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NOREPINEPHRINE: NOT TOO MUCH, TOO LONG

Martin, Claude; Medam, Sophie; Antonini, François; Alingrin, Julie; Haddam, Malik; Hammad, Emmanuelle; Meyssignac, Bertrand; Vigne, Coralie; Zieleskiewicz, Laurent; Leone, Marc

Shock: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches: October 2015 - Volume 44 - Issue 4 - p 305–309
doi: 10.1097/SHK.0000000000000426
Clinical Aspects
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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 μg/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 = 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 μg/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.

Service d’Anesthésie et de Réanimation, Hôpital Nord, Assistance Publique Hôpitaux de Marseille, and Aix Marseille Université, Marseille, France

Address reprint requests to Marc Leone, MD, PhD, Service d’anesthésie et de Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France. E-mail: marc.leone@ap-hm.fr.

Received 12 March, 2015

Revised 30 March, 2015

Accepted 8 June, 2015

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INTRODUCTION

Septic shock is diagnosed as sepsis-induced hypotension persisting despite adequate fluid administration requiring the initiation of vasopressors. According to guidelines, norepinephrine should be used as first line of vasopressor (1). A meta-analysis showed that treatment with norepinephrine had improved patients’ chance of survival compared with dopamine (2). However, the impact of high dosages of norepinephrine on the outcome remains unclear (3).

The literature often reports the concept of refractory dosage of catecholamine (4–7). In several studies, this concept was used in order to introduce the need for alternative therapeutics. Depending on the publications, these dosages of norepinephrine ranged from 0.5 to 4 μg/kg per minute (5,7–9). Existing data reveal a cumulative dosage of norepinephrine at 294 μg/kg (10). These data do not focus on patients with septic shock. In addition, at the bedside, a cumulative value may be difficult to assess.

The goals of our retrospective study were to determine which dosage of norepinephrine is associated with a death rate exceeding 90% and if norepinephrine dosage is a potential independent factor associated with mortality.

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PATIENTS AND METHODS

Patients

From January 2009 to May 2013, a retrospective, observational, and noninterventional study was conducted in a 15-bed intensive care unit (ICU) of a 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 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 ethics committee was needed to use routine data for an observational study.

We retrospectively examined the medical charts of all patients with septic shock. For each patient, we considered only the first episode of septic shock. They were treated according to local guidelines derived from the Surviving Sepsis Guidelines 2008 (1). Patients were included on the following criteria: age 18 years or older and first episode of septic shock on ICU admission or during the ICU stay. We excluded patients with shock states that were not related to sepsis and patients requiring an extracorporeal membrane oxygenation device. The initial fluid therapy was guided by preload indices. Depending on the patient conditions, dynamic indices or passive leg raising was used. Cardiac 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 output greater than 0.5 mL/kg per hour. Heart rate, mean arterial pressure, pulse oximetry, and end-tidal carbon dioxide (if required) were continuously measured (Patient monitor Intellivue MP 70; Philips, Andover, Mass). All patients had an arterial catheter and a central venous catheter.

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Data collection

Demographic and clinical data were collected from the medical charts. Hemodynamic data were extracted from medical charts. At the ICU admission, we collected data on age, gender, body mass index, Simplified Acute Physiology Score (SAPS) 2, and prior medical history. At the onset of norepinephrine infusion, we collected the following data: cause of shock; site of infection; Sequential Organ Failure Assessment (SOFA) score (11); the presence of at 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 creatinine concentration >110 μmol/L), and acute liver failure (bilirubin >20 μmol/L); and Glasgow coma scale score less than 15. At the maximal dosage of norepinephrine, we noted the following variables: heart rate, mean arterial pressure, volume of infused fluid volume during the last 24 h, arterial oxygen pressure related to inspired fraction of oxygen (PaO2/FIO2) ratio, plasma lactate concentration, central venous oxygen saturation if available, pH, base excess, glycemia, insulin infusion, bilirubin concentration, and renal replacement therapy. We also collected urine output during the 24 h following the hour of maximal dosage of norepinephrine. At the ICU discharge, we collected the total duration of norepinephrine infusion, ICU length of stay, use of epinephrine, terlipressin, dobutamine, isoproterenol, and hydrocortisone. Mortality was assessed during the ICU stay, stratifying the deaths during the septic shock episode, at 28 days, and during the hospital stay. Causes of mortality were assessed in patients dying with norepinephrine and those dying after norepinephrine cessation.

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Statistical analysis

We determined the maximal dosage of norepinephrine associated with a death rate greater than 90%. Statistics was performed using R-Project 3.1 (GNU Linux Ubuntu 14.10; Canonical Group Limited London, United Kingdom). Continuous data were expressed as mean and SD or median with interquartiles. Qualitative data were expressed as absolute numbers and percentages. The comparisons were performed using a Student t test or Mann-Whitney U test according to their distribution. We searched for predictors of mortality using a multidimensional analysis by logistic regression using the forward Wald stepwise model. All variables were tested by univariate analysis. Only the variables with P < 0.2 were included in the model. All comparisons were two-tailed, and P < 0.05 was required to exclude the null hypothesis.

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RESULTS

During the study period, we retrospectively included 324 patients with septic shock (Fig. 1). Their features are reported in Table 1. They were 62 ± 15 years of age with a median SAPS 2 of 44 (Q25-Q75, 33–61). At the onset of septic shock, the SOFA score was 8 (Q25-Q75, 6–10). Respiratory, renal, and hepatic failures were reported in 265 (82%), 188 (58%), and 91 (28%) patients. The ICU and hospital death rates were 44% and 48%, respectively. The main causes of ICU death were septic shock (n = 92 [59%]), limitations of life-sustaining treatments (n = 37 [24%]), and cardiac arrest (n = 10 [6.4%]).

Fig. 1

Fig. 1

Table 1

Table 1

The mortality rate reached 90% for the 20% of patients receiving more than 1 μg/kg per minute (Fig. 2). The distribution of patients according to the maximal dosage of norepinephrine is shown in Figure 2. The maximal dosage of norepinephrine was 0.79 μg/kg per minute (Q25-Q75, 0.03–10 μg/kg per minute). The duration of norepinephrine infusion was 60 h (Q25-Q75, 2–648 h). The duration of norepinephrine administration was not associated with the mortality rate (P = 0.09). At the time of maximal norepinephrine dosage, 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

Fig. 2

Table 2

Table 2

The maximal dosages of norepinephrine were 0.3 μg/kg per minute (Q25-Q75, 0.2–0.6 μg/kg per minute) in survivors and 0.8 μg/kg per minute (Q25-Q75, 0.4–1.4 μg/kg per minute) in nonsurvivors (P < 0.001) (Table 3). Using a multivariate analysis, four independent factors associated with mortality were identified: age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.00–1.04]; P = 0.019), thrombocytopenia (OR, 3.8; 95% CI, 1.8–8.5; P < 0.001), urine output less than 500 mL (OR, 8.7 [95% CI, 3.6–25]; P < 0.001), and dosage of norepinephrine greater than 1 μg/kg per minute (OR, 9.7 [95% CI, 4.5–23]; P < 0.001) (Table 4). Using this cutoff, we observed an increased 90-day mortality in the patients treated with norepinephrine dosage higher than 1 μg/kg per minute (Fig. 3).

Table 3

Table 3

Table 4

Table 4

Fig. 3

Fig. 3

Of note, death occurred in 102 patients during the norepinephrine infusion and 54 patients after the norepinephrine infusion cessation. The maximal dosage of norepinephrine was significantly higher in the patients dying during norepinephrine infusion than in those dying after norepinephrine 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 after norepinephrine infusion cessation (Fig. 2). The severity of the patients dying during the norepinephrine infusion was higher than that of those dying after the norepinephrine infusion cessation (Table 3). The main cause of death in the patients dying with norepinephrine was septic shock (n = 82 [81%]). In the patients dying after norepinephrine infusion cessation, the main causes of death were limitations of life-sustaining treatments (n = 23 [43%]) and a new septic shock episode (n = 10 [19%]).

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DISCUSSION

In our cohort of patients with septic shock, the infusion of norepinephrine at a dosage greater than 1 μg/kg per minute was associated with a mortality rate greater than 90%. This dosage represented 20% of our cohort. In addition, we found that a dosage of norepinephrine greater than 1 μg/kg per minute was the strongest independent factor associated with mortality in patients with septic shock. This result was found specifically in the patients dying during norepinephrine infusion. Because of the nature of study, unmeasured confounding factors may have a role in our findings (12,13).

In previous studies, the concept of catecholamine-resistant dosages was used in order to initiate adjunctive treatments. As discussed previously, there is a large variability of dosages between the different publications (4–10). The clinicians need to know what is the threshold associated with the high risk of mortality. In addition, there is a need to harmonize this concept for the consistency of guidelines and future clinical trials.

We found that a dosage of 1 μg/kg per minute was associated with a 90% ICU death rate. Jenkins et al. (14) reported a 3.6% survival for dosage of norepinephrine greater than 2 μg/kg per minute. However, only 64 patients were included in this study. Brown et al. (15) found a 20% survival in patients with septic shock receiving 1 μg/kg per minute of norepinephrine or more. In our study, the survival rate was 12% in this subgroup. Elsewhere, a dosage of 1 μg/kg per minute for a 5-h duration was associated with an increased mortality rate (10). Of note, all types of shock were included in the analysis, whereas we included only patients with septic shock. In our opinion, the inclusion of patients with septic shock may improve the consistency of our findings. In contrast, we did not find that the duration of norepinephrine infusion was an independent factor associated with ICU death.

Being older, having thrombocytopenia, producing a low urine output, and having a norepinephrine dosage greater than 1 μg/kg per minute were independently associated with mortality. Chou et al. (16) found that dosage of norepinephrine greater than 0.3 μg/kg per minute before renal replacement therapy onset was associated with an increased mortality rate. In addition, they also identified thrombocytopenia as an independent risk factor for mortality. Elsewhere, low urine flow, high lactate levels, high organ failure score, high prothrombin time, and need for epinephrine cotreatment were associated with mortality, whereas high doses of norepinephrine did not impact outcomes. However, in this study, only a small number of patients received 0.9 μg/kg per minute (17).

Our study has several limitations. First, we decided a mortality rate of 90% for determining the threshold of maximal norepinephrine dosage. Actually, we did not find an adequate definition in the literature. This choice should not be interpreted as a message to stop or withhold treatments, but it suggests a threshold for assessing new strategies. In addition, maximal dosage may have been attained only in the hour(s) just prior to death. One should note that, unless on patient presentation, maximal dosage of norepinephrine should not be considered as a risk factor but a reflection of the disease severity. Second, the study design was retrospective. Because of this design, our choices for the statistical approach are a matter of discussion. Third, our protocol recommends achieving at least a mean arterial pressure of 65 mmHg, according to the Surviving Sepsis Guidelines (1). Elsewhere, Dubin et al. (18) underlined the need for an individualized assessment. This finding was confirmed in several studies focusing on microcirculation (19,20). In septic shock, the optimal level of mean arterial pressure remains a matter of debate (21). Fourth, our sample size was good for a single hospital but small for this type of statistical analysis. These results need to be confirmed in a large, prospective 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 β-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 μg/kg per minute. In addition, our results clearly show that a dosage of norepinephrine greater than 1 μg/kg per minute is an independent factor associated with mortality in patients with septic shock.

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ACKNOWLEDGMENTS

The authors thank Charlotte Kelway for her assistance with the editing of this manuscript.

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Keywords:

Norepinephrine; septic shock; mortality; dosage

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