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Corrective treatment of expiratory central airway collapse (ECAC) consists of placement of airway stents or tracheobronchoplasty (TBP). The indication for corrective treatment is severe central airway collapse (>90 %), and severe symptoms that cause decline in quality of life. Patients are selected to undergo a trial of tracheal "Y" stent placement. If symptoms improve (positive trial) they undergo a TBP, provided they are good surgical candidates. Patients who are considered poor surgical candidates because of the severity of comorbidities can be offered permanent stenting to palliate symptoms. The anesthetic management of airway stent placement and TBP is complex. This article reviews the medical management and corrective treatment of ECAC, anesthetic management of airway stent placement, and considerations during TBP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Expiratory central airway collapse (ECAC) is a general term that incorporates tracheobronchomalacia (TBM) and excessive dynamic airway collapse (EDAC). TBM and EDAC are progressive, degenerative disorders of the tracheobronchial tree, causing airway collapse. Induction of general anesthesia can trigger intraoperative airway collapse in patients with these conditions. This crisis presents as the sudden inability to ventilate, which can lead to life-threatening hypoxemia and hypercapnia. This article reviews the definition, pathophysiology, diagnosis, and anesthetic implications of ECAC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Takotsubo cardiomyopathy (TCM) is characterized by transient ventricular dysfunction in the absence of obstructive coronary artery disease that may be triggered by an acute medical illness or intense physical or emotional stress. TCM is often confused with acute myocardial infarction given the similar electrocardiographic changes, cardiac enzymes, hemodynamic perturbations, and myocardial wall motion abnormalities. In the perioperative setting, the clinical picture may be more confusing because of the effect of anesthesia as well as hemodynamic changes related to the surgery itself. However, awareness of various other diagnostic modalities may enable clinicians to distinguish between the two, more systematically and with greater certainty. Despite the large body of literature, there still seems to be an overall paucity in our understanding of the etiopathogenesis, clinical characteristics, natural history, and management of this syndrome, especially in the perioperative setting. This narrative review seeks to present and synthesize the most recent literature on TCM and to identify gaps in current knowledge which can become the basis for future research., Competing Interests: None

Takotsubo cardiomyopathy (TCM) is a condition that is characterized as a transient ventricular dysfunction in the absence of obstructive coronary artery disease (CAD) and is usually triggered by an acute medical illness or intense physical or emotional stress. Multiple cases of perioperative TCM (pTCM) have been reported from around the world, but a qualitative analysis of these cases has not yet been done. For this systematic review, we searched PubMed for case reports and case series of pTCM published from 1966 to April 2015 with the objective being to evaluate whether differences in demographics, clinical features and outcomes exist between pTCM and nonperioperative (npTCM), as well as to attempt to identify any predictors of the severe form of pTCM, which requires mechanical circulatory support (MCS) devices or leads to death. A total of 93 articles describing 102 cases were retrieved and reviewed. The findings were compared with the analysis of the International Takotsubo Registry by Templin et al and a systematic review of mainly non-perioperative TCM (npTCM) by Gianni et al. Although we were unable to identify definitive risk factors for pTCM, our review suggests that pTCM appears to occur in younger patients and with a lower likelihood of ST segment elevations and T-wave abnormalities than in npTCM. No demographic or clinical factors were identified that were predictive of more severe outcomes. As TCM in general can be a life-threatening event, it would therefore be prudent to consider pTCM within a differential diagnosis in any patient who decompensates in the perioperative period.

Simultaneous orthogonal plane imaging with tilt enables the display of two 2D, real-time images and the evaluation of structures that cannot be seen by conventional single-plane transesophageal echocardiographic (TEE) imaging. After a step-wise examination protocol, we used simultaneous orthogonal plane imaging to obtain the short-axis view of the pulmonic valve (PV) and assessed flow in both images simultaneously using color Doppler imaging in 100 consecutive patients undergoing intraoperative TEE. Our goals were to assess the ability of this technique to visualize all 3 leaflets of the PV, assess feasibility of planimetry to measure valve area, and assess flow using color Doppler imaging. All study images were obtained by anesthesiologists who are diplomates in Advanced Perioperative Transesophageal Echocardiography. All 3 leaflets of the PV were successfully visualized in the short-axis view in 65% of cases, 2 leaflets were visualized in 32% of cases, and only 1 leaflet could be imaged in 3%. The flow across the valve could be evaluated using color Doppler imaging in all cases. Planimetry for valve area was possible when all 3 leaflets were seen. It is important to inspect the PV during a routine TEE examination; however, the orientation of the PV in respect to the esophagus makes this evaluation challenging. We present a simple protocol to evaluate the PV in long-axis and short-axis views simultaneously that can potentially help evaluate for pathologies involving the PV.

Thromboembolism continues to be a major concern in patients with mechanical heart valves, especially in those with unsatisfactory anticoagulation levels. The new On-X valve (On-X Life Technologies, Austin, TX, USA) has been reported as having unique structural characteristics that offer lower thrombogenicity to the valve. We report a case where the patient received no or minimal systemic anticoagulation after placement of On-X mitral and aortic valves due to development of severe mucosal arterio-venous malformations yet did not show any evidence of thromboembolism. This case report reinforces the findings of recent studies that lower anticoagulation levels may be acceptable in patients with On-X valves and suggests this valve may be particularly useful in those in whom therapeutic levels of anticoagulation cannot be achieved due to increased risk of bleeding.

Two patients in whom the bispectral index (BIS) decreased to zero following cardiac arrest during cardiothoracic surgery are described. The BIS value decreased to zero after cardiac arrest, and the value remained low for the remainder of the anesthetic despite successful cardiopulmonary resuscitation. Both patients were found to have severe brain injuries in the postoperative period.

Background: Estimation of right atrial pressure (RAP) from variations in the diameter of the inferior vena cava (IVC) during the respiratory cycle using transthoracic echocardiography (TTE) is used routinely to calculate pulmonary artery systolic pressure, adding to right ventricular systolic pressure (RVSP) from the jet velocity of tricuspid regurgitation. Using transesophageal echocardiography (TEE) we sought to determine if the inferior vena cava diameter (IVCD) could be used to derive the central venous pressure (CVP) in anesthetized, mechanically ventilated patients., Methods: The IVCD was measured in its long axis (bicaval view) at the cavo-atrial junction using TEE and ECG synchronization (to coincide with the end of the T-wave) in 95 anesthetized, mechanically ventilated patients undergoing elective cardiac surgery. Each patient received a pulmonary artery catheter (PAC) that allowed for continuous monitoring of the CVP. Three independent readers were assigned to document the IVCD and the CVP. Statistical analysis was performed using bivariate correlation, variance (ANOVA), linear regression, Bland-Altman and Passing-Bablock analysis of agreement., Results: The IVCD measured in millimeters at the cavo-atrial junction showed a positive correlation with the CVP (n = 95, r = 0.860, P < 0.0001, r(2)= 0.737, P < 0.0001). The linear regression equation [CVPc = (IVCD-4.004/0.751] was prospectively tested in a cohort of 12 anesthetized, mechanically ventilated patients under various hemodynamic conditions with a good correlation between the mean CVP (CVPm) and the calculated CVP (CVPc) (r = 0.923, P < 0.0001, r(2)= 0.851, P < 0.0001)., Conclusion: The TEE measured IVCD at the cavo-atrial junction showed a statistically significant correlation with the mean CVP. Using an equation derived from linear regression analysis, a reliable CVP can be estimated from the IVCD.

Tumor necrosis factor (TNF)-alpha is implicated in development of restenotic and atherosclerotic vascular lesions, which are pathological processes involving both proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Human VSMCs were recently found to contain heterogeneous subpopulations. We therefore examined whether TNF has different effects on distinct subpopulations of VSMCs. With the use of cloning techniques, two stable subpopulations of VSMCs were isolated from human saphenous vein: spindle- and epithelioid-shaped smooth muscle cells (Sp- and Ep-SMCs, respectively). We found that TNF stimulated growth in Sp-SMCs but had a toxic effect on Ep-SMCs. TNF did not induce apoptosis in Sp-SMCs as determined by nuclear staining and cellular DNA electrophoresis. In contrast, the reduction of viability in Ep-SMCs was associated with induction of apoptosis as characterized by cellular DNA fragmentation and nuclear condensation. Higher levels of the TNF-R1 receptor subtype were detected in membrane preparations from Ep-SMCs than in membranes from Sp-SMCs. Activation of caspase-3 was also selectively induced in Ep-SMCs but not in Sp-SMCs. Cycloheximide, an inhibitor of protein synthesis, enhanced the toxicity of TNF in Ep-SMCs. This effect of cycloheximide was not seen in Sp-SMCs. The data presented here demonstrate for the first time that TNF either promotes growth or induces apoptosis in human VSMCs depending on phenotype.

Reperfusion after cardiopulmonary bypass causes induction of reactive oxygen species (ROS), elevated plasma levels of bacterial lipopolysaccharide (LPS), and production of tumor necrosis factor-alpha (TNF) by the heart. Nuclear factor-kappaB (NF-kappaB) regulates the expression of TNF. Because NF-kappaB is activated by both LPS and ROS, we hypothesized that an inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC), would block release of TNF from the heart stimulated by these two agents. With Institutional animal care and use committee (IACUC) approval, rat hearts were perfused Langendorf style. LPS was infused and ROS were generated with a hypoxanthine/xanthine oxidase system. PDTC was added to the perfusion buffer. Other hearts were treated with forskolin in order to elevate cyclic AMP. Timed collections of coronary effluent were made for the determination of coronary flow and measurement of TNF. LPS stimulated TNF release to a maximum of 2247 +/- 133 pg/min at 150 minutes. PDTC inhibited LPS-stimulated TNF release. For instance, at 150 minutes, LPS-stimulated TNF release was 449 +/- 49 pg/min with 100 microM PDTC and was 70 +/- 65 pg/mL with 250 microM PDTC (P < 0.05 vs LPS alone). ROS stimulated TNF release was 1494 +/- 130 pg/min at 150 minutes and was not affected by PDTC. Forskolin almost completely blocked TNF release stimulated by LPS or ROS. These data are consistent with the notion that inhibitors of NF-kappaB block cytokine production stimulated by some agents but not others.

Neointimal proliferation with plaque formation is the principal cause of coronary artery disease. In the neointima, inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) are expressed by vascular smooth muscle cells (VSMCs). These cytokines stimulate proliferation and migration of VSMCs, events that are crucial to neointima formation. Stents, liberating rapamycin, have been shown to reduce neointima formation in human coronary arteries. The purpose of this study was to determine if rapamycin could inhibit the production of TNF-alpha by VSMCs. With institutional review board approval, VSMCs were cultured from saphenous vein segments obtained from five patients. Cells were identified as VSMC by immunostaining for smooth muscle alpha-actin. Cells were exposed to bacterial lipopolysaccharide (LPS), LPS plus rapamycin, or LPS plus isoproterenol for 24 hours. Cells with no treatment served as controls. The culture medium was then removed and analyzed for TNF-alpha. Additionally, the effect of treatment on viability was determined by assay of mitochondrial activity. TNF-alpha released into the culture medium is expressed as pg TNF-alpha/mg cell protein. Statistical analysis was by ANOVA. In control cells, TNF-alpha was undetectable in the culture medium. The addition of LPS (10 microg/mL) increased TNF-alpha release to 4312 +/- 705 pg/mg at 24 hours. The addition of 1 ng/mL rapamycin with LPS reduced TNF-alpha production 50 per cent (P < 0.01 vs LPS alone). A similar reduction of TNF-alpha release was seen with 1 microM isoproterenol. LPS, rapamycin, or isoproterenol did not affect cell viability. These data show that rapamycin effectively inhibits the release of TNF-alpha from VSMCs stimulated with inflammatory mediators like LPS. Rapamycin is as effective as agents that raise intracellular cyclic AMP (e.g., isoproterenol). Therefore, a potential mechanism for the effectiveness of rapamycin-releasing stents is reduction of inflammatory cytokine expression by VSMCs.

Thrombin has been implicated in the development of atherosclerosis and restenosis, in which migration of vascular smooth muscle cells (VSMC) is a crucial event. Thrombin-stimulated VSMC migration is associated with increased generation of reactive oxygen species (ROS), activation of mitogen-activated protein kinases (MAPKs), and production of growth factors and chemoattractants. In this study, we examined the interrelation of these signals to determine the pathway controlling thrombin-directed migration of human VSMC. Our results show that thrombin stimulated the production of ROS and activation of p38 MAPK. ROS were required for thrombin-induced VSMC migration since both generation of ROS and cell migration were significantly attenuated by inhibitors of NAD(P)H oxidase, diphenyleneiodonium (DPI) and apocynin (Apo.), and by the hydrogen peroxide scavenger, catalase (Cat.). Activation of p38 MAPK by thrombin was inhibited by DPI, Apo. and Cat., indicating ROS are used as messengers for activating this kinase. p38 MAPK is an important step since SB 203580, a selective inhibitor of p38 MAPK, suppressed the cell migration induced by thrombin. Furthermore, thrombin increased the expression of vascular endothelial growth factor (VEGF), a chemoattractant for VSMC, and this expression was inhibited by DPI, Apo., Cat. and SB 203580. Addition of anti-VEGF antibody significantly attenuated thrombin-induced migration. Collectively, the data presented here show that thrombin has stimulated VSMC migration and VEGF expression through an ROS-sensitive p38 MAPK pathway. VEGF synthesized and released by the cell served as a secondary mediator in thrombin-directed migration.

Aprotinin has been reported to reduce plasma levels of inflammatory cytokines associated with cardiopulmonary bypass (CPB). Because CPB is also associated with elevated levels of bacterial lipopolysaccharide (LPS) and LPS stimulates release of inflammatory cytokines from the heart we tested the hypothesis that aprotinin would inhibit cardiac release of tumor necrosis factor-alpha (TNF) provoked by LPS. Isolated rat hearts were perfused Langendorf style. After 30 minutes of equilibration LPS (100 ng/mL) was infused for 60 minutes. Timed samples of coronary effluent were collected at 0, 30, 60, 90, 120, and 150 minutes after the initiation of LPS for the measurement of coronary flow and the determination of TNF and cyclic AMP. Other hearts were perfused with buffer containing aprotinin [137 kallikrein-inhibiting units (KIU)/mL or 250 KIU/mL] and then infused with LPS. An additional group received forskolin (10 microM) and LPS. In hearts perfused as controls with buffer alone no TNF was detected in the coronary effluent. In hearts perfused with LPS TNF was reliably detected in the coronary effluent at 60 minutes (606 +/- 450 pg/min) and increased with time to a level of 1792 +/- 650 pg/min at 150 minutes. The addition of aprotinin had no significant effect on LPS-stimulated TNF release. For instance in hearts perfused with 137 KIU/mL aprotinin LPS-stimulated release at 150 minutes was 2141 +/- 732 pg/min and in hearts perfused with 250 KIU/mL LPS-stimulated TNF release was 2049 +/- 789 pg/min. Forskolin administration was associated with release of cyclic AMP from the heart and completely inhibited LPS-stimulated TNF release. We conclude that LPS stimulated release of TNF from the heart. Adding aprotinin to the perfusion buffer in either high or low concentrations did not attenuate LPS-stimulated cytokine release. Elevating myocardial cyclic AMP with forskolin completely attenuated LPS-stimulated TNF release.

Background: Gene expression induced by tumor necrosis factor-alpha (TNF-alpha) is involved in the regulation of vascular smooth muscle cell (VSMC) proliferation and migration, two events critical to formation of stenotic vascular lesions. In some systems, elevating adenosine 3',5'-cyclic monophosphate (cyclic AMP) inhibits TNF-alpha induced gene transcription. We recently demonstrated that interleukin-6 (IL-6) was chemotactic to VSMC. Therefore, we tested the hypothesis that elevating cyclic AMP would inhibit TNF-alpha-mediated IL-6 expression and VSMC migration., Materials and Methods: VSMC were cultured from saphenous vein remaining after coronary artery bypass grafting. Migration of VSMC through a porous membrane was determined. Intracellular cyclic AMP was elevated by exposing the cells to forskolin or 8-Br-cyclic AMP and was measured by radioimmunoassay. IL-6 was measured by enzyme-linked immunosorbent assay., Results: TNF-alpha induced migration of VSMC in a concentration-dependent manner. Incubation of cells with forskolin significantly increased cyclic AMP. Co-incubation of cells with TNF-alpha in combination with 8-Br-cyclic AMP or forskolin inhibited migration by approximately 25 and 70%, respectively. Incubation with TNF-alpha increased release of IL-6 from VSMC 18-fold over basal. This stimulated release was inhibited by either 8-Br-cyclic AMP or forskolin. In cells stimulated with TNF-alpha, addition of an antibody to IL-6 reduced migration by 25%., Conclusions: These data show that IL-6 produced by VSMC contributes to cell migration induced by TNF-alpha. Further, elevating cyclic AMP inhibited TNF-alpha-induced release of IL-6, and migration of VSMC. These results are consistent with the notion that mechanisms that increase intracellular cyclic AMP, such as activation of beta-adrenergic receptors on VSMC, act as a brake on cell migration.

Background: Cytokines such as tumor necrosis factor alpha (TNF-alpha) are produced by the myocardium in heart disease and might be stimulated by reactive oxygen. In some cell types, cyclic adenosine monophosphate (AMP) inhibits TNF-alpha production. The authors tested the hypothesis that stimulation of cardiac beta-adrenergic receptors would inhibit cytokine gene transcription induced by reactive oxygen., Methods: Rat hearts were perfused with buffer containing hypoxanthine. Reactive oxygen intermediates were generated by infusion of xanthine oxidase. Myocardial mRNA encoding 11 cytokines was determined. TNF-alpha, interleukin-6, and cyclic AMP were measured in the coronary effluent., Results: In control hearts, of the screened RNA, only mRNA encoding interleukin-1beta, -4, and -6 was detected. Stimulation with hypoxanthine-xanthine oxidase (HX-XO) induced detectable mRNA for TNF-alpha and interleukin-5 and increased mRNA band density for interleukin-1beta, -4, and -6. Simultaneous infusion of isoproterenol inhibited HX-XO-stimulated cytokine gene expression and caused release of cyclic AMP into the coronary effluent. In control hearts, TNF-alpha was not detected in the coronary effluent. After HX-XO administration, TNF-alpha was reliably detected at 60 min and interleukin-6 at 90 min. Simultaneous infusion of isoproterenol inhibited TNF-alpha and interleukin-6 release. Inclusion of propranolol in the perfusion buffer blocked the isoproterenol-induced inhibition of HX-XO-stimulated TNF-alpha release and release of cyclic AMP into the coronary effluent. In addition, elevating myocardial cyclic AMP with forskolin also blocked release of TNF-alpha stimulated by HX-XO. Finally, delaying infusion of isoproterenol until 30 min after HX-XO administration still suppressed release of TNF-alpha., Conclusions: Reactive oxygen species activate cytokine gene transcription in the myocardium. The sympathetic nervous system, acting through beta-receptors to elevate myocardial cyclic AMP, regulates cardiac cytokine production by inhibition of transcription.

Background: Inflammatory reaction and intimal proliferation of smooth muscle cells are characteristics of vascular stenotic lesions. Nuclear factor kappaB (NF-kappaB) is involved in regulation of inflammation and cell survival in a variety of cell types. We tested a hypothesis that selective inhibition of NF-kappaB by expression of a mutated, nondegradable inhibitor of NF-kappaB, IkappaB-alphaM, would inhibit proinflammatory cytokine expression and proliferation in human vascular smooth muscle cell., Materials and Methods: Smooth muscle cells were cultured from internal mammary artery and infected with recombinant adenovirus vectors., Results: Adenoviral expression of IkappaB-alphaM inhibited diverse signal-triggered cellular IkappaB-alpha degradation, subsequent NF-kappaB activation, and transactivation of proinflammatory cytokine genes. Expression of IkappaB-alphaM in low-density VSMC led to a 60% reduction in serum-stimulated cell growth and a 10% increment in apoptotic incidence but was without effect in high-density cultures. Coexpression of NF-kappaB p65 attenuated apoptosis in low-density cells induced by IkappaB-alphaM. Therefore, the susceptibility to apoptosis induction in the low-density cells correlated with lower constitutive NF-kappaB activity. The induction of apoptosis by IkappaB-alphaM and the rescue by NF-kappaB p65 might be explained by mutual control of NF-kappaB p65 and IkappaB-alphaM access to the nucleus., Conclusion: Our results suggest that expression of nondegradable IkappaB-alpha might have therapeutic potential in both vascular inflammatory reaction and smooth muscle cell proliferation., ((c)2001 Elsevier Science.)

The monoclonal theory of atherosclerosis postulates that a certain subpopulation of vascular smooth muscle cells (VSMC) is selectively expanded in response to pathological stimuli thereby contributing to the formation of atherosclerotic plaques. VSMC cloning experiments will be important in characterizing the phenotypic composition of VSMC in atherosclerotic plaques. However, the difficulty in cloning human VSMC is well recognized. Here a technique is described that produced multiple clones from human saphenous vein. The clones could be divided into two categories based on their distinctly different morphology: (1) spindle-shaped; and, (2) epithelioid-shaped. Each clone expressed smooth muscle-a-actin and calponin, two smooth muscle-specific differentiation markers. The clonal study presented here reports for the first time that phenotypically heterogeneous smooth muscle cells coexist within human saphenous veins.

Migration of vascular smooth muscle cells (VSMC) is a crucial event in the formation of vascular stenotic lesions. Tumor necrosis factor-alpha (TNF-alpha) is elaborated by VSMC in atherosclerosis and following angioplasty. We investigated the role of nuclear factor-kappaB (NF-kappaB) in human VSMC migration induced by TNF-alpha. Adenoviral expression of a mutant form of the inhibitor of NF-kappaB, IkappaB-alphaM, suppressed TNF-alpha-triggered degradation of cellular IkappaB-alpha, inhibited activation of NF-kappaB, and attenuated TNF-alpha-induced migration. Further, IkappaB-alphaM suppressed TNF-alpha-stimulated release of interleukin-6 and -8 (IL-6 and IL-8). Neutralization of IL-6 and IL-8 with appropriate antibodies reduced TNF-alpha-induced VSMC migration. Addition of recombinant IL-6 and IL-8 stimulated migration. Collectively, our data provide initial evidence that TNF-alpha-mediated VSMC migration requires NF-kappaB activation and is associated with induction of IL-6 and IL-8 which act in an autocrine manner.

Migration and proliferation of vascular smooth muscle cells (VSMC) contribute to angiogenesis and the lesions of atherosclerosis. Since, vascular endothelial growth factor (VEGF) is overexpressed by VSMC in intima of atherosclerotic human coronary arteries, we determined if VEGF could stimulate VSMC migration and the intracellular signals involved. VEGF induced VSMC migration but had no significant activity on proliferation. VEGF increased intracellular reactive oxygen species (ROS), NF-kappaB activation and IL-6 expression. Blockade of the generation of intracellular ROS by antioxidants inhibited VEGF-induced NF-kappaB activation, IL-6 expression, and cell migration indicating that generation of ROS was required for NF-kappaB activation and the chemotactic activity of VEGF. Expression of a mutated, nondegradable form of inhibitor of NF-kappaB (IkappaB-alphaM) suppressed VEGF-triggered activation of NF-kappaB and upregulation of IL-6 as well as VSMC migration. Neutralization of IL-6 by its antibody significantly attenuated the migration stimulated by VEGF. Collectively, our data provide the first evidence that intracellular ROS and NF-kappaB are required for VEGF-mediated smooth muscle cell migration. Further, IL-6 induced by VEGF is involved in the ability of the growth factor to stimulate migration., (Copyright 2001 Academic Press.)

Objectives: Beta-adrenergic receptor agonists such as isoproterenol inhibit production of tumor necrosis factor (TNF)-alpha in a number of cell types. Because the heart is a source of TNF-alpha, we hypothesized that isoproterenol would inhibit cardiac production of the cytokine., Design: Analysis of cardiac release of TNF-alpha., Setting: Medical research laboratory., Subjects: Rats., Interventions: None., Measurements and Main Results: With the approval of the Institutional Animal Care and Use Committee, rats were anesthetized and hearts were removed and perfused. After 30 mins, bacterial lipopolysaccharide (LPS) with or without isoproterenol was infused for 60 mins. At 30, 60, 90, 120, and 150 mins, coronary flow was measured and coronary effluent was analyzed for TNF-alpha. Cardiac production of TNF-alpha was expressed as pg/min. Cyclic adenosine monophosphate (AMP) in the coronary effluent was measured. TNF-alpha messenger RNA was determined in ventricular tissue. After 30 mins, TNF-alpha was undetectable in the coronary effluent However, 60 mins after the initiation of LPS infusion, TNF-alpha release was 875+/-255 pg/min and increased to 2164+/-721 pg/min at 150 mins. Simultaneous infusion of isoproterenol with LPS stimulated cyclic AMP release and inhibited TNF-alpha production. For instance, at 60 and 150 mins, TNF-alpha release was 75+/-38 and 58+/-29 pg/min, respectively (p < .05 vs. LPS alone). Simultaneous infusion of isoproterenol with LPS blocked the induction of TNF-alpha messenger RNA by LPS. Isoproterenol, begun 30 mins after the initiation of LPS infusion, still suppressed LPS-stimulated TNF-alpha release by 95% at 150 mins. Similar results were obtained with norepinephrine., Conclusions: Activation of beta-adrenergic receptors inhibits cardiac TNF-alpha release. This implies that cytokine production by the heart is inhibited by the sympathetic nervous system. In heart failure, the cardiac response to the sympathetic nervous system is impaired. This impairment may play a role in the high plasma levels of TNF-alpha found in heart failure.

Recent evidence suggests that inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-alpha), may play a role in heart disease. Elevated plasma levels of the cytokine have been reported in congestive heart failure and severe angina and after myocardial infarction. The exact role of TNF-alpha in heart disease and how production is stimulated and regulated in the heart are current areas of investigation. Regarding regulation of production, isoproterenol elevates cyclic AMP and inhibits TNF-alpha release in macrophages. Therefore we hypothesized that stimulation of beta-adrenergic receptors of the sympathetic nervous system would inhibit release of the cytokine from heart tissue. With Institutional Review Board approval and patient consent atrial tissue was obtained during preparation for cardiac bypass. The tissue was divided into segments, placed in culture medium, and incubated for various times in the presence or absence of lipopolysaccharide (LPS) (20 microg/mL) and/or isoproterenol (1 microM). The medium was removed and analyzed for biologically active TNF-alpha by the L929 cell cytotoxicity assay. Tissue samples were weighed and TNF-alpha release was expressed as pg TNF-alpha/mg tissue. Initially, to determine the time course of release, measurements were made at 2, 5, 10, 15, 30, 60, 120, 180, and 360 minutes after the addition of LPS. Elevated TNF-alpha levels in the culture medium were reliably detected at 360 minutes after exposure to LPS. In atrial tissue obtained from seven patients TNF-alpha released into the culture medium at 360 minutes was 6 +/- 3 pg/mg tissue. In the presence of LPS, levels of the cytokine in the culture medium increased to 604 +/- 233 pg/mg tissue (P < 0.05 vs LPS alone). When isoproterenol and LPS were simultaneously added to the culture medium release of TNF-alpha was reduced by 87 per cent to 82 +/- 40 pg/mg tissue (P < 0.05 vs LPS alone). Our results show that activation of the beta-adrenergic receptor inhibits myocardial production of TNF-alpha. This finding suggests that the sympathetic nervous system inhibits production of the cytokine and that impaired sympathetic function in heart failure may play a role in the elevated levels of TNF-alpha.

Implications: Malignant hyperthermia is an uncommon, heritable condition triggered by anesthesia and is followed by an increase in temperature that may be fatal without prompt treatment. It is rare with desflurane and in black individuals of African descent. We present a case of malignant hyperthermia in an African-American patient during desflurane anesthesia.

Background: Recently we reported that bacterial lipopolysaccharide (LPS) stimulates release of tumor necrosis factor alpha (TNF-alpha) from porcine coronary arteries and smooth muscle cells cultured from those vessels. It has also been reported that plasma levels of TNF-alpha are elevated after myocardial infarction. Since it is known that the production of reactive oxygen intermediates (ROI) occurs during ischemia and ROI are suggested activators of the nuclear regulatory factor kappaB (NF-kappaB), we tested the hypothesis that release of TNF-alpha from smooth muscle cells could also be stimulated with a ROI-generating system., Materials and Methods: Smooth muscle cells were isolated from porcine coronary arteries. Confluent cells in 48-well culture dishes were treated for 30 min with 0.003 units/ml xanthine oxidase (XO) and 2 mM hypoxanthine (HX) added to the culture medium. The medium was then removed and the cells were washed three times and fresh medium without HX-XO was added. Then, at 1, 3, and 6 h the medium was removed and analyzed for biologically active TNF-alpha. In other experiments, smooth muscle cells were treated with 20 micrograms/ml LPS for 6 h and aliquots of medium analyzed for TNF-alpha. Untreated cells served as controls. Data were analyzed by two-way ANOVA with repeated measures. Extracts of total cell protein were prepared and activation of NF-kappaB was determined by electrophoretic mobility shift assay., Results: Treatment of cells with HX-XO stimulated release of TNF-alpha, which rose to a maximum of 17.5 +/- 1.7 units/mg cell protein at 6 h. This was significantly higher (P < 0. 05) than release stimulated by LPS (10.2 +/- 1.0 units/mg at 6 h) or TNF-alpha detected in the culture medium from untreated control cells (4.2 +/- 0.9 units/mg protein at 6 h). Both HX/XO and LPS activated NF-kappaB., Conclusions: These results support the conclusion that coronary smooth muscle cells are a potential source of TNF-alpha during events that are associated with formation of ROI such as myocardial ischemia., (Copyright 1999 Academic Press.)

Background: Evidence suggests that tumor necrosis factor-alpha (TNF-alpha) is involved in heart diseases such as atherosclerosis. We used porcine coronary arteries and smooth muscle cells cultured from these vessels to study the regulation of production of TNF-alpha. The aims were to determine if bacterial lipopolysaccharide (LPS) could stimulate production; if activation of the nuclear regulatory factor, NF-kappaB, was associated with production; and if intracellular cAMP regulates TNF-alpha in coronary vasculature through a mechanism involving NF-kappaB., Material and Methods: LPS was used to stimulate TNF-alpha production. Forskolin (FSK) and 8-Br-cAMP were added to tissue and cells in order to elevate intracellular cAMP. TNF-alpha release into the bathing medium was measured by the L929 cell cytotoxicity assay. Intracellular cAMP was determined by radioimmunoassay. NF-kappaB activation was determined in whole cell extracts by electrophoretic mobility shift assay., Results: In segments of coronary arteries, LPS stimulated TNF-alpha release which increased with time to a maximum at 6 h (485 +/- 19 units/g tissue) and remained elevated at this level for 24 h. In contrast, the level of TNF-alpha measured at 24 h in medium from coronary tissue not exposed to LPS was 11.1 +/- 4.1 units/g tissue. In the presence of LPS, both FSK and 8-Br-cAMP significantly reduced TNF-alpha release. For instance at 6 h in the presence of LPS and FSK or 8-Br-cAMP, TNF-alpha was 126 +/- 24 and 71.6 +/- 22 units/g tissue, respectively (P < 0.05 vs LPS alone). Tissue levels of cAMP were significantly elevated in the presence of FSK. Similar results were obtained with smooth muscle cells cultured from the coronary arteries; i.e., LPS stimulated TNF-alpha release which was inhibited in a concentration-dependent manner by a rise in intracellular cAMP induced by FSK. In cultured cells release of TNF-alpha stimulated by LPS was associated with activation of NF-kappaB. Neither FSK nor 8-Br cAMP inhibited activation of NF-kappaB by LPS., Conclusions: Porcine coronary arteries produce TNF-alpha from a smooth muscle cell source. Production stimulated by LPS was inhibited by elevated intracellular cAMP and was associated with activation of NF-kappaB. However, activation of NF-kappaB was not inhibited by elevated cAMP, suggesting that the regulatory action of this cyclic nucleotide could lie downstream from activation of the TNF-alpha gene. These results support the view that coronary vessels can be a source of TNF-alpha possibly involved in heart disease., (Copyright 1998 Academic Press.)

Objectives: We recently reported that bacterial lipopolysaccharide stimulates release of tumor necrosis factor (TNF)-alpha from both human vascular tissue and cultured smooth muscle cells. In the current study, we tested the hypothesis that increased intracellular cyclic adenosine 3',5'-monophosphate (cAMP) could inhibit TNF-alpha release., Design: Prospective, repeated-measures analysis., Setting: Academic research laboratory., Subjects: Segments of internal mammary artery and saphenous vein from patients undergoing coronary artery bypass surgery., Measurements and Main Results: Segments of saphenous vein and internal mammary artery and confluent smooth muscle cells cultured from these vessels were incubated in the presence of 20 micrograms/mL bacterial lipopolysaccharide, alone or with the addition of forskolin or 8-Br-cAMP. At 0, 1, 3, 6, 18, and 24 hrs, the incubation medium was removed from vessel segments or cells and was analyzed for biologically active TNF-alpha, using the L929 cell cytotoxicity assay. cAMP was extracted from tissue and cells with 0.1 N HCl and was analyzed by radioimmunoassay. Bacterial lipopolysaccharide stimulated the release of TNF-alpha from internal mammary smooth muscle cells at all time points. For example, at 6 hrs, TNF-alpha concentration in the medium from lipopolysaccharide-stimulated cells was 20 +/- 1.6 U/mg of cell protein, compared with 0.9 +/- 0.5 U/mg of cell protein in control cell medium (p < .05). Forskolin-inhibited bacterial lipopolysaccharide stimulated TNF-alpha release. In the presence of lipopolysaccharide and forskolin, TNF-alpha release at 6 hrs was 8.6 +/- 1.5 U/mg of cell protein (p < .05 vs. in the presence of bacterial lipopolysaccharide alone). Bacterial lipopolysaccharide, alone, had no effect on intracellular cAMP. Forskolin increased intracellular cAMP levels to 74.0 +/- 12 pmol/mg of cell protein at 6 hrs from a control level of 7.7 +/- 0.4 pmol/mg (p < .05). The 8-Br-cAMP, an agent that mimics the action of intracellular cAMP, also inhibited TNF-alpha release stimulated by lipopolysaccharide. Similar inhibition by forskolin and 8-Br-cAMP on TNF-alpha release was obtained with smooth muscle cells from saphenous vein. Finally, in tissue segments from either internal mammary artery or saphenous vein, both forskolin and 8-Br-cAMP inhibited lipopolysaccharide-stimulated TNF-alpha release., Conclusions: These results are consistent with the conclusion that vascular tissue, particularly the smooth muscle cell, is a source of TNF-alpha. Further, bacterial lipopolysaccharide-stimulated tumor TNF-alpha release can be inhibited by increased intracellular cAMP.

Objective: To evaluate a new technique in which a hand-held external magnet is used to maneuver nasoenteral feeding tubes through the pylorus and into the duodenum., Design: Prospective case series., Setting: Critical care units and medical and surgical wards of a university-affiliated community hospital., Patients: Thirty-five patients were entered into the study after the attending physician requested assistance in tube placement., Interventions: A standard 12-Fr, 114-cm flexible nasoenteral feeding tube was modified by inserting a small magnet into the distal tip. The tube was inserted per nares into the stomach, using traditional technique. Next, an external magnet was placed over the right upper abdominal quadrant, at the midclavicular line to attract the tube tip along the lesser curvature of the stomach, through the pyloric sphincter, and into the duodenum. Portable abdominal radiography performed immediately after the procedure confirmed the anatomic location of the tube tip., Measurements and Main Results: Forty-two intubations were performed in 35 patients (in seven patients, the tube had to be reinserted due to inadvertent removal or surgery). In 37 (88%) of 42 intubations, the tube was passed through the pyloric sphincter and into the duodenum on the first attempt. The mean procedure time was 15 +/- 9 mins (range 10 to 45). There were no complications related to the procedure during the study period., Conclusions: This report describes a novel technique of enteral feeding tube placement, using external magnetic guidance. Transpyloric placement was achieved in 88% of cases. This reliable and convenient bedside method for rapid placement of the tube into the duodenum allows prompt and safe initiation of enteral nutrition.

Objectives: Based on our previous study that bacterial lipopolysaccharide stimulates release of tumor necrosis factor (TNF)-alpha from human vascular tissue and smooth muscle cells, we tested the hypothesis that release of TNF could be inhibited by pretreatment with glucocorticoids., Design: Prospective, repeated-measures analysis of concentration-response relationships., Setting: Academic anesthesiology research laboratory., Subjects: Segments of internal mammary artery and saphenous vein were obtained during coronary artery bypass surgery., Interventions: None., Measurements and Main Results: Confluent human smooth muscle cells, cultured from saphenous vein and internal mammary artery, were exposed to 20 micrograms/mL of bacterial lipopolysaccharide following pretreatment for 18 hrs with either 0.1, 1.0, or 10.0 microM of dexamethasone. At 1, 3, 6, 18, and 24 hrs, the culture medium was removed and analyzed for biologically active TNF-alpha using the L929 cell cytotoxicity assay. Smooth muscle cells exposed to bacterial lipopolysaccharide but not treated with dexamethasone served as controls. In control internal mammary cells, bacterial lipopolysaccharide stimulated TNF-alpha release in a time-dependent manner to a peak of 36 +/- 2.3 U/mg of cell protein at 6 hrs, compared with 0.7 +/- 0.3 U/mg of cell protein in cells not exposed to lipopolysaccharide. Dexamethasone inhibited bacterial lipopolysaccharide-stimulated release at all time points in a concentration-dependent manner. For instance, at 6 hrs, TNF-alpha was 12 +/- 2.2, 6.9 +/- 1.7, and 2.3 +/- 0.9 U/mg of cell protein for cells pretreated with 0.1, 1.0, and 10.0 microM of dexamethasone, respectively (p < .05 vs. control). In separate experiments, segments of internal mammary artery and saphenous vein were obtained from five patients who received 1 g of methylprednisolone intravenously during induction of anesthesia, and from seven patients who did not receive methylprednisolone. Bacterial lipopolysaccharide induced release of TNF-alpha from vascular tissues of untreated patients in a time-dependent manner (e.g., 733 +/- 44 U/g of tissue at 6 hrs in saphenous vein). In contrast, in patients treated with methylprednisolone, bacterial lipopolysaccharide did not stimulate release from vascular tissues incubated for up to 24 hrs., Conclusions: These results indicate that human vascular tissue, particularly the smooth muscle cell, may be a source of TNF-alpha and that glucocorticoids inhibit release stimulated by bacterial lipopolysaccharide.

We characterized the response of soluble guanylyl cyclase in smooth muscle cells cultured from cerebral vessels to the nitric oxide (NO)-producing vasodilators, nitroglycerin (NTG) and sodium nitroprusside (SNP) and determined the ability of these agents to induce tolerance. Smooth muscle cells were isolated from porcine basilar, anterior and middle cerebral, and internal carotid arteries. Following an initial series of experiments using NTG at various concentrations and times of exposure to determine conditions, concentration-response curves of intracellular guanosine 3',5'-cyclic monophosphate (cGMP) to NTG and SNP were determined in cells pretreated for 1 h with 100 mumol NTG to induce tolerance and compared with response curves in control cells. Basal cGMP levels were 2.1 +/- 0.4 pmol/mg cell protein (n = 16). Both NTG and SNP increased cGMP in nontolerant cells, and SNP was more effective. Maximum concentrations of SNP (1 mmol/L) increased cGMP to 163 +/- 5.9 pmol/mg versus 21 +/- 2.4 pmol/mg for 1 mmol/L NTG (p < 0.01). Cells made tolerant to NTG were unresponsive to NTG up to 1 mmol/L but remained responsive to SNP. However, the response curve to SNP was significantly depressed by approximately 25%. Following washout of NTG in tolerant cells, the response of cGMP to SNP returned to control within 12 h, while response to NTG required 36 h. Similar experiments were conducted in cells initially made tolerant to SNP. These results indicate that cerebral artery smooth muscle cells in culture express a functioning soluble guanylyl cyclase and the enzymes that are necessary to metabolize NTG to NO. Prolonged exposure of the cells to NTG induced tolerance as well as cross-tolerance to SNP.

Objectives: We determined the response of intracellular cyclic GMP in human arteries and veins and in smooth muscle cells cultured from these vessels to C-type natriuretic peptide in comparison with atrial natriuretic peptide., Design: Repeated-measures analysis of concentration-response curves., Setting: Anesthesia research laboratory., Subjects: Vascular smooth muscle cells from human blood vessels obtained with Institutional Review Board approval and patient consent., Measurements and Main Results: Segments of internal mammary artery and saphenous vein were obtained from patients undergoing coronary artery bypass surgery. Smooth muscle cells were cultured from these vessels. Concentration-response curves of intracellular cyclic GMP were determined and analyzed by two-way analysis of variance with repeated measures. In segments of intact saphenous vein, C-type natriuretic peptide was significantly more effective than atrial natriuretic peptide (16-fold increase in cyclic GMP in response to 1 microM of C-type natriuretic peptide vs. six-fold increase in cyclic GMP in response to 1 microM of atrial natriuretic peptide, p < .05). In rings of intact internal mammary artery, 1 microM of atrial natriuretic peptide (26-fold increase in cyclic GMP over basal value) was more effective than 1 microM of c-type natriuretic peptide (three-fold increase in cyclic GMP over basal value, p < .05). In cultured cells from these vessels, the pattern of response to C-type natriuretic peptide and atrial natriuretic peptide was the same as in the intact vessels., Conclusions: These results indicated that human smooth muscle cells in arteries and veins express both forms of natriuretic peptide receptors but that atrial natriuretic peptide acts primarily on the artery and C-type natriuretic peptide acts predominantly on the vein. Increased concentrations of C-type natriuretic peptide could contribute to venous pooling in septic shock.

Objectives: In septic shock, the principal source of increased plasma concentrations of tumor necrosis factor alpha (TNF) is considered to be the macrophage. Release from the macrophage is stimulated by bacterial lipopolysaccharide (endotoxin). We tested the hypothesis that vascular tissue also responds to endotoxin by releasing TNF., Design: Prospective repeated measures analysis of timed-release curves., Setting: Anesthesia research laboratory in an academic medical center., Subjects: With Institutional Review Board approval and patient consent, segments of internal mammary artery and saphenous vein were obtained during coronary artery bypass surgery., Interventions: None, Measurements and Main Results: Segments of saphenous veins were incubated for 24 hrs in the presence or absence of bacterial lipopolysaccharide. At 0.5, 1, 3, 6, and 24 hrs, medium was assayed for TNF. In other experiments, smooth muscle cells were cultured from saphenous veins, incubated with our without bacterial lipopolysaccharide, and a time-course of TNF release determined. Bacterial lipopolysaccharide (20 micrograms/mL) significantly stimulated release of TNF from venous tissue in a time-dependent manner. At 0.5 hrs, TNF was undetectable in untreated tissue and was 48 +/- 8 U/g wet tissue weight in the presence of bacterial lipopolysaccharide. At 3 hrs, TNF was 43 +/- 27 U/g wet tissue weight in untreated and 388 +/- 185 U/g wet tissue weight in treated (p < .01 vs. control) tissue. Segments of internal mammary artery responded in a similar manner. In smooth muscle cells cultured from saphenous vein and internal mammary artery, bacterial lipopolysaccharide triggered the release of TNF. At 3 hrs, the release of TNF in control cells was 0.2 +/- 0.15 U/mg cell protein and 17 +/- 2 U/mg in the presence of 20 micrograms/mL of bacterial lipopolysaccharide (p < .01 vs. control)., Conclusions: Human blood vessels, both artery and vein, produce TNF potentially from a smooth muscle cell source in response to bacterial lipopolysaccharide.

A major hypothesis for the mechanism of tolerance to nitroglycerin (NTG) is that continued use causes a decrease in thiol donors within the vascular smooth muscle cell that are essential for the effect of NTG. We tested this idea directly in the target cell. NTG tolerance, measured as reduced formation of intracellular cyclic guanosine monophosphate (cGMP), was induced in pig coronary smooth muscle cells. The consequence of altering intracellular levels of the thiol donors, glutathione (GSH) and L-cysteine (L-cys), was determined. Incubating cells with 100 microM NTG for 1 h caused an 83% reduction in cGMP formation in response to acute readministration of 200 microM NTG for 2 min but was not associated with a reduction in intracellular GSH or L-cys. This result was not altered when intracellular GSH levels were increased three-fold by including 1 mM GSH in the incubation buffer. Also, recovery from tolerance was not affected by supplementation with GSH. Further, the response of cGMP to NTG was not altered by inhibiting the synthesis of GSH and lowering intracellular levels of GSH by 77%. Similar findings were made with supplemental L-cys or N-acetyl-L-cysteine. These results do not support the hypothesis that tolerance to NTG is the result of a reduction of the thiol donors GSH and L-cys within vascular smooth muscle cells.

Regional anesthetic block of the cervical plexus is a safe and useful alternative to general endotracheal anesthesia for surgery of the neck, upper shoulder, and occipital scalp area. The sensory component of the cervical plexus can be blocked separately and easily by a superficial cervical plexus block. Both motor and sensory block can be obtained by deep cervical plexus block. Minor transient side effects are common to deep cervical plexus blocks, but they are rarely of any consequence. Recent years have seen an increase in interest in the use of the cervical plexus block, because its popularity for surgical procedures such as carotid endarterectomies has grown. An understanding of the anatomy and principles of this anesthetic technique will enable the clinician to offer the patient and surgeon an important anesthetic option.