Phenylephrine is a direct-acting, predominantly α1-agonist that exerts mild ionotropic effects when administered at high concentrations.1–3 It is 5 to 10 times more potent4,5 and has a 3-fold higher maximum attainable response4 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 beginning in 1949,7 phenylephrine is widely used in the practice of anesthesia (most commonly for the treatment of hypotension). 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 movement 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 biostatistical era, should be reexamined.
Thus, we critically examine the use of phenylephrine. Our initial search was conducted using the word phenylephrine in PubMed, limiting ourselves to randomized, controlled, human trials published in English. This resulted in 435 articles, the abstracts of which were reviewed for relevance. Articles that reported clinical outcomes (or important 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 elsewhere. Briefly, both human and animal studies offer conflicting data on changes in myocardial perfusion associated with these pure α1-agonists.10–15 Clearly, α1-agonists increase both left16–21 and right22 heart afterload in humans. Animal studies1,23–25 and some human studies26,27 suggest that α1-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 α1-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 least 1 case report of renal failure after phenylephrine administration in a human.39 Multiple human studies suggest that α1-agonism adversely affects bloodflow to the gastrointestinal tract.27,40
APPROACH TO VASOPRESSOR USE
Given the wide-ranging effects of α1-agonism, it seems reasonable to further explore the use of a drug whose primary effect in healthy patients is to increase afterload, which subsequently leads to increased arterial blood pressure, decreased heart rate, and decreased cardiac output. Several important points must be kept in mind, however.
First, the hemodynamic effects of various drugs in the setting of tightly controlled animal or healthy volunteer experiments may be different than those that occur in real-life clinical scenarios (e.g., vasoplegia after cardiopulmonary bypass). Thus, while the information gleaned from animal or healthy human experiments accurately reflects the particular situation(s) in which it was acquired, one must take care not to overextrapolate these data to clinically compromised patients who may not reflect experimental studies.
Second, in patients who require vasopressor support, afterload is just one part of a complex network of physiologic forces at work. In trying to pharmacologically manipulate an individual patient's hemodynamics, each practitioner must consider the additional effects of preload and contractility, the interplay between the left and right ventricles, the effects of drugs on the pulmonary vasculature, effects on individual organ bloodflow, and the concept of “reserve” (namely, that organs that cannot tolerate any additional decrease on oxygen delivery (DO2) should be favored over organs that can). Further complicating rational hemodynamic management is the evidence that various end-organs respond to the same drugs differently, that an individual's medical history may profoundly affect his or her response to various drugs, that drugs do not act in isolation, and that organ systems vary with respect to ease of monitoring (the heart being one of the easiest and most practical organs to monitor, on a real-time basis, for injury, the brain being one of the most difficult).
Last, and most important, is the rationale for vasopressor use. Vasopressors, and all drugs that affect hemodynamics, should be used when their effects, at the given dose, are expected to confer some clinical advantage to end-organs of interest. For vasopressors, this means increasing the delivery of oxygen to hypoxic end-organs, presumably by increasing blood pressure.
In certain physiologic states it may be advantageous to sacrifice global cardiac output if, in doing so, a particular drug will increase DO2 to an organ system that has very little reserve and is relatively resistant to the decreases in global bloodflow thought to accompany administration of said drug (e.g., use of phenylephrine to maintain coronary perfusion pressure (CPP) in severe aortic stenosis). To determine whether the drug of interest is truly beneficial, one must carefully consider the interaction of the physiologic variables mentioned above.
These variables and their interactions are so complex that it may be difficult to extrapolate from experimental studies. Keeping the above in mind, we sought to identify studies conducted on the use of phenylephrine (or, when data were not available, other vasopressors with α1-activity) in a variety of clinical situations in which critically ill or physiologically compromised patients have been studied.
In 1989, Charlson et al. studied the impact of intraoperative hemodynamics on the risk of death, myocardial infarction, or myocardial ischemia in a population of 254 hypertensive patients undergoing noncardiac surgery. In this particular study, hypotension and hypertension were defined as mean arterial blood pressure (MAP) changes of −20 or 20 mm Hg incomparison with a preoperative baseline, respectively. In patients who were hypotensive for 60 minutes or more, ischemic complications (including electrocardiogram changes or increases in myocardial enzymes consistent with myocardial infarction, cardiac arrest, or cardiac death) were increased by 19% (P = 0.03). In those who were hypotensive for 5 to 59 minutes, ischemic complications occurred only when in conjunction with 15 minutes or more of hypertension, i.e., in the face of significant hemodynamic instability (20% increase in ischemic complications, P = 0.02).41
Thirteen years later, Reich et al. examined the relationship between low MAP (defined as MAP <55 mm Hg) and negative surgical outcome (NSO, defined as death or postoperative length of stay >10 days with a morbid condition) on 797 patients undergoing noncardiac surgery. In patients with a Physiological and Operative Severity Score for the enUmeration of Mortality (POSSUM) score of <24, there was a trend towards an increased incidence of NSO in patients for whom a MAP of <55 mm Hg occurred intraoperatively (94%, 70%, and 39% increases in NSO for POSSUM <16, POSSUM 16 to 18, and POSSUM 19 to 23, respectively, P = 0. 34).42 In neither of these 2 studies was the treatment of hypotension considered.
In 2009, however, Saager et al. examined the impact of multiple hemodynamic and anesthetic variables, as well as their treatment, on the mortality of 23,999 noncardiac surgical patients. Isolated hypotension (defined as MAP <75 mm Hg) was not predictive of increased mortality, but the combination of hypotension and mean alveolar concentration (MAC) of anesthetic <0.7 was highly predictive of mortality (relative risk of 1 year mortality 1.75, P < 0.005). “Triple low” patients (defined as those who were hypotensive on average, had an average MAC <0.7, and an average bispectral index score <45) had the worst outcomes (relative risk of 1 year mortality 1.89, P < 0.005). Perhaps most interesting of all, of the 19,402 patients who did not experience a triple low event, 6464 (33.3%) were given a vasoactive drug (most commonly phenylephrine) at some point during surgery, and in these presumably prophylactically treated patients, the relative risk of mortality at 1 year was reduced (relative risk 0.77, P < 0.01) in comparison with the 12,938 nontriple low patients not treated with any vasoactive drugs.43
The above data suggest that intraoperative hypotension is associated with increased morbidity and mortality. Furthermore, the work by Saager et al. suggests that the treatment of hypotension (most commonly with phenylephrine) may confer a mortality benefit; however, it is important to note that none of these studies is prospective. Thus, although there is clearly an association between intraoperative hypotension and poor outcome, the efficacy of any intervention cannot be answered definitively outside of the context of a prospective trial.
Phenylephrine is commonly recommended as the most appropriate first-line treatment for hypotension in the patient with aortic stenosis.44 The rationale is 3-fold: (a) if left ventricular (LV) afterload is relatively fixed by the stenotic valve, increasing peripheral vascular resistance will have less of an effect on myocardial work than it would on an “unloaded” left ventricle; (b) increases in diastolic blood pressure will presumably increase CPP, and thus myocardial DO2; and (c) reflexive bradycardia reduces myocardial consumption of oxygen (VO2).
In 1977, Awan et al. administered phenylephrine (average dose 3 μcg/min) to 10 patients with critical aortic stenosis (valve area <0.4 cm2, average gradient 69 mm Hg), and measured their hemodynamic changes both before and after the infusion.45 As was expected, diastolic blood pressure increased from 59 to 74 mm Hg (P < 0.01), and heart rate trended downwards, from 72 beats per minute (bpm) to 67 bpm (P = ns). Cardiac index trended downwards, from 3.03 to 2.56 L/min/m2 (P = ns).
Interestingly, LV end diastolic pressure increased from 16 to 22 mm Hg (P < 0.05); however, as diastolic pressure increased substantially, CPP still improved (average increase of 9 mm Hg). One can reasonably conclude that myocardial DO2 was also improved; however, the impact on myocardial VO2 is more complicated.
LV systolic pressures increased from 191 to 211 mm Hg (P < 0.01), but LV stroke work index (as was calculated by Snell and Luchsinger46) did not change (100 vs. 99 g/m2, P = ns). Systemic vascular resistance (SVR) increased from 1110 to 1549 dyne · s · cm−5 (P < 0.01). Importantly, myocardial function (as measured by both Vmax and dP/dt) was not impacted by administration of phenylephrine. Importantly, constant stroke work in the setting of a downward trend in heart rate implies that mVO2 was likely reduced.
The authors concluded that “an acute rise in systemic vascular resistance accompanied by a rise in arterial blood pressure imposes a substantial burden on left ventricular function despite the presence of critical obstruction to aortic outflow,” [italics added]45 the implication being that SVR contributes to afterload in the setting of severe aortic stenosis.
This conclusion, however, makes the mistake of assuming that SVR is an accurate measure of afterload, which it is not.21 SVR is a calculated number, based on measured values of MAP and cardiac output, but afterload is a measure of the wall stress required to generate pump work. Thus, although SVR may approximate afterload in patients with no obstructive lesions (and in which radial artery pressures are similar to LV pressures), in the setting of aortic stenosis, radial artery pressures do not correlate with LV pressures and SVR cannot be relied upon as a complete measure of afterload.
Indeed, in Awan et al.'s study, phenylephrine increased systolic blood pressure by 28 mm Hg even though LV end systolic pressure increased only by 20 mm Hg. Similarly, diastolic blood pressure increased 16 mm Hg, while LV end diastolic pressure increased by 8 mm Hg. By all accounts, these patients' hearts produced more distal (and coronary) perfusion at relatively lower cost (i.e., ventricular pressures did not increase as much as did postvalve pressures).
Sixteen years later, Goertz et al. conducted a randomized, cross-over study of 18 patients with aortic stenosis (mean gradient 95 mm Hg). Patients were given either phenylephrine (1 μcg/kg), followed by norepinephrine (0.05 μcg/kg) after induction of anesthesia, or vice versa,20 and were examined using transesophageal echocardiography after administration of each drug. As in Awan et al.'s study, phenylephrine administration led to increased systemic blood pressure (MAP increased from 71 to 80 mm Hg) and decreased heart rate (decreasing from 55 to 51 bpm). Cardiac function, as measured by changes in fractional area change and velocity of fiber shortening (Vcvc), were not affected by phenylephrine (fractional area change went from 0.51 to 0.52 [P = ns], and Vcvc was unchanged at 0.82 circ/s in both groups). Because catheterization data were not available, myocardial work could not be measured.
LV Outflow Tract Obstruction
Phenylephrine is often advocated for the treatment of hypotension in hypertrophic subaortic stenosis (HSS)44 because, just as in aortic stenosis, HSS patients have increased muscle mass (and thus myocardial VO2 requirements) as well as an (dynamic) outflow obstruction. Phenylephrine has also been successfully used to treat hemodynamic decompensation in the setting of systolic anterior wall motion (SAM) abnormalities.47,48 The dynamic nature of both of these outflow obstructions (HSS and SAM) is such that they worsen as ventricular volume decreases because of increased contractility, thus drugs that enhance contractility (such as epinephrine, norepinephrine, and ephedrine) should likely be avoided.48,49 Phenylephrine, which has been shown not to significantly enhance contractility in the face of a fixed aortic lesion20,45 is thus an ideal choice for the treatment of hypotension in the setting of HSS and SAM, although its effects on the left ventricle have not been specifically studied outside of the context of small case reports in either of these patient populations.
Tetralogy of Fallot
The vast majority of available human and animal data suggest that pure α1-agonists increase afterload and in doing so increase blood pressure and decrease cardiac output. Patients born with tetralogy of Fallot have a right-to-left shunt, and thus may potentially benefit from a drug that increases left heart afterload more than right heart afterload. Phenylephrine appears to have such an effect.
Nudel et al. studied the effect of phenylephrine on 6 cyanotic pediatric patients (6 months to 7 years of age) with tetralogy of Fallot by infusing phenylephrine until systolic blood pressure increased by 40 mm Hg, and measured the corresponding increase in the arterial PO2. The mean increase in PaO2 was 14 mm Hg (range 4 to 28 mm Hg). Measured right-to-left shunt decreased by an average of 25% (range 10%–40%).50
Some of the physiologic derangements found in acute respiratory distress syndrome (ARDS), which has a mortality rate in excess of 30%,51 include poor lung compliance, pulmonary hypotension, and profound hypoxemia,52 the latter of which is presumed to be due to significant intrapulmonary shunting.53 Thus, although much attention has been paid towards optimizing tidal volumes and plateau pressures,51 there may be a role for pharmacologic management of ARDS as a means of improving oxygenation.
Nitric oxide, which selectively vasodilates lung regions that are ventilated, has been shown to reduce pulmonary shunting and improve arterial oxygenation in patients with ARDS,54–56 although it has not been shown to improve outcomes. Similarly, selective pulmonary vasoconstrictors (such as almitrine bismesylate) have also been shown to reduce pulmonary shunting and improve arterial oxygenation in patients with ARDS.57,58
On the basis of promising animal data, Doering et al. treated 12 ARDS patients with phenylephrine (titrated to a 20% increase in MAP), nitric oxide (40 parts per million [ppm]), and a combination of phenylephrine and nitric oxide. They found that phenylephrine alone increased PaO2 from 94 mm Hg to 109 mm Hg (P < 0.05). Furthermore, adding phenylephrine and nitric oxide increased PaO2 from 104 mm Hg to 154 mm Hg (P < 0.05). Of note, though not directly compared in sequence, the combined group had a higher PaO2 (154 mm Hg) than did the nitric oxide–only group (140 mm Hg).53
Importantly, phenylephrine had no statistically significant impact on cardiac output in either group. That said, because the average starting PaO2 was >90 mm Hg in all groups, the addition of phenylephrine could not have improved DO2 in these patients, because hemoglobin saturation was by definition close to 100% prior to the interventions. Whether or not phenylephrine has the ability to improve arterial oxygenation and, more important, DO2 in ARDS patients with critically low PaO2 values is unknown. However, on the basis of Doering et al.'s data, and given the lack of data to suggest otherwise, phenylephrine merits consideration as a drug with the potential to enhance hypoxemic vasoconstriction in patients with ARDS.
Ever since Kosnik and Hunt reported the reversal of neurologic deficits in 7 subarachnoid hemorrhage (SAH) patients after the initiation of hypertension and hypervolemia,59 “triple-H” therapy (hypertension, hypervolemia, and hemodilution) has been a mainstay for the prevention of vasospasm in patients with SAH. A recent survey of European and North American neurointensivists revealed that the majority of practitioners believe that increases in MAP reverse vasospasm in the setting of SAH, and 40% report that they initiate triple-H therapy prophylactically.60 Importantly, phenylephrine is still used to induce the hypertensive component of triple-H therapy.61
Reviews of the evidence supporting triple-H therapy consistently conclude that it is inadequate.62–64 In fact, the only evidence that demonstrates the efficacy of hypervolemic therapy is based on 146 patients.65,66 The quantity (and quality) of available data on hypertensive therapy is even less impressive.
Early accounts supported the use of hypertensive therapy in SAH; however, all 3 case series were small, including 7,59 4,67 and 2 patients,68 respectively. Awad et al. examined triple-H therapy in a larger, uncontrolled study of 118 patients, but their conclusions (that triple-H therapy “may lower the incidence of death and disability from vasospasm after subarachnoid hemorrhage”) [italics added]69 are complicated by the lack of a control group, and multiple treatment variables. Joseph et al. studied 16 SAH patients, showing that phenylephrine can increase bloodflow to an area of vasospasm (19.2 to 33.7 mL per 100 g/min); however, the qualitative changes in posterior circulation subcortical bloodflow (not quantified in their paper, but visible on Xenon computed tomography images) are striking.34 Indeed, on the basis of the sum of available data, the use of phenylephrine cannot be recommended for the prevention or reversal of vasospasm in the setting of SAH.
Traumatic Brain Injury (TBI)
The optimal cerebral perfusion pressure in patients with brain injuries has not been determined; however, the Brain Trauma Foundation Guidelines recommend maintaining systolic blood pressures >90 mm Hg, but acknowledge that this number is relatively arbitrary and not based on any prospective, randomized, controlled studies (thus assigning it a designation of level II evidence).70 Because hypotension is such a poor prognostic variable, level I evidence is not forthcoming. Further complicating matters is the lack of agreement on how to increase blood pressure.71–74 Many of the drugs used to increase MAP have significant vasoconstrictive effects, which could counteract any increase in blood pressure and lead to unchanged, or even reduced cerebral bloodflow.
The commonly cited cerebral perfusion pressure goal of 70 mm Hg was derived from an uncontrolled study of 158 TBI patients treated with combinations of phenylephrine, norepinephrine, and “renal protective” dopamine to maintain cerebral perfusion pressure >70 mm Hg.75 A randomized trial of 189 comatose adults compared intracranial pressure (ICP)–directed therapy (ICP <20 mm Hg, cerebral perfusion pressure >50 mm Hg) with “cerebral perfusion pressure-directed therapy” (ICP <20 mm Hg, cerebral perfusion pressure >70 mm Hg). The cerebral perfusion pressure-directed patients were more likely to require vasopressors (dopamine in 80% vs. 45% of patients, phenylephrine in 29% vs. 8% of patients, P values not reported), but exhibited a higher incidence of ARDS with no improvement in neurologic outcome.76 Thus, the Brain Trauma Foundation Guidelines currently recommend maintaining cerebral perfusion pressure between 50 and 70 mm Hg. Although not based on any level I evidence, norepinephrine has been promoted as the vasopressor of choice when treating hypotension in the setting of neurologic injury.72,73
Morelli et al. replaced norepinephrine (average dose 0.82 μcg/kg/min) with phenylephrine (average dose 4.39 μcg/kg/min) in vasopressor-dependent septic shock patients and found a statistically significant reduction in creatinine clearance (94.3 vs. 81.3 mL/min, P < 0.05) and a statistically significant increase in arterial lactate (1.4 vs. 1.7 mM, P < 0.05) 8 hours after initiating the phenylephrine infusion.77 They subsequently compared phenylephrine with norepinephrine in a randomized, controlled trial of first-line therapy in septic patients and found a statistically insignificant trend towards higher urine output in the norepinephrine group.78
The Surviving Sepsis Guidelines recommend norepinephrine or dobutamine as first-line treatments for hypotension in septic shock (grade 1C recommendation) and suggest that epinephrine be used as a second-line drug.79 In defending their recommendation for early, goal-directed therapy (a component of which includes maintenance of MAP >65 mm Hg), the Guidelines cite 2 studies: a large, single-site study of 263 patients80 in which MAP was kept >65 mm Hg in both study groups (the major difference between the two being the maintenance of central venous oxygen saturation [SCVO2] >70%), and a single-site observational study of 111 patients.81
Given that it is impossible to separate MAP goals from other forms of intervention in the majority of the data on which the Surviving Sepsis Guidelines are based, and the fact that phenylephrine is neither a first- nor second-line recommendation, phenylephrine does not seem to have a place in the treatment of septic shock on the basis of clinical evidence or theoretical considerations.
Carcinoid tumors, particularly those of the midgut, produce serotonin (5-hydroxytryptamine) but may also secrete 5-hydroxytryptophan, adrenocorticotropic hormone, or both.82–84 Importantly, general anesthesia may precipitate a carcinoid crisis, leading to serotonin-mediated hypotension, bronchospasm, flushing, and arrhythmias. Catecholamines, which exacerbate serotonin release in this setting, have traditionally been contraindicated for the treatment of hypotension,83,84 and alternative treatment modalities—such as phenylephrine, octreotide, antihistamine, and hydrocortisone—should be considered.
Thus, for the treatment of nonserotonin-mediated hypotension, avoidance of catecholamines is prudent, and phenylephrine would appear to be a reasonable first-line choice, because it is less likely to stimulate serotonin release. In the setting of an actual serotonin crisis, however, phenylephrine (and epinephrine) have been shown to be ineffective in the absence of treatment with a somatostatin analog.83 Catecholamines have been shown to be effective for the treatment of nonserotonin-mediated hypotension when administered after pretreatment with octreotide.83
Historically, obstetric anesthesiologists avoided the use of phenylephrine for treatment of hypotension in pregnancy, because data from pregnant ewes suggested that α1-agonists could reduce uterine bloodflow.85 The hypotensive, pregnant patient adds an interesting layer of complexity to the question of vasopressor choice, because the practitioner must contend with the supply and demand of oxygen in 2 interacting but separate hemodynamic systems.
There is relatively little autoregulation of the uterine vascular system, a design that lends itself to maximal (but pressure dependent) DO2 to the placenta. Vasoconstriction of uterine vessels secondary to sympathetically active drugs (external regulation) is still possible. A review of 7 randomized controls comparing phenylephrine with ephedrine in 292 pregnant patients showed no difference in maternal hypotension, neonatal acidosis (defined as pH <7.2), or APGAR scores, but slightly lower neonatal pH values in women who received ephedrine (mean difference 0.03).86
Since the publication of Lee et al.'s article, several investigators have attempted to determine which antihypotensive drug is most appropriate in the pregnant patient. Cooper et al. compared phenylephrine, ephedrine, and various combinations of the two in a prospective, randomized, double-blind trial in 143 pregnant women; they found no difference in blood pressure between groups, a significant difference in heart rate (with ephedrine producing significantly more tachycardia), and most important, a 10-fold increase in the incidence of fetal acidosis (defined as an umbilical artery pH <7.20) in parturients treated with ephedrine. These data suggest that ephedrine produces a less-favorable fetal energetic profile, presumably by increasing the metabolic rate of the fetus. This was later confirmed by Khaw.87 Importantly, these differences in fetal pH led to no significant differences in clinical outcome, with no difference in APGARs at either 1 or 5 minutes.88
Ngan Kee et al. also conducted a prospective, randomized, double-blind trial comparing phenylephrine, ephedrine, and combinations of the 2 in 125 parturients undergoing spinal anesthesia. As in Cooper et al.'s study, Ngan Kee et al.'s study showed that increasing amounts of ephedrine led to decreases in fetal pH, base excess, and umbilical arterial oxygen content, but no difference in umbilical venous oxygen content, also suggesting that the predominant differences between phenylephrine and ephedrine are due to VO2, not DO2.89
As maternal hemodynamic changes between phenylephrine and ephedrine are, for all practical purposes, equivocal, fetal considerations should predominate. Phenylephrine, which by all available evidence seems to produce a more favorable oxygen supply:demand balance, should be favored over ephedrine in the setting of maternal hypotension.
Phenylephrine, a pure α1 adrenergic receptor agonist, reduces global cardiac output, significantly increases myocardial wall stress, and increases myocardial oxygen requirements in healthy patients. The combination of physiologic effects that occur after unopposed α1 adrenergic receptor stimulation are likely beneficial in the setting of critical aortic stenosis, decompensated tetralogy of Fallot, and hypotension during caesarean delivery. The use of phenylephrine in other settings in which blood pressures are commonly manipulated (e.g., SAH, TBI, septic shock) is not supported on the basis of any available human data. Retrospective data support the use of phenylephrine for the prophylactic treatment of intraoperative hypotension in noncardiac surgery; however, this practice must be tempered by the lack of prospective data and the knowledge that in all clinical settings, phenylephrine reduces cardiac output, and in most clinical settings has been shown to significantly increase LV afterload. Thus, only in instances in which its regional effects are thought to outweigh its global effects should phenylephrine be used for the treatment of hypotension.
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