Association between brain tissue pH and brain injury during asphyxia in piglets

Bender, Thomas M.; Johnston, John; Manepalli, Anantha N.; Mink, Richard

doi:10.1016/s0300-9572(03)00207-7

Cited by 9 publications

(18 citation statements)

References 36 publications

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“…However, changes in pH i may not truthfully reflect pH brain alterations as transmembrane pH gradients are subject to change during HIE development, and furthermore, intracellular and extracellular pH have different targets via which they may change brain activity and energy consumption [15]. There are very limited data on pH brain changes elicited by PA/HIE from piglets [16], and these studies did not follow the course of pH brain beyond 4 hours after the completion of the hypoxic-ischemic stress. We now report quantitative cerebrocortical pH brain data in our well-characterized piglet PA/HIE model both during the PA and the first 24 hours of HIE development.…”

Section: Introductionmentioning

confidence: 99%

Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs

et al. 2020

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Brain interstitial pH (pH brain ) alterations play an important role in the mechanisms of neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia. The newborn pig is an established large animal model to study HIE, however, only limited information on pH brain alterations is available in this species and it is restricted to experimental perinatal asphyxia (PA) and the immediate reventilation. Therefore, we sought to determine pH brain over the first 24h of HIE development in piglets. Anaesthetized, ventilated newborn pigs (n = 16) were instrumented to control major physiological parameters. pH brain was determined in the parietal cortex using a pH-selective microelectrode. PA was induced by ventilation with a gas mixture containing 6%O 2 -20%CO 2 for 20 min, followed by reventilation with air for 24h, then the brains were processed for histopathology assessment. The core temperature was maintained unchanged during PA (38.4±0.1 vs 38.3±0.1˚C, at baseline versus the end of PA, respectively; mean±SEM). In the arterial blood, PA resulted in severe hypoxia (P a O 2 : 65±4 vs 23±1*mmHg, *p<0.05) as well as acidosis (pH a : 7.53 ±0.03 vs 6.79±0.02*) that is consistent with the observed hypercapnia (P a CO 2 : 37±3 vs 160 ±6*mmHg) and lactacidemia (1.6±0.3 vs 10.3±0.7*mmol/L). Meanwhile, pH brain decreased progressively from 7.21±0.03 to 5.94±0.11*. Reventilation restored pH a , blood gases and metabolites within 4 hours except for P a CO 2 that remained slightly elevated. pH brain returned to 7.0 in 29.4±5.5 min and then recovered to its baseline level without showing secondary alterations during the 24 h observation period. Neuropathological assessment also confirmed neuronal injury. In conclusion, in spite of the severe acidosis and alterations in blood gases during experimental PA, pH brain recovered rapidly and notably, there was no postasphyxia hypocapnia that is commonly observed in many HIE babies. Thus, the neuronal injury in our piglet model is not associated with abnormal pH brain or low P a CO 2 over the first 24 h after PA.

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Section: Introductionmentioning

confidence: 99%

Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs

et al. 2020

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“…The severe acidosis of the brain that takes place during asphyxia shows a prompt recovery to the alkaline direction after the end of the exposure (see Bender et al, 2003;Pospelov et al, 2020 and Fig. 5).…”

Section: Behavioral Seizures Emerge Following Intermittent Asphyxia mentioning

confidence: 96%

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Ala-Kurikka

Pospelov

Summanen

et al. 2020

Preprint

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Birth asphyxia (BA) is a pathologic condition that arises from severe perinatal hypoxia and hypercapnia.Recovery following BA is often associated with seizures which may exacerbate the ensuing hypoxicischemic encephalopathy (HIE). Drugs used to treat post-BA seizures are often ineffective and there are concerns over their safety. Therefore, novel seizure-suppressing therapies are urgently needed. Most rodent models of BA-induced seizures are based on exposing neonatal rats or mice to hypoxia (or hypoxiaischemia), and overlook the fact that the hypercapnic acidosis linked to asphyxia has brain-sparing effects by suppressing neuronal excitability and enhancing cerebral blood flow. Thus, the aim of the present study was to investigate the dependence of asphyxia-induced seizures on brain pH and oxygen (Po 2 ) levels in a rodent model of term BA based on postnatal day 11-12 rat pups. Cortical activity and electrographic seizures were recorded in freely-behaving animals using epidural electrodes. Simultaneous measurements of cortical local field potentials as well as intracortical pH and Po 2 were made using microelectrodes and microsensors in urethane-anesthesized animals. The pups were exposed either to steady asphyxia (duration 15 min; with ambient air containing 5 % O 2 plus 20 % CO 2 ) or to intermittent asphyxia (30 min; with repetitive 5 min steps from 9 % to 5 % O 2 at constant 20 % CO 2 ). Both protocols led to acidemia (blood pH <7.0) coupled to a fall in base excess by 20 mmol/l, and to a large increase in plasma copeptin (from 0.2 nM to about 5 nM), a biomarker of BA. Brain pH decreased from 7.3 to 6.7 by the end of intermittent asphyxia.Brain Po 2 was only transiently affected by 9% ambient O 2 , but it fell below the level of detection with steps to 5 % O 2 , during which neuronal activity was near-abolished. The Po 2 steps to 9% were associated with a moderate increase in pH (0.12 units) and a slight recovery (~10 % of baseline) in ongoing neuronal activity.Behavioral seizures spanning the entire Racine scale were triggered after intermittent but not steady asphyxia, and they were tightly associated with neocortical electrographic seizures. The seizures were strongly suppressed when the post-asphyxia brain pH recovery was slowed down by a low level (5 %) of ambient CO 2 . The post-asphyxia overshoot in brain Po 2 (from 30 to 85 mmHg) had no discernible effect on neuronal activity. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures once the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one where, consistent with the clinical picture of BA, robust behavioral and electrographic seizures are triggered after and not during the asphyxic insult. HIGHLIGHTS Experimental asphyxia induced severe acidemia and abolished most cortical activity. Cortical activity during asphyxia was closely linked with changes in brai...

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“…However, quantitative data on pH brain changes during/after PA in large animal models are very scarce in the literature, thus, our current observations provide important new information to the pathophysiology of HIE in piglets. We are aware of only one previous study [199] that assessed pH brain with similar technique after PA in piglets. In this study, Bender et al induced 30 min PA with a hypoxic-hypercapnic gas mixture (5-8% O 2 -7% CO 2 ) [199], at the end of PA the reported pH brain was 6.26±0.14, almost half pH unit higher than in our study likely at least in part due to the much lower P a CO 2 values (61±1 vs. 160±23 mmHg, [199] vs. present study, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…We are aware of only one previous study [199] that assessed pH brain with similar technique after PA in piglets. In this study, Bender et al induced 30 min PA with a hypoxic-hypercapnic gas mixture (5-8% O 2 -7% CO 2 ) [199], at the end of PA the reported pH brain was 6.26±0.14, almost half pH unit higher than in our study likely at least in part due to the much lower P a CO 2 values (61±1 vs. 160±23 mmHg, [199] vs. present study, respectively). In addition, the previous study did not follow up on pH brain changes beyond 4-hour survival, in contrast, our current measurements extended the observation period considerably, to 24 hours of survival.…”

Section: Discussionmentioning

confidence: 99%

Molecular hydrogen affords neuroprotection in a new translational piglet model of hypoxic-ischemic encephalopathy

Németh

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Hypoxic-ischemic encephalopathy (HIE) is the major consequence of perinatal asphyxia (PA) in term neonates. Although the newborn piglet is an accepted large animal PA/HIE model, there is no consensus on PA-induction methodology to produce clinically relevant HIE. We aimed to create and to characterize a novel PA model faithfully reproducing all features of asphyxiation including severe hypercapnia resulting in HIE, and to test whether H 2 is neuroprotective in this model. Piglets were anaesthetised, artificially ventilated, and intensively monitored (electroencephalography, core temperature, O 2 saturation, arterial blood pressure and blood gases). Asphyxia (20 min) was induced by ventilation with a hypoxic-hypercapnic (6%O 2 -20%CO 2 ) gas mixture. Asphyxia-induced changes in the cortical microcirculation were assessed with laser-speckle contrast imaging and analysis. Asphyxia was followed by reventilation with air or air containing hydrogen (2.1%H 2 , 4 hours). After 24 hours survival, the brains were harvested for neuropathology. Our PA model was characterized by the development of severe hypoxia (pO 2 = 27 ± 4 mmHg), and combined acidosis (pH = 6.76 ± 0.04; pCO 2 = 114 ± 11 mmHg; lactate = 12.12 ± 0.83 mmol/L), however, cortical ischemia did not develop during the stress. Severely depressed electroencephalography (EEG), and marked neuronal injury indicated the development of HIE. H 2 was neuroprotective shown both by the enhanced recovery of EEG and by the significant preservation of neurons in the cerebral cortex, hippocampus, basal ganglia, and the thalamus. H 2 appeared to reduce oxidative stress shown by attenuation of 8-hydroxy-2'-deoxyguanosine immunostaining. In summary, this new PA piglet model is able to induce moderate/severe HIE, and the efficacy of hydrogen post-treatment to preserve neuronal activity/function in this PA/HIE model suggests the feasibility of this safe and inexpensive approach in the treatment of asphyxiated babies.

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Association between brain tissue pH and brain injury during asphyxia in piglets

Cited by 9 publications

References 36 publications

Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs

Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Molecular hydrogen affords neuroprotection in a new translational piglet model of hypoxic-ischemic encephalopathy

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