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Vasopressors for Septic Shock (from the Surviving Sepsis Guidelines)
*PulmCCM is not affiliated with the Surviving Sepsis Campaign.
Vasopressors are provided for septic shock that does not respond to fluid resuscitation. Norepinephrine (Levophed), epinephrine, vasopressin, phenylephrine (Neo-Synephrine), and dopamine are the most commonly used vasopressors for septic shock.
To achieve adequate fluid resuscitation, the Surviving Sepsis Guidelines advise at least 30 ml/kg of crystalloids (1.5-3 liters) be infused for most patients (Grade 1C) in septic shock. Some patients will require more IV fluids; fluid should be aggressively infused for as long as the patient continues to improve hemodynamically (ungraded recommendation). A portion of infused resuscitation fluid can be given as "albumin-equivalent" (Grade 1C).
Vasopressors should be promptly begun in patients in persistent septic shock despite fluid resuscitation; vasopressors can be begun and continued simultaneously with fluid resuscitation, especially in patients with severe hypotension. The Surviving Sepsis Guidelines advise the following:
- Vasopressors should be begun initially to target a mean arterial pressure of 65 mm Hg (Grade 1C).
- Norepinephrine (Levophed) should be provided as the first-line vasopressor (Grade 1B).
- Epinephrine is considered the next-line agent for septic shock after norepinephrine in the Surviving Sepsis Guidelines. When norepinephrine is insufficient to maintain MAP 65 mm Hg, epinephrine should be added to or substituted for norepinephrine (Grade 2B).
- Vasopressin at 0.03 units/minute is appropriate to use with norephinephrine, either to improve perfusion (increase MAP) or to reduce the required dose of norepinephrine (ungraded recommendation).
- Vasopressin is not recommended for use as a single vasopressor for septic shock (ungraded recommendation).
- Vasopressin doses higher than 0.03 - 0.04 units/min are recommended to be reserved only for dire situations of septic shock refractory to standard doses of multiple vasopressors (ungraded recommendation).
- Dopamine is suggested to not be used as an alternative to norepinephrine in septic shock, except in highly selected patients such as those with inappropriately low heart rates (absolute or relative bradycardia) who are at low risk for tachyarrhythmias (Grade 2C). Dopamine is recommended to not be used in low doses in a so-called renal-protective strategy (Grade 1A).
- Phenylephrine is recommended to not be used for septic shock, except when 1) septic shock persists despite the use of 2 or more inotrope/vasopressor agents along with low-dose vasopressin; 2) cardiac output is known to be high, or 3) norepinephrine is considered to have already caused serious arrhythmias (Grade 1C).
- An arterial catheter for hemodynamic monitoring should be placed as soon as practical, if resources are available, for all patients requiring vasopressors (ungraded recommendation).
- Dobutamine should be tried for patients in septic shock who have low cardiac output with high filling pressures while on vasopressors, or who have persistent evidence of hypoperfusion after attaining an adequate mean arterial pressure and intravascular volume (with or without vasopressors) (Grade 1C).
- A dobutamine infusion up to 20 mcg/kg/min can be added to any vasopressor(s) in use. Dobutamine is also an appropriate first-line agent in patients with severe sepsis and low cardiac output, with a preserved mean arterial pressure (i.e., who are not in septic shock) (Grade 1C).
- Dobutamine is recommended not to be used to deliberately raise cardiac output to higher than normal levels in an attempt to improve perfusion (Grade 1B).
Mean Arterial Pressure (MAP) ≥ 65 mm Hg is Not An Absolute
The goal of attaining a mean arterial pressure (MAP) of ≥ 65 mm Hg for patients receiving vasopressors for septic shock is based on very limited evidence. The single research study cited in the Surviving Sepsis Guidelines to support the goal of MAP ≥ 65 mm Hg enrolled only 10 patients. Accordingly, the Surviving Sepsis Guidelines advise that "the optimal MAP should be individualized" during treatment of septic shock -- perhaps higher than 65 mm Hg in a patient with hypertension and known atherosclerosis; perhaps lower than 65 mm Hg in a young healthy patient with a baseline normal blood pressure -- and that other markers of perfusion such as serum lactate, skin appearance and temperature, urine output, and mental status should supplement the use of mean arterial pressure in all patients.
Why Norepinephrine (Levophed) for Septic Shock Instead of Other Vasopressors?
Norepinephrine (Levophed) is favored as the first-line vasopressor for septic shock in the Surviving Sepsis Guidelines (Grade 1B). Norepinephrine increases mean arterial pressure primarily through vasoconstriction, with little effect on heart rate, stroke volume, and cardiac output; dopamine increases MAP primarily through an increase in cardiac output (by increasing both heart rate and stroke volume). These characteristics make dopamine more likely than norepinephrine to cause potentially harmful tachyarrhythmias.
Norepinephrine and dopamine have been compared directly in at least 6 randomized trials, and less directly in meta-analyses. The Surviving Sepsis Campaign's own (unpublished) pooled analysis of these trials showed a relative risk for death of 0.91 (0.83-0.99) with the use of norepinephrine compared to dopamine as vasopressor therapy for septic shock. A 2012 meta-analysis including randomized and observational trials also concluded dopamine brings an increased risk for death compared with Levophed as a first-line vasopressor for septic shock.
Epinephrine is suggested as the next-line vasopressor after norepinephrine for septic shock, to be added or substituted if norepinephrine is inadequate (Grade 2B). Epinephrine has been compared to norepinephrine in at least 4 randomized trials, with no increase in the risk for death. Epinephrine may increase lactate concentrations by stimulating skeletal muscles' aerobic metabolism, thereby interfering with the use of lactate as a marker of perfusion during treatment of septic shock.
Phenylephrine can decrease stroke volume and is recommended to not be used except as salvage therapy, in known high cardiac output states, or if norepinephrine has caused tachyarrhythmias (Grade 1C).
Vasopressin (or its analogue terlipressin) has been compared to norepinephrine as a vasopressor for septic shock in 9 randomized trials (n=963); vasopressin / terlipressin carried a (non-significant) increased risk of death (albeit a lower risk of tachyarrhythmias) compared to norepinephrine.
Guide to Recommendations’ Strengths and Supporting Evidence in the Surviving Sepsis Guidelines:
- 1 = strong recommendation;
- 2 = weak recommendation or suggestion;
- A = good evidence from randomized trials;
- B = moderate strength evidence from small randomized trial(s) or upgraded observational trials;
- C = low strength evidence, well-done observational trials with control randomized controlled trials
- D = very low strength evidence, downgraded controlled studies or expert opinion.