Serum Lactate, an Independent Prognostic Marker in Normotensive Patients With Acute Pulmonary Thromboembolism

Objective: Serum lactate, a marker of tissue hypoxia, is an important prognostic factor in sepsis, trauma, and cardiogenic shock. Data on the direct correlation of serum lactate and in-hospital mortality in normotensive acute pulmonary thromboembolism (APE) patients, however, remains scarce. Material and methods: We analyzed normotensive APE patients admitted to our clinic from January 1, 2014, to December 31, 2021. Serum lactate was collected from arterial blood at admission. Results: The study sample included 161 patients with an average age of 68.61 ± 11.54 years. 54.94% were female. In-hospital mortality was 19.88%. In ROC analysis, serum lactate was a predictor of in-hospital mortality with an AUC of 0.662 (95%CI 0.584 – 0.735, p = 0.005). The cut-off level identified by the Youden index-associated criterion was > 38 mg/dL (34.38% sensitivity, 94.57% specificity). In multivariable analysis for in-hospital mortality alongside the biomarkers proposed by the 2019 ESC guidelines for severity assessment, lactate > 38 mg/dL was an independent predictor of mortality (OR 10.92, 95%CI 3.04 – 39.29, p < 0.001). The prediction model including PESI score, right ventricular dysfunction, troponin I, and lactate > 38 mg/dL had the best predictive performance for in-hospital mortality (AUC 0.807, p < 0.001). Conclusions: Elevated serum lactate is an independent predictor of all-cause in-hospital mortality of normotensive APE patients, with the optimal cut-off > 38 mg/dL. Adding the lactate level for mortality prediction outperformed the 2019 ESC guidelines algorithm for severity assessment of normotensive APE patients.


Introduction
Acute pulmonary thromboembolism (APE) represents the third most common cause of death from cardiovascular illnesses [1] with a downward trend of mortality rates in recent European registries [2] [3].Its incidence is, however, increasing [2], possibly due to overdiagnosis in the modern era, given the wide availability of computed tomography.
In these patients, hemodynamic status remains a main determinant of prognosis.Obstructive shock or refractory hypotension, indicating right ventricular dysfunction, poses the highest risk of early mortality with a prompt need for reperfusion therapy [4].
In normotensive APE patients, accurate and prompt risk stratification is of the utmost importance.In the latest guidelines of the European Society of Cardiology, it is recommended to use a multiparametric risk stratification system based on clinical presentation, the PESI or sPESI score, signs of right ventricular (RV) dysfunction on ultrasound or CT, and the increase of markers of myocardial injury and ventricular dysfunction, especially serum troponin [4] .
Serum lactate, a marker of tissue hypoxia, is one of the proposed potential biomarkers with prognostic value in need of further validation [4].As an important prognostic marker in sepsis, its increase is precursory to clinically evident hemodynamic instability [5].Moreover, its predictive use for severity assessment extends to patients with trauma [6] and cardiogenic shock [7].
Recently, elevated plasma lactate concentrations were associated with an increased risk of short-term mortality in APE patients as well [8].Furthermore, in a multicenter European prospective cohort study evaluating 496 normotensive APE patients, elevated serum lactate was an independent predictor of the composite endpoint of mortality and clinical deterioration through the onset of hemodynamic instability.The cumulative predictive value of parameters such as RV dysfunction, elevated serum troponin and serum lactate showed a 6.6-fold increase in the risk of short-term adverse events [9].
Data on the direct correlation of serum lactate and in-hospital mortality in normotensive APE patients, however, remains scarce.Therefore, the aim of this study was to determine the survival prognostic value of elevated serum lactate in normotensive APE patients and to determine the optimal cut-off value for in-hospital mortality prediction.

Material and Methods
In this observational cohort study, we analyzed the medical records of all consecutive patients diagnosed with APE admitted to the Cardiology Department of "Sf.Pantelimon" Emergency Hospital in Bucharest, Romania.

Study population
We evaluated all patients diagnosed with APE confirmed by contrast-enhanced chest CT scanning who were admitted consecutively to our clinic between January 1, 2014, and December 31, 2021.The exclusion criteria were: being aged under 18 years, lack of CT angiography evaluation, lack of arterial serum lactate measurement on admission, and the presence of hemodynamic instability.
The study protocol was reviewed and approved by the Ethics Committee of "Sf.Pantelimon" Emergency Hospital (license number 49/2018).At the time of admission, patients signed a consent form agreeing that their medical information could be used anonymously for research purposes.

Definitions
Hemodynamic instability was defined as: cardiac arrest, obstructive shock (systolic blood pressure (BP) <90 mmHg or vasopressor support required to maintain a BP ≥ 90 mmHg associated with signs of hypoperfusion), or persistent hypotension (systolic BP <90 mmHg or a systolic drop in BP ≥40 mmHg for >15 minutes, not caused by new-onset arrhythmias, hypovolemia or sepsis).
The patients were divided into two groups depending on the location of the thrombus on the thoracic CT examination: either central (thrombus present above or at the lobar arteries level) or distal (segmental or subsegmental) APE.

Serum lactate and biological samples
The serum lactate level was determined from arterial blood collected at the time of evaluation in the emergency room and expressed in mg/dL.Arterial blood gas (ABG) was collected, according to the Emergency Department's protocol, from all patients with dyspnea at mild effort or at rest, tachypnea, or O2 saturation in room air < 95%.An elevated level of serum lactate was considered above a value of 18 mg/dL (2 mmol/L).All other biological samples were collected from venous blood and were processed in the central laboratory, including troponin I.A value above 0.2 ng/dL of serum troponin I was considered elevated and indicative of myocardial injury.

Echocardiography
Transthoracic echocardiography was performed at the time of hospitalization by a team of certified doctors.RV dysfunction was defined as at least one of the following parameters: -RV dilatation in parasternal long axis view, -RV/left ventricle ratio >1 in the apical 4 chambers view, -Decreased tricuspid annulus systolic plane excursion (TASPE) below 16 mm, measured by M-mode in the apical 4-chamber view.

Study endpoint
In-hospital all-cause mortality was the primary endpoint.Length of hospital stay was the secondary endpoint.

Statistical analysis Data analysis was performed using IBM SPSS Statistics version 25 and EpiInfo 2007.
Quantitative variables were tested for normal distribution using the Shapiro-Wilk Test and expressed as means with standard deviations in the case of Gaussian distribution, or as medians with elevation in precordial leads, and the need for inotropic support (Table 2).
In multivariable analysis for in-hospital mortality alongside the PESI score, the lactate level evaluated as a continuous variable was an independent predictor for the outcome, with a 5% increase in risk of fatality with each 1 mg/dL increase in lactate value (Table 3).When the lactate level was assessed as a dichotomous variable, the derived limit > 38mg/dL was associated with an independent HR for mortality of 7.49 (95%CI 2.41 -23.25), while the limit > 18mg/dL lost statistical significance (Table 3).
The predictive model 3, derived from the multivariable analysis that included the PESI score and the lactate levels > 38 mg/dL with an AUC of 0.769, outperformed the predictive value of the PESI score alone for in-hospital mortality (AUC 0.725), as well as the predictive value of the 2019 ESC guidelines algorithm (PESI score, RV dysfunction and troponin -AUC 0.736).Adding lactate levels > 38 mg/dL to the ESC proposed algorithm rendered the optimal prediction power (AUC 0.807) (Table 4, Figure 3).interquartile ranges otherwise.Qualitative variables were expressed as absolute counts and percentages.
Quantitative variables were tested using Student T/Mann-Whitney U tests according to their distribution.Qualitative variables were tested using a two-tailed p Fisher's Exact test.Odds ratios with 95% confidence intervals were used to illustrate the measure of associations observed in the contingency tables.
ROC analysis was employed for determining the correlation between numerical and categorical variables.Youden's indexassociated criterion was used to establish the optimal cut-off values for lactate levels in the prediction of in-hospital all-cause mortality.
Multivariable logistical regression, specifically the Enter method, was used to identify independent predictors of in-hospital mortality, using the variables identified to be correlated with the outcome in univariable analysis.Prediction models were derived from the multivariable analysis.

Study cohort and lactate levels
161 normotensive APE patients with serum lactate levels determined on admission were included in the study from the initial cohort of 255 subjects (Figure 1).
The mean age was 68.61 ± 11.54 years.54.94% were female.The clinical and paraclinical characteristics are represented in Table 1.In-hospital mortality was 19.88%.The median duration of hospitalization was 10.5  days.
44.7% of patients had serum lactate levels above the upper limit of normal (> 2 mmol/L /18 mg/dL).Their hospital stay durations were similar to those of patients with normal lactate levels (p = 0.43).
In-hospital mortality was higher in patients with elevated lactate levels (27.78% versus 13.48%, p = 0.029).Except for a higher prevalence of deep vein thrombosis (DVT) (54.10% versus 36.25%,p = 0.04), the clinical parameters were similar among patients with increased versus normal lactate levels.Of the laboratory biomarkers, patients with higher lactate levels had increased troponin I (0.379

Lactate levels and in-hospital mortality
PESI score was the main driver of in-hospital mortality (Table 1).In ROC analysis, serum lactate was a predictor of in-hospital mortality with an AUC of 0.662 (95%CI 0.584 -0.735, p = 0.005).
The cut-off level identified by the Youden index-associated criterion was > 38 mg/dL with a 34.38% sensitivity and 94.57% specificity (Figure 2).
Higher lactate levels > 38 mg/dL were associated with higher PESI scores, hypoxia, the presence of a right heart thrombus, ST room for improvement [4].Echocardiographic parameters such as TAPSE and RV/LV ratio were previously associated with a negative prognosis [10], although with a rather low positive predictive value [11].Ultrasound technology, which can reveal indirect information on the adequacy of cardiac output, may not be available immediately and is still striving for standardization of the RV dysfunction evaluation.Troponin is another biomarker recommended by the current guidelines, based on its association with an increased risk of mortality, both in unselected as well as normotensive patients [12].
However, when evaluated alone, it has a low specificity and positive predictive value.

Discussions
Our study is among the few to confirm the independent predictive value of arterial lactate levels for in-hospital mortality in APE normotensive patients.Moreover, our data proved the superiority and added benefit of a predictive model using lactate alongside the guideline-directed evaluation by PESI score, right ventricular dysfunction, and troponin value.
The accuracy of risk stratification of normotensive APE patients is a crucial step for establishing an individualized treatment plan, aiming to optimize outcomes in this heterogeneous population.
While validated biomarkers play an essential role, there is still

HR -heart rate, SBP -systolic blood pressure, SBD -diastolic blood pressure, TAPSE -Tricuspid Annular Plane Systolic Excursion, DVT -deep vein thrombosis, RH -right heart, N/A -not applicable
associated with increased lactate levels.The latter, described since 1935 [14], represents a simple electrocardiographic parameter that is part of the ECG prognostic score as well as the HOPPE score [15] for the evaluation of patients with APE.In our cohort, elevated serum lactate values were also associated with echocardiographic RV dysfunction [16], NT-proBNP [17], and elevated serum creatinine [18], parameters with proven prognostic value.
Given the imperfect role of the current combination of clinical and biochemical predictors, the 2019 ESC guidelines identify this as an unmet need for optimal classification of APE severity [4].In this setting, by validating the independent and cumulative prognostic performance of the lactate level, our study brings an influential element for clinical practice, confirming previous findings [13] [8].
An indicator of tissue hypoxia, serum lactate was correlated in our cohort with additional markers of either right heart overload or myocardial distress, highlighting the pathophysiological mechanism.In our study, from the electrocardiographic parameters, the ST segment elevation in precordial leads and the S1Q3T3 sign were   have limited the reliability of the present results.Another limitation is that the plasma lactate level of each patient was measured only once.It is likely that repeated measurements would result in improved prognostic information.Higher mortality rates were observed in our cohort compared to previously reported data from large APE registries.We acknowledge a potential selection bias.Only hospitalized APE patients were considered for inclusion in this study; therefore, from the starting point, they had a higher overall risk of mortality, with most participants having PESI scores corresponding to class III or higher.Moreover, only patients with available ABG analysis were included, meaning that some APE patients that were admitted to the hospital, but did not fit into the ER protocol for ABG on admission, were not included in the study.

Conclusions
Elevated serum lactate is an independent predictor of all-cause in-hospital mortality of normotensive APE patients.We propose the > 38 mg/dL cut-off for survival prediction, associated with an OR of 9.12, 95%CI 3.17 -26.21, p < 0.001, for mortality.
The prediction model including lactate > 38 mg/dL alongside the PESI score, RV dysfunction, and troponin levels outperformed the 2019 ESC guidelines algorithm for severity assessment in predicting short term mortality in APE patients.

List of abbreviations
APE -acute pulmonary embolism, RV -right ventricle, TAPSE -tricuspid annulus systolic excursion, BP -blood pressure, SBPsystolic blood pressure, SBD -diastolic blood pressure, DVT -deep vein thrombosis, ESC -European Society of cardiology, LV -left ventricle, AUC -area under curve, ECG -electrocardiography, HRheart rate, RH -right heart, RBBB -right bundle branch block Recent data also categorize serum lactate as a metabolic marker of fresh venous thrombus, which may increase due to enhanced glycolysis in intrathrombus erythrocytes [19].Moreover, a study from 2020 suggests a new mechanism contributing to the negative impact of elevated lactate levels on prognosis in APE patients: hypofibrinolysis, associated with enhanced neutrophil extracellular trap formation [20].In our cohort, there was a significant correlation between the presence of either DVT or a right heart thrombus in transit and serum lactate > 38 mg/dL, strengthening the aforementioned hypotheses.
Another particularity of our study is the higher cut-off level for serum lactate > 38 mg/dL with better predictive performance for in-hospital mortality, and the prediction model derived by adding this parameter to the existing guideline-recommended protocol for evaluation.A higher cut-off for the lactate was also advocated by M. Ebner et al., who recommended ≥ 3.3 mmol/L (30 mg/dL) for venous samples, associating optimized predictive power and additional improvement in risk stratification when added to the 2019 ESC algorithm [21].
In our cohort, adding the lactate > 38 mg/dL to the 2019 ESC severity assessment protocol increased the predictive power for inhospital mortality, reaching the AUC 0.807, outperforming the AUC of 0.73 of the BOVA score reported by Fernandez et al. in the initial study that proposed this score [22].The AUC obtained by the FAST score in the cohort studied by Lankeit et el.was 0.85, similar to that of our study [23].The main advantage of our results by contrast is the wide availability of the used biomarkers, compared to the heart fatty acid-binding protein included in the FAST score, whose accessibility is scarce and costly.

Figure 1 -Figure 2 -
Figure 1 -PRISMA consort flow diagram of the study

Figure 3 -
Figure 3 -Comparison of in-hospital mortality prediction models

Table 1 -
Patients' characteristics * Data available for 80 patients; **Data available for 87 patients

Table 2 -
Predictors of elevated lactate levels > 38mg/dL * Data available for 80 patients

Table 3 -
Multivariable analysis for in-hospital mortality

Table 4 -
Predictive performance of the derived predictive models for inhospital mortality