Yafen Liang

BACKGROUND: While antiretroviral therapy has improved surgical safety for people living with HIV, comprehensive data on perioperative organ injury and its impact on patient safety remain limited. This study aimed to compare the incidence of perioperative organ injury, in-hospital mortality, hospital length of stay, and hospitalization costs between people living with HIV and HIV-negative individuals undergoing surgery in the United States. METHODS: This retrospective cohort study used data from the National Inpatient Sample (NIS) from 2016 to 2021. The population-based sample included adult patients (age >18 years) identified via International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Of 41,622,004 eligible surgical admissions, 2,088,307 (5.0%) were people living with HIV and 39,533,697 were HIV-negative. Primary outcomes were perioperative organ injury incidence and associated mortality; secondary outcomes included hospital length of stay and total hospital charges. Adjusted models accounted for baseline characteristics and surgical complexity. RESULTS: Among the 41,622,004 surgical admissions, people living with HIV were found to be older and carried a significantly higher comorbidity burden, with a Charlson Comorbidity Index of 8 compared to 1 in the HIV-negative group. Perioperative organ injury occurred in 1,348,363 of 2,088,307 people living with HIV (64.6%) compared with 7,867,547 of 39,533,697 HIV-negative patients (19.9%). Acute myocardial infarction (33.5%) and acute kidney injury (22.0%) were the most common injuries among people living with HIV. In-hospital mortality occurred in 66,935 of 2,088,307 people living with HIV (3.2%) compared with 872,170 of 39,533,697 HIV-negative patients (2.2%). Hospital length of stay and hospital charges were also significantly higher. Adjusted analyses demonstrated that HIV status was independently associated with higher in-hospital mortality (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.54–1.78), longer hospital length of stay ( β = 2.73 days; 95% CI, 2.56–2.90), a decreased likelihood of home discharge (hazard ratio [HR], 0.73; 95% CI, 0.72–0.73), and increased hospitalization costs ( β = $18,423; 95% CI, 16,712–20,134). Sensitivity analyses demonstrated that elevated perioperative risk persisted among patients with asymptomatic HIV infection, although the greatest risk was observed among patients with symptomatic HIV disease/AIDS. CONCLUSIONS: People living with HIV incur a significantly higher risk of perioperative organ injury and worse surgical outcomes despite advances in antiretroviral therapy. HIV status was independently associated with adverse perioperative outcomes in adjusted models, supporting its inclusion as a risk stratification variable in surgical planning. Future research should incorporate immunologic markers, such as CD4 count and viral load, to further refine perioperative risk prediction and optimize outcomes for this population.

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO ₂ ≤ 94%). Patients ( n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher ( n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2–associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.

Acute myocardial infarction is a leading cause of morbidity and mortality worldwide¹. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events^2–7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL1^7–11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A)^12–16—in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1–HIF2A–DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)^16,17 as a rhythmic target of the BMAL1–HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1–HIF2A–AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway’s circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated with the lowest mortality (10.8%). This was followed by acute myocardial infarction (incidence 0.6%, mortality 15.6%), stroke (incidence 0.6%, mortality 13.1%), pulmonary embolism (incidence 0.3%, mortality 20.0%), liver injury (incidence 0.1%, mortality 68.7%), and acute respiratory distress syndrome (incidence 0.1%, mortality 44.7%). These findings help prioritize interventions for preventing or treating individual types of perioperative organ injury.

As patients continue to live longer from diseases that predispose them to right ventricular (RV) dysfunction or failure, many more patients will require surgery for acute or chronic health issues. Because RV dysfunction results in significant perioperative morbidity if not adequately assessed or managed, understanding appropriate assessment and treatments is important in preventing subsequent morbidity and mortality in the perioperative period. In light of the epidemiology of right heart disease, a working knowledge of right heart anatomy and physiology and an understanding of the implications of right-sided heart function for perioperative care are essential for perioperative practitioners. However, a significant knowledge gap exists concerning this topic. This manuscript is one part of a collection of papers from the PeriOperative Quality Initiative (POQI) IX Conference focusing on “Current Perspectives on the Right Heart in the Perioperative Period.” This review aims to provide perioperative clinicians with an essential understanding of right heart physiology by answering five key questions on this topic and providing an explanation of seven fundamental concepts concerning right heart physiology.

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have questioned the excessive use of oxygen therapy and have identified specific cardiovascular diseases in which a more conservative approach to oxygen therapy could be beneficial compared with a more liberal approach. In this Review, we provide numerous perspectives on systemic and molecular oxygen homeostasis and the pathophysiological consequences of excessive oxygen use. In addition, we provide an overview of findings from clinical studies on oxygen therapy for myocardial ischaemia, cardiac arrest, heart failure and cardiac surgery. These clinical studies have prompted a shift from liberal oxygen supplementation to a more conservative and vigilant approach to oxygen therapy. Furthermore, we discuss the alternative therapeutic strategies that target oxygen-sensing pathways, including various preconditioning approaches and pharmacological HIF activators, that can be used regardless of the level of oxygen therapy that a patient is already receiving.

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1 ^–/– mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion ( Ent1 ^loxP/loxP Myosin Cre ⁺ mice) experienced smaller infarct sizes. Measurements of cardiac adenosine levels demonstrated that postischemic elevations of adenosine persisted during reperfusion after targeting ENTs. Finally, studies in mice with global or myeloid-specific deletion of the Adora2b adenosine receptor ( Adora2b ^loxP/loxP LysM Cre ⁺ mice) implied that Adora2b signaling on myeloid-inflammatory cells in cardioprotection provided by ENT inhibition. These studies reveal a previously unrecognized role for myocyte-specific ENT1 in cardioprotection by enhancing myeloid-dependent Adora2b signaling during reperfusion. Extension of these findings implicates adenosine transporter inhibitors in cardioprotection against ischemia and reperfusion injury.

We read with great interest the recent article published in Anesthesiology by Strandenes et al., titled “A Pilot Trial of Platelets Stored Cold versus at Room Temperature for Complex Cardiothoracic Surgery.”1 We congratulate the authors on their pioneering work in the field of transfusion medicine and efforts to identify methods to prolong the shelf life of platelets and preserve its efficacy.2,3 We have a few comments.First, we were surprised to see that the authors used the clinical assessment, chest tube output, as the primary outcome, because cardiothoracic surgery is an extremely complex procedure that will potentially introduce multiple confounding factors for clinical outcome, such as surgical technique and patient’s baseline characteristics. In this specific study, we noticed a large difference in the logistic Euro-score, the percentage of patients receiving preoperative antiplatelet medication, and the percentage of patients who had previous sternotomy among the three groups, which will all affect the chest tube output and the need for blood transfusion. With a relatively small sample size as a pilot study, the possibility of detecting a difference in clinical outcome is reduced. We are wondering what the rationale was for the authors to choose chest tube output as the primary endpoint instead of a laboratory analytical result?Second, under the safety endpoints, there appears to be a large difference in terms of time to extubation among the three groups. Could the authors kindly provide an explanation for this and the perceived potential impact on patient care?Third, we are wondering if the authors could comment on how the cold stored platelets were transfused? Were they thawed and warmed up to room temperature before transfusion or were they transfused over fluid warmer directly? What was the turnaround time for this practice? Because most intraoperative transfusions are deemed to be urgent in nature, excessive preparation time for blood products should be avoided.Last, we would like the authors to provide more detail on their practice and decision-making in ordering blood products. Because a lot of clinicians would order blood products during the rewarming phase of the cardiopulmonary bypass based on the laboratory results, was there a similar practice at the authors’ institution? This detail in clinical practice could help us to determine if the difference in blood product utilization was actually associated with intervention (transfusion of different types of platelets), or if it was a reflection of empirical practice.Cold stored platelets have been reported to be effective in trauma patients with active bleeding.4,5 No doubt, immediately postoperative patients after cardiothoracic surgery are another major group of patients that can benefit from this practice. We look forward to reading the authors’ future pivotal trial results!Support was provided solely from institutional and/or departmental sources.The authors declare no competing interests.