FDA Approval in 1998 (2)

Other FDA and Not FDA-labeled

• Indications not relevant to emergency medicine setting

Adult dose

• Injection site extravasation

  • 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 extravasation

  • Infants, children and adolescents: Infiltrate 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 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

• Not available in Chile

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/

Emergency Medicine Executive Summary

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).

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

• Tetanus prophylaxis dose: 250 units IM once.

Mechanism of Action and Usage

Tetanus Immune Globulin (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.

Indications

• Tetanus treatment: always administer TIG.

• Tetanus prophylaxis: Give TIG in individuals with <3 tetanus vaccination doses that suffered a wound considered not to be minor and clean (tetanus-prone wounds).

Updated tetanus prophylaxis scheme:

• 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: The actual recommended dose is 500 IU 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”.

• Tetanus prophylaxis: 250 Units IM*.

*FDA Approved in 1957

Pediatric dose

• Tetanus Prophylaxis:

<7 years: 4 IU/kg.

>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 Drug 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. Infections thought to be transmitted by this product should be reported to the manufacturer.

• 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