Red Blood Cell Distribution Width and Pediatric Post-operative Cardiac Function

doi:10.21203/rs.3.rs-4559712/v1

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Red Blood Cell Distribution Width and Pediatric Post-operative Cardiac Function

https://doi.org/10.21203/rs.3.rs-4559712/v1

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Introduction

: Red blood cell distribution width (RDW) has recently been introduced as an important related factor in surveying prognosis of chronic diseases. This study was performed to assess the relationship between RDW and cardiac function before and after congenital heart disease surgery in children.

Method

Seventy-six children with congenital heart disease (CHD) requiring surgery admitted in Modarres Hospital pediatric cardiology ward were enrolled in this cross-sectional descriptive study. Blood samples were taken for RDW determination. Two-dimensional, M-mode, Doppler flow velocity and Tissue Doppler Imaging (TDI) were applied to evaluate cardiac function by echocardiography on the day following operation.

Results

There was no relationship between Preoperative RDW levels and early postoperative heart function except for increased Aortic Velocity Time Integral (VTI) and Mitral Valve Systolic Velocity (MV S′) noted in patients with higher RDW percents. Also, patients with higher RDW showed a longer intra-operative pump time and mean ICU stay.

Conclusion

Higher RDW levels may predict longer duration of surgery and ICU stay in pediatric cardiac surgery, however it has no relationship with cardiac function in the early postoperative period.

Congenital heart disease (CHD)

Red blood cell distribution width (RDW)

Cardiac function

Congenital heart disease (CHD) is a major cause of morbidity and mortality in children. Inflammatory serological markers may increase in CHD, as they do in many other chronic diseases, especially in advanced stages (1).

Increasing number of studies, mostly performed on adult population, have assessed the relationship between Red Cell Distribution Width (RDW) and disease prognosis. RDW itself is affected by deficiency in micronutrients such as iron, folic acid and vitamin B12 and therefore can be used as a marker evaluating nutritional status (2).

Some studies have shown racial differences in RDW ranges, however the number of these studies is limited (3). In addition, they have not differentiated between RDW in Negros, Whites, and Hispanics (4). Patients with chronic kidney disease show endothelial dysfunction in carotid intima media thickness (CIMT) and flow mediated dilatation (FMD) in the brachial artery with increased RDW, independent of anemia and inflammation (CRP)(5).

Recent studies have investigated RDW index for a wide range of acute and chronic diseases including pulmonary hypertension, renal failure, acute myocardial infarction, heart failure, angina, stroke and other cardiovascular diseases (2, 6–8). This studies have demonstrated a relationship between elevated RDW and increased postoperative complications and mortality (9). One-fifth of children undergoing cardiac surgery, especially those with cyanotic heart disease, may experience morbidities such as prolonged cardiopulmonary bypass time and increased need for post-operative inotropic support(10).

There are few studies concerning the relationship between pre-operative RDW and post-operative cardiac function in children with congenital heart disease. As no related study has been performed in our country by far, we decided to evaluate this relationship in children following cardiac surgery for congenital heart disease.

In this cross-sectional descriptive study, all pediatric (age < 18 years) CHD patients requiring surgical intervention admitted to Modarres hospital pediatric cardiology ward from May 2019 to October 2020 were enrolled and evaluated. Patients with hereditary spherocytosis and other inherited anemias, hypothyroidism, liver cirrhosis, kidney failure, infectious diseases and recent blood products transfusion were excluded. Ultimately, 76 children met the criteria for inclusion in the study. Written consent was taken from their parents and research was done in accordance with the Declaration of Helsinki. Also school of medicine ethic Committee approved the study method. Also there was Funding from Shahid Beheshti school of medicine in our study. Our datas are available in the form of SPSS.

Demographic information for all patients were collected. Blood samples were drawn for Complete blood count (CBC) checking and RDW measurement by Sysmex KX-21N Hematology Analyzer (Sysmex Corporation-Japan). Patients demographic and laboratory data were recorded in the data sheet.

Cardiac echocardiographic examination was performed by a pediatric cardiologist at bedside in Intensive Care Unit (ICU) within 24 hours after cardiac surgery using Samsung HS70A ultrasound machine (Samsung Company- South Korea). Images were obtained using standard subcostal four chamber, apical four chamber, parasternal long axis and short axis and suprasternal long axis views, applying PE 2–4 and PA 3-8B phased array probes. All patients underwent comprehensive evaluation with 2-dimentional, pulsed-wave Doppler and tissue Doppler imaging through the mitral and tricuspid valves and left ventricular outflow tract.

Left ventricular ejection fraction (LVEF) and Tricuspid annular plane systolic excursion (TAPSE) were evaluated using M-mode biplane technique for left and right ventricular function evaluation. Left ventricular myocardial performance index (LV MPI) was calculated based on the equation: “ICT + IRT/ET” where ICT stands for isovolumetric contraction time, IRT for isovolumetric relaxation time and ET for ejection time to evaluate global ventricular function. Peak velocity of blood at early diastole (E), late diastole (A) and aortic velocity time integral (VTI) were measured using pulsed Doppler signals.

Tissue Doppler imaging (TDI), also measured peak velocity of mitral and tricuspid annulus in systole (S') and peak early and late diastolic filling velocities at lateral and medial annular mitral and lateral annular tricuspid valves. The ratio of early to late diastolic velocity of mitral and tricuspid valves (E’/A') and mitral peak velocity of early diastolic filling to early diastolic annular velocity (E/E') were calculated in the four-chamber apical view. The latest recommendations from the American Association of Echocardiography (ASE) were used to measure echocardiographic indicators (11). Findings were recorded in a data sheet (11).

CHD type, type of surgical procedure (palliative or corrective), total surgery duration, cardio pulmonary bypass pump duration, length of intensive care unit (ICU) and hospital stay, were recorded in the prepared data sheet.

Statistical Analysis

Data analysis was performed using SPSS 25 for Windows (SPSS. Inc., Chicago, IL). The normal distribution of quantitative data was investigated using the Kolmogorov-Smirnov test. Continuous variables were described using mean and standard deviation (mean ± SD). Comparison of continuous variables was performed using Mann-Whitney test. The correlation between RDW and various clinical and echocardiographic parameters as well as hospital and ICU stay durations were examined by Spearman correlation analysis (rho coefficient). All continuous variables were expressed as mean ± standard deviation, and P-values less than 0.05 were considered statistically significant. The ROC curve, with its vertical axis indicating the sensitivity of the RDW percent in patients who have been expired and its horizontal axis (1- RDW specificity) was applied. (it must be at least 0.7 to be significant).

In this study 76 CHD patients including 41 (53%) girls and 35 (47%) boys were examined. Mean patient’s age was 35 ± 4months (2-156 months). Mean RDW level was 14.6 ± 3 (10.7–27.8), 14 ± 3 (10.7–27.8) for girls and 15 ± 3 (12.2–25.9) for boys, showing no significant difference according to sex (p = 0.646). Palliative surgery was performed in 21 (27%) and complete corrective surgery in 55 (73%) patients.

There was no significant relationship between preoperative angiographic data (cardiac performance indices, pressure indices and pulmonary to systemic flow and resistance ratios) and RDW level. Total hospital stay was 19.09 ± 8.7 (8–52) days and ICU stay was 8.07 ± 7.4 (2–36) days in general. Cardiopulmonary bypass (CPB) time duration was 83.97 ± 42.56 (14–240) minutes and aortic cross clamp time duration was 55.37 ± 30.28 (12–139) minutes (Table-1).

Patients with higher RDW had longer CPB time (p = 0.024, r = 0.343) and ICU stay (p = 0.007, r = 0.32), but aortic cross clamp time and total hospital stay was not correlated with RDW (p = 0.138 and 0.091 respectively). There was no significant difference between cyanotic and acyanotic patients according to CPB time (p = 0.125), ICU stay (p = 0.175) or total hospital stay (p = 0.362).

Six patients (7%) passed away in operation room or during ICU stay and total morbidity rate was 15% (11 patient). Among Corrective surgery patients 3 (5%) died due to sepsis, hemodialysis complications and tracheal perforation. Morbidity rate was 5% (3 patients) due to low cardiac output syndrome, prolonged ICU stay, sepsis, diaphragmatic paralysis and complications of tracheostomy. Among palliative surgery cases, 3 (14%) died due to COVID-19, emergency shunt implantation complication and complications of tracheostomy. Morbidity rate was 14% (3 patients) reported as prolonged ICU stay, postoperative seizures and transient blindness.

Mean RDW was 14 ± 1 in deceased patients and 15 ± 3 in the survivors; the difference was not significant (p = 0.787). The area under ROC curve did not predict mortality in patients (the area was 0.53). Mean RDW was 14 ± 2 in patients with morbidity. Mann-Whitney analysis showed no correlation between RDW and mortality (p = 0.78) or morbidity (p = 0.545). Fishers Exact test analysis demonstrated no significant relationship between surgery type (palliative or corrective) and morbidity (p = 0.688) or mortality (p = 0.766).

Mean RDW was 14 ± 1 in patients with Down syndrome (12 patients) and 14 ± 3 in non-syndromic patients with no significant difference (p = 0.191). RDW was not significantly different according to hemoglobin level (p = 0.236) and different blood groups (p = 0.101).

Mean RDW was 16 ± 4 In cyanotic and 14 ± 1 in acyanotic patients with significant difference (p = 0.009). ICU stay time was shorter in patients with lower RDW (p = 0.007, r = o.32), although this difference was not significant among cyanotic patients (p = 0.356).

Corrective surgery group children showed significant positive correlation between RDW and ICU stay (p-value = 0.01) and hospital stay (p-value = 0.042) period; meanwhile palliative surgery patients showed no significant relationship between RDW and ICU stay (p-value = 0.509) or hospital stay (p-value = 0.535).

According to post-operative echocardiographic evaluation, RDW was correlated to some postoperative left ventricular systolic indices including aortic VTI (p = 0.035, r = o.271) and lateral mitral valve systolic velocity (p = 0.027, r = o.273). Other parameters were not impressed postoperatively (Table 2).

Table 1

pre-operative angiographic and surgery related data
	variable	mean ± SD	p-value	Spearman's rho with significant p
Angiographic data	QP/QS	2.5 ± 0.67	0.061
	Rp/Rs	0.1 ± 0.04	0.617
	RVSP (mmHg)	83 ± 37	0.398
	LVSP (mmHg)	112 ± 19	0.238
	systolic PAP (mmHg)	36 ± 17	0.220
	diastolic PAP (mmHg)	16 ± 10	0.093
	mean PAP (mmHg)	22 ± 12	0.113
Surgical data	CPB time (min)	83 ± 42	0.024	r = 0.343
	aortic cross clamp time (min)	55 ± 30	0.138
	ICU stay (days)	8 ± 7	0.007	r = 0.32
	hospital stay (days)	19 ± 8	0.091
Qp/Qs: pulmonary to systemic flow ratio, Rp/Rs: pulmonary to systemic resistance Ratio, RVSP: right ventricle systolic pressure, LVSP: left ventricle systolic pressure, PAP: pulmonary artery pressure, CPB cardiopulmonary bypass

Table 2

Relationship between RDW and postoperative echocardiographic indices
Echocardiographic indices	mean ± SD	P-value	Spearman's rho if p-value is significant
LVEDD (cm)	32 ± 10	0.926
FS (%)	30 ± 5	0.209
LVEF (%)	59 ± 7	0.701
Stroke volume (ml/beat)	35 ± 25	0.386
Cardiac output (L/min)	4.21 ± 3.03	0.359
Cardiac index (L/min/m²)	2.69 ± 1.87	0.229
Aortic VTI (cm)	17 ± 6	0.035	r = 0.271
MV E	74 ± 27	0.124
MV A	57 ± 28	0.469
MV E/A	1.52 ± 0.85	0.513
septal MV E’	14 ± 11	0.785
septal MV A’	14 ± 10	0.926
septal MV E’/A’	1.4 ± 1.5	0.484
Septal MV E/E’	7.62 ± 7.19	0.846
septal MV S’	18 ± 20	0.469
lateral MV E’	14 ± 8	0.304
lateral MV A’	18 ± 16	0.131
lateral MV E’/ A’	1.4 ± 1.02	0.929
lateral MV E/E'	7.43 ± 11.43	0.161
lateral MV S’	13 ± 9	0.027	r = 0.273
MPI	0.27 ± 0.12	0.423
TAPSE (mm)	8 ± 4	0.935
TV E	58 ± 24	0.699
TV A	49 ± 21	0.821
TV E/A	0.4 ± 0.5	0.100
TV E’	16 ± 9	0.324
TV A’	17 ± 12	0.171
TV E’/ A’	1.3 ± 1.05	0.374
TV E/E’	6.58 ± 7.78	0.335
TV S’	18 ± 19	0.070

RDW indicates variation in the size of circulating red blood cells as a laboratory parameter. It has traditionally been employed for investigation of causes of anemia and conditions leading to red blood cell destruction. However, it has recently been applied in a wider spectrum of clinical settings such as prediction of poor prognosis and mortality in cardiac disorders (12).

In the present study, we investigated the relationship between preoperative RDW levels and postoperative echocardiographic findings. We noticed that RDW showed significant alteration in functional indices such as aortic VTI and MV systolic velocity in the early period after cardiac surgery. Also, patients with higher preoperative RDW demonstrated longer duration of surgery and ICU stay in comparison to those with normal RDW levels.

Polat and colleagues studied 107 pediatric CHD patients and found a significant correlation between RDW and length of ICU and hospital stay, a finding that is consistent with our study, but on the other hand they noticed that RDW range was significantly higher in deceased patients and they suggested RDW as a predictive parameter for morbidity and mortality in pre and post-operative periods of CHD surgery which this was in contrast to our study results. This may be because of variation in causes and conditions resulting in mortality, including COVID-19, in our study (13).

Massin and colleagues, in their study on 688 CHD children who underwent cardiac surgery, showed a strong positive correlation between pre-operative high RDW and adverse outcomes. Mortality rate was 5 times higher among patients with RDW of 16% or more. Patients with higher RDW levels had longer duration of ICU stay (especially acyanotic children younger than 6 months) and hospital stay (especially acyanotic children with normal hemoglobin levels). They suggested RDW as an inflammatory marker predicting post-operative prognosis in CHD patients. In our study, mean RDW range was significantly higher in cyanotic patients and the duration of ICU stay was shorter with lower RDW, but it was not associated with cyanosis. It seems that other factors might have affected ICU stay in our study such as infections. In Massin study, risk of postoperative mortality for RDW ≥ 16% was five times higher, while in our study RDW ≥ 14% did not show increased mortality. As the mean age of studied patients in both surveys was similar, this difference in mortality could probably be due to differences in race and nutritional status (14).

Oh and colleagues studied 100 adult patients with acute heart failure. Their study revealed a significant positive correlation between RDW and MV E and E/E’. Their study group which was composed of patients mostly suffering from ischemic heart disease with RDW ≥ 13.45% and NT-pro BNP ≥ 2456pg/ml, showed E/E’ ≥15, which suggests increased LV filling pressure and diastolic dysfunction. They proposed RDW as a simple marker demonstrating hemodynamic status in these patients. In our study however, there was no significant relationship between these parameters (15). Our study showed a positive significant relationship between RDW and aortic VTI and mitral lateral S ̒, indicating ventricular systolic function. As we performed echocardiography in the early postoperative period, this might be the reason why our findings are different from theirs.

Mawlana and colleagues, in their study on 31 children with heart failure, demonstrated RDW level higher than 16.1% to be related to abnormal LV functional indices such as LVFS, MV A and MV E/A. They suggested using RDW as a simple and inexpensive marker of LV function (16). In our study, there was a significant relationship between RDW and two indicators of left ventricular systolic function, but there was no relationship between RDW and ventricular diastolic function. This could be related to different sample sizes.

Celik and colleagues evaluated 71 adult patients with diastolic dysfunction in whom RDW, NT-proBNP and CRP levels were significantly increased. They suggested RDW ≥ 13.6% and NT-proBNP ≥ 125pg/ml as factors indicating diastolic dysfunction possibly due to neurohormonal, renal or filling pressure variables (17). Although diastolic dysfunction was observed in some of our patients, it was not related to RDW level and this difference may be due to younger age range in our study (17).

Van Kimmenade and colleagues studied 205 adult patients with acute heart failure. They demonstrated a reverse relationship between RDW level and 1-year survival rate and otherwise no relationship between RDW and nutritional status, history of blood transfusions and inflammatory variables. They recommended to consider RDW as a prognostic factor in patients with acute heart failure (like NT-pro BNP). In the present study the patients were younger in age and RDW level was not corelated with mortality (18).

Allen and colleagues in Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry introduced RDW as a prognostic factor for increased morbidity and considered that RDW rise in adult patients with chronic heart failure may be due to inflammation and iron metabolism impairment. Different results in our study might be due to exclusion of anemic patients in our survey (19).

Alshawabkeh and colleagues studied 696 adult patients with CHD and showed worsening of HF and NYHA functional class, increased mortality, arrhythmia and cardiac hospitalization with increased RDW levels (more than 15%), especially in patients with Eisenmenger syndrome or complex cyanotic heart disease. Our patients did not show any change in morbidity or mortality according to RDW variation, perhaps according to different sample size and age range, however operation time and ICU stay was longer among them (20).

Kumar and colleagues in their study on 94 children with Tetralogy of Fallot (TF), demonstrated the reverse relationship between RDW levels and recovery time after TF repair. They showed increased ICU and hospital stay, duration of assisted ventilation implementation and surgical site infection with RDW more than 17.8%. They suggested non-infectious mechanisms (such as chronic inflammation) as probable reason for delay in wound healing and prolonged hospital stay, as microbial infection was not documented in the majority of their patients. They also suggested abnormal erythropoiesis and increase in free iron release due to CPB implementation, especially in cyanotic patients, as the cause of prolonged recovery after surgery. In our study, 55 (72%) children underwent CPB in whom RDW level was significantly related to the ICU and hospital stay duration. It seems that inflammation and oxidative stress both play important roles in elongating recovery time. However, a fundamental yet unanswered remaining question is that whether the relationship between RDW and cardiovascular disease is rather a cause or effect, and if anisocytosis is the result of common metabolic and nutritional disorders or inflammatory cytokines, oxidative stress and malnutrition in cardiovascular patients. As most CHD patients are already in inflammatory state, another hypothesis is that elevated RDW may be a comorbidity rather than merely a causative factor in the pathogenesis of cardiovascular disease. Certainly, the clinical role of RDW in the prognosis of patients with cardiac disease is not deniable (21).

Limitations of the Study

This study faced some potential limitations. Due to the available facilities, sample volume and the cross-sectional nature of the study, the cause-and-effect relationship could not be concluded. Confounding factors might have affected the results, regardless of the adjusted analysis. We did not evaluate the nutritional and cytokines proinflammatory status of the patients in our study, this might have influenced the RDW.

Various studies have shown RDW as an indicator of prognosis for cardiovascular disease. RDW can be an important preoperative parameter in children with CHD to predict the patient's duration of operation and ICU stay. It also has correlation with cardiac function in early postoperative period. It seems desirable to consider longer time for ICU hospitalization in children with higher RDW.

Suggestions:

We suggest simultaneous measurement of the levels of other inflammatory factors such as TNF & INF & HS-CRP, in upcoming studies.

We also suggest of prospective studies with larger patient’s populations and longer follow-up periods in different Iranian ethnic groups in order to evaluate the effects of RDW on long-term prognosis of children with cardiac disease.

Finally, we suggest investigation of the effect of RDW on delayed outcomes and long-term prognosis in CHD children in future studies.

Ethics approval and consent to participate:

Written consent was taken from their parents and research was done in accordance with the Declaration of Helsinki. Also school of medicine ethic Committee approved the study method.

Consent for publication:

Not applicable

Competing interests:

Not applicable

Funding:

there was Funding from Shahid Beheshti school of medicine in our study.

Authors' contributions:

F.A. invented main idea of study. K.V. and MR.K. prepared the tables. M.A. and S.K. prepared result and discussion part. S.A.T.Z prepared main manuscript. All authors reviewed the manuscript.

Acknowledgements:

We highly appreciate the efforts of doctor Goodarzipoor, our dear hematologic consultant colleague for his valuable guides regarding our study, may his soul rest in peace. The study was approved by the Research Ethics Committee (IR. SBMU. RETECH.REC.1398.334.)

The authors would like to thank the Clinical Research Development Center, Shahid Modarres Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, for their support, cooperation and assistance throughout the period of study.

Conflict of Interests
The authors declare no conﬂict of interests regarding publication of this paper.

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No competing interests reported.

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You are reading this latest preprint version

Red Blood Cell Distribution Width and Pediatric Post-operative Cardiac Function

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Abstract

Introduction

Method

Results

Conclusion

Introduction

Design and methods

Statistical Analysis

Results

Discussion

Limitations of the Study

Conclusion

Suggestions:

Declarations

References

Additional Declarations

Status:

Version 1