Is norepinephrine drip or phenylephrine drip preferred in a patient with tachycardia and low blood pressure who is in need of a pressor, and why?

Comment by InpharmD Researcher

The 2012 Surviving Sepsis Campaign guidelines recommend phenylephrine for the treatment of septic shock only in certain circumstances including when norepinephrine is associated with tachyarrhythmias or when cardiac output is known to be high and blood pressure is persistently low. Phenylephrine is suitable for patients with tachycardia likely due to its pure alpha-adrenergic agonist activity and lack of beta-adrenergic activity compared to norepinephrine, making it the least likely agent to cause tachycardia. Limited clinical studies have also observed phenylephrine to be associated with a lower heart rate compared to norepinephrine in septic shock. Due to the lack of available data evaluating phenylephrine use in septic shock, however, the updated 2016 Surviving Sepsis Campaign guidelines recommend phenylephrine’s use be limited until further research is conducted.

Background

According to the 2012 Surviving Sepsis Campaign international guidelines for the management of severe sepsis and septic shock, phenylephrine is not recommended in the treatment of septic shock except in circumstances where norepinephrine is associated with serious arrhythmias, cardiac output is known to be high and blood pressure persistently low, or as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve mean arterial pressure (MAP) target. Due to phenylephrine’s nearly pure alpha-adrenergic effects, it is least likely to cause tachycardia. However, it may decrease stroke volume and is therefore not recommended for use in the treatment of septic shock except in the circumstances described above. [1]

A 2019 review discussing the use of vasoactive agents in septic shock notes that phenylephrine is a pure alpha-adrenergic agonist, and an indirect decrease in heart rate and cardiac output may occur given its α1-mediated vasoconstriction effects, primarily increasing the afterload. Despite this notion, these effects have not been consistently demonstrated in high-quality clinical studies (see Tables 1 and 2 for exception), likely due to stimulation of α1 receptors in the myocardium causing positive inotropy (without chronotropy) and offsetting the theoretical decrease in heart rate and cardiac output. Of note, small studies have shown similar effects on cardiac output, heart rate, and stroke volume with phenylephrine in comparison with norepinephrine in patients with septic shock. [2]

The 2012 Surviving Sepsis Campaign guidelines recommend phenylephrine for patients with tachyarrhythmias associated with norepinephrine, those with optimal cardiac output and low blood pressure, or as salvage therapy after suboptimal response to other vasoactive agents. However, limited data comparing the use of phenylephrine and norepinephrine in septic shock have demonstrated no difference in clinical outcomes. Additionally, the updated 2016 Surviving Sepsis Campaign guidelines recommend limited use of phenylephrine until further research is conducted due to the lack of available data. While there is a lack of certainty surrounding the use of phenylephrine, some niche populations may benefit from phenylephrine use, including patients who develop tachyarrhythmias from vasoactive agents with ꞵ-adrenergic activity such as norepinephrine and epinephrine. Due to its lack of ꞵ-receptor activity, phenylephrine would also be a suitable alternative to norepinephrine or epinephrine in patients who already received vasopressin and developed tachyarrhythmias. [1], [2], [3]

References:

[1] Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. doi:10.1007/s00134-012-2769-8
[2] Sacha GL, Bauer SR, Lat I. Vasoactive Agent Use in Septic Shock: Beyond First-Line Recommendations. Pharmacotherapy. 2019;39(3):369-381. doi:10.1002/phar.2220
[3] Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is Norepinephrine drip or Phenylephrine drip preferred in a patient with tachycardia and low blood pressure who is in need of a pressor, and why?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

 

Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock

Design

Randomized, prospective, controlled trial

N= 54

Objective

To compare two vasoconstrictors, norepinephrine and phenylephrine, in the management of dopamine-resistant septic shock in intensive care unit patients

Study Groups

Phenylephrine (n= 27)

Norepinephrine (n= 27)

Inclusion Criteria

Persistent hypotension, evidence of one or more end-organ dysfunction, infection along with two or more of the following criteria: (1) body temperature higher than 38°C or less than 36°C, (2) heart rate (HR) greater than 90/min, (3) respiratory rate greater than 20/min, or arterial CO2 <32 mmHg, (4) WBC count > 12,000/mm3, or < 4,000/mm3 or > 10% immature band form

Exclusion Criteria

Acute coronary artery disease or underlying cardiac dysfunction [cardiac index (CI) <2.2 L/min/m2], acute mesenteric ischemia, severe liver disease (Child-Pugh grade C), chronic renal failure, and uncorrected shock due to blood loss

Methods

Eligible patients received either norepinephrine 0.5 to 3.5 mcg/kg/min or phenylephrine 0.5 to 8.5 mcg/kg/min over 30 minutes,  with each drug titrated to achieve targets of systolic blood pressure (SBP) > 90 mmHg, mean arterial pressure (MAP) > 75 mmHg, systemic vascular resistance index (SVRI) > 1,100 dynes.s/cm5m2, cardiac index (CI) > 2.8 L/min/m2, oxygen delivery index (DO2I) > 550 ml/min/m2, and oxygen consumption index (VO2I) > 150 ml/min/m2 for continuous 6 hours. Dose titrations, in increments of 0.5 mcg/kg/min for norepinephrine and increments of 1 mcg/kg/min for phenylephrine, were done within the specified dose range if targets were not achieved. 

All patients were mechanically ventilated (target PaO2: >60 mmHg; PaCO2: 35 to 40 mmHg) and received fentanyl and midazolam for sedation and analgesia. Dopamine infusion was continued at a rate of 25 mcg/kg/min throughout the study duration, and serial intravenous fluid challenges were also given throughout the study to maintain a central venous pressure (CVP) in the range of 8 to 15 mmHg and the pulmonary artery occlusion pressure (PAOP) between 12 to 18 mmHg

Duration

August 2008 to July 2009

Outcome Measures

Cardiovascular parameters

Baseline Characteristics

  

Phenylephrine (n= 27)

Norepinephrine (n= 27)

Age, years

 42.88 45.29

Male

55.56% 48.15%

Weight, kg

 64.55 63.22

APACHE II score

 17.66 19.11

Past medical history

ARDS

Pneumonia

Abscess

Polytrauma

Necrotizing fascitis

 

29.63%

14.81%

18.52%

25.93%

11.11%

 

25.93%

18.52%

25.93%

22.22%

7.41% 

APACHE, acute physiology and chronic health evaluation; ARDS, acute respiratory distress syndrome

Results

Endpoint

Phenylephrine (n= 27)

Norepinephrine (n= 27)

HR, beats/min

Pretreatment

Posttreatment

p-value

 

151.74 ± 7.62

115.66 ± 7.46

<0.001

 

152.66 ± 7.28

150.48 ± 12.72

0.44 

SBP, mmHg

Pretreatment

Posttreatment

p-value

 

73.66 ± 4.69

104.22 ± 13.54 

<0.001

 

74.59 ± 5.17

111.66 ± 11.20 

<0.001

PAOP, mmHg

Pretreatment

Posttreatment

p-value

 

15.40 ± 1.52

17.66 ± 1.90

<0.05

 

15.07 ± 1.03

15.29 ± 0.91

0.34

SVI, ml/m2

Pretreatment

Posttreatment

p-value

 

44.04 ± 1.61

54.68 ± 1.28

<0.001 

 

43.54 ± 1.43

44.18 ± 1.29 

0.167 

IV fluid infusion, liters

p-value comparing both groups

3.41 ± 0.18

0.283

3.50 ± 0.34

--

HR, heart rate; SBP, systolic blood pressure; PAOP, pulmonary artery occlusion pressure; SVI, stroke volume index; IV, intravenous

Changes from baseline for SBP, DO2I, VO21, SVRI, Lactate, MAP, hepatic vein oxygen saturation, and urine output were statistically significant for both groups. Change in CI from baseline was not statistically significant for either group. The maximum infusion requirement of phenylephrine and norepinephrine were 3.28 ± 1.02 mcg/kg/min and 2.96 ± 0.28 mcg/kg/min, respectively.

Adverse Events

Not disclosed

Study Author Conclusions

In conclusion, phenylephrine infusion is comparable to norepinephrine in reversing hemodynamic and metabolic abnormalities of sepsis patients, with the additional benefit of a decrease in HR and improvement in SVI. 

InpharmD Researcher Critique

 The study is limited by its small sample size and lack of consideration of potential confounding factors, including the use of concomitant supportive measures such as immune modulation, corticosteroids, and renal replacement therapy. Although phenylephrine had a significant decrease in HR and improvement in SVI from baseline while epinephrine did not, no direct comparison of change from baseline between groups was done. 



References:

Jain G, Singh DK. Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock. Indian J Crit Care Med. 2010;14(1):29-34. doi:10.4103/0972-5229.63033

 

Comparison of Heart Rate After Phenylephrine vs Norepinephrine Initiation in Patients With Septic Shock and Atrial Fibrillation

Design

Retrospective cohort study 

N= 1,847

Objective

To examine whether phenylephrine, which is a titratable catecholamine vasopressor without β-agonism, may be associated with lower heart rates than norepinephrine (NE) in critically ill patients with atrial fibrillation (AF) and shock

Study Groups

Phenylephrine (n= 901)

NE (n= 946)

Inclusion Criteria

Adult patients (≥ 18 years old) with sepsis, defined per sepsis-3 criteria, as suspicion of infection (receipt of antibiotics and sampling of bodily fluids for microbiologic culture) and organ dysfunction (acute increase in Sequential Organ Failure Assessment score ≥ 2); nurse-documented cardiac rhythm available on an approximate hourly basis in Medical Information Mart for Intensive Care (MIMIC)-IV database; identification of AF validated previously

Exclusion Criteria

 Not specified

Methods

The study was conducted using electronic health records data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, which contains comprehensive clinical data from nine ICUs at a single center. Among patients with sepsis, the study included the first episode in which a patient was initiated on either NE or phenylephrine therapy alone (Time 0) while in AF. Vasopressors must have been initiated in the ICU (not receiving vasopressors in the first hour of ICU admission) and after a vasopressor-free period of ≥ 1 h. There were no restrictions on other vasopressor use ≥ 1 h before Time 0 or any time after Time 0. The maximum heart rate for each hour from 12 h before and after Time 0 was collected.

Duration

Enrollment: not specified 

Outcome Measures

Primary: heart rate at 1 and 6 h after Time 0

Secondary: conversion into sinus rhythm during 6-h follow-up, occurrence of bradycardia (heart rate, < 60 beats/min) during the 6-h follow-up, vasopressor duration (hours from Time 0 to first hour without any vasopressor use), ICU and hospital length of stay, hospital death

Baseline Characteristics

  

Phenylephrine (n= 901)

NE (n= 946)

Age, years

74.4 ± 11.2 

75.6 ± 11.1

Female

339 (37.6%)

388 (41.0%)

White

660 (73.3%)

680 (71.9%)

History of congestive heart failure

391 (43.4%)

625 (66.1%)

Mechanically ventilated

402 (44.6%)

476 (50.3%)

Sequential Organ Failure Assessment score

5.1 ± 2.9

8.0 ± 3.2

Atrial fibrillation present on admission to ICU

375 (41.6%)

474 (50.1%)

Heart rate, beats/min

103.8 ± 22.6

96.4 ± 22.1

Heart rate change in 6 h before vasopressors, beats/min

13.2 ± 27.8

3.3 ± 21.9

Mean arterial pressure, mmHg

70.6 ± 13.0

68.9 ± 13.2

Vasopressor dose in NE-equivalent dose, mcg/kg/min

0.10 ± 0.15

0.10 ± 0.11

Use of rate/rhythm control agents 6 h before vasopressors

Amiodarone

Beta-blockers

Calcium channel blocker

Digoxin

 

44 (4.9%)

87 (9.7%)

23 (2.6%)

6 (0.7%)

 

43 (4.5%)

76 (8.0%)

12 (1.3%)

7 (0.7%)

Use of any vasopressors in the 6 h before inclusion

189 (21.0%)

279 (29.5%)

During 1-h follow-up

Maximum vasopressor dose in NE-equivalent dose, mcg/kg/min

Addition of any vasopressors in the first hour after inclusion

Use of rate/rhythm control agents

Amiodarone

Beta-blocker

Calcium channel blocker

Digoxin

 

0.12 ± 0.16

24 (2.7%)

 

51 (5.7%)

94 (10.4%)

29 (3.2%)

7 (0.8%)

 

0.12 ± 0.12

0 (3.2%)

 

54 (5.7%)

81 (8.6%)

18 (1.9%)

7 (0.7%)

During 6-h follow-up

Maximum vasopressor dose in the NE-equivalent dose, mcg/kg/min

Addition of any vasopressors in the first hour after inclusion

Use of rate/rhythm control agents

Amiodarone

Beta-blocker

Calcium channel blocker

Digoxin

 

0.15 ± 0.19

90 (10.0%)

 

66 (7.3%)

111 (12.3%)

29 (3.2%)

11 (1.2%) 

 

0.15 ± 0.17

118 (12.5%)

 

67 (7.1%)

102 (10.8%)

18 (1.9%)

10 (1.1%)

Results

Endpoint

 Full cohort (N= 1,847)
 

Adjusted Odds Ratio (OR) (95% CI)

 p-value

Secondary outcomesa

Conversion to sinusb

Bradycardiab

Vasopressor duration, hr

Length of stay, d

ICU

Hospital

Hospital deaths

 

1.1 (0.8 to 1.5)

1.1 (0.7 to 1.6)

-3.4 (-7.4 to 0.7)

 

-0.3 (-1.5 to 0.9)

-1.7 (-3.8 to 0.4)

1.0 (0.7 to 1.4)

 

0.7

0.7

0.1

 

0.6

0.1

0.9

aReference= norepinephrine

bWithin a 6-h follow-up period

Primary: after multivariable adjustment, phenylephrine was associated with a lower heart rate at 1 h (-4 beats/min; 95% CI, -6 to -1; p< 0.001) and 6 h (-4 beats/min; 95% CI, -6 to -1; p= 0.004). A higher heart rate before vasopressor administration was associated with a larger heart rate reduction in patients who received phenylephrine compared with norepinephrine. Results were similar in exploratory and sensitivity analyses.

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

In patients with sepsis and AF, the initiation of phenylephrine was associated with a modestly lower heart rate compared with norepinephrine. Heart rate at vasopressor initiation appeared to be an important effect modifier. 

InpharmD Researcher Critique

Given the nature of retrospective design, the effect of confounding by indication cannot be excluded. Although only patients initiated on monotherapy (norepinephrine or phenylephrine alone) were included, the study no standards on restrictions of other vasopressor use ≥ 1 h before Time 0 or any time after Time 0. The study found no differences in any secondary outcomes.



References:

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;162(4):796-803. doi:10.1016/j.chest.2022.04.147