Article

Usefulness of admission matrix metalloproteinase 9 as a predictor of early mortality after cardiopulmonary resuscitation in cardiac arrest patients

Unlabelled imageAmerican Journal of Emergency Medicine (2012) 30, 1804-1809

Original Contribution

Usefulness of admission matrix metalloproteinase 9 as a predictor of early mortality after cardiopulmonary resuscitation in cardiac arrest patients?

Kenan Ahmet Turkdogan MD a, Ali Zorlu MD c,?, Fatma Mutlu Kukul Guven MD a,

Ismail Ekinozu MD d, Umut Eryigit MD e, Mehmet Birhan Yilmaz MD b

aDepartment of Emergency, Cumhuriyet University Medical School, Sivas, Turkey bDepartment of Cardiology, Cumhuriyet University Medical School, Sivas, Turkey cDepartment of Cardiology, Bulanik State Hospital, Mus, Turkey

dDepartments of Cardiology, Duzce University Medical School, Duzce, Turkey

eDepartments of Emergency, Karadeniz Technical University Medical School, Trabzon, Turkey

Received 2 January 2012; revised 8 February 2012; accepted 27 February 2012

Abstract

Background: Matrix metalloproteinases have a central role in Disease progression after Ischemia-reperfusion injury. However, its prognostic significance in cardiac arrest patients having cardiopulmonary resuscitation (CPR) is unknown. The aim of this study was to investigate the relation between admission MMP-9 level and early mortality in CA patients.

Methods: A total of 96 in-hospital or out-of-hospital CA patients and 40 age- and sex-matched healthy volunteers as the control group were evaluated prospectively. The patients were classified according to the CPR response into a successful group (n = 46) and a failed group (n = 50).

Results: The MMP-9 levels were detected to be 56.9 +- 4.3, 69.5 +- 7.4, and 92.7 +- 10.1 ng/mL in the control group, the successful CPR group (acute responders), and the failed CPR group, respectively (P b

  1. for the 2 comparisons). The MMP-9 level on admission, presence of asystole, mean CA duration, out-of-hospital CPR, sodium and Potassium levels, and arterial pH were found to have prognostic significance in univariate analysis. In addition, MMP-9 levels were correlated with age, troponin level, and oxygen saturation. In multivariate logistic regression analysis with forward stepwise method, only MMP-9 level on admission (odds ratio, 1.504; P b .001) and mean CA duration before CPR (odds ratio, 1.257; P = .019) remained associated with post-CPR early mortality after adjustment of other potential confounders. In addition, optimal cutoff value of MMP-9 to predict failed CPR was found as greater than 82 ng/mL, with 88% sensitivity and 97.8% specificity.

Conclusions: High MMP-9 levels were associated with worse clinical and laboratory parameters, and it seems that MMP-9 helps risk stratification in CA patients.

(C) 2012

? Conftict of interest: All authors declare that they have no conftict of interest.

* Corresponding author. Tel.: +90 506 4183409; fax: +90 346 2191268.

E-mail address: [email protected] (A. Zorlu).

Introduction

Cardiopulmonary resuscitation (CPR) represents a brittle bridge between life and death, and any new data on this

0735-6757/$ – see front matter (C) 2012 http://dx.doi.org/10.1016/j.ajem.2012.02.017

bridge would have a vital role in establishing the risk stratification and treatment strategies for patients with Cardiac arrest . Although CPR provides patients with a chance to survive, when to end CPR in an unselected group of patients with CA is not defined by general rules; rather, individualizED decision making is performed [1-3].

Preliminary evaluation, based on clinical observations, still remains as the primary determinant of early mortality after CPR, but biomarker studies performed in the last decades have shown that the use of biomarker on top of clinical evaluation has an additional importance in determi- nation of prognosis [4-12]. However, there are no valid clinical and laboratory parameters to be used to indicate the success of CPR after CA.

Matrix metalloproteinases (MMPs) are a member of a family of endoproteinases with a capacity to disrupt all the components of the Extracellular matrix. These endopepti- dases are secreted in the latent form, require activation for proteolytic activity, and are inhibited by specific MMP tissue inhibitors with zinc in their active site [13-17]. The previous studies reported that MMPs were involved in various physiologic and pathologic processes such as angiogenesis, extracellular matrix degradation, signal transduction, mod- ulation of inftammatory response, disruption of physiologic barriers, compensatory tissue remodeling, myocardial stun- ning, apoptosis, and Cardiac rupture [18-23]. In addition, they were also shown to have a central role in disease progression after ischemia-reperfusion injury [24-30]. These studies consistently suggested that inhibition of the MMP activity could be useful in various disease settings [18-30].

In this study, considering that MMP-9 is released into

plasma of patients with CA and that it might be linked to post-CPR mortality, we aimed to investigate the relationship between admission MMP-9 and failed CPR.

Methods

Patient population and study design

A total of 110 in-hospital or out-of-hospital CA patients who were admitted to the emergency department (ED) of Cumhuriyet University Medical School Hospital were prospectively considered for enrolment between February 2010 and March 2011. Five patients with a history of cancer,

4 patients who developed hemolysis in their blood, and 6 patients who were transferred to our hospital from other hospitals were excluded. For the outpatients, the history of index CA was obtained from the ambulance medical staff: those with CPR duration of longer than 10 minutes inside the ambulance before getting into ED were not considered for the study. Finally, a total of 96 CA patients and 40 age- and sex-matched healthy volunteers as the control group were evaluated prospectively. The study was performed in accordance with the Declaration of Helsinki for Human

Research and was approved by the institutional ethics committee (Registry number: 2009-06/13).

Cardiac arrest was defined as the interruption of spontaneous respiratory efforts and the absence of any palpable pulses. Successful resuscitation was defined as the return of a palpable pulse and an electrocardiographic rhythm other than ventricular fibrillation or ventricular tachycardia. Cardiac arrest patients were classified according to the acute CPR response into a successful group (n = 46, acute responders) and a failed group (n = 50). Successful group was composed of patients with acute response to CPR within the ED, and hence, the group included those patients who were discharged from the ED alive. However, overall in-hospital or long-term survival after discharge from the ED and referral to other hospital units was not considered in the current study. Data included the age and sex of the patients, history of hypertension, diabetes mellitus, coronary artery disease and chronic obstructive pulmonary disease, and the conventional clinical and laboratory parameters. The data regarding the site and the time of CA were obtained from first-degree relatives and CPR staff. The initial electrocardio- grams, obtained at admission, were recorded. The study team was initially educated for high-quality CPR according to guidelines, and the Quality of CPR (qualitatively as poor- intermediate-good-ideal) was monitored by an independent senior emergency physician all through the study.

Biomarker testing

Blood sampling was performed as soon as venous and/or Arterial line was obtained in all patients with CA. Patients in whom blood sampling could not be made within 10 minutes after CPR were not included in the study. The 10-mL blood samples were centrifuged in gel-containing vacuumed biochemistry tubes at 400 rpm for 6 minutes, and the sera were stored in Eppendorf tubes at -23?C. Serum MMP-9 levels were measured by Boster human MMP-9 ELISA kit (Wuhan, China), based on standard sandwich enzyme- linked, immunosorbent assay technology.

Statistical analysis

Parametric data were expressed as mean +- SD, and categorical data, as percentages. SPSS 14.0 (SPSS, Inc, Chicago, IL) was used to perform statistical procedures. Receiver operator characteristic curve analysis was performed to identify the optimal cutoff point of MMP-9 (at which sensitivity and specificity would be maximal) for the prediction of mortality (failed CPR) after CPR. Areas under the curve (AUCs) were calculated as measures of the accuracy of the tests. We compared the AUC with the use of the Z test. Comparisons between groups were performed by using 1-way analysis of variance with post hoc analysis by Tukey Honestly Significant Difference (HSD) or an independent-samples t test, and the Kruskal-Wallis test or Mann-Whitney U test was

used for normally and abnormally distributed data, respec- tively. The categorical variables between groups were analyzed by using the ?2 test. Correlation was evaluated by the spearman correlation test. We used univariate Cox proportional hazards analysis to quantify the association of variables with mortality after CPR. Variables found to be statistically significant in univariate analysis and potential other confounders, age, troponin, and oxygen saturation were used in a multivariate logistic regression model with the forward stepwise method to determine the independent prognostic factors of mortality after CPR. A P value of .05 was considered statistically significant.

Results

Overall CPR quality was noted to be at least good in every patient with CA by the independent monitor, and hence, all patients were considered. The MMP-9 levels were detected to be 56.9 +- 4.3, 69.5 +- 7.4, and 92.7 +- 10.1 ng/mL in the control group, the successful CPR group, and the failed CPR group, respectively. The MMP-9 levels were observed to be significantly higher in patients with failed CPR compared with those with successful CPR and the control group (P b

Table 1 Baseline characteristics of study patients

Control group (n = 40) Successful CPR (n = 46) Failed CPR (n = 50) P

MMP-9 (ng/mL) 56.9 +- 4.3 69.5 +- 7.4 92.7 +- 10.1 b.001

/ P b .001 / / P b .001 /

Baseline characteristics

.001 and P b .001, respectively). In addition, those with successful CPR after CA were also detected to have a significantly higher MMP-9 level relative to the control group (P b .001) (Table 1).

A comparison of the baseline characteristics of the patients in the successful and failed CPR groups and the established conventional risk factors for failed CPR were briefty presented in Table 1. The presence of out-of-hospital CPR was more frequent among patients with failed CPR relative to patients with successful CPR. The mean duration of CA was longer in patients with failed CPR compared with those with successful CPR. The presence of asystole at admission was more frequent in patients who died compared with those who survived after CPR. Although statistically insignificant, patients with failed CPR were detected to be more acidotic, hyperkalemic, and hypernatremic. There was no statistical difference between the 2 groups in baseline characteristics and the other laboratory parameters (Table 1). The MMP-9 levels were mildly correlated with age (r = 0.251, P = .003), presence of out-of-hospital CPR (r = 0.254, P = .013), potassium level (r = 0.387, P b .001), and mean duration of CA before initiation of CPR (r = 0.410, P b

.001); moderately correlated with oxygen saturation (r =

-0.511, P b .001) and presence of asystole as the basic rhythm during admission to the ED (r = 0.641, P b .001) and

Age (y), mean +- SD

66 +- 7

66 +- 16

71 +- 13

.080

Male/Female

22/18

25/21

31/19

.704

Hypertension, n (%)

25 (54)

30 (60)

.576

Diabetes mellitus, n (%)

11 (24)

12 (24)

.992

Coronary artery disease, n (%)

29 (63)

32 (64)

.923

Chronic obstructive pulmonary disease, n (%)

Traditional predictors of failed CPR

11 (24)

6 (12)

.208

Out-of-hospital CPR, n (%)

17 (37)

32 (64)

.015

Duration of CA before CPR (min), mean +- SD

2.7 +- 4.1

8.8 +- 5.9

b.001

First electrocardiographic rhythm

Asystole, n (%)

11 (24)

38 (76)

b.001

Electromechanical dissociation

1 (2)

0 (0)

.479

pulseless ventricular tachycardia

2 (4)

0 (0)

.227

Laboratory analysis

Arterial pH

7.2 +- 0.2

7.1 +- 0.2

.067

Po2

67 +- 37

63 +- 28

.654

Pco2

48 +- 21

53 +- 27

.317

Bicarbonate (mmol/L)

19 +- 10

19 +- 7

.873

Oxygen saturation (%)

79 +- 15

78 +- 13

.709

Hemoglobin (g/dL)

12.8 +- 2.7

13.4 +- 2.3

.104

Platelet count x 103

258 +- 129

238 +- 89

.379

Sodium (mmol/L)

135 +- 7

138 +- 5

.080

Potassium (mmol/L)

4.7 +- 1

5.2 +- 1.3

.071

Troponin (ng/mL)

2.5 +- 12

2.3 +- 10

.943

Variable

Univariate

Multivariate

P

OR

95% CI

P

OR

95% CI

MMP-9 (ng/mL)

b.001

1.474

1.222-1.778

b.001

1.504

1.200-1.885

Presence of asystole

b.001

10.076

3.943-25.747

Mean duration of CA

b.001

1.244

1.133-1.366

.019

1.257

1.039-1.520

Out-of-hospital CPR

.009

3.033

1.320-6.967

Sodium (mmol/L)

.042

1.079

1.003-1.161

Potassium (mmol/L)

.061

1.403

0.985-2.001

Arterial pH

.070

0.127

0.014-1.186

Age (y)

.102

1.025

0.995-1.025

Troponin (ng/mL)

.942

0.999

0.963-1.036

Oxygen saturation (%)

.706

0.994

0.966-1.023

All the variables from Table 1 were examined, and only those significant at P b .1 level and those with a correlated MMP-9 level are shown in univariate analysis.

The multivariate logistic regression model included all univariate predictors and those with correlated MMP-9 level.

troponin level (r = 0.570, P b .001); and finally, strongly correlated with arterial pH (r = -0.887, P b .001). There was no significant correlation between MMP-9 level and the other laboratory findings (P N .05).

Table 2 univariate and multivariate analyses of mortality after CPR

All the parameters in Table 1 were evaluated by logistic regression analysis to detect the univariate predictors of mortality after CPR, and those with a P value of less than .1 are presented in Table 2. A total of 8 parameters were detected as the predictors of post-CPR mortality with the MMP-9 level, the presence of asystole, and the mean CA duration being the strongest ones. In multivariate logistic regression analysis with forward stepwise method, only MMP-9 level on admission (odds ratio [OR], 1.504; 95%

Fig Receiver operator characteristic curve for MMP-9 to predict failed CPR.

confidence interval [CI], 1.200-1.885; P b .001) and mean CA duration before the initiation of CPR (OR, 1.257; 95% CI, 1.039-1.520; P = .019) were found to be independent predictors of post-CPR mortality (Table 2).

The optimal cutoff value predicting post-CPR mortality for MMP-9 was greater than 82 ng/mL with a sensitivity of 88% and a specificity of 97.8% (AUC, 0.977; 95% CI,

0.923-0.997; Fig).

Discussion

This study, to the best of our knowledge for the first time in the literature, investigated the predictive value of MMP-9 levels on mortality after CPR in patients with CA. We demonstrated that circulating levels of MMP-9 were significantly increased in CA patients. Furthermore, the MMP-9 levels were correlated with worse clinical and laboratory parameters. However, even after controlling these parameters, we found that higher MMP-9 levels were strongly associated with death after efficient CPR.

Previous studies reported that advanced age, sex, duration of CPR, presence of pulseless electrical activity or asystole, partial pressure of end-tidal carbon dioxide, time of arrest, out-of hospital CPR, presence of comorbidity, arterial hyperoxemia or hypoxemia, arterial hypotension, poor Glasgow Coma Score, Serum potassium concentration, and acidosis were associated with unsuccessful CPR [31-40]. However, biomarker-based strategy might help predict the faith of the CPR after CA alone.

Considering that the use of biomarkers could also be beneficial in addition to Prognostic assessment based on clinical observation, relevant trials have been performed. Initially, Fogel el al [4] have shown that increased neuron- specific enolase (NSE) was a strong independent predictor of outcome in patients who have been resuscitated after CA. Missler et al [5] have shown that measuring blood

concentrations of S-100 protein periodically in the first

10 days after cerebral infarction helps to predict infarct volume and the long-term neurologic outcome more accurately than periodic measurements of blood concentra- tions of NSE. Tiainen et al [6] have shown that increasing levels of serum NSE but not S-100B was associated with poor outcome. However, several studies confirmed that serum NSE, S-100B, and also malondialdehyde were associated with morbidity and mortality after CPR in CA patients [7-9]. Geppert et al [10,11] found that von Willebrand factor, intracellular adhesion molecule 1, and plasminogen activator inhibitor type 1 might be useful adjunctive variables for early determination of outcome in CA patients after successful CPR. Finally, Turedi et al [12] demonstrated that ischemia- modified albumin may be a valuable prognostic marker in CA patients after CPR. The increase in the aforementioned biomarkers occurring during CA or at the beginning of CPR was mostly attributed to an increased oxidative stress and thus ischemia-reperfusion injury.

Based on their primary structure and substrate specificity,

MMPs are classified into 5 main groups, including collagenases, gelatinases, stromyelins, minimal MMPs, and membrane-type MMPs. Matrix metalloproteinase 9, together with MMP 2, is a member of the gelatinase group, which is involved in the disruption of gelatin, type IV collagen, and elastin with fibronectin-like structures in the catalytic sites. Thus, the macrophages and the leukocytes use this enzyme to be able to penetrate into various body tissue compartments during their migration [13-17]. Matrix metalloproteinase were shown to be associated with various Pathophysiologic mechanisms in the body. Currently, up on the results from recent trials, MMPs are known to be involved in the pathogenesis of cardiovascular diseases with a high mortality, such as atherosclerosis, heart failure, acute myocardial infarction, and restenosis, particularly via extracellular matrix degradation. Elucidation of these mechanisms led to a reduction of Left ventricular remodeling and the prevention of progression to heart failure by inhibition of the MMP activation through the use of MMP tissue inhibitor after acute myocardial infarction [13,41-44]. Cardiac arrest and CPR are known to be the source of major destruction in the human body. Occurrence of excessive oxidative stress owing to CA and CPR leads to an increased ischemia-reperfusion injury. Hence, associated increase in plasma MMP-9 levels seems to designate extracellular matrix degradation and, thus, diffuse cell death along with increased inftammatory cytokines and biomarkers of cell injury, such as troponins. In addition, although reperfusion can be achieved in a portion of patients after CPR, sequels remain as a result of diffuse

organ injury, particularly in the brain.

In patients with failed CPR, the incidence of out-of- hospital CPR, duration of CA before CPR, and the presence of asystole were more frequent as expected relative to the patients who acutely responded to CPR. These findings were compatible with the data, derived from previous studies

[31,36,38]. Although the basal oxygen saturation was normal in patients who died after CPR, the presence of acidemia and hyperkalemia was more frequent, and these findings were also compatible with the previous literature [39,40].

Limitations

Our study was limited by its monocentric nature, and hence, the findings should not be generalized to overall population of patients with CA. Besides, CA patient profile of the ED of Tertiary care centers might significantly differ from other centers, and hence, data should be considered with this regard. Although the quality of CPR in the ED was checked by a senior physician, outside the study, as requested by guidelines, the way the patients with out-of- hospital CA received CPR could not be evaluated strictly, although all ambulance staff had received careful monitoring from regulatory authorities for what they provided. The current study was also limited by its design such that the study did not consider long-term outcome after CPR because the Predictive role of the biomarker of interest is associated to very short outcome (dead or alive after CPR in the ED). Hence, the potential prognostic role of this biomarker with regard to long-term outcome such as discharge from the hospital remains to be established.

Conclusions

Admission MMP-9 levels were detected to be increased in patients with CA. The plasma MMP-9 levels were observed to be higher in patients with failed CPR relative to those who acutely responded as a biomarker sign of degradation of tissues. Besides, in the presence of the other clinical and laboratory parameters, the admission MMP-9 levels were shown to be an independent predictor of post- CPR early mortality. The MMP-9 paralleled the potassium and troponin levels and was negatively correlated with oxygen saturation and hence seems to designate irrevers- ible phase of CA. It seems that admission MMP-9 might provide physicians in charge of performing CPR with a piece of relatively strong information to decide whether to end CPR with a very high specificity value to decide “rule in for early mortality,” although we believe that it has to be repeated in different cohorts of patients. On the other hand, whether antagonism of MMP-9 could be useful in this setting remains to be established.

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