Outcome prediction in sepsis: Speckle tracking echocardiography based assessment of myocardial function

Transthoracic echocardiography was performed within 24 hours of meeting sepsis criteria with a Vivid 7 echocardiography machine (GE Medical Systems, Milwaukee, WI, USA) by research sonographers or research fellows fully trained in echocardiography and strain imaging. A comprehensive echocardiogram was performed according to American Society of Echocardiography guidelines [15]. Physiologic parameters were recorded at the time of echocardiography. LV systolic dysfunction was classified by ejection fraction: present (<55%) or absent (>55%), and mild (45 to 54%), moderate (30 to 44%) or severe (<30%). The RV was assessed at end expiration in a multimodal fashion as per American Society of Echocardiography guidelines (tricuspid annular plane systolic excursion, lateral tricuspid annular velocity, RV wall motion, FAC) [16] and was classified as normal, mild, moderate or severe dysfunction. Parameters for abnormal RV systolic function were defined as tricuspid annular plane systolic excursion <16 mm, FAC <35%, Tricuspid valve systolic motion velocity <10 cm/second or reduced RV wall motion. For severe dysfunction, RV wall motion was severely reduced and/or FAC was <17% [16]. RV size was measured – basal, mid and longitudinal dimensions (abnormal above 42 mm, 35 mm and 86 mm respectively) – and compared with the LV size. Images were analyzed by physicians fully trained in echocardiography (MM, JKO, JNP).

Three-beat two-dimensional digital clips were transferred to a Syngo Velocity Vector Imaging workstation (Siemens Medical Solutions USA Inc., Pleasanton, CA, USA) for STE analysis by SRO, who had performed more than 100 hours of analysis in STE prior to commencing the study. The endocardium was traced manually from the medial annulus with 7 to 15 points. LV values were averages of the 16 LV segments. If STE could not be calculated on one apical view, the LV was considered to have insufficient image quality. RV values were an average of the three free wall segments. Once accuracy of tracking was ensured, displacement, velocity, strain and strain rate curves were assessed for motion, smoothness, time to peak, delay and correlation (Figure 1a,b). The same cardiac cycle was chosen for STE values. All images were analyzed three times to ensure accuracy of results. Strain and strain rate are negative values; the more negative the value, the greater the degree of deformation and the better the function. Strain values were separated into normal (more negative than −21% for RV and more negative than −17% for LV), mild/moderately impaired (−21 to −13% for RV and −17 to −10% for LV) and severely abnormal (less negative than −13% for RV and less negative than −10% for LV). A consensus on normal values for strain of the RV and LV has yet to be defined primarily due to vendor differences in analysis methods [17]. The cutoff values chosen in this study are based on normal subjects at our institution [18] and on meta-analysis of normal subjects [19], and are similar to recent studies investigating LV ischemia [20] and pulmonary hypertension [21] as well as analysis of our sample group: receiver operating curve, interquartile range and logistic regression analysis.

There was no difference seen between survivors and nonsurvivors in any standard echocardiography measure of ventricle size or function at 30 days or 6 months, or in their peak systolic pulmonary artery pressures (Tables 2 and 3 and Figure 2). There was a significant difference in RV free wall strain between survivors and nonsurvivors at 6 months (−19% ± 5 vs. −16% ± 6, P = 0.02). There was no difference in survivors’ LV GLS or GLS rate compared with nonsurvivors.

The incidence of myocardial dysfunction was different based on the method of assessment (Table 4). Based on conventional assessment, 19 patients (32%) had RV dysfunction, 20 patients (33%) had LV dysfunction and 10 patients (17%) had both LV and RV dysfunction. Based on strain analysis, 43 patients (72%) had RV dysfunction, 36 patients (69%) had LV dysfunction and 30 patients (50%) had both LV and RV strain dysfunction. When subgroups were created based on severity of dysfunction, strain function analysis also revealed a greater portion of patients with severe RV or LV dysfunction.

Analysis of variance of the association between 6-month mortality and the RV strain dysfunction subgroups was significant (P <0.001). Separate analysis within these groups exposed those patients with severe RV strain dysfunction as having the statistically significant association (Table 5). Multivariate analysis (Table 6) showed that severe RV free wall strain dysfunction remained an independent predictor of outcome at 6 months, accounting for mechanical ventilation (P = 0.03). This subgroup was also associated with a greater severity of disease (SOFA score), lower arterial partial pressure of oxygen/fraction of inspired oxygen ratios, mechanical ventilation, worse LV GLS, reduced RV FAC, higher echo-based right atrial pressures, lower tricuspid velocity, and higher echo-based peak systolic pulmonary artery pressure (Figure 3). Furthermore, there was a tendency towards higher levels of lactate. There was no association with RV dimensions. By comparison, RV systolic functional assessment by FAC was only associated with reduced LV GLS, and increased echo-based right atrial and RV systolic pressures. Kaplan–Meier curves show severe RV free wall longitudinal strain dysfunction was associated with 1-year mortality (P <0.001) due to all patients in this subgroup dying before 6 months (Figure 4). Those with mild/moderate RV strain dysfunction and normal RV strain function had similar 1-year survival estimates (57.1% and 54.9% respectively).

Pulmonary hypertension was not an exclusion criterion, but no patient had a formal diagnosis at time of enrollment. Fifteen patients had echocardiograms performed in the preceding 6 months to admission and four of these patients had peak systolic pulmonary artery pressure estimation >36 mmHg, considered raised pulmonary pressure by the American Society of Echocardiography [16]. Although no significant RV dysfunction was reported, there may have been unrecognized prior RV strain dysfunction. Excluding these patients from the analysis did not alter the relationship between 6-month mortality and RV free wall strain dysfunction.

Blinded interrater variability for STE analysis was assessed by JNS on a random 10% subgroup. Bland–Altman analysis demonstrated good intraobserver and interobserver agreement. The interobserver and intraobserver mean difference (±standard deviation) were respectively: RV free wall longitudinal strain, –2 (±1.2) and −1.4 (±0.9); RV free wall longitudinal strain rate, −0.3 (±0.1) and −0.1 (±0.05); LV GLS, −0.9 (±0.9%) and −0.8 (±0.5); and LV GLS rate, −0.1 (±0.05) and −0.1 (±0.05).

This study is observational in nature and has a limited number of patients, and the imaging was not optimized for STE (for example, improved endocardial border definition, RV centric views, and so forth). One cannot exclude that weaker associations may be statistically significant in a cohort with a larger sample size. Repeated imaging and further STE analysis were not performed. Further dysfunction that would be seen by standard echo parameters may have occurred at a later stage. Larger, prospective studies with imaging focused for STE optimization and follow-up echocardiography STE analysis could be considered in future.

There are several drawbacks to current STE analysis that limit its clinical utility in the ICU at this time: STE requires adequate image quality, which can be challenging particularly in the mechanically ventilated patient (10 of the 14 patients excluded due to inadequate image quality), STE is time consuming to perform, and normal values have been difficult to elucidate partly due to vendor differences in the software algorithms [19]. Our cutoff values between normality, mild and moderate abnormality and severe abnormality are similar to recent studies on large populations of both normal controls [18, 19] and patients with cardiac dysfunction [25]. With technology advancing and expert groups such as the American Society of Echocardiography and the European Association of Echocardiography calling for concordance on vendor STE software analysis, and as the use of STE becomes more widespread, perhaps strain will become a more standard measurement in the future [17].