Utility of doppler ultrasound in early-onset neonatal sepsis: A case-control study

Abstract

Background

Early-onset sepsis is one of the leading causes of neonatal morbidity and mortality worldwide and timely diagnosis is, therefore, of paramount importance. As there is a lack of literature regarding early alteration of the cerebral blood flow (CBF) in neonatal sepsis, our study aimed to appraise changes in the CBF velocities and Doppler indices in neonates with early-onset neonatal sepsis (EONS) and to assess its diagnostic accuracy.

Methods

A total of 99 neonates were recruited in the study; 56 neonates with EONS, and the age-matched 43 neonates without any manifestations of sepsis. A Transcranial Doppler examination and cerebral hemodynamics were assessed in neonates during the first seventy-two hours of life. Doppler indices and CBFV were measured in the anterior cerebral artery (ACA), and middle cerebral artery (MCA), of either side. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated.

Results

A significantly lower resistance in Resistivity (RI) and Pulsatility (PI) indices, a significant high end-diastolic velocity (EDV), and relatively higher peak systolic velocity (PSV) in both ACA and MCA have been documented within 72 hours of birth in neonates with EONS compared to the control group of neonates without sepsis.

Conclusion

Our Study revealed that assessment of CBF at early hours of birth by Transcranial Doppler examination showed alteration in cerebral hemodynamics in neonates with EONS with an increase in the CBF and a decrease in the resistance. It can be adopted as a bedside, noninvasive tool with immediate diagnostic value.

Keywords

Doppler indices early-onset neonatal sepsis anterior cerebral artery middle cerebral artery transcranial doppler

Introduction

Neonatal sepsis is an infection involving the bloodstream in infants under 28 days old associated with clinical manifestation and hemodynamic changes [1]. It is common and often fatal and remains a leading cause of morbidity and mortality among neonates, especially in middle and lower-income countries, and is ranked the third leading cause of neonatal mortality [2, 3].

Neonates have a higher risk of sepsis than adults and children due to their immature immunity, potential intrauterine exposure to infection, and in preterms, altered skin and mucosal barriers [1, 4]. The earliest signs of sepsis in neonates are often elusive and nonspecific, so that high index of suspicion is needed for early diagnosis [5, 6].

Neonatal sepsis is divided into two groups based on the time of presentation after birth: early-onset sepsis (EONS) and late-onset sepsis (LONS). EONS refers to sepsis in neonates at or before 72 hours of life, hence representing fetal-maternal infection and LONS is defined as sepsis occurring at or after 72 hours of life LONS that can be hospital-acquired or community-acquired [3 , 7, 8]. Of newborns with early-onset sepsis, 85% present within 24 hours, 5% present at 24–48 hours, and a smaller percentage present within 48–72 hours [9].

The control of cerebral blood flow (CBF) involves complex neural and metabolic mechanisms, which are still immature enough in newborns and more liable to cerebral blood flow fluctuations [10]. Sepsis was found to have a higher prevalence of impaired cerebral autoregulation [11].

Both hypo and hyper-perfusion can cause brain damage in neonates with an increased risk of cerebral hemorrhage in hyper-perfusion and an increased risk of ischemia with hypo-perfusion [12 –14], therefore, studying the neonatal cerebral blood flow and velocities in sepsis is of concern [15, 16].

In this study, we sought to evaluate changes in CBF in cases of EONS with ultrasound Doppler examination by studying changes in values of peak systolic velocity (PSV), end-diastolic velocity (EDV), resistivity index (RI), and pulsatility index (PI) in the anterior cerebral (ACA) and middle cerebral artery (MCA) in neonates with EONS compared to age-matched neonates without any signs of sepsis.

Methods

This study is a prospective observational case-control study conducted over two years from July 2021 to June 2023 in the neonatal intensive care unit (NICU) at Mansheyet El Bakry General Hospital, a public hospital in Cairo city.

The study followed the Declaration of Helsinki [17] and was approved by the Research Ethics Committee (REC) of the Faculty of Medicine, Ain Shams University (FWA 000017858, dated 23/1/2021). Parents or caregivers of the recruited neonates were fully informed about the study objectives and procedures and gave oral consent before enrollment.

Subjects

The study population was the neonates who were admitted to the neonatal intensive care unit (NICU) at postnatal age <72 hours. EONS cases were identified as per the unit guidelines and controls were recruited from other cases admitted for causes other than EONS. Neonatal sepsis diagnosis was considered when two criteria related to risk factors for sepsis, and/or clinical presentation, and/or lab abnormality [18].

The study recruited 99 newborns, which were subsequently divided into two groups: the (Case group) contained 56 neonates with a diagnosis of EONS, while the (Control group) contained age-matched 43 newborns without any signs of sepsis.

Clinical and laboratory assessment

Perinatal history in detail was collected and a thorough clinical examination was made at admission to exclude congenital anomalies or any disease affecting cerebral hemodynamics other than EONS. Neonates who were receiving anticonvulsants or drugs such as caffeine and theophylline during the Doppler examination were also excluded.

Basic laboratory investigations were done covering Complete blood count CBC, blood culture, C-reactive protein CRP, erythrocytic sedimentation rate ESR, Plasma glucose, Lactate, Serum electrolytes, Arterial blood gas ABG, Coagulation profile, AST, ALT enzymes, urea, and creatinine. All neonates enrolled in the study received routine neonatal care.

Doppler examination

Enrolled neonates of both groups received a Transcranial Doppler Ultrasound (TCD) examination with assessment of CBFV. The same sonographer carried out all ultrasound examinations to avoid any interobserver variation. The TCD was done within 72 h after delivery, through the window of the incubator to keep the normothermal condition, the neonate lies supine with lateral tilting of the head to either side during the examination. A small amount of gel was applied during examination in quiet neonates, with rapid removal after the examination to avoid hypothermia. Assessment of blood flow velocity in the anterior [ACA] and middle cerebral arteries [MCA] using duplex pulsed Doppler ultrasound. Peak systolic velocity [PSV], end-diastolic velocity [EDV], Pulsatility index [PI], and resistive index [RI] were measured. All the [TCUS] studies were performed using SEMENS ACUSON X300 Ultrasound and Color Doppler machine, with a 5–13 MHz linear array transducer. The anterior fontanel as an acoustic window, CBF velocity was measured in the [ACA] in a longitudinal position (sagittal position). [MCA] was insonated using a transtemporal approach, the probe was placed on the temporal aspect of the head, cephalad to the zygomatic arch, and immediately anterior & slightly superior to the tragus of the ear in a transverse position. [PSV] and [EDV] were calculated from at least three consecutive cardiac cycles of optimal quality using the built-in calculation program. [PI] and [RI] of [ACA] and [MCA] were automatically calculated after recording both [PSV] and [EDV].

Statistical analysis

Data was coded and entered in a Microsoft Excel spreadsheet, then imported and analyzed using the statistical package SPSS version 23.0 (SPSS Inc., Chicago, IL, USA). Data were summarized using mean and standard deviation for quantitative variables. Frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Comparison of numerical variables was done using the Student t-test for independent samples in comparing two cases and controls when normally distributed and Mann– Whitney U test for independent samples when not normally distributed. For comparing categorical data between cases and controls, a Chi-square (χ²) test was performed. Fisher Exact test was used instead when the expected frequency is less than 5.

Comparison between case and control groups for cerebral blood flow velocity parameters was first made for all subjects according to the operational diagnosis of sepsis.

A further comparison was conducted by restricting the subjects to exclusively include culture-proven neonates, specifically culture-positive cases, compared to culture-negative controls.

Considering the timing of conducting the Transcranial Doppler examination, a comparison for cerebral blood flow velocity parameters was applied between case and control groups for the first 48 hours of life and after up to 72 hours.

Receiver– operating characteristic (ROC) curve analysis with measurement of area under the curve (AUC) was performed to identify the appropriate cut-off values. Sensitivity, specificity, PPV, NPV, diagnostic accuracy, and Likelihood ratio positive and negative were calculated at the selected appropriate cut-off values for cerebral blood flow velocity (CBFV) parameters. Correlations between quantitative variables were done using Pearson correlation coefficient.

P-values less than 0.05 were considered statistically significant.

Results

A total of 99 neonates were enrolled, including 56 in the case group and 43 in the control group. Both groups were comparable for gestational age, birth weight, intra-uterine growth retardation, mode of delivery and maternal age, and the postnatal date in days on undergoing the Transcranial Doppler Ultrasound examination to assess cerebral blood flow velocity.

Table 1 demonstrates the comparison of neonatal and maternal demographic parameters between the Case Group and Control Group. No statistically significant differences between the two groups regarding prematurity (p = 0.376), gestational ages in weeks (p = 0.145), birth weight (p = 0.398), fetal intra-uterine growth retardation (p = 0.645), however, the male neonates with EONS were more compared to females with a statistically significant difference (p = 0.019).

Table 1.

Comparison of neonatal and maternal demographic parameters.

Parameter	Sepsis Group	Non-sepsis Group	P Value
	Cases (n = 56)	Controls (n = 43)
Postnatal date in days, Mean ± SD, (median, range)	2.79 ± 0.46 (3, 1–3)	2.65 ± 0.61 (3, 1–3)	0.212^a
Gestational age in weeks, Mean ± SD, (median, range)	35.55 ± 0.89 (36, 32–37)	35.28 ± 0.96 (35, 34–37)	<0.145^a
Birth weight (g), Mean ± SD, (median, range)	2,479 ± 0.62 (2,500, 1,100–4,300)	2,371 ± 0.63	0.398^a
Intra-uterine growth retardation (n, %)	11 (19.6)	11 (25.6)	0.645^b
Male: Female	34 : 22	15 : 28	0.020^b
Mode of delivery
– SVD (n, %)	19 (33.9)	12 (27.9)	0.673^b
– Caesarian section (n, %)	37 (66.1)	31 (72.1)
Maternal age (years), Mean ± SD (median, range)	28.96 ± 5.83 (28, 18–41)	28.81 ± 6.10 (28, 18–42)	0.901^a

SVD Spontaneous vaginal delivery. (S) a significant difference, (NS) non-significant difference.

^aIndependent samples T-test.

^bChi-square test.

As regards maternal factors, there was no statistically significant difference between mothers of the neonates with EONS compared to mothers of the neonates without EONS regarding age in years (p = 0.901), and mode of delivery (p = 0.673).

Table 2 depicts details about clinical and laboratory workup in the Case Group compared to the Control Group. Out of 56 diagnosed with sepsis, 19 (33.9%) had positive blood cultures.

Table 2.

Comparison of clinical and laboratory workup between case and control groups.

Parameter	Sepsis Group	Non-sepsis Group	p Value
	Cases (n = 56)	Controls (n = 43)
Clinical Presentation
ARDS (Mean ± SD)	1.73 ± 0.50	1.68 ± 0.59	0.643a
– 0 (n, %)	6 (10.9)	8 (18.6)	0.474b
– 1 (n, %)	10 (18.2)	9 (20.9)
– 2 (n, %)	39 (70.9)	26 (40.0)
Jaundice, Yes, n (%): No, n (%)	4 (7.1%):52 (92.9%)	9 (20.9%):34 (79.1%)	0.087b
Laboratory Investigations
HB level (Mean ± SD)	16.28 ± 2.15	15.68 ± 2.00	0.163a
Blood Culture (+ve: –ve)	19 : 0	0 : 24	<0.001b
WBC Count
– WBC Count (Mean ± SD)	15.46 ± 6.90	10.36 ± 3.21	<0.001a
– Normal (5000–15000) [n,% ]	21 (37.5%)	42 (97.7%)	<0.001b
– Leukocytosis (>15000) [n,% ]	31 (55.4%)	0 (0.0%)
– Leucopenia (<5000) [n,% ]	4 (7.1%)	1 (2.3%)
Platelets Count (Mean ± SD)	235.88 ± 92.13	260.74 ± 67.15	0.139a
PT	19.13 ± 3.00	20.95 ± 4.79	0.023a
PTT	38.81 ± 5.46	39.30 ± 4.70	0.640a
INR	1.06 ± 0.08	1.04 ± 0.53	0.098a
CRP (Mean ± SD)	24.60 ± 25.64	3.58 ± 4.23	<0.001a
ABG PH	7.28 ± 0.77	7.34 ± 0.80	<0.001a
PCO2	48.18 ± 11.72	40.98 ± 8.58	0.001a
Glucose	75.09 ± 45.82	93.37 ± 40.43	0.041a
Lactate	2.71 ± 1.22	1.89 ± 0.81	<0.001a
HCO3	21.76 ± 6.07	20.04 ± 2.63	0.085a
BE	–3.35 ± 7.49	–11.38 ± 2.47	<0.001a

(S) a significant difference, (NS) non-significant difference.

^aIndependent samples T-test.

^bChi-square test or Fisher Exact.

Gram-positive organisms were the most detected; Staph Aureus 8 (42.1%), and Strep pneumoniae 5 (26.3%), while gram-negative organisms detected were: E coli 4 (21.1%), and Klebsiella 2 (10.5%) (Not in the table).

High significant differences were found between the two groups regarding CRB, WBC count, PT, APG PH, PCO2, Glucose, Lactate, and BE. No significant differences were found in the other parameters.

The Mean ± SD and the Median (IRQ range) of PSV, EDV, RI, and PI of ACA and MCA of neonates in case and control groups are depicted in Tables 3.1 and 3.2. A statistically significant differences are noted between the median values PI and RI indices of ACA and MCA with lower values among neonates in the case group compared to those in the control group. In addition, statistically significant differences are noted between the median values of EDV with higher values among neonates in the case group compared to those in the control group (p < 0.001). PSV in both ACA and MCA was higher in the case group compared to the control group, however, was not statistically significant.

Table 3.1.

Comparison of cerebral blood flow velocity of Anterior and Middle cerebral arteries between the sepsis group (Case) and non-sepsis group (Control), using duplex-pulsed Doppler ultrasound according to diagnosis based on criteria related to sepsis risk factors and culture-based diagnosis.

Parameters	Diagnosis based on			Diagnosis based on
	Clinical & Laboratory Criteria			culture-proven results
	Sepsis Group	Non-sepsis Group	P value	Sepsis Cases	Non-sepsis Controls	P value
	Cases (n = 56)	Controls (n = 43)	(2-tailed)	culture +ve (n = 19)	culture –ve (n = 24)	(2-tailed)
	Mean ± SD	Mean ± SD		Mean ± SD	Mean ± SD
	(Median, IRQ range)	(Median, IRQ range)		(Median, IRQ range)	(Median, IRQ range)
ACA PSV	72.75 ± 38.45	70.78 ± 34.06	0.792	71.20 ± 36.67	70.35 ± 37.64	0.981
	(69.00, 42.6–95.35)	(64, 50.70–94.60)		(69.70, 43.9–95.80)	(63.35, 40.50–94.60)
ACA EDV	31.26 ± 17.50	17.04 ± 8.49	<0.001	30.89 ± 17.61	18.64 ± 8.91	0.009
	(28.05, 18.80–37.75)	(14.05, 9.30–27.60)		(25.60, 17.00–38.90)	(18.70, 11.45–25.60)
ACA RI	0.57 ± 0.07	0.75 ± 0.07	<0.001	0.57 ± 0.07	0.73 ± 0.05	<0.001
	(0.56, 0.52–0.62)	(0.74, 0.70–0.81)		(0.55, 0.51–0.64)	(0.71, 0.69–0.76)
ACA PI	1.01 ± 0.29	1.59 ± 0.48	<0.001	0.91 ± 0.20	1.39 ± 0.29	<0.001
	(1.00, 0.77–1.14)	(1.42, 1.29–1.82)		(0.91, 0.74–1.07)	(1.33, 1.23–1.60)
MCA PSV	115.22 ± 45.42	101.82 ± 41.53	0.134	114.40 ± 41.68	102.83 ± 41.02	0.441
	(111.25, 78.05–133.40)	(99.70, 75.60–131.30)		(111.80, 72.20–137.30)	(98.15, 77.20–127.85)
MCA EDV	48.13 ± 26.57	22.66 ± 12.41	<0.001	47.81 ± 22.23	25.04 ± 13.02	<0.001
	(41.95, 29.95–59.60)	(22.30, 12.80–28.40)		(43.30, 31.90–61.30)	(22.85, 16.45–29.40)
MCA RI	0.58 ± 0.09	0.77 ± 0.73	<0.001	0.59 ± 0.07	0.76 ± 0.60	<0.001
	(0.59, 0.53–0.64)	(0.75, 0.72–0.82)		(0.54, 0.53–0.64)	(0.75, 0.71–0.80)
MCA PI	1.08 ± 0.30	1.68 ± 0.43	<0.001	1.01 ± 0.22	1.59 ± 0.29	<0.001
	(1.07, 0.86–1.25)	(1.60, 1.38–1.82)		(1.03, 0.85–1.13)	(1.59, 1.37–1.77)

ACA – Anterior cerebral artery, MCA – Middle cerebral artery, RI – Resistance index, PI – Pulsatility index, PSV – Peak systolic velocity. ^*Nonparametric independent t-test (Equal variances not assumed).

Table 3.2.

Comparison of cerebral blood flow velocity of anterior and middle cerebral arteries between the sepsis group (Case) and non-sepsis group (Control), according to the timing of conducting the duplex-pulsed Doppler ultrasound.

Parameters	Doppler before 48 hours of life			Doppler after 48 hours of life
	Sepsis cases'	Non-sepsis controls	P value	Sepsis Cases	Non-sepsis Controls	P value
	(n = 11)	(n = 12)	(2-tailed)	(n = 45)	(n = 31)	(2-tailed)
	Mean ± SD	Mean ± SD		Mean ± SD	Mean ± SD
	(Median, IRQ range)	(Median, IRQ range)		(Median, IRQ range)	(Median, IRQ range)
ACA PSV	75.45 ± 49.44	69.07 ± 41.30	0.902	72.09 ± 35.92	71.44 ± 31.57	0.870
	(51.00, 31.40–124.00)	(63.00, 35.75–90.75)		(69.40, 44.30–94.50)	(64.70, 52.20–95.50)
ACA EDV	35.00 ± 23.98	17.16 ± 9.71	0.039	30.34 ± 15.74	17.00 ± 8.14	<0.001
	(24.00, 16.20–60.00)	(15.50, 8.75–26.75)		(29.30, 19.60–36.60)	(14.50, 9.30–24.00)
ACA RI	0.53 ± 0.07	0.74 ± 0.06	<0.001	0.57 ± 0.07	0.75 ± 0.07	<0.001
	(0.52, 0.48–0.57)	(0.73, 0.70–0.77)		(0.57, 0.53–0.62)	(0.74, 0.70–0.82)
ACA PI	1.01 ± 0.49	1.59 ± 0.29	0.005	1.01 ± 0.23	1.58 ± 0.54	<0.001
	(0.78, 0.66–1.30)	(1.56, 1.36–1.82)		(1.00, 0.89–1.13)	(1.36, 1.28–1.81)
MCA PSV	123.58 ± 50.65	91.88 ± 35.58	0.124	113.17 ± 43.53	105.67 ± 43.53	0.650
	(129.50, 65.70–166.50)	(82.75, 61.80–126.15)		(110.70, 78.40–126.90)	(103.80, 76.10–137.40)
MCA EDV	58.14 ± 29.51	21.58 ± 11.57	<0.001	45.69 ± 25.20	23.08 ± 12.88	<0.001
	(47.90, 36.90–67.80)	(21.25, 12.75–28.40)		(39.20, 29.00–52.10)	(22.80, 12.80–27.10)
MCA RI	0.54 ± 0.08	0.77 ± 0.67	<0.001	0.59 ± 0.09	0.77 ± 0.08	<0.001
	(0.57, 0.46–0.59)	(0.79, 0.73–0.82)		(0.61, 0.54–0.64)	(0.75, 0.72–0.84)
MCA PI	1.03 ± 0.43	1.59 ± 0.30	0.007	1.08 ± 0.27	1.72 ± 0.47	<0.001
	(0.88, 0.77–1.22)	(1.62, 1.41–1.81)		(1.08, 0.90–1.25)	(1.60, 1.38–1.90)

Correlations between different parameters of CBF Velocity of the ACA and MCA are shown in Table 4.

Table 4.

Correlation^* between different parameters of Cerebral Blood Flow Velocity.

	ACA PSV	ACA EDV	ACA RI	ACA PI	MCA PSV	MCA EDV	MCA RI	MCA PI
ACA PSV	1	.779^**	0.122	0.094	.568^**	.324^**	–0.026	–0.028
ACA EDV	.779^**	1	–.461^**	–.404^**	.529^**	.688^**	–.533^**	–.460^**
ACA RI	0.122	–.461^**	1	.800^**	–0.103	–.665^**	.890^**	.712^**
ACA PI	0.094	–.404^**	.800^**	1	–0.129	–.565^**	.720^**	.792^**
MCA PSV	.568^**	.529^**	–0.103	–0.129	1	.636^**	–0.154	–0.118
MCA EDV	.324^**	.688^**	–.665^**	–.565^**	.636^**	1	–.739^**	–.544^**
MCA RI	–0.026	–.533^**	.890^**	.720^**	–0.154	–.739^**	1	.780^**
MCA PI	–0.028	–.460^**	.712^**	.792^**	–0.118	–.544^**	.780^**	1

ACA –Anterior cerebral artery, MCA – Middle cerebral artery, RI – Resistance index, PI – Pulsatility index. ^*Spearman’s rho-Test. ^**Correlation is significant at the 0.01 level- (2-tailed).

The predictive accuracy of RI, PI, and EDV parameters of ACA and MCA is shown in Table 5 (PSV parameters are not included, since there was no statistically significant difference between the case and control groups).

Table 5.

Predictive accuracy of different blood flow velocity parameters.

Parameter	AUC	Cut-Off	Sensitivity	Specificity	PPV	NPV	Diagnostic Accuracy	(LR+)	(LR–)
			(%)	(%)	(%)	(%)	(%)
ACA EDV	0.776	≥20.05^†	71.43	69.77	75.47	65.22	70.71	0.95	2.36
ACA RI	0.989	≤0.67^#	94.55	90.91	92.86	93.02	92.53	0.08	13.27
ACA PI	0.895	≤1.28^#	87.5	81.40	85.97	83.33	84.35	0.15	4.70
MCA EDV	0.850	≥27.75^†	82.14	74.42	80.70	76.19	78.32	0.24	3.21
MCA RI	0.976	≤0.67^#	89.29	97.67	98.04	87.5	92.42	0.11	38.83
MCA PI	0.897	≤1.30^#	82.14	88.37	90.20	79.17	84.38	0.20	7.08

ACA – Anterior cerebral artery, MCA – Middle cerebral artery, RI – Resistance index, PI – Pulsatility index. AUC – Area under the curve (AUC), PPV – Positive Predictive Value, NPV – Negative Predictive Value, LR+ – Positive Likelihood Ratio, LR- – Negative Likelihood Ratio. ^†Larger test result indicates a more positive test. ^#Smaller test result indicates a more positive test.

Among the various parameters measured the diagnostic accuracy of the Cut-Off points was highest for RI in both ACA (92.5%) and MCA (92.4%), followed by PI in both ACA (84.4%) and MCA (84.4%). It was the least for EDV in ACA (70.7%) and MCA(78.3%).

The sensitivity of the RI of the ACA and MCA was 94.6% and 89.3% respectively. The sensitivity of the PI of the ACA and MCA were 87.5% and 82.1% respectively. The sensitivity of the EDV of the ACA and MCA were 71.4% and 82.1% respectively.

The specificity of the RI of the ACA and MCA were 90.9% and 97.7% respectively. The specificity of the PI of the ACA and MCA were 81.4% and 88.4% respectively. The specificity of the EDV of the ACA and MCA were 69.38% and 74.4% respectively.

The positive likelihood ratio was highest for MCA RI (38.83) and ACA RI (13.27). The negative likelihood ratio was highest for ACA RI (0.08) and MCA RI (0.11).

Discussion

Cerebral blood flow velocity is a measure of the speed at which blood is flowing through the brain. It plays a crucial role in maintaining normal brain function. Monitoring cerebral blood flow velocity can provide valuable insights into the state of cerebral perfusion. [19] Several studies have suggested that alterations in cerebral blood flow velocity may be associated with sepsis [20, 21]. In this study, we explored the diagnostic value of the cerebral blood flow velocity in early-onset neonatal sepsis. A highly significant lower resistance (PI and RI), relatively higher peak systolic velocity, and higher end-diastolic velocity in both ACA and MCA within 72 hours of birth in neonates with EONS compared to the control group of neonates without sepsis.

This indicates a generalized increase in cerebral blood flow with a decrease in blood flow resistance as an early response to sepsis. These results support the findings reported by other studies [13 , 16, 22–25].

These hemodynamic alterations in cerebral blood flow might be explained that the inflammation of the placenta which results in EONS, is expected to impair the placenta’s ability to deliver oxygen to the fetus. As a result, fetuses respond to placental insufficiency by reducing the resistance in the arteries supplying these vital organs, including the brain, which accounts for the hemodynamic alterations seen in the increase in cerebral blood flow in neonates with EONS [26].

PSV in both ACA and MCA in neonates with EONS was found to be higher in the EONS group compared to the control group in our study, however, the differences were not statistically significant, a finding which was also reported in some other studies [13, 15].

Contradictory findings to the results of this study, and other studies with similar findings [13 , 16, 22–25], reported decreased CBFV along with higher PI in patients with sepsis [15 , 17, 28]. This reduction of CBF might be explained by the vasoconstriction of the resistance arterioles [27] and suggesting cerebral edema or venous congestion. It is believed that cytokines and interleukins produced during the sepsis cascade alter the activity of the endothelial nitric oxide synthase leading to the impairment of the microcirculation of the brain [29].

The receiver-operating-characteristic analysis of various studies revealed differences in the measurements of the ACA and MCA among neonates with and without EONS, and the ideal cut-off point for diagnoses. This could be attributed to the time of performance of the Doppler measurements and the number of culture positive cases, which differed in all the studies [24, 25].

Basu et al. [22] in their follow-up study documented an increase in the CBF before the clinical appearance of the frank features of sepsis which means that the inflammatory process first affected the cerebral circulation before it could affect any other body system, and pointed to the role of Transcranial Doppler in the assessment of EONS that can be used as an early marker of systemic inflammatory response syndrome (SIRS) and to identify the neonates who are going to develop EONS.

Among all the parameters studied in our study, sensitivity, specificity, and diagnostic accuracy for RI in both ACA and MCA were the highest, while, the parameters for PI were second and the lowest diagnostic accuracy was for EDV. These parameters were comparable to the results of other studies which also showed a higher performance of RI and PI indices in predicting sepsis [16 , 22 , 30, 31].

Our study is not free of limitations. One limitation is the single-time assessment of CBFV therefore could not assess the fluctuation of CBFV over time and link it with the short-term [22 , 32, 33] and long-run adverse consequences [34]. The inevitable associated morbidity among neonates in ICU, the perceived hemodynamic alterations could be partly related to the associated comorbidities. However, both groups of neonates with sepsis and other control groups were rigorously matched regarding the associated risk factors and potential confounders.

Selection of the EONS subjects in our study was based on confirming at least two criteria related to risk factors for sepsis, and/or clinical presentation, and/or lab abnormality.

To match the gold standard for the diagnosis of neonatal sepsis, it would be of value to limit the selection of subjects to culture-proven cases and controls to further confirm our study results.

Conclusion

Our research demonstrates that cerebral hemodynamics in neonates with EONS is altered with an increase in the CBF and a decrease in the resistance. Doppler ultrasonography examination can be utilized to evaluate CBF in the first few hours of birth and be used as a highly predictive bedside, noninvasive investigation with immediate diagnostic significance. It also permits the simultaneous assessment of cranial structures and the determination of absolute CBFV, with the added advantage of repeated and serial testing.

Footnotes

Acknowledgments

We thank the parents/caregivers of the neonates included in the study for their agreement, and patience in examining their neonates, and for allowing the time for the interview with them.

Financial support and sponsorship

Nil.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) parents/guardian has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity.

Conflicts of interest

There are no conflicts of interest.

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