The state of systemic circulation, collapsed or preserved defines the need for hyperoxic or normoxic resuscitation in neonatal mice with hypoxia-ischemia

Abstract

Background: The return of spontaneous circulation (ROSC) is a primary goal of resuscitation. For neonatal resuscitation the International Liaison Committee on Resuscitation (ILCOR) recommends oxygen concentrations ranging from 21% to 100%.

Aims and methods: This study (a) compared the efficacy of resuscitation with room air (RA) or 100% O(2) in achieving ROSC in 46 neonatal mice with circulatory collapse induced by lethal hypoxia-ischemia (HI) and (b) determined whether re-oxygenation with RA or 100% O(2) alters the extent of HI cerebral injury in mice with preserved systemic circulation (n=31). We also compared changes in generation of reactive oxygen species (ROS) in cerebral mitochondria in response to re-oxygenation with RA or 100% O(2).

Result: In HI-mice with collapsed circulation re-oxygenation with 100% O(2) versus RA resulted in significantly greater rate of ROSC. In HI-mice with preserved systemic circulation and regional (unilateral) cerebral ischemia the restoration of cerebral blood flow was significantly faster upon re-oxygenation with 100% O(2), than RA. However, no difference in the extent of brain injury was detected. Regardless of the mode of re-oxygenation, reperfusion in these mice was associated with markedly accelerated ROS production in brain mitochondria.

Conclusion: In murine HI associated with circulatory collapse the resuscitation limited to re-oxygenation with 100% O(2) is superior to the use of RA in achievement of the ROSC. However, in HI-mice with preserved systemic circulation hyperoxic re-oxygenation has no benefit over the normoxic brain recovery.

Fig. 1

A, representative tracing of changes in the ipsilateral (I) and contralateral (C) hemispheres and peripheral (P) blood flows in response to lethal HI and re-oxygenation with 100% O₂. Reproduced with permission: Ten V and Matsiukevich D Current Opinion in Pediatrics 2009. B, CBF in the ipsilateral hemisphere during HI and re-oxygenation with RA or 100% O₂ with time-points (arrows) of assessment of mitochondrial ROS emission rates. C, CBF (C contra and I ipsilateral hemispheres) and PBF (P) tracing during ligation of the right carotid artery and 90 minutes of recovery.

Fig. 2

A, PBF tracing during lethal HI and resuscitation in mice resuscitated with RA (closed dots, n = 21) and 100% O₂ (open dots, n = 22). B, duration of hypoxia which induced circulatory collapse in mice re-oxygenated with RA (black bar, n = 23) or 100% O₂ (striped bar, n = 23). C, Changes in CBF and PBF during HI limited to 20 minutes and re-oxygenation with RA (closed dots, n = 16) or 100% O₂ (open dots, n = 15). Squared are values significantly different compared to pre-hypoxic level (p < 0.01). * p < 0.05 compared to that recorded at the end of HI. D, TTC stained cerebral sections and infarct volume in HI-mice (group 2) re-oxygenated with RA (black bar, n = 16) or 100% O₂ (striped bar, n = 15).

Fig. 3

A, tracing of H₂O₂ fluorescence in mitochondria (Mito) isolated from the ipsilateral hemisphere in naïve, and HI-mice at 0 and 5 minutes of reperfusion. Arrows indicate rotenone (Rot) supplementation. B, C and D, H₂O₂ emission rates [B is total rate, C is rotenone-inhibited rate and D is C-I dependent rate (see methods)] from mitochondria isolated from naïve (open bar, n = 6), HI-mice at the 0 minutes of reperfusion (dotted bar, n = 6), re-oxygenated with 100% O₂ (black bar, n = 6) and RA (striped bar, n = 6). * p ≤ 0.03 compared to naives, # p < 0.0001 (in Fig. 3C p ≤ 0.02) compared to that prior to reperfusion. All data are mean ± SEM.