REVIEW ARTICLE CME The Clinical Implications of Isolated Alpha 1 Adrenergic Stimulation Robert H. Thiele, MD, Edward C. Nemergut, MD, and Carl Lynch III, MD, PhD Phenylephrine is a direct-acting, predominantly  1 adrenergic receptor agonist used by anesthesiologists and intensivists to treat hypotension. A variety of physiologic studies suggest that -agonists increase cardiac afterload, reduce venous compliance, and reduce renal bloodflow. The effects on gastrointestinal and cerebral perfusion are controversial. To better understand the effects of phenylephrine in a variety of clinical settings, we screened 463 articles on the basis of PubMed searches of “methoxamine,” a long-acting  agonist, and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Phenylephrine has been studied as an antihypo- tensive drug in patients with severe aortic stenosis, as a treatment for decompensated tetralogy of Fallot and hypoxemia during 1-lung ventilation, as well as for the treatment of septic shock, traumatic brain injury, vasospasm status–postsubarachnoid hemorrhage, and hypotension during cesarean delivery. In specific instances (critical aortic stenosis, tetralogy of Fallot, hypotension during cesarean delivery) in which the regional effects of phenyleph- rine (e.g., decreased heart rate, favorable alterations in Q p :Q s ratio, improved fetal oxygen supply:demand ratio) outweigh its global effects (e.g., decreased cardiac output), phen- ylephrine may be a rational pharmacologic choice. In pathophysiologic states in which no regional advantages are gained by using an  1 agonist, alternative vasopressors should be sought. (Anesth Analg 2011;113:297–304) P henylephrine is a direct-acting, predominantly  1 - agonist that exerts mild ionotropic effects when administered at high concentrations. 1–3 It is 5 to 10 times more potent 4,5 and has a 3-fold higher maximum attainable response 4 than its less-titratable, longer-acting analog, methoxamine. We reviewed the physiologic effects of phenylephrine in a companion paper. 6 Patented in 1934, with clinical reports of its use begin- ning in 1949, 7 phenylephrine is widely used in the practice of anesthesia (most commonly for the treatment of hypo- tension). But why, some 6 decades after its use was documented in humans, did we choose to review the clinical data supporting the use of this drug? First, because we find ourselves in the midst of a move- ment towards “goal-directed therapy,” 8 the use of a drug whose primary mechanism of action is an increase in afterload warrants further investigation and contemplation. Second, because much of medical lore was developed in the prestatistical era, there is growing consensus that much of what is considered “standard of care” needs to be formally evaluated by current standards of statistical rigor. 9 One can reasonably argue that the data supporting the use of phenylephrine, which were first synthesized (and subsequently adopted) decades before the biostatisti- cal era, should be reexamined. Thus, we critically examine the use of phenylephrine. Our initial search was conducted using the word phenyl- ephrine in PubMed, limiting ourselves to randomized, con- trolled, human trials published in English. This resulted in 435 articles, the abstracts of which were reviewed for relevance. Articles that reported clinical outcomes (or im- portant physiologic variables) in humans were included in this review. Relevant references discovered during our initial search and readings were also examined, and in some instances included, as were those brought to our attention in the peer-review process. PHYSIOLOGIC EFFECTS OF PHENYLEPHRINE The physiologic effects of phenylephrine (and its long- acting analog, methoxamine) have been reviewed else- where. Briefly, both human and animal studies offer conflicting data on changes in myocardial perfusion associated with these pure  1 -agonists. 10 –15 Clearly,  1 - agonists increase both left 16 –21 and right 22 heart afterload in humans. Animal studies 1,23–25 and some human studies 26,27 suggest that  1 -agonists decrease venous compliance and have the potential to increase venous return, at least temporarily, although the impact on cardiac output is controversial. 28 The effect of phenylephrine on cerebral bloodflow is also controversial. 29 –36 Animal studies suggest that pure  1 - agonists decrease bloodflow to the kidneys, 15,37,38 and although no human studies have evaluated the effect of phenylephrine on renal bloodflow specifically, there is at From the Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia. Accepted for publication January 17, 2011. Funding: Departmental. The authors declare no conflict of interest. Recuse Note: Edward C. Nemergut is Section Editor of Graduate Medical Education and Transplantation Anesthesiology for the Journal. This manu- script was handled by Jukka Takala, former Section Editor of Critical Care, Trauma, and Resuscitation, and Dr. Nemergut was not involved in any way with the editorial process or decision. Address correspondence to Robert H. Thiele, MD, Department of Anesthe- siology, University of Virginia Health System, P.O. Box 800710, Charlottes- ville, VA 22908. Address e-mail to rht7w@virginia.edu. Copyright © 2011 International Anesthesia Research Society DOI: 10.1213/ANE.0b013e3182120ca5 August 2011 • Volume 113 • Number 2 www.anesthesia-analgesia.org 297