Continuing Education Activity

The FDA-approved indication for intravenous (IV) phenylephrine hydrochloride is for increasing blood pressure in adults with clinically significant hypotension resulting primarily from vasodilation in such settings as septic shock or anesthesia. Phenylephrine HCL is also used over-the-counter in ophthalmic formulations to promote mydriasis and conjunctival blood vessel vasoconstriction, intranasal administration as a treatment for uncomplicated nasal congestion, and as an over-the-counter additive to topical hemorrhoid medications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, dose forms, monitoring, and toxicity of phenylephrine, so providers can direct patient therapy in treating the various conditions for which it is indicated, as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of phenylephrine therapy.
• Describe a hypotensive patient that would be most suitable for phenylephrine therapy based on known hemodynamics.
• Review the adverse event profile and contraindications of phenylephrine.
• Outline interprofessional team strategies for improving care coordination and communication to advance phenylephrine therapy and improve outcomes.

Indications

The FDA-approved indication for intravenous (IV) phenylephrine hydrochloride is for increasing blood pressure in adults with clinically significant hypotension resulting primarily from vasodilation in such settings as septic shock or anesthesia. Phenylephrine HCL is also used over-the-counter in ophthalmic formulations to promote mydriasis and conjunctival blood vessel vasoconstriction, intranasal administration as a treatment for uncomplicated nasal congestion, and as an over-the-counter additive to topical hemorrhoid medications.[1] Phenylephrine is less commonly used off-label as an additive to neuraxial/peripheral nerve blockade, to treat priapism and other conditions where local vasoconstrictive effects and reduced blood flow are the desired effect. In the setting of IV administration, phenylephrine is a commonly used anesthetic vasopressor for patients with normal cardiac function and hypotension secondary to the vasodilatory effect of anesthetic medications or non-cardiac shock states.

Phenylephrine is primarily an alpha-1 adrenergic receptor agonist with minimal to no beta-adrenergic activity; therefore, it is ideal for elevating mean arterial pressure. It does so by causing venous and arterial vasoconstriction and increasing cardiac preload without having any significant direct effect on cardiac myocytes.[2] Hypotension during general and neuraxial anesthesia remains one of the most commonly encountered problems for the anesthetic provider and must be addressed rapidly to avoid prolonged hypoperfusion states.[3] During any given surgical procedure, blood pressure can vary considerably based upon the patient’s underlying pathology, the dosage of anesthetic medications, volume status, the degree of surgical stimulation, and the presence of other blood pressure modulating medications. Vasopressor medications with short onset, short duration of action, and predictable dose-dependent responses such as phenylephrine are ideal for treating hypotensive patients.

Phenylephrine has been shown to be effective in offsetting commonly encountered hypotension associated with spinal anesthetics (60% to 70%) in obstetric patients and has become the preferred vasopressor in this setting.[3] Phenylephrine is also used in the intensive care unit (ICU) environment to treat septic and neurogenic shock. With the advent of the surviving sepsis campaign, management of sepsis has undergone more scrutiny and a more standardized approach to septic shock states has been developed with norepinephrine as the vasopressor/inotrope of choice.

Although phenylephrine is not recommended as the initial treatment of septic shock, it is an acceptable therapy in the case of norepinephrine associated arrhythmias, known high cardiac output with hypotension, and as a salvage therapy when combined inotrope and vasopressor drugs when low-dose vasopressin has failed to achieve MAP target.[4] Neurogenic shock secondary to acute traumatic spinal cord injury can similarly produce a systemic vasodilatory state, often in the setting of preserved cardiac output. These injuries frequently require higher target mean arterial pressures (85 to 90 mm Hg) to maintain spinal cord perfusion and reduce secondary injury, making phenylephrine a reasonable and safe choice in the hemodynamic maintenance of these patients.[5]

Mechanism of Action

Phenylephrine is a direct-acting sympathomimetic amine that functions as an alpha-1 adrenergic agonist. Its chemical structure is related to epinephrine and ephedrine and possesses potent vasoconstriction properties when given intravenously or applied directly to mucosal membranes. The overall effect of intravenous phenylephrine on cardiac output and end perfusion is likely more complex and variable based on bolus versus infusion dosing, volume status, baseline heart rate, autonomic tone, and cardiac pathology. These variations are attributable to the degree of venoconstriction which can temporarily increase preload, arterial constriction which will increase systemic vascular resistance and afterload, and the presence of reflex bradycardia leading to an overall mixed effect on cardiac output depending on the patient population.[6][7][8] Regarding ophthalmic administration, phenylephrine binds alpha-1 receptors that innervate the iris dilator muscle yielding smooth muscle contraction and subsequent dilation of the pupil which can assist in fundoscopic exams, exposure in certain surgeries, and treatment of various conditions.[9]

Administration

The most common routes of administration for phenylephrine include oral, topical, intravenous, intranasal, ophthalmic, and rectal. Less commonly, phenylephrine has been administered in the epidural space, as an adjunct to peripheral nerve blockade, in the intracavernous space, intramuscularly, and subcutaneously.[10][11] When administering phenylephrine intravenously, dosing is typically in 50 to 100 mcg aliquots and frequently requires redosing as it has a short onset of action (1 to 3 minutes) and short duration of action (5 to 20 minutes).[12] 

Additionally, phenylephrine dosing can be via weight-based or non-weight based infusion with typical dose ranges of 0.1 to 1.5 mcg/kg per minute.[13] Despite the classic teaching that all vasoactive medications require central venous access to avoid necrosis in the event of tissue extravasation, phenylephrine has demonstrated to be safe and effective when given through peripheral intravenous catheters when dilution, vein, and catheter selection, and frequent site inspection are appropriate.[14] 

Ophthalmic solutions of phenylephrine have a wide range of concentrations and additives depending on the desired effect.  Concentrations utilized by medical professionals generally come in doses of 1%, 2.5%, or 10%. The 1% formulations are often administered in combination with cyclopentolate 0.2% for dilated fundus and cycloplegic exams in newborns of less than three months. The 2.5% formulations are the most commonly used for dilated fundus exams in adults, children over three months, and as an aid in diagnosing conditions such as episcleritis. The 10% formulation is less commonly used (due to fear of systemic absorption) in dilated exams and to provide exposure during surgeries.

Over-the-counter (OTC) preparations of phenylephrine combination drops may come in concentrations as low as 0.12% and are marketed as a treatment of "red-eye" or uncomplicated conjunctivitis. Phenylephrine is available as an FDA-approved, over-the-counter decongestant in oral concentrations of up to 10 mg, nasal solutions typically ranging between 0.125% to  1% and are found as an additive in various OTC topical hemorrhoid creams.[15][16]

Adverse Effects

The most common adverse reactions include nausea, vomiting, headache, and nervousness in an awake patient. Because of phenylephrine’s sole alpha-receptor stimulation, it can cause baroreceptor-mediated reflex bradycardia. Clinicians should consider different classes of vasopressor medications in the bradycardic, hypotensive patient. In specific patient populations, primarily hypovolemic patients with cardiac dysfunction, phenylephrine can increase afterload more so than preload, causing decreased cardiac output and potentially an exacerbation of angina, heart failure, and pulmonary hypertension.[6]

Contraindications

There are no absolute contraindications to phenylephrine aside from hypersensitivity to the drug or any of its components. Phenylephrine contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity is unknown and probably low. Phenylephrine use requires caution in patients with a history of bradycardia, autonomic dysfunction, severe cardiac dysfunction, and hypovolemia.

Monitoring

There are no specific drug monitoring requirements for intravenous phenylephrine; however, vasoactive medications should not be given outside of the perioperative or intensive care settings, or in environments where heart rate/rhythm, blood pressure, and pulse oximetry monitoring are unavailable. Many traditional texts recommend the administration of all vasoactive medications through a central line; however, phenylephrine is routinely given peripherally in the operative setting and has been shown to be safe even in prolonged infusions in 18 to 20 g IV in large veins with frequent site inspections.[14] 

Despite the widespread use of peripherally administered intravenous phenylephrine, a systematic review of published articles involving peripherally administered vasoactive medications and reports of extravasation showed only two cases of skin necrosis in high-risk patients receiving peripherally administered phenylephrine.[17] It is still good practice to administer phenylephrine through central venous catheters when available or via the largest proximal vein possible with frequent inspection and aspiration of blood.

Topical, ophthalmic, and nasal administrations of phenylephrine are typically well-tolerated, but there is always the concern for systemic absorption. Although there have been case reports of hemodynamic instability following the administration of higher concentrations (10%) of ophthalmic phenylephrine, 2.5% concentrations lead to no statistically significant difference in heart rate or blood pressure.[18] Oral and nasal phenylephrine formulation have correlated with case reports of rare adverse events. However, there appears to be no appreciable effect on hemodynamics when administered in standard dosages.[19][15][20][21][22]

Toxicity

Currently, there is no available antidote for intravenous phenylephrine. Hypertension in the setting of excessive dosing or an exaggerated response is usually short-lived due to the short duration of action. The treatment for hypertension or symptomatic reflex bradycardia is discontinuing the administration of phenylephrine and chronotropic agents or vasodilators as needed. Treatment for tissue extravasation of peripherally administered phenylephrine is largely supportive care (aspiration of fluid, warming, elevation), but subcutaneous phentolamine is an option used.[23]

Enhancing Healthcare Team Outcomes

It is worth noting that phenylephrine is often administered in a variety of hospital environments (ICU, operating room [OR], labor and delivery [L and D], emergency room [ER], among others) and may require the participation of various health care providers (pharmacists, nurses, PAs, NPs, CRNAs, and physicians) in its dilution and administration. Manufacturers most commonly provide intravenous phenylephrine in highly concentrated doses (10 mg/ml) that require dilution before administration. Phenylephrine is frequently associated with medication errors and can account to up to 10% of all errors in the perioperative setting. Because of this, pharmacists and nursing, in particular, must maintain an open line of communication to ensure proper dosing and administration.

All providers administering phenylephrine should familiarize themselves with the appropriate dilution.[24] Manufacturer recommendations for the preparation of bolus dosing are to add 10 mg of phenylephrine to 99 mL of 5% dextrose or 0.9% sodium chloride solutions, yielding a 100 mcg/mL concentration. For continuous infusions, the recommendation is that 10 mg of phenylephrine be added to a 500 mL of 5% dextrose or 0.9% sodium chloride solutions, yielding a 20 mcg/mL concentration.

If both pharmacists and nurses are familiar with the correct dosing and dilution, they can serve as a double backstop for the physician, and verify that dosing is appropriate. COmmunicaitonlines should be such that they are free to contact the ordering physician with any concerns.

It is important to remember that although "Rapid Response" and "Code Teams" likely reduce morbidity and mortality, they are composed of members of varying degrees of education and experience.[25][26] Since phenylephrine may be the vasopressor of choice in many emergencies, any potential code team leader should be familiar with and rehearse the direction of its administration. Specific closed-loop communications ("Please dilute a 10-mg vial of phenylephrine in a 100-mL bag of normal saline and administer 2 mL of 100 mcg/mL through the patient's central line, and let me know when it has been given", rather than "Please give the patient 200 mcg of phenylephrine.") have been shown to not only reduce medication errors but to improve time-to-task completion in emergencies significantly.[27] 

The basis of this information is a prospective observational study with intervention level II evidence. It does demonstrate that a collaborative interprofessional team approach is the best means by which to optimize therapy with phenylephrine and prevent medication errors. [Level V]