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Vasopressor Cumulative Dose Requirement and Risk of Early Death During Septic Shock

An Analysis From The EPISS Cohort

Dargent, Auguste*,‡; Nguyen, Maxime*; Fournel, Isabelle; Bourredjem, Abderrahmane; Charles, Pierre-Emmanuel*,‡; Quenot, Jean-Pierre*,†,‡ and the EPISS study group

doi: 10.1097/SHK.0000000000001022
Clinical Science Aspects
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ABSTRACT Septic shock is the primary cause of death in intensive care units, with about 20% of patients dying in the first 3 days. To design future trials focused on early mortality, we require knowledge of early indicators that can detect patients at high risk of early death from refractory septic shock. The aim of this study was to assess whether the cumulative dose of vasopressors (CDV), calculated as the cumulative dose of epinephrine + norepinephrine, is a predictor of early death (within 72 h) attributable to refractory septic shock (EDASS). This substudy of the EPISS trial was based on 370 patients admitted to a French ICU for septic shock between 2009 and 2011. The area under the receiving operating characteristic curve was calculated for the CDV at 6, 12, 24, 36, and 48 h after vasopressor initiation, and a strategy to predict the risk of EDASS was built based on selected times and thresholds. Among the 370 patients included, 51 (14%) died within the first 72 h with 40 (11%) EDASS. A strategy in two steps (CDV ≥ 800 μg/kg at 6 h and/or CDV ≥ 2,600 μg/kg at 24 h) was able to predict EDASS with sensitivity of 45%, specificity 97%, positive predictive value 78% and negative predictive value 94%. Overall, our results confirm that early death directly attributable to septic shock could be effectively predicted by the CDV in the first hours of treatment. These results will help to select patients eligible for innovative therapies aimed at improving early mortality in septic shock.

*Department of Intensive Care, François Mitterrand University Hospital, Dijon, France

INSERM CIC1432, Clinical Epidemiology, University of Burgundy, Dijon, France

Lipness Team, INSERM Research Center LNC-UMR1231and LabExLipSTIC, University of Burgundy, Dijon, France

Address reprint requests to Auguste Dargent, MD, University Hospital Dijon, France, Hôpital F. Mitterrand, 14 Rue Paul Gaffarel, BP 77 908, 21079 Dijon Cedex, France. E-mail: auguste.dargent@chu-dijon.fr

Received 21 June, 2017

Revised 6 July, 2017

Accepted 5 October, 2017

The complete list of investigators participating in the EPISS study is given in the Appendix.

The authors have no conflict of interest to declare.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com).

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INTRODUCTION

Septic shock remains associated with abysmal prognosis and very high mortality in the intensive care unit (ICU). Accordingly, ICU mortality in France in patients with septic shock reaches up to 39.5%, and in-hospital mortality up to 48.7% (1). More than a third of patients who die from septic shock do so in the first 3 days of disease. Data on the causes of death in septic shock are scarce, especially with particular focus on the timing of death. In a retrospective study, Daviaud et al. (2) showed that most early deaths (0–3 days) in septic shock were attributable to primary infection-related multiorgan failure, after exclusion of mesenteric ischemia, iatrogenic hemorrhagic complications, and more rare causes. This contrasted with late deaths (occurring beyond three days), which are most frequently attributed to end-of-life decisions and secondary infections. This dichotomy corroborates the recent pathophysiologic models dividing mortality of sepsis into two distinct phases according to the state of activation of the immune system (3). Most patients who die within the first 3 days present with a state of persistent hypotension, refractory to conventional treatment and leading to multiple organ failure. The term “refractory septic shock” (RSS) is often used to describe this condition, which accounts for the abrupt early rise in the sepsis mortality curve. However, as yet, there is no consensual definition of RSS. Although the concept of RSS was first mentioned in the literature since as early as 1965 (4), there are almost as many definitions as publications mentioning it. Nonetheless, resistance to catecholamines is often used to describe RSS, and seems to be one of its hallmarks (5, 6).

The phenomenon of catecholamine resistance is enhanced in refractory shock patients, as demonstrated by Conrad et al. (7). In their study including 51 consecutive patients with septic shock, RSS patients (defined as the inability to sustain systolic blood pressure more than 90 mmHg for more than 24 h without norepinephrine) had a significantly lower mean arterial pressure response to phenylephrine. These results suggested RSS progression might reasonably be predicted in the early phase of vasopressor initiation. Although there are no evidence-based therapeutic options for RSS to date, the identification of high-risk patients is crucial in order to design appropriate trials addressing early mortality attributable to catecholamine resistance. Indeed, defining a concrete threshold indicative of nonresponse to therapy would help to identify patients who could yield the most benefit from new therapies, such as angiotensin II. This new vasopressor agent was recently shown to effectively increase blood pressure in patients with vasodilatory shock, but failed to demonstrate a significant effect on survival (8). In our opinion, this example emphasizes the need for better identification of patients at risk of dying due to vasopressor resistance. The main aim of the present study was to investigate the utility of a new metric, namely the cumulative dose of vasopressors (CDV) as a predictor of early death attributable to septic shock, i.e., within 3 days following vasopressor initiation. Secondary objectives were to determine the timing and causes of death from septic shock in our cohort and to identify the best strategy to predict early death.

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METHODS

Study population

The study population prospectively included consecutive patients with a diagnosis of septic shock admitted to the ICU of Dijon university teaching hospital, France, between November 2009 and September 2011, in the framework of the EPIdemiology of Septic Shock (EPISS) study, previously been reported in detail elsewhere (1). Briefly, 1,488 patients were enrolled in 14 French ICUs between November 2009 and September 2011 with a diagnosis of septic shock, according to the criteria of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Septic Shock study (9). The present report deals with patients included in Dijon university hospital only, for whom hourly doses of epinephrine and norepinephrine from introduction to weaning or death were available.

According to French legislation, patients (or their legal representative) were informed that their data were collected for research purposes and consent was obtained from the patient (or next of kin). Collection of nominative data was approved by the national authority for the protection of privacy and personal data, and by the ethics committee of the French Society of Intensive Care.

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Endpoints and definitions

The primary outcome of this study was the accuracy of the CDV to predict early death attributable to septic shock (EDASS). Secondary outcomes were the choice of the best time point at which to measure the CDV, and the choice of a clinically meaningful cutoff value for the most accurate marker.

EDASS was defined as fulfillment of the following criteria: death within the first 72 h following vasopressor initiation, ongoing vasopressor therapy at time of death, exclusion of a cause of death other than sepsis. The cause and exact timing of death in the 28 first days following septic shock were retrospectively reassessed by consensus by three senior critical care physicians (A.D., M.N., J.P.Q.), blinded to CDV.

The CDV was defined as the sum of norepinephrine and epinephrine doses, and was measured hourly, with intermediate cumulative totals calculated at 6, 8, 12, 24, 36, and 48 h after vasopressor initiation. Other vasopressors, such as vasopressin or dopamine, were not used, as they were not available in our center at the time of the study.

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Statistical analysis

Continuous variables are described as means and standard deviations for normally distributed variables, and otherwise, as median and interquartile range [IQR], and compared with the Student t test or nonparametric tests, as appropriate. Categorical variables are expressed as number (percentage) and were compared with the Chi square or Fisher's exact tests as appropriate. Cumulative probabilities of EDASS were described using the Kaplan–Meier method.

To determine the most pertinent predictive time points in terms of discriminatory power, the area under the receiver-operating characteristic (ROC) curve (AUROC) as calculated for the CDV (measured at 6, 8, 12, 24, 36, and 48 h after vasopressor initiation) as predictors of EDASS. For each relevant time-point, the cutoff of CDV was chosen based on the best compromise between the positive predictive value and the specificity. Finally, a strategy to predict the overall risk of EDASS was designed, based on the times and thresholds selected in the previous stage of analysis. The association between EDASS and the selected predictive strategy was assessed in a multivariate logistic regression model adjusted for baseline factors identified as predictors of mortality in the EPISS study multivariate model (namely sequential organ failure assessment (SOFA) score, presence or absence of bacteremia, and age). All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). All P values were two-sided. Results with a P-value <0.05 were considered significant.

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RESULTS

Study population

Among 404 consecutive patients with septic shock enrolled in Dijon university hospital, 18 patients were excluded from analysis because of unavailable hospital records. Sixteen further patients were excluded due to early end-of-life decisions (Fig. 1). Thereafter, the present study included a total of 370 patients whose baseline characteristics are shown in Table 1. As expected, patients with EDASS presented with significantly higher severity scores (SOFA, simplified acute physiology score II). They also required more mechanical ventilation and renal replacement therapy. The same differences were observed in the characteristics of patients dead before or after day 3 in ICU regardless of death cause, except for immunosuppression (including cancer) which was significantly more frequently present in patients dead after day 3 (supplemental Table 1, http://links.lww.com/SHK/A653). A numerically higher proportion of patients with EDASS had corticosteroids than among those without EDASS, but the difference between the two groups was not statistically significant (Table 1). Overall, 51 patients (17%) died within the first 72 h, of whom 40/51 died from EDASS, corresponding to 78.4% of those who died, and 11% of those included overall (40/404). The causes of death of the other 11/51 patients are specified in Fig. 1. Among the 319 patients alive at 72 h, four died from refractory multiorgan failure directly attributable to the initial episode of shock, all four between 72 and 96 h from vasopressor initiation.

Fig. 1

Fig. 1

Table 1

Table 1

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Cumulative dose of vasopressors and early death

As shown in Figure 2, the CDV of patients who had EDASS was significantly higher (P < 0.0001) at all-time points after the introduction of catecholamines than among those without EDASS. Vasopressor doses were similar in patients alive at 72 h and in those who died from other causes, whereas EDASS patients had higher CDV than both these groups.

Fig. 2

Fig. 2

The highest AUROC was observed at 24 h (Table 2). However, among the 40 patients with EDASS, 18 EDASS had already occurred before 24 h, hampering the clinical relevance of this time point. With only four EDASS occurring before 6 h and an AUROC of 83% [75%; 92%], 6 h after vasopressor initiation was considered the most clinically relevant early time point to assess CDV. Further evaluation at 8 and 12 h did not improve the AUROC compared with evaluation at 6 h. Based on these results, we proposed a combined two-step strategy, using CDV at 6 h plus CDV at 24 h. The first step at 6 h enables early recognition of patients presenting EDASS. Patients with CDV ≥ 800 μg/kg at 6 h were considered at high risk of EDASS. This cutoff yielded a specificity of 99%, sensitivity of 42%, positive predictive value of 83%, and negative predictive value of 93%.

Table 2

Table 2

The second step, based on CDV at 24 h, made it possible to improve the diagnostic accuracy for patients whose risk level at 6 h had not (yet) reached the threshold identified by our study to be associated with adverse outcome. With a cutoff of 2,600 μg/kg at 24 h, the CDV yielded a specificity of 98%, sensitivity of 64%, positive predictive value of 81%, and negative predictive value of 97%. Overall, this two-step strategy identified 18 high-risk patients at 6 h, of whom 15 presented EDASS. The second evaluation at 24 h allowed identification of nine further high-risk patients, of whom six subsequently had EDASS at 72 h. At 72 h, 313 (93%) of the patients classified as low risk were still alive (Fig. 3). Overall, the model yielded sensitivity of 53%, positive predictive value of 78%, specificity of 98%, and a negative predictive value of 96%.

Fig. 3

Fig. 3

Finally, the two-step strategy defined here remained strongly associated with EDASS (odds ratio = 67.3 [95% confidence interval, 17.9–252.2], P < 0.0001) after adjusting for baseline SOFA score, bacteremia and age. By multivariate analysis, the addition of corticosteroids to vasopressors did not change the overall results, and corticosteroid therapy was not found to be significantly associated with early death.

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DISCUSSION

Our study confirms that the new metric defined in our study, namely early CDV is a strong prognostic factor for mortality attributable to septic shock. The association between vasopressor doses and mortality in sepsis has previously been described in observational studies. In these studies, only the peak dose of vasopressors was considered with a given threshold such as 1 μg/kg/min (10, 11) or 2 μg/kg/min (12), regardless of when this threshold was reached. None of these studies recorded vasopressor dose at different time points over the course of disease. On the contrary, our study is the first, to the best of our knowledge, to propose a metric reflecting the cumulative dose of vasopressors based on hourly measurements, and to show the relation between this metric and the specific causes and timing of death. Our study further showed that vasopressor doses were similar in patients alive at 72 h and in patients who had died from other causes, whereas EDASS patients have much higher CDV, whatever the time point. This confirms the strong relation between early death and vasopressor resistance in sepsis. It was recently demonstrated that vasopressor dependency and refractory shock could be predicted by a mean arterial pressure-phenylephrine dose–response curve (7). Our results suggest that the simple calculation of CDV using a two-step strategy at 6 and 24 h of septic shock could predict the same outcome, probably because the CDV reflects the same underlying phenomenon of catecholamine resistance.

Our study enabled us to design a simple predictive model able to select patients at very high risk of mortality. The 6-h time point was chosen as it allowed an initial rapid and early evaluation of patients at high risk of EDASS. The patients with CDV below the first cutoff underwent a second evaluation at 24 h in order to refine their risk and identify any new patients with an increased risk of EDASS. Indeed, at 24 h, 55% of the patients who would subsequently die by 72 h were still alive, and therefore eligible for further therapeutic intervention. The predictive power of our two-step model remained high, even after adjustment for confounders.

For this model, we chose the thresholds (6 and 24 h) based on the best compromise between specificity and positive predictive value, rather than that of the best agreement rate (maximized at 89% with cutoffs at 300 μg/kg at 6 h and 1,300 μg/kg at 24 h), to select the patients at highest risk, with a low false-positive rate in the perspective of proceeding with a new therapeutic approach in these patients. This two-step strategy was chosen in order to best identify high-risk patients (according to the CDV) in order to guide therapy. Efficient and early selection of patients with a high mortality risk in a very short time is a major challenge if we are to test strategies to reduce early mortality in future trials. We believe that this kind of model might be a robust tool for the selection of patients in future clinical trials targeting early mortality attributable to vasopressor resistance. New vasopressors and vasoactive agents are currently under development, and have the potential to address the issue of catecholamine resistance, although we currently lack the means to identify patients who might yield the most benefit from these treatments. The recently published Angiotensin II for the Treatment of High-Output Shock-3 study reported that angiotensin II effectively increased blood pressure in patients with vasodilatory shock, but the effect on mortality was not statistically significant (8). In this trial, as in others, patient selection was based on an arbitrary norepinephrine flow rate cutoff. We think that in the setting of such trials, the early CDV could help to target, earlier and more accurately, the patients in need of additional vasopressor support.

Further studies with longer follow-up are warranted to consolidate these findings and refine cutoffs.

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Study limitations

The absence of consensus regarding the definition of refractory shock was a major impediment to this study. For this reason, we had to use customized criteria to define the “early death” group, although the criteria chosen were very pragmatic. We firmly believe that there is a compelling need to adopt a consensus definition to define this population.

A limitation of this study is the fact that only two vasopressors were taken into account. The findings may therefore not be extrapolated to patients treated with vasopressin, for example. However, previous publications chose to use coefficients for milrinone, vasopressin, and norepinephrine that would convert them to an integer value and thus give each medication equal weight in the calculation of the score (13, 14). This could allow our CDV score to be used in patients where the equivalence can be calculated.

In conclusion, the CDV within the first 6 h following ICU admission is strongly associated with the risk of early death attributable to septic shock. We describe a two-step model, which allows the identification of a very-high risk population in the first 24 h following vasopressor initiation.

Our results propose an original approach to the ill-defined concept of RSS. Although our analysis is limited to the “vasopressor resistance” component, we believe that the population identified by the new strategy described here represents a first step toward a more broadly accepted definition of “RSS.”

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APPENDIX: LIST OF INVESTIGATORS IN THE EPISS STUDY

J.P. Quenot, P.E. Charles, S. Prin, A. Pavon, S. Barbar, University Hospital Bocage, Dijon, France; K. Kuteifan, J. Mootien, P. Guiot, Centre Hospitalier, Mulhouse, France; F. Kara, Centre Hospitalier, Haguenau, France; M. Hasselmann, P. Sauder, F. Ganster, O. Martinet, NouvelHopital Civil, Strasbourg, France; V. Castellain, F. Schneider, HopitalHautepierre, Strasbourg, France; J.C. Navellou, G. Capellier, Centre HospitalierUniversitaire, Besancon, France; A. Noirot, P. Daoudal, Centre Hospitalier, Vesoul, France; O. Ruyer, M. Feissel, J.P. Faller, Centre Hospitalier, Belfort, France; B. Levy, A. Gerard, J. Perny, P. Perez, HopitalBrabois, Nancy, France; S. Gibot, P.E. Bollaert, D. Barraud, A. Cravoisy, Hopital Central, Nancy, France; A.M. Gutbub, P. Rerat, G. Laplatte, H. Lessire, Centre Hospitalier, Colmar, France; C. Mezher, Centre Hospitalier, Montbeliard, France; J. Cousson, T. Floch, Hopital Robert Debré, Reims, France; G. Louis, J.F. Poussel, Centre Hospitalier, Metz, France.

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Keywords:

Prognosis; refractory septic shock; septic shock; vasopressors

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