MRI and Withdrawal of Life Support From Newborn Infants With Hypoxic-Ischemic Encephalopathy

Abstract

The majority of deaths in infants with hypoxic-ischemic encephalopathy (HIE) follow decisions to withdraw life-sustaining treatment. Clinicians use prognostic tests including MRI to help determine prognosis and decide whether to consider treatment withdrawal. A recently published meta-analysis provided valuable information on the prognostic utility of magnetic resonance (MR) biomarkers in HIE and suggested, in particular, that proton MR spectroscopy is the most accurate predictor of neurodevelopmental outcome. How should this evidence influence treatment-limitation decisions? In this article I outline serious limitations in existing prognostic studies of HIE, including small sample size, selection bias, vague and overly inclusive outcome assessment, and potential self-fulfilling prophecies. Such limitations make it difficult to answer the most important prognostic question. Reanalysis of published data reveals that severe abnormalities on conventional MRI in the first week have a sensitivity of 71% (95% confidence interval: 59%-91%) and specificity of 84% (95% confidence interval: 68%-93%) for very adverse outcome in infants with moderate encephalopathy. On current evidence, MR biomarkers alone are not sufficiently accurate to direct treatment-limitation decisions. Although there may be a role for using MRI or MR spectroscopy in combination with other prognostic markers to identify infants with very adverse outcome, it is not possible from meta-analysis to define this group clearly. There is an urgent need for improved prognostic research into HIE. Pediatrics 2010;126:e451-e458Hypoxic-ischemic encephalopathy (HIE) is a major contributor to global child mortality and morbidity. 1 Although therapeutic hypothermia has recently emerged as a means of neuroprotection for infants with HIE, many infants still have an adverse outcome. Almost 50% of infants enrolled in recent trials and treated with hypothermia either died or were found to have severe disability at the 18-month follow-up. 2,3 In developed countries the majority of deaths of infants with HIE follow decisions to withdraw life-sustaining treatment. 4,5 Two-thirds of the deaths in the recent cooling trials followed treatment withdrawal. 3,6 One important factor that clinicians use in making such decisions is the severity of encephalopathy. In particular, infants with severe (Sarnat stage 3) 7 encephalopathy are generally believed to have a uniformly dire prognosis. 8,9 However, prognostication in infants with moderate encephalopathy is more difficult. 9-11 A variety of clinical, electrophysiological, and radiologic tools have been used to help prognosticate. 9 In particular, MRI has emerged as potentially one of the most useful tools for prognostication in HIE, 8,[12][13][14]

A failed attempt to conduct an individual patient data meta-analysis

“…In their meta-analysis, Thayyil and coworkers found that deep gray matter magnetic resonance biomarkers (especially measuring lactate/acetyl aspartate ratio) have good accuracy for predicting adverse outcome in neonatal encephalopathy [3]. Professor Wilkinson appropriately criticized this meta-analysis and suggested to perform an individual patient data meta-analysis [4], a challenge we accepted. The study protocol was published last year in Systematic Reviews [5].…”

Neonatal ischemic brain injury: what every radiologist needs to know

“…Real-time assessment of DWI and GRE images is useful to analyze the injury pattern and add additional sequences such as MRA, MRV and MR spectroscopy to a b c d MRI plays an important role in assessing response to therapeutic hypothermia and other treatment options [34]. MR imaging can also identify factors predicting poor patient outcome such as larger size of infarcts, involvement of critical areas, absolute decrease in NAA values in basal ganglia, low apparent diffusion coefficients in the non-infarcted brain and abnormal DWI signal in the corticospinal tracts [23,[35][36][37][38][39] withdrawal of life support and can be used as a patient selection tool for advanced treatment options like stem cell therapy [40,41].…”

Magnetic resonance spectroscopy as a prognostic marker in neonatal hypoxic-ischemic encephalopathy: a study protocol for an individual patient data meta-analysis

“…The suggestion that Lac/NAA might support early clinical decisions was criticized for several reasons [4]. Although based on available studies, the validity of the meta-analysis and the generalizability of the results were questioned [4].…”

“…Although based on available studies, the validity of the meta-analysis and the generalizability of the results were questioned [4]. It was suggested that the spectrum of the included patients was too broad, including very mildly (Sarnat 1) and very severely (Sarnat 3) affected patients; unclear selection criteria could undermine generalizability.…”

“…Concern was also expressed with respect to the post-hoc choice of ‘cut-off values’. Wilkinson [4] concluded: ‘It is not possible from published data to assess the usefulness of quantitative markers such as lactate/NAA peak/area ratio for predicting very adverse outcome […] or to look separately at its usefulness for infants with moderate encephalopathy’.…”