Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia

Peeters-Scholte, Cacha; Tweel, Evelyn van den; Ioroi, Tomoaki; Post, Ilka; Braun, Kees P.J.; Veldhuis, Wouter B.; Nicolay, Klaas; Groenendaal, Floris; Bel, Frank van

doi:10.1007/s00221-002-1182-x

Cited by 27 publications

(20 citation statements)

References 43 publications

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“…Increased CBV may indicate pronounced vasodilation in cerebral microcirculation due to exhausted autoregulatory vasodilation (14,23). Another factor influencing the increase in THI is the increase in oxygenated Hb content that results from decreased cerebral oxygen utilization caused by increased brain damage (24). Accordingly, FTOE was decreased in HIϩVEH piglets, as reported previously (14).…”

Section: Discussionsupporting

confidence: 54%

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Álvarez¹,

Lafuente²,

Rey-Santano³

et al. 2008

Pediatr Res

132

113

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ABSTRACT:To test the neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol (CBD), piglets received i.v. CBD or vehicle after hypoxia-ischemia (HI: temporary occlusion of both carotid arteries plus hypoxia). Nonhypoxic-ischemic sham-operated piglets remained as controls. Brain damage was studied by near-infrared spectroscopy (NIRS) and amplitudeintegrated electroencephalography (aEEG) and by histologic assessment (Nissl and FluoroJadeB staining). In HIϩvehicle, HI led to severe cerebral hemodynamic and metabolic impairment, as reflected in NIRS by an increase in total Hb index (THI) and a decrease in the fractional tissue oxygenation extraction (FTOE); in HIϩCBD the increase of THI was blunted and FTOE remained similar to SHAM. HI profoundly decreased EEG amplitude, which was not recovered in HIϩvehicle, indicating cerebral hypofunction; seizures were observed in all HIϩvehicle. In HIϩCBD, however, EEG amplitude recovered to 46.4 Ϯ 7.8% baseline and seizures appeared only in 4/8 piglets (both p Ͻ 0.05). The number of viable neurons decreased and that of degenerating neurons increased in HIϩvehicle; CBD reduced both effects by more than 50%. CBD administration was free from side effects; moreover, CBD administration was associated with cardiac, hemodynamic, and ventilatory beneficial effects. In conclusion, administration of CBD after HI reduced short-term brain damage and was associated with extracerebral benefits. (Pediatr Res 64: 653-658, 2008)

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Section: Discussionsupporting

confidence: 54%

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Álvarez¹,

Lafuente²,

Rey-Santano³

et al. 2008

Pediatr Res

132

113

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“…Also at the 20 h mark, the [HHb] of the insult-group piglets had a statistically significant correlation with the duration of ischemia (p Ͻ 0.05). However, the fact that there was only a significant difference at one time point-in addition to the results of Peeters-Scholte et al, (19) who found no change in [HHb] from baseline out to 24 h after severe hypoxia-ischemia in piglets-refutes the idea of using [HHb] in a prognostic capacity. In a previous study from our group, CMRO 2 was monitored for 6 h after resuscitation in piglets subjected to 30 min of hypoxia-ischemia (12); in support of the results from the present study, even though hypoxia-ischemia caused a significant and persistent 25% reduction in CMRO 2 , there were no group effects with the parameters used to determine CMRO 2 .…”

Section: Discussioncontrasting

confidence: 44%

Assessing the Severity of Perinatal Hypoxia-Ischemia in Piglets Using Near-Infrared Spectroscopy to Measure the Cerebral Metabolic Rate of Oxygen

et al. 2009

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Reduced cerebral function after neonatal hypoxiaischemia is an early indicator of hypoxic-ischemic encephalopathy. Near-infrared spectroscopy offers a clinically relevant means of detecting impaired cerebral metabolism from the measurement of the cerebral metabolic rate of oxygen (CMRO 2 ). The purpose of this study was to determine the relationship between postinsult CMRO 2 and duration of hypoxia-ischemia in piglets. Twelve piglets were subjected to randomly selected durations of hypoxia-ischemia (5-28 min) and five animals served as controls. Measurements of CMRO 2 were taken before and for 24 h after hypoxia-ischemia. Histology was carried out in nine piglets (six insults, three controls) to estimate brain injury. In the first 4 h after the insult, average CMRO 2 of the insult group was significantly depressed (33 Ϯ 3% reduction compared with controls) and by 8 h, a significant correlation developed, which persisted for the remainder of the study, between CMRO 2 and the duration of ischemia. Histologic staining suggested little brain damage resulted from shorter insult durations and considerable damage from more prolonged insults. This study demonstrated that near-infrared spectroscopy could detect early changes in CMRO 2 after hypoxia-ischemia for a range of insult severities and CMRO 2 could be used to distinguish insult severity by 8 h after the insult. (Pediatr Res 65: 301-306, 2009) P erinatal hypoxia-ischemia continues to be a significant cause of neurodevelopmental impairment and disability in the term infant. Results from animal and newborn human studies suggest a significant portion of hypoxic-ischemic brain damage can be delayed by 6 -72 h after resuscitation (1). Long-term outcome could be improved if mechanisms leading to delayed cell death could be suppressed during the latent period between insult and injury-a period termed the "therapeutic window" (2). The exact duration of the therapeutic window is unknown; however, the success rate of treatment strategies depends on early administration. Unfortunately, the clinical signs of perinatal hypoxia-ischemia can be subtle and there are as yet no proven methods capable of reliably and accurately assessing the severity of injury within the confines of the therapeutic window (2).For nearly 30 y it has been known that cerebral ischemia can cause long-term depression of cerebral metabolism despite resuscitation (3). Studies conducted in neonatal lambs demonstrated that a reduction in cerebral energy metabolism can be seen within 4 h after resuscitation from hypoxiaischemia (4,5) and metabolic impairment has been similarly observed in newborns within 18 h of birth by proton magnetic resonance spectroscopy (6), while delayed energy failure, as quantified by phosphorous magnetic resonance spectroscopy, can be used to predict neurologic outcome (7). The results of these studies suggest that a noninvasive measure of the cerebral metabolic rate of oxygen (CMRO 2 ) may be of particular interest to the clinical prognosis of hypoxia-ischemia.Recent tech...

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“…All parameters were averaged over the last three time points; i.e., after general of metabolism, and these signals have been noticeably insensitive to other markers of brain injury (23,25,27).…”

Section: Resultsmentioning

confidence: 99%

Changes in Cerebral Oxygen Consumption and High-Energy Phosphates During Early Recovery in Hypoxic-Ischemic Piglets: A Combined Near-Infrared and Magnetic Resonance Spectroscopy Study

et al. 2009

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Near-infrared spectroscopy (NIRS) offers the ability to assess brain function at the bedside of critically ill neonates. Our group previously demonstrated a persistent reduction in the cerebral metabolic rate of oxygen (CMRO 2 ) after hypoxia-ischemia (HI) in newborn piglets. The purpose of this current study was to determine the causes of this reduction by combining NIRS with magnetic resonance spectroscopy (MRS) to measure high-energy metabolites and diffusion-weighted imaging to measure cellular edema. Nine piglets were exposed to 30 min of HI and nine piglets served as controls. Proton and phosphorous MRS spectra, apparent diffusion coefficient (ADC) maps, and CMRO 2 measurements were collected periodically before and for 5.5 h after HI. A significant decrease in CMRO 2 (26 Ϯ 7%) was observed after HI. Incomplete recovery of nucleotide triphosphate concentration (8 Ϯ 3% Ͻcontrols) and reduced ADC (16 Ϯ 5%) suggested mitochondrial dysfunction. However, CMRO 2 did not correlate with any metabolite concentration during the last 3 h of the recovery period, and no significant changes were found in phosphocreatine and lactate levels. Therefore, the CMRO 2 decrease is likely a combination of impaired mitochondrial function and reduced energy demands during the acute phase, which has been previously observed in the mature brain. (Pediatr Res 65: 181-187, 2009) P erinatal hypoxia-ischemia (HI) is a major cause of neurologic injury in newborns, affecting one to six of every 1000 live term births (1). Evidence suggests that a significant proportion of brain injury manifests 1 to 3 d after the hypoxicischemic insult (2). The delay between insult and injury has given rise to the concept that there exists a brief period after HI when it may be possible to minimize tissue damage by interrupting the processes contributing to delayed neuronal death (2). Potential neuroprotective therapies include mild hypothermia, inhibitors of free radical production, and free radical scavengers (3,4). However, the efficacy of such therapies depends, in part, on early detection of the onset of delayed brain injury.Key to understanding the progression of brain injury after HI is the concept of secondary energy failure. Phosphorous magnetic resonance spectroscopy ( 31 P-MRS) studies found that the ratio of phosphocreatine (PCr) to inorganic phosphate (Pi) was normal soon after birth in infants with clinical symptoms of birth asphyxia, but progressively declined over the following days (5). Furthermore, the minimum PCr/Pi during secondary energy failure or, correspondingly, the maximum increase in the lactate (Lac) signal measured by proton magnetic resonance spectroscopy ( 1 H-MRS) strongly correlated with neurodevelopmental impairment at 1 and 4 years of age (6,7). The occurrence of secondary energy failure observed clinically has been replicated in animal models of perinatal HI, including piglets (8,9) and rat pups (10).The near complete recovery of high-energy phosphates during the early recovery phase observed in animal 31 P-MRS...

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Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia

Cited by 27 publications

References 43 publications

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Assessing the Severity of Perinatal Hypoxia-Ischemia in Piglets Using Near-Infrared Spectroscopy to Measure the Cerebral Metabolic Rate of Oxygen

Changes in Cerebral Oxygen Consumption and High-Energy Phosphates During Early Recovery in Hypoxic-Ischemic Piglets: A Combined Near-Infrared and Magnetic Resonance Spectroscopy Study

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