Cross-sectional association between red blood cell distribution width and regional cerebral tissue oxygen saturation over the first 14 days in preterm infants

doi:10.21203/rs.3.rs-2454923/v1

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Cross-sectional association between red blood cell distribution width and regional cerebral tissue oxygen saturation over the first 14 days in preterm infants

https://doi.org/10.21203/rs.3.rs-2454923/v1

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Background: Hypoxia can threaten the metabolic functions of various body systems of the immature neonate, particularly the central nervous system. Red blood cell distribution width (RDW) has been recently reported as a prognostic factor in neurologic diseases. This study examined the correlation between RDW and regional cerebral tissue oxygen saturation (rcSO₂).

Methods: This cross-sectional study, including 110 preterm infants with gestational age (GA) of <32 weeks or birth weight (BW) of <1500 g from January to June 2022 in our institution, monitored rcSO₂ with near-infrared spectroscopy. RDW was extracted from the complete blood count during the first 14 days of life. RDW and rcSO₂ measurements were analyzed using a cross-sectional research method.

Results: This study included 53 preterm neonates with rcSO₂≥55% and 57 preterm neonates with rcSO₂<55%. Mean rcSO₂ decreased with increasing RDW during the first 14 days of life. Significantly higher RDW levels were seen in the low rcSO₂ group compared with those of the high rcSO₂ group. According to threshold effect analysis, the value of rcSO₂ decreased with RDW levels above 17.84% (β, -0.03; 95% CI, -0.04– -0.02; p<0.0001). After adjusting for potential confounders, an RDW of ≥17.84% was determined as the predictive cutoff value for preterm infants with low rcSO₂ (Model I: OR, 3.31; 95% CI, 1.36–8.06; p=0.009; and Model II: OR, 3.31; 95% CI, 1.28–8.53; p=0.013).

Conclusions: An RDW of ≥17.84% was associated with a high risk of low rcSO₂ in preterm infants. A high RDW in preterm infants correlates with an increased risk of cerebral hypoxia.

Trial registration: This study was registered at ChineseClinicalTrials.gov (09/04/2022,ChiCTR2200058482).

red blood cell distribution width

regional cerebral tissue oxygen saturation

predictive cutoff value

cerebral hypoxia

preterm neonates

Brain vulnerability in critically ill preterm newborns poses an immense challenge despite recent improvements in perinatal care. Brain hypoperfusion during the immediate postnatal period has been reported to be related to cerebral damage in sick preterm infants [1]. Hypoxia can lead to poor clinical outcomes if not corrected in time, such as paralysis, disability, and death [2, 3].

Red Blood Cell Distribution Width

Standard complete blood count (CBC) includes the red cell distribution width (RDW) as a numerical expression of erythrocyte anisocytosis [4]. The RDW is calculated from the distribution of RBC volumes, measured by impedance, using the following formula:

RDW = standard deviation of RBC volume / MCV (mean corpuscular volume) × 100

The ‘width’ in RDW refers to the width of the volume distribution histogram, expressed as a coefficient of variation. With mixtures of small and large red blood cells, the histogram is wider; thus, the RDW value is higher. Contrariwise, with homogeneous red cell size, the histogram is narrower; thus, the RDW is lower. Since the methods of measuring the RBC size, instruments, experimenters, laboratory standards, and statistical approaches are not similar in different laboratories [5], there is no universal reference range until now [6]. The normal reference range of RDW most laboratories used was 11% (lower reference interval limit) to 15% (upper reference interval limit) [7]. About infants, in 1987, Dr. Robert Novak reported normal values of RDW was from 11.5–14.5% [8].

RDW has been recently reported as a strong prognostic factor in the cardiovascular, respiratory, renal, neurologic, and gastrointestinal diseases[9, 10, 11].

Preterm Cerebral Oxygen

Regional cerebral tissue oxygen saturation (rcSO₂ ) can be estimated with a frequently used noninvasive technique, near-infrared spectroscopy (NIRS) [12]. RcSO₂ primarily reflects the venous compartment but is also sensitive to changes in arterial and capillary oxygenation. Owing to the cerebral autoregulation, rcSO₂ remains largely stable within a certain range ; it is influenced by cerebral blood flow (CBF) and cerebral metabolism, namely, cerebral oxygen consumption [13]. RcSO₂ increases with time after birth and tends to reach a plateau at around 60% 8–10 min after birth [14, 15]. The SafeBoosC study group conducted an interventional trial to investigate the feasibility and benefits of reducing the burden of cerebral hypoxia and hyperoxia in preterm infants guided by NIRS monitoring [16, 17]. However, rcSO₂ monitoring does not adequately reflect the true relationship between pulse oxygen saturation (SpO₂), rcSO₂, and CBF [18].

Relationship Between RDW and rcSO₂

Due to the abilities to deform and flow in the microvascular network, RBCs have many vital physiological functions in our body, including carrying oxygen and carbon dioxide and gas exchange between blood and tissues[19]. However, alterations of osmolality under some pathophysiological conditions can decrease the ability of RBCs to deform and cause an increased RDW level, resulting in low microvascular perfusion [20]. A study shows that when the RDW level is more than 14%, the deformability of RBCs in microvascular disorders decreases[21]. One study reported that the baseline rcSO₂ values were lower in preterm neonates with higher hematocrits [22].

We aimed to investigate the relationship between RDW and rcSO₂ in preterm neonates. We hypothesized that high RDW was associated with an increased risk of low rcSO₂ based on analyses of existing clinical data.

Study Population

The study population consisted of 110 preterm infants born at < 32 weeks or < 1500 g from January to June 2022 at the neonatal intensive care unit (NICU) of the West China Second University Hospital, Sichuan University. All preterm infants born at < 32 weeks or < 1500 g were assessed for eligibility. Exclusion criteria were advanced resuscitation in the delivery room, cardiovascular instability requiring treatment with inotropes, anemia, and major congenital or chromosomal anomalies. The study was approved by the Ethics Committee of the West China Second University Hospital, Sichuan University (2022- 67). Written and verbal informed consent was obtained from the parents. The study was registered at ChineseClinicalTrials.gov (09/04/2022,ChiCTR2200058482).

Study Design

We performed a cross-sectional study. For this analysis, an EGOS-600B Cerebral/Somatic Oximeter device was used for rcSO₂ monitoring during the study period. Neonatal NIRS sensors (NIRSensor, Enginmed, A1Z2104110037) were placed on the frontoparietal regions of the infants. NIRS monitoring was performed thrice daily in the first 14 days of life. All data were obtained when the infants were mostly quiet or sleeping in the supine position. No handling or intervention was performed during NIRS monitoring. Recorded values were stored and used for offline analyses. NIRS data analysis was performed after the data were transferred to a computer in Excel format using a customized programmer for the EGOS device. Those with markers on them, likely related to an artifact (during handling, positioning, etc.), were excluded for data cleaning and were averaged afterward. RDW was extracted from the CBC from the enrolled children during the first 14 days, and the average was calculated. Neonatal and perinatal characteristics, including gestational age (GA), birth weight (BW), sex, mode of delivery, intrauterine growth restriction (IUGR), hypertension during pregnancy, chorioamnionitis (CA), gestational diabetes mellitus (GDM), premature rupture of membranes (PROM), multiple pregnancies, and the overall dose of antenatal corticosteroid treatment, were recorded prospectively. Neonatal morbidities included early-onset sepsis (EOS), late-onset sepsis (LOS), and intraventricular hemorrhage (IVH).

Statistical Analysis

For descriptive analyses, continuous variables were described as the means ± standard deviations (SD), categorical data were presented as numbers and percentages[23]. The distribution of each covariate of the rcSO₂ ≥ 55% and rcSO₂ < 55% groups was compared using the t-test (normal distribution) or the Kruskal–Wallis rank sum test (non-normal distribution) for continuous variables and the chi-squared test for categorical data (Table 1).

Table 1

Baseline characteristics of the study participants *(n = 110)*
rcSO₂-14d	rcSO₂ ≥ 55% (n = 53)	rcSO2 < 55% (n = 57)	Standardized difference	p-value
GA, weeks (mean ± SD)	31.09 ± 2.18	30.62 ± 2.25	0.21 (-0.16, 0.59)	0.273
BW, g (mean ± SD)	1523.87 ± 384.36	1432.49 ± 463.30	0.21 (-0.16, 0.59)	0.265
Sex (n, %)			0.14 (-0.24, 0.51)	0.471
Male	28 (52.83%)	34 (59.65%)
Female	25 (47.17%)	23 (40.35%)
RDW (mean ± SD)	16.47 ± 1.24	17.28 ± 2.11	0.47 (0.09, 0.84)	0.017
VD (n, %)			0.19 (-0.19, 0.56)	0.325
No	39 (73.58%)	37 (64.91%)
Yes	14 (26.42%)	20 (35.09%)
CA (n, %)			0.04 (-0.33, 0.42)	0.815
No	30 (56.60%)	31 (54.39%)
Yes	23 (43.40%)	26 (45.61%)
Hypertension during pregnancy (n, %)			0.06 (-0.31, 0.43)	0.753
No	44 (83.02%)	9 (16.98%)
Yes	9 (16.98%)	11 (19.30%)
GDM (n, %)			0.11 (-0.27, 0.48)	0.568
No	38 (71.70%)	38 (66.67%)
Yes	15 (28.30%)	19 (33.33%)
IUGR (n, %)			0.03 (-0.35, 0.40)	0.894
No	47 (88.68%)	51 (89.47%)
Yes	6 (11.32%)	6 (10.53%)
PROM (n, %)			0.02 (-0.35, 0.39)	0.914
No	34 (64.15%)	36 (63.16%)
Yes	19 (35.85%)	21 (36.84%)
Multiple pregnancies (n, %)			0.12 (-0.25, 0.50)	0.526
No	32 (60.38%)	31 (54.39%)
Yes	21 (39.62%)	26 (45.61%)
Overall dose of antenatal corticosteroid treatment (n, %)			0.07 (-0.31, 0.45)	0.717
No	13 (25.00%)	16 (28.07%)
Yes	39 (75.00%)	41 (71.93%)
IVH (n, %)			0.17 (-0.21, 0.54)	0.388
No	46 (86.79%)	46 (80.70%)
Yes	7 (13.21%)	11 (19.30%)
EOS (n, %)			0.21 (-0.16, 0.59)	0.275
No	49 (92.45%)	49 (85.96%)
Yes	4 (7.55%)	8 (14.04%)
LOS (n, %)			0.10 (-0.27, 0.48)	0.587
No	49 (92.45%)	51 (89.47%)
Yes	4 (7.55%)	6 (10.53%)
For explanation of abbreviations, see the main text

We used a generalized additive model (GAM) to investigate the dose–response relationship between the value of RDW and rcSO₂ (Fig. 1). We then used a two-piece-wise linear regression model to examine the threshold efect of the value of RDW on rcSO₂ (Table 2). The turning point for the value of RDW was determined using “exploratory” analyses, which is to move the trial turning point along the pre-defned interval and pick up the one which gave maximum model likelihood. We also performed a log-likelihood ratio test (LRT). We used the bootstrap resampling method to calculate the 95% CI for the turning point, as described in the previous analysis[24].

Table 2

Threshold effect analysis of RDW and rcSO₂ over the first 14 days using piece-wise linear regression
	Effect size (β)	95% CI	p-value
Turning point of RDW
< 17.84	0.01	0.00, 0.02	0.038
≥ 17.84	-0.03	-0.04, -0.02	< 0.0001
P value for LRT test			< 0.001
95% CI for turning point		17.03, 18.79
Adjusted for gestational age and birth weight
For explanation of abbreviations, see the main text

Next, univariate logistic regression (Table 3) and multivariate logistic regression models (Table 4) were used to examine whether the high RDW was associated with low rcSO₂ in preterm neonates. Statistical results were displayed as an odds ratio (OR), with their corresponding 95% confidence interval (CI). All the statistical analyses were performed using the EmpowerStats (www.empowerstats.com, X&Y solutions, Inc. Boston MA) and R sofware version 4.2.0 (http://www.r-project.org).

Table 3

Univariate analysis for rcSO₂ < 55% over the first 14 days
	Statistics	OR (95% CI)	p-value
RDW	16.89 ± 1.79	1.31 (1.04, 1.65)	0.020
RDW threshold value group
<17.84	78 (70.91%)	1.00
≥17.84	32 (29.09%)	3.31 (1.36, 8.06)	0.009
GA, weeks (mean ± SD)	30.85 ± 2.22	0.91 (0.76, 1.08)	0.272
BW, g (mean ± SD)	1476.52 ± 427.62	1.00 (1.00–1.00)	0.264
VD (n, %)
No	76 (69.09%)	1.00
Yes	34 (30.91%)	1.51 (0.66, 3.41)	0.327
CA (n, %)
No	61 (55.45%)	1.00
Yes	49 (44.55%)	1.09 (0.52, 2.32)	0.815
Hypertension during pregnancy (n, %)
No	90 (81.82%)	1.00
Yes	20 (18.18%)	1.17 (0.44, 3.09)	0.753
GDM (n, %)
No	61 (55.45%)	1.00
Yes	34 (30.91%)	1.27 (0.56, 2.86)	0.569
IUGR (n, %)
No	98 (89.09%)	1.00
Yes	12 (10.91%)	0.92 (0.28, 3.06)	0.894
PROM (n, %)
No	70 (63.64%)	1.00
Yes	40 (36.36%)	1.04 (0.48, 2.27)	0.914
Multiple pregnancies (n, %)
No	63 (57.27%)	1.00
Yes	47 (42.73%)	1.28 (0.60, 2.73)	0.526
Overall dose of antenatal corticosteroid treatment (n, %)
No	29 (26.36%)	1.00
Yes	81(73.64%)	0.85 (0.36, 2.00)	0.717
For explanation of abbreviations, see the main text

Table 4

Relationship between the RDW and rcSO₂ < 55% over the first 14 days according to different models
Variable	Crude model ^a		Adjusted model ^b
Variable	OR (95% CI)	p-value	OR (95% CI)	p-value
RDW	1.31(1.04,1.65)	0.020	1.31(1.02,1.67)	0.036
RDW value group
< 17.84	1.00		1.00
≥ 17.84	3.31(1.36,8.06)	0.009	3.31 (1.28, 8.53)	0.013
For explanation of abbreviations, see the main text
^a Crude model not adjusted.
^b Adjusted model adjusted for gestational age and birth weight

Baseline Characteristics

This study was conducted with 110 preterm neonates. Of these, 53 had rcSO₂ levels of ≥ 55%, and 57 had rcSO₂ levels of < 55%. The general characteristics of the study population are summarized in Table 1. There was no noticeable difference between the two groups regarding GA (31.09 ± 2.18 vs. 30.62 ± 2.25 weeks; p = 0.273), BW (1523.87 ± 384.36 vs. 1432.49 ± 463.30 g; p = 0.265), sex (male: female, 28:25 vs. 34:23; p = 0.471), VD (14/53 vs. 20/57; p = 0.325), CA (23/53 vs. 26/57; p = 0.815), hypertension during pregnancy (9/53 vs. 11/57; p = 0.753), GDM (15/53 vs. 19/57; p = 0.568), IUGR (6/53 vs. 6/57; p = 0.894), PROM (19/53 vs. 21/57; p = 0.914), multiple pregnancies (21/53 vs. 26/57; p = 0.526), overall dose of antenatal corticosteroid treatment (39/53 vs. 41/57; p = 0.717), IVH (7/53 vs. 11/57; p = 0.388), EOS (4/53 vs. 8/57; p = 0.275), and LOS (4/53 vs. 6/57; p = 0.587).

Association of RDW Levels With rcSO₂

To investigate the association of RDW levels with rcSO₂, subjects were divided into two groups according to RDW value. The piece-wise linear regression threshold effect analysis of RDW and rcSO₂ showed that the value of rcSO₂ decreased with RDW levels above 17.84% (β, -0.03; 95% CI, -0.04– -0.02; p < 0.0001) (Fig. 1, Table 2). Univariate analysis (Table 3) showed that the RDW was significantly correlated with preterm rcSO₂ values < 55% over the first 14 days (OR, 1.31; 95% CI, 1.04–1.65; p = 0.020). After multivariable risk adjustment for potential confounding factors (Table 4), including GA and BW in the adjusted model, the high RDW was still positively associated with low rcSO₂ in preterm neonates. In addition, an RDW of ≥ 17.84% over the first 14 days could significantly increase the risk of preterm rcSO₂ values < 55% over the first 14 days (adjusted model: OR, 3.31; 95% CI, 1.28–8.53, p = 0.013).

Despite significant improvements in survival for preterm infants, the rate of major neurodevelopmental impairment in survivors has not diminished [25]. The burden of neurodevelopmental disability due to preterm birth is still a significant challenge for neonatologists and public health. As a result, strategies designed to reduce adverse neurological outcomes have been a major perinatal research focus.

Experiments on piglets have demonstrated that rSO₂ values under a certain threshold for prolonged periods are associated with cerebral damage [26]. Subsequently, rcSO₂ may negatively impact the growing brains of preterm infants and their neurodevelopmental outcomes. Low rcSO₂ was associated with lower developmental scores in very preterm infants at 2 years of age [27]. A report found that children surviving with sequelae had lower rcSO₂ than children without sequelae. There was a direct correlation between the time spent with an rSO₂ of ≤ 40% and adverse cerebral outcomes or early death.

The relationship between SpO₂ and rcSO₂ is not well established, SpO₂ is not a reliable tool to fully inform about rcSO₂ [28, 29]. Therefore, automated FiO₂ control might be difficult to further improve the stability of rcSO₂ [30].

Current studies have validated that RDW statistically correlates with National Institutes of Health stroke scale scores and grading in patients with stroke [31]. In another study, Söderholm et al. developed the claim that the incidence of stroke and cerebral infarction increases with the level of RDW in individuals. In addition, they found evidence of an association between high RDW levels and increased intimal-medial thickness (IMT) in the common carotid artery, which has also been recognized as a risk factor in ischemic stroke [32, 33].

Various underlying metabolic abnormalities, such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation, and alteration of erythropoietin function lead to both impaired erythropoiesis and abnormal RBC survival. An increased RDW mirrors a profound deregulation of erythrocyte homeostasis[34].

Whether RDW plays an active role in health and disease or simply behaves as a biomarker, it is increasingly clear that its clinical use should now be broadened beyond its conventional application for troubleshooting anemia.

A retrospective study of 596 critically ill pediatric patients by Ramby et al. found an association between RDW and prolonged pediatric intensive care unit (PICU) stay in those without sepsis, with 1.17 increased odds for each 1% increase in RDW [8]. Elevated RDW in preterm newborns and infants with IUGR was also significantly associated with early mortality [8]. A higher RDW value was significantly associated with worse clinical parameters, including PICU mortality. Thus, RDW could be a promising prognostic factor with the advantages of simple and easy measurement in critically ill pediatric patients [35].

The influence of some confounding factors, such as GA, BW, and nursing factors, were excluded by statistical analysis using R (http://www.R-project.org). Our study found a statistically significant positive correlation between the RDW and preterm rcSO₂. An RDW of ≥ 17.84% over the first 14 days could significantly increase the risk of a preterm rcSO₂ value of < 55%. This value may be applied in clinical practice and used during routine monitoring processes for preterm rcSO₂ in NICU.

Accordingly, tools or biomarkers able to detect early infants at risk of cerebral hypoxia injury would be welcome, and our data suggest that RDW over the first 14 days could be one of these. In clinical settings, RDW is easily available to physicians as a parameter of the CBC and therefore does not incur additional costs, compared with other clinical biomarkers.

RDW, an easy, simple, inexpensive, and rapid tool, could be used in advance to predict preterm infants with low rcSO₂, which is correlated with cerebral hypoxia. Some high-risk factors that may cause high RDW should be avoided in the early stage to reduce cerebral hypoxia injury in preterm infants.

Our findings emphasize the necessity to improve medical measures to decrease the incidence of cerebral hypoxia in preterm neonates. In order to validate the reliability of the results of this study, future prospective studies on a larger population of preterm infants are required. In addition, in the later studies, we plan to develop a predictive model of the RDW for low rcSO₂ diagnosis through machine learning and then prospectively substantiate the model’s accuracy using more preterm infants.

BW, Birth weight

CBC, Complete blood count

CA, Chorioamnionitis

CI, Confidence interval

CBF, Cerebral blood flow

CVD, Cerebrovascular diseases

EOS, Early-onset sepsis

FiO₂, Fraction of inspiration

GA, Gestational age

GAM, Generalized additive model

GDM, Gestational diabetes mellitus

IMT, Intimal-medial thickness

IUGR, Intrauterine growth restriction

IVH, Intraventricular hemorrhage

LOS, Late-onset sepsis

LRT, Logarithm likelihood ratio test

MCV, Mean corpuscular volume

NICU, Neonatal intensive care unit

NIRS, Near-infrared spectroscopy

OR, Odds ratio

PE, Preeclampsia

PICU, Pediatric intensive care unit

PROM, Premature rupture of membranes

RBC, Red blood cell

RDW, Red blood cell distribution width

rcSO₂, Regional cerebral tissue oxygen saturation

SD, Standard deviations

SpO₂, Pulse oxygen saturation

VD, Vaginal delivery

Ethical approval and consent to participate

This study was approved by the Ethics Committee of the West China Second University Hospital, Sichuan University (2022- 67). Written and verbal informed consent was obtained from the parents. The study was registered at ChineseClinicalTrials.gov (09/04/2022,ChiCTR2200058482). All procedures were performed in accordance with relevant guidelines.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This work was supported by the Critical Care Project of National Natural Science Foundation of China (H16 82241036) and the department of Science and Technology of Sichuan Province (2021YJ0171).

Authors’ contributions

H W conceptualized and designed the work, provided feedback about the study design, helped draft the initial manuscript, assisted in the creation of the tables and figures, and critically reviewed and revised the manuscript. Y M performed the background research and data gathering, assisted in the study methodology, carried out the statistical analyses, developed the figures and tables, reviewed and revised the article. D M helped reviewed and revised the manuscript. M T, Y H, Y F, R L, Q H, S J, J H and S D assisted in the data gathering and sorting.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgments

The authors thank Sichuan University West China Second University Hospital for their assistance with data collection.

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No competing interests reported.

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Cross-sectional association between red blood cell distribution width and regional cerebral tissue oxygen saturation over the first 14 days in preterm infants

Status:

Version 1

Abstract

Figures

Background

Red Blood Cell Distribution Width

Preterm Cerebral Oxygen

Relationship Between RDW and rcSO₂

Methods

Study Population

Study Design

Statistical Analysis

Results

Baseline Characteristics

Association of RDW Levels With rcSO₂

Discussion

Conclusions

List of abbreviations

Declarations

References

Additional Declarations

Status:

Version 1

Cross-sectional association between red blood cell distribution width and regional cerebral tissue oxygen saturation over the first 14 days in preterm infants

Status:

Version 1

Abstract

Figures

Background

Red Blood Cell Distribution Width

Preterm Cerebral Oxygen

Relationship Between RDW and rcSO2

Methods

Study Population

Study Design

Statistical Analysis

Results

Baseline Characteristics

Association of RDW Levels With rcSO2

Discussion

Conclusions

List of abbreviations

Declarations

References

Additional Declarations

Status:

Version 1

Relationship Between RDW and rcSO₂

Association of RDW Levels With rcSO₂