Hypotension during spinal anesthesia for cesarean delivery should be minimized, both for maternal safety and comfort, and fetal wellbeing. Traditional teaching is that aortocaval compression predisposes the parturient to decreased venous return and hence cardiac output and blood pressure during spinal anesthesia for cesarean delivery. However, a variety of measures to improve venous return, including lateral tilt and numerous fluid administration regimens, have failed to eliminate hypotension.1 Recent studies focusing on the arterial circulation as a source for hypotension suggest that in the fluid-replete parturient undergoing elective cesarean delivery, moderate spinal hypotension (20% decrease from baseline) primarily reflects decreased systemic vascular resistance.2 – 4 In most cases, venous return is initially maintained and consequently there is a partial compensatory increase in cardiac output, mediated by an increase in stroke volume and heart rate. In this situation, the rapidly acting α-agonist phenylephrine seems to be the best option to restore baseline hemodynamics rapidly. Although ephedrine has traditionally been used to treat spinal anesthesia–induced hypotension, recent evidence suggests that ephedrine causes neonatal acidosis, and large doses may be harmful in a compromised fetus, by increasing oxygen demand and anaerobic metabolism.5,6 Ephedrine is also associated with a higher incidence of nausea and vomiting than phenylephrine.
The dose and method of administration of phenylephrine have been the subject of extensive investigation.7 – 12 In this issue of Anesthesia & Analgesia, 2 articles address this subject. First, Allen et al.13 compared placebo with the use of 4 different infusion rates of phenylephrine, in combination with a crystalloid coload, and assessed “hemodynamic stability” by heart rate and blood pressure. The aim was to maintain blood pressure within 20% of baseline values. They demonstrated that infusing phenylephrine at a fixed rate of 75 or 100 μg/min is associated with more episodes of hypertension than placebo, or the lower infusion rates of 25 or 50 μg/min, respectively. Seven patients in the group receiving 100 μg/min developed sinus bradycardia and were given glycopyrrolate. It may be more appropriate to treat baroreceptor-mediated bradycardia associated with a well-maintained blood pressure by discontinuing the infusion than by the administration of an anticholinergic. This would avert the reactive hypertension reported by the authors. This work suggests that to reduce hypotension and avoid hypertension and bradycardia, slower infusion rates of phenylephrine are a better starting point, with supplementary boluses as necessary, in keeping with the pharmacokinetic principle of the use of a bolus followed by an infusion to increase steady-state concentrations. Alternatively, the authors speculate, varying infusion rates could be used. The fact that some patients experienced bradycardia and hypertension even at the slower infusion rates suggests that bolus administration of phenylephrine, titrated as required in the individual case, may be a better option than prophylactic infusions.
In the second important contribution, Stewart et al.,14 using a suprasternal Doppler flow technique, described cardiac output changes associated with infusions of 25, 50, and 100 μg/min phenylephrine, respectively, after the administration of a rapid crystalloid preload, during spinal anesthesia for elective cesarean delivery. The aim was to maintain baseline blood pressure. The infusion of phenylephrine at 100 μg/min for 20 minutes was associated with a reduction in heart rate from 80 to 58 bpm and a reduction in cardiac output from 5.1 to 4.0 L/min. Neonatal outcomes were similar among groups. This is in agreement with a recent investigation of the hemodynamic effects of boluses of ephedrine and phenylephrine using pulse power analysis. Bolus administration of phenylephrine in response to hypotension (20% decrease from baseline blood pressure) was shown to reduce maternal cardiac output to close to baseline values (an effect strongly correlated with maternal heart rate) and restore blood pressure.2
In the non-obstetric population, phenylephrine (1:20,000) added to epidural lidocaine,15 and IV methoxamine administered during spinal anesthesia,16 have been shown to reduce cardiac output. The studies published in this issue examining the effects of phenylephrine infusions during spinal anesthesia for cesarean delivery suggest that the use of phenylephrine in doses that cause hypertension and sinus bradycardia is inappropriate.
How does phenylephrine influence cardiac output? The effect of α-agonists on venous return is controversial.17 It is likely that low doses of phenylephrine increase venous return, and thus cardiac output, by causing some degree of increase in splanchnic venous tone,18 particularly in the parturient at term, with her expanded blood volume. By contrast, high doses of phenylephrine cause a baroreceptor-mediated reduction in heart rate and dilation of splanchnic veins and a shift of blood into the splanchnic vasculature with a decrease in venous return.19 Although the indirect baroreceptor reflex-mediated sympathetic effects on the splanchnic circulation are blocked under spinal anesthesia, the heart rate- and direct receptor-mediated effects of high-dose phenylephrine persist. The latter may cause a significant increase in splanchnic arterial resistance, resulting in a decrease in splanchnic blood flow.20 Hepatic vein resistance may also be increased. Both effects would reduce venous return. It was interesting that Stewart et al. noted that larger doses of phenylephrine were required to maintain equivalent control of the blood pressure when the infusion rate was 100 μg/min. This would be in keeping with a dose-related decrease in venous return. Because the Corrected Flow Time Index is a measure of ventricular filling, the suprasternal Doppler flow technique, which incorporates this technology, could be used in future research to study a surrogate marker of cardiac filling and hence changes in venous return.
High-dose phenylephrine may also reduce cardiac output by decreasing stroke volume. Stroke volume may decrease in response to a marked increase in systemic vascular resistance and afterload. This decrease in stroke volume was not shown in the study by Stewart et al., because the effect is best demonstrated after bolus administration, using beat-by-beat measurements.2 A compensatory increase in stroke volume may occur via the Anrep effect,2,21 postulated to be the recovery from subendocardial ischemia induced by the increase in afterload, and subsequent correction by autoregulation of the coronary vascular bed.22 This effect would be undesirable if there is either coronary artery disease or ventricular dysfunction.
Animal studies have shown that under normal physiological conditions, uterine blood flow is higher than required for fetal oxygen demand,23 thus conferring a margin of safety under conditions of rapid changes in uterine flow. This could explain the lack of neonatal acidosis observed during the administration of large doses of phenylephrine, even in the face of decreases in cardiac output.7 – 9 However, as Stewart et al. rightly pointed out, significant reductions in maternal cardiac output could have deleterious effects on the outcome of a compromised fetus.14
In the absence of cardiac output monitoring in everyday practice, heart rate is a good surrogate marker of cardiac output. Usually, the initial response to spinal anesthesia for elective cesarean delivery is an increase in heart rate and a well-maintained or increased cardiac output.2,4 In this situation, restoring the heart rate to the baseline value using phenylephrine in conjunction with a rapid fluid coload should be the primary goal. Because a small proportion of patients respond to spinal anesthesia with hypotension and bradycardia,24 which usually reflects a decrease in cardiac output, anticholinergics and ephedrine (and occasionally epinephrine) do have a role to play, together with increasing lateral tilt and fluid administration.
The primary goal should thus be the maintenance of the baseline heart rate. In many cases, this can be achieved by simply using boluses of phenylephrine.25 Alternatively, variable rate infusions may be used, with supplementary boluses of phenylephrine (either administered as prophylaxis or in response to modest hypotension). These interventions will correct blood pressure and cardiac output simultaneously, and maintain the baseline resting physiological hemodynamics. This, after all, is what we are supposed to do as anesthesiologists.
Further research should explore the exact dose-related effects of phenylephrine on venous return in the term parturient. This would enable the anesthesiologist to fine-tune what is now a well-understood clinical scenario. The more difficult issue of establishing predictors for the rarer presentation of acute bradycardia and hypotension is far from resolved and requires further investigation.26
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