Surfactant Attenuates Air Embolism-Induced Lung Injury by Suppressing NKCC1 Expression and NF-κB Activation.

Excessive amounts of air can enter the lungs and cause air embolism (AE)-induced acute lung injury (ALI). Pulmonary AE can occur during diving, aviation, and iatrogenic invasive procedures. AE-induced lung injury presents with severe hypoxia, pulmonary hypertension, microvascular hyper-permeability, and severe inflammatory responses. Pulmonary AE-induced ALI is a serious complication resulting in significant morbidity and mortality. Surfactant is abundant in the lungs and its function is to lower surface tension. Earlier studies have explored the beneficial effects of surfactant in ALI; however, none have investigated the role of surfactant in pulmonary AE-induced ALI. Therefore, we conducted this study to determine the effects of surfactant in pulmonary AE-induced ALI. Isolated-perfused rat lungs were used as a model of pulmonary AE. The animals were divided into four groups (n = 6 per group): sham, air embolism (AE), AE + surfactant (0.5 mg/kg), and AE+ surfactant (1 mg/kg). Surfactant pretreatment was administered before the induction of pulmonary AE. Pulmonary AE was induced by the infusion of 0.7 cc air through a pulmonary artery catheter. After induction of air, pulmonary AE was presented with pulmonary edema, pulmonary microvascular hyper-permeability, and lung inflammation with neutrophilic sequestration. Activation of NF-κB was observed, along with increased expression of pro-inflammatory cytokines, and Na-K-Cl cotransporter isoform 1 (NKCC1). Surfactant suppressed the activation of NF-κB and decreased the expression of pro-inflammatory cytokines and NKCC1, thereby attenuating AE-induced lung injury. Therefore, AE-induced ALI presented with pulmonary edema, microvascular hyper-permeability, and lung inflammation. Surfactant suppressed the expressions of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby attenuating AE-induced lung injury.

Perfluorocarbons for the treatment of decompression illness: how to bridge the gap between theory and practice.

Decompression illness (DCI) is a complex clinical syndrome caused by supersaturation of respiratory gases in blood and tissues after abrupt reduction in ambient pressure. The resulting formation of gas bubbles combined with pulmonary barotrauma leads to venous and arterial gas embolism. Severity of DCI depends on the degree of direct tissue damage caused by growing bubbles or indirect cell injury by impaired oxygen transport, coagulopathy, endothelial dysfunction, and subsequent inflammatory processes. The standard therapy of DCI requires expensive and not ubiquitously accessible hyperbaric chambers, so there is an ongoing search for alternatives. In theory, perfluorocarbons (PFC) are ideal non-recompressive therapeutics, characterized by high solubility of gases. A dual mechanism allows capturing of excess nitrogen and delivery of additional oxygen. Since the 1980s, numerous animal studies have proven significant benefits concerning survival and reduction in DCI symptoms by intravenous application of emulsion-based PFC preparations. However, limited shelf-life, extended organ retention and severe side effects have prevented approval for human usage by regulatory authorities. These negative characteristics are mainly due to emulsifiers, which provide compatibility of PFC to the aqueous medium blood. The encapsulation of PFC with amphiphilic biopolymers, such as albumin, offers a new option to achieve the required biocompatibility avoiding toxic emulsifiers. Recent studies with PFC nanocapsules, which can also be used as artificial oxygen carriers, show promising results. This review summarizes the current state of research concerning DCI pathology and the therapeutic use of PFC including the new generation of non-emulsified formulations based on nanocapsules.

Embolia aérea cerebral masiva tras colangiopancreatografía retrógrada endoscópica. Presentación de un caso y revisión de la bibliografía / Massive cerebral air embolism following endoscopic retrograde cholangiopancreatography. A case report and review of the literature

Introducción. La embolia aérea cerebral tras procesos endoscópicos es una complicación infrecuente, pero que puede tener consecuencias catastróficas. Caso clínico. Varón de 85 años, diagnosticado de colangiocarcinoma distal con criterios de irresecabilidad, al cual se coloca una prótesis biliar de drenaje. Se realiza una colangiopancreatografía retrógrada endoscópica para el cambio de prótesis. Tras el procedimiento, el paciente sufre un deterioro de las constantes vitales y del nivel de consciencia, y requiere intubación orotraqueal. En la tomografía axial computarizada craneal se evidencia una embolia aérea masiva con focos de isquemia hiperaguda en ambos hemisferios. El paciente fallece posteriormente. Conclusiones. El embolismo aéreo cerebral tras una colangiopancreatografía retrógrada endoscópica es infrecuente, pero potencialmente letal. La manipulación de la pared biliointestinal en las exploraciones endoscópicas podría originar comunicaciones entre la luz y el sistema venoso. Esto, unido a la alta presión de insuflación para la realización de la prueba, condicionaría el paso de aire al sistema venoso portal y, de ahí, al sistema circulatorio. En el sistema nervioso central, las burbujas de aire provocarían una obstrucción vascular, con la consiguiente isquemia y necrosis del tejido. Es fundamental un diagnóstico precoz y una terapia de soporte vital. Su rápido manejo puede contribuir a un mejor pronóstico, que en principio es sombrío (AU)

Introduction. Cerebral air embolism following endoscopic processes is an infrequent complication, but can have catastrophic consequences. Case report. An 85-year-old male diagnosed with distal cholangiocarcinoma with criteria for unresectability who was submitted to placement of a biliary drainage prosthesis. Endoscopic retrograde cholangiopancreatography was performed to change the prosthesis. After the procedure, the patient’s vital signs and level of consciousness underwent a decline, and orotracheal intubation was required. A computerised axial tomography scan of the head showed evidence of a massive air embolism with focal points of hyperacute ischaemia in both hemispheres. The patient later died. Conclusions. Cerebral air embolism following endoscopic retrograde cholangiopancreatography is infrequent, but potentially lethal. Manipulation of the bilio-intestinal wall in endoscopic examinations could give rise to communications between the lumen and the venous system. This, together with the high insufflation pressure used to conduct this test, would condition the passage of air to the portal venous system, and from there to the circulatory system. In the central nervous system, air bubbles would lead to a vascular obstruction, with the subsequent ischaemia and necrosis of tissues. An early diagnosis and life support therapy are essential. Its timely management can contribute to a better prognosis which, at least initially, is gloomy (AU)

Pefluorocarbon inhibition of bubble induced Ca2+ transients in an in vitro model of vascular gas embolism.

Endothelial injury resulting from deleterious interaction of gas microbubbles occurs in many surgical procedures and other medical interventions. The symptoms of vascular air embolism (VAE), while serious, are often difficult to detect, and there are essentially no pharmaceutical preventative or post-event treatments currently available. Perfluorocarbons (PFCs), however, have shown particular promise as a therapeutic option in reducing endothelial injury both in- and ex-vivo. Recently, we demonstrated the effectiveness of Oxycyte, a third-generation PFC formulated in a phosphotidylcholine emulsion, using an in vitro model of VAE developed in our laboratory. This apparatus allows live cell imaging concurrent with precise manipulation of physiologically sized microbubbles so that they may be brought into individual contact with human umbilical vein endothelial cells dye-loaded with the Ca(2+) sensitive Fluo-4. Herein, we expand use of this fluorescence microscopy-based cell culture model. Specifically, we examined the concentration dependence of Oxycyte in reducing both the amplitude and frequency of large intracellular Ca(2+) currents that are both a hallmark of bubble contact and a quantifiable indication that abnormal intracellular signaling has been triggered. We measured dose dependence curves and fit the resultant data using a modified Black and Leff operational model of agonism. The half maximal inhibitory concentrations of Oxycyte for (i) inhibition of occurrence and (ii) amplitude reduction were 229 ± 49 µM and 226 ± 167 µM, respectively. This investigation shows the preferential gas/liquid interface occupancy of the PFC component of Oxycyte over that of mechanosensing glycocalyx components and validates Oxycyte's specific surfactant mechanism of action. Further, no lethality was observed for any concentration of this bioinert PFC, as it acts as a competitive allosteric inhibitor of syndecan activation to ameliorate cell response to bubble contact.

Body fat does not affect venous bubble formation after air dives of moderate severity: theory and experiment.

For over a century, studies on body fat (BF) in decompression sickness and venous gas embolism of divers have been inconsistent. A major problem is that age, BF, and maximal oxygen consumption (Vo2max) show high multicollinearity. Using the Bühlmann model with eight parallel compartments, preceded by a blood compartment in series, nitrogen tensions and loads were calculated with a 40 min/3.1 bar (absolute) profile. Compared with Haldanian models, the new model showed a substantial delay in N2 uptake and (especially) release. One hour after surfacing, an increase of 14-28% in BF resulted in a whole body increase of the N2 load of 51%, but in only 15% in the blood compartment. This would result in an increase in the bubble grade of only 0.01 Kisman-Masurel (KM) units at the scale near KM = I-. This outcome was tested indirectly by a dry dive simulation (air breathing) with 53 male divers with a small range in age and Vo2max to suppress multicollinearity. BF was determined with the four-skinfold method. Precordial Doppler bubble grades determined at 40, 80, 120, and 160 min after surfacing were used to calculate the Kisman Integrated Severity Score and were also transformed to the logarithm of the number of bubbles/cm(2) (logB). The highest of the four scores yielded logB = -1.78, equivalent to KM = I-. All statistical outcomes of partial correlations with BF were nonsignificant. These results support the model outcomes. Although this and our previous study suggest that BF does not influence venous gas embolism (Schellart NAM, van Rees Vellinga TP, van Dijk FH, Sterk W. Aviat Space Environ Med 83: 951-957, 2012), more studies with different profiles under various conditions are needed to establish whether BF remains (together with age and Vo2max) a basic physical characteristic or will become less important for the medical examination and for risk assessment.

Air bubble contact with endothelial cells causes a calcium-independent loss in mitochondrial membrane potential.

OBJECTIVE: Gas microembolism remains a serious risk associated with surgical procedures and decompression. Despite this, the signaling consequences of air bubbles in the vasculature are poorly understood and there is a lack of pharmacological therapies available. Here, we investigate the mitochondrial consequences of air bubble contact with endothelial cells. METHODS AND RESULTS: Human umbilical vein endothelial cells were loaded with an intracellular calcium indicator (Fluo-4) and either a mitochondrial calcium indicator (X-Rhod-1) or mitochondrial membrane potential indicator (TMRM). Contact with 50-150 µm air bubbles induced concurrent rises in intracellular and mitochondrial calcium, followed by a loss of mitochondrial membrane potential. Pre-treating cells with 1 µmol/L ruthenium red, a TRPV family calcium channel blocker, did not protect cells from the mitochondrial depolarization, despite blocking the intracellular calcium response. Mitigating the interactions between the air-liquid interface and the endothelial surface layer with 5% BSA or 0.1% Pluronic F-127 prevented the loss of mitochondrial membrane potential. Finally, inhibiting protein kinase C-α (PKCα), with 5 µmol/L Gö6976, protected cells from mitochondrial depolarization, but did not affect the intracellular calcium response. CONCLUSIONS: Our results indicate that air bubble contact with endothelial cells activates a novel, calcium-independent, PKCα-dependent signaling pathway, which results in mitochondrial depolarization. As a result, mitochondrial dysfunction is likely to be a key contributor to the pathophysiology of gas embolism injury. Further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeostasis and disease.

Development of AMPA receptor and GABA B receptor-sensitive spinal hyper-reflexia after spinal air embolism in rat: a systematic neurological, electrophysiological and qualitative histopathological study.

Decompression sickness results from formation of bubbles in the arterial and venous system, resulting in spinal disseminated neurodegenerative changes and may clinically be presented by motor dysfunction, spinal segmental stretch hyper-reflexia (i.e., spasticity) and muscle rigidity. In our current study, we describe a rat model of spinal air embolism characterized by the development of similar spinal disseminated neurodegenerative changes and functional deficit. In addition, the anti-spastic potency of systemic AMPA receptor antagonist (NGX424) or GABA B receptor agonist (baclofen) treatment was studied. To induce spinal air embolism, animals received an intra-aortic injection of air (50-200 µl/kg). After embolism, the development of spasticity was measured using computer-controlled ankle rotation. Animals receiving 150 or 200 µl of intra-aortic air injections displayed motor dysfunction with developed spastic (50-60% of animals) or flaccid (25-35% of animals) paraplegia at 5-7 days. MRI and spinal histopathological analysis showed disseminated spinal cord infarcts in the lower thoracic to sacral spinal segments. Treatment with NGX424 or baclofen provided a potent anti-spasticity effect (i.e., stretch hyper-reflexia inhibition). This model appears to provide a valuable experimental tool to study the pathophysiology of air embolism-induced spinal injury and permits the assessment of new treatment efficacy targeted to modulate neurological symptoms resulting from spinal air embolism.

Mechanotransductional basis of endothelial cell response to intravascular bubbles.

Vascular air embolism resulting from too rapid decompression is a well-known risk in deep-sea diving, aviation and space travel. It is also a common complication during surgery or other medical procedures when air or other endogenously administered gas is entrained in the circulation. Preventive and post-event treatment options are extremely limited for this dangerous condition, and none of them address the poorly understood pathophysiology of endothelial response to intravascular bubble presence. Using a novel apparatus allowing precise manipulation of microbubbles in real time fluorescence microscopy studies, we directly measure human umbilical vein endothelial cell responses to bubble contact. Strong intracellular calcium transients requiring extracellular calcium are observed upon cell-bubble interaction. The transient is eliminated both by the presence of the stretch activated channel inhibitor, gadolinium, and the transient receptor potential vanilliod family inhibitor, ruthenium red. No bubble induced calcium upsurge occurs if the cells are pretreated with an inhibitor of actin polymerization, cytochalasin-D. This study explores the biomechanical mechanisms at play in bubble interfacial interactions with endothelial surface layer (ESL) macromolecules, reassessing cell response after selective digestion of glycocalyx glycosoaminoglycans, hyaluran (HA) and heparin sulfate (HS). HA digestion causes reduction of cell-bubble adherence and a more rapid induction of calcium influx after contact. HS depletion significantly decreases calcium transient amplitudes, as does pharmacologically induced sydencan ectodomain shedding. The surfactant perfluorocarbon Oxycyte abolishes any bubble induced calcium transient, presumably through direct competition with ESL macromolecules for interfacial occupancy, thus attenuating the interactions that trigger potentially deleterious biochemical pathways.

Air bubble contact with endothelial cells in vitro induces calcium influx and IP3-dependent release of calcium stores.

Gas embolism is a serious complication of decompression events and clinical procedures, but the mechanism of resulting injury remains unclear. Previous work has demonstrated that contact between air microbubbles and endothelial cells causes a rapid intracellular calcium transient and can lead to cell death. Here we examined the mechanism responsible for the calcium rise. Single air microbubbles (50-150 µm), trapped at the tip of a micropipette, were micromanipulated into contact with individual human umbilical vein endothelial cells (HUVECs) loaded with Fluo-4 (a fluorescent calcium indicator). Changes in intracellular calcium were then recorded via epifluorescence microscopy. First, we confirmed that HUVECs rapidly respond to air bubble contact with a calcium transient. Next, we examined the involvement of extracellular calcium influx by conducting experiments in low calcium buffer, which markedly attenuated the response, or by pretreating cells with stretch-activated channel blockers (gadolinium chloride or ruthenium red), which abolished the response. Finally, we tested the role of intracellular calcium release by pretreating cells with an inositol 1,4,5-trisphosphate (IP3) receptor blocker (xestospongin C) or phospholipase C inhibitor (neomycin sulfate), which eliminated the response in 64% and 67% of cases, respectively. Collectively, our results lead us to conclude that air bubble contact with endothelial cells causes an influx of calcium through a stretch-activated channel, such as a transient receptor potential vanilloid family member, triggering the release of calcium from intracellular stores via the IP3 pathway.

Carbonic anhydrase activities from the rainbow trout lens correspond to the development of acute gas bubble disease.

Dissolved gas supersaturation is hazardous to fish and can result in gas bubble disease (GBD). Signs of GBD typically include bubbles in the eyes, fins, skin, lateral line, and gill filaments. Ocular abnormalities in diseased salmonids typically occur after aberrant gas production in the eyes. In this study, freshwater rainbow trout Oncorhynchus mykiss were exposed experimentally to percent total gas pressure (TGP%) levels of 104% (control) and 115%. No mortalities occurred during the 7-d experimental period. Effects of GBD were observed externally as a darkened skin, exophthalmia, localized hemorrhage in the eye, and gas bubbles on the operculum. Additional signs included increased swimming activity and, more frequently, panic episodes. Carbonic anhydrase (CA) enzyme activities from the lens and retina were determined at days 0, 1, 3, 5, and 7 of the study. Venous blood gases were also measured on day 7. Retinal pH did not differ between normal and affected fish, but blood characteristics such as the partial pressure of O2, partial pressure of CO2, carboxyhemoglobin level, and bicarbonate ion concentration were significantly elevated in affected fish relative to normal fish. Venous blood pH and oxyhemoglobin levels were not significantly different between affected and normal fish. Patterns of response to total dissolved gas levels differed between the lens and the retina. Mean CA activities in the lenses of fish exposed to a TGP% level of 115% were significantly below those of control fish. However, retinal CA activities did not significantly differ between the two groups over the course of the experiment. These findings show that dissolved gas supersaturation reduces CA activity in the rainbow trout lens.

Cerebral air embolism recognized by cerebral oximetry.

Absolute cerebral oximetry is useful in clinical settings to identify "catastrophic events" that may occur during the course of surgeries that would otherwise have gone unrecognized. This study reports a case in which cerebral desaturation occurred after commencing cardiopulmonary bypass. Consequently, the source of air entrainment was discovered and therapeutic measures implemented.

Predive sauna and venous gas bubbles upon decompression from 400 kPa.

INTRODUCTION: This study investigated the influence of a far infrared-ray dry sauna-induced heat exposure before a simulated dive on bubble formation, and examined the concomitant adjustments in hemodynamic parameters. METHODS: There were 16 divers who were compressed in a hyperbaric chamber to 400 kPa (30 msw) for 25 min and decompressed at 100 kPa x min(-1) with a 4-min stop at 130 kPa. Each diver performed two dives 5 d apart, one with and one without a predive sauna session for 30 min at 65 degrees C ending 1 h prior to the dive. Circulating venous bubbles were detected with a precordial Doppler 20, 40, and 60 min after surfacing, at rest, and after flexions. Brachial artery flow mediated dilation (FMD), blood pressure, and bodyweight measurements were taken before and after the sauna session along with blood samples for analysis of plasma volume (PV), protein concentrations, plasma osmolality, and plasma HSP70. RESULTS: A single session of sauna ending 1 h prior to a simulated dive significantly reduced bubble formation [-27.2% (at rest) to 35.4% (after flexions)]. The sauna session led to an extracellular dehydration, resulting in hypovolemia (-2.7% PV) and -0.6% bodyweight loss. A significant rise of FMD and a reduction in systolic blood pressure and pulse pressure were observed. Plasma HSP70 significantly increased 2 h after sauna completion. CONCLUSION: A single predive sauna session significantly decreases circulating bubbles after a chamber dive. This may reduce the risk of decompression sickness. Sweat dehydration, HSP, and the NO pathway could be involved in this protective effect.

Nitric oxide modulates air embolism-induced lung injury in rats with normotension and hypertension.

1. Air embolism the in lungs induces microvascular obstruction, mediator release and acute lung injury (ALI). Nitrite oxide (NO) plays protective and pathological roles in ALI produced by various causes, but its role in air embolism-induced ALI has not been fully investigated. 2. The purpose of the present investigation was to elucidate the involvement of NO and pro-inflammatory cytokines in the pathogenesis of ALI following air infusion into isolated perfused lungs from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. 3. The extent of ALI was evaluated by changes in lung weight, Evans blue dye leakage, the protein concentration in the bronchoalveolar lavage and pathological examination. We also measured nitrite/nitrate (NO(x)), tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations in lung perfusate and determined cGMP in lung tissue. 4. The NO synthase (NOS) inhibitors N(G)-nitro-l-arginine methyl ester (l-NAME) and l-N(6)-(1-iminoethyl)-lysine (l-Nil), as well as the NO donors sodium nitroprusside (SNP) and s-nitroso-N-acetylpenicillamine (SNAP), were administered 30 min before air embolism at a concentration of 10(-3) mol/L in the lung perfusate. 5. Air embolism-induced ALI was enhanced by pretreatment with l-NAME or l-Nil, but was alleviated by SNP or SNAP pretreatment, in both SHR and WKY rats. In both SHR and WKY rats, AE elevated levels of NO(x) (2.6 and 28.7%, respectively), TNF-alpha (52.7 and 158.6%, respectively) and IL-1beta (108.4 and 224.1%, respectively) in the lung perfusate and cGMP levels in lung tissues (35.8 and 111.2%, respectively). Pretreatment with l-LAME or l-Nil exacerbated, whereas SNP or SNAP abrogated, the increases in these factors, except in the case of NO(x) (levels were decreased by l-LAME or l-Nil pretreatment and increased by SNP or SNAP pretreatment). 6. Air embolism caused increases in the lung weight (LW)/bodyweight ratio, LW gain, protein concentration in bronchoalveolar lavage and Evans blue dye leakage. These AE-induced changes were less in lungs isolated from SHR compared with normotensive WKY rats. 7. The results suggest that ALI and associated changes following air embolism in lungs isolated from SHR are less than those in WKY rats. Nitric oxide production through inducible NOS isoforms reduces air embolism-induced lung injury and associated changes. Spontaneously hypertensive rats appear to be more resistant than WKY rats to air embolism challenge.

Effect of heliox, oxygen and air breathing on helium bubbles after heliox diving.

In helium saturated rat abdominal adipose tissue, helium bubbles were studied at 101.3 kPa during breathing of either heliox(80:20), 100% oxygen or air after decompression from an exposure to heliox at 405 kPa for one hour. While breathing heliox bubbles initially grew for 15-115 minutes then shrank slowly; three out of 10 bubbles disappeared in the observation period. During oxygen breathing all bubbles initially grew for 10-80 minutes then shrank until they disappeared from view; in the growing phase, oxygen caused faster growth than heliox breathing, but bubbles disappeared sooner with oxygen breathing than with heliox or air breathing. In the shrinking phase, shrinkage is faster with heliox and oxygen breathing than with air breathing. Air breathing caused consistent growth of all bubbles. With heliox and oxygen breathing, most animals survived during the observation period but with air breathing, most animals died of decompression sickness regardless of whether the surrounding atmosphere was helium or air. If recompression beyond the maximum treatment pressure of oxygen is required, these results indicate that a breathing mixture of heliox may be better than air during the treatment of decompression sickness following heliox diving.

Increased expired NO and roles of CO2 and endogenous NO after venous gas embolism in rabbits.

Venous gas embolism (VGE) is a feared complication in diving, aviation, surgery and trauma. We hypothesized that air emboli in the lung circulation might change expired nitric oxide (FeNO). A single intravenous infusion of air was given (100 mul kg(-1)) to three groups of anaesthetized mechanically ventilated rabbits: (A) one with intact NO production, (B) one with intact NO production and where end-tidal CO(2) was controlled, and (C) one with endogenous NO synthesis blockade (L: -NAME, 30 mg kg(-1)). Air infusions resulted in increased FeNO of the control group from 20 (4) [mean (SD)] ppb to a peak value of 39 (4) ppb within 5 min (P < 0.05), and FeNO was still significantly elevated [27 (2) ppb] after 20 min (P < 0.05). Parallel to the NO increase there were significant decreases in end-tidal CO(2 )(ETCO(2)) and mean arterial pressure and an increase in insufflation pressure. In group B, when CO(2) was supplemented after air infusion, NO was suppressed (P = 0.033), but was still significantly elevated compared with pre-infusion control (P < 0.05). In group C, all animals died within 40 min of air infusion whereas all animals in the other groups were still alive at this time point. We conclude that venous air embolization increases FeNO, and that a part of this effect is due to the concomitant decrease in ETCO(2). Furthermore, an intact NO production may be critical for the tolerance to VGE. Finally, FeNO might have a potential in the diagnosis and monitoring of pulmonary gas embolism.

Surfactants attenuate gas embolism-induced thrombin production.

BACKGROUND: There are no pharmacologic strategies to prevent embolism bubble-induced blood clot formation. The authors conducted experiments to measure thrombin production in sheared whole blood in the presence and absence of bubbles and three surface-active compounds. METHODS: Blood samples were obtained from six volunteers seven times. The thrombin-specific substrate Boc-VPR-MCA was added to citrated blood diluted with HEPES-buffered saline. Experimental groups were as follows: sparging (air microbubble embolization) with surfactant present; sparging alone; surfactant alone; and neither surfactant nor sparging. The surfactants were Dow Corning Antifoam 1510US, Perftoran, and Pluronic F-127. Blood was sheared by a cone-plate viscometer at 100 and 500 s-1 for 5, 10, and 20 min at 37 degrees C, pipetted into excess stop buffer, and evaluated fluorimetrically. Mean values of fluorescence intensity +/- SDs for each group were compared using ANOVA. Differences were considered significant at P < 0.05 using the Bonferroni correction. RESULTS: For fixed shear rate, thrombin production increased 2.3- to 5.7-fold (P < 0.05) as shear duration lengthened. For fixed shear duration, thrombin production increased 1.9- to 3.9-fold (P < 0.05) with increasing shear rate. For fixed shear rate and duration, sparging increased thrombin production 2.1- to 3.7-fold (P < 0.05). Surfactant addition without sparging did not change thrombin production (P > 0.05). Surfactants attenuated thrombin production in sparged samples 31.8-70.9% (P < 0.05). CONCLUSIONS: Thrombin production is shear rate and duration-dependent. Sparging increases thrombin production. Surfactants added before sparging attenuate thrombin production. Surfactants may have a clinical application to attenuate gas embolism-induced clotting.

Role of the endothelin system in secondary pulmonary hypertension related to air embolism: lessons learned from testing four classes of endothelin blockers in a rat model.

A rat model of acute pulmonary air embolism (APAE) was developed. These animals had a higher right ventricular systolic pressure (RVSP) (+ 69% at 15-minute peak, and 21-34% at 30-180 minutes), as well as a reduced mean arterial blood pressure (10-20% at 60-180 minutes), heart rate (20-26% at 60-180 minutes) and PaO2 (9-11% at 30-180 minutes) compared with control rats. The role of the endothelin (ET) system, known to be involved in pulmonary hypertension of various etiologies, was investigated by evaluating the effect of the four classes of ET blockers: ET-converting enzyme inhibitor (ECEi) (CGS 35066), selective endothelin-A receptor antagonist (ETA-Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ETB-Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ETA/B-Ra) (A-182086) in this animal model. All four were effective, to various degrees, at reducing the APAE-induced rise in RVSP. The relative efficacy of those compounds in reducing the acute elevation (15 minutes) of RVSP was ECEi >or= ETA/B-Ra >> ETA-Ra = ETB-Ra. The sustained elevation (30-180 minutes) of RVSP was totally abolished by ECEi and attenuated by other ET blockers with a relative efficacy of ETA-Ra > ETA/B-Ra >or= ETB-Ra. ET receptor antagonists did not affect right ventricular basal tone (control rats) whereas ECEi reduced it by up to 12% after 2 hours. The APAE reduction in mean arterial blood pressure was unaffected by ETARa, was completely normalized by ETB-Ra, but was further reduced by either ETA/B-Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ETA-Ra, was elevated by ETB-Ra, but was depressed by ETA/B-Ra and ECEi. All ET blockers maintained normal oxygen saturation in APAE. These results support a role for ETs in rat APAE, since ET blockers can attenuate the cardiopulmonary deterioration and blood gas exchange. However, modulation of the central hemodynamic profile is more complex and may limit the usefulness of some ET blockers.

Model predictions of gas embolism growth and reabsorption during xenon anesthesia.

BACKGROUND: It is not readily obvious whether an intravascular bubble will grow or shrink in a particular tissue bed. This depends on the constituent gases initially present in the bubble, the surrounding tissue, and the delivered gas admixture. The authors used a computational model based on the physics of gas exchange to predict cerebrovascular embolism behavior during xenon anesthesia. METHODS: The authors estimated values of gas transport parameters missing from the literature. The computational model was used with those parameters to predict bubble size over time for a range of temperatures (18 degrees -39 degrees C) used during extracorporeal circulation. RESULTS: Bubble size over time is highly nonlinearly dependent on multiple factors, including diffusivity, solubility, gas partial pressures, magnitude of concentration gradients, vessel diameter, and temperature. Xenon- and oxygen-containing bubbles continue to grow during xenon delivery. Bubble volume doubles from 50 to 100 nl in approximately 3-68 min, depending on initial gas composition and bubble shape. Bubble growth and reabsorption are relatively insensitive to temperature in the physiologic and surgical range. CONCLUSIONS: Xenon anesthesia results in gas exchange conditions that favor bubble growth, which may worsen neurologic injury from gas embolism. The concentration gradients can be manipulated by discontinuation of xenon delivery to promote reabsorption of xenon-containing bubbles. Estimated growth and reabsorption rates at normothermia can be applied to temperature extremes of cardiopulmonary bypass.

Effects of cerebral air embolism on brain metabolism in pigs.

OBJECTIVES: Cerebral air embolism was induced in pigs and changes in intracranial pressure (ICP), brain oxygen (PbrO2), brain carbon dioxide (PbrCO2), brain pH (brpH) and glucose, lactate and pyruvate levels were used to characterize this model. METHODS: In seven anesthetized pigs, ICP, PbrO2, PbrCO2 and brpH were measured continuously with multiparameter sensors and brain glucose metabolism by microdialysis. After injection of air into the internal carotid artery, these parameters were recorded for 2 h. RESULTS: ICP increased (433%) from 12 +/- 1 to 52 +/- 8 mmHg (P < 0.05). PbrO2 decreased from 25.7 +/- 6.2 to 11.9 +/- 5.2 mmHg. PbrCO2 increased (109%) from 57.7 +/- 2.7 to 120.4 +/- 21.5 mmHg (P < 0.05). Brain glucose decreased (38%) from 3.05 +/- 0.91 to 1.91 +/- 0.55 mmol, while brain lactate increased (384%) from 1.36 +/- 0.15 to 5.22 +/- 0.53 mmol/l (P < 0.05). CONCLUSIONS: Cerebral air embolism has a deleterious effect on ICP and brain metabolism. Therefore, this model may be suitable for testing therapeutic regimens in cerebral air embolism.