The authors have no relevant financial information or potential conflicts of interest to disclose.
High Plasma Lactate Levels Are Associated With Increased Risk of In-hospital Mortality in Patients With Pulmonary Embolism
Article first published online: 15 AUG 2011
© 2011 by the Society for Academic Emergency Medicine
Academic Emergency Medicine
Volume 18, Issue 8, pages 830–835, August 2011
How to Cite
Vanni, S., Socci, F., Pepe, G., Nazerian, P., Viviani, G., Baioni, M., Conti, A. and Grifoni, S. (2011), High Plasma Lactate Levels Are Associated With Increased Risk of In-hospital Mortality in Patients With Pulmonary Embolism. Academic Emergency Medicine, 18: 830–835. doi: 10.1111/j.1553-2712.2011.01128.x
Supervising Editor: Richard Sinert, DO.
- Issue published online: 15 AUG 2011
- Article first published online: 15 AUG 2011
- Received November 30, 2010; revision received February 20, 2011; accepted February 22, 2011.
ACADEMIC EMERGENCY MEDICINE 2011; 18:830–835 © 2011 by the Society for Academic Emergency Medicine
Objectives: The objective was to investigate the prognostic value of plasma lactate in patients with acute pulmonary embolism (PE).
Methods: This was a retrospective study at the emergency department (ED) of a third-level teaching hospital. The authors considered consecutive patients with a diagnosis of PE established by lung scan or spiral computed tomography (CT) and confirmed by pulmonary angiography if necessary. Only patients for whom plasma lactate levels had been tested within 6 hours from presentation to the ED were included. Primary outcome was in-hospital death due to any cause; secondary outcome was mortality related to PE.
Results: From September 1997 to June 2006, a total of 384 patients were diagnosed with PE in the ED. Of these patients, 287 had registered plasma lactate levels and were included in this analysis. Included patients had a mean age of 70 (SD ± 15 years, range = 18 to 100 years), 163 (57%) were female, 26 (9%) showed systolic blood pressure lower than 100 mm Hg at presentation, and 160 (56%) had echocardiographic evidence of right ventricular dysfunction (RVD). Twenty patients died during their hospital stay (7%). Plasma lactate levels ≥ 2 mmol/L were associated with in-hospital mortality from all causes (odds ratio [OR] = 4.60, 95% confidence interval [CI] = 1.57 to 13.53) and with PE-related mortality (OR = 4.94, 95% CI = 1.38 to 17.63), independent of hypotension or RVD at presentation.
Conclusions: High plasma lactate was associated with increased in-hospital mortality in this sample of patients with acute PE.
Pulmonary embolism (PE) represents the third leading cause of death due to cardiovascular disease.1 In contrast to stroke and acute coronary syndromes (ACS), its incidence and mortality have not decreased in recent decades, probably because of only minor advancements in short-term prognostication and treatment strategies. Few patients with PE present with clinically evident acute hemodynamic impairment (shock). These patients have the highest mortality rate and benefit from systemic thrombolysis.2 The majority of PE patients present without shock and are usually treated with heparin alone. Recent guidelines have suggested stratification of normotensive patients according to the presence of markers of right ventricular dysfunction (RVD) or injury.2 In fact, a large body of evidence shows that the presence of RVD, blood elevation of troponins, or natriuretic peptides are associated with adverse clinical outcomes.3–7 However, these tools have some important limitations. Echocardiography, which is the standard tool for RVD identification, is often not available within a 24-hour period. Troponins and natriuretic peptides share a good negative predictive value (NPV; >90%) but a low positive predictive value (PPV; about 10%) for adverse outcomes, probably precluding their usefulness as stand-alone tests to target more aggressive treatments than heparin alone.7
Plasma lactate concentration is a marker of the severity of the tissue oxygen supply-to-demand imbalance and may reflect tissue hypoperfusion also in the presence of normal blood pressure. Accordingly, in other critical settings such as sepsis, plasma lactate concentration rises before clinically overt hemodynamic impairment, and is considered a good tool for early identification of patients at increased risk of short-term adverse outcome.8 Furthermore, plasma lactate concentration can be easily and rapidly assayed on arterial blood samples using a blood gas analyzer, which is often available in the emergency department (ED). However, no previous study has investigated the prognostic role of plasma lactate levels in patients with acute PE.
This study investigates the association between plasma lactate concentration and in-hospital mortality in patients with acute PE. Furthermore, we tested whether the prognostic value of plasma lactate was independent of clinically evident acute hemodynamic impairment, RVD, and troponin I elevation.
This was a retrospective analysis of prospectively collected registry data. The study was approved by the hospital’s institutional review board.
Study Setting and Population
Consecutive adult patients who presented from September 1997 through June 2006 to the ED of a third-level teaching hospital (Careggi, Florence, Italy) and admitted for symptomatic PE were included in a prospective registry. Those with terminal illnesses and a life expectancy of less than 6 months were excluded. The registry database has specific items for clinical risk factors of PE, comorbidities, clinical complaints, arterial blood gas analysis, heart rate, arterial oxyhemoglobin saturation (SatO2), RVD assessed by echocardiography, PE diagnostic tests, PE therapy, and in-hospital adverse events, but not plasma lactate levels.3,9
Two physicians in training, supervised by a senior emergency physician (EP), retrospectively collected plasma lactate levels via the archived clinical charts. Patients without recorded plasma lactate levels on admission were excluded. A total of 150 patients also had troponin I values measured at presentation. The diagnosis of PE was established by perfusion lung scan, spiral computed tomography (CT), or high clinical probability associated with the diagnosis of deep vein thrombosis (DVT) by ultrasound studies.3,9 Patients with intermediate probability perfusion lung scans underwent CT scan or angiography. Only patients with proven PE were enrolled in the study.
Patients were managed by the treating physician according to the accepted protocol of our institution, which has been previously described.3,9,10 Briefly, the initial patient assessment in the ED included clinical history, physical examination, chest x-ray, 12-lead electrocardiogram, echocardiography, and arterial blood gas analysis. Intravenous unfractionated heparin at standard doses10 was administered as soon as PE was suspected; thrombolysis (100 mg intravenously over 2 hours) was instituted in patients with PE and shock/hypotension or in patients with acute RVD if no contraindications were present.
The primary endpoint was death by any cause during in-hospital stay, and the secondary outcome was in-hospital death related to PE. Fatal PE was defined as a fatal event occurring in the hours after an objectively diagnosed recurrent PE or at autopsy.9
Plasma Lactate Test. The plasma lactate concentration was determined on arterial blood samples by a blood gas analyzer (ABLTM700 analyzer, Radiometer Medical A/S, Brønshøj, Denmark) according to the manufacturer’s instructions. Arterial blood samples were taken in the ED within 6 hours of presentation, and among the other parameters, the blood gas analyzer routinely measured the plasma lactate concentration.
Echocardiographic Examination. Standard color two-dimensional echocardiographic Doppler examinations were performed within 1 hour of the diagnosis of PE, as previously described.3 Briefly, patients with at least one of the following findings were diagnosed with acute RVD: 1) RV dilatation (end-diastolic diameter > 30 mm or right/left ventricular end-diastolic diameter ratio > 1 in apical four-chamber view), 2) paradoxical septal systolic motion, or 3) pulmonary hypertension (Doppler pulmonary acceleration time < 90 msec or presence of a right ventricle/atrial gradient > 30 mm Hg).
Cardiac Troponin I Testing. In a subset of patients (n = 150), cardiac troponin I was determined on an ADVIA Centaur analyzer (Bayer VitalGmbH, Leverkusen, Germany) according to the manufacturer’s instructions. The investigator responsible for the measurements was unaware of the patients’ baseline parameters or clinical course.11
Data points are expressed as means (± SD). The unpaired Student’s t-test was used to compare normally distributed data, and the Fisher’s exact test was used for the comparison of noncontinuous variables expressed as proportions. ROC curve analysis was carried out to estimate the best lactate and troponin I cutoff values. To investigate the prognostic relevance of the baseline parameters listed in Table 1, including dichotomized plasma lactate, a multivariate binary logistic regression model was applied to the endpoint, taking into account those variables that were expected (based on previous studies) to have an association with the main outcome, or reached a probability value of < 0.10 in the univariate analysis. Multivariate analysis was performed with a stepwise backward regression model. p-values were two-sided, and a p-value of less than 0.05 was considered to indicate statistical significance. Calculations were performed using the SPSS statistical package (Version 13.0, SPSS, Chicago, IL).
|Characteristic||Included (n = 287)||Excluded (n = 97)||p-value|
|Age (yr)||70 (±15)||69 (±15)||0.616|
|Females||163 (57)||58 (60)||0.636|
|Malignancy||78 (27)||21 (22)||0.347|
|Risk factors for VTE|
|Permanent||108 (37)||28 (30)||0.141|
|Transient||80 (30)||39 (40)||0.030|
|Idiopathic||99 (34)||30 (31)||0.537|
|Syncope||33 (12)||9 (9)||0.707|
|Dyspnea||210 (73)||60 (62)||0.040|
|Tachycardia||115 (40)||24 (25)||0.007|
|SAP < 100 mm Hg||26 (9)||17 (18)||0.026|
|Thrombolysis||20 (7)||19 (20)||0.001|
|RVD||162 (56)||58 (60)||1.000|
|Plasma lactate (mmol/L)||1.68 (±2.19)|
|Troponin I (ng/ml)*||0.44 (±1.60)||0.52 (±1.33)||0.821|
|≥0.10 ng/mL||61 (41)||10 (44)||0.650|
|In-hospital death||20 (7)||5 (5)||0.639|
|Death related to PE||15 (5)||5 (5)||1.000|
Patients and Management
A total of 384 consecutive patients with an objectively confirmed acute PE were considered for this study. The diagnosis of PE was based on the results of a lung scan (74 patients, 19%), CT scan (269 patients, 70%), or pulmonary angiography (26 patients, 7%) or by a high clinical probability associated with the diagnosis of DVT by ultrasound studies (15 patients, 4%).
Of these, 97 patients (25%) were excluded from the analysis because they did not have registered plasma lactate levels within 6 hours from presentation. The remaining 287 patients included in the study (Table 1) had a mean (±SD) age of 70 (±15) years (range = 18 to 100 years), and 163 (57%) were female. Of these patients, 99 (34%) had an idiopathic PE, and transient risk factors were the cause of PE in 30% of cases, a proportion significantly lower than in the excluded patients. Moreover, the proportion of patients with hypotension was higher and with dyspnea and tachycardia was lower in the excluded patients compared to the included patients. Excluded patients were more often treated with thrombolytics than the included patients.
During in-hospital stay (mean [±SD] 12 [±6] days), 20 patients in the study died, resulting in a mortality rate (7%, 95% confidence interval [CI] = 4% to 11%) similar to that of the excluded patients (five patients, 5%, 95% CI = 2% to 12%). When mortality due to PE was considered, the mortality rates were the same between the two groups, 5% (95% CI = 3% to 8%) in the included and 5% (95% CI = 2% to 12%) in the excluded group.
Among the patients included in the study, 15 patients died from PE: six had shock at presentation in the ED, four developed shock during hospital stay, two died from recurrent thromboembolism without previous hypotension, and three died from malignant arrhythmia. The other five deaths were judged to be caused by cerebral haemorrhage (1), respiratory failure (1), sepsis (2), and ACS (1).
As expected, systolic blood pressure lower than 100 mm Hg (odds ratio [OR] = 7.03) and RVD (OR = 3.32) were associated with an increased risk of in-hospital death (Table 2). The presence of malignancy (OR = 2.93), RVD (OR = 3.32), and tachycardia (OR = 3.84) were also associated with the primary endpoint.
|Variables||Univariate OR (95% CI)||P value||Multivariate OR (95% CI)||p-value|
|SAP < 100 mm Hg||7.03 (2.50–19.70)||<0.001||3.85 (1.22–12.15)||0.022|
|Lactate ≥ 2 mmol/L||6.57 (2.43–17.75)||<0.001||4.60 (1.57–13.53)||0.005|
|Malignancy||2.93 (1.17–7.33)||0.033||3.24 (1.21–8.71)||0.020|
|Patients with troponin I values*|
|SAP < 100 mm Hg||6.55 (1.42–30.18)||<0.001||0.241|
|Lactate ≥ 2 mmol/L||4.76 (1.39–16.29)||0.013||4.03 (1.11–14.58)||0.034|
|Malignancy||3.75 (1.16–12.14)||0.029||4.57 (1.32–15.87)||0.017|
|RVD||7.12 (0.90–56.35)||0.035||6.66 (0.80–55.80)||0.080|
|Troponin I ≥ 0.10 ng/mL||3.68 (1.08–12.55)||0.038||0.217|
Plasma Lactate and In-hospital Mortality
Patients who died had significantly higher mean plasma lactate level (5.8 mmol/L, 95% CI = 3.2 to 8.4) than did survivors (1.3 mmol/L, 95% CI = 1.5 to 1.8; p < 0.001; Figure 1). The ROC curve analysis of the plasma lactate values revealed an area under the curve of 85% (95% CI = 76% to 93%; p < 0.001; Figure 2). Values of ≥ 2 mmol/L showed the best sensitivity (70%, 95% CI = 49% to 85%) and specificity (74%, 95% CI = 72% to 75%), with a derived PPV of 17% (95% CI = 12% to 20%) and NPV of 97% (95% CI = 95% to 99%). On univariate logistic regression analysis, plasma lactate ≥ 2 mmol/L was associated with in-hospital mortality (OR = 6.57, 95% CI = 2.43 to 17.75; Table 2). On multivariate analysis, plasma lactate ≥ 2 mmol/L was associated with in-hospital mortality (OR = 4.60, 95% CI = 1.57 to 13.53), independent of the presence of hypotension, malignancy, tachycardia, or RVD at presentation (Table 2). Similar results were obtained when death related to PE was considered (OR = 4.94, 95% CI = 1.38 to 17.63).
Plasma Lactate Versus Cardiac Troponin I for Risk Assessment in PE
Troponin I levels were tested in 150 of 287 patients (Table 1). In this subgroup of patients, as in the overall population, the mortality rate of patients with plasma lactate ≥ 2 mmol/L was higher (17%, 95% CI = 13% to 29%) than that of patients with plasma lactate < 2 mmol/L (4%, 95% CI = 2% to 6%), with an OR of 4.76 (95% CI = 1.39 to 16.29).
The mean troponin I values were higher in patients who died during their in-hospital stay (1.47 [±3] ng/mL) than in those who survived and were discharged (0.34 [±1.38] ng/mL; p = 0.031). ROC curve analysis of the troponin I values revealed an area under the curve of 68% (95% CI = 57% to 79%; p = 0.033). Values of ≥ 0.10 ng/mL showed the best sensitivity (70%, 95% CI = 44% to 87%) and specificity (62%, 95% CI = 60% to 64%). When troponin I values were dichotomized according to ROC curve analysis cutoff (0.10 ng/dL), we found that 9 of 61 patients with blood troponin I ≥ 0.10 ng/mL died during their in-hospital stay (15%, 95% CI = 9% to 19%), compared with 4 of 89 patients with troponin I < 0.10 ng/mL (4%, 95% CI = 2% to 8%; p = 0.038). On multivariate analysis, lactate ≥ 2 mmol/L was associated with primary outcome, independent of hypotension, RVD, malignancy, and troponin I elevation (Table 2).
To the best of our knowledge, this is the first reported study of patients with PE demonstrating an association between high plasma lactate levels and in-hospital mortality, independent of the presence of shock or echocardiographic evidence of RVD. Moreover, we found that risk assessment based on lactate values was independent of troponin I values.
In patients with PE, shock or sustained hypotension is associated with increased acute mortality. These patients benefit from a more aggressive treatment than heparin alone, such as systemic thrombolysis or endovascular clot removal techniques.2 Conversely, among the large group of normotensive patients, it is still a matter of debate which ones may benefit from an aggressive treatment. We have previously shown that acute right ventricular overload, as assessed by echocardiography, can be used to stratify PE patients with normal blood pressure according to their risk of death.3 However, echocardiography requires around-the-clock dedicated personnel and suffers from some disagreement about the criteria for RVD.
Plasma lactate levels are currently used in risk stratification of patients with sepsis or trauma,8,12,13 and this data point can be rapidly obtained by the use of a blood gas analyzer. We found no previous studies evaluating the prognostic value of plasma lactate in patients with PE. In this study, we found that PE patients with plasma lactate ≥ 2 mmol/L had a very high mortality rate (17%, OR = 6.75). The association was found also with PE-related death (OR = 7.50). This finding is very important because patients with PE usually show a high rate of comorbidity, in particular with malignancy, which can be the main cause of death rather than PE itself.
Although there are no other reported studies in PE patients with which to compare our results, it is important to note that a cutoff value similar to that used in this study (2 mmol/L) has been proposed for other types of critically ill patients,8 and it represents, in a physiopathologic sense, the threshold associated with the reduction of central venous oxygen saturation, a fundamental parameter for global tissue hypoperfusion recognition.14 There are multiple determinants of central venous oxygen saturation, including hemodynamic factors such as cardiac output and vascular resistance and nonhemodynamic factors such as arterial oxygen content and tissue oxygen consumption. Accordingly, in our analysis, the lactate prognostic value was found to be independent of both hypotension and RVD, suggesting that the high plasma lactate levels in PE patients had a significance beyond the hemodynamic status and that they could be a useful parameter to identify normotensive patients who might benefit from more aggressive treatment than heparin alone.
Other humoral parameters have been used for risk stratification of PE patients. In a recent meta-analysis, Becattini and coworkers4 showed that elevated levels of troponins were predictors of acute mortality in all patients with acute PE, including patients with acute PE and normal blood pressure. We therefore compared the prognostic value of plasma lactate with that of troponins in the subset of 150 patients who had both measurements. After multivariate analysis, we found that troponin I values were not independently associated with in-hospital death. We think that this finding is likely due to the very early determination of troponin I values in our patients (during initial evaluation in the ED), and it does not exclude the general prognostic value of troponin I, but indicates that the two prognostic factors are independent of each other. The “early sensibility” of plasma lactate values we found in our study, if confirmed in other studies, could support lactate use in ED.
The main limitation of this study is its retrospective nature. For this reason the study can demonstrate correlation, but is hypothesis-generating and not definitive. There are a large number (25%) of patients excluded due to the lack of lactate values during the initial evaluation in ED. This may limit the generalizability of our results. To minimize any potential error, we first compared the main characteristics of patients included in the study with those of patients excluded from the study because of missed plasma lactate values. We found that included patients were likely to be less compromised than excluded patients because a lower proportion were in shock. However, the selection of less compromised patients could have masked the relationship between plasma lactate and in-hospital mortality. This strengthens the potential prognostic value of plasma lactate in normotensive patients as well. Second, we choose a hard endpoint for prognostic analysis, i.e., overall mortality. This excluded any potential bias due to the accuracy of endpoint recognition. The findings about the comparison of lactate versus troponin are limited by the fact that only 150 of 287 (52%) had both measurements. Natriuretic peptides are useful markers to predict adverse outcomes;6,7 while it would be interesting to compare the relative abilities of natriuretic peptides versus lactate to predict mortality in patients diagnosed with PE, unfortunately natriuretic peptides data were not available in our cohort of patients.
In this single-center retrospective study, acute PE patients with early elevated plasma lactate levels appear to be at increased risk of in-hospital mortality. This finding was independent of hemodynamic status and right ventricular dysfunction. If confirmed in a prospective analysis, this finding may be useful in identifying patients who might benefit from aggressive treatment.