Background: Bone fracture increases alarmins and proinflammatory cytokines in the blood, and provokes macrophage infiltration and proinflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome; however, the impact of bone fracture on stroke outcome remains unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response. Methods: Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n = 10), infarct volume, neuronal death, and macrophages/microglia infiltration (n = 6–7) were analyzed after 3 days. Results: We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere ± SD: 30±7% vs. 12±3%, n = 6, P < 0.001), more severe neurobehavioral dysfunction, and more macrophages/microglia in the periinfarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction. Conclusions: These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke.

Background An increasing number of elderly patients are treated for aneurysmal subarachnoid hemorrhage. Given that elderly age is associated with both poor outcome and an increased risk of hydrocephalus, we sought to investigate the interaction between age and hydrocephalus in outcome prediction. Methods We enrolled 933 consecutive patients treated for subarachnoid hemorrhage between 2002 and 2010 and followed them for 1 yr after intensive care unit discharge. We first performed stepwise analyses to determine the relationship among neurologic events, elderly age (60 or more yr old), and 1-yr poor outcome (defined as Rankin 4-6). Within the most parsimonious model, we then tested for interaction between admission hydrocephalus and elderly age. Finally, we tested the association between age as a stratified variable and 1-yr poor outcome for each subgroup of patients with neurologic events. Results 24.1% (n=225) of subarachnoid hemorrhage patients were 60 yr old or more and 19.3% (n=180) had 1-yr poor outcomes. In the most parsimonious model (area under the receiver operating characteristic curve, 0.84; 95% CI: 0.82 to 0.88; P<0.001), elderly age and admission hydrocephalus were two independent predictors for 1-yr outcome (P<0.001 and P=0.004, respectively). Including the significant interaction between age and hydrocephalus (P=0.04) improved the model's outcome prediction (P=0.03), but elderly age was no longer a significant predictor. Finally, stratified age was associated with 1-yr poor outcome for hydrocephalus patients (P=0.007), but not for patients without hydrocephalus (P=0.87). Conclusion In this observational study, elderly age and admission hydrocephalus predicted poor outcome, but elderly age without hydrocephalus did not. An external validation, however, will be needed to generalize this finding.

Background During cerebral angiography, intracarotid infusion of sodium nitroprusside (SNP), an endothelium-independent nitric oxide donor, fails to increase cerebral blood flow (CBF) of human subjects. A confounding effect of intracranial pathology or that of radiocontrast could not be ruled out in these experiments. The authors hypothesized that, if nitric oxide was a significant regulator of CBF of primates, then intracarotid SNP will augment CBF of baboons. Methods In studies, CBF (intraarterial (133)Xe technique) was measured in healthy baboons during isoflurane anesthesia at (1) baseline and during (2) induced hypertension with intravenous phenylephrine, (3) concurrent infusions of intravenous phenylephrine and intracarotid SNP, and (4) intracarotid verapamil (positive control drug). In studies, the authors measured tissue cyclic guanosine monophosphate (cGMP) by radioimmunoassay after incubating vascular rings obtained from freshly killed baboons (1) with increasing concentrations of SNP and (2) after SNP exposure following preincubation with the radiocontrast agent, iohexhol. Results In the studies, coinfusion of intravenous phenylephrine and intracarotid SNP did not increase CBF. However, intracarotid verapamil significantly increased CBF (from 26 +/- 7 to 43 +/- 11 ml x 100 g(-1) x min(-1); P < 0.0001) without a change in mean arterial pressure. In the studies, incubation of intracranial arterial rings in SNP resulted in dose-dependent increases in cGMP concentrations. A similar increase in cGMP content was evident despite iohexhol preincubation. Conclusions Collectively, these results suggest that, in healthy baboons, intracarotid SNP does not decrease arteriolar resistance, although SNP could affect proximal arterial tone, as demonstrated by the increase in cGMP content of these vessels.

Background The recent resurgence of interest in the cerebrovascular effects of nitroprusside can be attributed to the possibility of using nitric oxide donors in treating cerebrovascular insufficiency. However, limited human data suggest that intracarotid nitroprusside does not directly affect cerebrovascular resistance. In previous studies, physiologic or pharmacologic reactivity of the preparation was not tested at the time of nitroprusside challenge. The authors hypothesized that if nitric oxide is a potent modulator of human cerebral blood flow (CBF), then intracarotid infusion of nitroprusside will augment CBF. Methods Cerebral blood flow was measured (intraarterial (133)Xe technique) in sedated human subjects undergoing cerebral angiography during sequential infusions of (1) intracarotid saline, (2) intravenous phenylephrine to induce systemic hypertension, (3) intravenous phenylephrine with intracarotid nitroprusside (0.5 microg x kg(-1) x min(-1)), and (4) intracarotid verapamil (0.013 mg x kg(-1) x min(-1)). Data (mean +/- SD) were analyzed by repeated-measures analysis of variance and post hoc Bonferroni-Dunn test. Results Intravenous phenylephrine increased systemic mean arterial pressure (from 83 +/- 12 to 98 +/- 6 mmHg; n = 8; P < 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with intravenous phenylephrine or with concurrent infusions of intravenous phenylephrine and intracarotid nitroprusside. Intracarotid verapamil increased CBF (43 +/- 9 to 65 +/- 11 ml x 100 g(-1) x min(-1); P < 0.05). Conclusions The authors conclude that, in humans, intracarotid nitroprusside sufficient to decrease mean arterial pressure during recirculation, does not augment CBF. Failure of intracarotid nitroprusside to augment CBF despite demonstrable autoregulatory vasoconstriction and pharmacologic vasodilation questions the significance of nitric oxide-mediated vasodilation in human cerebral circulation.

Background Adenosine-induced asystole has been used to induce transient systemic hypotension for various vascular procedures. Dose-response characteristics of adenosine-induced ventricular asystole have not been determined. Methods During endovascular embolization of cerebral arteriovenous malformations, the authors performed a series of adenosine test injections to establish a dose-response relation in each patient. After an interval of 3-10 min, the dose was escalated by 10-20 mg for each injection to achieve an end point of 20-30 s of stable mean arterial pressure (MAP) reduction to 25-30 mmHg. All patients received constant infusion of nitroprusside (approximately 1 microgram. kg-1. min-1) throughout the procedure. Results The authors studied four adult patients (age, 22-44 yr; two patients had two separate procedures) and one pediatric patient (age, 4 yr). Twenty-three adenosine injections resulted in measurable asystole. The adenosine dose was 0. 98 +/- 0.40 mg/kg (mean +/- SD), and the dose range was 0.24-1.76 mg/kg (6-90 mg). The duration of asystole, MAP < 30 mmHg, and MAP < 50 mmHg, were 8 +/- 3 s, 18 +/- 12 s, and 50 +/- 29 s, respectively. The minimum MAP and the MAP for the first 20 s were 16 +/- 3 mmHg and 30 +/- 9 mmHg, respectively. There was a linear relation between adenosine dose and the duration of hypotension with MAP < 30 mmHg and MAP < 50 mmHg. Conclusions In the dose range studied, a series of adenosine test injections can be used to determine optimal adenosine dose for induction of transient profound hypotension.

Background The authors hypothesized that if nitric oxide (NO) was a determinant of background cerebrovascular tone, intracarotid infusion of NG-monomethyl-L-arginine (L-NMMA), a NO synthase (NOS) inhibitor, would decrease cerebral blood flow (CBF) and intracarotid L-arginine would reverse its effect. Methods In angiographically normal cerebral hemispheres, after the initial dose-escalation studies (protocol 1), the authors determined the effect of intracarotid L-NMMA (50 mg/min for 5 min) on CBF and mean arterial pressure (MAP) over time (protocol 2). Changes in CBF and MAP were then determined at baseline, during L-NMMA infusion, and after L-NMMA during L-arginine infusion (protocol 3). To investigate effects of higher arterial blood concentrations of L-NMMA, changes in CBF and MAP were assessed at baseline and after a bolus dose of L-NMMA (250 mg/1 min), and vascular reactivity was tested by intracarotid verapamil (1 mg/min, protocol 4). CBF changes were also assessed during induced hypertension with intravenous phenylephrine (protocol 5). Results Infusion of L-NMMA (50 mg/min for 5 min, n = 7, protocol 2) increased MAP by 17% (86 +/- 8 to 100 +/- 11 mmHg; P < 0.0001) and decreased CBF by 20% (45 +/- 8 to 36 +/- 6 ml. 100 g-1. min-1; P < 0.005) for 10 min. Intracarotid l-arginine infusion after L-NMMA (protocol 3) reversed the effect of L-NMMA. Bolus L-NMMA (protocol 4) increased MAP by 20% (80 +/- 11 to 96+/-13 mmHg; P< 0.005), but there was no significant decrease in CBF. Intracarotid verapamil increased CBF by 41% (44+/- 8 to 62 +/- 9 ml. 100 g-1. min-1; P< 0.005). Phenylephrine-induced hypertension increased MAP by 20% (79 +/- 9 to 95 +/- 6 mmHg; P = 0.001) but did not affect CBF. Conclusions The results suggest that intracarotid L-NMMA modestly decreases CBF, and the background tone of cerebral resistance vessels may be relatively insensitive to NOS inhibition by the intraarterial route.

Background Reliable tests of correct anatomic placement of the laryngeal mask airway (LMA) may enhance safety during use and minimize the need for fiberoptic instrumentation during airway manipulation through the device. This study assessed the correlation between the outcomes of nine clinical tests to place the LMA and the anatomic position of the device as graded on a standard fiberoptic scale. Methods During 150 anesthetics, the outcome of nine clinical tests of correct placement was individually scored as satisfactory (positive) or unsatisfactory (negative) for clinical use of the LMA. Anatomic placement was assessed (by fiberoptic evaluation) by an anesthesiologist, who was blinded to the placement of the device, as grade 1, vocal cords not seen; grade 2, cords plus the anterior epiglottis seen; grade 3, cords plus the posterior epiglottis seen; and grade 4, only vocal cords seen. The outcomes of clinical tests were correlated with fiberoptic grade. Results Tests that correlated with the fiberoptic grade were the ability to generate an airway pressure of 20 cm water, the ability to ventilate manually, a black line on the LMA in midline, anterior movement of the larynx, outward movement of the LMA on inflation of the cuff, and movements of the reservoir bag with spontaneous breathing. Two tests, ability to generate airway pressure of 20 cm water and ability to ventilate manually, correlated with fiberoptic grades 4 and 3 combined (i.e., the epiglottis was supported by the LMA) and grade 2 (the epiglottis was not supported by the LMA). Tests with poor correlation with fiberoptic grade were the presence of resistance at the end of insertion, inability to advance LMA after inflation of the cuff, and presence of a capnographic trace. Conclusions The outcome of clinical tests correlates with the anatomic placement of LMAs, as judged by fiberoptic examination. Two tests that best correlated with the fiberoptic grade were the ability to generate airway pressure of 20 cm water and the ability to ventilate manually.

Background Remifentanil, a rapidly metabolized mu-opioid agonist, may offer advantages for neurosurgical procedures in which prolonged anesthetic effects can delay assessment of the patient. This study compared the effects of remifentanilnitrous oxide on cerebral blood flow (CBF) and carbon dioxide reactivity with those of fentanyl-nitrous oxide anesthesia during craniotomy. Methods After institutional approval and informed patient consent were obtained, 23 patients scheduled to undergo supratentorial tumor surgery were randomly assigned to remifentanil or fentanyl infusion groups in a double-blinded manner. Midazolam, thiopental, and pancuronium induction was followed by equipotent narcotic loading infusions of remifentanil (1 microg x kg(-1) x min(-1)) or fentanyl (2 microg x kg(-1) x min(-1)) for 5-10 min. Patients were ventilated with 2:1 nitrous oxideoxygen, and opioid rates were reduced and then titrated to a stable hemodynamic effect. After dural exposure, CBF was measured by the intravenous 133xenon technique at normocapnia and hypocapnia. Reactivity of CBF to carbon dioxide was calculated as the absolute increase in CBF per millimeters of mercury increase in the partial pressure of carbon dioxide (PaCO2). Data were analyzed by repeated-measures analysis of variance, unpaired Student's t-tests, or contingency analysis. Results In the remifentanil group (n = 10), CBF decreased from 36+/-11 to 27+/-8 ml x 100 g(-1) x min(-1) as PaCO2 decreased from 33+/-5 to 25+/-2 mmHg. In the fentanyl group (n = 8), CBF decreased from 37+/-11 to 25+/-6 ml x 100 g(-1) x min(-1) as PaCO2 decreased from 34+/-3 to 25+/-3 mmHg. Absolute carbon dioxide reactivity was preserved with both agents: 1+/-1.2 ml x 100 g(-1) x min(-1) x mmHg(-1) for remifentanil and 1.5+/-0.5 ml x 100 g(-1) x min(-1) x mmHg(-1) for fentanyl (P = 0.318). Conclusion Remifentanil and fentanyl have similar effects on absolute CBF, and cerebrovascular carbon dioxide reactivity is maintained.

Background Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized mu-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions. Methods Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micrograms.kg.-1. min-1) or remifentanil (n = 31; 1 mu.kg-1.min-1). After tracheal intubation, infusion rates were reduced to 0.03 microgram.kg-1.min-1 (fentanyl) or 0.2 microgram.kg-1.min-1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil (approximately 0.2 microgram.kg-1.min-1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7. Results Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar. Conclusions Remifentanil appears to be a reasonable alternative to fentanyl during elective supratentorial craniotomy.

Background Some patients who undergo cerebral aneurysm surgery require cardiopulmonary bypass and deep hypothermic circulatory arrest. During bypass, these patients often are given large doses of a supplemental anesthetic agent in the hope that additional cerebral protection will be provided. Pharmacologic brain protection, however, has been associated with undesirable side effects. These side effects were evaluated in patients who received large doses of propofol. Methods Thirteen neurosurgical patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest to facilitate clip application to a giant or otherwise high-risk cerebral aneurysm. Electroencephalographic burst suppression was established before bypass with an infusion of propofol, and the infusion was continued until the end of surgery. Hemodynamic and echocardiographic measurements were made before and during the prebypass propofol infusion and again after bypass. Emergence time also was determined. Results Prebypass propofol at 243 +/- 57 micrograms.kg-1.min-1 decreased vascular resistance from 34 +/- 8 to 27 +/- 8 units without changing heart rate, arterial or filling pressures, cardiac index, stroke volume, or ejection fraction. Propofol blood concentration was 8 +/- 2 micrograms/ml. Myocardial wall motion appeared hyperdynamic at the end of cardiopulmonary bypass, and all patients were weaned therefrom without inotropic support. After bypass, vascular resistance decreased further, and cardiovascular performance was improved compared to baseline values. Nine of the 13 patients emerged from anesthesia and were able to follow commands at 3.1 +/- 1.4 h. Three others had strokes and a fourth had cerebral swelling. Conclusions Propofol infused at a rate sufficient to suppress the electroencephalogram does not depress the heart or excessively prolong emergence from anesthesia after cardiopulmonary bypass and deep hypothermic circulatory arrest.

Background Although low-flow cardiopulmonary bypass (CPB) has become a preferred technique for the surgical repair of complex cardiac lesions in children, the relative hypotension and decrease in cerebral blood flow (CBF) associated with low flow may contribute to the occurrence of postoperative neurologic injury. Therefore, it was determined whether phenylephrine administered to increase arterial blood pressure during low-flow CPB increases CBF. Methods Cardiopulmonary bypass was initiated in seven baboons during fentanyl, midazolam, and isoflurane anesthesia. Animals were cooled at a pump flow rate of 2.5 l.min-1.m-2 until esophageal temperature decreased to 20 degrees C. Cardiopulmonary bypass flow was then reduced to 0.5 l.min-1.m-2 (low flow). During low-flow CPB, arterial partial pressure of carbon dioxide (Pco2) and blood pressure were varied in random sequence to three conditions: (1) Pco2 30-39 mmHg (uncorrected for temperature), control blood pressure; (2) Pco2 50-60 mmHg, control blood pressure; and (3) Pco2 30-39 mmHg, blood pressure raised to twice control by phenylephrine infusion. Thereafter, CPB flow was increased to 2.5 l.min-1.m-2, and baboons were rewarmed to normal temperature. Cerebral blood flow was measured by washout of intraarterial 133Xe before and during CPB. Results Phenylephrine administered to increase mean blood pressure from 23 +/- 3 to 46 +/- 3 mmHg during low-flow CPB increased CBF from 14 +/- 3 to 31 +/- 9 ml.min-1.100 g-1, P < 0.05. Changes in arterial Pco2 alone during low flow bypass produced no changes in CBF. Conclusions Although low-flow CPB resulted in a marked decrease in CBF compared with prebypass and full-flow bypass, phenylephrine administered to double arterial pressure during low-flow bypass produced a proportional increase in CBF.

Background Brain temperature is closely approximated by most body temperature measurements under normal anesthetic conditions. However, when thermal autoregulation is overridden, large temperature gradients may prevail. This study sought to determine which of the standard temperature monitoring sites best approximates brain temperature when deep hypothermia is rapidly induced and reversed during cardiopulmonary bypass. Methods Twenty-seven patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest in order for each to have a giant cerebral aneurysm surgically clipped. Brain temperatures were measured directly with a thermocouple embedded in the cerebral cortex. Eight other body temperatures were monitored simultaneously with less invasive sensors at standard sites. Results Brain temperature decreased from 32.6 +/- 1.4 degrees C (mean +/- SD) to 16.7 +/- 1.7 degrees C in 28 +/- 7 min, for an average cerebral cooling rate of 0.59 +/- 0.15 degrees C/min. Circulatory arrest lasted 24 +/- 15 min and was followed by 63 +/- 17 min of rewarming at 0.31 +/- 0.09 degrees C/min. None of the monitored sites tracked cerebral temperature well throughout the entire hypothermic period. During rapid temperature change, nasopharyngeal, esophageal, and pulmonary artery temperatures corresponded to brain temperature with smaller mean differences than did those of the tympanic membrane, bladder, rectum, axilla, and sole of the foot. At circulatory arrest, nasopharyngeal, esophageal, and pulmonary artery mean temperatures were within 1 degree C of brain temperature, even though individual patients frequently exhibited disparate values at those sites. Conclusions When profound hypothermia is rapidly induced and reversed, temperature measurements made at standard monitoring sites may not reflect cerebral temperature. Measurements from the nasopharynx, esophagus, and pulmonary artery tend to match brain temperature best but only with an array of data can one feel comfortable disregarding discordant readings.