Resistive index (RI), calculated from the cerebral arteries by cranial doppler ultrasonography, reflects cerebral hemodynamic changes in asphyxia, and has been evaluated as a bedside marker of risk of subsequent neurodevelopmental impairment in HIE [6]. Studies from high income countries have found decreased cerebral RI to differentiate asphyxiated neonates from healthy controls and to reasonably predict the risk of subsequent neurodevelopmental impairment [7-10]. There is paucity of data on the prognostic role of RI in low- and middle-income countries. This study was designed to evaluate the role of abnormal RI measured from anterior cerebral artery in predicting adverse neurodevelopmental outcomes among term neonates with HIE.

The primary outcome of the study was the risk of mortality and/or abnormal neurodevelopmental outcomes assessed between 6-12 months age. Death was defined as all-cause mortality occurring before 12 months of age or last follow up. Abnormal neurodevelopment was considered as either abnormal tone (assessed using Amiel-Tison’s method), or ‘suspect’ report on Denver Developmental Screening Test II (DDST II) performed by a trained developmental pediatrician blinded to the initial values of RI. Secondary outcomes were to evaluate the association of abnormal RI with short term morbidities such as death before discharge, neonatal seizures, shock, respiratory failure and abnormal electroencephalogram (EEG).

A RI between 0.56 and 0.80 was considered normal [8,13] and neonates were classified as having either normal or abnormal RI.

Based on the assumption that 20% and 70% neonates were likely to die or develop abnormal neurodevelop-mental outcomes in the normal and abnormal RI groups, respectively [9], with 80% power and 5% alpha error, 19 neonates were needed in each group. Assuming 20% attrition during follow-up, it was decided to enrol 25 neonates in each group. The primary outcome was evaluated using chi-square test. Continuous variables were compared using either Student’s t test or Mann Whitney U test. Institutional ethics committee approved the study. Data was analyzed using SPSS version 15.0 and P value <0.05 was considered statistically significant.

Among 82 term neonates admitted with HIE during the study period, 50 were included (Fig. 1). Neonates with normal RI (n=25) were comparable to those with abnormal RI (n=25) (Table I). Presence of an abnormal RI was associated with a significantly higher risk of death/ abnormal neurodevelopmental outcome at 6-12 months (75% (15/20) vs. 10% (2/20); RR (95% CI) = 7.5 (2.0, 8.6), P<0.01). An abnormal RI was also associated with 2.5 times higher risk of death or abnormal neurological examination before discharge (60% vs. 24%; RR (95% CI) = 2.5 (1.2,5.4), P=0.01), neonatal seizures as well as abnormal neurosonogram and EEG (Table II).

TABLE I Baseline Characteristics of Enrolled Population

*growth <10th centile for gestational age as per Fenton’s charts [15].

TABLE II Association of Resistive Index with Morbidity

Fig. 1 Study flow.

The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio of abnormal RI to detect the composite outcome of death or abnormal neurological outcome was 88%, 78%, 75%, 90% and 4.06, respectively.

In the present study, we observed that having an abnormal RI within 72 hours increased the risk of death or abnormal neurodevelopment at 6-12 months among term neonates with HIE. Short term morbidities such as abnormal neurological examination at discharge, seizures, abnormal neurosonogram and EEG were also higher among neonates with abnormal RI, although the study was not powered to determine these outcomes.

Loss of cerebral autoregulation in HIE can predispose to reduced/absent diastolic blood flow in cerebral arteries leading to increased RI (>0.80) or elevated diastolic flow due to arterial vasodilation resulting in reduced RI [10,14]. Decreased RI has been well documented in asphyxia and found to increase the risk of death or cerebral palsy by 23.4 times [7,8]. The negative predictive value (NPV) of RI was 90%, implying that finding a normal RI (0.56-0.80) within the first 72 hours in a neonate with HIE conferred 90% probability that the neonate will be subsequently normal. This was higher than the NPV of decreased RI in the study by Jongeling, et al. [8].

RI within 24 hours of age, could not be obtained. We acknowledge that formal developmental assessment such as Bayley Scales of Infant Development II (BSID-II) was desirable for identifying abnormal neurodevelopment.

Considering the modest prognostic potential of RI in neonates with HIE, it is desirable that neonatologists get familiar with the optimal usage of this imaging modality, especially in settings lacking sophisticated neuroimaging techniques. We need more studies evaluating the impact of neuroprotective strategies, especially therapeutic hypothermia on RI and its diagnostic accuracy.

Contributors: SK: designed the study protocol, recruited the participants, performed doppler ultrasonography, and drafted the initial manuscript; AC: supervised data collection, analyzed the data and revised the manuscript; RA: helped in designing the study, data collection, and critically reviewed the final manuscript; KG: study supervision and manuscript review. All authors approved the final manuscript

Funding: None; Competing interest: None stated.

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