Transnasal Humidified Rapid Insufflation Ventilatory Exchange in Endoscopic Esophageal Surgery.

OBJECTIVES: Transnasal humidified rapid insufflation ventilatory exchange (THRIVE) describes apneic oxygenation using humidified high flow nasal-cannula oxygen. Although it has been described as a sole mode of oxygenation in endoscopic laryngotracheal surgery, its use in endoscopic esophageal surgery under general anesthesia with neuromuscular paralysis has not previously been described. The objective of this study is to assess the safety and efficacy of THRIVE in esophagology. METHODS: We conducted a retrospective review of adult patients undergoing esophageal procedures under general anesthesia who were oxygenated using THRIVE at two academic institutions. Demographic, clinical, and anesthesiologic data were collected and analyzed. RESULTS: 14 cases performed from March 2021 to March 2022 met inclusion criteria. 13/14 (92.9%) of patients were able to maintain oxygenation throughout the entirety of their procedure. The mean apneic time was 17.9 minutes with a maximum of 32 minutes. One patient required "rescue" intubation due to failure to maintain oxygenation. Excluding the sole THRIVE failure, the median SpO2 at the conclusion of surgery was 99% (range 94-100%). A linear regression model yielded an increase in EtCO2 of 0.95 mmHg/min or 0.127 kPa/min. SpO2 was negatively associated with both tobacco pack-year smoking history (R2 = 0.343, P = .014) and BMI (R2 = 0.238, P = .038). CONCLUSION: THRIVE is a feasible, safe, and efficacious means of apneic oxygenation for patients undergoing esophageal endoscopic surgery under general anesthesia with neuromuscular paralysis, which may be particularly beneficial in patients with airway stenosis, as post-intubation changes can have severe clinical implications for this patient population. Obese patients and tobacco smokers may be at increased risk of oxygen desaturation when using THRIVE.

Low Pressure Low Frequency Jet Ventilation: Techniques, Safety and Complications.

OBJECTIVE: Manual jet ventilation is a specialized oxygenation and ventilation technique that is not available in all facilities due to lack of technical familiarity and fear of complications. The objective is to review our center's 15 year experience with low pressure low frequency jet ventilation (LPLFJV). METHODS: Retrospective review of procedures utilizing LPLFJV from 2005 to 2019 were performed collecting patient demographic, surgery type and complications. Fisher exact test, Chi square, and t-test were used to determine statistical significance. RESULTS: Four hundred fifty-seven patients underwent a total of 891 microlaryngeal surgeries-279 cases for voice disorders, 179 for lesions, and 433 for airway stenosis. The peak jet pressure for all cases did not exceed 20 psi and average peak pressure for the last 100 procedures in this case series was 14.9 ± 4.6 psi. The average lowest oxygen saturation for all cases was 95% ± 0.6%. Brief intubation was required in 154 cases (17%). Surgical duration was significantly longer for cases requiring intubation P < .001. The need for intubation was not associated with smoking or cardiopulmonary disease, but was strongly associated with body mass index (BMI). Intubation rates were 7% for normal weight (BMI < 25, N = 216), 13% for overweight (BMI 25-30, N = 282), 24% for obese (BMI 30-40, N = 342), and 37% for morbidly obese (BMI > 40, N = 52) patients. Three patients developed respiratory distress in the recovery unit and 2 patients required intubation. CONCLUSION: LPLFJV assisted by intermittent endotracheal intubation is an exceedingly safe and effective intraoperative oxygenation and ventilationmodality for a broad variety of laryngeal procedure.

Using NSQIP Data to Reduce Institutional Postoperative Pneumonia Rates in Non-ICU Patients: A Plan-Do-Study-Act Approach.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) is a program designed to measure and improve surgical care quality. In 2015, the study institution formed a multidisciplinary team to address the poor adult postoperative pneumonia performance (worst decile). STUDY DESIGN: The study institution is a 450+ bed tertiary care center that performs 12,000+ surgical procedures annually. From January 2016 to December 2019, the institution abstracted surgical cases and assigned postoperative pneumonia as a complication per the NSQIP operations manual. Using a plan-do-study-act approach, a multidisciplinary postoperative pneumonia prevention team implemented initiatives regarding incentive spirometry education, anesthetic optimization, early mobility, and oral care. The team measured the initiatives' success by analyzing semiannual reports (SAR) provided by the ACS NSQIP and regional adjusted percentile rankings provided by the Georgia Surgical Quality Collaborative (GSQC). RESULTS: The 2015 SAR postoperative pneumonia rate was 4.20% (odds ratio [OR] 3.86, confidence interval [CI] 2.92-5.11). After project initiation, the postoperative pneumonia rates decreased for all NSQIP cases, from 2.51% (OR 2.67, CI 1.89-3.77) in 2016 to 2.08% (OR 2.61, CI 1.82-3.74) in 2017, to 0.85% (OR 1.10, CI 0.69-1.75) in 2018, and then increased slightly to 1.14% (OR 1.27, CI 0.84-1.92) in 2019. The institution's adjusted percentile regional rank of participating regional ACS NSQIP hospitals' postoperative pneumonia rate improved from 14/14 (July 2015-June 2016) to 6/14 (July 2018-June 2019). CONCLUSIONS: The multidisciplinary postoperative pneumonia prevention team successfully decreased the postoperative pneumonia rate, therefore improving surgical patients' outcomes. Furthermore, this quality improvement project also saved valuable revenue for the hospital.

Platforms for delivery of macromolecules to sites of DNA double-strand break repair.

Double-strand break (DSB) repair foci are important therapeutic targets. Here we describe platforms for delivery of macromolecules, nanomaterials and nanomedicines to repair foci. The strategy is based on the high affinity of the human 53BP1 protein for modified chromatin present at sites of DNA damage. As proof of concept, we created, expressed, and purified an engineered fragment of 53BP1 and coupled it to fluorescent streptavidin, a model cargo with no intrinsic affinity for repair foci. This binary complex was in turn coupled to the iron carrier protein, transferrin, which engages a high-affinity cell surface receptor. In a different version of the complex, transferrin was omitted and a protein transduction domain was incorporated directly into the primary structure of the 53BP1. These complexes were efficiently taken up into human osteosarcoma cells and synchronously released from endocytic vesicles by brief exposure to far-red light in the presence of the photosensitizer, disulfonated aluminum phthalocyanine. Upon release, the streptavidin cargo entered the nucleus and was recruited to repair foci. 53BP1-based platforms provide a method for targeted, temporally controlled delivery of macromolecular agents to sites of double-strand break repair. With the delivery platforms, we are capable to visualize, modify and redirect DSB repair pathways by coupling various nanomaterials to study machinery or manipulate for therapy purpose in the future.

Celiac Plexus Block as a Predictor of Surgical Outcome for Sympathetically Mediated Abdominal Pain in a Case of Suspected Median Arcuate Ligament Syndrome: A Case Report.

Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, is an uncommon condition classically characterized by chronic abdominal pain, weight loss, and abdominal bruit. Chronic mesenteric ischemia caused by intermittent compression of the celiac artery by the MAL provokes upper abdominal pain that is sympathetically mediated via the celiac plexus. Because it is a diagnosis of exclusion, diagnosis of MALS in the clinical setting is typically challenging. We present an atypical case which highlights the utility of celiac plexus block as both an assistant diagnostic tool and a predictor of surgical outcomes for suspected MALS.

A thalidomide-hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes.

Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties.

Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species.

BACKGROUND AND PURPOSE: Endothelin-1 (ET-1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ETA receptor contributes to renal injury in a mouse model of sickle cell disease. EXPERIMENTAL APPROACH: Adult, humanized HbSS (homozygous for sickle Hb) mice had increased ET-1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ETA receptor mRNA expression was also elevated in HbSS (sickle) mice although ETB receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ETA receptors in the renal vascular tissue when compared with control mice. KEY RESULTS: In response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ETA antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ETA receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease. CONCLUSIONS AND IMPLICATIONS: These data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ETA receptor, and suggest a potential role for ETA receptor antagonism in a treatment strategy.

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain.

Sickle cell disease (SCD), a hemoglobinopathy, causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. A vast majority of SCD patients experience pain on a chronic basis, and many turn to opioids to provide limited relief. The side effects that come with chronic opioid use push for research into understanding the specific mechanisms of SCD-associated chronic pain. Current advances in SCD-associated pain have focused on alterations in the pain pathway including nociceptor sensitization and endogenous pain inducers. This article reviews the underlying pathophysiology of SCD, potential pain mechanisms, current treatments and their mechanism of action, and future directions of SCD-associated pain management. The information provided could help propel research in SCD-associated chronic pain and uncover novel treatment options for clinicians.

Receptor-mediated delivery of engineered nucleases for genome modification.

Engineered nucleases, which incise the genome at predetermined sites, have a number of laboratory and clinical applications. There is, however, a need for better methods for controlled intracellular delivery of nucleases. Here, we demonstrate a method for ligand-mediated delivery of zinc finger nucleases (ZFN) proteins using transferrin receptor-mediated endocytosis. Uptake is rapid and efficient in established mammalian cell lines and in primary cells, including mouse and human hematopoietic stem-progenitor cell populations. In contrast to cDNA expression, ZFN protein levels decline rapidly following internalization, affording better temporal control of nuclease activity. We show that transferrin-mediated ZFN uptake leads to site-specific in situ cleavage of the target locus. Additionally, despite the much shorter duration of ZFN activity, the efficiency of gene correction approaches that seen with cDNA-mediated expression. The approach is flexible and general, with the potential for extension to other targeting ligands and nuclease architectures.

Thalassemia-like phenotype in a novel complex hemoglobinopathy with α, ß, δ globin chain abnormalities.

The occurrence of multiple abnormalities of α, ß, δ, and γ globin genes may lead to unusual and complex phenotypes when they arise simultaneously in the same individual. Here, we report the findings of an African American boy who coinherited 3 heterozygous globin gene abnormalities: the unstable ß-globin chain variant; hemoglobin (Hb) Showa-Yakushiji [ß110(G12) Leu→Pro], the δ-globin chain variant; HbB2 [δ16(A13) Gly→Arg] and α-thalassemia (α-thal); (α-/αα). Hb Showa-Yakushiji had been previously described in Japanese, Indian, and European populations. We report its first occurrence in a child of African ancestry who presented with anemia not responsive to iron and an incomplete ß-thalassemia minor phenotype. Although the clinical and laboratory features of Hb Showa-Yakushiji mimic those of a ß-thalassemia, the coinheritance of the δ-globin chain variant Hb B2 suppressed the relative increase in Hb A2 usually observed in heterozygotes for the Hb Showa-Yakushiji mutation. Protein-based methods detected only a trace amount of HbB2 and failed to reveal presence of Hb Showa-Yakushiji and α-thal. The latter were only identified through DNA analyses. The diagnostic difficulties, molecular characteristics, and genotype/phenotype correlations of this novel complex hemoglobinopathy syndrome are reviewed.

Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms.

A novel series of thalidomide derivatives (4a-f) designed by molecular hybridization were synthesized and evaluated in vitro and in vivo for their potential use in the oral treatment of sickle cell disease symptoms. Compounds 4a-f demonstrated analgesic, anti-inflammatory, and NO-donor properties. Compounds 4c and 4d were considered promising candidate drugs and were further evaluated in transgenic sickle cell mice to determine their capacity to reduce the levels of the proinflammatory cytokine tumor necrosis factor α (TNFα). Unlike hydroxyurea, the compounds reduced the concentrations of TNFα to levels similar to those induced with the control dexamethasone (300 µmol/kg). These compounds are novel lead drug candidates with multiple beneficial actions in the treatment of sickle cell disease symptoms and offer an alternative to hydroxyurea treatment.

Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice.

Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and ß-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34(+) progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.

Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice.

OBJECT: Intracerebral hemorrhage (ICH) is associated with significant morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; but neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, the authors investigated whether the curry spice curcumin limited neurovascular injury following ICH in mice. METHODS: Intracerebral hemorrhage was induced in adult male CD-1 mice by intracerebral administration of collagenase or autologous blood. Clinically relevant doses of curcumin (75-300 mg/kg) were administered up to 6 hours after ICH, and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes. RESULTS: Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the proinflammatory mediators, tumor necrosis factor-α, interleukin-6, and interleukin-1ß. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH. CONCLUSIONS: Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.

Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4?

Traumatic brain injury is a devastating neurological injury associated with significant morbidity and mortality. Medical therapies to limit cerebral edema, a cause of increased intracranial hypertension and poor clinical outcome, are largely ineffective, emphasizing the need for novel therapeutic approaches. In the present study, pre-treatment with curcumin (75, 150 mg/kg) or 30 min post-treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin-1beta, a pro-inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin-4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL-1beta-induced aquaporin-4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of nuclear factor kappaB. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation.

Long-term outcome after anesthesia and surgery: remarks on the biology of a newly emerging principle in perioperative care.

There is a strong possibility that the risk from anesthesia and surgery carries over from the immediate perioperative period to more remote time points. This extended risk seems to influence the progression, severity, and complication rate of certain chronic illnesses, such as vascular heart disease and some of the malignancies, although other disease processes might be affected as well. With the recognition that the perioperative process could be responsible for later adverse events comes the need to reassess existing patient safety models, because some of the risk could be preventable. To confront these challenges, it is necessary to understand the underlying biology of this association, and immunology should be particularly helpful in this pursuit. It will be of special importance to integrate our knowledge of the host immune response to anesthesia and surgery with the recent revelations on the role of immunity in the progression of many of the chronic diseases. Additionally, we need to examine how genetic diversity or acquired defects alter the immune response to tissue injury and infection so that we can improve risk stratification and preemptive therapies. In the meantime, we must strive to improve short- and long-term outcomes by expanding our efforts to reduce disease activity preoperatively, to control the surgical stress response and infection rate, and to use tissue-preserving surgical techniques. Long-term patient safety after anesthesia and surgery is not a specialty-by-specialty endeavor; it requires a highly collaborative, institutional, and national effort to foster innovative research and health care process improvements.

Anesthesia drugs, immunity, and long-term outcome.

PURPOSE OF REVIEW: We provide an overview of the immunological effects of commonly used anesthetic drugs and highlight their potential impact on long-term outcome after surgery. RECENT FINDINGS: Clinical trials provide preliminary evidence that the perioperative process can influence long-term patient outcome. Immunology may begin to elucidate the biology of this safety concern and open new therapeutic opportunities. In this context, awareness of the immunological properties of drugs administered in the perioperative period may assist in their deliberate use to modulate this risk. Statins, beta-blockers, and clonidine can potentially improve long-term cardiac risk. Volatile anesthetics appear to suppress effector functions of both the innate and adaptive immunity, assist tumor growth in animal models, and facilitate aggregation of certain neurodegenerative disease proteins. Local anesthetics block neurons, but are also potent antiinflammatory drugs. Morphine has recognized immunosuppressive functions, which the newer, synthetic opioids don't seem to share. The cholinergic nervous system has antiinflammatory control functions that are largely unexploited. SUMMARY: Long-term outcome after surgery is a new safety concern in perioperative care. We are faced with enormous challenges in healthcare and research. As providers, tailoring an anesthetic plan to patients' needs will become increasingly critical, and immunology should help in this pursuit.