Phenylephrine ORGANS AND SYSTEMS

Cardiovascular
GENERAL INFORMATION The FDA and the National Registry of Drug-induced Ocu-
lar Side Effects (Casey Eye Institute, Portland, Oregon)
Phenylephrine is seldom given systemically but is still
have received 11 reports of adverse systemic reactions to
commonly used as a mydriatic for both diagnostic and
a single dose of topical ocular phenylephrine 10% applied
therapeutic purposes. Ocular application of phenylephrine
in pledget form [4]. There were eight men and three
10% in pledget form is used to produce hemostasis in laser-
women, aged 1–76 years. Most of the patients noted sys-
assisted in-situ keratomileusis (LASIK) surgery and other
temic effects within minutes of applying phenylephrine,
ophthalmic surgical procedures. Phenylephrine is in some
and the adverse systemic reactions included severe hyper-
countries available in a non-prescription concentration of
tension, pulmonary edema, cardiac dysrhythmias, cardiac
0.12% for use as an ocular decongestant. Phenylephrine
arrest, and subarachnoid hemorrhage.
(up to 10 mg intramuscularly) has similar properties and
In a meta-analysis of cardiovascular adverse reactions
uses to other alpha-adrenoceptor agonists. The incidence
to topical phenylephrine 2.5% or 10% in eight random-
of adverse reactions is high with 10% phenylephrine, but
ized controlled trials in 916 participants neither blood
less with lower concentrations. Systemic reactions also
pressure nor heart rate changed after 0.25% phenyleph-
increase with increased frequency of use and when phen-
rine at either 20–30 minutes or 60 minutes [5]. Blood
ylephrine is applied in a pledget. The package inserts for
pressure increased at 5 and 10 minutes after application
10% phenylephrine in the USA and Australia require that
of phenylephrine 10% (mean difference 15 mmHg; 95%
the drug should not be used more often than once an hour.
CI ¼ 12, 19) but fell to baseline after 20–30 minutes. The
A large number of severe systemic reactions, including
heart rate increased by 5/minute (95% CI ¼ 1, 8) at 20–30
death, have been reported in more than 20 articles in
minutes and returned to baseline after 60 minutes.
peer-reviewed ophthalmic journals. For this reason 10%
A 10% solution of phenylephrine has sometimes caused
phenylephrine eye-drops should be used with caution in
extremely severe cardiovascular complications, including
patients with cardiac disease, significant hypertension, or
myocardial infarction.
advanced arteriosclerosis, and in frail elderly people.
In neonates the benefit of accurate assessment of gesta-
It can never be emphasized enough that the eyes are a
tional age by examination of the anterior vascular capsule
potential route for systemic drug administration. This has
of the lens and the value of funduscopic examination in ill
been illustrated by a British case of pulmonary edema in a
premature babies must be weighed against the possible
child, apparently attributable to systemic absorption of
risks of the associated increase in blood pressure produced
phenylephrine eye-drops [1].
by the pupillary dilators. Since there is no increase in myd-

An 8-year-old boy was admitted for unilateral retinal detach- riatic effect with repeated instillation or increasing concen-
ment surgery. Phenylephrine 2.5% and cyclopentolate 1% as tration, and their small body mass places premature
premedication were prescribed but not given. In theatre the neonates at increased risk of phenylephrine overdose, it is
assistant surgeon administered 2–5 drops of 10% phenylephrine prudent to use the lowest possible concentration, as well as
to the right eye. During the operation the boy developed bra-
the most effective combination of mydriatics for indirect
dycardia and was given glycopyrrolate, but shortly afterwards
ophthalmoscopy in premature infants when such examina-
the systolic arterial pressure rose to 211 mmHg and the pulse
rate to 160 beats/minute, with multifocal atrial and ventricular tion is absolutely necessary. The hypertensive effect is
ectopic beats. Labetalol was given and the pulse and blood likely to be maximal at some time within the first 20
pressure fell to normal, but he then developed clinical and minutes, and whenever possible (or when risk factors are
radiological signs of pulmonary edema, which resolved present) the blood pressure should be monitored.
spontaneously. A severe hypertensive crisis occurred after ocular appli-
cation of phenylephrine in a healthy 2-year-old [6].
The management of this case was subsequently criticized
The selective a-adrenoceptor agonist phenylephrine is
by correspondents in the same journal [2]. They suggested
used in some clinical settings to reverse hypotension. An
that a lower ocular dose of phenylephrine should be used
example is spinal anesthesia for caesarean sections, as
routinely, that oxymetazoline might in any case be safer,
described in a report of cardiac dysrhythmias [7].
and that labetalol might have been hazardous, owing to its
beta-blocking properties. In their reply the authors
A 31-year-old woman who required emergency cesarean sec-
pointed out that they used the lowest concentration of tion after failure to progress during labor was given phenyleph-
phenylephrine available for ocular use, that oxymetazo- rine 200 micrograms by infusion immediately after intrathecal
line is not licensed for use as a mydriatic agent, and that injection of bupivacaine and diamorphine; the dose was
the patient had tachycardia and ventricular extra beats, repeated whenever the blood pressure fell below baseline.
which made the beta-blocking properties of labetalol clin- Within seconds of starting the infusion she developed ventric-
ically desirable. ular bigeminy at a rate of 94/minute, which persisted until
delivery, sinus rhythm returned without treatment. The blood
It is always wise to advocate nasolacrimal occlusion by
pressure was between 122/76 and 143/80 mmHg.
digital compression of the lacrimal drainage system when
using phenylephrine eye-drops in patients at risk or in The mechanism of this effect was unclear. The authors
patients in whom higher concentrations are necessary [3]. suggested that there may have been increased after-load,

ã 2016 Elsevier B.V. All rights reserved.

 Phenylephrine 703

leading to increased ventricular stretch, but this was compound is neurotoxic in any case. Another correspon-
speculative. dent commented that tetracaine itself may be more toxic

A child developed cardiac dysrhythmias, severe hypertension, than other local anesthetics [13]; the authors did not
and pulmonary edema after the intraoperative administration address this point in their reply (see below under
of ocular phenylephrine [1]. DRUG–DRUG INTERACTIONS).

A 2-month-old child given perioperative phenylephrine drops
during cataract extraction developed ventricular extra beats,
very severe hypertension, and pulmonary edema requiring
intensive therapy [8]. Extubation was possible within 3 hours,
Sensory systems
and she recovered with no untoward consequences. With phenylephrine, several cases of allergic blepharocon-
The authors commented that changes in arterial blood junctivitis have been seen, even at low concentrations; the
pressure are well described with phenylephrine eye- reaction begins 3–4 hours after drug application, persists
drops, especially in infants. Clearly precise dosage is diffi- for 12 hours, and regresses gradually within 72 hours [14].
cult in these very young patients and they suggested that Biopsy of the conjunctiva reveals marked infiltration with
microdrops might be a safer mode of administration. cells of various types; there is some evidence that a sensi-
Phenylephrine eye-drops are used to dilate the pupils to tization mechanism is involved.
enable fundoscopy and is used in neonates when an oph- However, blepharoconjunctivitis can occur [15,16], as
thalmic examination is conducted to assess the presence of can other complications.
retinopathy of prematurity. However, it can cause serious
Acute periorbital dermatitis and conjunctivitis occurred in a 69-
cardiovascular adverse events. In 42 neonates there were year-old man given phenylephrine 5% eye- drops for ophthal-
no adverse effects of phenylephrine 2.5%, in combination mological examination [17]. Subsequent patch-testing was
with tropicamide 0.5% eye-drops, on heart rate or blood strongly positive for phenylephrine eye-drops.
pressure [9].
The rise in blood pressure that phenylephrine causes
may itself be hazardous, even if it is not given systemically, Skin
or at least not intentionally [10].
There have been a few reports of allergic contact derma-

A 23-year-old African–American man developed ischemic pri-
titis caused by phenylephrine, and little is known about
apism as a result of sickle cell disease. After intracavernosal
injection of phenylephrine 500 micrograms he complained of cross-reactivity between the phenylephrine, adrenaline,
very severe headache and a CT scan showed subarachnoid and ephedrine.
hemorrhage. His blood pressure was 180/100 mmHg, compared
A 62-year-old man developed contact dermatitis after using
to his baseline reading of 130/88 mmHg. He was given enalapril phenylephrine eye-drops (Neosynerphin POS) [18]. The
(dose not stated) and his blood pressure fell. Fortunately, he inflammation affected both eyelids symmetrically and resolved
had no neurological symptoms then or later. rapidly on withdrawal of the eye-drops and application of top-
ical glucocorticoids. Skin-testing confirmed hypersensitivity to
The authors very reasonably suggested reducing the stan-
phenylephrine but no cross-sensitization to ephedrine or
dard dose to be injected in these circumstances to 200
adrenaline.
micrograms, to be repeated if necessary.
Local phenylephrine as an insert caused an acute
blepharoconjunctivitis with eyelid eczema [19], confirmed
by patch testing. Generalized eczema can develop when
Ear, nose, throat
phenylephrine is given intravenously.
When used as a nasal decongestant, phenylephrine can
cause local nasal irritation and even perforation of the
anterior nasal septum.
Immunologic

A 69-year-old woman developed perforation of the nasal sep-
tum after overuse of a common over-the-counter nasal spray Phenylephrine was the drug that most often caused sensi-
containing phenylephrine [11]. tization in patients with contact allergy after the applica-
tion of mydriatic eye-drops. Since several eye-drops are
The authors attributed this effect to both vasoconstriction
often used in the same patient, it is always important to
and physical irritation.
find out which drug or preservative is the allergen
[17,18,20,21].

Nervous system
It has been suggested that sodium bisulfite, a preservative LONG-TERM EFFECTS
in phenylephrine solutions for injection, may have been
responsible for transient neurological symptoms that have Drug abuse
been observed in some patients [12]. However, the origi-
nal authors rejected this, since the dose of bisulfite was Abuse of alpha-adrenoceptor agonist nose-drops can
small and since there is uncertain evidence whether the cause a chronic rhinitis [22] and psychoses [23].

ã 2016 Elsevier B.V. All rights reserved.

704 Phenylephrine

SUSCEPTIBILITY FACTORS [9] Willems L, Allegaert K, Casteels I. Prospective assessment

of systemic side effects of topical ophthalmic drug admin-
Phenylephrine should be used cautiously in elderly people istration for screening for retinopathy of prematurity. Paed
and in patients with hypertension, coronary heart disease, Perinat Drug Ther 2006; 7(3): 121–2.
aneurysms, and diabetic autonomic neuropathy [24]. [10] Davila HH, Parker J, Webster JC, Lockhart JL, Carrion RE.
Subarachnoid hemorrhage as complication of phenylephrine
injection for the treatment of ischemic priapism in a sickle cell
disease patient. J Sex Med 2008; 5(4): 1025–8.
[11] Vilensky W. Illicit and licit drugs causing perforation of the
DRUG–DRUG INTERACTIONS nasal septum. J Forensic Sci 1982; 27(4): 958–62.
[12] Tanaka M, Nishikawa T. Is phenylephrine of sodium bisul-
See also Terbutaline
fite neurotoxic? Anesthesiology 1998; 89(1): 272–3.
[13] Lambert DH. Transient neurologic symptoms when phen-
ylephrine is added to tetracaine spinal anesthesia—an alter-
Monoamine oxidase inhibitors native. Anesthesiology 1998; 89(1): 273.
[14] Mehelas TJ, Kollarits CR, Martin WG. Cystoid macular
Patients taking monoamine oxidase inhibitors, anticholin- edema presumably induced by dipivefrin hydrochloride
ergic drugs (such as tricyclic antidepressants), propranolol, (Propine). Am J Ophthalmol 1982; 94(5): 682.
reserpine, guanethidine, and methyldopa should be moni- [15] Geyer O, Neudorfer M, Lazar M. Phenylephrine prodrug.
tored closely if phenylephrine is also used [25]. Ophthalmology 1991; 98(10): 1483.
[16] Geyer O, Yust I, Lazar M. Allergic blepharoconjunctivitis
due to phenylephrine. J Ocul Pharmacol 1988; 4(2): 123–6.
[17] Wigger-Alberti W, Elsner P, Wuthrich B. Allergic contact
Tetracaine dermatitis to phenylephrine. Allergy 1998; 53(2): 217–18.
[18] Erdmann SM, Sachs B, Merk HF. Allergic contact derma-
When phenylephrine was used together with tetracaine in titis from phenylephrine in eyedrops. Am J Contact Der-
spinal anesthesia, 10 of 80 patients developed transient mat 2002; 13(1): 37–8.
dysesthesia [26]. Provocation of myocardial ischemia [19] Dewachter P, Mouton-Faivre C. Anaesthetists should be
[27], acute edema of the lung [28], and ischemic colitis aware of delayed hypersensitivity to phenylephrine. Acta
Anaesthesiol Scand 2007; 51: 637–9.
[29] were not so clear-cut.
[20] Villarreal O. Reliability of diagnostic tests for contact
allergy to mydriatic eyedrops. Contact Dermatitis 1998;
38(3): 150–4.
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ã 2016 Elsevier B.V. All rights reserved.