Fan Therapy for Dyspnea in Lung Transplant Recipients in the Intensive Care Unit: A Before-and-After Study.

Introduction Fan therapy has gained attention as a non-pharmacological treatment for alleviating dyspnea in patients receiving palliative care and in those with chronic progressive diseases. However, the effectiveness of fan therapy for dyspnea in critically ill patients in intensive care units (ICUs) remains unclear. This study aimed to investigate the efficacy and safety of fan therapy for lung transplant patients in the ICU. Methods Fan therapy was performed on lung transplant recipients (age >18 years) who experienced dyspnea during their ICU stay. A tabletop portable fan was used to blow air on the patient's face for five minutes providing fan therapy. The intensity of dyspnea before and after the fan therapy was determined, and a statistical analysis was conducted using a paired t-test to evaluate the changes. Results Between May 2023 and February 2024, 16 patients who were admitted to the ICU following lung transplantation were screened, and eight patients received fan therapy. Fan therapy was performed at a median of postoperative day 12. Seven patients (87.5%) received mechanical ventilation via tracheostomy. The mean (±standard deviation) numerical rating scale (NRS) for dyspnea before and after fan therapy was 5.6±2.3 and 4.4±1.5, respectively (p = 0.08). The mean (±standard deviation) respiratory distress observation scale (RDOS) before and after fan therapy was 4.8 ± 2.0 and 3.8 ± 1.7, respectively (p = 0.03). No serious adverse events were observed, and no significant alterations were observed in the respiratory rate, oxygen saturation levels, pulse rate, or blood pressure. Conclusion The findings suggest that fan therapy can be safely used to relieve dyspnea in lung transplant recipients during their ICU stay. Further evaluations in larger trials are required to confirm the results of this study.

Remimazolam in perioperative management of Eisenmenger syndrome: a case report.

BACKGROUND: Eisenmenger syndrome (ES) is characterized by severe and irreversible pulmonary hypertension stemming from an uncorrected intracardiac shunt of significant size. The imbalance between systemic and pulmonary artery pressures predisposes patients with ES to the risk of cardiac arrest. Remimazolam has caused less circulatory depression, which may be advantageous for ES. However, no studies reported the use of remimazolam in perioperative ES management. CASE PRESENTATION: A 45-year-old female patient with ES derived from a ventricular septal defect was scheduled to undergo bilateral adnexectomy for an ovarian tumor. Her oxygen saturation was 80% with 3 L/min oxygen at rest, and her pulmonary and systemic flow ratio was 0.53. She underwent general anesthesia with remimazolam, and intraoperative hemodynamics was stable without hypotension or reduced oxygen saturation. CONCLUSIONS: Our successful management of ovarian tumor surgery in a patient with ES using remimazolam reveals its potential effectiveness in perioperative care.

Chest CT findings in severe acute respiratory distress syndrome requiring V-V ECMO: J-CARVE registry.

BACKGROUND: Chest computed tomography findings are helpful for understanding the pathophysiology of severe acute respiratory distress syndrome (ARDS). However, there is no large, multicenter, chest computed tomography registry for patients requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO). The aim of this study was to describe chest computed tomography findings at V-V ECMO initiation and to evaluate the association between the findings and outcomes in severe ARDS. METHODS: This multicenter, retrospective cohort study enrolled patients with severe ARDS on V-V ECMO, who were admitted to the intensive care units of 24 hospitals in Japan between January 1, 2012, and December 31, 2022. RESULTS: The primary outcome was 90-day in-hospital mortality. The secondary outcomes were the successful liberation from V-V ECMO and the values of static lung compliance. Among the 697 registry patients, of the 582 patients who underwent chest computed tomography at V-V ECMO initiation, 394 survived and 188 died. Multivariate Cox regression showed that traction bronchiectasis and subcutaneous emphysema increased the risk of 90-day in-hospital mortality (hazard ratio [95% confidence interval] 1.77 [1.19-2.63], p = 0.005 and 1.97 [1.02-3.79], p = 0.044, respectively). The presence of traction bronchiectasis was also associated with decreased successful liberation from V-V ECMO (odds ratio: 0.27 [0.14-0.52], p < 0.001). Lower static lung compliance was associated with some chest computed tomography findings related to changes outside of pulmonary opacity, but not with the findings related to pulmonary opacity. CONCLUSIONS: Traction bronchiectasis and subcutaneous emphysema increased the risk of 90-day in-hospital mortality in patients with severe ARDS who required V-V ECMO.

Pharmacokinetics of GS-441524, the active metabolite of remdesivir, in patients receiving continuous renal replacement therapy: A case series.

Remdesivir plays a key role in the treatment of coronavirus disease in 2019 (COVID-19). Haemodialysis is sometimes required for hospitalised patients with COVID-19, and patients undergoing haemodialysis are at an increased risk of severe COVID-19. In the present study, we report the serum concentrations of GS-441524, the active metabolite of remdesivir, in four patients undergoing continuous renal replacement therapy (CRRT). Patient 1, a male aged 70s, received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg remdesivir from day 2, according to the package insert as in non-haemodialysis patients. The mean trough serum concentration of GS-441524 was 783.5 ng/mL, which was approximately 7-fold higher than the mean for patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. Patients 2-4 received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg once every 2 days from day 2. The mean trough serum concentrations of GS-441524 were 302.2 ng/mL, 585.8 ng/mL and 677.3 ng/mL, respectively. These were 3 to 6-fold higher than the mean for patients with eGFR ≥60 mL/min. The target doses for patients 1, 2, 3, and 4 receiving CRRT were 13.6 mL/kg/h, 6.0-12.5 mL/kg/h, 20.1 mL/kg/h, and 15.1 mL/kg/h, respectively, using a polysulphone membrane. The package insert dose of remdesivir is an overdose for CRRT patients with a target dose of 10-20 mL/kg/h. In low-intensity CRRT, as in Japan, it may be necessary to extend the interval between the doses of remdesivir.

High versus low positive end-expiratory pressure setting in patients receiving veno-venous extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome: study protocol for the multicentre, randomised ExPress SAVER Trial.

INTRODUCTION: While limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute respiratory distress syndrome (ARDS) is widely accepted, the best setting for positive end-expiratory pressure (PEEP) is still controversial. This study is being conducted to investigate whether a higher PEEP setting (15 cmH2O) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting. METHODS AND ANALYSIS: The study is an investigator-initiated, multicentre, open-label, two-arm, randomised controlled trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The subjects of the study are patients with severe ARDS who require V-V ECMO support. Eligible patients will be randomised equally to the high PEEP group or low PEEP group. Recruitment to the study will continue until a total of 210 patients with ARDS requiring V-V ECMO support have been randomised. In the high PEEP group, PEEP will be set at 15 cmH2O from the start of V-V ECMO until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmH2O. Other treatments will be the same in the two groups. The primary endpoint of the study is the number of ECMO-free days until day 28, defined as the length of time (in days) from successful libration from V-V ECMO to day 28. The secondary endpoints are mortality on day 28, in-hospital mortality on day 60, ventilator-free days during the first 60 days and length of ICU stay. ETHICS AND DISSEMINATION: Ethics approval for the trial at all the participating hospitals was obtained on 27 September 2022, by central ethics approval (IRB at Hiroshima University Hospital, C2022-0006). The results of this study will be presented at domestic and international medical congresses, and also published in scientific journals. TRIAL REGISTRATION NUMBER: The Japan Registry of Clinical Trials jRCT1062220062. Registered on 28 September 2022. PROTOCOL VERSION: 28 March 2023, version 4.0.

The short-term feeding of low- and high-histidine diets prior to market affects the muscle carnosine and anserine contents and meat quality of broilers.

Functional dipeptides carnosine and anserine are abundant in muscle. We determined the effect of short-term dietary histidine (His) content on muscle carnosine and anserine contents and meat quality of broilers. Three groups of 28-day-old female broilers were fed diets with His contents of 67%, 100%, or 150% of requirement for 10 days before market (His contents 0.21%, 0.32%, and 0.48%, respectively). The carnosine and anserine contents of 0-h aged muscle significantly increased with dietary His content; in particular, the carnosine content was 162% higher in the His 0.48% group than in the His 0.32% group. The contents of both peptides also increased with dietary His content in 48-h aged muscle, but carnosine was not detected in 0- and 48-h aged muscle of the His 0.21% group. The drip loss, cooking loss, shear force, and pH of meat were not affected by the dietary His content. The 2-thiobarbituric acid-reactive substances contents of 24- and 48-h aged muscles were lower in the His 0.48% group than in the other groups, and the a* and b* values were lower in the His 0.21% group. These results suggest that short-term dietary His content affects imidazole dipeptide contents, antioxidative capacity, and color of broiler meat.

Provider-Documented Dyspnea in Intensive Care Unit After Lung Transplantation.

BACKGROUND: Dyspnea is an important problem that might affect the clinical course after lung transplantation; however, the prevalence, risk factors, and relevant outcomes of dyspnea in the intensive care unit (ICU) after lung transplantation remain unknown. METHODS: This retrospective, observational study enrolled consecutive patients aged ≥ 20 years who were admitted to the ICU after lung transplantation between January 2010 and December 2020. The main outcome measure was provider-documented dyspnea identified based on a comprehensive retrospective chart review to extract dyspnea episodes (e.g., documented words related to "dyspnea," "shortness of breath," or "breathlessness"). RESULTS: This study included 184 lung transplant recipients, including 115 bilateral (63%) and 69 single (37%) lung transplants. Fifty-four transplants were from living donors (29%), and 130 were from deceased donors (71%). Dyspnea was documented in 116 patients (63%). Multivariate analysis identified bilateral lung transplantation (odds ratio = 5.127; 95% confidence interval, 2.020-13.014; P < .001) as a risk factor for dyspnea. In addition, postoperative anxiety (odds ratio = 18.605; 95% confidence interval, 7.748-44.674; P < .001) was independently associated with dyspnea. Patients with documented dyspnea showed delayed rehabilitation (P < .001) and weaning from mechanical ventilation (P < .001) and a longer ICU stay (P < .001). CONCLUSION: This study demonstrated that the prevalence of dyspnea in the ICU after lung transplantation was frequent and identified bilateral lung transplantation as a risk factor. Dyspnea caused a delay in rehabilitation and weaning from mechanical ventilation. Extensive evaluation and care for dyspnea and anxiety may enhance patient recovery.

Non-invasive ventilation using a novel ventilator and non-vented full-face mask for patients with respiratory failure during the COVID-19 pandemic: Report of three cases.

The Japanese government's latest manual on COVID-19 management mentions non-invasive ventilation (NIV). Before this version, we experienced three cases in which COVID-19 was a concern. Each case had one of the following conditions: obesity hypoventilation syndrome, amyotrophic lateral sclerosis, acute heart failure with acute kidney injury with hypercapnia. The guidelines indicate that patients with these diseases are good candidates for NIV. NIV was used in a negative pressure room with staff in personal protective equipment. We describe the use of NIV instruments with anti-viral filters and a non-vented mask, including a new NIV machine for COVID-19 respiratory care.

Intraoperative High Fraction of Inspiratory Oxygen is Independently Associated with Worse Outcome After Living-Donor Liver Transplantation: A Retrospective Study.

BACKGROUND: Ischemia and reperfusion injury is an important factor that determines graft function after liver transplantation, and oxygen plays a crucial role in this process. However, the relationship between the intraoperative high fraction of inspiratory oxygen (FiO2) and living-donor-liver-transplantation (LDLT) outcome remains unclear. PATIENTS AND METHODS: A total of 199 primary adult-to-adult LDLT cases in Kyoto University Hospital between January 2010 and December 2017 were enrolled in this study. The intraoperative FiO2 was averaged using the total amount of intraoperative oxygen and air and defined as the calculated FiO2 (cFiO2). The cutoff value of cFiO2 was set at 0.5. RESULTS: Between the cFiO2 <0.5 (n = 156) and ≥0.5 group (n = 43), preoperative recipients' background, donor factors, and intraoperative parameters were almost comparable. Postoperatively, the cFiO2 ≥0.5 group showed a higher early allograft dysfunction (EAD) rate (P = 0.049) and worse overall graft survival (P = 0.036) than the cFiO2 <0.5 group. Although the cFiO2 ≥0.5 was not an independent risk factor for EAD in multivariable analysis (OR 2.038, 95%CI 0.992-4.186, P = 0.053), it was an independent risk factor for overall graft survival after LDLT (HR 1.897, 95%CI 1.007-3.432, P = 0.048). CONCLUSION: The results of this study suggest that intraoperative high FiO2 may be associated with worse graft survival after LDLT. Avoiding higher intraoperative FiO2 may be beneficial for LDLT recipients.

Successful lung-protective ventilatory management during the VV-ECMO in a severe COVID-19 pneumonia patient with extensive pneumomediastinum and subcutaneous emphysema: a case report.

BACKGROUND: Ventilatory management of respiratory failure with pneumomediastinum/subcutaneous emphysema is not established. Herein, we report a case of severe COVID-19 pneumonia with extensive pneumomediastinum/subcutaneous emphysema, rescued by thorough lung-protective ventilatory management after applying the VV-ECMO. CASE PRESENTATION: A 68-year-old male with no medical history was admitted to a local hospital and diagnosed with COVID-19 pneumonia. His pulmonary parameters worsened during invasive ventilation due to the development of pneumomediastinum/subcutaneous emphysema, and then he was transferred to our hospital. On arrival, we immediately decided to apply VV-ECMO and switch to ultraprotective ventilation. After maintaining the initial ventilation with a neuromuscular blocking agent for 2 days, we gradually increased PEEP while limiting PIP to 25 cmH2O. The patient was weaned off VV-ECMO on day 10; he was transferred to the medical ward after extubation. CONCLUSIONS: Lung-protective ventilatory management should be performed thoroughly during VV-ECMO in severe COVID-19 pneumonia with pneumomediastinum/subcutaneous emphysema.

Intraoperative Diagnosis of Bronchovenous Fistula During Lung Transplantation Using Transesophageal Echocardiography.

Bronchovenous fistula (BVF) is a rare complication and can cause arterial gas embolism in vital organs, including the heart and the brain, resulting in a high mortality rate. A 51-year-old man developed a BVF during pneumonectomy for lung transplantation, which quickly was diagnosed by transesophageal echocardiography (TEE). He required highairway-pressure ventilation due to his severely restrictive ventilatory impairment and had severe left pleural adhesion due to a history of pleurodesis. Intraoperatively, he had a coronary air embolism and required temporary treatment with central venoarterial extracorporeal membrane oxygenation (VA-ECMO), but showed no postoperative cardiac or neurologic complications. BVF may be formed during lung transplantation because lung transplantation recipients often receive high-airway-pressure ventilation and are vulnerable to bronchi and pulmonary vessel injuries during surgery. Intraoperative TEE can contribute to the early detection of air bubbles in the left heart circulation and is helpful for the prevention of arterial gas embolism.

Population pharmacokinetic modeling of GS-441524, the active metabolite of remdesivir, in Japanese COVID-19 patients with renal dysfunction.

Remdesivir, a prodrug of the nucleoside analog GS-441524, plays a key role in the treatment of coronavirus disease 2019 (COVID-19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID-19 with special characteristics. In this study, we aimed to measure serum GS-441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS-441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution (Vd ) of GS-441524. A one-compartment model described serum GS-441524 concentration data. The CL and Vd of GS-441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS-441524 using retrospectively obtained serum GS-441524 concentrations in Japanese patients with COVID-19, which would be helpful for optimal individualized therapy of remdesivir.

Successful treatment of COVID-19-related acute respiratory distress syndrome with a rare blood type: A case report.

Extracorporeal membrane oxygenation is indispensable for critically severe COVID-19 patients. However, it would be inapplicable to patients with a rare blood type or blood transfusion refusal. In that case, severely conservative fluid management with the sacrifice of renal functions and hydrocortisone therapy should be considered for better oxygenation.

Sulfide catabolism ameliorates hypoxic brain injury.

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

Activation of the ß-adrenergic receptor exacerbates lipopolysaccharide-induced wasting of skeletal muscle cells by increasing interleukin-6 production.

The skeletal muscle mass has been shown to be affected by catecholamines, such as epinephrine (Epi), norepinephrine (NE), and isoproterenol (ISO). On the other hand, lipopolysaccharide (LPS), one of the causative substances of sepsis, induces muscle wasting via toll-like receptors expressed in skeletal muscle. Although catecholamines are frequently administered to critically ill patients, it is still incompletely understood how these drugs affect skeletal muscle during critical illness, including sepsis. Herein, we examined the direct effects of catecholamines on LPS-induced skeletal muscle wasting using the C2C12 myoblast cell line. Muscle wasting induced by catecholamines and/or LPS was analyzed by the use of the differentiated C2C12 myotubes, and its underlying mechanism was explored by immunoblotting analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and the TransAM kit for p-65 NF-κB. Epi augmented myosin heavy chain (MHC) protein loss and reduction of the myotube diameter induced by LPS. LPS induced C/EBPδ protein, Atrogin-1 and inteleukin-6 (IL-6), and these responses were potentiated by Epi. An IL-6 inhibitor, LMT28, suppressed the potentiating effect of Epi on the LPS-induced responses. NF-κB activity was induced by LPS, but was not affected by Epi and recombinant IL-6, and the NF-κB inhibitor, Bay 11-7082, abolished Atrogin-1 mRNA expression induced by LPS with or without Epi. NE and ISO also potentiated LPS-induced IL-6 and Atroign-1 mRNA expression. Carvedilol, a nonselective ß-adrenergic receptor antagonist, suppressed the facilitating effects of Epi on the Atrogin-1 mRNA induction by LPS, and abolished the effects of Epi on the MHC protein loss in the presence of LPS. It was concluded that Epi activates the ß-adrenergic receptors in C2C12 myotubes and the IL-6-STAT3 pathway, leading to the augmentation of LPS-induced activation of the NF-κB- C/EBPδ-Atrogin-1 pathway and to the exacerbation of myotube wasting.

Invasive Respiratory or Vasopressor Support and/or Death as a Proposed Composite Outcome Measure for Perioperative Care Research.

BACKGROUND: There is a need for a clinically relevant and feasible outcome measure to facilitate clinical studies in perioperative care medicine. This large-scale retrospective cohort study proposed a novel composite outcome measure comprising invasive respiratory or vasopressor support (IRVS) and death. We described the prevalence of IRVS in patients undergoing major abdominal surgery and assessed the validity of combining IRVS and death to form a composite outcome measure. METHODS: We retrospectively collected perioperative data for 2776 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or esophageal resection) at Kyoto University Hospital. We defined IRVS as requirement for mechanical ventilation for ≥24 hours postoperatively, postoperative reintubation, or postoperative vasopressor administration. We evaluated the prevalence of IRVS within 30 postoperative days and examined the association between IRVS and subsequent clinical outcomes. The primary outcome of interest was long-term survival. Multivariable Cox proportional regression analysis was performed to adjust for the baseline patient and operative characteristics. The secondary outcomes were length of hospital stay and hospital mortality. RESULTS: In total, 85 patients (3.1%) received IRVS within 30 postoperative days, 15 of whom died by day 30. Patients with IRVS had a lower long-term survival rate (1- and 3-year survival probabilities, 66.1% and 48.5% vs 95.2% and 84.0%, respectively; P < .001, log-rank test) compared to those without IRVS. IRVS was significantly associated with lower long-term survival after adjustment for the baseline patient and operative characteristics (adjusted hazard ratio, 2.72; 95% confidence interval, 1.97-3.77; P < .001). IRVS was associated with a longer hospital stay (median [interquartile range], 65 [39-326] vs 15 [12-24] days; adjusted P < .001) and a higher hospital mortality (24.7% vs 0.5%; adjusted P < .001). Moreover, IRVS was adversely associated with subsequent clinical outcomes including lower long-term survival (adjusted hazard ratio, 1.78; 95% confidence interval, 1.21-2.63; P = .004) when the analyses were restricted to 30-day survivors. CONCLUSIONS: Patients with IRVS can experience ongoing risk of serious morbidity and less long-term survival even if alive at postoperative day 30. Our findings support the validity of using IRVS and/or death as a composite outcome measure for clinical studies in perioperative care medicine.

Near-infrared spectroscopy underestimates cerebral oxygenation in hemodialysis patients.

Regional cerebral oxygen saturation (rSO2) measured using near-infrared spectroscopy has been reported to be significantly lower in hemodialysis (HD) patients than in non-HD ones, but the mechanisms are unknown. The aim of this prospective study was to assess the accuracy of near-infrared spectroscopy to estimate cerebral oxygenation in HD patients undergoing cardiovascular surgery. Our hypothesis was that rSO2 values would underestimate cerebral oxygenation in HD patients. This study included 113 patients (7 HD patients and 106 non-HD ones) undergoing cardiac or major aortic surgery between December 2015 and November 2017. We evaluated the validity of rSO2 by comparing it with ipsilateral jugular venous oxygen saturation (SjvO2). In HD and non-HD patients, rSO2 and SjvO2 showed a weak correlation (R2: 0.46 and 0.28 in HD and non-HD patients, respectively). Bland-Altman analysis revealed that bias (95% limits of agreement) of rSO2 compared to SjvO2 was - 19.2% ( - 41.7-3.3%) in HD patients and - 1.9% (- 19.3-15.5%) in non-HD ones. The large negative bias suggests that the rSO2 values measured using near-infrared spectroscopy substantially underestimate cerebral oxygenation in HD patients.