ICU Physiology in 1000 Words: Phenylephrine Pushes & Stroke Volume
About a decade ago, a handful of terrific reviews and investigations about phenylephrine – an alpha1 agonist – were published [1-3]. While this vasoactive medication might be thought only to ‘increase afterload,’ phenylephrine’s hemodynamic effects are knotty and noteworthy. Therefore, this dedicated dispatch delineates the difficulties encountered when predicting the hemodynamics of a phenylephrine bolus; that is, this piece takes no position on phenylephrine infusions . To focus matters, the hemodynamic variable under consideration is the stroke volume [SV]; in other words, how does a push of phenylephrine affect SV? Briefly and expectedly, the answer is that ‘it depends.’
Diminished stroke volume?
In 2011, Meng and colleagues evaluated the effects of phenylephrine [100 – 200 mcg] and ephedrine [5 – 20 mg] boluses on cardiac output and cerebral oxygenation during post-induction hypotension ; esophageal Doppler was used to measure blood flow. Notably, they observed that while phenylephrine rectified hypotension, it significantly reduced heart rate [HR], SV – and, therefore, total cardiac output [CO] – as well as cerebral oxygenation [SctO2]. By contrast, ephedrine also effectively treated hypotension, but preserved HR, SV, CO and SctO2. No mechanistic details are offered as to why SV fell significantly; the authors were more interested in the relationship between global [i.e., CO] and regional [i.e., SctO2] blood flow. Might phenylephrine’s SV-depressant effect be due to increased afterload? Or could a push of phenylephrine, perchance, depress preload [6, 7]?
A lesser-known investigation from nearly 40 years ago offers one explanatory model. Yamazaki et al. evaluated phenylephrine in 7 critically-ill patients with ‘hyperdynamic’ sepsis [defined as sepsis with CO above 6.0 litres/minute] and 8 critically-ill ‘cardiac’ patients [5 of whom had pulmonary edema] . In the former group, stroke index [i.e., SV] increased significantly, while in the latter group, stroke index fell in response to phenylephrine. The authors postulated [see their figure 4], that while phenylephrine increases preload in both groups – by recruiting unstressed venous blood – this would raise SV only in the hyperdynamic, septic group because of Frank-Starling reserve. By contrast, in the ‘cardiac’ group, with exhausted reserve, the afterload augmenting effect of phenylephrine would predominate and depress SV [1, 8].
Preload reserve is predictive
In a truly elegant porcine study, Cannesson et al. evaluated the hypothesis initially put forth by Yamazaki and colleagues . In their experimental set-up, Cannesson and colleagues investigated the effect of phenylephrine boluses [0.5-to-4.0 mcg/kg] on SV when the heart was ‘preload dependent’ [i.e., ascending portion of the Starling curve] and when the heart was ‘preload independent’ [i.e., flat portion of the Starling curve]. In the former group, phenylephrine increased SV and this rise was preceded, temporally, by enhanced flow through the inferior vena cava – suggesting recruited venous blood, as Yamazaki and colleagues postulated. On the other hand, in the ‘preload independent’ state, phenylephrine boluses decreased SV and this fall was followed, temporally, by diminished flow through the inferior vena cava – suggesting that afterload impaired left ventricular output and this was then transmitted backwards to the venous system, again as hypothesized by Yamazaki et al. In all instances, pulse pressure variation [PPV] fell in response to phenylephrine, implying that cardiac preload was enhanced by phenylephrine. Additionally, elevated PPV at baseline [i.e., more than 16%] predicted whether or not SV would rise following phenylephrine bolus. This observation makes sense because high PPV predicts when the heart is ‘preload dependent’ and therefore amenable to increased venous return.
In response to Cannesson’s study, Sondergaard and Moller  suggest that reduced SV in the ‘preload independent’ state is not a consequence of systemic afterload augmentation by phenylephrine, but rather pulmonary vasoconstriction – which increases right heart preload, but decreases left heart preload. While this hypothesis is a worthy explanation and accounts for both decreased SV and PPV, it isn’t borne out by other observations. If diminished pulmonary venous return and left ventricular preload are the primary drivers of SV reduction, then one expects left ventricular end-diastolic volume to fall. Yet in both cardiac surgery patients  and patients without cardiovascular disease  given a phenylephrine bolus [1.0-to-2.0 mcg/kg] and monitored with trans-esophageal echocardiography, end-diastolic area did not fall, while end-systolic area significantly increased – suggesting increased afterload as the cause of diminished SV. Additionally, McKay and colleagues  report a left ventricular pressure-volume loop in a normal individual given phenylephrine – revealing diminished SV with increased end-diastolic and end-systolic volumes, observations inconsistent with diminished LV preload, but consistent with elevated afterload.
Subsequently, Rebet and colleagues studied the effect of phenylephrine boluses [50-to-150 mcg] on preload ‘dependent’ and ‘independent’ patients . Consistent with Cannesson et al. above, preload ‘independent’ patients [defined as having a PPV less than 13%] significantly reduced SV and corrected flow time – measured by esophageal Doppler – following phenylephrine bolus. By contrast, preload ‘dependent’ patients had an upward trend in SV and a significant rise in corrected flow time. Notably, the SV increase was not statistically significant despite PPV falling from 17% to 14% following phenylephrine. While suggested that this may have been an SV measurement inaccuracy , another possibility is that these patients were not that preload dependent at baseline. In the porcine study above, the average PPV in the preload dependent state was at least 44%, as compared to 17% noted by Rebet et al. Further, in a later study comprised entirely of preload ‘dependent’ humans, Kalmar et al. did observe a significant increase in SV following phenylephrine bolus [2.0 mcg/kg] . In Kalmar’s investigation, the patients were preload dependent as a consequence of general anesthesia, epidural analgesia and leg-down positioning for sigmoidectomy. Accordingly, the baseline PPV was 20%, suggesting greater preload dependency prior to phenylephrine administration.
The effect of a phenylephrine bolus on stroke volume likely depends on the functional state of the heart. If the Frank-Starling, or Sarnoff, cardiac function curve is flattened and the patient is preload ‘independent,’ then phenylephrine bolus is likely to decrease SV, ostensibly because of afterload augmentation. By contrast, if the cardiac function curve is steep and the patient is preload ‘dependent’ then any venous blood recruitment by alpha-agonism is more likely to increase SV.
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