THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 5, Number 2, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2014.0027
The Inflammatory Marker suPAR After Cardiac Arrest Malin Rundgren, MD, PhD,1 Stig Lyngbaek, MD,2 Helle Fisker, MSc,3 and Hans Friberg, MD, PhD1
Background: Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long-term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response. This pilot study aimed at investigating suPAR levels in relation to outcome after CA and mild induced hypothermia. Methods: suPAR levels were measured at 6, 36, and 72 hours in patients treated with hypothermia after CA. suPAR levels were analyzed in relation to survival after 6 months. Receiver operating characteristic curve (ROC)-analyses were performed, and area under the curve (AUC) was calculated. Time to return of spontaneous circulation (ROSC) was correlated to suPAR levels. Results: Fifty-five patients (40 male, median 65 years) were included, and 33 (60%) were alive after 6 months. The suPAR levels were significantly higher in nonsurviving patients compared with survivors at 6 and 36 hours ( p = 0.006 and 0.034 respectively), but not at 72 hours. The suPAR levels increased from 6 to 72 hours ( p < 0.0001). Time to ROSC correlated positively with suPAR levels at 6 hours ( p = 0.003) but not at 36 and 72 hours. ROC analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. Conclusion: suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups was substantial, reducing the prognostic value. There was a significant increase in suPAR levels during the first 72 hours after CA.
freeze-thaw cycles (Kofoed et al., 2006). It is released in response to an inflammatory reaction and is measurable in plasma (Thunoe et al., 2009; Lyngbæk et al., 2012). suPAR has been suggested for use in assessment of prognosis (survival) in a broad range of diseases associated with inflammation, such as sepsis (Giamarellos-Bourboulis et al., 2012; Suberviola et al., 2013), mechanically ventilated patients ( Jalkanen et al., 2013), a mixed intensive care unit (ICU) population (Koch et al., 2011), ST elevation myocardial infarction (STEMI) (Lyngbæk et al., 2012), and a wide range of cancers (Langkilde et al., 2011). Efforts have also been made to use suPAR as a diagnostic tool, for instance to differentiate SIRS with bacteraemia from SIRS without bacteraemia (Hoenigl et al., 2013). So far, no study has investigated a CA population characterized by a high incidence of acute myocardial infarction and, in addition, an inflammation triggered by the ischemia/reperfusion response. The aim of this study was to evaluate the prognostic capability of suPAR in patients with return of spontaneous circulation (ROSC) after CA, resuscitation and mild induced hypothermia. The primary outcome was to study suPAR as a prognostic marker in relation to survival during 6 months of follow up.
Introduction
T
he ischemia/reperfusion injury initiated by a cardiac arrest (CA) and subsequent resuscitation elicits a systemic inflammatory response syndrome (SIRS) recognized as the post-CA syndrome, characterized by pathophysiological processes similar to the circulatory response in sepsis (Neumar et al., 2008). Elevated levels of inflammatory markers have been demonstrated after CA and successful resuscitation (Adrie et al., 2002; Annborn et al., 2013; Dankiewicz et al., 2013). During the past decade, soluble urokinase plasminogen activator receptor (suPAR) has been put forward as a prognostic inflammatory marker in both lifethreatening and stable disease (Eugen-Olsen et al., 2010; Backes et al., 2012). suPAR is the soluble form of urokinase plasminogen activatior receptor (uPAR, CD87). uPAR is present on several cell types, for instance immune cells (granulocytes, monocytes, activated T-lymphocytes, and NK-cells) (Pleissner et al., 1997), where it contributes to chemo attraction, adherence, and cell migration in response to inflammation. Inflammatory stimuli result in cleaving of uPAR from the cell surface to the soluble form suPAR (Beaufort et al., 2004). suPAR has good stability in plasma, and it is not sensitive to 1 2 3
Department of Clinical Sciences, Anaesthesia and Intensive Care, Skane University Hospital, Lund University, Lund, Sweden. Copenhagen University Hospital, Glostrup, Denmark. ViroGates, Birkerød, Denmark.
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The secondary outcomes were to assess suPAR as a prognostic marker for neurological outcome, and the correlation of suPAR with the severity of insult and the post CA syndrome.
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vasoactive medication, equivalent to circulatory SOFA 2–3 points; and group 3, high-grade vasoactive medication, equivalent to circulatory SOFA 4 points. suPAR analysis
Materials and Methods
Blood samples were collected from CA patients treated at the ICU of Lund University Hospital, Sweden, 2003–2006. The study was approved by the Regional Ethical Review Board at Lund University (411/2004, 223/2008). Informed consent was sought from next of kin or retrospectively from the patient. All CA patients with sustained ROSC, regardless of first monitored rhythm or location of arrest, were considered for hypothermia treatment. Exclusion criteria for hypothermia were terminal disease, CA secondary to intracerebral hemorrhage, aortic dissection, or major trauma (Rundgren et al., 2006). Mild induced hypothermia, 33C – 1C, was initiated (*30 mL/kg cold saline iv) as soon as possible after initial stabilization, controlled ventilation, and sedation (Propofol or Midazolam in combination with Fentanyl). Nondepolarizing muscular relaxant (Rocuronium) was used if necessary to control shivering and to enhance temperature control. If indicated, urgent coronary angiography and percutaneous coronary intervention were performed en route to the ICU. Hypothermia was maintained for 24 hours on target temperature. Rewarming rate was controlled at 0.5C/h. After rewarming, sedation was stopped or kept at a minimum to allow for assessment of level of consciousness. Extubation was performed taking into account neurological, respiratory, circulatory, and fluid balance parameters. Patients not regaining consciousness received full intensive care for at least 3 days after return to normothermia (4.5–5 days after CA), at which time the level of care was decided by a neurologist and an intensivist based on the neurological examination, supported by results of somatosensory evoked potentials, electroencephalography, and, if available, magnetic resonance imaging. Patients were assessed using the Cerebral Performance Categories (CPC) scale ( Jennett and Bond, 1975), when leaving the ICU, the hospital and at 6 months after the CA. A CPC of 1–2 at any time after the CA was considered a good neurological outcome. Serial plasma samples were collected during the first 3 days after CA. The plasma samples were centrifuged and frozen ( - 70C) immediately after collection. The samples were thawed once, centrifuged at 4000 rpm for 5 minutes, aliquoted, and refrozen at - 70C. During aliquoting, the samples were kept on ice. In this study, plasma samples from 6, 36, and 72 hours after the CA were used. The analysis of suPAR was made from the frozen plasma samples retrospectively. Patients with samples available from both 6 and 36 hours after CA were included in the analysis. Seventy-two hours samples were included when available. Epidemiological and CA data were collected prospectively. Acute Physiology and Chronic Health Evaluation II (APACHE II)-data and the daily Sequential Organ Failure Assessment (SOFA) scores for circulation were recorded prospectively and retrieved from the Swedish Intensive Care registry database. The circulatory SOFA scores were used to group patients into three groups based on circulatory instability: group 1, no vasoactive medication; group 2, low-grade
The suPAR analysis was performed in duplicate on plasma samples using a commercial kit (suPARnostic; ViroGates A/ S, Birkerød, Denmark), according to the manufacturer’s instructions. The detection limit was 0.1–20 ng/mL, with an upper limit of 3.5 ng/mL for a normal population. The intraassay coefficient of variation was 3.1%. Data on suPARlevels from blood donors show that women have higher plasma levels than men and that there is an increase with increasing age. As an example, women 51–65 years old had a median plasma level of 2.7 ng/mL (IQR 2.3–3.2) while men had a median level of 2.4 ng/mL (2.2–2.9) (Haastrup et al., 2014). Measurements were performed at ViroGates laboratory, Birkerød, Denmark. Technicians performing the analyses were blinded to the clinical information. Statistical analysis
Continuous data are presented as median and range, whereas categorical data are presented as counts and percentages. The material was dichotomized for survival at 6 months after CA and best neurological outcome, respectively. Mann–Whitney test was used to test for difference in suPAR levels at the analyzed time-points. Wilcoxon-signed rank test was used for paired data, and Kruskal–Wallis test was used for the circulatory compromise analyses. Spearman correlations were used to analyze correlations between continuous data. Receiver operating characteristic curve (ROC) analyses were performed; the area under the curve (AUC), 95% confidence intervals (CI), and sensitivity and specificity were calculated. p < 0.05 was considered significant. Bonferroni corrections were applied as appropriate. The statistical analyses were performed using GraphPad Prism 6.0 (GraphPad Software, Inc., CA). Results Patient material
Fifty-five patients, with a median age of 65 years (range 14–87 years), were included in the study. Forty (73%) of the patients were men. The majority of the CAs occurred out of hospital (47/55, 85%), were witnessed (48/55, 87%), and had a primary recorded rhythm of ventricular fibrillation or pulseless ventricular tachycardia (40/53, 75%); see Table 1. Forty-one (41/55, 75%) of the CAs were assessed to be of cardiac origin, and acute angiography was performed in 30 patients. Thirty-three patients (60%) had a best CPC of 1–2. Twenty-two patients were dead at 6-months follow up; 16 remained unconscious and died after withdrawal of intensive care therapy median at 7 days after the CA (range 4–9 days). One died due to circulatory collapse, and one died due to multi-organ failure during intensive care. One was diagnosed as brain-dead according to Swedish legislation, and three died before 6 months of follow up due to myocardial reinfarction, sepsis, and malignancy, respectively. Paired suPAR samples at 72 hours were available in 44 patients. Missing samples were due to lack of sample material (n = 8); patients had regained consciousness and left the ICU before
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Table 1. Patient Characteristics Sex (male) Location of arrest (OHCA) Witnessed arrest By-stander CPR Initial rhythm (VT/VF) (n = 53) Time to ROSC (minutes) Best CPC 1–2 during 6 months Alive at 6 months APACHE II-score (n = 51)
40 47 48 24 41 17.5 33 33 29
(73%) (85%) (87%) (44%) (75%) (IQR 13–25) (60%) (60%) (IQR 26–32)
Numbers are given as counts and percentages. n = 55 if not otherwise stated. APACHE II, Acute Physiology and Chronic Health Evaluation II; CPC, cerebral performance categories scale; CPR, cardio-pulmonary resuscitation; IQR, inter-quartile range; OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation; VT/VF, ventricular tachycardia/ventricular fibrillation.
72 hours after CA (n = 2), and death before 72 hours (n = 1). Five of the eight patients (62%) with lack of sample material were alive with a good neurological outcome at 6 months after CA, and three died during the ICU stay.
Table 2. Plasma Levels of suPAR (ng/mL) at 6, 36, and 72 Hours After Cardiac Arrest in Relation to Survival at 6 Months Follow-Up Time after CA (hours) 6 6 36 36 72 72
Outcome (n)
suPAR median (ng/mL)
suPAR IQR (ng/mL)
suPAR range (ng/mL)
Alive (33) Dead (22) Alive (33) Dead (22) Alive (26) Dead (18)
3.1 3.8 3.5 4.4 5.8 8.0
2.4–3.7 3.4–4.3 2.6–4.4 3.5–6.0 5.3–9.3 5.5–10.7
1.6–4.6 1.5–7.3 1.6–5.3 1.3–8.4 3.7–12.4 3.0–15.1
CA, cardiac arrest; suPAR, soluble urokinase plasminogen activator receptor.
suPAR and survival at 6 months after CA
The median (inter-quartile range) temperatures were 33.2C (32.9–33.6C), n = 44 at 6 hours, 36.5C (36–36.8C), n = 45 at 36 hours, and 37.6C (37.3–37.7C) at 72 hours after CA. The median suPAR levels for all samples were 3.4 ng/ mL (1.5–7.3 ng/mL) at 6 hours, 3.8 ng/mL (1.3–8.4 ng/mL) at 36 hours, and 6.85 ng/mL (3.0–15.1 ng/mL) at 72 hours, respectively. There was a significant change from 6 to 36 hours and from 6 to 72 hours ( p = 0.025 at 6–36 hours and p < 0.0001 at 6–72 hours, respectively) (Fig. 1). The suPAR levels increased in 43 out of 44 (98%) of patients between 6 and 72 hours.
Thirty-three (60%) of the patients were alive at 6 months after the CA. Measured suPAR levels are shown in Table 2. There were significant differences in suPAR levels between survivors and nonsurvivors at 6 hours ( p = 0.006) and 36 hours ( p = 0.034), but not after 72 hours (Fig. 2). ROC analysis with patient outcomes dichotomized into dead or alive 6 months after CA showed an AUC 0.76 (95% CI 0.63– 0.89) at 6 hours, 0.73 (95% CI 0.59–0.86) at 36 hours, and 0.61 (95% CI 0.43–0.78) at 72 hours (Fig. 3). A suPAR value of 4.15 ng/mL at 6 hours resulted in a specificity of 91% and a sensitivity of 41% for death within 6 months of CA. Post-hoc, an ROC analysis including only the patients with CA of cardiac cause (n = 41) dichotomized into dead (n = 14) or alive (n = 27) at 6 months was performed. The AUC at 6 hours was 0.84 (95% CI 0.72–0.97) and at 36 hours, it was 0.79 (95% CI 0.64–0.94) (Fig. 4).
FIG. 1. Boxplot showing soluble urokinase plasminogen activator receptor (suPAR) levels at 6, 36, and 72 hours after cardiac arrest (CA) in all patients. The line in the box denotes the median value, the box inter-quartile range, and the whiskers range.
FIG. 2. Boxplot showing suPAR levels at 6, 36, and 72 hours in relation to survival at 6 months after CA. The line in the box denotes the median value, the box inter-quartile range, and the whiskers range.
Plasma suPAR
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RUNDGREN ET AL. Correlation between time to ROSC and suPAR
There was a significant correlation between time to ROSC and suPAR levels at 6 and 36 hours, but not at 72 hours after CA, r = 0.41 p = 0.003 at 6 hours, and r = 0.31 p = 0.03 at 36 hours, respectively. suPAR versus SOFA and APACHE II
No significant differences in suPAR levels were noted between the circulatory SOFA groups at 12 or 48 hours after CA (data not shown). There were no significant correlations between the APACHE II-score and suPAR levels at 6 or 36 hours ( p = 0.52 [6 hours]; and 0.12 [36 hours], respectively). Discussion
FIG. 3. Receiver operating characteristic (ROC) analysis of plasma suPAR at different time-points after CA with the material dichotomized into death or survival at 6 months after CA. The area under the curve (AUC) was 0.76, 0.73, and 0.61 at 6, 36, and 72 hours after CA, respectively.
suPAR and neurological outcome
Thirty-three of the patients had a good neurological outcome (defined as best CPC 1–2 at any time during 6 months follow up). There were significant differences in suPAR levels between the good and the poor outcome groups at both 6 and 36 hours after CA ( p = 0.006 at 6 hours and 0.019 at 36 hours), but not at 72 hours after CA. ROC analysis showed an AUC 0.77 (95% CI 0.63–0.90) at 6 hours, 0.74 (95% CI 0.61–0.87) at 36 hours, and 0.61 (95% CI 0.43–0.79) at 72 hours.
FIG. 4. ROC analysis of plasma suPAR at different timepoints after CA in the subgroup of patients suffering a CA of cardiac cause (n = 41) with the material dichotomized into death or survival at 6 months after CA. The AUC was 0.84 and 0.79 at 6 and 36 hours after CA, respectively.
In this pilot study, the prognostic potential of suPAR in a CA population was investigated. The main results were that suPAR levels were higher in patients with a poor longterm outcome both with regard to survival and neurological outcome, and that there was a substantial increase in suPAR during the first 3 days after CA regardless of patient outcome. In our CA population, patients with a poor long-term outcome had higher initial suPAR levels than survivors. The 6 hours suPAR levels were in ranges similar to those noted in STEMI patients (Lyngbæk et al., 2012). In the referred study, the levels of suPAR were stable during repetitive tests during the first 24 hours after admission, but the patients with higher suPAR levels on admission had an increased long-term mortality and a higher incidence of recurrent myocardial infarctions. Repetitive measurements of suPAR have also been carried out in critically ill patients (Koch et al., 2011) with no significant change over the first week of intensive care, neither in a septic cohort nor in a nonseptic cohort of patients; however, suPAR levels were higher in the septic patient cohort. Contrary to the findings in the study by Koch et al., we noted a significant increase in suPAR levels during the first 72 hours after CA (Fig. 1). There may be several possible explanations for this. First, the insult in CA is biphasic with the initial arrest and myocardial stunning being followed by an SIRS-like response (Adrie et al., 2002; Neumar et al., 2008). The increase in suPAR levels between 6 and 72 hours may reflect a response to the inflammation caused by the reperfusion injury, possibly influenced by or delayed by the hypothermia treatment. The second set of samples was collected at 36 hours after CA, which was approximately when the patients resumed normothermia (Thunoe et al., 2009; Rundgren et al., 2010). Since cleavage of suPAR from uPAR is performed by a variety of proteases (Thunoe et al., 2009), the activity of these proteases may have been attenuated by hypothermia, which could affect the timing of the increase in suPAR levels. Second, compared with the situation in critically ill patients in general (Koch et al., 2011), the ‘‘time-point zero’’ differs. The samples in our study were collected in relation to the time of initiation of the ischemia/reperfusion process (CA), which usually is easy to define. On the contrary, the initiation of the process of inflammation in septic patients may have occurred many hours, even days before deterioration to septic shock (Glickman et al., 2010). Thus, the biochemical response to the insult may have evolved during a
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longer time in critically ill patients in general compared with the CA cohort. As expected, there was a significant correlation between suPAR levels and time to ROSC. We used time to ROSC as a marker reflecting the burden of ischemia and reperfusion injury. The time from CA to ROSC is a composite time including several critical factors influencing patient outcome; for instance, time from collapse to emergency call, presence of by-stander cardio-pulmonary resuscitation, time to defibrillation, and the variable/unknown quality of cardiopulmonary resuscitation. Whether the correlation between time to ROSC and suPAR levels reflects a higher burden of disease (and therefore primarily higher suPAR levels) before CA, leading to longer time to ROSC or ‘‘immediate post-CA inflammation,’’ has yet to be determined. Another possibility is that suPAR reflects the disease status before the CA and that patients with higher suPAR levels are more difficult to resuscitate, resulting in the significant difference in suPAR levels at 6 hours between survivors and nonsurvivors and the correlation between time to ROSC and suPAR levels at 6 hours. One way of investigating this would be to measure suPAR during resuscitation by comparing suPAR levels in patients in whom resuscitation failed with long-term survivors and long-term nonsurvivors. We noted a significant difference in suPAR levels at 6 and 36 hours after CA between patients with a good and a poor outcome, both with regard to survival and neurological outcome. From a prognostic point of view, this difference is probably of minor importance, as the overlap between groups was large (Fig. 2). Based on this limited study, suPAR may not be used for assessment of prognosis in individual CA patients of mixed origin. Interestingly, in the subgroup analysis of CA patients of cardiac origin, suPAR performed better, which may trigger investigations in a larger, selected CA cohort. Limitations
This is a pilot study including a limited number of patients. We expected suPAR levels to be relatively stable during the first days of intensive care (Koch et al., 2011) and decided to include patients with paired samples from 6 and 36 hours, and add 72 hours if available. The missing data from 72 hours is a limitation that could bias the conclusions regarding an increase of suPAR levels over time after resuscitation. However, when recalculating the results, substituting missing suPAR levels at 72 hours with the paired data at 6 hours, the difference was still significant ( p < 0.0001). Another limitation relates to the prolonged storage of samples frozen at - 70C and thawed once, but suPAR has previously been shown to be stable under these conditions and even during repetitive freeze thaw cycles (Kofoed et al., 2006; Eugen-Olsen et al., 2010). The patient cohort was included during the years 2003– 2006, which is a limitation in comparison with more recent patient materials. During the years 2003–2011, there were no major protocol changes regarding level of temperature control, sedation, or withdrawal of intensive care policy in the department. In conclusion, suPAR levels obtained early after resuscitation from CA patients were significantly higher in patients who eventually died and among patients with a poor neuro-
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logical outcome. suPAR levels correlated with the severity of the initial insult and increased over the first 3 days after CA. Acknowledgments
The authors are grateful to Dr. Martin Annborn for acquisition of APACHE and SOFA registry data. This study was supported by the Center for Resuscitation Science in the ¨ resund region and Skane county council’s research and O development foundation. Authors’ Contributions
All authors are responsible for the planning of this study (M.R., H.F, and H.F), patient database (M.R.), statistical analysis (M.R.), and drafting and revising this article (M.R., H.F., S.L., and H.F.). All authors approved the final article. Disclosure Statement
The authors M.R., S.L., and H.F. declare that they have no competing interests. H.F. is employed by ViroGates. References
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Address correspondence to: Malin Rundgren, MD, PhD Department of Clinical Sciences, Anaesthesia and Intensive Care Skane University Hospital Lund University Lund 221 82 Sweden E-mail: [email protected]
The Inflammatory Marker suPAR After Cardiac Arrest Malin Rundgren, MD, PhD,1 Stig Lyngbaek, MD,2 Helle Fisker, MSc,3 and Hans Friberg, MD, PhD1
Background: Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long-term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response. This pilot study aimed at investigating suPAR levels in relation to outcome after CA and mild induced hypothermia. Methods: suPAR levels were measured at 6, 36, and 72 hours in patients treated with hypothermia after CA. suPAR levels were analyzed in relation to survival after 6 months. Receiver operating characteristic curve (ROC)-analyses were performed, and area under the curve (AUC) was calculated. Time to return of spontaneous circulation (ROSC) was correlated to suPAR levels. Results: Fifty-five patients (40 male, median 65 years) were included, and 33 (60%) were alive after 6 months. The suPAR levels were significantly higher in nonsurviving patients compared with survivors at 6 and 36 hours ( p = 0.006 and 0.034 respectively), but not at 72 hours. The suPAR levels increased from 6 to 72 hours ( p < 0.0001). Time to ROSC correlated positively with suPAR levels at 6 hours ( p = 0.003) but not at 36 and 72 hours. ROC analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. Conclusion: suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups was substantial, reducing the prognostic value. There was a significant increase in suPAR levels during the first 72 hours after CA.
freeze-thaw cycles (Kofoed et al., 2006). It is released in response to an inflammatory reaction and is measurable in plasma (Thunoe et al., 2009; Lyngbæk et al., 2012). suPAR has been suggested for use in assessment of prognosis (survival) in a broad range of diseases associated with inflammation, such as sepsis (Giamarellos-Bourboulis et al., 2012; Suberviola et al., 2013), mechanically ventilated patients ( Jalkanen et al., 2013), a mixed intensive care unit (ICU) population (Koch et al., 2011), ST elevation myocardial infarction (STEMI) (Lyngbæk et al., 2012), and a wide range of cancers (Langkilde et al., 2011). Efforts have also been made to use suPAR as a diagnostic tool, for instance to differentiate SIRS with bacteraemia from SIRS without bacteraemia (Hoenigl et al., 2013). So far, no study has investigated a CA population characterized by a high incidence of acute myocardial infarction and, in addition, an inflammation triggered by the ischemia/reperfusion response. The aim of this study was to evaluate the prognostic capability of suPAR in patients with return of spontaneous circulation (ROSC) after CA, resuscitation and mild induced hypothermia. The primary outcome was to study suPAR as a prognostic marker in relation to survival during 6 months of follow up.
Introduction
T
he ischemia/reperfusion injury initiated by a cardiac arrest (CA) and subsequent resuscitation elicits a systemic inflammatory response syndrome (SIRS) recognized as the post-CA syndrome, characterized by pathophysiological processes similar to the circulatory response in sepsis (Neumar et al., 2008). Elevated levels of inflammatory markers have been demonstrated after CA and successful resuscitation (Adrie et al., 2002; Annborn et al., 2013; Dankiewicz et al., 2013). During the past decade, soluble urokinase plasminogen activator receptor (suPAR) has been put forward as a prognostic inflammatory marker in both lifethreatening and stable disease (Eugen-Olsen et al., 2010; Backes et al., 2012). suPAR is the soluble form of urokinase plasminogen activatior receptor (uPAR, CD87). uPAR is present on several cell types, for instance immune cells (granulocytes, monocytes, activated T-lymphocytes, and NK-cells) (Pleissner et al., 1997), where it contributes to chemo attraction, adherence, and cell migration in response to inflammation. Inflammatory stimuli result in cleaving of uPAR from the cell surface to the soluble form suPAR (Beaufort et al., 2004). suPAR has good stability in plasma, and it is not sensitive to 1 2 3
Department of Clinical Sciences, Anaesthesia and Intensive Care, Skane University Hospital, Lund University, Lund, Sweden. Copenhagen University Hospital, Glostrup, Denmark. ViroGates, Birkerød, Denmark.
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The secondary outcomes were to assess suPAR as a prognostic marker for neurological outcome, and the correlation of suPAR with the severity of insult and the post CA syndrome.
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vasoactive medication, equivalent to circulatory SOFA 2–3 points; and group 3, high-grade vasoactive medication, equivalent to circulatory SOFA 4 points. suPAR analysis
Materials and Methods
Blood samples were collected from CA patients treated at the ICU of Lund University Hospital, Sweden, 2003–2006. The study was approved by the Regional Ethical Review Board at Lund University (411/2004, 223/2008). Informed consent was sought from next of kin or retrospectively from the patient. All CA patients with sustained ROSC, regardless of first monitored rhythm or location of arrest, were considered for hypothermia treatment. Exclusion criteria for hypothermia were terminal disease, CA secondary to intracerebral hemorrhage, aortic dissection, or major trauma (Rundgren et al., 2006). Mild induced hypothermia, 33C – 1C, was initiated (*30 mL/kg cold saline iv) as soon as possible after initial stabilization, controlled ventilation, and sedation (Propofol or Midazolam in combination with Fentanyl). Nondepolarizing muscular relaxant (Rocuronium) was used if necessary to control shivering and to enhance temperature control. If indicated, urgent coronary angiography and percutaneous coronary intervention were performed en route to the ICU. Hypothermia was maintained for 24 hours on target temperature. Rewarming rate was controlled at 0.5C/h. After rewarming, sedation was stopped or kept at a minimum to allow for assessment of level of consciousness. Extubation was performed taking into account neurological, respiratory, circulatory, and fluid balance parameters. Patients not regaining consciousness received full intensive care for at least 3 days after return to normothermia (4.5–5 days after CA), at which time the level of care was decided by a neurologist and an intensivist based on the neurological examination, supported by results of somatosensory evoked potentials, electroencephalography, and, if available, magnetic resonance imaging. Patients were assessed using the Cerebral Performance Categories (CPC) scale ( Jennett and Bond, 1975), when leaving the ICU, the hospital and at 6 months after the CA. A CPC of 1–2 at any time after the CA was considered a good neurological outcome. Serial plasma samples were collected during the first 3 days after CA. The plasma samples were centrifuged and frozen ( - 70C) immediately after collection. The samples were thawed once, centrifuged at 4000 rpm for 5 minutes, aliquoted, and refrozen at - 70C. During aliquoting, the samples were kept on ice. In this study, plasma samples from 6, 36, and 72 hours after the CA were used. The analysis of suPAR was made from the frozen plasma samples retrospectively. Patients with samples available from both 6 and 36 hours after CA were included in the analysis. Seventy-two hours samples were included when available. Epidemiological and CA data were collected prospectively. Acute Physiology and Chronic Health Evaluation II (APACHE II)-data and the daily Sequential Organ Failure Assessment (SOFA) scores for circulation were recorded prospectively and retrieved from the Swedish Intensive Care registry database. The circulatory SOFA scores were used to group patients into three groups based on circulatory instability: group 1, no vasoactive medication; group 2, low-grade
The suPAR analysis was performed in duplicate on plasma samples using a commercial kit (suPARnostic; ViroGates A/ S, Birkerød, Denmark), according to the manufacturer’s instructions. The detection limit was 0.1–20 ng/mL, with an upper limit of 3.5 ng/mL for a normal population. The intraassay coefficient of variation was 3.1%. Data on suPARlevels from blood donors show that women have higher plasma levels than men and that there is an increase with increasing age. As an example, women 51–65 years old had a median plasma level of 2.7 ng/mL (IQR 2.3–3.2) while men had a median level of 2.4 ng/mL (2.2–2.9) (Haastrup et al., 2014). Measurements were performed at ViroGates laboratory, Birkerød, Denmark. Technicians performing the analyses were blinded to the clinical information. Statistical analysis
Continuous data are presented as median and range, whereas categorical data are presented as counts and percentages. The material was dichotomized for survival at 6 months after CA and best neurological outcome, respectively. Mann–Whitney test was used to test for difference in suPAR levels at the analyzed time-points. Wilcoxon-signed rank test was used for paired data, and Kruskal–Wallis test was used for the circulatory compromise analyses. Spearman correlations were used to analyze correlations between continuous data. Receiver operating characteristic curve (ROC) analyses were performed; the area under the curve (AUC), 95% confidence intervals (CI), and sensitivity and specificity were calculated. p < 0.05 was considered significant. Bonferroni corrections were applied as appropriate. The statistical analyses were performed using GraphPad Prism 6.0 (GraphPad Software, Inc., CA). Results Patient material
Fifty-five patients, with a median age of 65 years (range 14–87 years), were included in the study. Forty (73%) of the patients were men. The majority of the CAs occurred out of hospital (47/55, 85%), were witnessed (48/55, 87%), and had a primary recorded rhythm of ventricular fibrillation or pulseless ventricular tachycardia (40/53, 75%); see Table 1. Forty-one (41/55, 75%) of the CAs were assessed to be of cardiac origin, and acute angiography was performed in 30 patients. Thirty-three patients (60%) had a best CPC of 1–2. Twenty-two patients were dead at 6-months follow up; 16 remained unconscious and died after withdrawal of intensive care therapy median at 7 days after the CA (range 4–9 days). One died due to circulatory collapse, and one died due to multi-organ failure during intensive care. One was diagnosed as brain-dead according to Swedish legislation, and three died before 6 months of follow up due to myocardial reinfarction, sepsis, and malignancy, respectively. Paired suPAR samples at 72 hours were available in 44 patients. Missing samples were due to lack of sample material (n = 8); patients had regained consciousness and left the ICU before
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Table 1. Patient Characteristics Sex (male) Location of arrest (OHCA) Witnessed arrest By-stander CPR Initial rhythm (VT/VF) (n = 53) Time to ROSC (minutes) Best CPC 1–2 during 6 months Alive at 6 months APACHE II-score (n = 51)
40 47 48 24 41 17.5 33 33 29
(73%) (85%) (87%) (44%) (75%) (IQR 13–25) (60%) (60%) (IQR 26–32)
Numbers are given as counts and percentages. n = 55 if not otherwise stated. APACHE II, Acute Physiology and Chronic Health Evaluation II; CPC, cerebral performance categories scale; CPR, cardio-pulmonary resuscitation; IQR, inter-quartile range; OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation; VT/VF, ventricular tachycardia/ventricular fibrillation.
72 hours after CA (n = 2), and death before 72 hours (n = 1). Five of the eight patients (62%) with lack of sample material were alive with a good neurological outcome at 6 months after CA, and three died during the ICU stay.
Table 2. Plasma Levels of suPAR (ng/mL) at 6, 36, and 72 Hours After Cardiac Arrest in Relation to Survival at 6 Months Follow-Up Time after CA (hours) 6 6 36 36 72 72
Outcome (n)
suPAR median (ng/mL)
suPAR IQR (ng/mL)
suPAR range (ng/mL)
Alive (33) Dead (22) Alive (33) Dead (22) Alive (26) Dead (18)
3.1 3.8 3.5 4.4 5.8 8.0
2.4–3.7 3.4–4.3 2.6–4.4 3.5–6.0 5.3–9.3 5.5–10.7
1.6–4.6 1.5–7.3 1.6–5.3 1.3–8.4 3.7–12.4 3.0–15.1
CA, cardiac arrest; suPAR, soluble urokinase plasminogen activator receptor.
suPAR and survival at 6 months after CA
The median (inter-quartile range) temperatures were 33.2C (32.9–33.6C), n = 44 at 6 hours, 36.5C (36–36.8C), n = 45 at 36 hours, and 37.6C (37.3–37.7C) at 72 hours after CA. The median suPAR levels for all samples were 3.4 ng/ mL (1.5–7.3 ng/mL) at 6 hours, 3.8 ng/mL (1.3–8.4 ng/mL) at 36 hours, and 6.85 ng/mL (3.0–15.1 ng/mL) at 72 hours, respectively. There was a significant change from 6 to 36 hours and from 6 to 72 hours ( p = 0.025 at 6–36 hours and p < 0.0001 at 6–72 hours, respectively) (Fig. 1). The suPAR levels increased in 43 out of 44 (98%) of patients between 6 and 72 hours.
Thirty-three (60%) of the patients were alive at 6 months after the CA. Measured suPAR levels are shown in Table 2. There were significant differences in suPAR levels between survivors and nonsurvivors at 6 hours ( p = 0.006) and 36 hours ( p = 0.034), but not after 72 hours (Fig. 2). ROC analysis with patient outcomes dichotomized into dead or alive 6 months after CA showed an AUC 0.76 (95% CI 0.63– 0.89) at 6 hours, 0.73 (95% CI 0.59–0.86) at 36 hours, and 0.61 (95% CI 0.43–0.78) at 72 hours (Fig. 3). A suPAR value of 4.15 ng/mL at 6 hours resulted in a specificity of 91% and a sensitivity of 41% for death within 6 months of CA. Post-hoc, an ROC analysis including only the patients with CA of cardiac cause (n = 41) dichotomized into dead (n = 14) or alive (n = 27) at 6 months was performed. The AUC at 6 hours was 0.84 (95% CI 0.72–0.97) and at 36 hours, it was 0.79 (95% CI 0.64–0.94) (Fig. 4).
FIG. 1. Boxplot showing soluble urokinase plasminogen activator receptor (suPAR) levels at 6, 36, and 72 hours after cardiac arrest (CA) in all patients. The line in the box denotes the median value, the box inter-quartile range, and the whiskers range.
FIG. 2. Boxplot showing suPAR levels at 6, 36, and 72 hours in relation to survival at 6 months after CA. The line in the box denotes the median value, the box inter-quartile range, and the whiskers range.
Plasma suPAR
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RUNDGREN ET AL. Correlation between time to ROSC and suPAR
There was a significant correlation between time to ROSC and suPAR levels at 6 and 36 hours, but not at 72 hours after CA, r = 0.41 p = 0.003 at 6 hours, and r = 0.31 p = 0.03 at 36 hours, respectively. suPAR versus SOFA and APACHE II
No significant differences in suPAR levels were noted between the circulatory SOFA groups at 12 or 48 hours after CA (data not shown). There were no significant correlations between the APACHE II-score and suPAR levels at 6 or 36 hours ( p = 0.52 [6 hours]; and 0.12 [36 hours], respectively). Discussion
FIG. 3. Receiver operating characteristic (ROC) analysis of plasma suPAR at different time-points after CA with the material dichotomized into death or survival at 6 months after CA. The area under the curve (AUC) was 0.76, 0.73, and 0.61 at 6, 36, and 72 hours after CA, respectively.
suPAR and neurological outcome
Thirty-three of the patients had a good neurological outcome (defined as best CPC 1–2 at any time during 6 months follow up). There were significant differences in suPAR levels between the good and the poor outcome groups at both 6 and 36 hours after CA ( p = 0.006 at 6 hours and 0.019 at 36 hours), but not at 72 hours after CA. ROC analysis showed an AUC 0.77 (95% CI 0.63–0.90) at 6 hours, 0.74 (95% CI 0.61–0.87) at 36 hours, and 0.61 (95% CI 0.43–0.79) at 72 hours.
FIG. 4. ROC analysis of plasma suPAR at different timepoints after CA in the subgroup of patients suffering a CA of cardiac cause (n = 41) with the material dichotomized into death or survival at 6 months after CA. The AUC was 0.84 and 0.79 at 6 and 36 hours after CA, respectively.
In this pilot study, the prognostic potential of suPAR in a CA population was investigated. The main results were that suPAR levels were higher in patients with a poor longterm outcome both with regard to survival and neurological outcome, and that there was a substantial increase in suPAR during the first 3 days after CA regardless of patient outcome. In our CA population, patients with a poor long-term outcome had higher initial suPAR levels than survivors. The 6 hours suPAR levels were in ranges similar to those noted in STEMI patients (Lyngbæk et al., 2012). In the referred study, the levels of suPAR were stable during repetitive tests during the first 24 hours after admission, but the patients with higher suPAR levels on admission had an increased long-term mortality and a higher incidence of recurrent myocardial infarctions. Repetitive measurements of suPAR have also been carried out in critically ill patients (Koch et al., 2011) with no significant change over the first week of intensive care, neither in a septic cohort nor in a nonseptic cohort of patients; however, suPAR levels were higher in the septic patient cohort. Contrary to the findings in the study by Koch et al., we noted a significant increase in suPAR levels during the first 72 hours after CA (Fig. 1). There may be several possible explanations for this. First, the insult in CA is biphasic with the initial arrest and myocardial stunning being followed by an SIRS-like response (Adrie et al., 2002; Neumar et al., 2008). The increase in suPAR levels between 6 and 72 hours may reflect a response to the inflammation caused by the reperfusion injury, possibly influenced by or delayed by the hypothermia treatment. The second set of samples was collected at 36 hours after CA, which was approximately when the patients resumed normothermia (Thunoe et al., 2009; Rundgren et al., 2010). Since cleavage of suPAR from uPAR is performed by a variety of proteases (Thunoe et al., 2009), the activity of these proteases may have been attenuated by hypothermia, which could affect the timing of the increase in suPAR levels. Second, compared with the situation in critically ill patients in general (Koch et al., 2011), the ‘‘time-point zero’’ differs. The samples in our study were collected in relation to the time of initiation of the ischemia/reperfusion process (CA), which usually is easy to define. On the contrary, the initiation of the process of inflammation in septic patients may have occurred many hours, even days before deterioration to septic shock (Glickman et al., 2010). Thus, the biochemical response to the insult may have evolved during a
SUPAR
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longer time in critically ill patients in general compared with the CA cohort. As expected, there was a significant correlation between suPAR levels and time to ROSC. We used time to ROSC as a marker reflecting the burden of ischemia and reperfusion injury. The time from CA to ROSC is a composite time including several critical factors influencing patient outcome; for instance, time from collapse to emergency call, presence of by-stander cardio-pulmonary resuscitation, time to defibrillation, and the variable/unknown quality of cardiopulmonary resuscitation. Whether the correlation between time to ROSC and suPAR levels reflects a higher burden of disease (and therefore primarily higher suPAR levels) before CA, leading to longer time to ROSC or ‘‘immediate post-CA inflammation,’’ has yet to be determined. Another possibility is that suPAR reflects the disease status before the CA and that patients with higher suPAR levels are more difficult to resuscitate, resulting in the significant difference in suPAR levels at 6 hours between survivors and nonsurvivors and the correlation between time to ROSC and suPAR levels at 6 hours. One way of investigating this would be to measure suPAR during resuscitation by comparing suPAR levels in patients in whom resuscitation failed with long-term survivors and long-term nonsurvivors. We noted a significant difference in suPAR levels at 6 and 36 hours after CA between patients with a good and a poor outcome, both with regard to survival and neurological outcome. From a prognostic point of view, this difference is probably of minor importance, as the overlap between groups was large (Fig. 2). Based on this limited study, suPAR may not be used for assessment of prognosis in individual CA patients of mixed origin. Interestingly, in the subgroup analysis of CA patients of cardiac origin, suPAR performed better, which may trigger investigations in a larger, selected CA cohort. Limitations
This is a pilot study including a limited number of patients. We expected suPAR levels to be relatively stable during the first days of intensive care (Koch et al., 2011) and decided to include patients with paired samples from 6 and 36 hours, and add 72 hours if available. The missing data from 72 hours is a limitation that could bias the conclusions regarding an increase of suPAR levels over time after resuscitation. However, when recalculating the results, substituting missing suPAR levels at 72 hours with the paired data at 6 hours, the difference was still significant ( p < 0.0001). Another limitation relates to the prolonged storage of samples frozen at - 70C and thawed once, but suPAR has previously been shown to be stable under these conditions and even during repetitive freeze thaw cycles (Kofoed et al., 2006; Eugen-Olsen et al., 2010). The patient cohort was included during the years 2003– 2006, which is a limitation in comparison with more recent patient materials. During the years 2003–2011, there were no major protocol changes regarding level of temperature control, sedation, or withdrawal of intensive care policy in the department. In conclusion, suPAR levels obtained early after resuscitation from CA patients were significantly higher in patients who eventually died and among patients with a poor neuro-
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logical outcome. suPAR levels correlated with the severity of the initial insult and increased over the first 3 days after CA. Acknowledgments
The authors are grateful to Dr. Martin Annborn for acquisition of APACHE and SOFA registry data. This study was supported by the Center for Resuscitation Science in the ¨ resund region and Skane county council’s research and O development foundation. Authors’ Contributions
All authors are responsible for the planning of this study (M.R., H.F, and H.F), patient database (M.R.), statistical analysis (M.R.), and drafting and revising this article (M.R., H.F., S.L., and H.F.). All authors approved the final article. Disclosure Statement
The authors M.R., S.L., and H.F. declare that they have no competing interests. H.F. is employed by ViroGates. References
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Address correspondence to: Malin Rundgren, MD, PhD Department of Clinical Sciences, Anaesthesia and Intensive Care Skane University Hospital Lund University Lund 221 82 Sweden E-mail: [email protected]
