Biomedical subjects
M A Moskowitz
Publications and source records attributed to M A Moskowitz.
Predicting in-hospital mortality. A comparison of severity measurement approaches.
Hospital mortality statistics derived from administrative data may not adjust adequately for patient risk on admission. Using clinical data collected from the medical record, this study compared the ability of six models to predict in-hospital death, including one model based on administrative data (age, sex, and principal and secondary diagnoses), one on admission MedisGroups score, and one on an approximation of the Acute Physiology Score (APS) from the revised Acute Physiology and Chronic Health Evaluation (APACHE II), as well as three empirically derived models. The database from 24 hospitals included 16,855 cases involving five medical conditions, with an overall in-hospital mortality rate of 15.6%. The administrative data model fit least well (R-squared values ranged from 1.9-5.5% across the five conditions). Admission MedisGroups score and the proxy APS score did better, with R-squared values ranging from 4.9% to 25.9%. Two empirical models based on small subsets of explanatory variables performed best (R-squared values ranged from 18.5-29.9%). The preceding models had the same relative performances after cross-validation using split samples. However, the high R-squared values produced by the full empirical models (using 40 or more explanatory variables) were not preserved when they were cross-validated. Most of the predictive clinical findings were general physiologic measures that were similar across conditions; only a fifth of predictors were condition-specific. Therefore, an efficient approach to risk-adjusting in-hospital mortality figures may involve adding a small subset of condition-specific clinical variables to a core group of acute physiologic variables. The best predictive models employ condition-specific weighting of even the generic clinical findings.
Self-report versus medical record functional status.
The importance of assessing functional status in the hospitalized patient is gaining recognition. However, the availability and accuracy of medical record functional status data are uncertain. We collected data on 2,504 patients greater than 65 years of age discharged alive. A personal interview conducted 2 days before discharge recorded the patient's self-reported ability to perform 5 activities of daily living scales. Medical record abstraction was used independently to determine ability to perform the same activities of daily living scales. Patients who required any human assistance to perform a function were considered dependent. Patients were also contacted after discharge to determine the site of posthospital care (28% discharged to a nursing home). The amount of missing medical record functional status data varied by function from 20% for bathing to 50% for dressing. Ten percent of patients had no medical record functional status documentation concerning any of the five functions. The prevalence of self-reported dependence at discharge varied by function from 24% for feeding to 93% for bathing. The total number of dependencies differed between the two methods (medical records, 2.3 +/- 1.9; self-report data, 3.2 +/- 1.5). There was exact agreement between the two methods on the total number of dependencies in 28% of cases and differences of greater than or equal to 3 in 20%. In a stepwise logistic model predicting discharge to a nursing home and adjusting for other relevant variables, the number of dependencies as determined by self-report and medical record data each remained significant (Odds Ratios = 1.6). Self-report and medical record functional status data differ substantially, and the medical record data remain independently associated with nursing home placement. Several possible explanations for this finding are explored.
Postoperative adverse events of common surgical procedures in the Medicare population.
Mortality rates are the most widely used measure in assessing patient outcome from hospitalization. However, they may be an insensitive measure of quality for surgical patients because death is a relatively rare outcome. A random sample of patient data (n = 8126) selected from the Medicare files of seven states was used to identify, through chart abstraction, clinical postoperative complications of surgery that could serve as measures of quality. Four surgical procedures were studied: 1) coronary artery bypass grafting; 2) coronary angioplasty; 3) cholecystectomy; and 4) prostatectomy. Severity at admission was controlled for using severity-of-illness models developed with chart-abstracted data to predict adverse events after these four procedures. 30-day mortality rates ranged from 1.0% to 6.6%, while the prevalence of postoperative adverse events identified from chart review was greater (6.9% to 33.3%). There were significant differences between patients with and without adverse events. For example, coronary artery bypass graft patients with adverse events had prolonged postsurgical lengths of stay (18.5 +/- 13.2 vs. 13.2 +/- 6.2, P less than 0.001) and higher mortality rates (15.2% vs. 2.6%, P less than 0.001). The R-square values using clinical indicators at admission to predict the occurrence of any adverse event ranged from 0.05 to 0.13. Clinically meaningful adverse events of surgery can be successfully identified through chart abstraction and appear to be valid measures of postoperative complications among surgical patients. Severity adjustment at admission only modestly predicts the occurrence of these adverse events.
L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia.
L-Arginine (> or = 30 mg kg-1, i.v.), but not D-arginine (300 mg kg-1) administered 5 min after unilateral common carotid/middle cerebral artery occlusion increased regional cerebral blood flow (rCBF) within the dorsolateral ischaemic cortex in spontaneously hypertensive rats. L-Arginine (300 mg kg-1) increased rCBF from 22 +/- 2.7 to 33 +/- 4% of baseline as measured by laser-Doppler flowmetry. This increase may explain the ability of L-arginine to reduce infarct size following focal cerebral ischaemia, as reported previously. The mechanism appears to be mediated by nitric oxide since topical L-NAME (1 microM), a nitric oxide synthase inhibitor, decreased pial arteriole calibre from 115 +/- 2.2 to 106 +/- 0.9% of baseline following L-arginine infusion (300 mg kg-1).
CP-93,129, sumatriptan, dihydroergotamine block c-fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges.
1. The effects of intravenously administered 5-HT1B receptor agonists were examined on c-fos like immunoreactivity, an indicator of neuronal activation, within the brain stem. C-fos was induced by injecting an algesic, vasoconstrictor substance (0.3 ml of autologous blood) or a pro-inflammatory molecule, carrageenin (1 mg in 0.1 ml saline) into the cisterna magna of pentobarbitone-anaesthetized Sprague-Dawley rats and was visualized in serial sections (50 micrometers) by use of a polyclonal antiserum. 2. As previously reported, the injection of blood caused significant labelling within laminae I, IIo of the trigeminal nucleus caudalis, a major nociceptive brain stem nucleus, as well as within nucleus of the solitary tract and area postrema. A similar pattern of expression with fewer cells per section was detected after carrageenin instillation. The number of expressing cells was reduced by 54% in trigeminal nucleus caudalis but not within the nucleus of the solitary tract or area postrema when blood was injected in adult rats neonatal capsaicin treatment. 3. Pretreatment with 5-HT1 agonists with some selectivity for the 5-HT1B receptor, CP-93,129 (460 nmol kg-1 x 2, i.v.), sumatriptan (720 nmol kg-1 x 2, i.v.) or dihydroergotamine (86 nmol kg-1 x 2, i.v.) reduced positive cells by 39%, 31%, and 33% respectively in trigeminal nucleus caudalis but not in nucleus of the solitary tract or area postrema after blood instillation. Pretreatment with the analgesic morphine (15 mumol kg-1, s.c.) also decreased the number of positive cells by 63% in trigeminal nucleus caudalis. 4. CP-93,129 (460 nmol kg-1 x 2, i.v.) reduced the number of c-fos labelled cells by 47% within lamina I, IIo after carrageenin instillation. 5. Drug-induced blockade appeared to be tissue-dependent. Pretreatment with sumatriptan (720 nmol kg-1 x 2, i.v.) did not block c-fos expression in trigeminal nucleus caudalis following formalin application to the nasal mucosa.6. Drug-induced blockade may be mediated by an action on primary afferent (trigeminovascular) fibres in as much as CP-93,129 (460 nmol kg-' x 2, i.v.) did not reduce the number of expressing cells within the trigeminal nucleus caudalis following blood instillation in rats treated as neonates with capsaicin.7. We infer from these results that the analgesic actions of agonists at 5-HTB receptors (the receptor subtype analogous to 5-HTID in man) need not depend upon the presence of vasodilatation and, that 5-HTID receptor-mediated blockade of neurotransmission contributes significantly to the analgesic effects of these drugs in headache.8. Based on the demonstrated effects of 5-HTB/D agonists against the actions of two chemicallyunrelated meningeal stimulants, we suggest that treatment with 5-HTID agonists may be useful for the alleviation of pain in other headache conditions associated with meningeal irritation. Bacterial, viral(including AIDS meningovascular inflammation) and other forms of chemical meningitis merit further investigation.
Pial vessel caliber and cerebral blood flow become dissociated during ischemia-reperfusion in cats.
The relationship between pial arteriolar caliber and cerebral blood flow (CBF) was examined in 11 cats subjected to reperfusion for up to 120 min after 10 min of global cerebral ischemia induced by four-vessel occlusion and systemic hypotension. Thirty minutes after reperfusion CBF, as assessed by radiolabeled microsphere injection, had increased to 588% of control in middle cerebral artery (MSEC) cortical gray matter territory. The caliber of MSEC pial arterioles measured using the closed cranial window technique (greater than 33 to less than 213 microns) increased to 172% of baseline. By 60 min of reperfusion, CBF was 76% of basal levels, but pial arterioles remained 133% of baseline. After 120 min, CBF approximated baseline values, but pial dilatation persisted (115% of control). Intracranial pressure measurements did not differ significantly from resting values. At 45 min and beyond, total cerebrovascular resistance did not differ from resting values. The coexistence of vasodilatation within pial arterioles and normal blood flow in cortical gray matter indicates that pial vessels (greater than 33 microns) cannot be responsible for normal blood flow restoration following postocclusive hyperemia. Resistance during the posthyperemic phase must be increased selectively within parenchymal vessels to account for normal total cerebrovascular resistance, pial vessel dilatation, and normal-low parenchymal blood flow. Whether obstruction rather than vasoconstriction explains the resistance changes within intraparenchymal vessels remains for further study.
Oxygen radicals in cerebral ischemia.
Superoxide production was measured as the superoxide dismutase (SOD)-inhibitable portion of nitro blue tetrazolium (NBT) reduction after cerebral ischemia-reperfusion in anesthetized cats equipped with cranial windows. Significant superoxide production was found in the early reperfusion period and continued for more than 1 h after ischemia. Superoxide was not detected in control animals not subjected to ischemia, during ischemia, and at 120 min of reperfusion. After ischemia, the vasoconstrictor response to arterial hypocapnia was reduced. This effect was prevented by pretreatment with SOD plus catalase or by deferoxamine. The response to topical acetylcholine was converted to vasoconstriction after ischemia. The normal vasodilator response reappeared spontaneously at 120 min of reperfusion. The vasodilator response to acetylcholine was preserved in animals pretreated with SOD plus catalase. Blood-brain barrier permeability to labeled albumin and horseradish peroxidase was increased after ischemia. These effects were minimized by pretreatment with SOD and catalase. We conclude that superoxide generation occurs during reperfusion after cerebral ischemia for a fairly long period and that superoxide and its derivatives are responsible at least in part for the vasodilation and the abnormal reactivity as well as for the increase in blood-brain barrier permeability to macromolecules seen after ischemia. Furthermore, the findings suggest that the agent responsible for the vascular abnormalities is hydroxyl radical generated via the iron-catalyzed Haber-Weiss reaction.
L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR.
L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.
Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles.
The cerebral vasodilator response induced by topical nitroglycerin and nitroprusside was examined in cats equipped with cranial windows for the observation of the cerebral microcirculation. In cats subjected to chronic unilateral trigeminal ganglionectomy, the vasodilator responses to nitroprusside and nitroglycerin were markedly depressed on the denervated side. Application of a selective calcitonin gene-related peptide (CGRP) antagonist [CGRP(8-37)] on the innervated side reduced the response to nitrodilators to the same extent as seen on the denervated side. The vasodilator response to acetylcholine was unaffected by trigeminal ganglionectomy. CGRP(8-37) almost abolished the vasodilator response to nitroglycerin and sodium nitroprusside and to CGRP, but did not affect the response to adenosine or to adenosine diphosphate. Pretreatment with LY83583, a drug that lowers cyclic GMP levels, diminished the vasodilation to CGRP and to nitroprusside but not to adenosine. We conclude that the nitrovasodilators activate sensory fibers to release CGRP, which in turn relaxes cerebral vascular smooth muscle by activating guanylate cyclase. Hence, nitrovasodilators possess a novel mechanism of action within the cephalic circulation which may explain both the occurrence of vasodilation and headache.
The trigemino-vascular system and migraine.
Neurogenic inflammation has been proposed as a possible pathogenetic mechanism for migraine and cluster headache. Antidromic stimulation of trigeminal fibers causes plasma protein extravasation, mast cell activation and degranulation, vacuolation and increase in endothelial vesicle number within post capillary venules in rat dura mater. The antimigraine drugs sumatriptan and dihydroergotamine block the development of plasma extravasation and ultrastructural changes, as well as plasma calcitonin gene-related peptide (CGRP) increase in the superior sagittal sinus following electrical trigeminal ganglion stimulation. Sumatriptan and dihydroergotamine bind with high affinity to the 5-HT1D/1B receptors, thus suggesting that their neurogenic antiinflammatory activity is mediated by activation of 5-HT autoreceptors present on sensory fibers innervating blood vessels in dura mater.
Focal ischemia in rats causes time-dependent expression of c-fos protein immunoreactivity in widespread regions of ipsilateral cortex.
c-Fos protein expression was examined in brain by immunohistochemistry following permanent middle cerebral artery (MCA) occlusion above the rhinal fissure and ipsilateral common carotid artery (CCA) occlusion in Long-Evans rats. In sham-operated animals, c-fos protein-like immunoreactivity (CFPLI) was confined to neuronal nuclei of the hypothalamus and was not present in other regions including cerebral cortex. In the core territory of the MCA, CFPLI was not detected when examined at 15 and 30 min, 1, 4 and 8 h and 1, 2, 4 and 7 days after occlusion. Focal ischemia induced two temporal and spatial patterns of CFPLI. At 1 h, c-fos protein was expressed in the nuclei of many neurons in layers II-V of the ipsilateral cortex both immediately adjacent to and remote from the ischemic territory. Within regions outside the MCA territory (e.g. cingulate gyrus and piriform cortices), CFPLI in these neurons peaked at 2-4 h and was undetectable after 2 days. Neurons in the zone immediately surrounding the ischemic core within MCA territory also expressed CFPLI, but in contrast, continued to express c-fos up to 4 days after ischemia. Immunoreactivity surrounding the ischemic core was found in neuronal nuclei predominantly, although from 1 to 4 days, CFPLI was found in perikarya and dendrites as well. MK-801 (3 mg/kg, i.p., 30 min prior to occlusion) completely blocked the early c-fos protein induction in all regions but expression within neurons surrounding the ischemic core was present 1 day after a single injection.(ABSTRACT TRUNCATED AT 250 WORDS)
Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions.
The results of recent investigations designed to elucidate the neuroeffector functions of sensory fibres, the cause of migraine headache and the mechanism of action of antimigraine drugs are reviewed and discussed. Neurogenic inflammation (vasodilatation and neurogenic plasma extravasation) is one explanation for the development of headaches and the blood flow changes which occur during migraine headache. Numerous studies have recently been carried out on rats and guinea-pigs into the effects of antimigraine agents, including ergot alkaloids, sumatriptan and non-steroidal anti-inflammatory drugs (NSAIDs), on neurogenic plasma protein extravasation in the dura mater induced by electrical stimulation of trigeminal ganglia or systemic administration of capsaicin. It is known that the dura mater is able to produce headaches in man. Ergot alkaloids have been shown to block neurogenic inflammation via a C-fibre dependent neuronal mechanism. Sumatriptan appears to act fairly similarly although, whereas the ergot alkaloids are non-selective for either 5-hydroxytryptamine (5-HT; serotonin) receptors or 5-HT1, sumatriptan is selective for 5-HT1 receptors. The antimigraine action of NSAIDs may be via either an effect on blood vessels or an effect on the nerve fibre. The antimigraine effects of ergot alkaloids, sumatriptan and NSAIDs are discussed in the light of the common vasoconstrictor actions of these agents and knowledge that vasodilatation is apparently not responsible for migraine headache pain in most cases.
Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion.
Vasoactive neuropeptides, present in unmyelinated C-fibers, can be released from perivascular sensory axons by antidromic stimulation, to mediate vasodilation and extravasation of plasma protein (neurogenic inflammation). In this report, the effects of antidromic trigeminal stimulation on levels of calcitonin gene-related peptide (CGRP) in plasma were examined in the superior sagittal sinus and the effects of drugs that have been shown previously to block extravasation of neurogenic plasma determined. The levels of immunoreactive CGRP in plasma were measured both before and during electrical stimulation of the trigeminal ganglion (0.1-1.0 mA, 5 msec, 5 Hz, 3-5 min), using a highly specific and sensitive immunochemiluminometric assay. Levels of CGRP increased and became maximal within the first minute of stimulation. The increases were detectable at intensities of current as small as 0.1 mA. Peak levels related to the intensity of the stimulus. Samples from femoral arterial blood did not show concomitant increases at 1 min. Pretreatment with dihydroergotamine (DHE) (50 micrograms/kg i.v.) did not change the baseline levels but decreased levels of CGRP during stimulation (0.3 mA), by 55% at 1 min and 50% at 3 min. Sumatriptan (GR43175) (300 micrograms/kg) attenuated the increase by 57% at 3 min (0.1 mA, 5 msec, 5 Hz) but not after 1 min of stimulation, although decreases were observed at the latter time during an individual experiment. Drug-induced attenuation of levels of CGRP in plasma may reflect inhibition of release, to thereby provide evidence to explain blockade of neurogenic extravasation of plasma.
Jun B, c-jun, jun D and c-fos mRNAs in nucleus caudalis neurons: rapid selective enhancement by afferent stimulation.
In situ hybridization using cDNAs complementary to specific regions of the mRNAs encoding 3 members of the jun transcription factor gene family and c-fos reveals modest levels of hybridization over superficial laminae of the nucleus caudalis of the spinal tract of the trigeminal in sections taken from unstimulated brains. Jun B expression is markedly and rapidly enhanced ipsilateral to electrical stimulation of the trigeminal ganglion. C-fos mRNA levels also show changes, especially after higher intensity stimulation. Smaller alterations in c-jun (jun A) and jun D do not reach statistical significance. In each instance of altered expression, more neurons express hybridization densities above background levels after stimulation. Parallels between these alterations and changes in the expression of preproenkephalin in these same neuronal populations are discussed.
Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells.
Mast cells are involved in allergic reactions, but may also participate in neurogenic inflammation. The morphology of mast cells in rat dura mater and tongue was evaluated by histochemistry, as well as by scanning and transmission electron microscopy following unilateral trigeminal ganglion stimulation (5 min, 5 Hz, 5 ms, and 0.02, 0.1 or 1.0 mA). Mast cells in dura and tongue of normal animals were numerous, perivascular and often in close proximity to nerve fibers. After 5 min of electrical stimulation, mast cells contralateral to the stimulation showed histochemical characteristics of normal peripheral tissue mast cells (Safranin-positive), and by electron microscopy appeared homogeneous with numerous intact electron-dense granules. On the stimulated side, however, the staining characteristics of mast cells showed changes indicating progressive intracellular loss of their granular content. In addition, the total number of stainable mast cells decreased at all three stimulus intensities, but reached significance only at 0.1 and 0.02 mA. Ultrastructural evidence of granule changes consistent with secretion were observed although degranulation was not observed until 20 min after stimulation. There were no mast cell changes after electrical trigeminal stimulation in adult rats treated as neonates with capsaicin to destroy small caliber sensory afferent axons. These results suggest that mast cells may secrete in response to electrical stimulation of trigeminal axons, possibly mediated by antidromic release of neuropeptides, and may participate in the development of neurogenic inflammation.
Parasympathetic denervation of rat pial vessels significantly increases infarction volume following middle cerebral artery occlusion.
Studies were undertaken in Long Evans rats to examine the hypothesis that chronic unilateral sectioning of vasodilating nerve fibers (parasympathetic and/or sensory) innervating the circle of Willis increases infarction volume following unilateral branch occlusion of the middle cerebral artery (MCA) combined with temporary (45 min) bilateral common carotid occlusion. Infarct size was measured 24 h after surgical occlusion from seven coronal slices. Infarction volume (mean +/- SD) in sham animals (group A) and surgically naive animals (group B) measured 153 +/- 43 and 131 +/- 38 mm3, respectively. After lesions of both sensory (nasociliary nerve) and parasympathetic efferents at the ethmoidal foramen (group C, combined lesion) or selective lesions of parasympathetic efferents (group D), infarction volume increased [214 +/- 47 mm3 (p less than 0.01) and 209 +/- 46 mm3 (p less than 0.05), respectively]. No increases were detected after cutting the nasociliary nerve alone (group E) or occluding the external ethmoidal artery (group F) [145 +/- 39 mm3 (p greater than 0.05) and 124 +/- 63 mm3 (p greater than 0.05), respectively]. The infarct was predominantly located within cortical gray matter and became enlarged on its superior and inferior aspects after parasympathectomy. Large infarcts were noted whether animals breathed spontaneously (all of the above) or were artificially respired or whether animals were anesthetized with xylazine and ketamine or chloral hydrate. Taken together, these studies suggest a previously unrecognized protective role for autonomic parasympathetic fibers in the pathophysiology of focal cerebral ischemia that is not shared by sensory fibers. The importance of autonomic vasodilating fibers to blood flow in ischemic brain merits further study.
Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion.
Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.