Date: June 2nd, 2020

Reference: Permpikul et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial. Respir Crit Care Med 2019.

Guest Skeptic: Dr. Max Hockstein trained as an Emergency Medicine physician at University of Texas Southwestern and is finishing his Intensive Care fellowship at Emory. Max is then going to Georgetown to be an attending in both EM and ICU.

Case: It’s another day in your emergency department (ED).  Six hours into your shift, you finish dispo’ing the “really quick sign-out” from the night before.  The triage nurse places a 61 year-old-man with fever, hypotension, cough into the smallest room in the ED.  You scan through the EMR and see the blood pressure is 60/40.  Being an astute emergency physician, you surmise that this value is one number column short of normal.  It’s uncomfortably low – is it time to start a norepinephrine infusion?

Background: I think we have covered sepsis more often than any other topic on the SGEM. It was the landmark paper published 19 years ago by Dr. Emanuel Rivers on early goal directed therapy in the treatment of severe sepsis and septic shock that sensitized the medical community (Rivers et al NEJM 2001).

  • SGEM#44: Pause (Etomidate and Rapid Sequence Intubation in Sepsis)
  • SGEM#69: Cry Me A River (Early Goal Directed Therapy) ProCESS Trial
  • SGEM#90: Hunting High and Low (Best MAP for Sepsis Patients)
  • SGEM#92: ARISE Up, ARISE Up (EGDT vs. Usual Care for Sepsis)
  • SGEM#113: EGDT – ProMISe(s) ProMISe(s)
  • SGEM#174: Don’t Believe the Hype – Vitamin C Cocktail for Sepsis
  • SGEM#207: Ahh (Don’t) Push It – Pre-Hospital IV Antibiotics for Sepsis.

One of the goals of the early treatment of septic shock is to restore end-organ perfusion.  Significant effort has been placed on the administration of IV crystalloids to address concerns for hypovolemia in septic shock.  However, it has become evident that patients are often over-resuscitated with IV fluids which adversely impacts outcome.  As such, the idea of the early norepinephrine administration to restore end-organ perfusion in septic shock has been suggested.

Monitor-Oriented Outcomes (MOOs)

Trials that examine outcomes in shock, historically, have examined two types of outcomes: patient-oriented outcomes (POOs) and monitor-oriented outcomes (MOOs).  POOs focus on occurrences that matter to patients while MOOs do not.  Many trials examining vasoactive infusions use MOOs as an endpoint(s) targeted to the medication’s intended use (i.e. increase in MAP).  Much like titrating a therapy to an outcome, MOOs are frequently easier to monitor (ex: blood pressure, heart rate, mean arterial pressure, oxygen saturation, etc).

An old adage in resuscitating the hypotensive patient “first, fill the tank” has gone largely unchallenged over the past several years.  Oddly enough, however, shortening the duration of shock time-to-shock-resolution hasn’t translated to any measurably better outcomes.

Clinical Question: Does starting norepinephrine earlier in septic shock lead to earlier shock control?

Reference: Permpikul et al.Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial. Respir Crit Care Med 2019.

  • Population: Adult patients (18 year of age and older) presenting to the ED with a mean arterial pressure (MAP) < 65 mmHg. Infection needed to be the suspected cause of the hypotension. Patients also had to meet 2012 surviving sepsis diagnostic criteria.
    • Exclusions: Acute cardiac and cerebral conditions, pulmonary edema, status asthmaticus, gastrointestinal bleeding, pregnancy, burn, drug overdose, trauma, need immediate surgery and cancer.
  • Intervention: Early norepinephrine adjusted to 0.05ug/kg/min for 24hrs plus usual care
  • Comparison: Placebo plus usual care (intravenous fluids, appropriate antibiotics, source control and organ support as directed by the attending physician)
  • Outcome:
    • Primary Outcome: Shock control (sustained MAP > 65mmHg) by six hours after diagnosis of sepsis with hypotension together with adequate tissue perfusion (urine flow >0.5ml/kg/h for two consecutive hours or a decrease in serum lactate by > 10% from the initial lactate level).
    • Secondary Outcomes: 28-day mortality and hospital mortality, time from initial treatment to achieving target MAP and tissue perfusion goal (and within six hours), urine output within six hours, rate of respiratory failure requiring mechanical ventilator support, rate of renal failure requiring renal replacement therapy, lactate clearance, and number of organ support-free days to day 28 were also recorded.

Authors’ Conclusions: Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice.”      

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Unsure
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure

Key Results: There were 310 patients included in the trial. The median age was in the late 60’s with slightly more females. The main sources of infections were urinary tract 30%, pneumonia 25%, intra-abdominal 20%, skin and soft tissue 10%.

Shock control was significantly higher in early norepinephrine group

  • Primary Outcome: Shock control by six hours was 76.1% in early norepinephrine group vs. 48.4% in the control group.

1) Time-to-Shock-Control: Intuitively, you would think that the less time that people spend in hemodynamic “shambles“, the better they would do. Think of all the trials that tried to improve time-to-shock-control like the CORTICUS trial.ed This probably has something to do with our evolution and the human ability to withstand wide ranges of hemodynamic derangements.  Regardless, no study has been able to show that the less time patients spend in shock, the better they will do.

The metric they used for shock-control (urine output and lactate clearance) were suboptimal. Neither of these clearly demonstrates shock control.  Lactate clearance is unreliable and can be misleading- especially in patients that are receiving therapies that increase the concentration of glycolytic intermediates or increase their clearance.

2) Blinding: There is a possibility that the study was unblinded. This is because the norepinephrine gives a rapid rise blood pressure which could be noticed by the treating clinician. The unblinding could have introduced some bias into the trial. The researchers could have checked on this by asking the clinicians to guess patient group allocation.

3) MOOs and POOs: Do you really think patients care how long it took them to get shock-control, what their lactate level or urine output is per hour or what was their MAP? These are monitor-oriented outcomes (MOOs). What patients care about more is being dead or alive (80’s tune Dead or Alive) which would be a patient- oriented outcome (POO). An even better POO would be alive and physically well.

4) Intravenous Fluids: Early norepinephrine use didn’t decrease the amount of volume people received. So, maybe, despite having earlier shock control, the tendency was to complete 30 mL/kg mandate.  It is a weird predicament we’ve placed ourselves into where we have to think about a catecholamine as a “fluid-sparing agent.”  Our goal should be to stop people from going from raisin to grape, so we don’t have to take them from grape to raisin later (if we get the chance).

5) Adverse Events: The observed adverse events in this trial also told us what we already know: skin necrosis rates were equal between the two groups. Also note that half of the patients got norepinephrine through a peripheral line.  There was less cardiogenic pulmonary edema in the early norepinephrine group, however, this was puzzling since the groups received approximately the same amount of IV fluid.  This may be because of the (trivial) beta-1 effects of the norepinephrine.  There were also less new-onset arrhythmias in the early norepinephrine group.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors that norepinephrine raises blood pressure, MAP, urinary output and lactate clearance.  However, we did not need a study to tell us that information.  This makes the paper’s conclusion no better than the ATHOS-3 trial.  This paper showed that giving NE early is feasible and not unreasonable.

SGEM Bottom Line: Early norepinephrine can change some MOOs (MAP, lactate, urinary output) but does not seem to change any POOs  (in-hospital or 28-day mortality) in adult patients with septic shock.

Case Resolution: While a bag of isotonic crystalloid of choice is being infused through one peripheral IV, fixed-dose norepinephrine at 0.05 ug/kg/min is started through the other.  The patient is then taken to the intensive care unit where he makes a full recovery after three days of treatment for his community acquired pneumonia.

Dr. Max Hockstein

Clinical Application: This trial does not change anything for me. Hypotension is an emergency and as emergency physicians, we are good at treating it. This was a well-designed trial that should generate tempered enthusiasm for early norepinephrine while further trials are being performed. The ongoing CLOVERS trial will hopefully shed some light on many of the hypothesis-generating questions that the secondary outcomes of this trial left us with.

What Do I Tell My Patient? You have a pneumonia. This is an infection in your lungs. It is making your blood pressure dangerously low. We can increase your blood pressure by giving you some IV fluids. We can also raise your blood pressure with a medicine called norepinephrine. This medicine can be turned up to keep you blood pressure closer to normal while we give the antibiotics time to work.

Keener Kontest: Last weeks’ winner was Dr. Florencia García Pintos. She knew the motor vehicle mortality in the US was 36,560

Listen to the SGEM podcast to hear this weeks’ question. Send your answer to with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.