Clonidine suppresses plasma and cerebrospinal fluid concentrations of TNF-alpha during the perioperative period.

UNLABELLED: The analgesic properties of alpha(2)-agonists are well known. In experimental models, tumor necrosis factor (TNF)-alpha regulates adrenergic responses in the brain. Constitutive TNF-alpha, in brain regions involved in pain perception, is decreased after the administration of clonidine. We investigated patients undergoing lower-extremity revascularization. Seven patients were treated with clonidine 0.2 mg per os (low), and three patients received 0.4 mg per os clonidine (high) before surgery. Eight patients received placebo and served as controls. Continuous spinal anesthesia was provided by insertion of a pliable catheter into the subarachnoid space. Baseline plasma and cerebrospinal fluid (CSF) samples were obtained before injection of local anesthetic. Samples were analyzed for TNF-alpha using a biologic assay. Systemic and central release of catecholamines were assessed by high-pressure liquid chromatography measurement of norepinephrine in plasma and CSF, vanillylmandelic acid and methoxy hydroxyl phenyl glycol in 24-h urinary excretion, respectively. Clonidine 0.2 mg pretreatment decreased TNF-alpha concentrations both in plasma and CSF. Patients receiving clonidine had lower pain visual analog scale scores and required less morphine compared with the Placebo group (P < 0.01). Preoperative administration of clonidine decreased catecholamine release in the periphery, as well as in the central nervous system. A smaller norepinephrine concentration in plasma and CSF, and less secretion of vanillylmandelic acid (P < 0.01) and methoxy hydroxyl phenyl glycol in the urine, were observed. Larger dose clonidine (0.4 mg) resulted in no detectable TNF-alpha in CSF. These results suggest that an interaction between TNF-alpha and the function of adrenergic neurons in the central nervous system may contribute to the sedative and analgesic effects of adrenergic agonists. IMPLICATIONS: Preoperative administration of clonidine decreases both plasma and cerebrospinal fluid concentrations of inflammatory cytokines, resulting in perioperative analgesia and decreased sympathetic tone.

What is the relationship between paresthesia and nerve stimulation for axillary brachial plexus block?

BACKGROUND AND OBJECTIVES: To quantify the motor threshold current of a needle following elicitation of paresthesia during axillary brachial plexus block (ABPB). METHODS: This is a prospective, observational study of ABPB in 72 patients. Having elicited paresthesia, the minimum current required to produce a motor response was noted. The development and success of the block were subsequently followed. RESULTS: Nineteen blocks were excluded (18 because of arterial puncture and 1 blocked needle). Of the remaining 53 blocks, 41 (77%) produced a motor response at 0.5 mA or less. The median current was 0.17 mA (range, 0.03 to 3.3 mA). The site of initial paresthesia and subsequent motor response were related in 43 (81%) of cases. CONCLUSIONS: A needle position causing paresthesia produced a motor response at 0.5 mA or less in 77% of cases studied. This current may, therefore, be a reasonable threshold to aim for when performing an ABPB.

Role of macrophage inflammatory protein-2 in aspiration-induced lung injury.

OBJECTIVE: To determine the role of the chemokine, macrophage inflammatory protein (MIP)-2, in the pathogenesis of aspiration-induced lung injury in the rat. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratories. SUBJECTS: Adult, male Long-Evans rats. INTERVENTIONS: Anesthetized rats underwent induction of lung injury by well-described models of aspiration triggered by intra-tracheal delivery of acid alone, gastric particles alone, or the combination. After injury, induction of MIP-2 messenger RNA in whole lungs and immunoreactive MIP-2 in bronchoalveolar lavage (BAL) fluids was determined. The contribution of MIP-2 to BAL fluid chemotactic activity was defined by using an in vitro chemotaxis assay. The in vivo effect of blocking MIP-2 on pulmonary vascular leak, BAL fluid neutrophils, PaO2/FIO2 ratio, and alveolar-arterial oxygen tension gradient in acid-induced lung injury was determined. MEASUREMENTS AND MAIN RESULTS: Induction of MIP-2 messenger RNA and protein over time was observed in response to all three stimuli. A significant portion (25% to 41%) of the chemotactic activity in BAL fluids from injured rats was inhibited by anti-MIP-2 antibody. After acid injury, blocking of MIP-2 was associated with a 53% decrease in BAL fluid neutrophils and a 33% decrease in pulmonary vascular leak. Although acid injury both impaired oxygenation and increased venous admixture, in vivo blocking of MIP-2 was associated with improved oxygenation as well as decreased venous admixture. CONCLUSIONS: MIP-2 was up-regulated during the development of aspiration-induced lung injury in rats. MIP-2 contributed to lung accumulation of neutrophils via a chemotactic mechanism. Although oxygenation and venous admixture are worsened by acid-induced lung injury in vivo, blocking of MIP-2 at the onset of injury improved these physiologic alterations. Because the aspiration event often is witnessed, chemokines may be valid therapeutic targets for inhibiting the subsequent inflammatory response.

Acid aspiration increases sensitivity to increased ambient oxygen concentrations.

Previously we have demonstrated that prolonged exposure to 100% ambient oxygen leads to a marked loss in functional lung volume and lung compliance, hypoxemia, and surfactant system abnormalities similar to acute respiratory distress syndrome (ARDS). However, 50% oxygen administration is believed to be safe in most clinical settings. In the present study, we have evaluated the effects of a 24-h exposure to 50% oxygen in rabbits immediately following experimental gastric acid aspiration. Mild hypoxemia, but no changes in mortality, lung volume, lung compliance, surfactant metabolism, or edema formation occurred after 24 h of normoxia postacid aspiration. Conversely, a relatively short (24-h) exposure to 50% oxygen after acid aspiration results in increased pulmonary edema, physical signs of respiratory distress, and mortality, as well as decreased arterial oxygenation, lung volume, lung compliance, and type II alveolar cell surfactant synthesis. These results suggest that acid aspiration alters the "set point" for oxygen toxicity, possibly by "priming" cells through activation of inflammatory pathways. This pathogenic mechanism may contribute to the progression of aspiration pneumonia to ARDS.

Capsular polysaccharide and O-specific antigen divergently modulate pulmonary neutrophil influx in an Escherichia coli model of gram-negative pneumonitis in rats.

Enteric gram-negative bacilli cause a severe, often life-threatening pneumonia. An improved understanding of the pathogenesis of this infection may lead to improved treatment. Nearly all of the responsible gram-negative bacilli possess capsular polysaccharides and/or an O-specific antigen as part of their lipopolysaccharide (LPS). We hypothesized that these surface polysaccharides may modulate the pulmonary host response. To investigate this, a rat pneumonitis model was used, and pulmonary neutrophil influx, a critical aspect of host defense, was measured. To assess for the effect of the capsule and O-specific antigen on this host response, three proven, isogenic derivatives that are deficient in capsular polysaccharide alone (CP9.137), the O-specific antigen moiety of the LPS alone (CP921), and both the capsular polysaccharide and O-specific antigen (CP923), as well as their wild-type parent (CP9), were used as challenge strains at various intratracheal challenge inocula (CI). Total lung myeloperoxidase (MPO), a surrogate marker for neutrophils, was measured for 15 h post-bacterial challenge. To determine the effect of capsule and the O-specific antigen on the measured MPO levels, a mathematical model was developed and used to describe the MPO levels as a function of time for each CI of each of the four strains. The results from this analysis demonstrated that in the absence of the K54 capsule, 80.7 times the CI is necessary to achieve the same maximum MPO level relative to K54 positive strains (P < 0.0001). In contrast, a diametric effect was observed in the absence of the O-specific antigen, where 0.13 times the CI was necessary to achieve the same maximum MPO level relative to O4-positive strains (P = 0.0032). No interactive effect was observed between the capsule and the O-specific antigen. These findings demonstrate that these surface polysaccharides modulate pulmonary neutrophil influx and suggest that the K54 capsular polysaccharide is a proinflammatory mediator and that the O4-specific antigen attenuates the proinflammatory response. If these speculations are substantiated, an understanding of how the capsule and the O-specific antigen modulate host response could have significant therapeutic implications. The potential use of biologic modulators directed against the host response, as well as approaches based on inactivating bacterial components (e.g., surface polysaccharides) in attempts to modify sepsis syndromes, could be developed.

Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain.

The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.

Systemic perfluorocarbons suppress the acute lung inflammation after gastric acid aspiration in rats.

UNLABELLED: Perflurocarbons (PFCs) are used during liquid ventilation and as hemoglobin substitutes. PFCs reduce free radical generation and damage to the lung during liquid ventilation. Thus, we examined the effects of parenteral administration of PFCs on lung injury after acid aspiration. Rats were treated with intraperitoneal injection of either FC-77 or IV injection of Fluosol. Controls received intraperitoneal or IV normal saline (NS) before or at the time of injury and then were injured by instillation of NS + HCl (pH = 1.25) into their lungs via a tracheotomy. The animals were exposed to air or 98% oxygen, breathing spontaneously. The rats were injected with 0.05 microCi of (125)I-albumin (bovine serum albumin) before injury. The extent of lung injury was assessed 5 h postinjury by compliance and lung albumin permeability index measurement. Myeloperoxidase (MPO) activity and histologic examination were used to assess neutrophilic infiltration. Both FC-77 and Fluosol decreased the permeability index compared with controls (1.05 +/- 0.08; 1.08 +/- 0. 12, respectively, versus 1.34 +/- 0.21) and improved lung compliance after intratracheal instillation of 1.2 mL/kg of HCl/NS, pH = 1.25 + hyperoxia injury (P < 0.05). Lung MPO activity decreased in the FC-77 group and was associated with a concomitant decrease in neutrophil infiltration. MPO activity of the spleen increased after FC-77 treatment. The administration of FC-77 decreased the severity of lung permeability changes associated with acid in the presence or absence of hyperoxia exposure. These data suggest that attenuation of neutrophilic infiltration by PFCs decreases lung injury. IMPLICATIONS: Intraperitoneally administered perfluorocarbons in rats attenuate the neutrophilic infiltration in the lung after acid aspiration, thereby decreasing the alveolar protein leakage and improving pulmonary compliance.

Effects of open versus closed kinetic chain training on knee laxity in the early period after anterior cruciate ligament reconstruction.

Knee extensor resistance training using open kinetic chain (OKC) exercise for patients recovering from anterior cruciate ligament reconstruction (ACLR) surgery has lost favour mainly because of research indicating that OKC exercise causes greater ACL strain than closed kinetic chain (CKC) exercise. In this prospective, randomized clinical trial the effects of these two regimes on knee laxity were compared in the early period after ACLR surgery. Thirty-six patients recovering from ACLR surgery (29 males, 7 females; age mean = 30) were tested at 2 and 6 weeks after ACLR with knee laxity measured using the Knee Signature System arthrometer. Between tests subjects trained using either OKC or CKC resistance of their knee and hip extensors in formal physical therapy sessions three times per week. Following adjustment for site of treatment, pretraining injured knee laxity, and untreated knee laxity at post-training, the use of OKC exercise, when compared to CKC exercise, was found to lead to a 9% increase in looseness with a 95% confidence interval of -8% to +29%. These results indicate that the great concern about the safety of OKC knee extensor training in the early period after ACLR surgery may not be well founded.

Brain-derived TNFalpha mediates neuropathic pain.

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague-Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58 degrees C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.

High-dose nitric oxide inhalation increases lung injury after gastric aspiration.

BACKGROUND: Inhaled nitric oxide is often used in patients with adult respiratory distress syndrome. However, nitric oxide also may be significantly toxic, especially if administered concurrently with hyperoxia. The authors evaluated the isolated effect of nitric oxide and the combined effects of nitric oxide and hyperoxia on lung injury in rats after acid aspiration. METHODS: Animals were injured by instillation of 1.2 ml/kg hydrogen chloride in low-pH saline (the acid group) or acidified gastric particles (the casp group) into the lungs under halothane anesthesia via a tracheal catheter. Controls received no injury vehicle but rather underwent the surgical process. After recovery from anesthesia, the animals were exposed to 20% or 90% oxygen with or without 20, 40, or 80 ppm nitric oxide for 5 h. The permeability index, alveolar-arterial oxygen difference, the ratio of oxygen pressure to the inspired fraction of oxygen, and the ratio of wet to dry weight were assessed 5 h after injury as indices of lung injury. Data were assessed using analysis of variance. RESULTS: Each group included 6-10 rats. Exposure to nitric oxide (80 ppm) in air increased protein permeability in the lungs to a permeability index of 1.42+/-0.12 after acid aspiration. The combination of nitric oxide (80 ppm) and hyperoxia further increased protein leakage to a permeability index of 2.1+/-0.25. Exposure to lower concentrations of nitric oxide (e.g., 20 and 40 ppm) increased the permeability index of the lungs (1.44+/-0.21, 1.75+/-0.29, respectively) in the presence of hyperoxia, although it did not affect the permeability index of the lungs during exposure to air. Pretreatment of animals with deferoxamine and methylene blue partially inhibited the adverse effect of hyperoxia and nitric oxide, which suggested a complex underlying mechanism involving both reactive-species generation and pulmonary vasomotor changes. CONCLUSIONS: These results show that inhaled nitric oxide at 80 ppm for a short duration (5 h) increases the severity of the inflammatory microvascular lung injury after acid aspiration. The pulmonary damage is exacerbated further in the presence of high oxygen concentrations. Although lower concentrations of nitric oxide did not increase the extent of lung injury, longer exposure times need to be assessed.

The role of tumor necrosis factor-alpha in the pathogenesis of aspiration pneumonitis in rats.

BACKGROUND: Aspiration pneumonitis is characterized by proteinaceous pulmonary edema and acute infiltration of neutrophils into the alveolar space. This study examined the role of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), on the pathogenesis of the injury produced by the different components that may be present in the aspirate, acid, or gastric particles. METHODS: Rats were injured by intratracheal instillation of a vehicle containing acid or gastric particles. TNF-alpha concentration of bronchoalveolar lavage fluid was determined using a bioassay. upregulation of lung TNF-alpha mRNA was also measured. The effect of intratracheal anti-rat TNF-alpha treatment was assessed by lung protein permeability, blood gases, and lung myeloperoxidase activity. RESULTS: Injury vehicle alone and acid injury resulted in a small TNF-alpha peak 1-2 h after injury in the lavage fluid. Both particulate and acidic particulate groups produced a much more robust TNF-alpha signal that reached a plateau at 2-4 h after injury and declined at 8 h. Upregulation of TNF-alpha mRNA was only detected in the particulate-containing groups. Acidic particulate exposure yielded a synergistic increase in protein permeability and decrease in blood oxygenation. Anti-TNF-alpha treatment reduced protein permeability and myeloperoxidase activity and increased blood oxygenation in the groups exposed to only acid. Such treatment had no effect on either of the particulate containing injuries. CONCLUSIONS: TNF-alpha is differentially manifested according to the components that make up the aspirate but the levels of TNF-alpha expression do not correlate with the severity of the resultant injury. However, the reduction in acid-induced lung injury by anti-TNF-alpha treatment indicates that TNF-alpha plays a role in the pathogenesis of aspiration pneumonitis.

Ca2+-induced Ca2+ release involved in positive inotropic effect mediated by CGRP in ventricular myocytes.

To investigate the effects and mechanisms of calcitonin gene-related peptide (CGRP) on ventricular contractility, ventricular myocytes isolated from adult rat and mouse hearts were exposed to CGRP. Myocyte contractility was assessed by a video edge motion detector, and the intracellular [Ca2+] transients were measured by a spectroflurophotometer in fura 2-loaded myocytes. CGRP exerted a potent concentration-dependent (10 pM-10 nM, EC50 = 44.1 pM) positive inotropism on rat ventricular myocytes. CGRP (1 nM) increased cell shortening during contraction by 140 +/- 40% above baselines and increased maximum velocity of contraction and relaxation by 98 and 106%, respectively. CGRP failed to produce any response in the presence of the CGRP1 receptor antagonist. CGRP induced similar inotropic response in mouse ventricular myocytes. CGRP increased the amplitude of [Ca2+] transients of ventricular myocytes by 120 +/- 25% above baseline and shortened the time of half-maximum myoplasmic Ca2+ clearance by 30 +/- 5%. Increase in intracellular Ca2+ mobilization by CGRP was dependent on Ca2+ influx through the activation of the L-type Ca2+ channel, because nifedipine blocked the CGRP-induced increase in [Ca2+] transients. Furthermore, CGRP failed to increase [Ca2+] transients after the inhibition of protein kinase A in ventricular myocytes. These data indicate that stimulation of mammalian ventricular myocardial CGRP1 receptors enhances [Ca2+] transients through the activation of protein kinase A, which in turn activates voltage-dependent L-type Ca2+ channels. These events lead to Ca2+-induced intracellular Ca2+ release and enhanced myocyte contraction and facilitated relaxation.

Reactive oxygen species contribute to oxygen-related lung injury after acid aspiration.

UNLABELLED: Hyperoxia increases pulmonary damage after acid aspiration. We hypothesize that free radicals play a role in acute lung injury. To examine this hypothesis, we injured rats by intratracheal instillation of acidic isotonic sodium chloride solution (NS) (pH 1.25); NS + gastric particles (particle pH 5.3); or acid + particles (pH 1.25). Animals were exposed to 98% oxygen or air for 5 h. Superoxide (HO2) generation was measured in either an aliquot of white blood cells (WBCs) recovered from bronchoalveolar lavage (BAL) or from blood. Lungs were analyzed for thiobarbituric acid-reactive substances (TBARS) and carbonylated proteins. The antioxidant capacity was measured using a 2-2'-azo-bis-amidinopropane hydrochloride neutralizing assay. Generation of HO2 by WBCs in peripheral blood was greater in animals exposed to 98% O2 (89.8 +/- 12.5 U. min-1.10(5) neutrophils) compared with air exposure (37.5 +/- 9.2 U.min-1.10(5) neutrophils) after combined injury (P < 0.05). Similarly, HO2 generation by WBCs retrieved from BAL was higher in oxygen-exposed rats (987.74 +/- 128 U.min-1.10(5) WBC) compared with air-exposed animals after an identical injury (348 +/- 9.2 U. min-1.10(5) WBC) (P < 0.05). TBARS and carbonylated protein levels in the lungs of oxygen-exposed animals (587.9 +/- 58.6 and 55.8 +/- 3.1 pmol/mg of protein, respectively) were higher than those in air-exposed rats after combined injury (342.8 +/- 15.1 and 28.6 +/- 4.6 pmol/mg of protein, respectively) and compared with air-exposed uninjured rats (340.6 +/- 9.8 and 18.3 +/- 2.8 pmol/mg of protein, respectively; P < 0.01). Antioxidant capacity decreased in acid and combined injury groups (2.41 +/- 0.13 min and 1.94 +/- 0.15 min, respectively) compared with the uninjured group after 5 h of exposure to 98% oxygen (4.85 +/- 0.19 min; P < 0.01). We demonstrated evidence of increased oxidant activity on lipids and proteins in injured lungs after oxygen exposure. The decrease in antioxidant capacity after low pH aspiration with exposure to hyperoxia may contribute to this increase. IMPLICATIONS: Oxygen administration results in a lung pathology known as oxygen toxicity. This effect is usually not significant if the duration of exposure is limited to < 24 h. In the presence of acute inflammatory lung injury, exposure to hyperoxia results in lung damage in a shorter time. We demonstrate that sufficiently decreased lung antioxidant reserve capacity may be accountable for this early toxicity.

Adrenergic regulation of macrophage-derived tumor necrosis factor-alpha generation during a chronic polyarthritis pain model.

Increases in the levels of proinflammatory cytokines, such as TNF alpha, have been intricately linked with arthritis and the pathogenesis of several models of neuropathic pain. In addition, arthritis (as well as other types of persistent pain) is associated with increased sympathetic activity and alterations of other responses in autonomic nervous activity. Adrenergic regulation of LPS-stimulated TNF production by M phi isolated from rats with streptococcal-cell-wall (SCW)-induced arthritis has been examined. Serum TNF levels and the cellular composition of peritoneal exudates have also been assessed. M phi were obtained from: (1) normal control rats, (2) animals injected with complete Freund's adjuvant (CFA), 3 rats injected with SCW and arthritic, and (4) those injected with SCW, which failed to develop arthritis. Serum levels of TNF alpha in rats that develop arthritis are significantly greater (2.4 fold) than levels from the other groups. The proportion of OX19-positive T cell subpopulations are the same in peritoneal exudates from all groups. Immunocytochemical staining also reveals differences between M phi subgroups in the degree of activation. Peritoneal exudates from rats that develop arthritis contain a greater proportion of the high TNF producing subclass of M phi, as identified by positive ED3 staining (p < 0.001). In contrast, Ia antigen presenting M phi (OX6-positive) in the peritoneal exudate cells are only elevated in rats administered CFA. The selective blockade of adrenergic receptors by idazoxan or propranolol demonstrates that the constitutive involvement of either alpha 2 or beta-adrenergic regulation of M phi-derived TNF production is pronounced in rats with arthritis (p < 0.001). These investigations demonstrate a distinctive pattern of peripheral M phi populations in rats that develop chronic polyarthritic pain. We believe that identification of interactions between the adrenergic responses and proinflammatory cytokines will lead to the development of improved strategies to treat patients with chronic pain.

Alterations in the course of acid-induced lung injury in rats after general anesthesia: volatile anesthetics versus ketamine.

UNLABELLED: Pulmonary aspiration of gastric acid is a complication that occurs during anesthesia. The effects of the often used anesthetics on the inflammatory response after aspiration of acid are not known. We examined the effects of three different inhaled anesthetics--halothane, enflurane, and isoflurane--as well as parenteral ketamine, on the associated immediate mortality, alveolar protein leakage, and morphometric changes after intrapulmonary instillation of acidic solution in rats. Animals in deep state of anesthesia had a higher mortality after the instillation of acidic solutions than those in lighter stages (82.5% vs 31.6%). Protein leakage over 5 h was greater in the animals receiving volatile anesthetics (range 0.9-1.2) compared with those receiving ketamine (0.6 +/- 0.05). Desferoxamine did not decrease protein leakage in acid-injured animals (1.1 +/- 0.06 vs 1.02 +/- 0.08). Furthermore, volatile anesthetics resulted in an increase in the acute inflammatory response and leukocytic infiltration compared with ketamine in acid-injured lungs. We conclude that the administration of inhaled anesthetics was associated with exacerbation of an acute inflammatory response after aspiration of acidic solution. Lung injury was not increased with ketamine anesthesia. This difference was the result of the hypotensive effects of inhaled anesthetics. IMPLICATIONS: This study reveals that the use of inhaled anesthetics aggravates inflammation secondary to gastric aspiration and should be avoided on diagnosis of the situation.

Observations and predictions of secondary neutrons on Space Shuttle and aircraft.

The Cosmic Radiation Effects and Activation Monitor has flown on six Shuttle flights between September 1991 and February 1995 covering the full range of inclinations as well as altitudes between 220 and 570 km, while a version has flown at supersonic altitudes on Concorde between 1988 and 1992 and at subsonic altitudes on a SAS Boeing 767 between May and August 1993. The Shuttle flights have included passive packages in addition to the active cosmic ray monitor which comprises an array of pin diodes. These are positioned at a number of locations to investigate the influence of shielding and local materials. Use of both metal activation foils and scintillator crystals enables neutron fluences to be inferred from the induced radioactivity which is observed on return to Earth. Supporting radiation transport calculations are performed to predict secondary neutron spectra and the energy deposition due to nuclear reactions in silicon pin diodes and the induced radioactivity in the various scintillator crystals. The wide variety of orbital and atmospheric locations enables investigation of the influence of shielding on cosmic ray, trapped proton and solar flare proton spectra.

Volatile anesthetic effects on ischemic myocardium.

Volatile anesthetics, particularly the new generation of agents, have a very rapid onset and offset of action. These properties allow for quick recovery from clinical anesthesia. Because there is additional evidence that these agents have protective effects during myocardial ischemia, there may be advantages for 'fast tracking' patients undergoing coronary revascularization procedures.

Hyperoxia exacerbates microvascular lung injury following acid aspiration.

OBJECTIVES: To examine the effects of an increase in ambient oxygen (O2) concentrations on the extent of inflammatory pulmonary damage following acid aspiration. DESIGN: Prospective, controlled laboratory study. SETTINGS: University-affiliated animal research facility. SUBJECTS: Male, Long Evans rats weighing 250 to 300 g. INTERVENTION: Rats were injured by instillation of 1.2 mL/kg normal saline solution/HCl, pH= 1.25 (acid), into the lungs via a tracheotomy. Animals were allowed to awaken and were exposed to 21%, 50%, or 98% O2 for 0 to 5 h (n/group > or = 10). In a separate set of experiments, injured rats exposed to 98% O2 were treated with different doses of deferoxamine, just prior to injury. Uninjured rats and rats injured with normal saline solution, pH = 5.3, were used as the control group. MEASUREMENTS: Injury was determined by assessing lung function (lung compliance and arterial blood gases) and alveolar-capillary wall integrity (wet/dry weight, lung albumin permeability index [PI], and intrapulmonary hemorrhage [HI]). RESULTS: Intrapulmonary instillation of acid increased PI, HI, and decreased static lung compliance compared to uninjured control animals. Increased ambient oxygen following acid aspiration decreased lung compliance, 1.06+/-0.03 mL/kg/cm H2O, in oxygen-exposed lungs when compared to the lungs exposed to air, 1.26+/-0.04, following a low pH aspirate (p<0.05). An increase in protein leakage into the lung tissue was noted in oxygen-exposed animals, PI=1.33+/-0.10, vs air-exposed rats, 0.89+/-0.07 (p<0.05). The hyperoxia-induced increase in lung injury was prevented by 30 mg/kg or higher deferoxamine treatment, 0.78+/-0.05 (p<0.05). Exposure of animals to 98% O2 for 2 h was sufficient to produce the same increase in microvascular protein leakage as 5-h exposure to O2 following low pH aspirate. CONCLUSION: Hyperoxia increases acid aspiration-induced inflammatory microvascular lung injury. This appears to be mediated by production of reactive species of O2.