Precision Anesthesia in 2050.

Over the last few decades, the field of anesthesia has advanced far beyond its humble beginnings. Today's anesthetics are better and safer than ever, thanks to innovations in drugs, monitors, equipment, and patient safety.1-4 At the same time, we remain limited by our herd approach to medicine. Each of our patients is unique, but health care today is based on a one-size-fits-all approach, while our patients grow older and more medically complex every year. By 2050, we believe that precision medicine will play a central role across all medical specialties, including anesthesia. In addition, we expect that health care and consumer technology will continually evolve to improve and simplify the interactions between patients, providers, and the health care system. As demonstrated by 2 hypothetical patient experiences, these advancements will enable more efficient and safe care, earlier and more accurate diagnoses, and truly personalized treatment plans.

Negative pressure suction test: An intraoperative airway maneuver to assess effectiveness of surgical correction of tracheobronchomalacia.

BACKGROUND: Surgical correction of tracheobronchomalacia (TBM) has evolved greatly over the past decade, with select pediatric institutions establishing dedicated surgery and anesthesia teams to navigate the complexities and challenges of surgical airway repairs. Although anesthetic techniques have evolved internally over many years to improve patient safety and outcomes, many of these methods remain undescribed in literature. TECHNIQUE: In this article, we describe the intraoperative negative pressure suction test. This simulates the negative pressure seen in awake and spontaneously breathing patients, including the higher pressures seen during coughing which induce airway collapse in patients with TBM. Also known as the Munoz maneuver in surgical literature, this test has been performed on over 300 patients since 2015. DISCUSSION: The negative pressure suction test allows for controlled intraoperative assessment of surgical airway repairs, replaces the need for risky intraoperative wake-up tests, increases the chances of a successful surgical repair, and improves anesthetic management for emergence and extubation. We provide a guide on how to perform the test and videos demonstrating its efficacy in intraoperative airway evaluation. CONCLUSIONS: As surgeries to repair TBM become more prevalent in other pediatric institutions, we believe that pediatric patients and anesthesia providers will benefit from the insights and methods described here.

Risk Factors for Development and Progression of Scoliosis After Pediatric Cardiothoracic Operations.

BACKGROUND: The purpose of this study was to determine the incidence and risk factors for the development and rate of progression of scoliosis and moderate/severe scoliosis in patients undergoing cardiothoracic operations (CTOs). METHODS: Included were patients aged younger than 12 years who underwent CTOs in 1995 to 2006 with a preoperative chest roentgenogram (CRG) and a CRG at least 8 years after CTOs. Scoliosis and moderate/severe scoliosis were defined as a Cobb angle of 10 degrees or more and an angle of 25 degrees or more or the need for surgical intervention, respectively. Risk factors were analyzed using nonparametric and parametric survival analyses. For patients that developed scoliosis, progression rate was analyzed using linear regression models for repeated measures using CRG at 6-month intervals. RESULTS: The study included 871 patients (380 girls [44%]). Median CRG follow-up was 11 years (interquartile range, 9 to 13 years). Overall 10-year incidence of scoliosis and moderate/severe scoliosis was 12% and 3%, respectively. Independent predictors for scoliosis included female sex (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.2 to 2.5), syndrome (HR, 1.9; 95% CI, 1.3 to 2.8), and isolated developmental delay (HR, 2.4; 95% CI, 1.4 to 4.2). For development of moderate/severe scoliosis, independent risk factors included female sex (HR, 2.8; 95% CI, 1.4 to 5.8), syndrome (HR, 3; 95% CI, 1.5 to 6.1), isolated developmental delay (HR, 3.1; 95% CI, 1 to 9.2]), and prematurity for neonates/infants (HR, 2.3; 95% CI, 1 to 5.2). Rate of angle progression was 0.17 times the current angle per year. Age, syndrome, and developmental delay were risk factors for angle progression. CONCLUSIONS: Patients that undergo pediatric CTO, regardless of the operative approach, are at increased risk for development of scoliosis and moderate/severe scoliosis. Long-term follow-up of these patients is warranted, in particular for girls and patients with genetic syndromes or developmental delay.

Derivation and maturation of synthetic and contractile vascular smooth muscle cells from human pluripotent stem cells.

AIMS: Embryonic vascular smooth muscle cells (vSMCs) have a synthetic phenotype; in adults, they commit to the mature contractile phenotype. Research shows that human pluripotent stem cells (hPSCs) differentiate into vSMCs, but nobody has yet documented their maturation into the synthetic or contractile phenotypes. This study sought to control the fate decisions of hPSC derivatives to guide their maturation towards a desired phenotype. METHODS AND RESULTS: The long-term differentiation of hPSCs, including the integration-free-induced PSC line, in high serum with platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-ß1, allowed us to induce the synthetic vSMC (Syn-vSMC) phenotype with increased extracellular matrix (ECM) protein expression and reduced expression of contractile proteins. By monitoring the expression of two contractile proteins, smooth muscle myosin heavy chain (SMMHC) and elastin, we show that serum starvation and PDGF-BB deprivation caused maturation towards the contractile vSMC (Con-vSMC) phenotype. Con-vSMCs differ distinctively from Syn-vSMC derivatives in their condensed morphology, prominent filamentous arrangement of cytoskeleton proteins, production and assembly of elastin, low proliferation, numerous and active caveolae, enlarged endoplasmic reticulum, and ample stress fibres and bundles, as well as their high contractility. When transplanted subcutaneously into nude mice, the human Con-vSMCs aligned next to the host's growing functional vasculature, with occasional circumferential wrapping and vascular tube narrowing. CONCLUSION: We control hPSC differentiation into synthetic or contractile phenotypes by using appropriate concentrations of relevant factors. Deriving Con-vSMCs from an integration-free hiPSC line may prove useful for regenerative therapy involving blood vessel differentiation and stabilization.

The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking.

The orphan G-protein coupled receptor, GPR84 is highly expressed in the bone marrow, and in splenic T cells and B cells. In this study, GPR84-deficient mice were generated to understand the biological function of this orphan receptor. The proliferation of T and B cells in response to various mitogens was normal in GPR84-deficient mice. Interestingly, primary stimulation of T cells with anti-CD3 resulted in increased IL-4 but not IL-2 or IFN-gamma production in GPR84(-/-) mice compared to wild-type mice. Augmented IL-4 production in GPR84-deficient T cells was not related to increased frequency of IL-4-secreting cells in response to anti-CD3 stimulation. In fact, stimulation with anti-CD3 and anti-CD28 resulted in increased levels of IL-4 but not IFN-gamma steady-state mRNA in GPR84(-/-) T cells. In addition, Th2 effector cells generated in vitro from GPR84(-/-) mice produced higher levels of IL-4, IL-5 and IL-13 compared to wild-type mice. However, there was no detectable difference in the extent of IL-4 and IL-5 production between the two groups of mice in response to antigen stimulation of spleen cells, isolated from mice previously immunized with OVA in alum. These studies reveal a novel role for GPR84 in regulating early IL-4 gene expression in activated T cells.

CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease.

Chemokine receptors play an important role in the trafficking of various immune cell types to sites of inflammation. Several chemokine receptors are differentially expressed in Th1 and Th2 effector populations. Th2 cells selectively express CCR3, CCR4, and CCR8, which could direct their trafficking to sites of allergic inflammation. Additionally, increased expression of the CCR8 ligand, TCA-3, has been detected in affected lungs in a mouse model of asthma. In this study, CCR8-deficient mice were generated to address the biological role of CCR8 in a model of allergic airway disease. Using two different protocols of allergen challenge, we demonstrate that absence of CCR8 does not affect the development of pulmonary eosinophilia and Th2 cytokine responses. In addition, administration of anti-TCA-3-neutralizing Ab during allergen sensitization and rechallenge failed to inhibit airway allergic inflammation. These results suggest that CCR8 does not play an essential role in the pathogenesis of inflammation in this mouse model of allergic airway disease.