Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect?

Abstract

BackgroundBreathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.Design/MethodsAfter the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37°C, HT35°C, HT32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.ResultsImmediate HT32°C (p = 0.042), but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.ConclusionsCombining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.

Timing still key to treating hypoxic ischaemic brain injury

“…The eff ect of delay in treatment with xenon in small animals is variable. A study showed an additive benefi t only with immediate but not delayed treatment, 9 whereas in other studies benefi t was noted when treatment was delayed by as much as 4-6 h after hypoxia-ischaemia. 5 Thus, preclinical evidence strongly suggests that xenon needs to be started soon after resuscitation to allow neuroprotection, and defi nitely within 6 h. Although Azzopardi and colleagues reported no apparent eff ects related to timing of treatment with xenon, only seven (15%) of 46 infants started xenon before 6 h of age.…”

Inhaled Gases for Neuroprotection of Neonates: A Review

“…A combined therapy of xenon and hypothermia was found to decrease infarct volume and improved short and long-term functional testing compared to each treatment alone (11,12). However, a recent study with a larger sample size by the same group failed to replicate the results and did not show a synergistic effect (55). In another study, neonatal rats received xenon combined with hypothermia after undergoing hypoxia for 150 min due to common carotid ligation.…”

Neurologic and cognitive outcomes associated with the clinical use of xenon: a systematic review and meta-analysis of randomized-controlled trials

“…It is quite surprising that in the RCTs xenon exposure conferred no added benefit to therapeutic hypothermia in asphyxiated neonates and cardiac arrest patients given the encouraging pre-clinical animal data. [10][11][12][13][14]17,61,62 We postulate that the RCTs may not have been sufficiently powered. In the study by Azzopardi et al, 35 only 92 of 138 intended subjects were recruited.…”

“…Xenon is a noble gas with potential benefits when used for general anesthesia. 1,2 Neurologic and cognitive outcomes associated with xenon administration have been tested in various pre-clinical in vitro and in vivo models 3,4 (Table 1) concerned with neurotoxicity, [3][4][5][6][7][8][9] neonatal asphyxia, [10][11][12][13][14] cardiac arrest, [15][16][17] and ischemic [18][19][20][21][22][23] and traumatic [24][25][26] brain injury. Most of the pre-clinical investigations showed positive central nervous system (CNS)-related outcomes.…”

“…For instance, xenon has been shown to prevent isofluraneinduced neurotoxicity and neuroapoptosis in rats. 4,5,9 Xenon has also been shown to improve outcomes following neonatal asphyxia [10][11][12][13][14] and cardiac arrest 17 when combined with conventional therapeutic hypothermia in rodent and porcine models.…”