Long-term outcome after hypothermia-treated hypoxic-ischaemic encephalopathy

Abstract

Hypoxic-ischaemic encephalopathy (HIE) is a major cause of acquired brain injury in newborn infants. It is a potentially life-threatening condition that leaves survivors at substantial risk of life-long debilitating sequelae including cerebral palsy, epilepsy, intellectual disability, sensory disruption, behavioural issues, executive difficulties and autism spectrum disorder. More subtle cognitive impairments are common among survivors free of major neuromotor disability. Therapeutic hypothermia (TH) reduces the risk of death and disability in nearterm/term new-born infants with moderate and severe HIE. Outcomes in adolescence and adulthood following HIE treated with TH are not yet known.

The majority of infants with HIE also suffer multi-organ dysfunction resulting from the hypoxic-ischaemic insult. The kidneys are particularly sensitive to hypoxia-ischaemia, with up to 72% of asphyxiated infants suffering acute kidney injury (AKI) prior to the advent of TH. Evidence point to AKI being independently associated with increased neonatal morbidity and mortality. To date, very little is known about long-term renal consequences following neonatal AKI in asphyxiated infants treated with TH. The overall aim of this thesis was to contribute to the improved treatment and care of infants with HIE by means of increased knowledge about the predictive value of early aEEG, neonatal AKI, and long-term outcomes in the era of TH.

In a small population-based cohort, the predictive value of early amplitude-integrated EEG (aEEG) was demonstrated to be altered in infants treated with TH due to HIE. Poor outcome at the age of 1 year was only seen among infants with a persisting abnormal aEEG background pattern at and beyond 24 hours of age.

In a population-based, prospective, longitudinal study including all children treated with TH between 2007 and 2009 in Stockholm, Sweden, we assessed neuromotor, neurologic, cognitive and behavioural outcomes at 6-8 and 10-12 years of age. Seventeen per cent of survivors developed CP. Survivors free of major neuromotor impairment had cognitive abilities within normal range. Repeated assessment in early adolescence revealed new deficits in 26% of children with previously favourable outcome. The proportion of children with executive difficulties in this patient population appears to be higher than in the general population. Outcomes in children with a history of moderate HIE remain heterogenous also in the era of TH.

In a population-based cohort of all children treated with TH between 2007 and 2009 in Stockholm, Sweden, 45% suffered neonatal AKI. Severe AKI necessitating kidney support therapy was rare. Among infants with AKI, 20% fulfilled only the urinary output criterion of the neonatal modified KDIGO (Kidney Disease Improving Global Outcomes) definition. Mortality was higher among infants with AKI. At 10-12 years of age, 21% of children had decreased glomerular filtration rate (GFR) estimated from creatinine with the Schwartz-Lyon equation.

A more in-depth assessment of renal functions in the above-mentioned population-based cohort demonstrated that renal sequelae (defined as decreased GFR, albuminuria, hypertension or normal high blood pressure, reduced renal volume on magnetic resonance imaging, or elevated Fibroblast Growth Factor 23) were rare at 10-12 years of age following perinatal asphyxia and TH. The Schwarz-Lyon equation appears to underestimate GFR in this patient population.