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Abstract

Objective

To evaluate the correlation between Acute Physiology and Chronic Health Evaluation II (APACHE II) score and plasma concentrations of copeptin, C-reactive protein (CRP) and procalcitonin in patients with sepsis.

Methods

Patients with sepsis were prospectively enrolled. APACHE II scores were determined during the first 24 h after admission to the intensive care unit. Plasma copeptin, CRP and procalcitonin were quantified at admission, 24 h, 48 h, and 72 h. Survival at 28 days after admission was recorded.

Results

APACHE II score was significantly positively correlated with plasma copeptin, CRP and procalcitonin concentrations. Survivors (n = 15) had significantly lower APACHE II scores and copeptin, CRP and procalcitonin concentrations than nonsurvivors (n = 26). APACHE II score, copeptin at 72 h, CRP at 48 h and procalcitonin at 24 h were independent risk factors for death.

Conclusion

Plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, and reflected disease severity.

Keywords

Sepsis APACHE II copeptin C-reactive protein procalcitonin

Introduction

Sepsis has a mortality rate of ∼25%¹ globally and its clinical management presents an important medical challenge. The rapid progression of sepsis requires correspondingly swift adjustments in therapy, and accurate evaluation of disease severity is therefore important for predicting prognosis, preventing complications and reducing mortality. The Acute Physiology and Chronic Health Evaluation II (APACHE II) is the standard method for evaluating sepsis,² but other diagnostic and prognostic biomarkers are being investigated.

Copeptin, a short peptide derived from a preprohormone consisting of vasopressin, neurophysin II and copeptin, is one possible sepsis biomarker. Vasopressin is released on exposure to stress such as severe infection and sepsis, but its small molecular size and short half-life make detection impractical.³ Copeptin is a useful surrogate for vasopressin because it is stable in plasma and is released in similar quantities.⁴ Plasma copeptin concentrations were found to be significantly higher in patients with septic shock than in healthy control subjects (59–1572 pmol/l vs 0.3–18 pmol/l).⁵

C-reactive protein (CRP) is an acute-phase protein synthesized by the liver in response to inflammation. Normal plasma CRP concentrations (<8 mg/l) rise significantly during the early phase of sepsis.⁶ Procalcitonin is a 116 amino acid precursor of calcitonin. Plasma procalcitonin concentrations are below the limits of detection in healthy individuals (0.5 ng/ml), and can rise to 1000 ng/ml in severe bacterial infection or sepsis.⁷ Procalcitonin has a half-life of 15–20 h in the blood,⁸ and concentrations are correlated with severity of sepsis in patients in the intensive care unit (ICU).⁹

The aim of this study was to determine plasma concentrations of copeptin, CRP and procalcitonin in patients with sepsis, and evaluate their correlations with APACHE II scores. The diagnostic and prognostic value of these biomarkers is discussed.

Patients and methods

Study population

This prospective study included patients with sepsis who were treated in the ICU of Dalian Medical University First Hospital, Dalian, Liaoning, China between May 2012 and December 2012. Sepsis was diagnosed according to guidelines of the Surviving Sepsis Campaign 2012.¹⁰ Exclusion criteria were: (i) cardiovascular disease (e.g. acute coronary syndrome, rheumatic heart disease, congenital heart disease); (ii) multiple trauma with injury severity score >15; (iii) heart failure; (iv) death within 72 h of admission; (v) incomplete clinical data.

This study was approved by the ethics committee of DaLian Medical University First Hospital, and written informed consent was obtained from each patient or their next-of-kin.

Data collection

Venous blood (10 ml) was collected on admission to ICU, and at 24 h, 48 h and 72 h after admission. Uncoagulated blood was centrifuged at 2500 g for 15 min at –4℃ and the resulting plasma was analysed. Copeptin, CRP and procalcitonin were quantified using enzyme linked immunosorbent assay kits (Phoenix Pharmaceuticals, Burlingame, CA, USA; Roche, Basel, Switzerland; and BRAHMS Diagostica GmbH, Germany, respectively), according to the manufacturers’ instructions. APACHE II scores were assigned, based on the most pessimistic clinical and laboratory data obtained during the first 24 h following admission. Patients were followed-up for 28 days after admission, and the 28-day mortality rate was calculated.

Statistical analyses

Continuous data were expressed as mean ± SD and compared using Kruskal–Wallis or Mann–Whitney U-test. Categorical data were expressed as n (%) and compared using χ²-test. Spearman’s rank correlation coefficient was used to evaluate associations between APACHE II score and plasma concentrations of copeptin, CRP and procalcitonin. Prognostic factors were analysed using multivariate logistic regression analysis. Receiver operating characteristic (ROC) curves of copeptin, CRP and procalcitonin were generated and the area under the curve (AUC) was calculated. All statistical analyses were performed using SPSS® version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows®. P-values <0.05 were considered statistically significant.

Results

The study included 41 patients (25 male/16 female; mean age 62.07 ± 11.89 years, range 49–74 years).

Mortality rates were 11.1% (1/9), 62.5% (5/8), and 83.3% (20/24) for patients with APACHE II scores ≤15, 15 to 25, and ≥25, respectively (P < 0.05). The mean APACHE II score was significantly higher in patients who died within 28 days of admission (n = 26) compared with survivors (n = 15; 25.54 ± 9.87 vs 10.63 ± 6.18; P < 0.01).

There were significant positive correlations between APACHE II score and plasma copeptin, CRP and procalcitonin concentrations at all timepoints (Table 1).

Table 1.

Correlations between Acute Physiology and Chronic Health Evaluation II (APACHE II)² score and plasma concentrations of copeptin, CRP and procalcitonin in patients with sepsis (n = 41).

Parameter	Time after admission to ICU, h
	0		24		48		72
	r	P	r	P	r	P	r	P
Copeptin	0.997	<0.01	0.993	<0.01	0.0.968	<0.01	0.950	<0.01
CRP	0.948	<0.01	0.887	<0.01	0.808	<0.01	0.807	<0.01
Procalcitonin	0.999	<0.01	0.998	<0.01	0.956	<0.01	0.881	<0.01

Spearman’s rank correlation coefficient analysis.

ICU, intensive care unit.

Data regarding plasma concentrations of copeptin, CRP and procalcitonin in patients stratified according to APACHE II scores are given in Table 2. Concentrations of copeptin and procalcitonin were significantly higher in patients with APACHE II scores ≥25 than those with scores <25 (≤15 or 15–25) at all timepoints (P < 0.05 for each comparison). CRP concentrations were significantly higher in patients with APACHE II scores ≥25 than those with scores <25 (≤15 or 15–25) at 24 h, 48 h and 72 h after admission (P < 0.05 for each comparison).

Table 2.

Plasma concentrations of copeptin, C-reactive protein and prolactin in patients with sepsis, stratified according to Acute Physiology and Chronic Health Evaluation II (APACHE II)² score.

Parameter	APACHE II score
Parameter	≤15 n=9	15–25 n=8	>25 n=24
Plasma copeptin, ng/ml
Admission to ICU	1.28±0.67	5.25±1.57	18.99±3.62 ^a,b
24 h	1.87±0.77	7.44±1.89	21.09±3.47 ^a,b
48 h	2.74±0.86	11.00±1.69	23.66±4.01 ^a,b
72 h	3.91±1.18	14.40±2.66	25.79±3.23 ^a,b
Plasma C-reactive protein, mg/l
Admission to ICU	58.43±4.82	70.60±4.82	94.16±6.47
24 h	62.84±9.30	75.46±6.58	106.96±8.05 ^a,b
48 h	66.10±9.80	79.88±5.44 ^a	117.39±6.16 ^a,b
72 h	57.71±7.05	72.11±5.01	97.60±4.02 ^a,b
Plasma prolactin, ng/ml
Admission to ICU	0.97±0.81	5.57±0.76	10.81±1.76 ^a,b
24 h	1.62±1.35	8.29±1.02	11.84±1.10 ^a,b
48 h	1.03±0.89	4.56±0.40	8.44±1.24 ^a,b
72 h	0.52±0.54	3.14±0.51	5.62±0.67 ^a,b

Data presented as mean±SD.

P < 0.05 vs APACHE II score ≤15 at same timepoint;

^bP < 0.05 vs APACHE II score 15–25 at same timepoint; Kruskal–Wallis or Mann–Whitney U-test.

ICU, intensive care unit.

Plasma concentrations of copeptin, CRP and procalcitonin were significantly higher in patients who died within 28 days of admission compared with survivors (P < 0.05, Table 3).

Figure 1.

Receiver operating characteristic curves for plasma concentrations of copeptin, procalcitonin (PTC) and C-reactive protein (CRP) in predicting survival of patients with sepsis. Times shown are after admission to intensive care unit

Table 3.

Plasma concentrations of copeptin, C-reactive protein and prolactin in patients with sepsis, stratified according to survival at 28 days after admission to intensive care unit (ICU).

Parameter	Survivors n=15	Nonsurvivors n=26	Statistical significance^a
Copeptin, ng/ml
Admission to ICU	4.67±5.09	16.89±6.63	P < 0.05
24 h	5.99±5.83	18.95±6.64	P < 0.05
48 h	7.52±6.08	21.83±6.65	P < 0.05
72 h	9.53±7.08	24.09±6.01	P < 0.05
C-reactive protein, mg/l
Admission to ICU	65.79±11.42	90.91±11.22	P <0.05
24 h	71.55±14.80	102.43±14.87	P <0.05
48 h	79.51±22.29	109.95±16.57	P <0.05
72 h	70.39±19.65	91.65±11.01	P <0.05
Prolactin, ng/ml
Admission to ICU	3.44±3.09	10.04±2.89	P <0.05
24 h	4.90±4.04	11.22±2.26	P <0.05
48 h	2.98±2.47	7.83±2.15	P <0.05
72 h	2.02±1.90	5.17±1.37	P <0.05

Data presented as mean±SD.

Kruskal–Wallis or Mann–Whitney U-test.

Significant risk factors for death in patients with sepsis were APACHE II score (odds ratio [OR] 1.09, 95% confidence intervals [CI] 1.054, 1.128), copeptin at 72 h (OR 1.508, 95% CI 1.161, 1.958), CRP at 48 h (OR 1.009, 95% CI 1.003, 1.015), and procalcitonin at 24 h (OR 1.085, 95% CI 1.036, 1.108). The AUC of the ROC curves were 0.951, 0.837 and 0.811 for copeptin at 72 h, procalcitonin at 24 h and CRP at 48 h, respectively (P < 0.05; Figure 1).

Discussion

Plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, in the present study. These three biomarkers reflected disease severity and could be used to predict outcome.

Vasopressin is released by the hypothalamic–pituitary–adrenal axis that also produces adrenocorticotropic hormone and cortisol. Serum cortisol concentrations have been shown to reflect an individual’s stress levels and can be used to predict the outcome of patients with sepsis or pneumonia.¹¹ Copeptin concentrations provide a more accurate reflection of stress severity than cortisol levels.¹²

Copeptin concentration can independently predict the survival of critically ill patients with haemorrhagic and septic shock,¹³ and is significantly elevated in patients with lower respiratory tract infections compared with healthy controls.¹⁴ Additionally, copeptin concentration has been shown to be associated with the severity of pneumonia, as based on a pneumonia severity index. Plasma copeptin concentrations increased significantly with higher APACHE II scores in the present study, reflecting the severity of sepsis. In addition, plasma copeptin concentrations were significantly higher in patients who died within 28 days of admission than in patients who survived. In accordance with previous findings,^8,13,15–18 our study showed that plasma copeptin could be used to evaluate the severity of sepsis. In addition, the present finding that elevated copeptin concentration at 72 h after admission was associated with increased mortality suggests that this parameter could be used to predict sepsis-related patient death.

Elevated CRP concentrations represent an acute-phase response to acute tissue injuries such as those produced by surgery, infection or acute inflammation, and signify the body’s attempt to neutralize the inflammatory agent and promote healing of the injured tissue.^18,19 Plasma CRP can reach 1000-fold normal concentrations during the acute-phase response,²⁰ and CRP has therefore been used to monitor disease activity in conditions including sepsis. Plasma CRP concentrations were positively correlated with APACHE II scores and reflected the severity of sepsis in the present study, in accordance with the findings of others.²¹

Animal studies indicate that procalcitonin plays a pathophysiological role in the development of severe sepsis and is associated with mortality. Treatment with procalcitonin was shown to double the death rate in animals,²¹ whereas injection with an antiprocalcitonin antibody increased the survival of animals with sepsis.^21–24 Procalcitonin is an accurate biomarker for severe infection,^25,26 and for the diagnosis of bacterial sepsis and bacteraemia.²⁷ Procalcitonin concentration has also been used to guide the empirical antibiotic treatment of sepsis patients,²⁸ and, in accordance with our findings, is known to reflect the severity of infection as well as having prognostic implications for critically ill patients.²⁹ An advantage of procalcitonin over other biomarkers is that its production is not significantly affected by nonsteroidal or steroidal anti-inflammatory drugs.^30–32

Our study has several limitations. The sample size was small and caution should be used when interpreting the results. In addition, copeptin concentrations at 72 h after admission were a less-useful predictive factor for death compared with procalcitonin at 24 h, since patients may have already died by 72 h after admission.

In conclusion, plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, and therefore reflected disease severity. APACHE II score, copeptin concentration at 72 h, CRP concentration at 48 h and procalcitonin concentration at 24 h were independent risk factors for death in patients with sepsis.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Plasma concentrations of copeptin,C-reactive protein and procalcitonin are positively correlated with APACHE II scores in patients with sepsis

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Patients and methods

Study population

Data collection

Statistical analyses

Results

Discussion

Footnotes

Declaration of conflicting interest

Funding

References