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Hypothermia is Neuroprotective in Severe Hypoxic-Ischaemic Injury, with Infection as Co-morbidity

Mari Falck 1 Damjan Osredkar 1,2 Elke Maes 1 Torun Flatebo 1 Thomas Wood 1 Hemmen Sabir 1,3 Marianne Thoresen 1,4
1Department of Physiology, University of Oslo, Institute of Basic Medical Sciences
2Department of Paediatric Neurology, University Children’s Hospital
3Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine University
4School of Clinical Sciences, University of Bristol

Background: Perinatal infections increase the neonatal brain’s vulnerability to hypoxic-ischemic (HI) injury. Systemic inflammation induced through TLR-4 (LPS), negates hypothermic neuroprotection in a model of moderate brain injury.1 We recently showed that after inflammatory pre-sensitisation induced through TLR-2, mimicking a Gram-positive infection, therapeutic hypothermia (TH) provided 80% neuroprotection.2 HT has been shown not to be effective in severe brain injury3, still we treat babies with severe neurological dysfunction with HT. Whether HT is neuroprotective in severe brain injury with inflammatory pre-sensitisation is unknown.

Objective: To examine the effect of TH after severe unilateral neonatal brain injury, with inflammatory pre-sensitisation with a TLR2 agonist (PAM3CSK4).

Methods: 196 seven-day-old (P7) Wistar rats received 0.9% NaCl (Veh) or PAM3CSK4 (1 mg/kg), intraperitoneally. After an 8-hour delay, the left carotid artery was ligated followed by hypoxia8%O2. Pups were randomized to 5h of normothermia37°C or TH32°C after the insult. Hemispheric (He) and hippocampal (Hi) area loss analyses was performed at P14.

Results: Normothermic PAM3CSK4-animals (PAM-NT) had similar median area loss (He: 60% (33-66); Hi: 61% (29-67) as Veh-animals (Veh-NT) (He: 58% (11-64); Hi: 60% (19-68)), defined as severe brain injury. TH significantly reduced hemispheric injury in control groups (p=0.048) and in PAM3CSK4-animals (p=0.03) (Fig 1). Hypothermia was also neuroprotective at the hippocampal level (Veh-HT vs Veh-NT: p=0.042; PAM-HT vs PAM-NT: p=0.027) (Fig 2).

Conclusion: In this double hit model of severe brain injury with inflammatory pre-sensitisation through TLR-2, TH significantly reduced injury in PAM3CSK4-animals and in Veh-animals. These findings indicates that the question of hypothermic neuroprotection in case of severe injury is not finally determined, and furthermore, that a gram-positive infection would not negate the therapeutic effect of HT at any degree of brain injury.

  1. Osredkar, D. et al. Resuscitation 85, 567–572 (2014)
  2. Falck, M. et al. http://www.abstracts2view.com/pas/view.php?nu=PAS16L1_4615.4 (2016)
  3. Sabir, H. et al., Stroke 43, 364-370 (2012)

    Fig 1 Hemispheric (1) and hippocampal (2) area loss after severe HI brain injury
Mari Falck
Mari Falck
UIO








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