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Via the emergence of new bronchoscopic technologies and techniques, there is enormous growth in the number of procedures being performed in nonoperating room settings. This, coupled with a greater focus from the Centers for Medicare and Medicaid Services for mandated anesthesiology oversight of procedural sedation for bronchoscopy by the pulmonologists has led to a more frequent working partnership between interventional pulmonologists and anesthesiologists. This article offers the interventional pulmonologist insight into how the anesthesiologist thinks and approaches anesthetic care delivery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nitric oxide (NO) has come far since being discovered serendipitously to relax vascular smooth muscle. Initially, administered to animals to reduce pulmonary artery pressures and improve oxygenation. It now enjoys FDA approval for administration to newborns with pulmonary hypertension but is used common place for other critical cardiopulmonary ailments. While never quite living up to expectations, newer applications show greater promise as a therapy especially in the area of ischemia-reperfusion. The following will give a clinical overview of inhaled nitric oxide as a gas, as applied to the pediatric patient population, and to those adults suffering with cardiopulmonary and hematologic disease. Lastly, due to more recent discoveries, the effects of how NO may be used to treat disorders such as ischemia-reperfusion, will also be reviewed., (Copyright © 2015. Published by Elsevier Inc.)

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were $1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.

Reducing tidal volume as a part of a protective ventilation strategy may result in hypercapnia. In this study, we focused on the influence of hypercapnia on endothelial-neutrophil responses in models of inflammatory-stimulated human pulmonary microvascular endothelial cells (HMVEC) and in an animal model of lipopolysaccharide (LPS)-induced acute lung injury. Neutrophil adhesion and adhesion molecules expression and nuclear factor-kappaB (NF-kappaB) were analyzed in TNF-alpha and LPS-treated HMVEC exposed to either eucapnia or hypercapnia. In the in vivo limb, bronchoalveolar lavage fluid cell counts and differentials, adhesion molecule and chemokine expression were assessed in LPS-treated rabbits ventilated with either low tidal volume ventilation and eucapnia or hypercapnia. In both the in vitro and in vivo models, hypercapnia significantly increased neutrophil adhesion and adhesion molecule expression compared to eucapnia. Activity of NF-kappaB was significantly enhanced by hypercapnia in the in vitro experiments. IL-8 expression was greatest both in vitro and in vivo under conditions of hypercapnia and concomitant inflammation. CD11a expression was greatest in isolated human neutrophils exposed to hypercapnia+LPS. Our results demonstrate that endothelial-neutrophil responses per measurement of fundamental molecules of adhesion are significantly increased during hypercapnia and that hypercapnia mimics conditions of eucapnia+inflammation.

Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation.

The objective of this study was to determine the outcomes of gynecological oncology patients requiring intensive care unit (ICU) admission following surgery. A computerized database identified postsurgical ICU admissions from January 1, 1999 to December 31, 2004 at a university hospital. Abstracted data included: demographics, preoperative diagnosis, reason(s) for ICU admission, consultations, interventions, length of stay (LOS), Acute Physiology and Chronic Health Evaluation (APACHE) II score, and 30-day mortality. Statistical analysis was performed with the Student's t-test. A total of 185 surgical gynecological oncology ICU patients was identified. Median age was 60 years (range, 21-92 years), and 63% of patients were white. Only 72% of patients had ovarian, endometrial, or cervical cancer. The most common indications for ICU admission were volume resuscitation (108 patients) and respiratory insufficiency (80 patients). Median ICU LOS was 1 day (range, 1-55 days). Patients surviving their hospital admission had a mean APACHE II score of 11.5 (range, 2-37) compared to a mean of 21.2 (range, 13-44) for patients who died prior to hospital discharge (P < 0.001). The overall mortality rate was 12%. A substantial number of gynecological oncology patients will be admitted to the ICU following surgery. Patient outcomes are favorable if APACHE II scores are low and ICU LOS is short.

Protective ventilation strategies have been universally embraced because of reduced mortality. We tested the hypothesis that tidal volume (VT) in an in vivo model of mechanical ventilation would modulate bactericidal function of alveolar macrophages (AMs). Adult New Zealand White rabbits were mechanically ventilated for 4 h with a VT of 6 ml/kg (low) or a VT of 12 ml/kg (traditional), with each group receiving 3 cm H2O positive end-expiratory pressure with and without intratracheal lipopolysaccharide (LPS) instillation (20 mg/kg). AMs were isolated from bronchoalveolar lavage fluid taken from the whole left lung and used for bacterial killing assays. There were no significant differences in steady-state levels of nitrite or AM phagocytosis and killing of Klebsiella pneumoniae, although these values trended to be slightly higher in the traditional VT group. However, bronchoalveolar lavage fluid protein concentrations were significantly increased in traditional VT groups receiving LPS compared with animals ventilated with a low VT (1,407.8 +/- 121.4 versus 934.7 +/- 118.2; P < 0.001). Lung wet:dry weight ratio in the traditional VT group was increased when compared with the low VT group without LPS (7.3 +/- 0.4 versus 6.1 +/- 0.3, respectively; P < 0.05). Additionally, IL-8 expression was significantly greater under conditions of LPS treatment and mechanical ventilation at VT of 12 ml/kg. These results suggest that the traditional ventilator approach (12 ml/kg VT) in a model of in vivo mechanical ventilation results in lung pathology without affecting AM antibacterial function.

Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P(50)). Concomitantly, vasodilation is initiated at the P(50), suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta93cys residue decreases the heme redox potential (ie, decreases E(1/2)), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow.

Background: Human serum albumin is used clinically to maintain colloid osmotic pressure and is viewed to serve an antioxidant role in the vascular compartment via binding of redox-active metal complexes, transport of nitric oxide, and the oxidant-scavenging reactions of the single thiol of human serum albumin, cys34. Because of these potentially desirable adjunctive actions, we evaluated the purity and thiol redox state and compared the relative effects of clinically available 25% human serum albumin preparations with a starch-derived colloid, 6% hydroxyethyl starch, in in vitro models of inflammatory vascular injury., Methods: Bovine aortic endothelial cell responses to chemical, enzymatic, and cell-derived reactive inflammatory mediators in the presence of human serum albumin or hydroxyethyl starch were assessed., Results: The cys34 thiol of fresh human serum albumin preparations was 70-85% oxidized and contained a population of human serum albumin (approximately 25% of total) having the cys34 resistant to reduction by 2-mercaptoethanol and NaBH4. Treatment of bovine aortic endothelial cells with human serum albumin dose-dependently protected from HOCl-mediated 14C-adenine release, with this protective effect of human serum albumin not dependent on protein thiol status. Addition of human serum albumin to cell media provided no protection from the cytotoxic actions of peroxynitrite and xanthine oxidase-derived reactive species. Binding of activated polymorphonuclear leukocytes to bovine aortic endothelial cells was significantly amplified by hydroxyethyl starch and inhibited by human serum albumin administration. The binding of neutrophil-derived myeloperoxidase to bovine aortic endothelial cells, a mediator of multiple oxidative and nitric oxide-consuming reactions, was also inhibited by human serum albumin and enhanced by hydroxyethyl starch., Conclusions: Clinical human serum albumin preparations show modest intrinsic non-thiol-dependent antiinflammatory properties in vitro, a phenomenon that was not observed with hydroxyethyl starch.

There has been a resurgence in interest in the in-hospital management of pain, largely related to results of investigations into the role of analgesia in outcome and cost-efficiency. The traditional aim of analgesia as simply an altruistic goal has been supplanted by the goal of impacting on the altered physiology accompanying critical illness and trauma. Elucidation of the effect of pain and the accompanying stress response on pulmonary dysfunction in particular, but also on myocardial ischemia and coagulation, has suggested that the provision of adequate analgesia by time-honored methods may not in itself effect a reduction in morbidity without attention to the method of analgesic delivery and choice of agent.

Ventilator strategies allowing for increases in carbon dioxide (CO(2)) tensions (hypercapnia) are being emphasized to ameliorate the consequences of inflammatory-mediated lung injury. Inflammatory responses lead to the generation of reactive species including superoxide (O(2)(-)), nitric oxide (.NO), and their product peroxynitrite (ONOO(-)). The reaction of CO(2) and ONOO(-) can yield the nitrosoperoxocarbonate adduct ONOOCO(2)(-), a more potent nitrating species than ONOO(-). Based on these premises, monolayers of fetal rat alveolar epithelial cells were utilized to investigate whether hypercapnia would modify pathways of.NO production and reactivity that impact pulmonary metabolism and function. Stimulated cells exposed to 15% CO(2) (hypercapnia) revealed a significant increase in.NO production and nitric oxide synthase (NOS) activity. Cell 3-nitrotyrosine content as measured by both HPLC and immunofluorescence staining also increased when exposed to these same conditions. Hypercapnia significantly enhanced cell injury as evidenced by impairment of monolayer barrier function and increased induction of apoptosis. These results were attenuated by the NOS inhibitor N-monomethyl-L-arginine. Our studies reveal that hypercapnia modifies.NO-dependent pathways to amplify cell injury. These results affirm the underlying role of.NO in tissue inflammatory reactions and reveal the impact of hypercapnia on inflammatory reactions and its potential detrimental influences.

Purpose: The purpose of this study is to determine if monitoring urinary bladder PCO2, PO2, and calculated intramucosal pH would be a reliable index of tissue perfusion., Materials and Methods: This nonrandomized controlled study was conducted in a laboratory at a university medical center. Eight immature female Yorkshire pigs were studied with T-9 aortic cross-clamping for 30 minutes followed by a 60-minute period of reperfusion. Cystotomy was performed for placement of a Foley catheter and Paratrend 7 O2/CO2 sensor., Results: Baseline hemodynamic and metabolic measurements were obtained along with measurements of bladder mucosal PO2 and PCO2 (mean+/-SEM). Blood flow measured with microspheres confirmed absence of blood flow during occlusion and hyperemia during reperfusion. Bladder mucosal PO2 decreased from 42+/-14.0 mm Hg (5.6 kPa) to 1.3+/-1.3 mm Hg (1.4 kPa) during the 30-minute interval of ischemia. This was followed by an increase of bladder PO2 to greater than baseline values at the end of the reperfusion period. Bladder mucosal Pco2 increased from 57+/-4.7 mm Hg (7.6 kPa) to 117+/-7.1 mm Hg (15.6 kPa) (P < .05) during ischemia. During reperfusion the Pco2 returned to baseline levels (55+/-4.0 mm Hg [7.3 kPa]). Calculated bladder mucosal pHi declined from 7.31+/-0.04 to 7.08+/-0.05 (P < .05) during the ischemic period and after reperfusion pHi was 7.17+/-0.03., Conclusions: Monitoring urinary bladder PO2, PCO2, or calculating pHi may provide a simple and reliable means of monitoring tissue perfusion.

Although pain is a common fear to most, our overall ability to recognize pain, and assess and intervene with appropriate therapies is mediocre at best. However, if made a priority, substantial gains can be made in improving patient satisfaction with pain control and in rectifying deficits in the knowledge of health-care professionals. This goal is not easily obtained and generally requires time, patience, and a multidisciplinary team approach. Pain can induce numerous metabolic and neuroendocrine responses. While seemingly homeostatic, these changes can have significant physiologic and sometimes adverse consequences. Anesthesia and analgesia, especially by way of neural blockade, can alleviate some of the changes and sometimes improve unwanted consequences. While at times these techniques have not significantly altered outcome, at other times significant benefits have been observed. More sophisticated techniques and pharmacotherapies are being developed and introduced with increased frequency, but alone they will probably have only minimal impact on overall morbidity and mortality. The integration of a multimodal approach seems logical in the critical care setting, with analgesia as the cornerstone.