Compendium of the most significant studies with reference to properties, intake, effects.

Kumar V, Schoenwald RD, Chien DS, Packer AJ, Choi WW. Systemic absorption and cardiovascular effects of phenylephrine eyedrops. Am J Ophthalmol. 1985 Feb 15;99(2):180-4. doi: 10.1016/0002-9394(85)90229-6.

Abstract. We studied 24 patients undergoing vitreoretinal surgery to compare the systemic absorption and cardiovascular effects of 2.5% aqueous and 10% viscous ophthalmic solutions of phenylephrine hydrochloride. Plasma levels measured in patients receiving two drops of 10% viscous solution were consistently higher ten, 20, and 60 minutes after instillation (P less than .02). Although the mean systolic and diastolic blood pressure was generally higher with the 10% viscous solution, the difference was not statistically significant. Blood pressure was high in several isolated cases. Because maximum plasma levels are achieved within ten to 20 minutes after topical instillation, phenylephrine eyedrops should be administered under close observation so that if an adverse reaction occurs it can be readily treated.

Atkinson HC, Potts AL, Anderson BJ. Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review. Eur J Clin Pharmacol. 2015 Aug;71(8):931-8. doi: 10.1007/s00228-015-1876-1. 

Abstract. Background: Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects. Methods: MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol. Results: There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg). Conclusions: Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.

Ro Y, Huh J, Min S, Han S, Hwang J, Yang S, Kim DK, Kim C. Phenylephrine attenuates intra-operative hypothermia during spinal anaesthesia. J Int Med Res. 2009 Nov-Dec;37(6):1701-8. doi: 10.1177/147323000903700605. 

Abstract. Inadvertent hypothermia is common during spinal anaesthesia. This study was based on the hypothesis that phenylephrine might attenuate core hypothermia by inhibiting core-to-peripheral redistribution of body heat during spinal anaesthesia. In this prospective randomized study, 20 patients who underwent elective orthopaedic surgery under spinal anaesthesia were randomly assigned to receive either normal saline (control group) or continuously-infused phenylephrine 0.5 microg/kg per min (phenylephrine group). Core temperature, heart rate (HR) and mean arterial pressure (MAP) were monitored. Mean +/- SE core temperature at the end of surgery was significantly higher in the phenylephrine-treated group compared with the control group (35.9 +/- 0.1 degrees C versus 35.0 +/- 0.1 degrees C, respectively), although there was no significant difference in baseline core temperature (both groups 36.3 +/- 0.1 degrees C). Mean HR and MAP were not significantly different between the two groups. In conclusion, continuously-infused phenylephrine attenuated core hypothermia during spinal anaesthesia without any haemodynamic complications.

Antonopoulos A, Nikolopoulos D, Georgiou EK, Kyriakidis M, Proukakis C. Blood pressure elevation after phenylephrine infusion may adversely affect myocardial perfusion in patients with coronary artery disease. Int J Cardiol. 2002 Aug;84(2-3):201-9. doi: 10.1016/s0167-5273(02)00146-8.

Abstract. Background: Although blood pressure is a major determinant of myocardial oxygen-demand, little information is currently available regarding the changes in blood pressure (BP) during myocardial ischemia. Since BP elevation may cause left ventricular (LV) wall stress and an increase in oxygen demand, infusion of an alpha-adrenergic agonist, such as phenylephrine (PH), may provoke changes in myocardial perfusion in coronary artery disease (CAD) patients. As the effects of BP changes alone on myocardial perfusion have never been assessed by thallium-201 (Tl) scintigraphy, we investigated the effects of BP elevation after PH infusion, in order to study the hypothesis that pressure loading alone without increases in heart rate, may provoke transient impairment of regional myocardial perfusion, in CAD patients. Patients and methods: Forty-one (41) patients with angiographically documented CAD, aged 54+/-8 years, were included in our study. Each patient was given, without any complications, a PH (0.1 mg/ml) dose infused at a rate of 0.8 ml/mm, determined by a standardisation procedure and producing a mean blood pressure elevation of approximately 30% above baseline levels and a heart rate response to levels of no less than 50 bpm. One minute after the desired blood pressure and heart rate responses were reached, 2 mCi of Tl were injected and the PH infusion continued until the termination of the test. Tl scintigraphy was performed both 2 min after Tl injection and 4 h later, while the results were correlated to coronary angiography findings.  Results: PH scintigraphy produced 152 total defects. The mean perfusion defect size (%) was 14+/-12 and was directly related to the number of diseased vessels, i.e., 2% for one-vessel disease, 15% for two-vessel disease and 25% for three-vessel disease (P<0.05). The lowest percentage Tl activity values were 56+/-14 and were inversely related to the number of diseased vessels (P<0.01). The mean Tl lung counts/pixel values were 25+/-8 while it increased as the number of diseased vessels increased (P<0.01). The mean lung/heart ratio values were 0.31+/-0.08 while it increased as the number of diseased vessels increased (P<0.01).  Conclusion: BP elevation after PH loading, produces a significant impairment of myocardial perfusion, that correlates well with the extend of angiographic findings.

Kalmar AF, Allaert S, Pletinckx P, Maes JW, Heerman J, Vos JJ, Struys MMRF, Scheeren TWL. Phenylephrine increases cardiac output by raising cardiac preload in patients with anesthesia induced hypotension. J Clin Monit Comput. 2018 Dec;32(6):969-976. doi: 10.1007/s10877-018-0126-3.

Abstract. Induction of general anesthesia frequently induces arterial hypotension, which is often treated with a vasopressor, such as phenylephrine. As a pure α-agonist, phenylephrine is conventionally considered to solely induce arterial vasoconstriction and thus increase cardiac afterload but not cardiac preload. In specific circumstances, however, phenylephrine may also contribute to an increase in venous return and thus cardiac output (CO). The aim of this study is to describe the initial time course of the effects of phenylephrine on various hemodynamic variables and to evaluate the ability of advanced hemodynamic monitoring to quantify these changes through different hemodynamic variables. In 24 patients, after induction of anesthesia, during the period before surgical stimulus, phenylephrine 2 µg kg-1 was administered when the MAP dropped below 80% of the awake state baseline value for > 3 min. The mean arterial blood pressure (MAP), heart rate (HR), end-tidal CO2 (EtCO2), central venous pressure (CVP), stroke volume (SV), CO, pulse pressure variation (PPV), stroke volume variation (SVV) and systemic vascular resistance (SVR) were recorded continuously. The values at the moment before administration of phenylephrine and 5(T5) and 10(T10) min thereafter were compared. After phenylephrine, the mean(SD) MAP, SV, CO, CVP and EtCO2 increased by 34(13) mmHg, 11(9) mL, 1.02(0.74) L min-1, 3(2.6) mmHg and 4.0(1.6) mmHg at T5 respectively, while both dynamic preload variables decreased: PPV dropped from 20% at baseline to 9% at T5 and to 13% at T10 and SVV from 19 to 11 and 14%, respectively. Initially, the increase in MAP was perfectly aligned with the increase in SVR, until 150 s after the initial increase in MAP, when both curves started to dissociate. The dissociation of the evolution of MAP and SVR, together with the changes in PPV, CVP, EtCO2 and CO indicate that in patients with anesthesia-induced hypotension, phenylephrine increases the CO by virtue of an increase in cardiac preload.

Guthrie S, Jensen T, Hartley RC, Ramaesh K, Lockington D. Assessing the accuracy of intracameral phenylephrine preparation in cataract surgery. Eye (Lond). 2018 Oct;32(10):1615-1620. doi: 10.1038/s41433-018-0143-y. 

Abstract. Purpose: Unpreserved phenylephrine is often used as an off-licence intracameral surgical adjunct during cataract surgery to assist with pupil dilation and/or stabilise the iris in floppy iris syndrome. It can be delivered as a neat 0.2 ml bolus of either 2.5 or 10% strength, or in a range of ad-hoc dilutions. We wished to assess the accuracy of intracameral phenylephrine preparation in clinical practice. Methods: Phenylephrine 0.2 ml was analysed both neat (2.5 and 10%) and in diluted form (ratio of 1:1 and 1:3). Samples were analysed using the validated spectrophotometric method. Results: A total of 36 samples were analysed. The standard curve showed linearity for phenylephrine (R2 = 0.99). Wide variability was observed across all dilution groups. There was evidence of significant differences in the percentage deviations from intended results between dilutions (p < 0.001). Mean percentage deviation for 1:3 dilution was significantly greater than neat (p = 0.003) and 1:1 dilution (p = 0.001). There was no evidence of a significant difference between 1:1 and neat (p = 0.827). Conclusions: Current ad-hoc dilution methods used to prepare intracameral phenylephrine are inaccurate and highly variable. Small volume 1 ml syringes should not be used for mixing or dilution of drug. Commercial intracameral phenylephrine products would address dosage concerns and could improve surgical outcomes in cases of poor pupil dilation and/or floppy iris syndrome.