Article
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.
OBJECTIVE
The study authors sought to examine if early norepinephrine administration in patients diagnosed with septic shock improved shock control by 6 hours compared with standard care.
Background
Septic shock, defined as systemic vasodilation and vascular leakage arising from systemic inflammation induced by a serious infection, presents a uniquely difficult pathologic process managed in the emergency department. From one year to the next, various campaigns and committees alter existing protocols and develop new protocols to optimize tissue perfusion, end organ preservation, and infection control. The staples of many protocols are fluid resuscitation, goal-directed antibiotic therapy, and vasopressor support when necessary. The authors of this study sought to elucidate whether the earlier initiation of vasopressor support, in the form of norepinephrine, as opposed to later positively impacted control of septic shock within 6 hours compared to standard care.
Study Design
- Phase II, randomized, double-blind, placebo-controlled trial
- 310 patients from a single university-based tertiary referral center in Bangkok, Thailand
- Inclusion Criteria
- 18 years and older
- Hypotension – [mean arterial blood pressure (MAP) <65 mmHg]
- Infection as the suspected cause
- Exclusion Criteria
- Patients who met septic shock criteria for > 1 hour before randomization
- Acute cerebral vascular event
- Acute coronary syndrome
- Acute pulmonary edema
- Status asthmaticus
- Active cardiac arrhythmias
- Active gastrointestinal hemorrhage
- Pregnancy
- Seizure
- Drug overdose
- Burn injury
- Trauma
- A requirement for immediate surgery
- Advanced stage cancer
- Patients who refused medical treatment
- Randomization
- Patients were randomly assigned in a 1:1 ratio by their sequential number of enrollment to receive early norepinephrine or placebo together with fluid resuscitation
- Randomization was performed using a computer-generated randomization table by a study investigator who had no other role in patient enrollment or management
- Other investigators, patients, patients’ relatives, attending physicians, and nurses were all blinded
- Study drug
â–ª 4 mg of norepinephrine was mixed with 250 mL of 5% dextrose in water, giving a final concentration of 16 mcg/mL and infused at a rate of 0.05 mcg/kg/min for 24 hours
- Study drug (norepinephrine or placebo) was prepared by a pharmacist who had no other role in the trial
- Study drugs were packaged in identically shaped containers labeled with sequential numbers according to the randomization table order
Population Characteristics
- 465 were evaluated, 320 underwent randomization
- 162 were assigned to early norepinephrine
â–ª 7 withdrew consent
- 158 were assigned to placebo
â–ª 3 withdrew consent
- Early Norepinephrine Group = 155 patients
- Median Age = 65 years of age
- Percent Male = 71%
- Median APACHE II Score = 21 (15-26)
- Placebo Group = 155 patients
- Median Age = 68 years of age
- Percent Male = 77%
- Median APACHE II Score = 20 (16-26)
Outcome Measures
- Primary outcome
- Shock control rate by 6 hours after diagnosis of sepsis with hypotension, defined as achievement of sustained MAP of at least 65 mmHg together with evidence of adequate tissue perfusion
â–ª Adequate tissue perfusion defined as urine flow at >0.5 mL/kg/hr for 2 consecutive hours or decrease in serum lactate by >10% from initial lactate level
- Secondary outcomes
- 28-day mortality and hospital mortality
- Rate of respiratory failure requiring mechanical ventilator support
- Rate of renal failure requiring renal replacement therapy
- Number of organ support-free days to day 28
- Safety Outcomes
- New onset cardiac arrhythmia
- Organ ischemia
- Cardiogenic or non-cardiogenic pulmonary edema
Results
- Median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group than standard treatment group (93 mins vs 192 mins, P<0.001)
- Shock control rate by 6 hours after initiation of resuscitation was higher in the early norepinephrine group than in standard group (76.1% vs 48.4%; odds ratio [OR]: 3.4; 95% confidence interval [CI]: 2.09–5.53; P<0.001)
- Achievement of individual target MAP, urine output, and lactate clearance were all significantly higher in the early norepinephrine group (all P<0.05)
- More patients achieved all targets by 6 hours than patients in the standard treatment group (31.0% vs 17.4%, P=0.005)
- More patients in the study group achieved both target MAP and urine output than in the standard treatment group (35.5% vs 24.5%, P=0.04)
- Achievement of both target MAP and target lactate clearance >10% within 6 hours was not different between groups (9.7% vs 6.5%, P=0.3)
- The median time to achieving target MAP >65 mmHg was shorter in the early norepinephrine group (3:30 hours vs 4:45 hours, P<0.001)
- Median time from diagnosis to achieve shock control was shorter in the study group than in the standard treatment group (4:45 hours vs 6:02 hours, P<0.001)
- Mortality at 28 days was 15.5% for the early norepinephrine group vs 21.9% in the standard treatment group (relative risk [RR]: 0.79, 95%CI: 0.53-1.11; P=0.15)
- Additionally, patients in the early norepinephrine group had lower rates of cardiogenic pulmonary edema (14.4% vs 27.7%, P=0.004) and new onset arrhythmia (11% vs 20%, P=0.03)
- No difference between groups in the volume of intravenous fluids administered at any time
- Fluid after 1st hour, median (800 mL vs 800 mL, P=0.64)
- Fluid administered in hours 0 to 6, median (2450 mL vs 2600 mL, P=0.33)
- Fluid administered in day 1, median (5032 mL, vs 5025 mL, P=0.66)
- Early norepinephrine group received a higher median dosage during 2nd to 5th hours, however, both groups received the same dosage after the 6th hour
- Median maximum open-label norepinephrine dosage was the same between groups
- 0.1 mcg/kg/min vs 0.1 mcg/kg/min (P= 0.59)
- No difference between the groups was found for rates of mechanical ventilator support, renal replacement therapy, or median number of organ support-free days at day 28
Strengths
- Randomized, double-blind, placebo-controlled
- Large sample size
- Norepinephrine dosage (0.05 mcg/kg/min) was at the low end of recommended dosing for septic shock patients and benefits were still demonstrated
- Illness severity between groups was equal and adequate to extrapolate to how it would impact similarly ill patients
Limitations
- Single institution limits the generalizability
- Vasopressor usage on general medical floors is often not feasible in most hospitals
- The physiologic effects of norepinephrine, the rapid increase in blood pressure, may have clued physicians into what group patients were assigned
- Mortality was not specifically evaluated in relation to early norepinephrine administration, only a secondary outcome measure
Conclusions
The pathophysiology of septic shock requires a delicate balance between adequate fluid resuscitation, management of vascular tone, and maintaining adequate end-organ perfusion. The current study presents data demonstrating significant improvement in control of shock with the initiation of early vasopressors. Vasopressor support is currently recommended for the 6-hour sepsis bundle for patients who don’t respond to initial fluid resuscitation. However, in the context of these study results it may benefit patients to initiate vasopressor support earlier, alongside fluid resuscitation, to improve vascular tone in addition to the fluid displacement that occurs with septic shock.
ED Take Away Points
In patients presenting with septic shock and a suspected infectious source, early norepinephrine initiation may be considered in addition to standard fluid resuscitation measures to optimize control of shock. The current sepsis guidelines recommend vasopressors for septic shock not responsive to fluid resuscitation within 6 hours of presentation, but it may be beneficial to initiate pressor support earlier as opposed to later. While the current study demonstrates an improvement of blood pressure and adequate perfusion, more data is needed to evaluate the mortality benefit of early norepinephrine usage. The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial will further elucidate this topic as we seek to determine what interventions are most critical and beneficial for our patients presenting to the emergency department with sepsis.