Short-term mortality from septic shock has decreased significantly during the last decade; however, more than one third of these patients will die during hospitalization (1,2). This syndrome affects a heterogeneous group of patients (3,4). One of the unmet clinical needs in this population is our ability to more accurately risk stratify these patients into homogeneous levels of severity.
Arginine vasopressin (AVP) is synthesized as a prohormone and then cleaved to the mature active hormone. Synthesis of preprovasopressin occurs in neurons of paraventricular and supraoptic nuclei of the hypothalamus. Provasopressin is packaged in neurosecretory granules that are transported to the posterior pituitary. Subsequently, there is a conversion to the active AVP (5–7). However, because of its considerable association with platelets, reliable measurement of circulating vasopressin is difficult to achieve (8,9). The CT-proAVP (C terminal part of preprovasopressin) is secreted in equimolar amounts with AVP (10). In septic shock patients, some authors described a biphasic secretion pattern of the CT-proAVP, characterized by an initial increase, followed by a decrease afterward (11). It has been suggested that the CT-proAVP could be used as a surrogate biomarker for AVP concentration (12). Plasma levels of the CT-proAVP at admission have been shown to be a good predictor of 28-day mortality (13–16).
Sharshar et al. (17) using magnetic resonance imaging in three patients with septic shock showed a depletion of vasopressin stores in the neurohypophysis. Landry et al. (18) also showed that exogenous AVP infusion in septic shock increased arterial pressure. These authors hypothesized that a relative AVP deficiency may occur in septic shock. If confirmed, this hypothesis could help physicians identify patients in need of exogenous AVP (19–21). Our hypothesis is that, in septic shock, patients requiring prolonged vasopressor support may have a relative vasopressin deficiency expressed by lower levels of CT-proAVP plasma concentrations as compared with those becoming rapidly vasopressor-free.
The primary objective of this study was to determine if plasma CT-proAVP measured within 24 h of sepsis onset is associated with vasopressor need and if patients with a sustained need of vasopressors feature lower levels of CT-proAVP across time. Secondary objectives were to confirm previous data on the ability of CT-proAVP to predict 28-day mortality and to describe CT-proAVP plasma concentrations during the time course of sepsis.
MATERIALS AND METHODS
This analysis was designed as a single-center, prospective, observational, cohort study in a tertiary university hospital (Cliniques universitaires Saint-Luc, Brussels, Belgium). Consecutive patients with sepsis were prospectively recruited in our medical and surgical intensive care unit (ICU) in a sepsis cohort.
One hundred thirteen patients were included in this analysis. One hundred two patients were admitted to the ICU for severe sepsis and septic shock. Sepsis was defined by an identifiable source of infection, evidence of a systemic inflammatory response manifested by at least two of the following criteria: 1) temperature more than 38°C or less than 36°C; 2) heart rate more than 90 beats/min; 3) respiratory rate more than 20 breaths/min; 4) white blood cell count more than 12,000 or less than 4,000/mm3 (22). Severe sepsis and septic shock were defined according to the literature (23). Patients were recruited within 24 h of sepsis onset. The only exclusion criterion was age less than 18 years. Eleven patients also admitted to the ICU, during the same period but without sepsis and without vasopressor support, were analyzed as a control group. The study was designed according to the requirements of the Declaration of Helsinki and approved by the local institutional review board. Written informed consent was obtained from all patients or their closest relatives.
In all study patients, demographic data, medical history, and clinical parameters were documented at study entry. After ICU admission, the Sepsis-related Organ Failure Assessment (SOFA) score (24,25) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (26) were calculated from worst laboratory and clinical parameters. Source of infection was also collected for the sepsis group. Vital status was collected at ICU discharge, at hospital discharge, and 28 days after sepsis onset either by chart review or through a phone call to the patient. Patients were classified into three groups: no sepsis, severe sepsis, and septic shock. The septic shock group was further divided in two groups: 1) patients still requiring vasopressors or dead at day 7 after sepsis onset and 2) patients alive and weaned from vasopressors at day 7. Values of CT-proAVP were compared among these groups. The absolute decrease in CT-proAVP expressed in picomolar was computed between days 1 to 2 and days 3 to 4 (Absolute delta CT-proAVP 2_1 = CT-proAVP Days 1–2 minus CT-proAVP Days 3–4) and between days 1 to 2 and days 6 to 7 (Absolute delta CT-proAVP 3_1 = CT-proAVP Days 1–2 minus CT-proAVP Days 6–7). The relative decrease expressed as a percentage in CT-proAVP between days 1 to 2 and days 3 to 4 (Relative delta CT-proAVP 2_1 = CT-proAVP Days 1–2 minus CT-proAVP Days 3–4/CT-proAVP Days 1–2) and between days 1 to 2 and days 6 to 7 was also computed. The value of CT-proAVP at days 1 to 2 was considered to be 100%.
Blood was withdrawn at three different time points: at day 1 or 2 (Days 1–2), at day 3 or 4 (Days 3–4), and at day 6 or 7 (Days 6–7) after sepsis onset. Venous blood samples were collected in tubes containing EDTA. After centrifugation, aliquots of EDTA-plasma samples were stored at −80°C until assayed. These aliquots were used to determine CT-proAVP plasma concentration using a sandwich immunoluminometric assay (BRAHMS LUMItest CTproAVP, BRAHMS AG, Hennigsdorf/Berlin, Germany) as previously described. In healthy individuals, median CT-proAVP values are 4.2 pmol/L (range, 1–13.8 pmol/L; 95% confidence interval [95% CI], 4.0–4.4 pmol/L) (27).
Descriptive statistics used frequencies (percentages) for qualitative variables and medians (interquartile ranges [IQRs]) for quantitative ones. For quantitative variables, means were compared using 1-way analysis of variance. Multiple comparisons were corrected using Bonferroni method. Categorical variables where compared using χ2 test. Normality was tested using Kolmogorov-Smirnov test; values were log transformed as appropriate. Pearson correlation coefficient was used to explore the relation between variables. A 2-sided value of P < 0.05 was considered statistically significant. Analyses were performed using SPSS software, version 17 (IBM, Chicago, Ill), and GraphPad Prism 5.0 (GraphPad Software, La Jolla, Calif).
One hundred thirteen patients were included in this analysis, 74 men and 39 women. Thirty-five patients had severe sepsis, and 67 had septic shock. The control group was composed of 11 patients admitted to the ICU with no signs of sepsis. Median age at admission was 67 years (55–75 years), with 75% of patients aged 55 years or older. The number of comorbidities at admission was similar among the three groups. Eleven patients were immediately intubated at ICU admission, nine in the septic shock group and two in the severe sepsis group. Median APACHE II score at admission was 27 (21–32), and median SOFA score was 10 (7–12) for the whole cohort. In 94 (86.2%) patients, at least one organ dysfunction was present. Cardiovascular dysfunction was the most frequent organ dysfunction and was found in 66 (60.6%) patients. Source of infection was the lung in 55 (48.7%) patients, the abdomen in 25 (22.1%) patients, and the urinary tract in 17 (15%) patients. Median length of stay in the ICU was 10 days (5–20 days), and median hospital length of stay was 24 days (12–43 days) (Table 1).
The median CT-proAVP at days 1 to 2 was 122 (75–226) pmol/L in the septic shock group, 65 (46–133) pmol/L in the severe sepsis group, and 33 (20–66) pmol/L in the nonseptic group (as per Fig. 1). Level of CT-proAVP decreased from days 1 to 2 to days 6 to 7 in the septic shock and the severe sepsis groups, whereas it remained roughly stable in the nonseptic group (Fig. 1). The CT-proAVP decrease between days 1 to 2 and days 3 to 4 expressed in picomolar or in percentage was similar in the severe sepsis group as compared with the septic shock group. Whereas CT-proAVP decrease between days 1 to 2 and days 6 to 7 was more pronounced and statistically significant in the septic shock group (P = 0.039 if expressed in picomolar and P = 0.029 if expressed in percentage).
We compared in the septic shock group CT-proAVP levels among patients still in need of vasopressors or dead at day 7 as compared with patients free of vasopressors at day 7. Levels of CT-pro-AVP were higher in patients in need of vasopressors at day 7, although it was only statistically significant for CT-proAVP measured at days 3 to 4. We then evaluated the ability of CT-proAVP to predict death or vasopressor need at day 7 by measuring the area under the curve (AUC). The AUC was 0.681 (0.574–0.788) for CT-proAVP Days 1–2 and 0.736 (0.633–0.839) for CT-proAVP Days 3–4 (see Table, Supplemental Digital Content 1, at http://links.lww.com/SHK/A310). Absolute and relative changes in CT-proAVP plasma levels were found similar in patients with a sustained need of vasopressors at day 7 as compared with patients weaned from vasopressors (Table 2). Antibiotics were similarly adequate in these two groups (P = 0.115).
Table 3 describes the clinical and biological parameters based on 28-day all-cause mortality. The overall 28-day mortality was 32.1% for the whole cohort. APACHE II score and SOFA score were statistically higher in patients who died at 28 days. The CT-proAVP was found to be higher in patients who died within 28 days at the three time periods: days 1 to 2, days 3 to 4, and days 6 to 7.
The initial rapid increase in plasma CT-proAVP levels in septic shock is mainly related to its release from secretory stores in the neurohypophysis. It has been suggested that a relative AVP deficiency in septic shock patients may be related to depletion of these secretory stores (17). The primary objective of this study was to determine if plasma CT-proAVP measured within 24 h of sepsis onset was associated with vasopressor need. Our hypothesis was that patients still in need of vasopressors at day 7, being more severe, could potentially present a higher decrease in CT-proAVP levels and have lower levels of CT-proAVP during the course of sepsis. Plasma levels of CT-proAVP declined during the course of sepsis. However, patients with a sustained need of vasopressors featured similar or even higher (at days 3–4) plasma CT-proAVP levels as compared with patients weaned from vasopressors. This study did not show differences in absolute or relative CT-proAVP changes across time among septic shock patients still in need of vasopressors as compared with patients weaned from vasopressors. Furthermore, baseline plasma CT-proAVP at days 1 to 2 featured a lower ability to predict the need for vasopressors at day 7 (AUC, 0.681 [0.574–0.788]) than CT-proAVP at days 3 to 4 (AUC, 0.736 [0.633–0.839]). The Ct-proAVP at days 3 to 4 features similar ability to APACHE II score and SOFA score to predict severity at day 7 in septic shock patients. The CT-proAVP at days 3 to 4 seems more accurate than procalcitonin or CT-proAVP at days 1 to 2 to predict severity at day 7 in septic shock patients. At the present time, no study has demonstrated an association between septic shock with sustained vasopressor requirement and AVP deficiency. Therefore, the subgroup of patients who could benefit from AVP supplementation still needs to be defined.
Our study further showed that CT-proAVP plasma concentrations were correlated with severity and outcome in severe sepsis and septic shock. Septic shock had higher levels of CT-proAVP as compared with severe sepsis and no-sepsis at days 1 to 2 and days 3 to 4. When analyzing 28-day all-cause mortality, the CT-proAVP measured at the three time points was found to be higher in nonsurvivors as compared with survivors. Our results confirm previously published data on the ability of CT-proAVP to predict 28-day all-cause mortality (14). Levels of CT-proAVP declined during the course of sepsis but remained more elevated in septic shock as compared with severe sepsis.
Jochberger et al. (28), comparing patients with infection, severe sepsis, and septic shock, showed that the initial level of CT-proAVP was higher in septic shock as compared with severe sepsis and infection. At days 3 and 4, these authors found similar levels of CT-proAVP in septic shock and in severe sepsis, whereas in our population, CT-proAVP plasma levels remained higher in septic shock at days 3 to 4. One possible explanation for this difference may be the difference in sample size. Jochberger et al. (28) analyzed 28 patients with septic shock and 22 patients with severe sepsis when we included 67 patients with septic shock and 35 patients with severe sepsis.
Our study has some limitations. The CT-proAVP was determined at regular intervals, but some samples were missing for a few patients. Vasopressor need at admission and at day 7 was not protocol based. Administration of vasopressors was initiated or stopped by the attending physician. Implementation in future studies of guidelines on the management of vasopressors could avoid potential bias related to physician practice in vasopressor management. In this exploratory study, a priori sample size and power calculation were not performed. Thus, we cannot exclude that negative results may be related to a low sample size. This was a single-center study, and no validation cohort was analyzed. A similar larger multicenter prospective study might be indicated to confirm our observations.
In summary, our study showed that CT-proAVP is not a good predictor of vasopressor need in septic shock. The present study also illustrates the potential interest of measuring the CT-proAVP in severe sepsis and in septic shock to predict 28-day mortality. Future studies are needed to better define the CT-proAVP usefulness in septic shock management, especially in defining a specific subgroup of patients in need of AVP supplementation.
The authors thank Suzanne Renard, Marie-France Dujardin, and Caroline Berghe, research nurses in our intensive care unit, for logistical support.
1. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med
2003; 348 16:1546–1554.
2. Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulmé R. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med
2002; 28 2:108–121.
3. Annane D, Bellissant E, Cavaillon JM. Septic shock
2005; 365 9453:63–78.
4. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med
2003; 348 2:138–150.
5. Treschan TA, Peters J. The vasopressin
system: physiology and clinical strategies. Anesthesiology
2006; 105 3:599–612.
6. Mutlu GM, Factor P. Role of vasopressin
in the management of septic shock
. Intensive Care Med
2004; 30 7:1276–1291.
7. Wilson MF, Brackett DJ, Hinshaw LB, Tompkins P, Archer LT, Benjamin BA. Vasopressin
release during sepsis and septic shock
in baboons and dogs. Surg Gynecol Obstet
1981; 153 6:869–872.
8. Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin
in human plasma. J Clin Invest
1973; 52 9:2340–2352.
9. Kluge M, Riedl S, Erhart-Hofmann B, Hartmann J, Waldhauser F. Improved extraction procedure and RIA for determination of arginine8-vasopressin
in plasma: role of premeasurement sample treatment and reference values in children. Clin Chem
1999; 45 1:98–103.
10. Jochberger S, Morgenthaler NG, Mayr VD, Luckner G, Wenzel V, Ulmer H, Schwarz S, Hasibeder WR, Friesenecker BE, Dünser MW. Copeptin and arginine vasopressin
concentrations in critically ill patients. J Clin Endocrinol Metab
2006; 91 11:4381–4386.
11. Morgenthaler NG, Muller B, Struck J, Bergmann A, Redl H, Christ-Crain M. Copeptin, a stable peptide of the arginine vasopressin
precursor, is elevated in hemorrhagic and septic shock
2007; 28 2:219–226.
12. Bolignano D, Cabassi A, Fiaccadori E, Ghigo E, Pasquali R, Peracino A, Peri A, Plebani M, Santoro A, Settanni F, et al. Copeptin (CTproAVP), a new tool for understanding the role of vasopressin
in pathophysiology. Clin Chem Lab Med
2014; 52 10:1447–1456.
13. Lesur O, Roussy JF, Chagnon F, Gallo-Payet N, Dumaine R, Sarret P, Chraibi A, Chouinard L, Hogue B. Proven infection-related sepsis induces a differential stress response early after ICU admission. Crit Care
2010; 14 4:R131.
14. Guignant C, Voirin N, Venet F, Poitevin F, Malcus C, Bohé J, Lepape A, Monneret G. Assessment of pro-vasopressin
and pro-adrenomedullin as predictors of 28-day mortality
in septic shock
patients. Intensive Care Med
2009; 35 11:1859–1867.
15. Boeck L, Eggimann P, Smyrnios N, Pargger H, Thakkar N, Siegemund M, Morgenthaler NG, Rakic J, Tamm M, Stolz D. The Sequential Organ Failure Assessment score and copeptin for predicting survival in ventilator-associated pneumonia. J Crit Care
2012; 27 5:523e1-523 e9.
16. Barrett LK, Singer M, Clapp LH. Vasopressin
: mechanisms of action on the vasculature in health and in septic shock
. Crit Care Med
2007; 35 1:33–40.
17. Sharshar T, Carlier R, Blanchard A, Feydy A, Gray F, Paillard M, Raphael JC, Gajdos P, Annane D. Depletion of neurohypophyseal content of vasopressin
in septic shock
. Crit Care Med
2002; 30 3:497–500.
18. Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D’Alessandro D, Oz MC, Oliver JA. Vasopressin
deficiency contributes to the vasodilation of septic shock
1997; 95 5:1122–1125.
19. Mastropietro CW, Mahan M, Valentine KM, Clark JA, Hines PC, Walters HL 3rd, Delius RE, Sarnaik AP, Rossi NF. Copeptin as a marker of relative arginine vasopressin
deficiency after pediatric cardiac surgery. Intensive Care Med
2012; 38 12:2047–2054.
20. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al. Vasopressin
versus norepinephrine infusion in patients with septic shock
. N Engl J Med
2008; 358 9:877–887.
21. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin
in the treatment of vasodilatory septic shock
. J Trauma
1999; 47 4:699–703.
22. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med
2003; 29 4:530–538.
23. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med
1992; 20 6:864–874.
24. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med
1998; 26 11:1793–1800.
25. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med
1996; 22 7:707–710.
26. Knaus WA, Zimmerman JE, Wagner DP, Draper EA, Lawrence DE. APACHE-Acute Physiology and Chronic Health Evaluation: a physiologically based classification system. Crit Care Med
1981; 9 8:591–597.
27. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin
. Clin Chem
2006; 52 1:112–119.
28. Jochberger S, Dorler J, Luckner G, Mayr VD, Wenzel V, Ulmer H, Morgenthaler NG, Hasibeder WR, Dünser MW. The vasopressin
and copeptin response to infection, severe sepsis
, and septic shock
. Crit Care Med
2009; 37 2:476–482.