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SHOCK, Vol. 44, No. 4, pp.

305–309, 2015

NOREPINEPHRINE: NOT TOO MUCH, TOO LONG

Claude Martin, Sophie Medam, François Antonini, Julie Alingrin, Malik Haddam,
Emmanuelle Hammad, Bertrand Meyssignac, Coralie Vigne,
Laurent Zieleskiewicz, and Marc Leone
Service d’Anesthésie et de Réanimation, Hôpital Nord, Assistance Publique Hôpitaux de Marseille, and
Aix Marseille Université, Marseille, France

Received 12 Mar 2015; first review completed 30 Mar 2015; accepted in final form 8 Jun 2015

ABSTRACT—The study was designed to assess whether high dosages of norepinephrine are associated with increased
death rate and to determine the dosage of norepinephrine associated with an intensive care unit (ICU) death rate greater
than 90%. We conducted a retrospective, noninterventional, observational study in a single ICU (15 beds) of an academic
hospital. From January 2009 to May 2013, data of all patients with a diagnosis of septic shock were extracted from our
database. Data were collected at the time of the admission in ICU, at the onset of septic shock, and when the maximal
posology of norepinephrine was reached. Mortality was assessed in ICU, in hospital, and at day 90. Among the 324 patients
with septic shock, the death rate was 48%. The death rate reached 90% for the quantile of patients receiving more than 1 mg/
kg per minute of norepinephrine. In our cohort, four independent factors associated with mortality were identified: age (odds
ratio, 1.02 [95% confidence interval, 1.00–1.04]; P ¼ 0.02), thrombocytopenia (odds ratio, 3.8 [95% confidence interval,
1.8–8.5]; P < 0.001), urine output less than 500 mL (odds ratio, 8.7 [95% confidence interval, 3.6–25]; P < 0.001), and
dosage of norepinephrine greater than 1 mg/kg per minute (odds ratio, 9.7 [95% confidence interval, 4.5–23]; P < 0.001).
However, because of the study’s design, unmeasured confounding factors should be taken into account in our findings.
KEYWORDS—Norepinephrine, septic shock, mortality, dosage

INTRODUCTION 968-bed university hospital (Hôpital Nord, Marseille, France). As our electronic
data collection system was set up in 2009, we assessed the interval period from
Septic shock is diagnosed as sepsis-induced hypotension 2009 to 2013. According to French Legislation (articles L.1121-1 paragraph 1
and R1121-2, Public Health Code), neither informed consent nor approval of the
persisting despite adequate fluid administration requiring the ethics committee was needed to use routine data for an observational study.
initiation of vasopressors. According to guidelines, norepi- We retrospectively examined the medical charts of all patients with septic
nephrine should be used as first line of vasopressor (1). A shock. For each patient, we considered only the first episode of septic shock.
They were treated according to local guidelines derived from the Surviving
meta-analysis showed that treatment with norepinephrine had Sepsis Guidelines 2008 (1). Patients were included on the following criteria: age
improved patients’ chance of survival compared with dopamine 18 years or older and first episode of septic shock on ICU admission or during
(2). However, the impact of high dosages of norepinephrine on the ICU stay. We excluded patients with shock states that were not related to
sepsis and patients requiring an extracorporeal membrane oxygenation device.
the outcome remains unclear (3). The initial fluid therapy was guided by preload indices. Depending on the
The literature often reports the concept of refractory dosage patient conditions, dynamic indices or passive leg raising was used. Cardiac
of catecholamine (4–7). In several studies, this concept was ultrasound was used routinely in all patients. Norepinephrine infusion was
targeted to achieve at least a mean arterial pressure of 65 mmHg and a urine
used in order to introduce the need for alternative therapeutics. output greater than 0.5 mL/kg per hour. Heart rate, mean arterial pressure, pulse
Depending on the publications, these dosages of norepi- oximetry, and end-tidal carbon dioxide (if required) were continuously
nephrine ranged from 0.5 to 4 mg/kg per minute (5, 7–9). measured (Patient monitor Intellivue MP 70; Philips, Andover, Mass). All
patients had an arterial catheter and a central venous catheter.
Existing data reveal a cumulative dosage of norepinephrine
at 294 mg/kg (10). These data do not focus on patients with Data collection
septic shock. In addition, at the bedside, a cumulative value
Demographic and clinical data were collected from the medical charts.
may be difficult to assess. Hemodynamic data were extracted from medical charts. At the ICU admission,
The goals of our retrospective study were to determine which we collected data on age, gender, body mass index, Simplified Acute Physi-
dosage of norepinephrine is associated with a death rate ology Score (SAPS) 2, and prior medical history. At the onset of norepinephrine
infusion, we collected the following data: cause of shock; site of infection;
exceeding 90% and if norepinephrine dosage is a potential Sequential Organ Failure Assessment (SOFA) score (11); the presence of at
independent factor associated with mortality. least one of the following organ failures: acute respiratory failure defined by a
ratio of arterial pressure in oxygen to the fraction of inspired oxygen (PaO2/FIO2
ratio) less than 300, thrombocytopenia (<100 G/L), acute renal failure (plasma
PATIENTS AND METHODS creatinine concentration >110 mmol/L), and acute liver failure (bilirubin
>20 mmol/L); and Glasgow coma scale score less than 15. At the maximal
Patients dosage of norepinephrine, we noted the following variables: heart rate, mean
arterial pressure, volume of infused fluid volume during the last 24 h, arterial
From January 2009 to May 2013, a retrospective, observational, and non- oxygen pressure related to inspired fraction of oxygen (PaO2/FIO2) ratio, plasma
interventional study was conducted in a 15-bed intensive care unit (ICU) of a lactate concentration, central venous oxygen saturation if available, pH, base
excess, glycemia, insulin infusion, bilirubin concentration, and renal replace-
Address reprint requests to Marc Leone, MD, PhD, Service d’anesthésie et de ment therapy. We also collected urine output during the 24 h following the hour
Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France. E-mail: of maximal dosage of norepinephrine. At the ICU discharge, we collected the
marc.leone@ap-hm.fr. total duration of norepinephrine infusion, ICU length of stay, use of epineph-
DOI: 10.1097/SHK.0000000000000426 rine, terlipressin, dobutamine, isoproterenol, and hydrocortisone. Mortality was
Copyright ß 2015 by the Shock Society assessed during the ICU stay, stratifying the deaths during the septic shock

305
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306 SHOCK VOL. 44, No. 4 MARTIN ET AL.

episode, at 28 days, and during the hospital stay. Causes of mortality were TABLE 1. Features of the patients with septic shock
assessed in patients dying with norepinephrine and those dying after
norepinephrine cessation. Variables (n ¼ 324)
Demographics
Statistical analysis Age, mean  SD, y 62  15
Sex (male), n (%) 222 (69)
We determined the maximal dosage of norepinephrine associated with a SOFA score, median (Q25–Q75) 8 (6–10)
death rate greater than 90%. Statistics was performed using R-Project 3.1 (GNU SAPS2 score, median (Q25–Q75) 44 (33–61)
Linux Ubuntu 14.10; Canonical Group Limited London, United Kingdom). Days in ICU, mean  SD 15  23
Continuous data were expressed as mean and SD or median with interquartiles.
Qualitative data were expressed as absolute numbers and percentages. The Days in hospital, mean  SD 27  29
comparisons were performed using a Student t test or Mann-Whitney U test Cause of septic shock, n (%)
according to their distribution. We searched for predictors of mortality using a Community pneumonia 30 (9.2)
multidimensional analysis by logistic regression using the forward Wald Hospital-acquired pneumonia 99 (31)
stepwise model. All variables were tested by univariate analysis. Only the Abdominal 92 (29)
variables with P < 0.2 were included in the model. All comparisons were two- Urinary tract 29 (9.0)
tailed, and P < 0.05 was required to exclude the null hypothesis. Gynaecological 2.0 (0.6)
Central nervous system 4.0 (1.3)
Skin and soft tissue 9.0 (2.7)
RESULTS Surgical site infection 30 (9.2)
Catheter related infections 3.0 (1.0)
During the study period, we retrospectively included 324 Unknown 26 (8.0)
patients with septic shock (Fig. 1). Their features are reported in Organ failure, n (%)
Table 1. They were 62  15 years of age with a median SAPS 2 Respiratory 265 (83)
of 44 (Q25-Q75, 33–61). At the onset of septic shock, the Renal 188 (58)
SOFA score was 8 (Q25-Q75, 6–10). Respiratory, renal, and Liver 91 (28)
Glasgow Coma Scale score <14 44 (14)
hepatic failures were reported in 265 (82%), 188 (58%), and 91 Thrombocytopenia (<100 G/L) 65 (20)
(28%) patients. The ICU and hospital death rates were 44% and Norepinephrine
48%, respectively. The main causes of ICU death were septic Maximal dose, mean  SD 0.79  1.03
shock (n ¼ 92 [59%]), limitations of life-sustaining treatments Day of maximal dose, median (Q25–Q75) 1 (1–2)
(n ¼ 37 [24%]), and cardiac arrest (n ¼ 10 [6.4%]). Duration of maximal dose, median (Q25–Q75), h 1 (1–3)
Cumulative time, median (Q25–Q75), h 39 (20–70)
The mortality rate reached 90% for the 20% of patients
receiving more than 1 mg/kg per minute (Fig. 2). The distri-
bution of patients according to the maximal dosage of norepi- The maximal dosages of norepinephrine were 0.3 mg/kg per
nephrine is shown in Figure 2. The maximal dosage of minute (Q25-Q75, 0.2–0.6 mg/kg per minute) in survivors and
norepinephrine was 0.79 mg/kg per minute (Q25-Q75, 0.03– 0.8 mg/kg per minute (Q25-Q75, 0.4–1.4 mg/kg per minute) in
10 mg/kg per minute). The duration of norepinephrine infusion nonsurvivors (P < 0.001) (Table 3). Using a multivariate
was 60 h (Q25-Q75, 2–648 h). The duration of norepinephrine analysis, four independent factors associated with mortality
administration was not associated with the mortality rate were identified: age (odds ratio [OR], 1.02; 95% confidence
(P ¼ 0.09). At the time of maximal norepinephrine dosage, interval [CI], 1.00–1.04]; P ¼ 0.019), thrombocytopenia (OR,
dobutamine, isoproterenol, and epinephrine were administered
to 16 (5%), 68 (21%), and 21 (6%) patients, respectively.
Terlipressin and hydrocortisone were used in 42 (13%) and
68 (21%) patients, respectively (Table 2).

FIG. 2. Observed associations between norepinephrine quartiles


and death rate. Light gray represents the proportion of patients dying during
norepinephrine infusion. Dark gray represents the proportion of patients dying
after norepinephrine infusion cessation. Each bar corresponds to 20% of the
cohort. A dosage greater than 1 mg/kg per minute was associated with a death
rate greater than 90%. The dosages of norepinephrine correspond to the
FIG. 1. Flowchart of inclusion. maximal dosage applied.

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SHOCK OCTOBER 2015 MAXIMAL DOSAGE OF NOREPINEPHRINE 307
TABLE 2. Adjuvant drugs at the maximal dosage of norepinephrine with norepinephrine dosage higher than 1 mg/kg per minute
Maximal dosage of (Fig. 3).
No. of norepinephrine Of note, death occurred in 102 patients during the norepi-
patients (%) (mg/kg per minute) nephrine infusion and 54 patients after the norepinephrine
Terlipressin 42 (13) 1.62 infusion cessation. The maximal dosage of norepinephrine
Dobutamine 16 (5) 1.44 was significantly higher in the patients dying during norepi-
Isoproterenol 68 (21) 1.32
nephrine infusion than in those dying after norepinephrine
Epinephrine 21 (6) 1.60
Hydrocortisone 68 (21) 1.00 infusion cessation (OR, 1.0 [95% CI, 0.5–1.5] vs. 0.4 [95%
CI, 0.3–0.6]; P < 0.001) (Table 3). Of note, the mortality
reached 90% only in the patients dying during norepinephrine
infusion (Fig. 2). This result was not found in the patients dying
3.8; 95% CI, 1.8–8.5; P < 0.001), urine output less than after norepinephrine infusion cessation (Fig. 2). The severity of
500 mL (OR, 8.7 [95% CI, 3.6–25]; P < 0.001), and dosage the patients dying during the norepinephrine infusion was
of norepinephrine greater than 1 mg/kg per minute (OR, 9.7 higher than that of those dying after the norepinephrine infusion
[95% CI, 4.5–23]; P < 0.001) (Table 4). Using this cutoff, we cessation (Table 3). The main cause of death in the patients
observed an increased 90-day mortality in the patients treated dying with norepinephrine was septic shock (n ¼ 82 [81%]). In

TABLE 3. Comparison of patients according to ICU survival


Death occurring
With Without
Survivors Nonsurvivors norepinephrine norepinephrine
Variables (n ¼ 168) (n ¼ 156) P (n ¼ 102) (n ¼ 54) P
Age, median (Q25–Q75), y 59 (51–73) 65 (55–77) 0.01 65 (56–77) 64 (52–76) 0.8
Males, n (%) 108 (64) 114 (73) 0.11 71 (69) 43 (79) 0.09
SAPS2 score at admission, median (Q25–Q75) 41 (32–54) 50 (34–68) 0.00 53 (35–69) 47 (33–68) 0.14
SOFA at maximal dosage, median (Q25–Q75) 7 (6–9) 9.0 (8–12) 0.00 11 (8–12) 8 (7–9) 0.00
Length of stay in ICU, median (Q25–Q75), d 9 (5–17) 8 (2–20) 0.47 5 (2–10) 13 (9–30) 0.00
Length of stay in hospital, median (Q25–Q75), d 27 (18–47) 8 (2–23) 0.00 5 (2–10) 21 (10–35) 0.00
Organ failure, n (%)
Respiratory 127 (76) 138 (90) 0.00 93 (91) 45 (83) 0.08
Renal 76 (46) 112 (72) 0.00 77 (75) 35 (64) 0.15
Liver 37 (22) 54 (35) 0.01 38 (37) 16 (29) 0.3
Glasgow Coma Scale score <14 13 (8) 31 (20) 0.00 19 (18) 12 (22) 0.5
Thrombocytopenia <100 G/L 17 (10) 48 (31) 0.00 35 (34) 13 (24) 0.14
Norepinephrine
Maximal dose administered, median 0.3 (0.2–0.6) 0.8 (0.4–1.4) 0.00 1.0 (0.5–1.5) 0.4 (0.3–0.6) 0.00
(Q25–Q75), mg/kg per minute
Duration of maximal dose, median 1.0 (1.0–3.0) 2.0 (1.0–3.0) 0.2 2.0 (1.0–4.0) 1.0 (1.0–3.0) 0.3
(Q25–Q75), h
Cumulative time, median (Q25–Q75), h 37 (21–63) 44 (19–91) 0.09 34 (15–81) 54 (37–96) 0.5
Hemodynamic adjuvant treatment, n (%)
Dobutamine 4.0 (2.4) 12 (7.7) 0.05 12 (11) 0 (0) 0.03
Isoproterenol 20 (12) 48 (31) 0.00 36 (35) 12 (22) 0.5
Epinephrine 3 (1.8) 18 (12) 0.00 17 (16) 1 (2) 0.04
Terlipressin 9 (5.4) 33 (21) 0.00 29 (28) 4 (7.4) 0.00
Hydrocortisone 32 (19) 36 (23) 0.45 23 (22) 13 (24) 0.7
Baseline features at the day of maximal dose of norepinephrine, median (Q25–Q75)
Mean arterial pressure, mmHg 60 (55–64) 54 (48–60) 0.00 52 (44–58) 58 (52–62) 0.00
Heart rate, beats/min 120 (106–136) 126 (113–141) 0.02 126 (113–140) 123 (112–144) 0.8
Crystalloid, L 1.0 (0.0–2.5) 1.0 (0.0–2.0) 0.03 1.0 (0.1–0.2) 1.5 (0.3–2.5) 0.02
Colloid, L 0.1 (0.0–0.5) 0.0 (0.0–0.5) 0.26 0 (0.0–0.5) 0.0 (0.0–0.8) 0.6
Cumulative fluid administration, L 1.5 (0.9–3.0) 1.0 (0.5–2.0) 0.03 1.0 (0.5–2.0) 2 (0.6–3.0) 0.02
PaO2/FIO2 ratio 166 (107–223) 124 (83–195) 0.00 109 (77–162) 174 (119–260) 0.00
Plasma lactate levels, mmol/L 2.5 (1.8–3.7) 3.5 (2.0–8.0) 0.00 4.8 (2.4–8.8) 2.4 (1.8–4.1) 0.00
ScvO2, % 76 (70–83) 75 (67–83) 0.19 74 (66–82) 77 (68–83) 0.2
Urine output 24 h, mL 1,734 (1,261–2,452) 763 (202–1,548) 0.00 419 (128–1,290) 1,427 (822–2,097) 0.00
Renal replacement therapy, n (%) 7 (4) 28 (18) 0.00 23 (22) 5 (9) 0.03
Creatinine plasma levels, mmol/L 105 (70–158) 140 (91–218) 0.00 152 (95–233) 117 (80–163) 0.00
Bilirubin plasma levels, mmol/L 12 (7–23) 15 (9–47) 0.00 15 (10–51) 14 (5–40) 0.4
pH (plasma) 7.3 (7.3–7.4) 7.2 (7.1–7.3) 0.00 7.2 (7.0–7.3) 7.3 (7.3– 7.4) 0.00
Base excess, mmol/L 3.4 (6.3 to 0.6) 6.8 (12.1 to 1.6) 0.00 7.9 (14 to 3.1) 3.5 (6.9 to 1.5) 0.00
Glycemia, mmol/L 7.6 (5.4–8.9) 7.2 (5.0–8.7) 0.16 6.1 (4.3–8.2) 7.5 (6.3–9.0) 0.03
Insulin administration, % 62 47 0.2
ScvO2 indicates central venous oxygen saturation.

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308 SHOCK VOL. 44, No. 4 MARTIN ET AL.

TABLE 4. Multivariate analysis: independent predictors of mortality was associated with an increased mortality rate (10). Of note,
Variables OR (95% CI) P all types of shock were included in the analysis, whereas we
Age 1.02 (1.00–1.04) 0.019 included only patients with septic shock. In our opinion, the
Thrombocytopenia <100 G/L 3.8 (1.8–8.5) 0.002 inclusion of patients with septic shock may improve the
Dose of norepinephrine 9.7 (4.5–23) <0.00 consistency of our findings. In contrast, we did not find that
1 mg/kg per minute the duration of norepinephrine infusion was an independent
Urine output <500 mL/24 h 8.7 (3.6–25) <0.00
factor associated with ICU death.
Being older, having thrombocytopenia, producing a low
urine output, and having a norepinephrine dosage greater than
the patients dying after norepinephrine infusion cessation, the 1 mg/kg per minute were independently associated with
main causes of death were limitations of life-sustaining treat- mortality. Chou et al. (16) found that dosage of norepinephrine
ments (n ¼ 23 [43%]) and a new septic shock episode (n ¼ 10 greater than 0.3 mg/kg per minute before renal replacement
[19%]). therapy onset was associated with an increased mortality rate.
In addition, they also identified thrombocytopenia as an inde-
pendent risk factor for mortality. Elsewhere, low urine flow,
DISCUSSION
high lactate levels, high organ failure score, high prothrombin
In our cohort of patients with septic shock, the infusion of time, and need for epinephrine cotreatment were associated
norepinephrine at a dosage greater than 1 mg/kg per minute was with mortality, whereas high doses of norepinephrine did not
associated with a mortality rate greater than 90%. This dosage impact outcomes. However, in this study, only a small number
represented 20% of our cohort. In addition, we found that a of patients received 0.9 mg/kg per minute (17).
dosage of norepinephrine greater than 1 mg/kg per minute was Our study has several limitations. First, we decided a
the strongest independent factor associated with mortality in mortality rate of 90% for determining the threshold of maximal
patients with septic shock. This result was found specifically in norepinephrine dosage. Actually, we did not find an adequate
the patients dying during norepinephrine infusion. Because of definition in the literature. This choice should not be interpreted
the nature of study, unmeasured confounding factors may have as a message to stop or withhold treatments, but it suggests a
a role in our findings (12, 13). threshold for assessing new strategies. In addition, maximal
In previous studies, the concept of catecholamine-resistant dosage may have been attained only in the hour(s) just prior to
dosages was used in order to initiate adjunctive treatments. As death. One should note that, unless on patient presentation,
discussed previously, there is a large variability of dosages maximal dosage of norepinephrine should not be considered as
between the different publications (4–10). The clinicians need a risk factor but a reflection of the disease severity. Second, the
to know what is the threshold associated with the high risk of study design was retrospective. Because of this design, our
mortality. In addition, there is a need to harmonize this concept choices for the statistical approach are a matter of discussion.
for the consistency of guidelines and future clinical trials. Third, our protocol recommends achieving at least a mean
We found that a dosage of 1 mg/kg per minute was associated arterial pressure of 65 mmHg, according to the Surviving
with a 90% ICU death rate. Jenkins et al. (14) reported a 3.6% Sepsis Guidelines (1). Elsewhere, Dubin et al. (18) underlined
survival for dosage of norepinephrine greater than 2 mg/kg per the need for an individualized assessment. This finding was
minute. However, only 64 patients were included in this study. confirmed in several studies focusing on microcirculation (19,
Brown et al. (15) found a 20% survival in patients with septic 20). In septic shock, the optimal level of mean arterial pressure
shock receiving 1 mg/kg per minute of norepinephrine or more. remains a matter of debate (21). Fourth, our sample size was
In our study, the survival rate was 12% in this subgroup. good for a single hospital but small for this type of statistical
Elsewhere, a dosage of 1 mg/kg per minute for a 5-h duration analysis. These results need to be confirmed in a large, pro-
spective cohort. Finally, our study did not suggest an alternative
management in patients requiring high-dosage norepinephrine.
One can note that, in a randomized clinical trial, use of
b-blockers in patients with septic shock was associated with
a marked reduction in norepinephrine requirements (22).
In conclusion, although unmeasured confounding factors
may account for our findings, a norepinephrine dosage was
associated with a 90% ICU death rate, corresponding to a
dosage of 1 mg/kg per minute. In addition, our results clearly
show that a dosage of norepinephrine greater than 1 mg/kg per
minute is an independent factor associated with mortality in
patients with septic shock.

ACKNOWLEDGMENTS
FIG. 3. Survival analysis at day 90 according to norepinephrine (NE) The authors thank Charlotte Kelway for her assistance with the editing of
dosage with a cutoff at 1 mg/kg per minute. this manuscript.

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SHOCK OCTOBER 2015 MAXIMAL DOSAGE OF NOREPINEPHRINE 309
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