Frederic T. BillingsIV

Background: The best approaches to supplemental oxygen administration during surgery remain unclear, which may contribute to variation in practice. This study aimed to assess determinants of oxygen administration and its variability during surgery. Methods: Using multivariable linear mixed-effects regression, the study measured the associations between intraoperative fraction of inspired oxygen and patient, procedure, medical center, anesthesiologist, and in-room anesthesia provider factors in surgical cases of 120 min or longer in adult patients who received general anesthesia with tracheal intubation and were admitted to the hospital after surgery between January 2016 and January 2019 at 42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry. Results: The sample included 367,841 cases (median [25th, 75th] age, 59 [47, 69] yr; 51.1% women; 26.1% treated with nitrous oxide) managed by 3,836 anesthesiologists and 15,381 in-room anesthesia providers. Median (25th, 75th) fraction of inspired oxygen was 0.55 (0.48, 0.61), with 6.9% of cases less than 0.40 and 8.7% greater than 0.90. Numerous patient and procedure factors were statistically associated with increased inspired oxygen, notably advanced American Society of Anesthesiologists classification, heart disease, emergency surgery, and cardiac surgery, but most factors had little clinical significance (less than 1% inspired oxygen change). Overall, patient factors only explained 3.5% (95% CI, 3.5 to 3.5%) of the variability in oxygen administration, and procedure factors 4.4% (95% CI, 4.2 to 4.6%). Anesthesiologist explained 7.7% (95% CI, 7.2 to 8.2%) of the variability in oxygen administration, in-room anesthesia provider 8.1% (95% CI, 7.8 to 8.4%), medical center 23.3% (95% CI, 22.4 to 24.2%), and 53.0% (95% CI, 52.4 to 53.6%) was unexplained. Conclusions: Among adults undergoing surgery with anesthesia and tracheal intubation, supplemental oxygen administration was variable and appeared arbitrary. Most patient and procedure factors had statistical but minor clinical associations with oxygen administration. Medical center and anesthesia provider explained significantly more variability in oxygen administration than patient or procedure factors. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.

Objective To examine whether supraphysiological oxygen administration during surgery is associated with lower or higher postoperative kidney, heart, and lung injury. Design Observational cohort study. Setting 42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry. Participants Adult patients undergoing surgical procedures ≥120 minutes’ duration with general anesthesia and endotracheal intubation who were admitted to hospital after surgery between January 2016 and November 2018. Intervention Supraphysiological oxygen administration, defined as the area under the curve of the fraction of inspired oxygen above air (21%) during minutes when the hemoglobin oxygen saturation was greater than 92%. Main outcomes Primary endpoints were acute kidney injury defined using Kidney Disease Improving Global Outcomes criteria, myocardial injury defined as serum troponin >0.04 ng/mL within 72 hours of surgery, and lung injury defined using international classification of diseases hospital discharge diagnosis codes. Results The cohort comprised 350 647 patients with median age 59 years (interquartile range 46-69 years), 180 546 women (51.5%), and median duration of surgery 205 minutes (interquartile range 158-279 minutes). Acute kidney injury was diagnosed in 19 207 of 297 554 patients (6.5%), myocardial injury in 8972 of 320 527 (2.8%), and lung injury in 13 789 of 312 161 (4.4%). The median fraction of inspired oxygen was 54.0% (interquartile range 47.5%-60.0%), and the area under the curve of supraphysiological inspired oxygen was 7951% min (5870-11 107% min), equivalent to an 80% fraction of inspired oxygen throughout a 135 minute procedure, for example. After accounting for baseline covariates and other potential confounding variables, increased oxygen exposure was associated with a higher risk of acute kidney injury, myocardial injury, and lung injury. Patients at the 75th centile for the area under the curve of the fraction of inspired oxygen had 26% greater odds of acute kidney injury (95% confidence interval 22% to 30%), 12% greater odds of myocardial injury (7% to 17%), and 14% greater odds of lung injury (12% to 16%) compared with patients at the 25th centile. Sensitivity analyses evaluating alternative definitions of the exposure, restricting the cohort, and conducting an instrumental variable analysis confirmed these observations. Conclusions Increased supraphysiological oxygen administration during surgery was associated with a higher incidence of kidney, myocardial, and lung injury. Residual confounding of these associations cannot be excluded. Trial registration Open Science Framework osf.io/cfd2m

In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8⁺ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.

Introduction: Acute kidney injury (AKI) affects 10% of patients following major surgery and is independently associated with extra-renal organ injury, development of chronic kidney disease, and death. Perioperative renal ischemia and reperfusion (IR) contributes to AKI by, in part, increasing production of reactive oxygen species (ROS) and leading to oxidative damage. Variations in inhaled oxygen may mediate some aspects of IR injury by affecting tissue oxygenation, ROS production, and oxidative damage. We tested the hypothesis that provision of air (normoxia) compared to 100% oxygen (hyperoxia) during murine renal IR affects renal ROS production and oxidative damage. Methods: We administered 100% oxygen or air to 8-9 week-old FVB/N mice and performed dorsal unilateral nephrectomy with contralateral renal ischemia/reperfusion surgery while mice spontaneously ventilated. We subjected mice to 30 minutes of ischemia and 30 minutes of reperfusion prior to sacrifice. We obtained an arterial blood gas (ABG) by performing sternotomy and left cardiac puncture. We stained the kidney with pimonidazole, a marker of tissue hypoxia; 4-HNE, a marker of ROS-production; and measured F 2 -isoprostanes in homogenized tissue to quantify oxidative damage. Results: Hyperoxia during IR increased arterial oxygen content compared to normoxia, but both groups of mice were hypoventilating at the time of ABG sampling. Renal tissue hypoxia following reperfusion was similar in both treatment groups. ROS production was similar in the cortex of mice (3.8% area in hyperoxia vs. 3.1% in normoxia, P=0.19) but increased in the medulla of hyperoxia-treated animals (6.3% area in hyperoxia vs. 4.5% in nomoxia, P=0.02). Renal F 2 -isoprostanes were similar in treatment groups (2.2 pg/mg kidney in hyperoxia vs. 2.1 pg/mg in normoxia, P=0.40). Conclusions: Hyperoxia during spontaneous ventilation in murine renal IR did not appear to affect renal hypoxia following reperfusion, but hyperoxia increased medullary ROS production compared to normoxia.

The dysfunctional chronic pain (Dysfunctional CP) phenotype is an empirically identifiable CP subtype with unclear pathophysiological mechanisms that cuts across specific medical CP diagnoses. This study tested whether the multidimensional pain and psychosocial features that characterize the dysfunctional CP phenotype are associated broadly with elevated oxidative stress (OS). Measures of pain intensity, bodily extent of pain, catastrophizing cognitions, depression, anxiety, sleep disturbance, pain interference, and function were completed by 84 patients with chronic osteoarthritis before undergoing total knee arthroplasty. Blood samples were obtained at the initiation of surgery before incision or tourniquet placement. Plasma levels of F2-isoprostanes and isofurans, the most highly specific measures of in vivo OS, were quantified using gas chromatography/negative ion chemical ionization mass spectrometry. The results indicated that controlling for differences in age, sex, and body mass index, higher overall OS (mean of isoprostanes and isofurans) was associated with significantly (P < 0.05) greater pain intensity, more widespread pain, greater depressive symptoms and pain catastrophizing, higher pain interference, and lower function. OS measures were not significantly associated with sleep disturbance or anxiety levels (P >0.10). The results build on prior case-control findings suggesting that presence of a CP diagnosis is associated with elevated OS, highlighting that it may specifically be individuals displaying characteristics of the dysfunctional CP phenotype who are characterized by elevated OS. Clinical implications of these findings remain to be determined.

Purpose Present clinical updates, current research findings, and consensus statements relevant to the care of the acute kidney injury (AKI) patient. Principal findings Acute kidney injury is one of the most frequent and debilitating complications of surgery and critical illness. Consensus criteria use serum creatinine and urine output measurements to diagnose AKI and allow for objective diagnosis and more accurate comparisons across populations. New serum and urine biomarkers may provide earlier evidence of AKI, but their clinical utility, while increasing, remains limited. Avoidance of nephrotoxins, intravascular fluid management, and maintenance of renal perfusion are the mainstays of preventive management and treatment of AKI. Optimal timing for the initiation of renal replacement therapy is controversial and remains under investigation. Conclusions Acute kidney injury continues to affect large numbers of patients receiving surgery or in the intensive care unit, but specific advances in resuscitation techniques, endpoint refinements, epidemiology, biomarkers, and pathology are providing the necessary framework to reduce AKI and associated morbidity.

Background: Scientists use preclinical models of acute kidney injury (AKI) to decipher mechanisms and develop therapy, but translation of therapies to patients remains poor. Models that better resemble patients, including those within clinical care, should be considered. Summary: Mice provide many advantages to the study of human disease including an ability to dictate precise experimental conditions. To best isolate and measure phenomena, scientists reduce experimental variability – identical animals, environmental conditions, experimental exposures, and outcome assessments. This technique reduces effect size variability and increases power but dissociates these model organisms from the clinical patients they intend to represent, potentially accounting for the poor translation of findings into patient care. Clinical research, conversely, is often plagued by heterogeneous patients, heterogenous environmental factors, and heterogenous renal insults. A compromise between these 2 extremes – a model of AKI that is more similar to human disease but still provides opportunities for rigorous investigation – should be utilized. Cardiac surgery provides a clinical model for the study of AKI due to mechanism overlap it shares with other clinical conditions (improved generalizability) and characteristics that provide distinct opportunities for research. The high rate of AKI following cardiac surgery and the relative homogeneity (decreased variability) of cardiac surgery subjects, their environment, and renal insults increase power and the opportunity to make discoveries and advance care. Moreover, the elective nature of cardiac surgery provides opportunities to perform detailed baseline assessments and pretreat select patients. Key Messages: Models that better reflect clinical AKI are needed to decipher mechanisms and develop effective treatments. Cardiac surgery is an important clinical model form for the study of AKI.