Phenylephrine in Patients with Septic Shock

Phenylephrine

Phenylephrine is a potent alpha-adrenergic agonist that primarily acts on alpha-1 adrenergic receptors. By doing so, it causes vasoconstriction, which increases systemic vascular resistance, arterial blood pressure, and a decrease in heart rate and cardiac output.

Phenylephrine has a rapid onset of action and a relatively short duration of action, lasting up to 20 minutes. It is mainly metabolized by the liver and excreted in the urine.

Although phenylephrine has been used to control heart rate and reverse hemodynamic and metabolic abnormalities, its use may also have adverse effects. For instance, it may lead to splanchnic vasoconstriction, which can reduce blood flow to the gastrointestinal tract, potentially leading to ischemia and necrosis of the bowel [1]. Additionally, phenylephrine may cause a decrease in cerebral perfusion, leading to cerebral ischemia and neurological dysfunction [2].

Moreover, studies have suggested that phenylephrine may increase the mortality risk, especially in patients with septic shock or those undergoing surgery. Therefore, phenylephrine should be carefully considered, and its benefits and risks should be evaluated before administration [3].

The Rationale for Using Phenylephrine for Tachycardia​

Phenylephrine is a drug that was first suggested as an effective treatment of paroxysmal supraventricular tachycardia. However, it can cause short ventricular tachycardia, especially in patients with preexisting heart conditions. Although phenylephrine is generally considered safe for patients without heart disease, it is essential to exercise caution in patients with a history of or risk for ventricular arrhythmias. In these cases, alternative treatments should be considered [4].

In 1974, an article presented five cases of recurrent wide QRS complex tachycardia that could be terminated with phenylephrine. These cases met all the criteria for ventricular tachycardia, and carotid sinus massage with and without edrophonium hydrochloride did not affect the ventricular activity. However, phenylephrine was effective in terminating the tachycardia. The mechanism of action of phenylephrine in these cases is unclear.

This study has important implications. Firstly, phenylephrine may help terminate certain casesof ventricular tachycardia. Secondly, the termination of an unknown, regular, wide QRS complex tachycardia by phenylephrine and possibly other pressors can no longer be taken as proof of a supraventricular mechanism [5].

In 1982, A study evaluated the cardiac function in patients with hyperdynamic sepsis and heart disease through acute pressure loading with phenylephrine. The results showed that patients with hyperdynamic sepsis responded positively to phenylephrine, as a cardiac index and stroke index increased significantly, while the systemic vascular resistance index remained unchanged. However, patients with heart disease had a negative response, as the cardiac index and stroke index decreased significantly while the systemic vascular resistance index increased significantly. These findings suggest that patients with hyperdynamic sepsis do not have cardiac dysfunction [6].

Haiduc M, et al. 2021​

A newer study investigated whether switching septic shock patients with rapid atrial fibrillation from norepinephrine to phenylephrine would have a clinical effect on achieving rate control. The study included 67 patients, with 28 patients switched to phenylephrine. The unadjusted hazard ratio for achieving rate control was significant for the phenylephrine group, suggesting a potential clinical effect. However, the adjusted hazard ratio was insignificant, and there were no statistically significant differences in mortality or ICU length of stay between the two groups. The study suggests that switching to phenylephrine may have a potential clinical effect on achieving rate control in septic shock patients with rapid atrial fibrillation. However, further research is needed to determine if this strategy benefits mortality or length of stay outcomes in critically ill patients [7]. ​

Law et al. 2022

This study aimed to compare the effect of phenylephrine and norepinephrine initiation on heart rate among sepsis patients with atrial fibrillation (AF). The study included 1847 patients, with phenylephrine initiation associated with modestly lower heart rates compared to norepinephrine initiation at 1 and 6 hours after vasopressor administration. Patients who received phenylephrine showed a larger heart rate reduction if they had a higher heart rate before vasopressor administration. Secondary outcomes, such as conversion to sinus rhythm, bradycardia, vasopressor duration, ICU and hospital length of stay, and hospital death, did not differ between the two groups. The study suggests that phenylephrine initiation was associated with modestly lower heart rates in sepsis patients with AF, but further studies are needed to investigate if this reduction is associated with clinical outcomes [8].

Arishi H, et al. 2022​

This retrospective cohort study aimed to compare the outcomes of septic shock patients treated with norepinephrine with phenylephrine versus norepinephrine with vasopressin. The study included 158 patients treated with norepinephrine with phenylephrine and 129 with norepinephrine with vasopressin. The results showed no significant difference in in-hospital mortality, ICU length of stay, or hospital length of stay between the two groups. Multivariate analysis also showed no significant association of norepinephrine with phenylephrine with in-hospital mortality compared to norepinephrine with vasopressin. The study suggests that phenylephrine used as a second-line vasoactive agent combined with norepinephrine may be a reasonable option compared to vasopressin. Still, further randomized controlled trials are necessary to validate this finding [9].​

He, D et al. 2023​

The study aimed to evaluate the effect of combining phenylephrine (PE) with norepinephrine (NE) compared to NE alone on all-cause hospital mortality in patients with septic shock. The retrospective cohort study included 1,747 adult patients with septic shock, with 1,055 receiving NE alone and 692 receiving NE-PE.​

The results showed that NE-PE had a higher hospital mortality rate than NE alone. Patients in the NE-PE group had longer lengths of stay in ICU and hospitals and received mechanical ventilation for longer durations. ​

We need to consider that Patients in the NE-PE group had higher SOFA scores & heart rates at baseline, higher rate of arrhythmias history, and higher initial doses of pressors, which might contribute to mortality.

The study suggests that combining PE with NE may be inferior to NE alone in patients with septic shock, and further research is necessary to confirm these findings [10]​

Does Phenylephrine Increase Mortality in Septic Shock Patients? ​

During the national norepinephrine shortage, a study aimed to evaluate the impact of this shortage on patient care and outcomes in the United States. The retrospective cohort study included 27,835 adults admitted to 26 hospitals with septic shock between July 2008 and June 2013. During the norepinephrine shortage, its use declined, and phenylephrine was the most frequently used alternative vasopressor. Patients admitted to hospitals during quarters of norepinephrine shortage had a higher rate of in-hospital mortality than those admitted during quarters of normal use, with an absolute risk increase of 3.7%. The study suggests that drug shortages may significantly impact patient care and outcomes, and measures should be taken to address and prevent such scarcity in the future; moreover, the study raised a concern regarding the relation between increased phenylephrine use and mortality [11].

A former study compared the effects of first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock. The study enrolled 32 septic shock patients who were randomly allocated to receive either norepinephrine or phenylephrine infusion. The study found no differences in the investigated parameters between the two groups after 12 hours of treatment. The study concludes that the initial hemodynamic support with phenylephrine instead of norepinephrine in septic shock patients does not affect cardiopulmonary performance, global oxygen transport, and regional hemodynamics. Moreover, The length of ICU stay and the ICU mortality were similar between groups. 12

A retrospective chart review compared 28-day mortality and surgical intensive care unit (SICU) length of stay in septic shock patients treated with phenylephrine and norepinephrine. The study included 30 patients, with 15 patients treated with each vasopressor. No statistically significant difference was found in either 28-day mortality or SICU length of stay between the two groups, even when patients with known cardiac disease were specifically evaluated. The study concludes that while phenylephrine does not increase the risk of mortality or prolong SICU length of stay compared with norepinephrine in septic shock patients, its use also does not improve outcomes. 13

A recent retrospective chart review evaluated the use of phenylephrine in the management of septic shock. The study included 499 adult patients admitted to an ICU for the management of septic shock, with 148 patients receiving phenylephrine. The primary outcome was mortality, and the study found that phenylephrine was associated with an increase in mortality compared to patients who did not receive phenylephrine. Secondary outcomes of days on vasopressors and ICU length of stay were not different between the two groups. Subgroup analyses revealed that patients with ongoing tachycardia who received phenylephrine had a higher mortality rate. The study concludes that the use of phenylephrine in septic shock patients, especially those with ongoing tachycardia, is associated with an increased rate of mortality. 14

Which primary agent would you use for septic shock patients with tachycardia >120 beats/min?

• 0%Phenylephrine
• 0%Vasopressin
• 0%Norepinephrine
• 0%Other, please comment in the comment section.

How can we incorporate the results of these studies into our clinical practice?

While the studies suggest that phenylephrine may lower heart rate compared to norepinephrine, further research is necessary to determine its effects on clinical outcomes, such as mortality and length of stay. The question is whether patients with septic shock and tachycardia represent a more critically ill group, resulting in higher mortality rates, or if phenylephrine may directly impair organ perfusion and increase mortality. Additional studies with larger sample sizes and randomized controlled designs may help to provide more robust evidence on the potential benefits and risks of using phenylephrine in these patients.​

In my opinion, until further studies are conducted, it is advisable to avoid using phenylephrine in patients with septic shock and consider using vasopressin as an alternative unless there is a specific indication to use phenylephrine.

REFERENCES:

1. Kalmar AF, Allaert S, Pletinckx P, et al. Phenylephrine increases cardiac output by raising cardiac preload in patients with anesthesia induced hypotension. J Clin Monit Comput. 2018;32(6):969–76. https:// doi. org/ 10. 1007/ s10877-​018-​0126-3.

2. Larson S, Anderson L, Thomson S. Effect of phenylephrine on cerebral oxygen saturation and cardiac output in adults when used to treat intraoperative hypotension: a systematic review. JBI Evid Synth. 2021;19(1):34–58. https://doi. org/10.11124/JBISR IR-D-​19-​0035.

3. Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA. 2017;317(14):1433. https:// doi. org/ 10. 001/ jama. 2017. 2841.

4. Donegan CK, Townsend CV. PHENYLEPHRINE HYDROCHLORIDE IN PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA. JAMA. 1955;157(9):716–718. doi:10.1001/jama.1955.02950260022004d. Link

5. WAXMAN, M. E. N. A. S. H. E. B., DOWNAR, E. U. G. E. N. E., BERMAN, N. E. I. L. D., & FELDERHOF, C. L. A. R. E. N. C. E. H. (1974). Phenylephrine (neo-synephrine) terminated ventricular tachycardia. Circulation, 50(4), 656–664. https://doi.org/10.1161/01.cir.50.4.656. Link

6. Yamazaki T, Shimada Y, Taenaka N, Oshumi H, Takezawa J, Yoshiya I. Circulatory responses to afterloading with phenylephrine in hyperdynamic sepsis. Crit Care Med. 1982 Jul;10(7):432-5. doi: 10.1097/00003246-198207000-00003. PMID: 7083867. Link

7. Haiduc M, Radparvar S, Aitken SL, Altshuler J. Does Switching Norepinephrine to Phenylephrine in Septic Shock Complicated by Atrial Fibrillation With Rapid Ventricular Response Improve Time to Rate Control? J Intensive Care Med. 2021 Feb;36(2):191-196. doi: 10.1177/0885066619896292. Epub 2020 Jan 2. PMID: 31893966. Link

8. Law AC, Bosch NA, Peterson D, Walkey AJ. Comparison of Heart Rate After Phenylephrine vs Norepinephrine Initiation in Patients With Septic Shock and Atrial Fibrillation. Chest. 2022 Oct;162(4):796-803. doi: 10.1016/j.chest.2022.04.147. Epub 2022 May 5. PMID: 35526604; PMCID: PMC9808602. Link

9. Arishi H, AlQahtani S, Tamim H, Sadat M, Alenezi FZ, Bin Humaid F, AlWehaibi W, Arabi YM. Combination of norepinephrine with phenylephrine versus norepinephrine with vasopressin in critically ill patients with septic shock: A retrospective study. J Crit Care. 2022 Dec;72:154121. doi: 10.1016/j.jcrc.2022.154121. Epub 2022 Jul 28. PMID: 35908329. Link

10. He, D., Hu, H., Hong, L. et al. Norepinephrine combined with phenylephrine versus norepinephrine in patients with septic shock: a retrospective cohort study. BMC Infect Dis23, 221 (2023). https://doi.org/10.1186/s12879-023-08142-x.

11. Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association Between US Norepinephrine Shortage and Mortality Among Patients With Septic Shock. JAMA. 2017;317(14):1433–1442. doi:10.1001/jama.2017.2841. Link

12. Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Laderchi A, Bachetoni A, D'Alessandro M, Van Aken H, Pietropaoli P, Westphal M. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care. 2008;12(6):R143. doi: 10.1186/cc7121. Epub 2008 Nov 18. PMID: 19017409; PMCID: PMC2646303. link

13. Santoriello, Lisa MDa; Schweiger, Krislyn PharmDb; Aronowitz, Danielle MDa,; Maisch, Nicole PharmDb; Smith, Candace PhDb; Wu, Wenchen RPh, MBA, PhDb; Patel, Vihas MDa; Coppa, Gene MDa; Barrera, Rafael MDa. Effect of phenylephrine versus norepinephrine on 28-day mortality and SICU length of stay in septic shock. International Journal of Surgery: Global Health 3(4):p e19, July 2020. | DOI: 10.1097/GH9.0000000000000019 link

14. Patel VV, Sullivan JB, Cavanaugh J. Analysis of Mortality in Patients Treated With Phenylephrine in Septic Shock. Journal of Pharmacy Practice. 2023;36(1):15-18. doi:10.1177/08971900211000218 Link

Hemodynamic Course Presentations

Buy Now