Resuscitation and emergency care in drowning: A scoping review.

BACKGROUND: The ILCOR Basic Life Support Task Force and the international drowning research community considered it timely to undertake a scoping review of the literature to identify evidence relating to the initial resuscitation, hospital-based interventions and criteria for safe discharge related to drowning. METHODS: Medline, PreMedline, Embase, Cochrane Reviews and Cochrane CENTRAL were searched from 2000 to June 2020 to identify relevant literature. Titles and abstracts and if necessary full text were reviewed in duplicate. Studies were eligible for inclusion if they reported on the population (adults and children who are submerged in water), interventions (resuscitation in water/boats, airway management, oxygen administration, AED use, bystander CPR, ventilation strategies, ECMO, protocols for hospital discharge (I), comparator (standard care) and outcomes (O) survival, survival with a favourable neurological outcome, CPR quality, physiological end-points). RESULTS: The database search yielded 3242 references (Medline 1104, Pre-Medline 202, Embase 1722, Cochrane reviews 12, Cochrane CENTRAL 202). After removal of duplicates 2377 papers were left for screening titles and abstracts. In total 65 unique papers were included. The evidence identified was from predominantly high-income countries and lacked consistency in the populations, interventions and outcomes reported. Clinical studies were exclusively observational in nature. CONCLUSION: This scoping review found that there is very limited evidence from observational studies to inform evidence based clinical practice guidelines for drowning. The review highlights an urgent need for high quality research in drowning.

An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction.

Apolipoprotein E (apoE) modifies glial activation and the CNS inflammatory response in an isoform-specific manner. Peptides derived from the receptor-binding region of apoE have been demonstrated to maintain the functional activity of the intact protein, and to improve histological and functional deficits after closed head injury. In the current study, APOE2, APOE3, and APOE4 targeted replacement (TR) mice expressing the human apoE protein isoforms (apoE2, apoE3 and apoE4) were used in a clinically relevant model of closed head injury to assess the interaction between the humanized apoE background and the therapeutic apoE mimetic peptide, apoE(133-149). Treatment with the apoE-mimetic peptide reduced microglial activation and early inflammatory events in all of the targeted replacement animals and was associated with histological and functional improvement in the APOE2TR and APOE3TR animals. Similarly, brain beta amyloid protein (Abeta)(1-42) levels were increased as a function of head injury in all of the targeted replacement mice, while treatment with apoE peptide suppressed Abeta(1-42) levels in the APOE2TR and APOE3TR animals. These results suggest a pharmacogenomic interaction between the therapeutic effects of the apoE mimetic peptide and the human apoE protein isoforms. Furthermore, they suggest that administration of apoE-mimetic peptides may serve as a novel therapeutic strategy for the treatment of acute and chronic neurological disease.

Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.

Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) reduces oxidative stress and improves outcome from experimental cerebral ischemia. Rats that were subjected to 90 min focal ischemia and 7 d recovery were given MnTE-2-PyP(5+) (or vehicle) intracerebroventricularly 60 min before ischemia, or 5 or 90 min or 6 or 12 hr after reperfusion. Biomarkers of brain oxidative stress were measured at 4 hr after postischemic treatment (5 min or 6 hr). MnTE-2-PyP(5+), given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP(5+), given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP(5+) treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 +/- 60 mm(3); MnTE-2-PyP(5+), 300 ng, 60 +/- 68 mm(3)). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP(5+) effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP(5+) prevented mitochondrial aconitase inactivation and reduced 8-hydroxy-2'-deoxyguanosine formation when it was given 5 min or 6 hr after ischemia. In mice, MnTE-2-PyP(5+) reduced infarct size and improved neurologic scores when it was given intravenously 5 min after ischemia. There was no effect of 150 or 300 ng of MnTE-2-PyP(5+) pretreatment on selective neuronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marked neuroprotective effects against focal ischemic insults when it was given up to 6 hr after ischemia. This was associated with decreased postischemic superoxide-mediated oxidative stress.

Reaction of a polydentate cysteine-based ligand and its nickel(ii) complex with electrophilic and nucleophilic methyl-transfer reagents - from S-methylation to acetyl coenzyme A synthase reactivity.

The L-cysteine derived N2S2 ligand precursor H2L and its nickel(ii) complex L2Ni2 were investigated with respect to their behaviour in contact with electrophilic and nucleophilic methylation reagents (H2L = (N,N'-dimethyl-(2R,5R)-bis-(sulfanylmethyl)-piperazine). Treatment of deprotonated L(2-) with MeI led to the selective methylation of the thiolate groups thus generating a novel potential ligand, Me2L, which is neutral and contains two thioether donors. The coordinating properties of Me2L were demonstrated by the synthesis of a first nickel(ii) complex: reaction with NiBr2 led to a mononuclear complex 2 where all donor atoms coordinate to the nickel ion, which completes its octahedral coordination sphere by the two bromide ligands. If, however, the complex [LNi]2 (1) is treated with MeI only one thiolate function per ligand moiety is methylated, while the other one remains a thiolate. This leads to [MeLNi](+) complex metal fragments, which trimerize including a µ3-bridging iodide ion to give the compound 3 that was tested with regards to ACS reactivity. While it behaved inert towards CO, attempts to replace the bridging iodide ligand by methyl units in reactions with nucleophilic methylation reagents led to a product, which could not be identified but reacted with CO. Work-up showed that this protocol had converted the thiolate function of MeL(-) into a thioester function, which corresponds to an ACS-like reactivity.

The role of new vessels and macrophages in the development and resolution of edema following a cortical freeze lesion in the mouse.

The role of an influx of macrophages and neovascularity in the resolution of vasogenic edema is not well defined. The inhibition of these processes with x-irradiation or parenteral corticosteroid administration was used to evaluate their contribution to the resolution of edema around a cortical freeze lesion in mice. The resorption of Evans blue, a marker of protein extravasation, was delayed in x-irradiated mice on the second day following a freeze lesion (p = 0.0075), which correlates with a delay in macrophage infiltration around the lesion. The specific gravity of the lesion and its border regions was significantly less in x-irradiated animals on day 7 than in controls (p = 0.00062), which correlates with a delay in new vessel formation around the lesion. Administration of corticosteroids from the time of production of the freeze lesion resulted in a specific gravity significantly less than control when measured eight days after the lesion (p = 0.01). Macrophages may participate by inhibiting the development of the macromolecular portion of vasogenic edema. The development of neovascularity correlates with the resorption of the aqueous portion of vasogenic edema. As with x-irradiation, corticosteroids administered from the time of freeze lesion inhibited the resorption of the aqueous portion of vasogenic edema, but they may suppress the spread of edema in this experimental model.

The influence of a cryogenic brain injury on the cerebrovascular response to isoflurane in the rabbit.

To determine if an acute neurologic injury alters the cerebrovascular response to isoflurane, rabbits were anesthetized with morphine/N2O, mechanically ventilated, surgically instrumented, and assigned to one of three groups. Group 1 animals (n = 8) served as controls and received no injury. In Groups 2 (n = 9) and 3 (n = 8), a 30-s cryogenic injury was produced in the left parietal region using liquid N2 poured into a funnel affixed to the surface of the skull. Regional CBF was measured using microspheres. In Groups 2 and 3, flow was determined before and then 30 and 90 min after injury or at equivalent times in Group 1. After the 90-min data were collected, 1% [approximately 0.5 minimal alveolar concentration (MAC)] and then 2% (approximately 1.0 MAC) isoflurane was administered to uninjured rabbits in Groups 1 and to lesioned rabbits in Group 3. A mean arterial pressure of greater than or equal to 80 mm Hg was maintained during isoflurane administration by an infusion of angiotensin II. In uninjured rabbits (Group 1), 2% isoflurane produced bilaterally symmetrical increases in hemispheric CBF, from 76 +/- 21 (mean +/- SD) to 150 +/- 48 ml 100 g-1 min-1. CBF in the hindbrain increased from 91 +/- 25 to 248 +/- 102 ml 100 g-1 min-1. By contrast, in the lesioned rabbits of Group 3, 2% isoflurane resulted in CBF in the lesioned hemisphere changing from 56 to only 77 ml 100 g-1 min-1 (NS), while in the contralateral hemisphere, CBF rose from 68 to 97 ml 100 g-1 min-1 (also NS). These results indicate that a cryogenic injury attenuates the normal CBF response to a volatile anesthetic, both in the damaged hemisphere as well as in apparently uninjured regions distant from the injury focus. In a separate group of animals, a similar cryogenic injury abolished the CBF response to changing PaCO2 in the injured hemisphere, but not in either the contralateral hemisphere or the cerebellum. It is possible that the CBF effects of isoflurane may be mediated via some intermediary neurogenic and/or biochemical process.

Reversible focal ischemia in the rat: effects of halothane, isoflurane, and methohexital anesthesia.

Barbiturates and the volatile anesthetic isoflurane reduce CMR to similar values. If the mechanism of barbiturate protection against focal ischemic injury is due to a reduction in cellular energy requirements, then isoflurane should similarly reduce ischemic injury. To evaluate this, spontaneously hypertensive rats underwent 2 h of reversible middle cerebral artery occlusion (MCAO) while receiving deep methohexital, isoflurane, or halothane anesthesia. Ninety-six hours postischemia, neurologic deficits were present but without a difference between groups. Mean +/- SD infarct volume, as assessed by triphenyl tetrazolium chloride staining and computerized planimetry, was significantly less in the methohexital group (n = 8; 166 +/- 74 mm3) than in either the halothane (n = 9; 249 +/- 71 mm3; p less than 0.04) or the isoflurane (n = 9; 243 +/- 62 mm3; p less than 0.03) groups. One possible explanation for the lack of protective effect for isoflurane might be related to its vasodilative properties, which could result in a cerebral vascular steal. To examine this possibility, rats anesthetized with methohexital or isoflurane underwent autoradiographic determination of CBF with or without MCAO. In isoflurane-anesthetized sham rats (n = 5; no ischemia), CBF was approximately three times greater than in methohexital-treated (n = 5) sham rats. During ischemia, although a regional reduction in flow was noted in both anesthetic groups, mean flow remained greater in the isoflurane group.(ABSTRACT TRUNCATED AT 250 WORDS)

Microwave fixation for the determination of cerebral blood volume in rats.

The cerebral blood volume (CBV) is sensitive to changing hydrostatic pressures. Thus, measurement methods that rely on removing tissue from unfixed brain may lead to underestimates of the CBV due to the loss of blood from the tissue. In situ fixation of tissue before removal may offer improved accuracy. We employed a triple-label method to measure simultaneously whole brain CBF and CBV in halothane-anesthetized Sprague-Dawley rats, which were then killed either by focused microwave irradiation (approximately 8 kW of incident power x 770 ms) or by decapitation. CBF was measured with [3H]nicotine while the CBV was determined as the sum of the cerebral red cell volume (CRCV--measured with 99mTc-labeled red cells) and the cerebral plasma volume (CPV--measured with [14C]dextran). Animals were studied during hypocarbic (PaCO2 approximately 25 mm Hg), normocarbic, or hypercarbic (PaCO2 approximately 70 mm Hg) conditions. Added studies were performed to verify that the microwave irradiation scheme used was capable of fixing previously administered tracers in place, and also halting the entry of tracer given after irradiation. Results indicate that the method of killing had no effects on CBF measurements, as assessed either by absolute values during normocarbia or responsiveness to changing PaCO2. However, all three volume measurements made using nondiffusible tracers (CRCV, CPV, and CBV) were significantly lower in animals killed by decapitation. Furthermore, CO2 responsiveness for all three variables (as assessed by the slope of the PaCO2/volume) was not evident in decapitated animals. We conclude that in situ fixation offers significant advantages when examining the cerebral distribution space of nondiffusible tracers.

In vivo models of cerebral ischemia: effects of parenterally administered NMDA receptor glycine site antagonists.

Both in vitro and in vivo experiments have implicated extracellular glycine in the pathogenesis of ischemic brain damage. Recently, halogenated derivatives of quinoxaline-2,3-dione have been synthesized that possess bioavailability when parenterally administered and minimal psychotomimetic properties. Such compounds have allowed investigation into the efficacy of glycine receptor antagonism as a strategy for protection against cerebral ischemic insults. Rats underwent either 90 min of middle cerebral artery filament occlusion or 10 min of forebrain ischemia with recovery while receiving intraperitoneal injections of either a glycine receptor antagonist (ACEA-1021, ACEA-1031, or ACEA-1011) or vehicle (dimethyl sulfoxide). Both ACEA-1021 and ACEA-1031 reduced cerebral infarct volumes and were associated with a reduced incidence of hemiparesis resulting from MCA occlusion. ACEA-1011, administered in a smaller dose had no effect. In the forebrain ischemia model, glycine receptor antagonism had no effect on delayed neuronal necrosis in the hippocampal CA1 sector, neocortex, or caudoputamen. We conclude that pharmacologic antagonism of glycine at the strychnine-insensitive glycine receptor presents a neuroprotective profile similar to that previously observed for antagonists of glutamate at the N-methyl-D-aspartate complex with a potential for fewer side effects.

The role of electrode size on the incidence of spreading depression and on cortical cerebral blood flow as measured by H2 clearance.

Cerebral blood flow was measured by the H2 clearance method 30 and 60 min after the implantation of 300, 250, 125, or 50 microns diameter platinum-iridium electrodes 2 mm deep into the right parietal cortex of normothermic, normocarbic halothane-anesthetized rats. Another group of animals had 50 microns electrodes inserted 1 mm. In all animals, the presence or absence of a wave of spreading depression (SD) was noted at the time of implantation, with recordings made with glass micropipettes. H2 flow values were compared with those measured in gray matter from the same anatomical region (but from different rats), using [3H]nicotine. The incidence of SD ranged from 60% following insertion of 300 microns electrodes to 0% with 50 microns electrodes. H2 clearance flows also varied with electrode size, from 77 +/- 21 ml 100 g-1 min-1 (mean +/- standard deviation) with 300 microns electrodes to 110 +/- 31 and 111 +/- 16 ml 100 g-1 min-1 with 125 and 50 microns electrodes, respectively (insertion depth of 2 mm). A CBF value of 155 +/- 60 ml 100 g-1 min-1 was obtained with 50 micron electrodes inserted only 1 mm. Cortical gray matter blood flow measured with [3H]nicotine was 154 +/- 35 ml 100 g-1 min-1. When the role of SD in subsequent flow measurements was examined, there was a gradual increase in CBF between 30 and 60 min after electrode insertion in those animals with SD, while no such change was seen in rats without SD.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of cerebral metabolism in determining the local cerebral blood flow effects of volatile anesthetics: evidence for persistent flow-metabolism coupling.

The effects of equipotent doses of halothane (1.05%) versus isoflurane (1.38%) anesthesia on CMRglc were determined autoradiographically using the 2-[14C]deoxyglucose technique in the rat. Eight anatomically standardized coronal sections were selected and digitized from the autoradiographs. Mean CMRglc was determined for hemispheric, neocortical, and subcortical regions at each anatomic level, and a neocortical/subcortical CMRglc ratio was calculated. In addition, the current CMRglc autoradiographs, as well as previous CBF autoradiographs obtained under identical experimental conditions were examined to characterize and compare flow/metabolism relationships for the two anesthetics. For this analysis, CBF was determined in 80 selected anatomic areas, and the values from each area were plotted against CMRglc values obtained from identical areas. In all major regions, mean CMRglc was greater with halothane than with isoflurane. The neocortical/subcortical ratio, reflecting the pattern of CMRglc distribution, was also greater during halothane anesthesia. This suggests that isoflurane has a disproportionate effect on neocortical metabolism resembling patterns previously seen for CBF. Analysis of CBF versus CMRglc plots for each anesthetic group showed two parallel lines with nearly identical slopes, but different Y intercepts. We conclude that the distribution of CMRglc observed during 1 MAC (minimum alveolar concentration) halothane and isoflurane anesthesia parallels the distribution of CBF. This finding supports the conclusion that flow-metabolism coupling is intact during halothane and isoflurane anesthesia, and that drug induced changes in cerebral metabolism may play an important role in determining the CBF response to that drug. Furthermore, there is evidence that, at a given level of CMRglc, isoflurane may have greater vasodilating capabilities than halothane.

Neuroprotective effect of NMDA receptor glycine recognition site antagonism persists when brain temperature is controlled.

Several lines of inquiry have indicated that glycine plays an important role in both glutamatergic neurotransmission and pathophysiology of cerebral ischemia. However, subacute outcome trials demonstrating the efficacy of glycine antagonists as neuroprotectants have not been performed with rigorous control of brain temperature. In this study, we investigated the effect of N-methyl-D-aspartate (NMDA) receptor glycine recognition site antagonism in a temperature-controlled rodent model of transient focal ischemia. Male Wistar rats underwent 75 min of intraluminal middle cerebral artery occlusion (MCAO). During MCAO and the first 24 h of reperfusion, rats (n = 10) were administered e55-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021) i.v. as a bolus infusion of 5 mg/kg followed by 3.5 mg/kg/h (Low-Dose) or 10 mg/kg followed by 7 mg/kg/ h (High-Dose) for 24 h. Cortical temperature was controlled at 38.0 +/- 0.1 degrees C during MCAO and the first 6 h of reperfusion. A 7-day recovery interval was allowed. Mean total infarct volume was reduced by approximately 40% in both high- and low-dose groups (p < 0.01). The preponderance of infarct reduction occurred in the cortex (p < 0.01). Neurologic function correlated with the size of cerebral infarct (p = 0.001). Neurologic grade was similarly improved by treatment with either dose (p = 0.01). These results demonstrate that neuroprotection achieved by antagonism of the glycine recognition site persists when brain temperature is controlled, indicating a potent mechanism of action other than attenuating a hyperthermic response to ischemia.

Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia.

Recent evidence suggests that apolipoprotein E (ApoE) plays a role in neurologic disease. This experiment compared the neurologic and histologic outcome of ApoE-deficient mutant and wild-type mice subjected to a 60- or 90-minute episode of middle cerebral artery filament occlusion and a recovery interval of 24 hours. With 60 minutes of ischemia, there was no mortality. Apolipoprotein E-deficient mice had larger infarcts (cortex: ApoE deficient = 20 mm3 +/- 12, wild-type = 9 +/- 7 mm3, P = 0.03; subcortex: ApoE deficient = 22 +/- 7 mm3, wild-type = 16 +/- 7 mm3, P = 0.07). Hemiparesis was less severe in wild-type animals (P = 0.02). After 90 minutes of ischemia, mortality in ApoE-deficient mice (n = 10) was 40% versus 0% in wild-type mice (n = 10; P = 0.09). Intraparenchymal hemorrhage was found in 3 of the 4 dead mice. No difference in cortical (ApoE deficient = 37 +/- 8 mm3; wild-type = 31 +/- 18 mm3; P = 0.49) or subcortical (ApoE deficient = 30 +/- 11 mm3; wild-type = 32 +/- 18 mm3; P = 0.78) infarct volumes was present among survivors. ApoE-deficient mice had a prolonged activated partial thromboplastin time and increased fibrinogen concentration. This data supports the hypothesis that apolipoprotein E plays a role in the pathophysiology of ischemic brain damage.

Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice.

Apolipoprotein E (apoE), a 34-KD glycosylated lipid-binding protein, is expressed as three common isoforms in humans (E2, E3, or E4). Clinical evidence suggests that the apoE genotype (APOE) may be a risk factor for poor outcome after acute central nervous system injury. This was examined further in transgenic mice constructed with the human APOE3 or APOE4 gene under the control of human promoter and tissue expression elements. Presence of human apoE3 and apoE4 proteins in brains of human APOE homozygous transgenic mice was confirmed by Western blotting. APOE3 (n = 12) and APOE4 (n = 10) mice underwent 60 minutes of middle cerebral artery occlusion. After 24-hour recovery, infarct size was measured. Infarct volumes (mean +/- standard deviation) were smaller in the APOE3 group (cortex: APOE3 = 18 +/- 4 mm3; APOE4 = 30 +/- 11 mm3, P = 0.04; subcortex: APOE3 = 12 +/- 4 mm3; APOE4 = 18 +/- 4 mm3, P = 0.003). Hemiparesis was less severe in APOE3 mice (P = 0.02). These data indicate that human isoform-specific effects of apoE are relevant to acute pathomechanisms of focal ischemic brain damage when examined in the mouse. APOE transgenic mice may provide an appropriate model to examine the mechanistic basis for the differential effects of human apoE isoforms in acute central nervous system injury.

Interactions between NMDA and AMPA glutamate receptor antagonists during halothane anesthesia in the rat.

There is increasing evidence that pharmacologic antagonism of glutamatergic neurotransmission can potentiate the anesthetic effects of drugs such as halothane. The purpose of this study was to examine the anesthetic interaction between glutamate receptor antagonists. A competitive NMDA receptor antagonist (CGS 19755) and an AMPA receptor antagonist (NBQX) were administered either alone or in combination prior to determination of the minimum alveolar concentration (MAC) for halothane in the rat. CGS 19755 caused a dose-dependent maximum reduction in halothane MAC of approximately 80%. Doses of NBQX, which were low enough to cause no change in MAC when administered alone, substantially reduced MAC when administered with subanesthetic doses of CGS 19755. This effect decreased as the dose of CGS 19755 was increased. Finally, halothane MAC was reduced to zero when NBQX, in a dose sufficient to reduce halothane MAC by approximately 35% if given alone, was added to a pharmacodynamically similar dose of CGS 19755. Although MAC is believed to predominantly reflect nocioception at the spinal cord level, the results suggests that pharmacologic blockade of glutamatergic neurotransmission is sufficient to result in deep levels of anesthesia. Further, the effect of combinations of NMDA and AMPA receptor antagonists on halothane MAC is consistent with an in vivo physiologic interaction between the NMDA and AMPA receptors.

Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures.

Apolipoprotein E (apoE) is a 34-kD protein with multiple biological properties. Recent clinical and preclinical observations implicate a role for apoE in modifying the response of the brain to focal and global ischemia. One mechanism by which apoE might exert these effects is by reducing glutamate-induced excitotoxic neuronal injury associated with ischemic insults. We demonstrate that human recombinant apoE confers a mild neuroprotective effect in primary neuronal-glial cultures exposed to 100 microM N-methyl-D-aspartate. Furthermore, a peptide derived from the receptor-binding region of apoE (residues 133-149) maintained a significant helical population as assessed by circular dichroism, and completely suppressed the neuronal cell death and calcium influx associated with N-methyl-D-aspartate exposure. Neuroprotection was greatest when the peptide was added concurrently with N-methyl-D-aspartate; however, a significant protection was observed when peptide was preincubated and washed off prior to N-methyl-D-aspartate exposure. These results suggest that one mechanism by which apoE may modify the CNS response to ischemia is by partially blocking glutamate excitotoxicity. Moreover, small peptide fragments derived from the receptor-binding region of apoE have enhanced bioactivity compared with the intact holoprotein, and may represent a novel therapeutic strategy for the treatment of brain ischemia.

Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia.

Transgenic mice, which had been transfected with the human extracellular superoxide dismutase gene, causing an approximate five-fold increase in brain parenchymal extracellular superoxide dismutase activity, were used to investigate the role of extracellular superoxide dismutase in ischemic brain injury. Transgenic (n = 21) and wild-type (n = 19) mice underwent 90 min of intraluminal middle cerebral artery occlusion and 24 h of reperfusion. Severity of resultant hemiparesis and cerebral infarct size were measured. Wild-type mice had larger infarcts (cortex: wild type =37+/-14 mm3, transgenic = 27+/-13 mm3, P=0.03; subcortex: wild type = 33+/-14 mm3, transgenic = 23+/-10 mm3, P = 0.02). Neurological scores, however, were similar (P = 0.29). Other mice underwent autoradiographic determination of intra-ischemic cerebral blood flow. The volume of tissue at risk of infarction (defined as volume of tissue where blood flow was <25 ml/100g/min) was similar between groups (cortex: wild type = 51+/-15 mm3, transgenic = 47+/-9 mm3, P=0.65; subcortex: wild type = 39+/-16 mm3, transgenic= 37+/-17 mm3, P=0.81). These results indicate that antioxidant scavenging of free radicals by extracellular superoxide dismutase plays an important role in the histological response to a focal ischemic brain insult.

The hemispheric cerebrovascular response to hemodilution is attenuated by a focal cryogenic brain injury.

Experimental brain injury attenuates the normal increase in cerebral blood flow (CBF) that accompanies a fall in PaO2, and this may contribute to the well-known detrimental effects of hypoxia following closed head injury. Anemia is also known to adversely affect posttraumatic survival, and it is reasonable to hypothesize that this too may be related to an altered cerebrovascular response. Therefore, to examine this possibility, pentobarbital-anesthetized rabbits were subjected to a left posterior parietal cryogenic cortical injury, followed 90 min later by isovolemic hemodilution with hetastarch. Unlesioned control animals underwent an identical degree of hemodilution. CBF was measured using radioactive microspheres. In control animals, hemodilution was accompanied by a marked increase in CBF in all brain regions. For example, in the left posterior cortex, CBF increased from 30 +/- 14 mL/100 g/min (baseline Hct = 42 +/- 2%, mean +/- SD) to 100 +/- 20 mL/100 g/min at Hct = 12 +/- 1%. By contrast, there was a markedly attenuated response throughout the left (ipsilateral) hemisphere of injured animals, even in cortical regions distant from the injury. For example, in the left posterior cortex, CBF changed from a baseline of 32 +/- 21 mL/100 g/min (baseline) to 40 +/- 14 mL/100 g/min at the lowest Hct. CBF responses to hemodilution were unaltered in the contralateral hemisphere and in the hindbrain. These data indicate that a localized brain lesion can produce widespread ipsilateral alterations in the CBF response to hemodilution, with resultant compromise in cerebral O2 delivery. These data support the argument that the CBF increase produced by hemodilution is an active vasodilatory process rather than a passive response to changing blood viscosity.

Extracellular superoxide dismutase overexpression improves behavioral outcome from closed head injury in the mouse.

Oxidative stress is known to play an important role in the response of brain to traumatic insults. We tested the hypothesis that increased extracellular superoxide dismutase (EC-SOD) expression can reduce injury in a mouse model of closed head injury. Neurologic, cognitive, and histologic outcomes were compared between transgenic mice exhibiting a fivefold increase in EC-SOD activity and wild-type littermate controls. Severe or moderate transcranial impact was induced in anesthetized and physiologically controlled animals. After severe impact, transgenic mice had better neurological outcome at 24 hr postinjury (p = 0.038). Brain water content was increased, but there was no difference between groups. Moderate impact resulted in predominantly mild neurologic deficits in both groups at both 24 hr and 14 days postinjury. Morris water maze performance, testing cognitive function at 14-17 days after trauma, was better in EC-SOD overexpressors (p = 0.018). No differences were observed between groups for histologic damage in hippocampal CA1 and CA3. We conclude that EC-SOD has a beneficial effect on behavioral outcome after both severe and moderate closed head injury in mice. Because EC-SOD is believed to be predominantly located in the extracellular space, these data implicate an adverse effect of extracellular superoxide anion on outcome from closed head injury.

Isoflurane improves long-term neurologic outcome versus fentanyl after traumatic brain injury in rats.

Despite routine use of fentanyl in patients after traumatic brain injury (TBI), it is unclear if it is the optimal sedative/analgesic agent. Isoflurane is commonly used in experimental TBI. We hypothesized that isoflurane would be neuroprotective versus fentanyl after TBI. Rats underwent controlled cortical impact (CCI) and received 4 h of N2O/O2 (2:1) and either fentanyl (10 microg/kg i.v. bolus, 50 microg/kg/h infusion) or isoflurane (1% by inhalation) with controlled ventilation. Shams underwent identical preparation, without CCI. Functional outcome (beam balance, beam walking, Morris water maze [MWM] tasks) was assessed over 20 days. Lesion volume and hippocampal neuron survival were quantified on day 21. Additional rats underwent identical CCI and anesthesia with intracranial pressure (ICP) monitoring, and brain water content was assessed. Motor and MWM performances were better in injured rats treated with isoflurane versus fentanyl (p < 0.05). CA1 hippocampal damage was attenuated in isoflurane-treated rats (p < 0.05). Fentanyl-treated rats had higher mean arterial blood pressure after injury (p < 0.05); however, ICP and brain water were similar between groups. Isoflurane improved functional outcome and attenuated damage to CA1 versus fentanyl in rats subjected to CCI. Isoflurane may be neuroprotective by augmenting cerebral blood flow and/or reducing excitotoxicity, not by reducing ICP or brain water content. Alternatively, fentanyl may be detrimental. Isoflurane may mask beneficial effects of novel agents tested in TBI models. Additionally, fentanyl may not be optimal early after TBI in humans.