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Phenylephrine
General information
Phenylephrine is seldom given systemically but is still commonly used as a mydriatic for both diagnostic and therapeutic purposes. Ocular application of phenylephrine 10% in pledget form is used to produce hemostasis in laser-assisted in-situ keratomileusis (LASIK) surgery and other ophthalmic surgical procedures. Phenylephrine is in some countries available in a non-prescription concentration of 0.12% for use as an ocular decongestant. Phenylephrine (up to 10 mg intramuscularly) has similar properties and uses to other alpha-adrenoceptor agonists. The incidence of adverse reactions is high with 10% phenylephrine, but less with lower concentrations. Systemic reactions also increase with increased frequency of use and when phenylephrine is applied in a pledget. The package inserts for 10% phenylephrine in the USA and Australia require that the drug should not be used more often than once an hour. A large number of severe systemic reactions, including death, have been reported in more than 20 articles in peer-reviewed ophthalmic journals. For this reason 10% phenylephrine eye-drops should be used with caution in patients with cardiac disease, significant hypertension, or advanced arteriosclerosis, and in frail elderly people.
It can never be emphasized enough that the eyes are a potential route for systemic drug administration. This has been illustrated by a British case of pulmonary edema in a child, apparently attributable to systemic absorption of phenylephrine eye-drops [ ].
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An 8-year-old boy was admitted for unilateral retinal detachment surgery. Phenylephrine 2.5% and cyclopentolate 1% as premedication were prescribed but not given. In theatre the assistant surgeon administered 2–5 drops of 10% phenylephrine to the right eye. During the operation the boy developed bradycardia and was given glycopyrrolate, but shortly afterwards the systolic arterial pressure rose to 211 mmHg and the pulse rate to 160 beats/minute, with multifocal atrial and ventricular ectopic beats. Labetalol was given and the pulse and blood pressure fell to normal, but he then developed clinical and radiological signs of pulmonary edema, which resolved spontaneously.
The management of this case was subsequently criticized by correspondents in the same journal [ ]. They suggested that a lower ocular dose of phenylephrine should be used routinely, that oxymetazoline might in any case be safer, and that labetalol might have been hazardous, owing to its beta-blocking properties. In their reply the authors pointed out that they used the lowest concentration of phenylephrine available for ocular use, that oxymetazoline is not licensed for use as a mydriatic agent, and that the patient had tachycardia and ventricular extra beats, which made the beta-blocking properties of labetalol clinically desirable.
It is always wise to advocate nasolacrimal occlusion by digital compression of the lacrimal drainage system when using phenylephrine eye-drops in patients at risk or in patients in whom higher concentrations are necessary [ ].
Organs and systems
Cardiovascular
The FDA and the National Registry of Drug-induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon) have received 11 reports of adverse systemic reactions to a single dose of topical ocular phenylephrine 10% applied in pledget form [ ]. There were eight men and three women, aged 1–76 years. Most of the patients noted systemic effects within minutes of applying phenylephrine, and the adverse systemic reactions included severe hypertension, pulmonary edema, cardiac dysrhythmias, cardiac arrest, and subarachnoid hemorrhage.
In a meta-analysis of cardiovascular adverse reactions to topical phenylephrine 2.5% or 10% in eight randomized controlled trials in 916 participants neither blood pressure nor heart rate changed after 0.25% phenylephrine at either 20–30 minutes or 60 minutes [5]. Blood pressure increased at 5 and 10 minutes after application of phenylephrine 10% (mean difference 15 mmHg; 95% CI = 12, 19) but fell to baseline after 20–30 minutes. The heart rate increased by 5/minute (95% CI = 1, 8) at 20–30 minutes and returned to baseline after 60 minutes.
A 10% solution of phenylephrine has sometimes caused extremely severe cardiovascular complications, including myocardial infarction.
In neonates the benefit of accurate assessment of gestational age by examination of the anterior vascular capsule of the lens and the value of funduscopic examination in ill premature babies must be weighed against the possible risks of the associated increase in blood pressure produced by the pupillary dilators. Since there is no increase in mydriatic effect with repeated instillation or increasing concentration, and their small body mass places premature neonates at increased risk of phenylephrine overdose, it is prudent to use the lowest possible concentration, as well as the most effective combination of mydriatics for indirect ophthalmoscopy in premature infants when such examination is absolutely necessary. The hypertensive effect is likely to be maximal at some time within the first 20 minutes, and whenever possible (or when risk factors are present) the blood pressure should be monitored.
A severe hypertensive crisis occurred after ocular application of phenylephrine in a healthy 2-year-old [ ].
The selective α-adrenoceptor agonist phenylephrine is used in some clinical settings to reverse hypotension. An example is spinal anesthesia for caesarean sections, as described in a report of cardiac dysrhythmias [ ].
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A 31-year-old woman who required emergency cesarean section after failure to progress during labor was given phenylephrine 200 micrograms by infusion immediately after intrathecal injection of bupivacaine and diamorphine; the dose was repeated whenever the blood pressure fell below baseline. Within seconds of starting the infusion she developed ventricular bigeminy at a rate of 94/minute, which persisted until delivery, sinus rhythm returned without treatment. The blood pressure was between 122/76 and 143/80 mmHg.
The mechanism of this effect was unclear. The authors suggested that there may have been increased after-load, leading to increased ventricular stretch, but this was speculative.
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A child developed cardiac dysrhythmias, severe hypertension, and pulmonary edema after the intraoperative administration of ocular phenylephrine [ ].
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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 [ ]. Extubation was possible within 3 hours, and she recovered with no untoward consequences.
The authors commented that changes in arterial blood pressure are well described with phenylephrine eye-drops, especially in infants. Clearly precise dosage is difficult in these very young patients and they suggested that microdrops might be a safer mode of administration.
Phenylephrine eye-drops are used to dilate the pupils to enable fundoscopy and is used in neonates when an ophthalmic examination is conducted to assess the presence of retinopathy of prematurity. However, it can cause serious cardiovascular adverse events. In 42 neonates there were no adverse effects of phenylephrine 2.5%, in combination with tropicamide 0.5% eye-drops, on heart rate or blood pressure [ ].
The rise in blood pressure that phenylephrine causes may itself be hazardous, even if it is not given systemically, or at least not intentionally [ ].
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A 23-year-old African–American man developed ischemic priapism as a result of sickle cell disease. After intracavernosal injection of phenylephrine 500 micrograms he complained of very severe headache and a CT scan showed subarachnoid hemorrhage. His blood pressure was 180/100 mmHg, compared to his baseline reading of 130/88 mmHg. He was given enalapril (dose not stated) and his blood pressure fell. Fortunately, he had no neurological symptoms then or later.
The authors very reasonably suggested reducing the standard dose to be injected in these circumstances to 200 micrograms, to be repeated if necessary.
Ear, nose, throat
When used as a nasal decongestant, phenylephrine can cause local nasal irritation and even perforation of the anterior nasal septum.
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A 69-year-old woman developed perforation of the nasal septum after overuse of a common over-the-counter nasal spray containing phenylephrine [ ].
The authors attributed this effect to both vasoconstriction and physical irritation.
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