Prevalence and Outcome of Sepsis-induced Myocardial Dysfunction in Children with ‘Sepsis’ ‘With’ and ‘Without Shock’—A Prospective Observational Study

Prevalence and Outcome of Sepsis-induced Myocardial Dysfunction in Children with ‘Sepsis’... Abstract Objective To estimate the prevalence and effects of sepsis-induced myocardial dysfunction (SIMD) in children with septic shock. Methodology Enrolled children with septic shock (n = 31) and sepsis (n = 30) underwent echocardiography and cardiac troponin-I (cTnI) estimation within first 3 h. SIMD was defined as presence of systolic/diastolic dysfunction by echocardiography. Results The prevalence of SIMD was 71% in ‘septic shock’ and 23% in ‘sepsis’. Diastolic dysfunction (45.2%) was more prevalent than systolic dysfunction (32.3%). Children with SIMD had higher requirement of inotropes [81 vs. 44%; adjusted odds ratio: 1.41 (1.04–1.92)] in first 48 h. cTnI had low sensitivity (62.5%) and specificity (55.1%) for detecting SIMD. On follow-up at 3 months, there was no residual dysfunction in the majority (71.3%). Conclusion SIMD, especially diastolic dysfunction, is common in septic shock and may increase inotrope requirement. It is reversible in majority. Sepsis patients may have asymptomatic underlying SIMD. cTnI does not correlate with the degree of SIMD. cardiac troponin-I (cTnI), sepsis-induced myocardial dysfunction (SIMD), septic shock, systolic dysfunction, diastolic dysfunction, ejection fraction, E’, E/A, MPI, myocardial performance index INTRODUCTION Septic shock is a major cause of morbidity and mortality (40–70%) in children [1]. Sepsis-induced myocardial dysfunction (SIMD) is increasingly being recognized. Initial studies on SIMD documented a decreased ejection fraction (EF) in these patients [2–6]. An increased end diastolic volume with concomitant decreased EF may be protective according to one school of thought [2]. Independent of systolic dysfunction, diastolic dysfunction may also coexist in these patients [7–9]. SIMD may be reversible in 7–10 days, after the acute illness subsides [2, 4, 6]. For detecting myocardial damage, cardiac troponins (cTn) are the most sensitive and specific biochemical markers [10, 11] and also the preferred marker for detecting myocardial cell injury in myocardial infarction [12]. Myocardial cell damage has been demonstrated by increased cTnl in septic shock patients [10, 13] and found to correlate with the duration of hypotension [13], requirement of vasopressors [14] and mortality [15, 16]. A few studies in children have documented systolic [17–19] or diastolic dysfunction [20, 21]. Documentation raised cTnI levels, and its correlation with myocardial dysfunction is also meagre [17, 18, 20]. With this background, the aim of this study was to evaluate the prevalence of SIMD in children with sepsis and septic shock and its effect on the clinical course and outcomes in these children. Children with SIMD were also followed up at 3 months to look for any residual myocardial dysfunction. PATIENTS AND METHODS Design and setting This prospective observational study was conducted in a 16-bedded tertiary care intensive care unit from November 2010 to March 2012. Facilities for echocardiography are available immediately adjacent to the paediatric intensive care unit (PICU). Objectives and outcomes Our primary objectives were to estimate the prevalence of SIMD (systolic, diastolic and global) assessed by echocardiography and myocardial damage by cTnI in children with sepsis and septic shock. The secondary objectives were to assess (i) the effect of SIMD on the clinical course and outcome of these children, such as fluid and inotrope requirement, need for mechanical ventilation, duration of PICU stay and death or discharge from the ICU and (ii) the presence of residual myocardial dysfunction at 3 months. Enrolment Consecutive children aged 3 months to 18 years admitted to the PICU with features of sepsis and septic shock [22] were enrolled into the study after obtaining informed written consent from a parent/guardian. Children <3 months were excluded, as they are known to have high cTnI because of physiological mechanisms [23]. Patients who had a primary cardiac disease (congenital, endocardial, myocardial, or pericardial), chest trauma, cardiothoracic surgery, meningococcemia [24], dengue [25], receiving cardiopulmonary resuscitation (before enrolment) or cardiotoxic drugs were excluded from the study. The study was approved by the institute ethics committee. Methodology Enrolled children were initially stabilized with fluids and inotrope infusions, mechanical ventilation and antibiotic therapy as per recommendations of the American college of critical care medicine [22]. Echocardiography was done within first 3 h of enrolment (i.e. within first 3 h of admission to the ICU) and cTnI at 24 and 48 h. Electrocardiography findings suggestive of myocardial dysfunction were defined as flattened, inverted or abnormally tall T waves, a horizontal or sloping ST segment depression or an ST segment elevation [26]. Those with myocardial dysfunction who survived were followed up at 3 months to detect any residual myocardial dysfunction. Echocardiography After primary stabilization, patients belonging to either group underwent echocardiography by a single assigned paediatric cardiologist, using Philips HD11XE machine. The following three parameters were assessed: EF was assessed using M mode echocardiography to detect the presence of systolic dysfunction. A value <0.55 was taken as abnormal [27]. E’: It indicates the Doppler Tissue Velocity during early ventricular filling and is independent of other factors such as preload and heart rate making it a better indicator of diastolic dysfunction than blood flow velocities across the mitral valve in diastole (E). E’ was measured at the septal and lateral ends of the mitral valve annulus, and their average was taken and compared with reference values (Supplementary Content S1) [28]. Myocardial performance index/Tei index: Myocardial performance index (MPI) represents global myocardial performance and is especially sensitive for detecting diastolic dysfunction. It is calculated by dividing the total isovolemic time [iso-volemic relaxation time (IVRT) +iso-volemic contraction time] by the ejection time with the age-specific reference values (Supplementary Content S1) [29]: Systolic dysfunction was defined as an abnormal EF. Diastolic dysfunction was defined as an abnormal E’ and an abnormal MPI. Global dysfunction was defined as an abnormal systolic and diastolic dysfunction. For the study purpose, myocardial dysfunction was present if systolic/diastolic/global dysfunction was present. cTn levels In the first 24 and 48 h after enrolment, blood samples were obtained from both groups for cTnI. cTnI levels were assayed by ELISA (Calbiotech) on EVOLIS Twin Plus (BIORAD), and >0.5 ng/ml was taken as abnormal (manufacturer recommendations). Statistical analysis Data were analysed using statistical package Stata version 11.0 (College Station, TX: StataCorp LP). Continuous variables were presented as mean (SD), or median [interquartile range (IQR)] as appropriate. Categorical variables were presented as absolute numbers (%). Continuous variables were compared between the groups using either independent Student’s t-test or Wilcoxon rank-sum test (based on the distribution of the data). Categorical data were compared using chi-squared test or Fisher’s exact test as appropriate. p-value of <0.05 was considered statistically significant. The discriminatory power of cTnI was also calculated to predict systolic/diastolic dysfunction using the receiver operating characteristic curve. RESULTS Of the 43 septic shock and 67 sepsis patients admitted to the ICU during the study period, 31 and 30 children were enrolled, respectively, in the two groups (Figure 1). The baseline characteristics are described in Table 1. The median age was higher (8 vs. 1.25 years) in Group 1 (septic shock). Commonest cause of sepsis was abdominal infection (39%) in Group 1 and pneumonia (37%) in Group 2 (sepsis). Table 1 Baseline characteristics of the enrolled children Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Note: Data represented as n, % unless otherwise indicated; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamic pyruvic transferase; DIC, disseminated intravascular coagulation; PT, prothrombin time; PTT, partial thromboplastin time; PIM, paediatric index of mortality. Table 1 Baseline characteristics of the enrolled children Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Note: Data represented as n, % unless otherwise indicated; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamic pyruvic transferase; DIC, disseminated intravascular coagulation; PT, prothrombin time; PTT, partial thromboplastin time; PIM, paediatric index of mortality. Fig. 1. View largeDownload slide Study flow. Fig. 1. View largeDownload slide Study flow. The prevalence of SIMD was 71% in Group 1 as compared with 23% in Group 2. Group 1 children had considerably higher systolic (22, 32.3%), diastolic (14, 45.2%) and global (2, 6.5%) dysfunction (Table 2). Table 2 Prevalence of myocardial dysfunction by echocardiography and cTnI Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Note: Data represented as n, % unless otherwise indicated; FS, fractional shortening. p-values in bold are significant. Table 2 Prevalence of myocardial dysfunction by echocardiography and cTnI Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Note: Data represented as n, % unless otherwise indicated; FS, fractional shortening. p-values in bold are significant. The median cTnI level was higher in Group 2 than Group 1 (0.60 vs. 0.48) at admission but was not statistically significant. The cTnI levels fell in Group 2 at 48 h but not in Group 1 (Table 2). Four children in Group 1 had only raised cTnI levels without any evidence of myocardial dysfunction on echocardiography. cTnI had low sensitivity (62.5%) and specificity (55.1%) for detecting SIMD. Group 1 patients with myocardial dysfunction had considerably higher requirement of inotropes [81 vs. 44%, 2.65 (1.15–6.15); p = 0.004] especially dobutamine in the first 48 h, as well as mean inotrope scores (16 307.27) than those without myocardial dysfunction (1428.67) (p < 0.0001) (Table 3). This association was significant on multivariate analysis after adjusting for key demographic and clinical variables (Table 4). The RR [95% confidence interval CI)] was 1.41 (1.04–1.92; p = 0.02). The mortality rate in Group 1 patients was 40% (9) in those with myocardial dysfunction and 22.2% (2) in those without myocardial dysfunction. Even though the requirement of fluids, ventilation, duration of PICU stay and mortality were high in the group with myocardial dysfunction, the difference was not statistically significant (Table 3). Table 3 Clinical course and outcome of children with septic shock ‘with’ and ‘without myocardial dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Table 3 Clinical course and outcome of children with septic shock ‘with’ and ‘without myocardial dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Table 4 Multivariate analysis of factors associated with SIMD during the hospital course in children ‘with’ and ‘without dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Note: PIM, paediatric index of mortality. Table 4 Multivariate analysis of factors associated with SIMD during the hospital course in children ‘with’ and ‘without dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Note: PIM, paediatric index of mortality. Among the 22 children with septic shock with myocardial dysfunction, 9 expired during ICU stay, 1 expired at home and 7 were followed up at 3 months. Only two of these seven patients (28%) had residual dysfunction. None of the patients of sepsis with SIMD had any residual dysfunction at 3 months. DISCUSSION The major findings of our study is the high prevalence of SIMD (71%) compared to previous studies in children with septic shock. The findings are similar to previous studies in adults with fluid refractory septic shock. Individually systolic and diastolic dysfunctions were also more common in children with septic shock. However, we found that EF was decreased in only 32% of septic shock patients, much lower than previously reported (50–80%) [5, 18, 30, 31]. This wide variation may result from differences in patient selection (i.e. all septic shock or only fluid refractory septic shock), cut-off values used for defining low EF (0.45–0.56), requirement of ventilation, choice of inotropes and co morbidities in the various studies [30–32]. Interestingly, diastolic dysfunction was commoner than systolic dysfunction and independent of it. Only two children had concomitant systolic and diastolic dysfunction. E’ was found to be abnormal in almost all the septic shock patients (87%), similar to previous adult studies [6]. MPI/Tei index representative of global myocardial dysfunction [26, 32–34] was abnormal in half of the patients with septic shock. Only few paediatric studies have reported use of these parameters in children with septic shock and dengue [20, 25]. We therefore used both abnormal E’ and MPI for detecting diastolic dysfunction to increase the accuracy of our results. The proposed mechanism for diastolic dysfunction in this group of patients could be sepsis-induced derangements in activation–inactivation processes involved in ventricular relaxation [6]. A significant proportion of sepsis patients had SIMD (23%), although it did not manifest clinically. Diastolic dysfunction (13%) was again more common than systolic dysfunction (10%). None of these patients developed septic shock subsequently except for one who acquired nosocomial sepsis and shock. Previously, Jafri et al. [7] have reported systolic and diastolic dysfunction in patients with sepsis. The frequency of these abnormalities is however not mentioned. No other data exist regarding the prevalence and significance of these findings in children with sepsis. In comparison with echocardiography, cTnI level estimation was not particularly helpful in our study. Although cTnI levels were elevated in more than half of the children with septic shock, the sensitivity (62.5%) and specificity (55.1%) were low for the cut-off of 0.5 ng/ml. Previous studies have shown a higher sensitivity (93–88%) and specificity (46–77%) of cTnI with different cut-offs (0.1–1 ng/ml) based on the kit used and the manufacturer recommendations [17, 18, 20]. Our study found cTnI to be raised in both groups in contrast to previous studies in which incidence of elevated cTnI was higher in children with septic shock (15–90%) [17, 18, 20] than sepsis (<1 to 25%) [20, 35]. One possible explanation could be that myocyte injury may occur sub-clinically in children with sepsis. Another explanation is a lower mean age of 1.25 years in the sepsis group (vs. 8 years) because in younger children, cTnI is released as a result of cardiac remodelling [23]. Persisting levels of high cTnI in septic shock but not sepsis suggests that continued myocyte injury may have a major role to play in deciding the clinical course. Myocyte injury occurring with use of inotropes/vasoactive agents, and early intervention and disease–host interactions may have a role in continued myocyte injury [36–38]. Children with SIMD had higher inotrope requirement in the first 48 h. However, SIMD did not affect the total duration of inotropes or mortality. A single study on adults with septic shock documented improvement in left ventricular systolic dysfunction with use of inotropes. However, duration of inotrope requirement and other secondary outcome measures including mortality were not affected [5]. The mortality rate in patients with septic shock was 35.5% compared with 6.7% in sepsis. The high mortality rates are attributed to delays in presentation, identification and resuscitation of these patients. Interestingly, in our study, we observed that within the septic shock group, those with myocardial dysfunction had higher mortality (40.9%) than those without myocardial dysfunction (22.2%). Finally, we also observed that there was no residual myocardial dysfunction at 3 months follow-up in 71% of children who survived the acute illness. This reversible character of SIMD has been demonstrated previously in adults in 7–10 days [2, 6]. The strength of our study adds to the literature of our understanding of SIMD in children with sepsis and septic shock. We also understand that myocardial dysfunction may be the cause rather than the effect of refractory shock, as it occurs much early in the course of illness in asymptomatic sepsis patients. Our study also reports on the short-term outcomes of SIMD in children and suggests that SIMD is reversible unlike other causes of myocarditis. Limitations The major limitations of our study are that (i) it is a single-centre study, (ii) age-matched controls were not used and (iii) there are limited data available on the precision/accuracy of echocardiography in infants and small children. CONCLUSION To conclude, prevalence of SIMD and diastolic dysfunction in particular is high in children with septic shock, and the dysfunction is reversible in most cases. Sepsis patients without shock may have asymptomatic underlying SIMD. Presence of myocardial dysfunction is associated with increased requirement of inotropes in first 48 h. cTnI levels may be used to supplement the echocardiographic diagnosis of SIMD and should not be used as a single diagnostic tool in this condition. SUPPLEMENTARY DATA Supplementary data are available at Journal of Tropical Pediatrics online). ACKNOWLEDGEMENTS The authors would like to thank Dr NK Dubey for his help and support with conducting the study and critical review of the study proposal. 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Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate . Am J Physiol Heart Circ Physiol 2002 ; 283 : H792 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Prevalence and Outcome of Sepsis-induced Myocardial Dysfunction in Children with ‘Sepsis’ ‘With’ and ‘Without Shock’—A Prospective Observational Study

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Abstract

Abstract Objective To estimate the prevalence and effects of sepsis-induced myocardial dysfunction (SIMD) in children with septic shock. Methodology Enrolled children with septic shock (n = 31) and sepsis (n = 30) underwent echocardiography and cardiac troponin-I (cTnI) estimation within first 3 h. SIMD was defined as presence of systolic/diastolic dysfunction by echocardiography. Results The prevalence of SIMD was 71% in ‘septic shock’ and 23% in ‘sepsis’. Diastolic dysfunction (45.2%) was more prevalent than systolic dysfunction (32.3%). Children with SIMD had higher requirement of inotropes [81 vs. 44%; adjusted odds ratio: 1.41 (1.04–1.92)] in first 48 h. cTnI had low sensitivity (62.5%) and specificity (55.1%) for detecting SIMD. On follow-up at 3 months, there was no residual dysfunction in the majority (71.3%). Conclusion SIMD, especially diastolic dysfunction, is common in septic shock and may increase inotrope requirement. It is reversible in majority. Sepsis patients may have asymptomatic underlying SIMD. cTnI does not correlate with the degree of SIMD. cardiac troponin-I (cTnI), sepsis-induced myocardial dysfunction (SIMD), septic shock, systolic dysfunction, diastolic dysfunction, ejection fraction, E’, E/A, MPI, myocardial performance index INTRODUCTION Septic shock is a major cause of morbidity and mortality (40–70%) in children [1]. Sepsis-induced myocardial dysfunction (SIMD) is increasingly being recognized. Initial studies on SIMD documented a decreased ejection fraction (EF) in these patients [2–6]. An increased end diastolic volume with concomitant decreased EF may be protective according to one school of thought [2]. Independent of systolic dysfunction, diastolic dysfunction may also coexist in these patients [7–9]. SIMD may be reversible in 7–10 days, after the acute illness subsides [2, 4, 6]. For detecting myocardial damage, cardiac troponins (cTn) are the most sensitive and specific biochemical markers [10, 11] and also the preferred marker for detecting myocardial cell injury in myocardial infarction [12]. Myocardial cell damage has been demonstrated by increased cTnl in septic shock patients [10, 13] and found to correlate with the duration of hypotension [13], requirement of vasopressors [14] and mortality [15, 16]. A few studies in children have documented systolic [17–19] or diastolic dysfunction [20, 21]. Documentation raised cTnI levels, and its correlation with myocardial dysfunction is also meagre [17, 18, 20]. With this background, the aim of this study was to evaluate the prevalence of SIMD in children with sepsis and septic shock and its effect on the clinical course and outcomes in these children. Children with SIMD were also followed up at 3 months to look for any residual myocardial dysfunction. PATIENTS AND METHODS Design and setting This prospective observational study was conducted in a 16-bedded tertiary care intensive care unit from November 2010 to March 2012. Facilities for echocardiography are available immediately adjacent to the paediatric intensive care unit (PICU). Objectives and outcomes Our primary objectives were to estimate the prevalence of SIMD (systolic, diastolic and global) assessed by echocardiography and myocardial damage by cTnI in children with sepsis and septic shock. The secondary objectives were to assess (i) the effect of SIMD on the clinical course and outcome of these children, such as fluid and inotrope requirement, need for mechanical ventilation, duration of PICU stay and death or discharge from the ICU and (ii) the presence of residual myocardial dysfunction at 3 months. Enrolment Consecutive children aged 3 months to 18 years admitted to the PICU with features of sepsis and septic shock [22] were enrolled into the study after obtaining informed written consent from a parent/guardian. Children <3 months were excluded, as they are known to have high cTnI because of physiological mechanisms [23]. Patients who had a primary cardiac disease (congenital, endocardial, myocardial, or pericardial), chest trauma, cardiothoracic surgery, meningococcemia [24], dengue [25], receiving cardiopulmonary resuscitation (before enrolment) or cardiotoxic drugs were excluded from the study. The study was approved by the institute ethics committee. Methodology Enrolled children were initially stabilized with fluids and inotrope infusions, mechanical ventilation and antibiotic therapy as per recommendations of the American college of critical care medicine [22]. Echocardiography was done within first 3 h of enrolment (i.e. within first 3 h of admission to the ICU) and cTnI at 24 and 48 h. Electrocardiography findings suggestive of myocardial dysfunction were defined as flattened, inverted or abnormally tall T waves, a horizontal or sloping ST segment depression or an ST segment elevation [26]. Those with myocardial dysfunction who survived were followed up at 3 months to detect any residual myocardial dysfunction. Echocardiography After primary stabilization, patients belonging to either group underwent echocardiography by a single assigned paediatric cardiologist, using Philips HD11XE machine. The following three parameters were assessed: EF was assessed using M mode echocardiography to detect the presence of systolic dysfunction. A value <0.55 was taken as abnormal [27]. E’: It indicates the Doppler Tissue Velocity during early ventricular filling and is independent of other factors such as preload and heart rate making it a better indicator of diastolic dysfunction than blood flow velocities across the mitral valve in diastole (E). E’ was measured at the septal and lateral ends of the mitral valve annulus, and their average was taken and compared with reference values (Supplementary Content S1) [28]. Myocardial performance index/Tei index: Myocardial performance index (MPI) represents global myocardial performance and is especially sensitive for detecting diastolic dysfunction. It is calculated by dividing the total isovolemic time [iso-volemic relaxation time (IVRT) +iso-volemic contraction time] by the ejection time with the age-specific reference values (Supplementary Content S1) [29]: Systolic dysfunction was defined as an abnormal EF. Diastolic dysfunction was defined as an abnormal E’ and an abnormal MPI. Global dysfunction was defined as an abnormal systolic and diastolic dysfunction. For the study purpose, myocardial dysfunction was present if systolic/diastolic/global dysfunction was present. cTn levels In the first 24 and 48 h after enrolment, blood samples were obtained from both groups for cTnI. cTnI levels were assayed by ELISA (Calbiotech) on EVOLIS Twin Plus (BIORAD), and >0.5 ng/ml was taken as abnormal (manufacturer recommendations). Statistical analysis Data were analysed using statistical package Stata version 11.0 (College Station, TX: StataCorp LP). Continuous variables were presented as mean (SD), or median [interquartile range (IQR)] as appropriate. Categorical variables were presented as absolute numbers (%). Continuous variables were compared between the groups using either independent Student’s t-test or Wilcoxon rank-sum test (based on the distribution of the data). Categorical data were compared using chi-squared test or Fisher’s exact test as appropriate. p-value of <0.05 was considered statistically significant. The discriminatory power of cTnI was also calculated to predict systolic/diastolic dysfunction using the receiver operating characteristic curve. RESULTS Of the 43 septic shock and 67 sepsis patients admitted to the ICU during the study period, 31 and 30 children were enrolled, respectively, in the two groups (Figure 1). The baseline characteristics are described in Table 1. The median age was higher (8 vs. 1.25 years) in Group 1 (septic shock). Commonest cause of sepsis was abdominal infection (39%) in Group 1 and pneumonia (37%) in Group 2 (sepsis). Table 1 Baseline characteristics of the enrolled children Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Note: Data represented as n, % unless otherwise indicated; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamic pyruvic transferase; DIC, disseminated intravascular coagulation; PT, prothrombin time; PTT, partial thromboplastin time; PIM, paediatric index of mortality. Table 1 Baseline characteristics of the enrolled children Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Variable Septic shock (N = 31) Sepsis (N = 30) Age (years) (median, IQR) 8 (3, 12) 1.25 (0.8, 7) Gender (female) (n, %) 19 (61.3) 16 (53.3) Weight for height—Z-score (median, IQR) −2.63 (−3.56, −0.67) −2.34 (−3.42, −0.98) Proportion with Z-score <−2 SD (n, %) 8 (26) 9 (30) PIM-2 score (mean, SD) 1.6 (0.58) 1.01 (0.23) Diagnosis (n, %)  Pneumonia 5 (16.3) 11 (36.7)  Meningitis 7 (22.6) 4 (13.3)  Urosepsis 0 (0.0) 2 (6.67)  Abdominal sepsis 12 (38.7) 6 (20.0)  Malaria 0 (0.0) 1 (3.3)  Skin and soft tissue infection 3 (9.7) 2 (6.7)  Septicemia without focus 4 (12.9) 4 (13.3) Clinical parameters  Pulse rate (mean, SD) 132.4 (28.7) 136.6 (32.1)  Pulse volume (abnormal) 29 (93.5) 0 (0.0)  Respiratory rate (median, IQR) 32 (22, 44) 49 (30, 66)  Capillary refill time (mean, SD) 3 (0.63) 2 (0)  Mean arterial pressure (mean, SD) 57 (22.1) 70.1 (8.9)  Pallor 15 (48.4) 9 (30.0)  Edema 5 (16.1) 3 (10.0)  Hepatomegaly 15 (48.4) 21 (70.0)  Altered sensorium 17 (54.9) 8 (26.7) Laboratory investigations  Hemoglobin (mean, SD) 8.4 (2.4) 9.1 (2.2)  Total leucocyte count (median, IQR) 11 000 (5600, 18 100) 16 350 (12 000, 27 800)  Neutrophils (mean, SD) 74.6 (10.6) 67.3 (17.4)  Platelets (median, IQR) 1.6 (0.8, 3) 3 (2, 3.6)  Urea (median, IQR) 36 (20, 48) 26 (20, 40)  Creatinine (median, IQR) 0.7 (0.6, 0.9) 0.75 (0.6, 0.9)  SGOT (median, IQR) 61 (40, 129) 48 (26, 61)  SGPT (median, IQR) 38 (15, 55) 30.5 (24.5, 44.5)  ALP (median, IQR) 500 (281, 693) 372.5 (218, 535.5)  DIC (abnormal PT/aPTT) (mean, SD) 10 (32) 3 (10)  Death 11 (35.5) 2 (6.7) Note: Data represented as n, % unless otherwise indicated; SGOT, serum glutamic oxaloacetate transaminase; SGPT, serum glutamic pyruvic transferase; DIC, disseminated intravascular coagulation; PT, prothrombin time; PTT, partial thromboplastin time; PIM, paediatric index of mortality. Fig. 1. View largeDownload slide Study flow. Fig. 1. View largeDownload slide Study flow. The prevalence of SIMD was 71% in Group 1 as compared with 23% in Group 2. Group 1 children had considerably higher systolic (22, 32.3%), diastolic (14, 45.2%) and global (2, 6.5%) dysfunction (Table 2). Table 2 Prevalence of myocardial dysfunction by echocardiography and cTnI Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Note: Data represented as n, % unless otherwise indicated; FS, fractional shortening. p-values in bold are significant. Table 2 Prevalence of myocardial dysfunction by echocardiography and cTnI Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Variable Septic shock (N = 31) Sepsis (N = 30) p-value Myocardial dysfunction (%; 95% CI) 22 (71; 53.4 to 84) 7 (23.3; 12 to 41) 0.001  Systolic dysfunction 10 (32.36; 19 to 50) 3 (10.0; 3.5 to 26) 0.06  Diastolic dysfunction 14 (45.16; 29 to 62) 4 (13.3; 5.3 to 30) 0.01  Global dysfunction 2 (6.45; 1.8 to 21) 0 (0.00; -) 0.49 EF (mean, SD) 0.56 (0.12) 0.62 (0.12) 0.04  Patients with abnormal EF 10 (32.3) 3 (10.0) 0.06 FS (mean, SD) 28.3 (7.3) 32.2 (7.7) 0.05  Patients with abnormal FS 8 (25.8) 3 (10) 0.18 E (mean, SD) 1.08 (0.3) 1.19 (0.2) 0.12  Patients with abnormal E 19 (63.3) 21 (70) 0.58 A (mean, SD) 0.81 (0.27) 0.81 (0.27) 0.84  Patients with abnormal A 27 (90) 22 (73.3) 0.18 E/A (mean, SD) 1.43 (0.4) 1.57 (0.4) 0.13  Patients with abnormal E/A 15 (50) 6 (20) 0.01 E’ average (mean, SD) 0.10 (0.04) 0.110 (0.02) 0.47  Patients with abnormal E’ 27 (87) 14 (46) 0.001 A’ average(mean, SD) 0.07 (0.02) 0.07 (0.02) 0.60  Patients with abnormal A’ 10 (32.3) 8 (26.77) 0.63 IVRT(mean, SD) 0.05 (0.05) 0.05 (0.01) 0.43  Patients with abnormal IVRT 21 (67.7) 17 (57) 0.37 MPI (mean, SD) 0.47 (0.14) 0.42 (0.13) 0.07  Patients with abnormal MPI 15 (48.4) 10 (33.3) 0.23 Proportion with raised cTnI 16 (51.6) 17 (56.7) 0.7 Patients of myocardial dysfunction with abnormal cTnI 12 (38.7) 2 (6.7) 0.005 cTnI levels (ng/ml) (median, IQR)  Day 1 0.48 (0.16, 1.28) 0.59 (0.21, 1.36) 0.62  Day 2 0.41 (0.16, 0.94) 0.21 (0.08, 0.48) 0.21 Note: Data represented as n, % unless otherwise indicated; FS, fractional shortening. p-values in bold are significant. The median cTnI level was higher in Group 2 than Group 1 (0.60 vs. 0.48) at admission but was not statistically significant. The cTnI levels fell in Group 2 at 48 h but not in Group 1 (Table 2). Four children in Group 1 had only raised cTnI levels without any evidence of myocardial dysfunction on echocardiography. cTnI had low sensitivity (62.5%) and specificity (55.1%) for detecting SIMD. Group 1 patients with myocardial dysfunction had considerably higher requirement of inotropes [81 vs. 44%, 2.65 (1.15–6.15); p = 0.004] especially dobutamine in the first 48 h, as well as mean inotrope scores (16 307.27) than those without myocardial dysfunction (1428.67) (p < 0.0001) (Table 3). This association was significant on multivariate analysis after adjusting for key demographic and clinical variables (Table 4). The RR [95% confidence interval CI)] was 1.41 (1.04–1.92; p = 0.02). The mortality rate in Group 1 patients was 40% (9) in those with myocardial dysfunction and 22.2% (2) in those without myocardial dysfunction. Even though the requirement of fluids, ventilation, duration of PICU stay and mortality were high in the group with myocardial dysfunction, the difference was not statistically significant (Table 3). Table 3 Clinical course and outcome of children with septic shock ‘with’ and ‘without myocardial dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Table 3 Clinical course and outcome of children with septic shock ‘with’ and ‘without myocardial dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) RR (95% CI); p-value Clinical parameters at 6 h (mean, SD)  Heart rate 140 (30.8) 130 (24.8) 0.20  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.12  Central venous pressure 13 (3.5) 6.37 (3.6) <0.001  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 0.99 Proportion attaining therapeutic endpoints in 6 h (n, %) 6 (27) 6 (67) 0.40 (0.17–0.93); 0.05 Fluid requirement (ml/kg/h) (mean, SD)  Day 1 8.42 (4.25) 6.63 (1.44) 0.232 Number of patients requiring inotropes in first 48 h (n, %) 18 (81) 4 (44) 2.65 (1.15–6.15); 0.004 Dopamine requirement (µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 10) 0.191  Day 2 17.5 (0, 20) 10 (0, 20) 0.315 Dobutamine(µg/kg/min) (median, IQR)  Day 1 10 (0, 20) 0 (0, 5) 0.086  Day 2 17.5 (7.5, 20) 0 (0, 10) 0.023 Inotrope score (mean, SD) 16 307.27 (4600.8) 1428.67 (698) <0.0001 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 2.25 (0.61 to 8.18); 0.15 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 0.11 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 0.11 Number of patients who died (n, %) 9 (41) 2 (22) 1.84 (0.49–6.9); 0.43 Table 4 Multivariate analysis of factors associated with SIMD during the hospital course in children ‘with’ and ‘without dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Note: PIM, paediatric index of mortality. Table 4 Multivariate analysis of factors associated with SIMD during the hospital course in children ‘with’ and ‘without dysfunction’ Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Variable Septic shock with myocardial dysfunction (N = 22) Septic shock without myocardial dysfunction (N = 9) Adjusted odds ratio (95% CI) p-value Clinical parameters at 6 h [mean (SD)]  Heart rate 140 (30.8) 130 (24.8) 0.96 (0.93–1.01) 0.14  Mean arterial pressure 66.4 (12.2) 68.1 (14.1) 0.98 (0.88–1.09) 0.82  Central venous pressure 13 (3.5) 6.37 (3.6) 1.2 (0.96–1.98) 0.13  Superior venal caval saturation 74.1 (9.3) 74.1 (8.4) 1.02 (0.68–1.5) 0.91 PIM-2 score (mean, SD) −2.6 (1.32) −1.96 (1.58) 0.93 (0.50–1.76) 0.82 cTnI levels Day 2 (median, IQR) 0.22 (0.08–0.48) 0.31 (0.1–0.6) 0.33 (0.09–1.18) 0.09 Need for inotropes in first 48 h (n, %) 18 (81) 4 (44) 1.41 (1.04–1.92) 0.02 Fluid requirement (litres) [mean (SD)] Day 1 8.42 (4.25) 6.63 (1.44) 1.52 (0.94–1.46) 0.08 Number of patients ventilated (n, %) 11 (50) 2 (22.2) 0.12 (0.01–16.4) 0.75 Duration of ventilation (days) (median, IQR) 1.45 (0, 5) 0 (0, 1.5) 1.07 (0.95–1.21) 0.22 Duration of stay in PICU (days) (median, IQR) 7 (4, 11.5) 4 (3.12, 7) 1.0 (0.99–1.00) 0.64 Note: PIM, paediatric index of mortality. Among the 22 children with septic shock with myocardial dysfunction, 9 expired during ICU stay, 1 expired at home and 7 were followed up at 3 months. Only two of these seven patients (28%) had residual dysfunction. None of the patients of sepsis with SIMD had any residual dysfunction at 3 months. DISCUSSION The major findings of our study is the high prevalence of SIMD (71%) compared to previous studies in children with septic shock. The findings are similar to previous studies in adults with fluid refractory septic shock. Individually systolic and diastolic dysfunctions were also more common in children with septic shock. However, we found that EF was decreased in only 32% of septic shock patients, much lower than previously reported (50–80%) [5, 18, 30, 31]. This wide variation may result from differences in patient selection (i.e. all septic shock or only fluid refractory septic shock), cut-off values used for defining low EF (0.45–0.56), requirement of ventilation, choice of inotropes and co morbidities in the various studies [30–32]. Interestingly, diastolic dysfunction was commoner than systolic dysfunction and independent of it. Only two children had concomitant systolic and diastolic dysfunction. E’ was found to be abnormal in almost all the septic shock patients (87%), similar to previous adult studies [6]. MPI/Tei index representative of global myocardial dysfunction [26, 32–34] was abnormal in half of the patients with septic shock. Only few paediatric studies have reported use of these parameters in children with septic shock and dengue [20, 25]. We therefore used both abnormal E’ and MPI for detecting diastolic dysfunction to increase the accuracy of our results. The proposed mechanism for diastolic dysfunction in this group of patients could be sepsis-induced derangements in activation–inactivation processes involved in ventricular relaxation [6]. A significant proportion of sepsis patients had SIMD (23%), although it did not manifest clinically. Diastolic dysfunction (13%) was again more common than systolic dysfunction (10%). None of these patients developed septic shock subsequently except for one who acquired nosocomial sepsis and shock. Previously, Jafri et al. [7] have reported systolic and diastolic dysfunction in patients with sepsis. The frequency of these abnormalities is however not mentioned. No other data exist regarding the prevalence and significance of these findings in children with sepsis. In comparison with echocardiography, cTnI level estimation was not particularly helpful in our study. Although cTnI levels were elevated in more than half of the children with septic shock, the sensitivity (62.5%) and specificity (55.1%) were low for the cut-off of 0.5 ng/ml. Previous studies have shown a higher sensitivity (93–88%) and specificity (46–77%) of cTnI with different cut-offs (0.1–1 ng/ml) based on the kit used and the manufacturer recommendations [17, 18, 20]. Our study found cTnI to be raised in both groups in contrast to previous studies in which incidence of elevated cTnI was higher in children with septic shock (15–90%) [17, 18, 20] than sepsis (<1 to 25%) [20, 35]. One possible explanation could be that myocyte injury may occur sub-clinically in children with sepsis. Another explanation is a lower mean age of 1.25 years in the sepsis group (vs. 8 years) because in younger children, cTnI is released as a result of cardiac remodelling [23]. Persisting levels of high cTnI in septic shock but not sepsis suggests that continued myocyte injury may have a major role to play in deciding the clinical course. Myocyte injury occurring with use of inotropes/vasoactive agents, and early intervention and disease–host interactions may have a role in continued myocyte injury [36–38]. Children with SIMD had higher inotrope requirement in the first 48 h. However, SIMD did not affect the total duration of inotropes or mortality. A single study on adults with septic shock documented improvement in left ventricular systolic dysfunction with use of inotropes. However, duration of inotrope requirement and other secondary outcome measures including mortality were not affected [5]. The mortality rate in patients with septic shock was 35.5% compared with 6.7% in sepsis. The high mortality rates are attributed to delays in presentation, identification and resuscitation of these patients. Interestingly, in our study, we observed that within the septic shock group, those with myocardial dysfunction had higher mortality (40.9%) than those without myocardial dysfunction (22.2%). Finally, we also observed that there was no residual myocardial dysfunction at 3 months follow-up in 71% of children who survived the acute illness. This reversible character of SIMD has been demonstrated previously in adults in 7–10 days [2, 6]. The strength of our study adds to the literature of our understanding of SIMD in children with sepsis and septic shock. We also understand that myocardial dysfunction may be the cause rather than the effect of refractory shock, as it occurs much early in the course of illness in asymptomatic sepsis patients. Our study also reports on the short-term outcomes of SIMD in children and suggests that SIMD is reversible unlike other causes of myocarditis. Limitations The major limitations of our study are that (i) it is a single-centre study, (ii) age-matched controls were not used and (iii) there are limited data available on the precision/accuracy of echocardiography in infants and small children. CONCLUSION To conclude, prevalence of SIMD and diastolic dysfunction in particular is high in children with septic shock, and the dysfunction is reversible in most cases. Sepsis patients without shock may have asymptomatic underlying SIMD. Presence of myocardial dysfunction is associated with increased requirement of inotropes in first 48 h. cTnI levels may be used to supplement the echocardiographic diagnosis of SIMD and should not be used as a single diagnostic tool in this condition. SUPPLEMENTARY DATA Supplementary data are available at Journal of Tropical Pediatrics online). ACKNOWLEDGEMENTS The authors would like to thank Dr NK Dubey for his help and support with conducting the study and critical review of the study proposal. 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Journal of Tropical PediatricsOxford University Press

Published: Jan 3, 2018

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