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Emerg Med J. 2007 November; 24(11): 769–773.
PMCID: PMC2658321

Role of brain natriuretic peptide (BNP) in risk stratification of adult syncope

Abstract

Aims

To assess the value of a near‐patient brain natriuretic peptide (BNP) test to predict medium term (3 month) serious outcome for adult syncope patients presenting to a UK emergency department (ED).

Methods

This was a prospective cohort pilot study. Consecutive patients aged [gt-or-equal, slanted]16 years presenting with syncope over a 3 month period were eligible for prospective enrolment. All patients who were medium or high risk according to our ED's existing syncope guidelines underwent near‐patient BNP testing using the Triage point of care machine.

Results

99 patients were recruited. 72 of 82 high and medium risk patients underwent BNP measurement. 11 patients had a serious outcome, 9 of whom had BNP measured. In 25 (35%) patients, BNP was [gt-or-equal, slanted]100 pg/ml, and in 3 of these it was >1000 pg/ml. 6 of the 25 patients (24%) with a BNP >100 pg/ml, and all 3 patients with a BNP >1000 pg/ml, were in the serious outcome group. BNP was raised over 100 pg/ml in 6 of the 9 serious outcome patients having a BNP measured (66%), and over 1000 pg/ml in 3 (33%).

Conclusions

This early work suggests that BNP may have a role in the risk assessment of syncope patients in the ED. Further work is required to see how BNP interacts with other clinical variables. Near‐patient BNP testing may be shown to be an independent predictor of adverse outcome either alone or incorporated into existing syncope clinical decision rules and scores in order to improve their sensitivity and specificity. Further studies are required to evaluate this.

Syncope is a transient, self limited loss of consciousness usually leading to falling.1 It accounts for 3% of emergency department (ED) visits and 1–6% of hospital medical admissions, affecting 6 per 1000 people per year.2,3 In 1983, Kapoor et al4 published the first prospective syncope study showing a 12 month mortality of 14%. Mortality was greatest in patients in whom a cardiovascular cause was identified (30%). Subsequent studies have shown that underlying heart disease in patients with syncope is associated with a poor prognosis.5

Recent emphasis has focused on risk stratifying syncope patients. With growing pressures on acute medical beds and an increasingly elderly population, there is a need to identify high risk populations requiring further investigation, and low risk patients who may be discharged safely. Accurate identification of such groups would enable specific targeting of resources and prevent excessive investigation of patients with benign causes of syncope. No risk stratification studies have yet investigated the role of biochemical markers in risk stratification.

Brain (or B‐type) natriuretic peptide (BNP), which is secreted in response to an increase in ventricular volume and pressure load, is known to be an excellent marker of prognosis in patients with heart failure or cardiac disease.6,7 As previously mentioned, it is well established that prognosis in syncope is related to the presence of underlying heart disease,5 and all existing syncope clinical decision rules include either a history of congestive heart failure8,9,10,11 or of underlying cardiac disease.12,13 Tanimoto et al in 2004 conducted the only syncope study to date that has utilised BNP.14 This study evaluated the usefulness of BNP to separate cardiac and non‐cardiac causes of syncope. The investigators retrospectively evaluated 148 consecutive syncope patients admitted to hospital; 61 of these patients were found to have a cardiac cause for their syncope. A BNP value of [gt-or-equal, slanted]40 pg/ml was found to be 82% sensitive and 92% specific for identifying cardiac syncope.

We therefore hypothesised that BNP could be an excellent ED marker of medium term (3 month) syncope outcome. The aim of this pilot study was to assess the value of a near‐patient BNP test to predict medium term (3 month) serious outcome for syncope patients presenting to a UK ED, and to compare the performance of BNP with our existing departmental syncope guidelines (table 11)) based on the European Society of Cardiology,1,15 the American College of Physicians,16,17 and the American College of Emergency Physicians guidelines.18

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Table 1 Our existing emergency department syncope guidelines based on the European Society of Cardiology,1,15 the American College of Physicians,16,17 and the American College of Emergency Physicians guidelines18

Methods

Setting

The ED of the Royal Infirmary of Edinburgh (85 000 adult attendances per annum).

Inclusion criteria

Consecutive patients presenting with syncope aged 16 years or over between 7 November 2005 and 7 February 2006 were eligible for prospective enrolment. Syncope was defined as a transient loss of consciousness with an inability to maintain postural tone, followed by a spontaneous recovery without need for therapeutic or electrical intervention. Data from this same patient cohort were used to compare our existing ED guidelines with the San Francisco Syncope Rule10,11 and the OESIL score,13 and has been published previously.19

Exclusion criteria

Patients under 16 years of age, those previously recruited, and those having a history of seizure with prolonged post‐ictal phase were excluded. Patients who were unable to give either written or verbal informed consent were also excluded.

Study enrolment

Eligible patients were flagged at the ED high dependency triage area and a data collection form was placed in the patient's records. The treating doctor was responsible for deciding eligibility. Assessment of patients was carried out by routine ED clinical staff. A decision to enrol a patient was not overturned later by the study team and enrolled patients were analysed on an intention to treat basis. Written consent was obtained from all enrolled patients. This study received ethical approval from Lothian's Regional Ethical Committee.

Assessment

All patients underwent a standardised assessment using 31 pre‐determined variables (11 focused on clinical features, 9 on past medical history, and 11 concerning current medication), 28 examination variables and 26 electrocardiogram (ECG) variables. After a full history and examination, all patients who were medium or high risk according to our ED's existing syncope guidelines also had near‐patient BNP testing. BNP was measured using a whole blood immunoassay technique utilising the Triage point of care machine. Treating physicians were not blinded to the result of the BNP test. Admitted patients also underwent a laboratory based troponin I at least 12 h post‐syncope at the discretion of the admitting team. Patients were admitted, referred to medical outpatients, or discharged according to our ED's existing syncope guidelines and a study data collection form was completed for each patient.

End point measures

The primary end point was serious outcome at 3 months. Serious outcomes were pre‐defined and were all cause death, acute myocardial infarction (history of chest pain or ECG changes and troponin I >2.0), life threatening arrhythmia (documented on monitor or ECG during inpatient stay or on outpatient Holter monitoring, and requiring treatment), pulmonary embolus (confirmed on ventilation perfusion scan (VQ) or CT pulmonary angiography scan (CTPA), and requiring treatment), cerebrovascular accident/subarachnoid haemorrhage (CT or lumbar puncture diagnosis), haemorrhage requiring a blood transfusion of 2 units or more during inpatient stay, and an acute surgical procedure or endoscopic intervention secondary to a suspected cause of syncope.

Once 3 months had elapsed following ED attendance, the hospital computer system was interrogated to see whether each patient had returned to any hospital in the Lothian region. The hospital records were reviewed for all patients who had attended the ED or outpatient department or who had been admitted as an inpatient. Any deceased patient in the Lothian region was also able to be identified via the hospital computer system and hospital records were acquired.

Hospital notes were reviewed to determine whether each patient had had a serious outcome within 3 months of their attendance to the ED with syncope. All patients were followed up. Two recruited patients from outside Lothian were contacted by phone. Hospital notes were available for all patients.

Review of missed patients

In order to determine the recruitment rate of patients into the study, a retrospective search was conducted of all ED electronic patient records (EPR) between 7 November 2005 and 7 February 2006 looking for the keywords “syncope”, “collapse”, “faint”, “loss of consciousness” or “loc” appearing anywhere on the EPR. All EPRs with one of these terms were then hand searched and a decision was made from the notes whether the patient fitted the study's inclusion criteria. A list was compiled of all patients who fitted the study inclusion criteria but who had not been enrolled, along with their demographic details, and these were compared to those patients who had been enrolled into the study.

Statistical analysis

All patient data were entered into a specially designed Microsoft Access database and exported into Microsoft Excel for statistical analysis. Sensitivity, specificity, predictive values and likelihood ratios were calculated for BNP >100 pg/ml, BNP >1000 pg/ml and for current ED guidelines, and serious and non‐serious outcome groups were compared using the Fisher exact test. The small sample size precluded calculation of receiver operator curves. The BNP cut off values of 100 pg/ml and 1000 pg/ml were decided before the study. The Triage point of care BNP assay defines any BNP value >100 pg/ml as an abnormal value. This value and a value 10‐fold greater were arbitrarily chosen for analysis. This upper cut off was chosen as it was thought to be potentially high enough to be a possible rule‐in value. A future larger study will attempt to define possible rule‐in and rule‐out levels using receiver operator curves.

The “study group” and the “missed group” were compared using the χ2 test and the Mann–Whitney U test, and the “BNP group” and the “missed BNP” group were compared using the Fisher exact test.

Results

Ninety‐nine consecutive adult patients were recruited over a 3 month period between 7 November 2005 and 7 February 2006. It was thought that 100 patients had been enrolled; however, one patient episode had been erroneously duplicated during data entry. Forty‐four patients were admitted to hospital and 55 were discharged from the ED. Eight of the 11 patients with a serious outcome had this by 7 days, and three further patients had developed a serious outcome by 3 months. In total, therefore, 11 patients (11.1%) had a serious outcome by 3 months. Of these, five patients had died and six others had an alternative serious outcome (table 22).). All 11 had been admitted to hospital from the ED (table 33).

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Table 2 Description of the 11 patients with a serious outcome
Table thumbnail
Table 3 Summary of results

Seventy‐two of the 82 medium and high risk patients had BNP measured, nine of whom had a serious outcome (12.5%) (fig 11).). Those medium and high risk patients who did not undergo BNP measurement were missed because of either enrolling doctor error (seven patients) or BNP Triage point of care machine or operator error (three patients). The percentage serious outcome in those high and medium risk patients having BNP measured (72 patients) and the percentage serious outcome in the high and medium risk patients who did have BNP measured (10 patients) was not significantly different (p = 0.617, ns, Fisher exact test).

figure em48413.f1
Figure 1 Relation between brain natriuretic peptide (BNP) level and outcome of study patients at 3 months.

A BNP cut off of [gt-or-equal, slanted]100 pg/ml was more sensitive than current ED guidelines for predicting medium term (3 month) serious outcome for syncope patients presenting to our ED (0.667 vs 0.636) with a similar specificity (table 44).). A BNP cut off of [gt-or-equal, slanted]1000 pg/ml had a specificity of 1 compared to that of 0.716 for current ED guidelines. While the BNP in two of these patients would have been unlikely to affect a decision to admit (acute myocardial infarction and massive upper gastrointestinal bleed both apparent on admission), in the third, there was no suspicion of likely poor outcome at the time of the patient's initial presentation to the ED.

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Table 4 Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and p value of selected characteristics

Thirty of those admitted had troponin I measured, and only one of these was raised (14.40 ng/ml). This was thought to be due to an acute myocardial infarction. Of the 11 patients who developed a serious outcome, six had troponin measured and in only one was it raised.

A total of 263 patients presenting during the study period were identified from the EPR search as fitting the study's inclusion criteria. The study therefore enrolled 37.6% of patients eligible for inclusion. There were 74 men (45%) and 90 women in the “missed group”, compared to 48 men (48%) and 51 women in the “study group” (p = 0.60, ns, χ2). Neither the ages of the “study group” or “missed group” were normally distributed. Median age of the “study group” was 71.0 years (interquartile range (IQR) 47–81 years) and of the “missed group” was 62.5 years (IQR 29–78 years) (p = 0.047, significant at the 5% level, Mann–Whitney U test).

Discussion

This is the first study that has looked at using biochemical markers to aid rapid risk stratification of patients presenting to the ED with syncope. There are currently several risk stratification scores8,9,10,11,12,13 and also various guidelines to help the emergency physician decide who should be admitted for further investigation, and who could be safely discharged. Some of these rules have been derived to predict short term outcome (7 days) and some to predict longer term outcome (12 months).

We chose to look at a medium term (3 month) serious outcome. The goal of an ED risk stratification tool is to detect patients who are at risk of an imminent serious outcome, the course of which may be altered by early investigation, admission and intervention. A proportion of the short term (7 day) serious outcomes were expected to include such conditions as ruptured abdominal aortic aneurysms and subarachnoid haemorrhages. BNP is unlikely to be useful at predicting serious outcome in this non‐cardiac syncope group. We also decided not to measure BNP in patients who were classified as low risk. This was because of the expected very low rate of serious outcome in this group.

Only one patient who had an adverse outcome had a raised troponin I at 12 h. This suggests that the good sensitivity that BNP shows for serious outcome is not due to it acting as a marker of myocardial ischaemia.

Patients who had been “missed” for inclusion into the study were statistically slightly younger compared to those enrolled into the “study” group. This is probably due to ED staff failing to enrol some younger syncope patients into the study. These patients would be more likely to be low risk and would therefore not have been eligible for BNP and troponin I testing. This difference is therefore unlikely to have biased the study findings.

This study shows that BNP may be a very useful predictor of serious outcome in syncope patients presenting to the ED. The advantage of the near‐patient test is its immediate availability which makes it extremely useful for rapid ED decision making. BNP should now be included as a predictor variable in a large derivation and validation study of syncope to see if it is an independent predictor of adverse outcome and, if so, whether it has a role alone or as part of a clinical decision rule to aid the management of patients presenting with possible cardiac syncope to the ED. A power calculation suggests that 500 patients would be required in both the derivation and validation arms of such a study.

Conclusions

This early work suggests that BNP may have a role in the risk assessment of syncope patients in the ED. Further work is required to see how BNP interacts with other clinical variables. A BNP cut off of [gt-or-equal, slanted]100 pg/ml has a reasonable sensitivity for serious outcome, while a cut off of [gt-or-equal, slanted]1000 pg/ml has an excellent positive predictive value and specificity. Near‐patient BNP testing may be shown to be an independent predictor of adverse outcome either alone or incorporated into existing syncope clinical decision rules and scores in order to improve their sensitivity and specificity. Further studies are required to evaluate this.

Acknowledgements

Thanks to Ina Sutherland in medical records and to the medical and nursing staff in the Edinburgh Royal Infirmary Emergency Department.

Abbreviations

BNP - brain natriuretic peptide

CT - computed tomography

ECG - electrocardiogram

ED - emergency department

EPR - electronic patient records

IQR - interquartile range

Footnotes

Competing interests: The near‐patient BNP test strips and Triage point of care machine were supplied by Biosite.

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