Thomas J. K. Toung

Estrogen-Mediated Neuroprotection After Experimental Stroke in Male Rats

BACKGROUND AND PURPOSEnWe have previously shown that 17beta-estradiol reduces infarction volume in female rats. The present study determined whether single injection or chronic implantation of estrogen confers neuroprotection in male animals with middle cerebral artery occlusion (MCAO) and whether there is an interaction with endogenous testosterone.nnnMETHODSnMale Wistar rats were treated with 2 hours of reversible MCAO. In protocol 1, acute versus chronic estrogen administration was examined in groups receiving the following: Premarin (USP) 1 mg/kg IV, immediately before MCAO (Acute, n=13, plasma estradiol=171+/-51 pg/mL); 7 days of 25 microg (E25, n=10, 10+/-3 pg/mL) or 100 microg 17beta-estradiol (E100, n=12, 69+/-20 pg/mL) by subcutaneous implant; or saline (SAL, n=21, 3+/-1 pg/mL). Laser-Doppler flowmetry was used to monitor the ipsilateral parietal cortex throughout the ischemic period and early reperfusion. At 22 hours of reperfusion, infarction volume was determined by 0 2,3,5-triphenyltetrazolium chloride staining and image analysis. In protocol 2, rats were castrated to deplete endogenous testosterone and then treated with estradiol implants: castration only (CAST, n= 13, estradiol=5+/-2 pg/mL), sham-operated (SHAM, n= 10, 4+/-2 pg/mL), estradiol implant 25 microg (CAST+E25, n=16, 7+/-2 pg/mL) or 100 microg (CAST+E100, n=14, 77+/-14 pg/mL).nnnRESULTSnCortical infarct volumes were reduced in all estrogen-treated groups: Acute (21+/-4% of ipsilateral cortex), E25 (12+/-5%), and E100 (12+/-3%) relative to SAL (38+/-5%). Caudate infarction was similarly decreased: Acute (39+/-7% of ipsilateral striatum), E25 (25+/-7%), and E100 (34+/-6%) relative to SAL (63+/-4%). Castration did not alter ischemic outcome; cortical and caudate infarction (percentage of respective ipsilateral regions) were 37+/-5% and 59+/-5% in CAST and 39+/-7% and 57+/-5% in SHAM, respectively. Estrogen replacement reduced infarction volume in castrated animals in cortex (19+/-4% in CAST+E25 and 12+/-4% in CAST+E100) and in caudate (42+/-6% in CAST+25 and 20+/-7% in CAST + 100). Laser-Doppler flowmetry results during ischemia and reperfusion was not different among groups.nnnCONCLUSIONSnBoth acute and chronic 17beta-estradiol treatments protect male brain in experimental stroke. Testosterone availability does not alter estradiol-mediated tissue salvage after MCAO.

Diagnosis and Treatment of Vascular Air Embolism

Vascular air embolism is a potentially life-threatening event that is now encountered routinely in the operating room and other patient care areas. The circumstances under which physicians and nurses may encounter air embolism are no longer limited to neurosurgical procedures conducted in the “sitting position” and occur in such diverse areas as the interventional radiology suite or laparoscopic surgical center. Advances in monitoring devices coupled with an understanding of the pathophysiology of vascular air embolism will enable the physician to successfully manage these potentially challenging clinical scenarios. A comprehensive review of the etiology and diagnosis of vascular air embolism, including approaches to prevention and management based on experimental and clinical data, is presented. This compendium of information will permit the healthcare professional to rapidly assess the relative risk of vascular air embolism and implement monitoring and treatment strategies appropriate for the planned invasive procedure.

Hypertonic saline: First-line therapy for cerebral edema?

This article highlights the experimental and clinical data, controversies and postulated mechanisms surrounding osmotherapy with hypertonic saline (HS) solutions in the neurocritical care arena and builds on previous reviews on the subject. Special attention is focused on HS therapy on commonly encountered clinical paradigms of acute brain injury including traumatic brain injury (TBI), post-operative retraction edema, intracranial hemorrhage (ICH), tumor-associated cerebral edema, and ischemia associated with ischemic stroke.

Effect of intra-alveolar meconium on pulmonary surface tension properties.

To evaluate the effect of meconium on pulmonary surface tension properties, the mechanics of 30 excised, separated canine pulmonary lobes were studied. Meconia were blended in normal saline to produce solutions of 10% and 20%. Solutions were filtered to remove large particles and instilled endobronchially into the canine lobes. The static pressure-volume deflation curve of each lobe was determined before and 4 h after instillation of either normal saline or meconium solution. In the saline control group (eight lobes), the curve was essentially unchanged before and after instillation. In the 10% meconium group (14 lobes), the curve was significantly depressed after instillation, especially at a transpulmonary airway pressure of 10 cm H2O (p <.05) and 5 cm H20 (p <.005). In the 20% meconium group (eight lobes), the depression of the pressure-volume curve was essentially the same as that of the 10% solution group. It is concluded that meconium depresses the surface-active properties of the alveolar linings.

Neuroprotective κ-Opioid Receptor Agonist BRL 52537 Attenuates Ischemia-Evoked Nitric Oxide Production In Vivo in Rats

Background and Purpose— &kgr;-Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl) methylpiperidine], on infarct volume and nitric oxide production after transient focal ischemia in the rat. Methods— With the use of the intraluminal filament technique, halothane-anesthetized male Wistar rats (weight, 250 to 300 g) were subjected to 2 hours of focal cerebral ischemia confirmed by Doppler flowmetry. In a blinded randomized fashion, rats were treated with intravenous saline or 1 mg/kg per hour BRL 52537 infusion, initiated 15 minutes before occlusion and maintained until 2 hours of reperfusion. In a second experiment, rats were treated during reperfusion with saline or 1 mg/kg per hour BRL 52537, initiated at onset of reperfusion and continued for 22 hours. In a final experiment, in vivo striatal nitric oxide production was estimated via microdialysis by quantification of citrulline recovery after labeled arginine infusion in striatum of intravenous BRL 52537– or saline-treated rats. Results— In rats treated with BRL 52537 during ischemia and early reperfusion, infarct volume was significantly attenuated in cortex (16±6% versus 40±7% of ipsilateral cortex in saline group) and in caudoputamen (30±8% versus 66±6% of ipsilateral caudoputamen in saline group). Infarct volume was also reduced by treatment administered only during reperfusion in cortex (19±8% in BRL 52537 group [n=10] versus 38±6% in saline group) and in caudoputamen (35±9% versus 66±4% in saline group). BRL 52537 treatment markedly attenuated NO production in ischemic striatum compared with saline-treated controls. Conclusions— These data demonstrate that (1) the selective KOR agonist BRL 52537 provides significant neuroprotection from focal cerebral ischemia when given as a pretreatment or as a posttreatment and (2) attenuation of ischemia-evoked nitric oxide production in vivo may represent one mechanism of ischemic neuroprotection.

Increased mediastinal pressure and decreased cardiac output during laparoscopic Nissen fundoplication

BACKGROUNDnLaparoscopic Nissen fundoplication (LNF) is gaining popularity. Although the hemodynamic effects of the typical pneumoperitoneum have been studied, the additional consequences of the hiatal dissection necessary for LNF have not.nnnMETHODSnSeven female pigs were anesthetized, intubated, and ventilated with a volume ventilator and hemodynamic and mechanical pressure monitoring devices were placed. Pressures were recorded every 15 minutes for 1 hour after each of four interventions: (1) anesthesia induction, (2) CO2 pneumoperitoneum (15 mm Hg), (3) LNF, and (4) release of pneumoperitoneum (and removal of ports).nnnRESULTSnRight atrial, inferior vena caval, mediastinal, pleural, airway, and pulmonary capillary wedge pressures all increased after pneumoperitoneum (p < 0.05). Only mediastinal pressure (8.6 vs 13.7 mm Hg, pneumoperitoneum vs LNF; p < 0.05) and pleural pressure (2.6 vs 3.5 mm Hg, pneumoperitoneum vs LNF; p < 0.05) showed a further significant increase after LNF. In addition, cardiac output fell significantly after LNF (5.9 vs. 4.6 L/min; p < 0.05). Mediastinal pressure and cardiac output remained significantly altered after the release of pneumoperitoneum.nnnCONCLUSIONSnSurgical disruption of the esophageal hiatus during LNF causes both increased mediastinal and pleural pressure and a significant reduction in cardiac output. These findings uncover a previously unsuspected physiologic detriment that may occur during LNF.

Effect of PEEP and Jugular Venous Compression on Canine Cerebral Blood Flow and Oxygen Consumption in the Head Elevated Position

Cerebral blood flow (CBF) (radiolabelled microspheres) and oxygen consumption (CMRO2) were studied in nine dogs during 30 min of either neck vein compression or application of positive end-expiratory pressure (PEEP) ventilation. With the animal in the prone position, elevation of the head from horizontal to 30 cm above the heart markedly decreased cisterna magna (PCSF) and dorsal sagittal sinus pressure (PCV). With the head elevated, compression of neck veins using neck tourniquet (pressure 40 mmHg) increased PCSF and PCV from 3.6 2.2 to 6.8 4.8 and −2.5 2.7 to 2.3 2.3 mmHg (mean SE, P < 0.05), respectively, while total or regional CBF and CMRO2 remained unchanged. Application of PEEP (15 cm H2O) increased right atrial pressure (-4.7 1.7 to −0.1 3.4 mmHg, P < 0.05), but did not affect PCSF or PCV (3.4 3.3 to 3.3 3.7 and −3.5 2.6 to −4.1 2.4 mmHg, respectively, P > 0.05). Total or regional CBF and CMRO2 were also unaffected. These data demonstrate that, although neither maneuver affects CBF or CMRO2, neck vein compression elevates PCV above atmospheric pressure, but PEEP does not. In patients at risk for cerebral venous embolism, intermittent neck vein compression should be used as a prophylactic measure to prevent air embolism.

Effects of pentoxifylline on cerebral blood flow, metabolism, and evoked response after total cerebral ischemia in dogs

ObjectiveTo test the hypothesis that pentoxifylline improves recovery of cerebral electrical activity and metabolic function after a transient cerebral global ischemia by improving cerebral blood flow during the reperfusion period. DesignRandomized, controlled, prospective study. SettingUniversity research laboratory. SubjectsForty male beagle dogs. InterventionsSix control dogs received pentoxifylline (40 mg/kg bolus followed by infusion at 0.2 mg/kg/hr) without ischemia. Thirteen dogs received Ringers lactate solution with 12 mins of cerebral global ischemia (by aortic occlusion). Nine dogs received pentoxifylline before ischemic insult. Six dogs received pentoxifylline on reperfusion, and six dogs received pentoxifylline 30 mins after reperfusion. Measurements and Main ResultsTotal and regional cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potentials were measured during 180 mins of reperfusion. Pentoxifylline did not affect cerebral blood flow, oxygen consumption, or somatosensory evoked potentials without ischemia. Pre-treatment with pentoxifylline resulted in attenuated postischemic hyperemia at 10 mins of reperfusion (94 ± 15 vs. 133 ± 11 [SEM] mL/min/100 g; p < .05), but there was no difference in total cerebral blood flow or oxygen consumption during later points of reperfusion. Pentoxifylline treatment during reperfusion resulted in no recovery of cerebral blood flow or oxygen consumption. All ischemic groups demonstrated a rapid ablation of somatosensory evoked potential amplitude and there were no differences in the decrement of the amplitude on ischemia. At 180 mins of reperfusion, somatosensory evoked potentials recovered to the following percentages of the baseline control values: 28 ± 4% in dogs treated with Ringers lactate solution; 58 ± 4% in the pentoxifylline pretreated group (p < .05); 40 ± 5% in dogs receiving pentoxifylline at reperfusion (p > .05); and 53 ± 8% in dogs receiving pentoxifylline at 30 mins of reperfusion (p < .05). ConclusionsPentoxifylline treatment improves recovery of cerebral electrical function after complete transient cerebral global ischemia by a mechanism that does not involve improvement in cerebral blood flow or global oxygen consumption. (Crit Care Med 1994; 22:273–281)

Effect of hypertonic saline concentration on cerebral and visceral organ water in an uninjured rodent model

Objective:Hypertonic saline has been shown to be an effective osmotic agent to reduce brain water and hence brain volume and intracranial pressure. A direct correlation between dose and effect has been demonstrated, but no studies have compared the effects of different concentrations of the same osmotic load of hypertonic saline over time. We compared the effects of different tonicity of infused hypertonic saline on cerebral, lung, and small bowel water extraction over time under controlled conditions. Design:Laboratory study. Setting:Medical school. Subjects:Male Wistar rats (280–450 g). Interventions:Anesthetized rats were randomized to a 15-min intravenous bolus infusion of 0.9% NaCl or five equisodium but different concentrations of hypertonic saline: 4.2%, 7.5%, 10%, 23.4%, and 30%. Following infusion, animals remained anesthetized for 60, 180, or 300 mins without additional fluids given (n ≥ 6 per group). Blood was sampled, total urine output was measured, and the animal was then killed under deep anesthesia. Cerebral, lung, and small bowel water contents were derived by wet/dry weight measures. Measurements and Main Results:After 60 mins, hypertonic saline administered at 50 mosm/kg resulted in an increase in serum osmolarity in all hypertonic saline groups (p < .05 vs. normal saline), with a significantly greater increase measured using 23.4% or 30% hypertonic saline (23.4%, 365.0 ± 8.8 mosm/L, p < .05 vs. other lesser hypertonic saline doses). The durable effect was present throughout the 300-min period by all but the lowest hypertonic saline (4.2% NaCl). Lung but not small bowel organ water was diminished by hypertonic saline. Brain water content (79.1 ± 0.2% in normal saline controls) was, however, significantly reduced. Conclusions:Hypertonic saline is effective in reducing organ water content in a setting of preserved blood-brain barrier but is not as effective in visceral organs. At equiosmotic doses of hypertonic saline, concentration plays no substantial role in altering serum osmolarity but appears to benefit duration of action. At very high concentrations, such as 23.4% NaCl, additional water extraction is also manifested. At such high concentration of NaCl, tonicity, indeed, matters, especially in water shifts across the blood-brain barrier.

Comparison of equivolume, equiosmolar solutions of mannitol and hypertonic saline with or without furosemide on brain water content in normal rats

Background:Mannitol and hypertonic saline (HS) are used by clinicians to reduce brain water and intracranial pressure and have been evaluated in a variety of experimental and clinical protocols. Administering equivolume, equiosmolar solutions in healthy animals could help produce fundamental data on water translocation in uninjured tissue. Furthermore, the role of furosemide as an adjunct to osmotherapy remains unclear. Methods:Two hundred twenty isoflurane-anesthetized rats were assigned randomly to receive equivolume normal saline, 4.2% HS (1,368 mOsm/L 25% mannitol (1,375 mOsm/L), normal saline plus furosemide (8 mg/kg), or 4.2% HS plus furosemide (8 mg/kg) over 45 min. Rats were killed at 1, 2, 3, and 5 h after completion of the primary infusion. Outcome measurements included body weight; urinary output; serum and urinary osmolarity and electrolytes; and brain, lung, skeletal muscle, and small bowel water content. Results:In the mannitol group, the mean water content of brain tissue during the experiment was 78.0% (99.3% CI, 77.9–78.2%), compared to results from the normal saline (79.3% [99.3% CI, 79.1–79.5%]) and HS (78.8% [99.3% CI, 78.6–78.9%]) groups (P < 0.001), whereas HS plus furosemide yielded 78.0% (99.3% CI, 77.8–78.2%) (P = 0.917). After reaching a nadir at 1 h, brain water content increased at similar rates for mannitol (0.27%/h [99.3% CI, 0.14–0.40%/h]) and HS (0.27%/h [99.3% CI, 0.17–0.37%/h]) groups (P = 0.968). Conclusions:When compared to equivolume, equiosmolar administration of HS, mannitol reduced brain water content to a greater extent over the entire course of the 5-h experiment. When furosemide was added to HS, the brain-dehydrating effect could not be distinguished from that of mannitol.