The goal of hemodynamic support in septic shock patients is to:
Improve vital organ perfusion
Minimize the risk of arrhythmias
Minimize the risk of digital ischemia
Minimize the risk of visceral ischemia and renal failure
Based on the 2021 surviving sepsis campaign guidelines, the approach to management using vasopressors in septic shock can be summarized as the following:
First line: Norepinephrine to be started early to maintain MAP (mean arterial pressure) above 65mmHg. Phenylephrine is discouraged. Vasopressin can be used instead of norepinephrine in cases of tachyarrhythmias, and dopamine can be used in cases of bradycardia.
Second line: Add vasopressin when norepinephrine dose reaches 0.3-0.6 mcg/kg/min. Norepinephrine can be increased if needed. There is no data on the maximum dosage to use, but we tend to limit norepinephrine at 1-1.5 mcg/kg/min.
Third line: Epinephrine at 0-1 mcg/kg/min, especially if the patient has cardiac dysfunction.
Fourth line: Angiotensin II, but evidence is weak and evolving.
THE EVIDENCE BEHIND THE GUIDELINES:
Dopamine versus Norepinephrine
In a systematic review and meta-analysis of 32 RCTs with 3,544 patients, norepinephrine was found to have a lower mortality (RR, 0.89; 95% CI, 0.81–0.98), lower risk for major adverse events (RR, 0.34; 95% CI, 0.14-0.84), and lower risk of arrhythmias (RR, 0.48; 95% CI, 0.40–0.58) when compared with dopamine [1]. No additional mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine, and vasopressin/terlipressin [1]. The use of dopamine as an alternative to norepinephrine in septic shock is recommended only in highly selected patients (e.g., with absolute or relative bradycardia and a low risk of tachyarrhythmias).
Epinephrine versus Norepinephrine
A randomized blinded study that included 280 patient comparing epinephrine with norepinephrine in patients with shock showed no difference in time to achieve the MAP goal (RR, 0.88; 95% CI, 0.69-1.12; P = 0.26), 90-day mortality (HR, 0.88; 95% CI, 0.63–1.25), and vasopressor-free days [2]. There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59-1.12; P = 0.18) [2].
Vasopressin versus Norepinephrine
The VANISH trial studied the effect of vasopressin versus norepinephrine on kidney failure in patients with septic shock. It included a total of 409 patients in 18 centers in the United Kingdom. The trial demonstrated no risk difference concerning kidney injury (RR, 0.89; 95% CI, 0.72–1.11). However, there was a reduction in renal replacement therapy (RRT) requirement with the use of vasopressin (RR, 0.71; 95% CI 0.53–0.97). 28-day mortality was not significantly different between the two agents (30.9% vs 27.5%; RR, 1.13 [95% CI, 0.85–1.51]) [3].
Norepinephrine versus Norepinephrine and Vasopressin
The VASST study demonstrated that adding vasopressin (0.01−0.03 U/min) to norepinephrine in severe septic shock patients did not result in a better 28-day mortality rate (44.0% and 42.5%, respectively; P=0.76). However, in a subgroup of patients with less severe septic shock, the addition of vasopressin to norepinephrine resulted in a reduction of 28-day mortality (26.5% vs. 35.7%, P=0.05) [4].
A meta-analysis that included 23 randomized clinical trials and 3088 patients showed that the addition of vasopressin to norepinephrine reduced the risk of atrial fibrillation [5].
A meta-analysis of patients with septic shock from 4 RCTs provided evidence that vasopressin alone, or in combination with norepinephrine, led to a higher risk of digital ischemia (risk difference [RD] 1.7%; 95% CI, 0.3−3.2) but lower risk of arrhythmia (RD, -2.8%; 95% CI, -0.2 to -5.3) compared with norepinephrine alone [6].
Both VANISH and VASST demonstrated a catecholamine-sparing effect of vasopressin; as such, the early use of vasopressin in combination with norepinephrine may help reduce the adrenergic burden associated with traditional vasoactive agents.
Phenylephrine versus Norepinephrine
Phenylephrine is a pure α-agonist with vasoconstrictive effects similar to norepinephrine but doesn't demonstrate chronotropic or inotropic effects. This leads to increased afterload, reflex bradycardia, and possibly a drop in cardiac output.
A small study of 32 patients showed that there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when compared with norepinephrine [7]. However, it is not recommended as an initial vasopressor due to its potential association with reduced splanchnic blood flow in septic shock patients.
During the shortage of norepinephrine in the US in 2011, a cohort study of 27,835 patients revealed an association between the norepinephrine shortage and mortality among adults with septic shock, during this period, the most commonly administered alternative vasopressor was phenylephrine [8].
Therefore, we discourage the use of phenylephrine in general. If used, we recommend to limit it to patients who:
Develop tachyarrhythmias on norepinephrine, epinephrine, or dopamine.
Have persistent shock despite use of two or more vasopressor/inotropic agents including vasopressin (salvage therapy).
Or have high cardiac output with persistent hypotension.
Shock requiring High Dose Vasopressors
Refractory septic shock has a high mortality. It is associated with ischemic and arrhythmogenic complications from high dose vasopressor requirements. In refractory cases requiring high-dose norepinephrine, the addition of another α1 receptor agonist such as epinephrine may not be useful as the α1 receptors may already be saturated and downregulated. It may be more appropriate to add vasopressin in this scenario.
Selepressin versus Norepinephrine
Selepressin is a selective V1A agonist that induces vasoconstriction via stimulation of vascular smooth muscle without affecting V1b and V2 receptors. It was proposed as an alternative to norepinephrine. However, in a large randomized control trial including 828 patients, selepressin failed to improve ventilator-free days, renal replacement therapy-free days, and mortality [9].
Angiotensin II in Septic Shock
Angiotensin II (AT II) is a natural hormone with marked vasoconstrictor effects that are triggered through stimulation of the renin-angiotensin system. AT II activates AT1a and AT1b receptors to increase intracellular calcium in smooth muscle and activate the myosin contractile mechanism, thus promoting vasoconstriction. A synthetic human ATII preparation has become available for clinical use and has been studied in multiple clinical trials.
The largest RCT (ETHOS-3) included 344 patients with vasodilatory shock and demonstrated a favorable hemodynamic response in the AT II treatment group (69.9%) compared to the conventional group (23.4%) with statistical significance (p < 0.001), but without a mortality benefit [10]. However, a meta-analysis demonstrated a marginally significant reduction in 28-day mortality with a shorter length of mechanical ventilation, improved renal function, and an increased 6-hour shock reversal success rate. This beneficial effect occurred at the expense of an increased risk of hyponatremia and digital ischemia [11]. However, a recent study with real-world experience using ATII as a third-line vasopressor at a single tertiary care medical center failed to show benefits in mortality, hemodynamic response, ICU length of stay, or hospital length of stay [12].
Terlipressin versus Norepinephrine
Terlipressin is a pro-drug which is converted to lysine vasopressin by endothelial peptidases. It is more specific for V1 receptors and has a “slow release” effect with a 6-hour half life. In a randomized controlled trial compared with norepinephrine, 28-day mortality was 40% for terlipressin and 38% for norepinephrine (OR, 0.93; 95% CI, 0.55–1.56, P = 0.80) without any significant difference in SOFA score at day 7 or vasopressor-free days. Serious side effects were much higher in the terlipressin group as 12% of patients had digital ischemia and 3 out of 260 patients developed mesenteric ischemia [13]. A meta-analysis that included 6 studies suggested that terlipressin added no survival benefit in septic shock when compared with norepinephrine [14].
REFERENCES
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9. Laterre, Pierre-Francois et al. “Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.” JAMA vol. 322,15 (2019): 1476-1485. doi:10.1001/jama.2019.14607.
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13. Liu ZM, Chen J, Kou Q et al (2018) Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial. Intensive Care Med 44(11):1816–1825
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