Introduction

The neonatal period is a critical stage in life. Neonatal sepsis is a recognized cause of morbidity and mortality at this age. In developing countries, sepsis is the commonest cause of neonatal mortality and reported to be responsible for about 50% of the total neonatal deaths annually (2). Sepsis poses a demanding constraint on the heart (3). Cardiovascular complications, myocyte damage, and modification of blood flow of the heart induced by inflammation are consequences of sepsis in neonates (4). Clinical manifestations of neonatal sepsis can range from vague nonspecific symptoms to collapse. Early recognition of cardiovascular complications in neonates with sepsis enables the physician to start proper supportive treatment, to monitor response to treatment and to improve outcome (5). The use of conventional echocardiography and tissue Doppler has gradually increased in the Neonatal Intensive Care Unit (NICU) to enable proper hemodynamic assessment, and provide immediate prompt intervention (6). We aimed to study the frequency of myocardial dysfunction (MD) in neonatal sepsis- in full term neonates admitted to Fayoum University NICU between December 2019 and December 2020.

Subjects and Methods

This prospective case control study included all 103 newborns with confirmed neonatal sepsis who did not suffer from cardiac structural defects admitted to Fayoum University NICU between December 2019 and December 2020. The study included a control group of 30 healthy sex and age matched full term newborns. The study was approved by the Research Ethics Committee, Faculty of Medicine, Fayoum University, Egypt (IRB: M481). Care takers consented to the trial. The study complied to the Declaration of Helsinki for trials (7).

Participants

All full term newborn less than 28 days of life with Score ≥ 2 on Griffin Neonatal Sepsis Score (8) were included. Those with history of perinatal asphyxia, those whose mothers were diabetic, those with structural heart defects, preterm newborn and neonates with chromosomal anomalies or dysmorphism were not included in the study.  

Methods

The collected data included history (perinatal, natal, and postnatal) including gestational age, APGAR score, Ballard score (9), and thorough clinical general and local examination.

They underwent lab investigations as indicated by the clinical judgment: complete blood count with differential, arterial blood gases, CRP, blood culture, liver function tests, kidney function tests, are relevant chest X-ray.

Echocardiography was performed using GE Vivid 5 echo machine (General Electric, USA) with 5 MHz transducer. A complete echocardiographic examination to exclude the presence of cardiac structural defect (CSD) with great emphasis on right ventricle (RV) dimensions, cardiac function, left ventricle (LV) internal dimensions with assessment of LV ejection fraction. Estimations were made through the standard transthoracic windows, LV end diastolic diameter (LVEDD), LV end systolic diameter (LVESD), LV posterior wall (LVPW), and LV ejection fraction (EF). Transmitral E wave velocity (E) and (A) wave velocity were averaged to generate the mean value.

The myocardial performance index (MPI), also called Tei index, was calculated by dividing the sum of IVRT and IVCT by ejection time (ET). It increases in diastolic dysfunction. (LV MPI = (IVCT + IVRT) / LVET). Systolic dysfunction was considered abnormal if EF was less than 55 % and FS was less than 26%, diastolic dysfunction was considered abnormal if MPI/Tei index was higher than normal for age; i.e. in term newborns, the RVMPI value on the first day of life was 0.42 ± 14, dropping to 0.29 ± 0.09 after PDA closure, and finally reaching 0.22 ± 0.09 on the 28th DOL. The LVMPI for term neonates in successive measurements was 0.37 ± 0.10, 0.39 ± 0.07 (10).

Statistical Analysis

The collected data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 22 (SPSS Inc, USA). For quantitative data, the mean, standard deviation (SD), and range were calculated. Independent t-test was used in comparing between the two groups of the study. Qualitative data were presented as number and percentages, chi square (χ²) was used as a test of significance. Pearson correlation was run to identify relation between Tei index with other study parameters.

Results

The study included 103 neonates with neonatal sepsis. Of them 30 patients (29.12%) were found to have myocardial dysfunction. Global myocardial dysfunction was encountered in 16 (53.3%), isolated right ventricle dysfunction in 8 (26.6%) cases, isolated left ventricle dysfunction among 6 (20%). The dysfunction was systolic and diastolic in 2 (6.6%) cases, isolated systolic in 6 (20%), and isolated diastolic in 22 (73.3 %). The demographic characteristics and clinical presentations and laboratory findings of the studied groups are presented in Tables 1,  2 and 3. It is notable that among those with myocardial dysfunction 16 cases suffered from hypothermia of 35.63 ± 0.5°C (range= 35.4-37.2 °C), respiratory distress in 22 cases (73.3%) and apnea in 8 cases (26.7%). The clinical features of heart failure were present in 6 neonates (20) % in the form tachycardia, increased respiratory rate, gallop rhythm, and hepatomegaly were present in 6 cases only (2 cases mild heart failure, 2 cases moderate and 2 cases severe heart failure according to the Ross modified classification (11) and all of them progressed to cold shock. 

Table 1. Demographic characteristics, vital signs and clinical manifestations of the study groups.

Table 2. Clinical presentation and outcome of the studied groups.

Table 3. Laboratory investigations of the studied groups.

CRP: C-reactive protein; CoNS: Coagulase negative Staphylococci; MERSA: Methicillin-resistant Staphylococcus aureus; RBS: random blood sugar; WBCs: white blood cells

Echocardiographic data of the study groups are summarized in Table 4. Global myocardial dysfunction was encountered in 16 (53.3%), isolated right ventricle dysfunction in 8 (26.6%), and isolated left ventricle dysfunction among 6 patients (20%). The dysfunction was both systolic and diastolic among 2 (6.6%), isolated systolic dysfunction among six (20%) cases, and isolated diastolic among 22 (73.3 %). diastolic among 22 (73.3 %). There was no significant difference between both groups regarding pulmonary artery pressure (p-value 0.090). Pulmonary hypertension was present in 15 (50%) cases of group 1 (3 of them had pneumonia (10%)) with mean ±SD pulmonary pressure of 43±7 mm Hg, 8 of them had RV dysfunction, while in group 2 it was high in 30 cases (41%); (10 (13.7%) had pneumonia) with mean ± SD of 40 ±4 mm Hg.  

Nineteen (63.3%) of the neonates with sepsis and myocardial dysfunction needed ventilator support and 19 cases (63.3%) were shocked; 17 were in cold shock in spite of IV fluids and received inotropes in the form of noradrenaline and dobutamine.

Seven cases (23.3%) received ampicillin and aminoglycosides, 16 cases (53.3%) received vancomycin and carbapenem, 6 cases (20.0%) received quinolones and only 1 case 3.3% received colistin. Among those with sepsis without myocardial dysfunction; 38 (52%) needed ventilator support, 35 (47.9%) were in septic shock (distributed) and received intravenous fluids and inotropes. Thirty (41%) received ampicillin and aminoglycosides, 40 (54.7%) received vancomycin and carbapenem, and 10 (13.6%) received quinolones.

The outcome of those with myocardial dysfunction and neonatal sepsis was guarded as 17 cases (56.7%) died with septic shock and 6 of them had impaired systolic function and the other 11 patients had diastolic dysfunction (2 of them had no cardiovascular signs), versus 13 cases (43.3%) survived while in patients with sepsis without myocardial dysfunction mortality rate was 41% (73 patients). The cultures of the non-surviving patients were positive in 10 patients; 5 with Klebsiella pneumoniae and 1 with each of the following: Enterococcus faecalis , Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus and Candida Albicans.

The Mean RVTei index for surviving neonates was 0.40±0.02 while for non-surviving patients 0.43±0.02 (p = 0.001). Regarding LVTei index for surviving patients was 0.40±0.032 while for non-surviving patients 0.45±0.031 (p<0.0001). No noted risk factors were associated with myocardial dysfunction like age(p=0.193), weight(p=0.100), gender  (p=0.130) or type of bacterial infection (p=0.125). Improvement in cardiac function parameters has been observed in surviving neonates of group 1 (13 cases) and all the discharged patients had normal systolic and diastolic function by echocardiography study repeated 1 week after discharge. Only 43 (59%) patients of group 2 survived.

Table 4. Echocardiography parameters in the studied groups.

AO: aortic root; E/A: E wave/A wave; EF: ejection fraction; ET: ejection time; FS: fraction shortening; IVCT: isovolumic contraction time; IVRT: isovolumic relaxation time;  LAD: left atrial diameter; LVIDD; left ventricular internal diameter end diastole; LVISD; left ventricular end systole; MV: mitral valve; PAP: pulmonary artery pressure; TAPSE; tricuspid annular plane systolic excursion; TV: tricuspid valve.

Discussion

Neonatal myocardial dysfunction is known to be primary associated with inborn errors of metabolism, mitochondrial disorders or neuromuscular disorders or secondary to other conditions as sepsis. Our study revealed that a third of full term babies with neonatal sepsis suffered from myocardial dysfunction despite not having an underlying cardiac structural defects. It is not clear if this dysfunction is part of the neonatal sepsis systemic inflammatory response (SIRS) associated with infection, or related to the neonatal immaturity of the immune system that is overwhelmed by infection. Or due to down-regulation of β-adrenergic receptors at the cardiomyocyte level that is mediated by many substances and toxins secreted by bacteria called the myocardial depressant factors (12). We did not study the immune response or immune profile among our studied neonates. We cannot rule out the possibility that those with myocardial dysfunction had underlying inborn errors of metabolism, mitochondrial disorders or neuromuscular disorders, as they did not undergo neonatal screening for metabolic or genetic diseases (13). We cannot rule out drug/toxemia induced mitochondrial fluidity membrane damage as well. The high frequency of myocardial dysfunction (29.12%), among full term babies in our study might not reflect the true frequency of myocardial dysfunction in neonatal sepsis,  as cases are referred from all over the government to our tertiary care center.

Myocardial dysfunction among full term neonates with sepsis was associated with higher mortality than those without myocardial dysfunction (56% versus 41%), yet this difference did not mount to statistical significance. It is a serious complication or association of neonatal sepsis that should be promptly diagnosed and managed (14–16). Hence, it seems necessary to search for the underlying cause of this dysfunction among high risk neonates with sepsis. We command the neonatal screening program for metabolic diseases among high risk neonates admitted to neonatal intensive care units established in Egypt since 2021 (17).

The myocardial dysfunction in our studied cohort was not typical, it was global myocardial dysfunction, isolated right ventricle dysfunction, or isolated left ventricle dysfunction. The dysfunction was both systolic and diastolic, isolated systolic or isolated diastolic. The lack of uniformity suggests a multifactorial etiology, type of bacteria, or immune response. It is important to highlight that 13(43.3%) of those with myocardial dysfunction had culture negative sepsis, hence SIRS might be a possibility, or mitochondrial depletion (18–21). In neonates with sepsis, the discharge of cytokines, acidosis and hypoxia may result in the advancement of pulmonary hypertension and in this way right ventricular dysfunction, whereas right-heart dysfunction will impair left-heart function (22). In our study, however, pulmonary artery pressure was slightly elevated in  cases than control group but did not mount to statistical significance. It suggests that myocardial dysfunction in sepsis was multifactorial and can be due to direct respiratory failure, hypoxemia, hypercapnia, acidosis and mechanical ventilation induced.

It is surprising however, that cardiogenic shock developed in both groups, and myocardial dysfunction was not an essential predictive step for cardiogenic shock.

Early recognition by echocardiography and proper supportive therapy of myocardial dysfunction in patients with sepsis was essential to initiate prompt management (12, 23).  Moreover we did not come across cases that progressed to cardiomyopathy, which is congruent to previous reports (24). A dramatic improvement in systolic and diastolic cardiac function parameters was observed by comparing the echocardiographic parameters during and after resolution of sepsis 1 week after resolution of sepsis.

Conclusion

Full terms with neonatal sepsis can experience significant cardiovascular dysfunction despite lack of structural defects. The myocardial dysfunction is either global or limited to right or left ventricle. The dysfunction might be systolic or diastolic or both. Myocardial dysfunction among neonates with sepsis might be self-limiting or progressive increasing risk of morbidity and mortality. Echocardiography is an important diagnostic tool in Neonatal Intensive Care Unit. Neonatal Screening for inborn errors of metabolism is necessary to exclude underlying cause.

Author Contributions:

All authors contributed to the study conception and design. All read and approved the final manuscript.

FUNDING

Authors declare there was no extramural funding provided for this study.

CONFLICT OF INTEREST

The authors declare no conflict of interest in connection with the reported study. Authors declare veracity of information.