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Keywords:

  • Biomarker;
  • cardiac arrest;
  • C-reactive protein;
  • procalcitonin;
  • therapeutic hypothermia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

Eur J Clin Invest 2010; 40 (4): 376–381

Abstract

Introduction  The aim of this study was to investigate time course of procalcitonin (PCT), C-reactive protein (CRP) and white blood cell (WBC) levels in patients with therapeutic hypothermia after cardiac arrest.

Methods  We retrospectively assessed laboratory and clinical data in a consecutive cohort of patients admitted to the medical intensive-care-unit of the University Hospital in Basel, Switzerland, in whom therapeutic hypothermia was induced because of cardiac arrest between December 2007 and January 2009. Infection was considered based on microbiological evidence (restricted definition) and/or clinical evidence of infection with prescription of antibiotics (extended definition).

Results  From 34 included patients, 25 had respiratory tract infection based on the clinical judgment and in 18 microbiological cultures turned positive (restricted definition). PCT concentrations were highest on the first day after hypothermia and showed a steady decrease until day 7 without differences in patients with and without presumed infection. CRP concentrations increased to a peak level at days 3–4 followed by a steady decrease; CRP concentrations were higher in patients with clinical diagnosis of infection on day 4 (P = 0·02); and in patients with evidence of bacterial growth in cultures on days 4 and 5 (P = 0·01 and P = 0·006). WBC remained unchanged after hypothermia without differences between patients with and without infection.

Conclusion  High initial values of PCT and high peak levels after 3–4 days of CRP were found in patients with induction of hypothermia after cardiac arrest. This increase was unspecific and mirrors rather an inflammatory reaction than true underlying infection, limiting the diagnostic potential for early antibiotic stewardship in these patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

Despite recent advances in defibrillation and cardiopulmonary resuscitation, sudden cardiac arrests have an important mortality and morbidity rate, and many survivors have substantial neurological deficits [1]. Two large trials [2,3] and one meta-analysis [4] found that the outcome of postcardiac arrest patients was improved by the induction of mild hypothermia for 12–24 h. For this reason, the International Liaison Committee on Resuscitation recommends hypothermia after cardiac arrest, except in the presence of shock, coagulopathy, or arrhythmia [5]. However, there can also be important adverse effects from hypothermia, including electrolyte issues, arrhythmia, hyperglycaemia and infection [5]. Although hypothermia is thought to alter the immune response and increase proinflammatory cytokines [6], the rate of patients with pneumonia was not higher than expected from normothermic patients after cardiac arrest occurring with an incidence of 30–40% of patients [3].

Enormous attempts have been undertaken to correlate levels of different mediators, particularly C-reactive protein (CRP) and procalcitonin (PCT), with the presence of bacterial infections and sepsis [7–9]. PCT has been demonstrated to be clinically useful in the diagnosis of bacterial infections, particularly in respiratory tract infections. Antibiotic stewardship based on PCT cut off ranges has shown great effectiveness in patients with suspected respiratory tract infection [10–17]. However, PCT can be increased in non-infectious conditions, such as in severely ill patients and after surgery [18,19,20]. A recent study showed that in contrast to the acute phase reactant interleukin-6, PCT was not significantly elevated during uncomplicated acute myocardial infarction except in patients with refractory cardiogenic shock [21]. Other studies in post cardiac arrest patients, showed increased PCT values particularly in patients with adverse clinical outcome suggesting a prognostic value of PCT [22–24]. Our objective was to study the time profile of PCT, CRP and white blood cells (WBC) in patients with mild hypothermia after cardiac arrest, particularly as hypothermia can induce and augment proinflammatory cytokines [6], and to assess whether these biomarker levels could be used as diagnostic markers of infection.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

This retrospective cohort study was conducted at the Intensive care Unit of the University Hospital Basel in Switzerland, a 950-bed tertiary healthcare center. To retrieve all consecutive patients between December 2007 and January 2009 in whom therapeutic hypothermia was conducted because of cardiac arrest, we performed a query of our inhospital electronic medical data system (care view system). All patients received therapeutic hypothermia because of coma following resuscitation from witnessed cardiac arrest. All patients received standardized medical treatment and hypothermia was induced according to our intensive care unit protocol based on the protocol of two large published trials [2,3]. In brief, all patients were intubated and ventilated. Sedation was induced and maintained by the intravenous administration of midazolam and fentanyl. To prevent shivering, paralysis was achieved by the intravenous administration of pancuronium. The body core temperature was measured with a bladder-temperature probe (Foley catheter). The hypothermia goal temperature was 32–34 °C, which was maintained for 12–24 h, and thereafter reversed by a (targeted) rewarming rate of 0·1 °C/h.

To obtain demographic, clinical, microbiological, radiographic, and laboratory data on admission and during follow up, patient records were retrospectively reviewed. More specifically, CRP, PCT and WBC concentrations were recorded daily between day 1 and day 7 after induction of hypothermia. PCT was measured with a high sensitive time-resolved amplified cryptate emission (TRACE) technology assay (PCT Kryptor®, B.R.A.H.M.S. AG, Hennigsdorf, Germany). The assay has a detection limit of 0·02 μg L−1 and functional assay sensitivity of 0·06 μg L−1, i.e. 3- to 10-fold above normal mean values. CRP concentrations were determined by an enzyme immunoassay having a detection limit of < 5 mg dL−1 (EMIT; Merck Diagnostica, Zurich, Switzerland). The results of bacterial cultures (blood, urine or tracheal aspirates from unprotected specimens) and the use of antibiotics were retrieved from the medical records.

For the diagnosis of infection we used two different definitions: first, we used an extended definition, where all patients were classified as infected when there was clinical evidence of infection and patients received antibiotics by the treating physicians (with or without documented positive bacterial cultures). Second, we used a restricted definition, where only patients with microbiological confirmation of bacterial growth were classified as infected.

Statistical analyses

Frequency comparison was done by chi-square test. Two-group comparison of normally distributed data was performed by Student’s t-test. For data not normally distributed, the Mann–Whitney U-test was used. We further compared the overall discriminatory ability of the different biomarker levels by calculating receiver operating characteristic (ROC) analysis. Thereby the area under the ROC curve (AUC) is a summary measure over criteria and cut-point choices. The AUC summary equals the probability that the underlying classifier will score a randomly drawn positive sample higher than a randomly drawn negative sample. For all calculations we used stata 9.2 statistical software (Stata Corp, College Station, TX, USA). All testing was two tailed and P-values less than 0·05 were considered to indicate statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

A total of 34 patients (median age, 60 years; IQR, 48–67 years, 73·5% men) were included in this analysis. All patients received therapeutic hypothermia because of cardiac arrest and were treated using the same protocol as outlined in the methods section. Cardiac arrest occurred in 24 patients (70·6%) because of underlying coronary heart disease; in the remaining 10 patients no coronary heart disease was found on coronary catheterization. The overall median length of ICU stay in survivors was 8 days (IQR 6–11). Nine patients died after a median of 5 days (IQR 3–9) during the hospital stay; thus the inhospital mortality rate was 27%. Baseline demographic characteristics and clinical data are presented in Table 1.

Table 1.   Baseline characteristics
CharacteristicsAll patients (n = 34)
Demographic characteristics
 Age (years) – median (IQR)60 (50–67)
 Sex (female) –n (%)9 (27)
Underlying cardiac disease –n (%)
 Coronary heart disease24 (70·6)
 Primary arrhythmia9 (26·5)
 Hypertrophic obstructive cardiomyopathy1 (2·9)
Laboratory findings – median (IQR)
 Procalcitonin (ng mL−1): initial value0·68 (0·31–2·83)
  Peak value0·85 (0·56–4·22)
 C-reactive protein (mg L−1) initial value48 (30–92)
  Peak value196 (138–235)
 White blood cells (×109 L−1) initial value10·6 (8·8–12·8)
  Peak value13·2 (11·0–16·2)
 Peak creatinine level (μmol L−1)142 (76–108)
 Peak creatine-kinase level (U L−1)1719 (517–3856)
Diagnostic workup for infection –n (%)
 Positive blood cultures0 (0)
 New or increasing infiltrate on chest X-ray19 (55·92)
 Bronchoscopy with bronchoalveolar lavage12 (35·3)
Clinical diagnosis of infection
 Respiratory tract infection- n (%)25 (73·5)
 Initiation of antibiotic therapy –n (%)25 (73·5)
 Duration of antibiotic therapy – median (IQR)7 (6–10)
Microbiologically confirmed infection –n (%)
 Pathological strains in bronchoscopy or tracheal aspirate18 (53·5)
Outcomes
 Length of ICU stay (days) – median (IQR)8 (6–11)
 Inhospital mortality –n (%)9 (27·3)
 Time to death (days) – median (IQR)5 (3–9)

In 25 patients (74%) respiratory tract infection was diagnosed after a median of 3 days (IQR 2–4) based on the clinical judgment of the treating physicians and appropriate antibiotic therapy was initiated (extended definition). Sixteen patients received amoxicillin and clavulanate (Augmentin®), three patients received cephalosporins (Ceftriaxone, Rocephin®) and six patients received broad spectrum coverage with Piperacillin and Tazobactam (Tazobac®). In 18 patients (53%) evidence of bacteria based on tracheal aspirate and/or bronchoalveolar lavage was possible (restricted definition). In 10 patients Staphylococcus aureus alone or in combination with other strains was found; Enterobacteriacea were found in three patients, Klebsiella pneumoniae and Streptococcus pneumoniae were found in two patients each. Blood cultures did not show growth of microorganisms in any patient and no other concomitant infection was found.

Figure 1 shows the course of PCT (right y-axis) and CRP (left y-axis) within the first 7 days after therapeutic hypothermia in all patients (upper panel), separated by clinical diagnosis of infection (extended definition, middle panel), and separated by evidence of bacterial growth (restricted definition, lower panel). PCT concentrations were highest on the first day after hypothermia (PCT 3·63 ng mL−1) and showed an about 4-fold decrease (PCT 0·91 ng mL−1) on day 7. There was no difference in PCT levels in patients with and without infection on any time point using both definitions. Similarly, ROC analysis confirmed no significant discriminatory ability of PCT on any time point using both definitions. CRP concentrations increased within the first 3–4 days after hypothermia followed by a steady decrease. CRP concentrations were higher in patients with clinical diagnosis of infection on day 4 (P = 0·02); and in patients with microbiological confirmed diagnosis of infection on days 4 and 5 (P = 0·01 and P = 0·006), respectively. ROC curve analysis showed of AUCs of 0·79 (95% CI 0·63–0·96) and 0·72 (95% CI 0·51–0·92) and days 4 and 5 using the clinical definition as the goldstandard and AUCs of 0·84 (95% CI 0·70–0·99) and 0·80 (95% CI 0·63–0·96) when using the microbiological definition. At a cut off value of 180 mg dL−1, CRP had a high specificity of 86% and 100%, with a low sensitivity of 54% and 67% to diagnose infection when using the microbiological or clinical goldstandard diagnosis. The respective specifities and sensitivities for the same cut off on day 5 were 86% and 87%, and 43% and 53% respectively.

image

Figure 1.  PCT and CRP levels in patients with induction of mild hypothermia after cardiac arrest.

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Figure 2 shows the course of WBC in all patients and separated by clinical diagnosis of infection (extended definition, middle panel), and separated by microbiological diagnosis for infection (restricted definition, lower panel). WBC remained stable after hypothermia. There was no difference between patients with and without infection using both definitions and WBC could not separated infected from non infected patients. Similarly, ROC analysis showed no significant discriminatory ability of BWC on any time points using both definitions.

image

Figure 2.  WBC levels in patients with induction of mild hypothermia after cardiac arrest.

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Prognostic assessment revealed no difference in either PCT, CRP or WBC levels in survivors as compared to non survivors on admission and during all days of follow up.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

Within this study we investigated the diagnostic potential of PCT, CRP and WBC in patients with and without infections after cardiac arrest and induction of therapeutic hypothermia. We found that all biomarkers of infection are highly elevated in these patients independent of underlying infection with, however, different biomarker kinetics. While PCT peaks within the first 24 h and gradual decreases later, CRP has a late peak after 3–4 days, and WBC remains slightly elevated in all patients. Only CRP showed a significant difference on days 4 and 5 between infected and non-infected patients with, however, considerable overlap between both groups as demonstrated in ROC analysis.

Respiratory tract infection in patients after cardiac arrest and induction of therapeutic hypothermia is the most frequent infectious complication in this setting and if not treated adequately negatively affects the prognosis of patients. However, correctly diagnosing pulmonary infection in these patients is challenging, because most patients present with a systemic inflammatory response syndrome, and a true gold standard to differentiate pneumonitis due to aspiration from bacterial (super-) infection does often not exist. Based on the results of this and previous studies [24,25], it can be concluded that the high increase of PCT and CRP rather reflects the nonspecific systemic inflammatory response due to the underlying disease and hypothermia than true bacterial infection and these biomarkers are thus of no diagnostic value in this particular situation. However, knowledge of the biomarker-specific time course in patients after cardiac arrest is important and may help to prevent unnecessary antibiotic usage.

Previous studies have focused on finding a sensitive diagnostic marker for differentiating bacterial infection from other, viral causes in patients with suspicion of lower respiratory tract infections. Unlike CRP and WBC, different studies have shown that PCT can be used for antibiotic stewardship and safely reduce antibiotic exposure [10–15]. Importantly, in these studies, high sensitive PCT assays and cut off ranges of 0·1–0·25 ng mL−1 were used to maximize sensitivity, and thus safety of patients. This concept was proven successful because PCT remained low in patients with non-bacterial respiratory tract infections. In contrast, the presented cohort of patients has strongly elevated PCT levels, which limits the diagnostic potential of PCT, especially for diagnosing ‘low grade’ pulmonary (super-) infection as often suspected in patients after cardiac arrest and induction of hypothermia. The results of this study suggest that in this particular situation CRP has more clinical potential and very high CRP values (i.e. > 180 mg dL−1) may point to infection. However, safely ruling out infection based on CRP values is not possible based on the results of this study.

The prognostic value of PCT after cardiac arrest has been investigated in previous studies. Two previous German studies reported increased PCT values in cardiac arrest survivors with highest levels in patients with adverse neurological outcome independent of underlying infection [24,25]. Similarly, another study reported increased PCT levels in patients undergoing elective heart surgery with cardiopulmonary bypass and patients admitted after out-of-hospital cardiac arrest, particularly in patients who died of refractory shock [23]. In children with after a cardiac arrest PCT increased and was significantly higher in non-surviving children after 24 h after hospital admission [22]. Similarly to our study, a very recent retrospective analysis of post-resuscitation patients found a poor overall performance of PCT to establish the diagnosis of pneumonia and hypothesize that the post-resuscitation disease itself could play a major role in this lack of specificity and predictive value of PCT [26]. This study complements these previous studies and investigates the 7 days time course of PCT, CRP and WBC in a specific cohort of patients with induction of hypothermia after cardiac arrest and is thus noteworthy.

Limitations of this study are the retrospective design, the small sample size not allowing for further subgroup analysis and the lack of a true diagnostic goldstandard to diagnose respiratory tract infection in these patients. The extend of ischaemia and associated reperfusion syndrome was not accurately documented in these patients, but may have importantly influenced the production of biomarker levels. In addition, physicians were unblinded to biomarker results, which may have influenced their clinical decision to suspect infection and prescribe antibiotics. To circumvent this bias, we used two different definitions of ‘infection’, one relying more strictly on microbiological criteria (restricted definition). As this study shows similarity of all biomarkers in both groups independent of the definition applied, we believe that this bias is at least conservative.

In conclusion, high initial values of PCT and high peak levels after 3–4 days of CRP should be expected in patients with induction of hypothermia after cardiac arrest and do not per se point to underlying infection. A thorough clinical, radiological and microbiological workup should be conducted in these patients in order to limit antibiotic overuse.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

We thank Stefan Ott for technical assistance and the staff of the Intensive care unit for careful treatment of patients according to the clinical protocol.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

No commercial sponsor had any involvement in design and conduct of this study. PS received support from BRAHMS and bioMerieux to attend meetings and fulfilled speaking engagements in relation to other biomarker studies. All other authors have no conflict of interest to disclose.

Address

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References

Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA (P. Schuetz); Department of Intensive Care Medicine, University Hospital Basel, Basel, Switzerland (B. Affolter, S. Hunziker, C. Winterhalder, M. Fischer, G. M. Balestra, P. Hunziker, S. Marsch).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Source of funding
  9. Conflict of interest
  10. Address
  11. References
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