The majority of clinical trials on vasopressor use in septic shock have focused on one of three areas, the timing of vasopressor therapy, choice of vasopressor agents and the target of mean arterial pressure (MAP). Outcome measures of these trials include resolution of shock, improvement of hemodynamic profile, and a decrease in mortality.
Traditionally, intensivists are taught to aim for a target mean arterial pressure (MAP) of 65-70 mmHg. The origin of this desired range stems from various studies on autoregulation of microcirculation. The clinical question of whether a higher MAP may be associated with a better outcome, as it provides a better circulatory recruitment, has been answered by the SEPSISPAM trial. The higher MAP of 80-85 mm Hg showed no difference in 28- or 90-day mortality in patients with septic shock compared to a MAP of 65-70 mm Hg. However, patients with history of chronic hypertension had a lower rate of renal injury. This has not been reproduced in the 65 Trial where older patients (≥65 years) with chronic hypertension did not have an increased rate of kidney injury, even with a lower MAP of 65 mmHg. The trial showed that permissive hypotension in older patients (60-65 mmHg) was not associated with improved mortality and was safe. Please note that this excludes patients with increased intra-abdominal pressure or increased intracranial pressure who may benefit from a higher MAP to maintain adequate perfusion pressure of these respective organs.
Guidelines recommend the use of vasopressor agents only if hypotension persist after adequate fluid resuscitation with an initial fluid bolus of at least 30 mL/kg. However, starting vasopressors at the same time of fluid resuscitation is a novel concept that is implemented in many intensive care units. It is known that longer periods of hypotension are associated with worse patient outcomes. Therefore, early use of vasopressors may reduce the duration of hypotension whilst preventing over-resuscitation with fluid and its associated complications. A single center randomized controlled trial in Thailand (the CENSER trial) has demonstrated faster resolution of shock and better lactic acid clearance in early use of vasopressors [1-4]. Some experts advise for the initiation of vasopressor through peripheral venous access if central line is not available yet which would help achieve faster drug delivery [5].
The choice of vasopressor agents have been discussed extensively in a previous blog. Norepinephrine remains the first-line agent of choice and vasopressin can be added if the target mean arterial blood pressure is not achieved with increasing dosages of norepinephrine. Terlipressin is a prodrug that is converted to lysine vasopressin by endothelial peptidases. It is more specific for V1 receptors than norepinephrine and has a “slow release” effect with 6-hour half-life. In a randomized controlled trial comparing terlipressin 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 difference in Sequential Organ Failure Assessment (SOFA) score at day 7 or vasopressor-free days. Serious side effects were much higher in the terlipressin group with 12% of patients had digital ischemia and 3 out of 260 patients developed mesenteric ischemia [6]. A meta-analysis that included 6 studies suggested that terlipressin added no survival benefit for septic shock when compared with norepinephrine [7].
A new study was published in the Indian Journal of Critical Care Medicine comparing the combination of norepinephrine and terlipressin with norepinephrine alone in patients with septic shock. The authors reported a faster resolution of shock, a lower noradrenaline requirement, a better urine output, and a faster lactate clearance in the combination group. However, the study has many limitations including a small patients cohort (50 participants), a short intervention period of 12 hours (inadequate period to show medication effect), and the inappropriate use of intravenous infusion of terlipressin (a half-life of 50 minutes and active metabolites for up to 6 hours). It is also very concerning that 28% of patients in the combination group developed digital ischemia [8]. Therefore, further studies comparing the combination of norepinephrine and terlipressin versus norephinephrine alone are required to draw conclusions on the topic.
REFERENCES
1. . Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370(17):1583–1593. DOI: 10.1056/NEJMoa 1312173.
2. Vincent JL, Nielsen ND, Shapiro NI, Gerbasi ME, Grossman A, Doroff R, et al. Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. Ann Intensive Care 2018;8(1):107. DOI: 10.1186/s13613-018-0448-9.
3. Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med 2019;199(9):1097–1105. DOI: 10.1164/rccm.201806-1034OC.
4. Elbouhy MA, Soliman M, Gaber A, Taema KM, Abdel-Aziz A. Early use of norepinephrine improves survival in septic shock: earlier than early. Arch Med Res 2019;50(6):325–332. DOI: 10.1016/ j.arcmed.2019.10.003.
5. Delaney A, Finnis M, Bellomo R. Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: a retrospective cohort study. Emerg Med Australas 2020;32:210–219. DOI: 10.1111/1742-6723.13394.
6. 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
7. Huang P.O. et al. Terlipressin Versus Norepinephrine for Septic Shock: A Systematic Review and Meta-Analysis. Frontiers in Pharmacology December 2019.
8. Sahoo et al. Comparison of Norepinephrine and Terlipressin vs Norepinephrine Alone for Management of Septic Shock: A Randomized Control Study. Indian J Crit Care Med 2022;26(6):669-675.
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