Effects of asphyxia on the fetal lamb brain

Haan, Harmen H. de; Reempts, J. L. H. Van; Vles, Johan S.H.; Haan, J. de; Hasaart, T. H. M.

doi:10.1016/0002-9378(93)90424-h

Cited by 50 publications

(28 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, asphyxiated fetal lambs with the highest CSF hypoxanthine and xanthine levels had the most extensive histologic brain damage (12). In this respect, the significantly (p < 0.01) higher levels of CSF hypoxanthine in nonsurviving animals compared with surviving fetuses during asphyxia may be of importance and may even predict fetal death.…”

Section: --30mentioning

confidence: 95%

See 1 more Smart Citation

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

et al. 1994

Self Cite

View full text Add to dashboard Cite

During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 r 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 ? 0.03 and a base excess of -17.0 ? 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that I ) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3 ) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses. 4) The rate of increase of ATP catabolites in CSF is higher in the nonsurviving animals and may therefore be predictive for fetal death. (1) and preferential streaming of well-oxygenated blood in the heart (2), the fetal cerebrum is provided with as much oxygen as possible. During severe or sustained oxygen shortage, however, the brain too resorts to anaerobic metabolism. Lack of oxygen impairs mitochondria1 functioning, leading to energy shortage (3); ATP becomes degraded to AMP and, after dephosphorylation, further to adenosine, inosine, and hypoxanthine. Serum levels of hypoxanthine are considered a sensitive indicator of the hypoxic insult (4). Moreover, formation of hypoxanthine and xanthine may aggravate outcome after such an insult, because during reoxygenation hypoxanthine and xan-

show abstract

Section: --30mentioning

confidence: 95%

“…The experiment was ended when either the fetus died or, in case of fetal survival, after 3 d. When the fetus was still alive after 3 d, a relaparotomy was performed under general anesthesia. The fetus was perfused in vivo with a fixative solution so histologic analysis of the brain could be performed (12).…”

Section: Surgerymentioning

confidence: 99%

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

et al. 1994

Self Cite

View full text Add to dashboard Cite

show abstract

“…Brief, total clamping of the uterine artery or umbilical cord leads to a rapid reduction of fetal oxygenation within a few minutes (27–29). In contrast, gradual partial occlusion induces a slow fetal metabolic deterioration without the initial fetal cardiovascular responses of bradycardia and hypertension; this is a function of the speed and relative depth of hypoxia that was attained (30). During profound asphyxia, corresponding with a severe reduction of uterine blood flow to 25% or less and a fetal arterial oxygen content of less than 1 mmol/L, the fetus responds very differently than during mild to moderate hypoxia.…”

Section: Asphyxia Hypotension and Hypoxic-ischemic Brain Injurymentioning

confidence: 99%

Fetal Hypoxia Insults and Patterns of Brain Injury: Insights from Animal Models

Gunn

Bennet

2009

Clinics in Perinatology

159

167

View full text Add to dashboard Cite

Synopsis The outcome of perinatal hypoxia-ischemia is highly variable, with only a very broad relationship to the ‘severity’ of oxygen debt as shown by peripheral base deficit and the risk of damage. The present review examines the pathophysiology of asphyxial injury. We dissect the multiple factors that modify the risk of injury, including the depth (‘severity’), duration, and repetition of the insult, the maturity, and condition of the fetus, pre-existing hypoxia, and exposure to pyrexia and infection/inflammation.

show abstract

“…Inasmuch as lubeluzole is known to inhibit glutamate release during an ischemic insult (24), this drug may be neuroprotective in such an animal model. However, when brain injury is induced by systemic asphyxia, the extent and location of neuronal cell loss often vary widely (52)(53)(54) and there is a considerable rise in the fetal abortion rate. Because hardly any neuroprotective effect can be demonstrated under such conditions, we preferred the fetal sheep model of global cerebral ischemia caused by occlusion of both carotid arteries.…”

Section: Discussionmentioning

confidence: 99%

Lubeluzole Pretreatment Does Not Provide Neuroprotection Against Transient Global Cerebral Ischemia in Fetal Sheep Near Term

et al. 2002

View full text Add to dashboard Cite

The aim of the present study was to test the neuroprotective effect of the novel benzothiazol compound lubeluzole on neuronal cell damage in fetal sheep arising from global cerebral ischemia. Thirteen fetal sheep were prepared at a mean gestational age of 127 Ϯ 1 d (term is at 147 d). Six fetuses were treated with lubeluzole (0.33 mg/kg estimated body weight) before induction of global cerebral ischemia (Ϫ90, Ϫ60, and Ϫ30 min), while the remainder (n ϭ 7) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. Cerebral blood flow was measured by injecting radiolabeled microspheres before (Ϫ90 min), during (ϩ3 min and ϩ27 min), and after (ϩ40 min, ϩ3 h, and ϩ72 h) cerebral ischemia. Neuronal cell damage was assessed in the cerebrum and deeper brain structures by light microscopy. Values are given as means Ϯ SD. In control fetuses, blood flow to the cerebrum was reduced from 100 Ϯ 25 mL·100 g Ϫ1 min Ϫ1 to less than 20 mL·100 g Ϫ1 min Ϫ1 during ischemia. Shortly after ischemia, hyperperfusion occurred (217 Ϯ 66 mL·100 g Ϫ1 min Ϫ1 ) followed by a tendency toward hypoperfusion (72 Ϯ 17 mL·100 g Ϫ1 min Ϫ1 ) later on (ϩ3 h). Significant differences in blood flow to the various brain structures between the control and study groups could not be observed. Neuronal cell damage was concentrated in the parasagittal regions of the cerebrum. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity including long-term neurologic sequelae in term and preterm fetuses (1). Although over the last decade many therapeutic strategies have been developed in various animal models to reduce neuronal cell damage caused by ischemic insults, their clinical application has often been rejected due to major drug-related side-effects (2). Especially after application of calcium antagonists and inhibitors of NOS, alterations of fetal cardiovascular control have been observed (3, 4). However, the recently developed benzothiazole compound lubeluzole seems to justify further research in this field. The neuroprotective efficiency of this drug has been shown in a variety of in vitro as well as in vivo experiments (5-10). In clinical safety studies, severe drugrelated side-effects could be excluded (11). Phase III trials have provided different results. Whereas Grotta (12) described a neuroprotective effect of lubeluzole in patients suffering from acute ischemic stroke, this finding could not be confirmed in other trials (13,14).The present knowledge on the safety profile and efficiency of lubeluzole seems to be promising enough to warrant further studies in immature animals. Recently, we were able to show that lubeluzole does not affect fetal circulatory centralization during acute asphyxia. This mechanism is of major importance, because it protects the fetal brain from neuronal injury by increasing blood flow to the central organs, i.e. brain, heart, adrenals, when oxygen is in short supply (15). The present study was performed to clarify whether lubeluzole protects the ...

show abstract

Effects of asphyxia on the fetal lamb brain

Cited by 50 publications

References 27 publications

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Fetal Hypoxia Insults and Patterns of Brain Injury: Insights from Animal Models

Lubeluzole Pretreatment Does Not Provide Neuroprotection Against Transient Global Cerebral Ischemia in Fetal Sheep Near Term

Contact Info

Product

Resources

About