Sudden cardiac arrest (SCA) is still associated with significant long-term mortality [1], which most likely results from damage to the organs susceptible to acute ischaemia and secondary generalized inflammatory responses impairing the mechanisms involved in the restoration of systemic homeostasis [2]. The present study aimed at determining whether the presence and concentration of inflammatory reaction markers (the selected cytokines) were correlated significantly with survival and status of SCA patients.

METHODS

The study protocol was approved by the Bioethics Committee of the Medical University of Łódz.

Patients hospitalized immediately after SCA were enrolled. In all patients, SCA developed in the course of acute coronary syndrome. The treatment was provided according to the patient`s clinical condition; coronary angiography with coronary angioplasty was performed, intraaortal counterpulsation, mechanical lung ventilation and pharmacotherapy were used. Patients with SCA accompanied by trauma or end-stage chronic debilitating diseases, including severe chronic inflammatory diseases, were excluded.

After day 1 of hospitalization, 3 patients died, after 2 days – 1 patient, after 3 days – another two.

Ultimately, patients were divided into two groups – 27 SCA survivors (SCA-S), who were discharged or transferred to other wards for further treatment and 24 non-survivors (SCA-NS), who died during hospitalization.

Immediately after admission and over the two successive days, patients were clinically evaluated in the morning using the Simplified Acute Physiology Score II (SAPS II) and Multiple Organ Dysfunction Score (MODS) [4].

In all patients, the examinations were carried out shortly after SCA. Routine laboratory tests were performed using ELISA; moreover, concentrations of interleukin-6 (Il-6), interleukin-10 (Il-10) and tumour necrosis factor (TNF) were determined applying the following diagnostic kits: Human Il-6 Immunoassay, Human Il-10 Immunoassay and Human TNF-α/TNFSF1A Immunoassay (R&D Systems Inc., USA) and Microplate Reader Model Σ 960 (Metertech Inc., Taiwan).

Values of quantitative parameters related to inflammation were compared between the SCA-S and SCA-NS groups using parametric and non-parametric tests. Correlations between these quantitative variables and in comparison with the SAPS II and MODS values during the consecutive three days were assessed by calculating the Pearson’s r correlation coefficient of linear regression.

The relation between the concentration of cytokines and post-SCA survival was analysed using the univariate model based on logistic regression. Moreover, the Kaplan-Meier survival analysis was used for this purpose, comparing survival rates after SCA for cytokine concentrations above and below their threshold values. These values, optimally discriminating survival and death after SCA, were determined using ROC curves. Statistical significance was set at p<0.05.

RESULTS

The study included 51 patients, aged 62±12 years, 35 males and 16 females. Out-of-hospital SCA occurred in 45% of patients, in-hospital SCA in 55%. The SCA mechanisms were ventricular fibrillation or tachycardia without pulse – 78% and asystole – 22%. The characteristics of both groups are presented in Table 1.

In non-survivors, whose clinical status during hospitalization (according to SAPS II and MODS) was worse compared to SCA-S, the Il-6 levels were found to be significantly higher and levels of Il-10 and TNF-α – higher (Table 2).

The levels of Il-6 were significantly correlated both with clinical status evaluated using SAPS II and MODS and levels of the remaining cytokines (Table 3). Furthermore, the concentration of TNF-α was correlated with clinical status after SCA in the next 2 days following SCA and with the concentration of Il-10.

The univariate model, based on logistic regression, revealed that the concentration of Il-6 was significantly correlated with SCA survival (Table 4).

The Kaplan-Meier analysis documented the variability of the relation between post-SCA survival and Il-6 concentration. Fig. 1 presents the values calculated using the ROC curve, which demonstrates the optimal values of sensitivity and specificity of anticipated SCA survival (53% and 86%, respectively).

Moreover, there was no correlation found between the concentration of Il-10 and survival after SCA (p=0.12), yet the trend towards the relation between survival and concentration of TNF-α was observed (Fig. 2).

DISCUSSION

The present study findings disclosed that the concentration of cytokines measured immediately after SCA was correlated with the further hospital post-resuscitation period. Amongst few papers regarding the discussed issues, we found only one with similar results in patients after SCA [2]. The authors demonstrated unfavourable prognosis in patients after SCA with higher concentrations of Il-6, Il-10, and TNF-α soluble receptor II. Our results revealed a significant relation not only with survival but also with clinical status of patients during the early post-SCA period.

Amongst the cytokines analysed, the Il-6 was most strictly correlated both with general condition of patients in the first post-SCA days, assessed according to SAPS II and MODS, and with early SCA survival. According to Fisman and co-workers [5], who examined patients with acute myocardial infarction and unstable coronary disease, i.e. the diseases which underlain SCA, high concentration of Il-6 was the adverse prognostic factor. Similar results were presented by Ziakas and co-workers [6] in patients after acute myocardial infarction treated thrombolitically; the concentration of Il-6 in those patients was of prognostic value both during hospital observation and the 6-month post-hospital period. According to some Polish studies, in patients after myocardial infarction and elevated Il-6 levels, mortality rates were higher over the period of 12 months [7]. Such a relation was also documented in the 5-year observation period [8].

An interesting explanation of the clear relation between the Il-6 concentration and survival of patients with acute coronary syndrome is found in other studies. It was demonstrated that the concentration of Il-6 in patients after SCA was correlated with the extent of CNS impairment evaluated after 6 months [9]. Moreover, the unfavourable prognostic value of high levels of Il-6 in patients with acute myocardial infarction complicated by cardiogenic shock within the period of 30 post-infarction days was documented; the comparison of organ consequences of cardiogenic shock of septic etiology and Il-6 concentrations accompanying them revealed that in both cases they were related to the extent of multiple organ dysfunction [10]. Thus, it may be concluded that in our study the concentration of Il-6 was the marker of multiple organ damage after SCA and hence correlated well with the clinical condition of patients and prognosis. Moreover, the correlation of Il-6, TNF-α and Il-10 concentrations confirmed in the present study is likely to indicate multidirectional effects of these cytokines on post-resuscitation inflammatory response [11].

Furthermore, markedly higher mean concentrations of TNF-α were observed in SCA-NS compared to SCA-S, which, however, did not reach the significance limits; additionally, the trend towards the relation between survival after SCA and TNF-α concentration was found. It appears, however, that TNF-α may be essentially involved in the pathophysiology of post-resuscitation period and lack of statistical significance is likely to result from limited sizes of SCA-NS and SCA-S groups. In animal studies, a significant correlation between high concentrations of TNF-α after SCA and the extent of systolic dysfunction during the post-resuscitation period was demonstrated [12]. Moreover, the correlation between the systolic function and the size of the left ventricle vs TNF-α concentration was documented in patients with dilated cardiomyopathy [13].  Therefore, it is likely that the relation between the clinical status of patients during the next two days after SCA and TNF-α concentration observed in our study indirectly evidences the relation with the extent of their cardiovascular dysfunction during the post-resuscitation period.

Il-10 is attributed with the role of suppressing the inflammatory reaction [14]. It is likely that in our study, the lack of relations between its concentration assessed immediately after SCA and results of further clinical observation is associated with the fact that its clinical effects reveal after some time once the inflammatory response has been more fully developed. According to some authors, Il-10 concentrations in patients with acute myocardial infarction and unstable coronary disease were elevated compared to patients with stable coronary disease or healthy volunteers [15]. Moreover, protective effects of Il-10 in patients after myocardial infarction without ST elevation were demonstrated; the decreased Il-6:Il-10 ratio was related to lower risk of new coronary events within 12 months [16].

CONCLUSION

In patients with SCA in the course of acute severe coronary syndrome, the concentration of Il-6, determined immediately after the SCA incident, is a relevant prognostic factor of survival and clinical status in the early post-resuscitation period.

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REFERENCES

1.    Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, Rowan K: Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 2007; 62: 1207–1216.

2.    Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, Fraisse F, Dinh-Xuan AT, Carli P, Spaulding C, Dhainaut JF, Cavaillon JM: Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002; 106: 562-568.

3.    Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270: 2957-2963.

4.    Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23: 1638-1652.

5.    Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y, Tanne D, Matas Z, Tenenbaum A: Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol 2006; 98:14-18.

6.    Ziakas A, Gavrilidis S, Giannoglou G, Souliou E, Gemitzis K, Kalampalika D, Vayona MA, Pidonia I, Parharidis G, Louridas G: In-hospital and long-term prognostic value of fibrinogen, CRP, and IL-6 levels in patients with acute myocardial infarction treated with thrombolysis. Angiology 2006; 57: 283-293.

7.    Marciniak A, Gierbliński I, Stefański R, Łapiński M, Gaciong Z, Bartłomiejczyk I, Zegarska J: Predictive value of plasma interleukin 1, interleukin 6, interleukin 8 and C-reactive protein (CRP) in patients with myocardial infarction. Pol Arch Med Wewn 2003; 109: 15-22.

8.    Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, Arveiler D, Fruchart JC, Ducimetiere P; PRIME Study Group: C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the PRIME Study. Arterioscler Thromb Vasc Biol 2003; 23: 1255-1261.

9.    Oda Y, Tsuruta R, Kasaoka S, Inoue T, Maekawa T: The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims. Resuscitation 2009; 80: 189-193.

10.    Geppert A, Dorninger A, Delle-Karth G, Zorn G, Heinz G, Huber K: Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction. Crit Care Med 2006; 34: 2035-2042.

11.    Pedersen BK: IL-6 signalling in exercise and disease. Biochem Soc Trans 2007; 35: 1295-1297.

12.    Niemann JT, Garner D, Lewis RJ: Tumor necrosis factor-alpha is associated with early postresuscitation myocardial dysfunction. Crit Care Med 2004; 32:1753-1758.

13.    Satoh M, Nakamura M, Akatsu T, Shimoda Y, Segawa I, Hiramori K: C-reactive protein co-expresses with tumor necrosis factor-alpha in the myocardium in human dilated cardiomyopathy. Eur J Heart Fail 2005; 7: 748-754.

14.    Dennis VA, Jefferson A, Singh SR, Ganapamo F, Philipp MT: Interleukin-10 anti-inflammatory response to Borrelia burgdorferi, the agent of Lyme disease: a possible role for suppressors of cytokine signaling 1 and 3. Infect Immun 2006; 74: 5780-5789.

15.    Mizia-Stec K, Gasior Z, Zahorska-Markiewicz B, Janowska J, Szulc A, Jastrzebska-Maj E, Kobielusz-Gembala I: Serum tumour necrosis factor-alpha, interleukin-2 and interleukin-10 activation in stable angina and acute coronary syndromes. Coron Artery Dis 2003; 14: 431-438.

16.    Kilic T, Ural D, Ural E, Yumuk Z, Agacdiken A, Sahin T, Kahraman G, Kozdag G, Vural A, Komsuoglu B: Relation between proinflammatory to anti-inflammatory cytokine ratios and long-term prognosis in patients with non-ST elevation acute coronary syndrome. Heart 2006; 92: 1041-1046.

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address:

*Zbigniew Sablik
Klinika Kardiologii
I Katedry Kardiologii i Kardiochirurgii,
Uniwersytet Medyczny w Łodzi
ul. Sterlinga 1/3, 91-425 Łódź
tel.: 0-42 6644298, fax: 0-42 6429444
e-mail: zbyszek.lek1@poczta.fm

received: 01.03.2010
accepted: 02.05.2010