By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

SYNOPSIS: Adult patients experiencing sepsis with hypotension but who did not meet the definition of septic shock received a median of 800 mL of intravenous fluid prior to initiation of norepinephrine 0.05 mcg/kg/min as a non-titratable infusion. Patients in this early vasopressor group had much lower odds of failing to achieve their primary outcome of adequate mean arterial pressure and tissue perfusion when early norepinephrine was provided.

SOURCE: Permpikul C, Tongyoo S, Viarasilpa T, et al. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med 2019;199:1097-1105.

The initial management of sepsis includes recognizing and treating the causative infection with antimicrobial therapy and providing intravenous (IV) fluid resuscitation to support end-organ perfusion.1 The current Surviving Sepsis Campaign guidelines provide a strong recommendation for administering at least 30 mL/kg of IV crystalloid fluid within the first three hours of resuscitation, but they are silent on the specific time to initiate vasopressor therapy.1 Observational studies previously have suggested that earlier initiation of norepinephrine decreases the time to achieve target mean arterial pressure (MAP) and reduces in-hospital mortality.2,3 This trial was performed to determine if administering low-dose norepinephrine soon after sepsis-induced hypotension is recognized accelerates shock control.4

Researchers conducted a randomized, double-blind trial in a large, tertiary referral center in Thailand.4 Patients experiencing sepsis with hypotension (MAP < 65 mmHg) who had not been in shock for more than one hour were randomized to 24 hours of norepinephrine 0.05 mcg/kg/min as a non-titratable infusion or dextrose 5% in water at the same infusion rate. Patients were eligible to receive open-label norepinephrine at the discretion of the attending physician and received additional supportive care as guided by the 2012 Surviving Sepsis Campaign guidelines.5 Patients who were hemodynamically stable without open-label norepinephrine, mechanical ventilation, or renal replacement therapy were transferred from the emergency department to the general medical ward, and all other patients received subsequent care in an intensive care unit. The primary outcome was shock control rate at six hours after sepsis diagnosis, defined as sustained MAP > 65 mmHg with evidence of adequate tissue perfusion (urine output > 0.5 mg/kg/hour for two consecutive hours or a decrease in serum lactate by > 10% from the initial level).

Patients in both groups received a median of 800 mL of crystalloid prior to study drug initiation and a median of approximately 30 mL/kg of crystalloid prior to open-label, titratable norepinephrine initiation (67.7% in the early norepinephrine group vs. 80% in the control group, P = 0.01). The early norepinephrine group had a median norepinephrine initiation time of 70 minutes (interquartile range 50-90 minutes). The total volume of IV fluid at all time points from hour 1 to day 3 was similar between groups; however, significantly more patients in the control group experienced cardiogenic pulmonary edema (14.4% vs. 27.7%, P = 0.004).

More patients in the early norepinephrine group achieved target MAP and tissue perfusion by hour 6 (76.1% vs. 48.4%, P < 0.001). More patients in the early norepinephrine group achieved all targets (i.e., MAP, urine output, and lactate clearance) by hour 6 (31% vs. 17.4%, P = 0.005) and target MAP and urine output by hour 6 (35.5% vs. 24.5%, P = 0.04). In contrast, achievement of target MAP and lactate clearance by 10% at hour 6 did not differ significantly between the groups (9.7% vs. 6.5%, P = 0.30). Mortality at 28 days was numerically lower in the early norepinephrine group (15.5% vs. 21.9%, P = 0.15), but it was not statistically significant. Intensive care unit and hospital lengths of stay as well as days alive and free from end-organ support to day 28 were similar between the groups.

COMMENTARY

Because vasodilation and capillary leakage are prominent features of sepsis with hypotension, restoring end-organ perfusion through an initial combination of IV fluid and vasopressor therapies theoretically may improve patient outcomes compared to IV fluid alone. Permpikul and colleagues found improved odds of achieving their primary outcome of adequate MAP and tissue perfusion when early norepinephrine was provided (odds ratio [OR], 3.4; 95% confidence interval, 2.09-5.53; P < 0.001). Although lactate clearance was similar between groups, this serves as an imperfect surrogate marker for disease status.6 Additionally, although similar IV fluid amounts were provided between groups, patients who received early norepinephrine had lower odds of developing cardiogenic edema, suggesting that the vasoconstrictive and inotropic effects of this intervention were highly effective. They also had lower rates of new-onset arrhythmia development (11% vs. 20%, P = 0.03), which suggests improved management of sepsis and portends better outcomes.7

Although the 28-day mortality rates were similar between groups, the trial was inadequately powered to detect the observed 6.4% mortality difference because of the small sample size. Because the macrocirculation and microcirculation parameters favored the early norepinephrine group, a larger, multicenter trial evaluating mortality with the early initiation of norepinephrine in adults experiencing sepsis and hypotension is warranted.

Clinicians looking to apply these findings to their practice should have at least a few considerations. Patients in this trial received a continuous, non-titratable norepinephrine infusion in the medical ward with 3:1 nurse staffing. If wards do not have that level of staff or prohibit continuous infusions from being administered, then care may need to be provided in an ICU or an intermediate care unit. Additionally, infusions were initiated through a peripheral line in most patients, which has been found to be safe for short periods of time with more proximal access sites, but may necessitate a change in practice and/or policy at some institutions.8 Additionally, providers should not expect to provide a significantly smaller amount of IV resuscitative fluid, so the best practices of evaluating the patient’s fluid status will remain essential. Similar rates of acute limb and/or intestinal ischemia occurred between the groups (3.2% vs. 1.9%, P = 0.47) when these other resuscitative measures were provided.

Implementation of this type of practice should be coordinated with emergency medicine physicians and intensivists as well as nurses in emergency departments and ICUs to streamline the process and reduce the risk of complications. Finally, the results of a multicenter trial comparing early vasopressor initiation to liberal IV crystalloid therapy will provide more insight into the benefits and harms of both practices.9

REFERENCES

  1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45:486-552.
  2. Morimatsu H, Singh K, Uchino S, et al. Early and exclusive use of norepinephrine in septic shock. Resuscitation 2004;62:249-254.
  3. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care 2014;18:532.
  4. Permpikul C, Tongyoo S, Viarasilpa T, et al. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med 2019;199:1097-1105.
  5. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228.
  6. Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA 2019;321:654-664.
  7. Bosch NA, Cohen DM, Walkey AJ. Risk factors for new-onset atrial fibrillation in patients with sepsis: A systematic review and meta-analysis. Crit Care Med 2019;47:280-287.
  8. Cardenas-Garcia J, Schaub KF, Belchikov YG, et al. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med 2015;10:581-585.
  9. Schoenfeld DA. Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS). Available at: https://clinicaltrials.gov/ct2/show/NCT03434028. Accessed June 2, 2019.