Epinephrine

Epinephrine and phenylephrine previously have been identified as high-alert medications, a designation that results from the narrow margin of safety associated with their use. (1) The Joint Commission on Accreditation of Healthcare Organizations (JCAHO), AORN, the United States Pharmacopeia (USP), and the Institute for Safe Medication Practices all have received reports of adverse events involving epinephrine and phenylephrine in the OR and other surgical settings. These adverse events most frequently were related to solutions being diluted incorrectly or the wrong concentration being used.

A case involving mislabeled epinephrine 1:1,000 that resulted in the death of a seven-year-old child in a Florida OR was reported widely in both the professional and consumer media. The Joint Commission has received sentinel event reports for occurrences in the OR in which side effects from nasally applied phenylephrine resulted in death, as well as reports in which the use of epinephrine in the OR resulted in adverse events or death. The USP, through its Medmarx medication error reporting program, has received multiple reports of epinephrine medication errors in the OR. One resulted in a patient's death, another in cardiac arrest, and several others placed patients at risk of injury. None of the adverse events reported to Medmarx also were reported to JCAHO. Medmarx also contains medication error reports of multiple mishaps with epinephrine in day surgery settings and postanesthesia care units.

In addition to the errors reported to Medmarx and JCAHO, there are a number of documented cases of intraoperative cardiac complications resulting from the use of one of these medications, alone or in combination with other medications (eg, cocaine), during otorhinolaryngologic procedures. (2) Other case reports (n = 12) of severe hypertension have been documented after the intraoperative use of topical phenylephrine, submucosal epinephrine, or both during nasal surgery, for intubation purposes, or when injected into the submucosal area of the palate. (3) Epinephrine when combined with cocaine during septoplasty also has been associated with myocardial ischemia in unsuspected coronary artery disease. (4)

WHAT IS EPINEPHRINE?

Epinephrine (ie, adrenaline) stimulates alpha, beta-one, and beta-two sympathetic effector cells in a dose-related fashion. Its most prominent actions are on the beta receptors of the heart, vascular muscles, and other smooth muscles (Table 1). The dose, strength, and concentration of epinephrine all are related closely to the purpose of its use and a patient's general condition and age. (5)

Epinephrine is supplied and used in various concentrations (Table 2). Clinicians handling and administering epinephrine must verify both the dose form and concentration. Clinicians need to understand that 1:1,000 is the most concentrated form of epinephrine when compared to 1:100,000 or 1:200,000, which are much less concentrated forms of the medication in solution. Epinephrine can be used for a variety of purposes in the perioperative setting, including

* relieving bronchospasm,

* treating sensitivity reactions,

* restoring cardiac rhythm during cardiac arrest,

* treating cardiac arrhythmias,

* prolonging action of local and regional anesthetics,

* providing local vasoconstriction,

* reducing conjunctival congestion, or

* treating mucosal congestion.

Bronchospasm or hypersensitivity reactions. For severe anaphylaxis or asthma, the usual initial dose is 0.1 mg to 0.5 mg (ie, 0.1 mL to 0.5 mL of a 1:1,000 injection) given subcutaneously or intramuscularly. If given via the intramuscular (IM) route, the buttocks should be avoided.

Cardiac arrest and cardiac arrhythmia. During cardiopulmonary resuscitation and when treating certain cardiac arrhythmias, epinephrine generally is administered by IV, but it also can be instilled directly into the tracheobronchial tree via an endotracheal tube, intraosseous infusion, or intracardiac injection. During cardiopulmonary resuscitation, the usual adult dose is 0.5 mg to 1 mg (ie, usually as 5 mL to 10 mL of a dose of a 1:10,000 injection). (6)

Anesthesia and local vasoconstriction. One common use of epinephrine in the OR involves its topical administration via cotton or gauze to mucous membranes or other tissues. In this instance, concentrations used can vary from 1:1,000 to 1:50,000. In combination with local anesthetics, epinephrine may be used in concentrations of 1:50,000 to 1:500,000. The most frequently used concentration in local anesthetics is 1:200,000. (7) When used for intranasal procedures, there may be unpredictable medication absorption. (8)

For vasoconstriction, epinephrine often is diluted with varying amounts of normal saline or other solution for use as an irrigating solution. For example, a solution for a hip or shoulder arthroscopy may consist of epinephrine 1 mg (ie, 1 mL of a 1:1,000 solution) in 3 L of normal saline. Tumescent solution, which is used during plastic surgery, may include epinephrine 1 mg (ie, 1 mL of a 1:1,000 solution) in 1,000 mL of normal saline along with 500 mg or 1,000 mg of lidocaine and 12.5 mEq of sodium bicarbonate. (9)

WHAT ARE THE EFFECTS OF RECEIVING TOO MUCH EPINEPHRINE?

Excessive doses of epinephrine can result in circulatory collapse and death. Signs and symptoms of excessive doses include increases in systolic and diastolic blood pressure, increases in venous pressure, dysrhythmias, precipitation of angina pectoris, and cerebrovascular or other hemorrhage and hemiplegia. The treatment for excessive doses is supportive medical and nursing care. The pressor effects of epinephrine may be counteracted by medications such as phentolamine and phenoxybenzamine.

ARE THERE CERTAIN PATIENTS WHO ARE MORE SENSITIVE TO EPINEPHRINE?

Yes--epinephrine always should be used with caution. It should not be administered with sympathomimetic agents due to possible additive effects. Also, epinephrine may interact with alpha- and beta-adrenergic blocking agents such as propranolol and phentolamine.

Certain general anesthetics that increase cardiac irritability also may sensitize the myocardium to epinephrine and result in arrhythmias. Epinephrine is contraindicated for use with chloroform and trichloroethylene and should be used with caution, if at all, with other halogenated hydrocarbon anesthetics such as halothane. (10) Epinephrine should not be used in patients receiving high doses of cardiac glycosides. Epinephrine may be potentiated by tricyclic antidepressants, some antihistamines, and thyroid hormones. (11)

WHAT IS RACEPINEPHRINE?

Racepinephrine is a racemic mixture or isomer of epinephrine. Racemic means that this preparation is a different formulation of epinephrine that is about one-half as active as epinephrine; (12) however, it should be used with the same caution as epinephrine. The doses of racepinephrine are different for children than for adults, and clinicians should refer to medication references for the most up-to-date information about dosing and administration.

WHAT IS PHENYLEPHRINE?

Phenylephrine is a sympathomimetic amine that has direct effects on alpha-adrenergic receptors and no effect on the beta receptors of the heart. Phenylephrine is indicated for

* treatment of mild to moderate hypotension,

* prolongation of spinal anesthesia,

* vasoconstriction for regional anesthesia,

* treatment of paroxysmal supraventricular tachycardia,

* dilation of the pupil, and

* vasoconstriction in the eye or mucosa.

In the OR, the various uses require vastly different dose strengths and administration procedures. For mild or moderate hypotension in adults, the subcutaneous or IM dose ranges from 1 mg to 10 mg, with 2 mg to 5 mg most commonly used. For vasoconstriction during regional anesthesia, the optimum concentration is 1:20,000. (13) Before ocular surgery, phenylephrine is used with atropine to dilate the pupil. When used as an ophthalmic solution, the dose is one to two drops of a 2.5% or 10% solution.

As a vasoconstrictor, phenylephrine may be used alone or in combination with other medications before or during surgery to reduce swelling and enhance visualization of the nasal and pharyngeal membranes. In this instance,

The intranasal application of phenylephrine, however, may result in unpredictable medication absorption. (15) When used as a local vasoconstrictor, a total phenylephrine dose of 2 mg to 4 mg is recommended. Phenylephrine usually is available as a 1% solution containing 10 mg/mL. The maximal total recommended dose of 2 mg is achieved by adding 0.2 mL of 1% solution to the total volume of local anesthetic to be used. (16)

WHAT ARE THE EFFECTS OF RECEIVING TOO MUCH PHENYLEPHRINE?

Phenylephrine can cause restlessness, anxiety, nervousness, weakness, palpitation, tachycardia, premature ventricular contractions, increased perspiration, hypertension, and respiratory distress. Overdose can cause hypertension, headache, seizures, cerebral hemorrhage, palpitations, paresthesia, vomiting, severe bradycardia, and decreased cardiac output. (17)

ARE THERE CERTAIN PATIENTS WHO ARE MORE SENSITIVE TO PHENYLEPHRINE?

Patients taking certain medications, including alpha- and beta-adrenergic blocking agents, oxytocic medications, sympathomimetic agents, general anesthetics, and monoamine oxidase inhibitors are more sensitive. Atropine, digitalis, ergot alkaloids, and diuretics may interact with phenylephrine. (18)

ISSUES SPECIFIC TO THESE MEDICATIONS IN THE OR AND OTHER SURGICAL SETTINGS

Clinicians working the OR and other perioperative settings confront unique practice issues when handling and administering these medications. Problems encountered involve epinephrine and phenylephrine being transferred into unlabeled containers and syringes. Furthermore, both topical and parenteral solutions of these medications are available for use in the OR, and their indications and the correct administration procedures can be misinterpreted easily. Another problematic common practice is that physicians and surgeons may ask to have epinephrine diluted according to their preference for use as an irrigating solution or for injection purposes, which can result in clinicians incorrectly diluting the solution.

Epinephrine and phenylephrine are provided in various concentrations, strengths, and percentages, and their labels may be subject to misinterpretation by clinicians. Epinephrine and phenylephrine may be used for significantly different purposes and in different strengths in the OR, leading to possible misinterpretation when accessing and administering these medications. The fact that in many ORs medications often are chosen from stock supplies without direct pharmacist involvement further contributes to the potential for error.

Epinephrine also is used in local anesthetics, leading to the possibility of misinterpretation of its appropriateness as the right product when a local anesthetic with a dilute solution of epinephrine is indicated. For example, plain epinephrine 1:1,000 may be used when lidocaine with epinephrine 1:100,000 is indicated. Unpredictable absorption rates of both epinephrine and phenylephrine when administered in the nasal submucosal area during surgery also can result in unexpected patient outcomes. (19) There are reports of topical ocular phenylephrine 10% causing adverse effects, including severe hypertension, subarachnoid hemorrhage, and ventricular arrhythmias. (20) These factors, alone or in combination, may result in adverse clinical events.

STRATEGIES TO PREVENT HARM

* Label all medication containers in the OR with the name, concentration, dose, and route. Any solution that only can be administered topically should be marked clearly with that information.

* Verify all medication orders and communicate them in a standard and consistent fashion using terminology for doses that is appropriate to the specific medication.

* Confirm verbal orders by repeating the complete order using a digit-by-digit technique for dose (ie, one-two, not twelve). (21)

* Do not dilute medications on the surgical field.

* Standardize preparation of all diluted solutions involving these medications.

* Use only premixed solutions, and limit the number of medication concentrations.

* Dilutions of medications should be prepared by a registered pharmacist. Each facility should determine the specific dilutions that will be used in any clinical setting. If needed, these dilutions should be prepared so they are in ready-to-use or ready-to-administer labeled containers that will allow for sterile delivery of the container's contents to the sterile field.

* If medications absolutely must be diluted in the OR, instructions for diluting should be precalculated by a pharmacist and readily available for clinician use.

* Store products in a manner that minimizes confusion. For example, separate products such as epinephrine and ephedrine, phenylephrine for topical administration and parenteral forms of phenylephrine, by shelf or drawer.

* Clinicians should perform independent double checks of labels when preparing medications, transferring them to the sterile field, and at the time of their administration.

* When passing a medication to the licensed professional performing the procedure, visually and verbally verify the medication, strength, and dose with that practitioner by reading the medication label aloud. (22)

* One RN and another qualified licensed individual should verify and double check any medication calculations.

* Individually verify each medication and complete its preparation for administration, delivery to the sterile field, and labeling on the field before another medication is prepared. (23)

* Discard any solution or medication found in the OR without an identification label. (24)

* At shift change or break relief, all medications and their labels on the sterile field should be noted and verified concurrently by the entering and exiting personnel. (25)

* Clinicians in the OR should communicate verbally all doses of all medications to be administered and clarify the maximum dose with the anesthesia care provider and surgeon.

* Provide a readily available dose conversion chart on code carts reflecting concentrations of these medications available in specific clinical units.

* Members of the health care team should report all medication errors and near misses according to facility policy and address system-related problems.

ADDITIONAL MEASURES

* Nurses and unlicensed personnel should receive education about handling these medications and their purposes, doses, and concentrations, as well as strategies to ensure their safe handling.

* Clinician competency in medication handling and administration should be assessed and validated in a regular, ongoing manner.

* Constraints and forcing functions should be used to minimize risks related to medication management and administration. Constraints are approaches that make a medication error difficult. Examples of constraints include dose limit protocols, automatic stop orders, triple checking medications, labeling all medication containers in the OR, and having the pharmacy premix all dilutions of epinephrine. Forcing functions are approaches that make a medication error impossible. Examples of forcing functions include removing certain medications (eg, multidose containers of epinephrine) from the OR. (26)

SUMMARY

Epinephrine and phenylephrine always should be used with extreme caution, especially in their most concentrated solutions. This is especially true in the OR where these medications are used for purposes involving extreme variations in doses and strengths. Although these medications may be handled and administered daily, clinicians must be vigilant in their efforts to ensure safe handling practices. Clinicians should monitor patients carefully for any adverse side effects. Practitioners should review up-to-date references for all products, including epinephrine and phenylephrine, and follow the recommended strategies and measures to reduce risks when preparing, handling, or administering these medications in the OR.

NOTES

(1.) M R Cohen, C M Kilo, "High-alert medications: Safeguarding against error," in Medication Errors, ed M R Cohen (Washington, DC: American Pharmaceutical Association, 1999) 5.1-5.5.40; "It doesn't pay to play the percentages," ISMP Medication Safety Alert (Oct 16, 2002) http://www.ismp.org/ msaarticles/pay.htm (accessed 7 Feb 2003); M R Cohen, J Senders, N M Davis, "Failure mode and effects analysis: A novel approach in avoiding dangerous medication errors and accidents," Hospital Pharmacy 29 (April 1994) 319-330.

(2.) M Ashchi, H P Wiedemann, K B James, "Cardiac complication from use of cocaine and phenylephrine in nasal septoplasty," Archives of Otolaryngology--Head & Neck Surgery 121 (June 1995) 681-684; D Young, J J Glauber, "Electrocardiographic changes resulting from acute cocaine intoxication," American Heart Journal 34 (August 1947) 272-279; Y C Chiu et al, "Myocardial infarction with topical cocaine anesthesia for nasal surgery," Archives of Otolaryngology--Head & Neck Surgery 112 (September 1986) 988-990; S C Littlewood, H D Tabb, "Myocardial ischemia with epinephrine and cocaine during septoplasty," Journal of Louisiana State Medical Society 139 (May 1987) 15-18.

(3.) M Kalyanaraman et al, "Cardiopulmonary compromise after use of topical and submucosal alpha-agonists: Possible added complication by the use of beta-blocker therapy," Otolaryngology and Head and Neck 117 (July 1997) 56-61.

(4.) Littlewood, Tabb, "Myocardial ischemia with epinephrine and cocaine during septoplasty," 15-18.

(5.) G K McEvoy, ed, AHFS Drug Information (Bethesda, Md: American Society of Health-System Pharmacists, 2002).

(6.) Ibid.

(7.) Ibid.

(8.) Kalyanaraman et al, "Cardiopulmonary compromise after use of topical and submucosal alpha-agonists: Possible added complication by the use of beta-blocker therapy," 56-61.

(9.) J A Klein, "Tumescent technique for regional anesthesia permits lidocaine doses of 35mg/kg for liposuction," Journal of Dermatologic Surgery & Oncology 16 no 3 (1990) 248-263.

(10.) N M Woldorf, P N Pastore, "Extreme epinephrine sensitivity with a general anesthesia," Archives of Otolaryngology 96 (September 1972) 272-277; McEvoy, ed, AHFS Drug Information.

(11.) McEvoy, ed, AHFS Drug Information.

(12.) Ibid.

(13.) Facts and Comparisons Staff, Drug Facts and Comparisons (St Louis: Facts and Comparisons, 2003) 564.

(14.) D F Stone, T J Gall, "Airway management," in Anesthesia, fifth ed, R D Miller, ed (Philadelphia: Churchill Livingstone, 2000) 1414-1451.

(15.) Kalyanaraman et al, "Cardiopulmonary compromise after use of topical and submucosal alpha-agonists: Possible added complication by the use of beta-blocker therapy," 56-61.

(16.) P O Bridenbaug, M E Cruz, S H Shelton, "Anesthesia for otolaryngologic procedures," in Otolaryngology, Volume 4, third ed, M M Paparella et al, eds (Philadelphia: Saunders, 1991) 2949-2970.

(17.) McEvoy, ed, AHFS Drug Information.

(18.) Ibid.

(19.) Kalyanaraman et al, "Cardiopulmonary compromise after use of topical and submucosal alpha-agonists: Possible added complication by the use of beta-blocker therapy," 56-61.

(20.) F T Fraunfelder, A F Scafidi, "Possible adverse effects from topical ocular 10% phenylephrine," American Journal of Ophthalmology 8 (April 1978) 447-453.

(21.) "AORN guidance statement: Safe medication practices in perioperative practice settings," in Standards, Recommended Practices, and Guidelines (Denver: AORN, Inc, 2003) 135-136.

(22.) Ibid.

(23.) Ibid.

(24.) Ibid.

(25.) Ibid.

(26.) Ibid.

Editor's note: Medmarx is a registered service mark of the United States Pharmacopeia, Rockville, Md. To the best of the authors' knowledge, this article reflects currently accepted clinical practice; nevertheless, it cannot be considered absolute or universal. For individual patient core situations, refer to the latest and most up-to-date product information or medication references.

Suzanne C. Beyea, RN, PhD, FAAN, is director of nursing research, Dartmouth-Hitchcock Medical Center, Lebanon, NH. She was director of research at AORN, Denver, at the time this article was written.

Rodney W. Hicks, RN, MSN, MPA, is a research coordinator, United States Pharmacopeia, the Center for the Advancement of Patient Safety, Rockville, Md.

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