Blockade of endothelial Mas receptor restores the vasomotor response to phenylephrine in human resistance arterioles pretreated with captopril and exposed to propofol.

BACKGROUND: Hypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1-7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril. METHODS: The internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10-9 to 10-5 M) in the presence and absence of propofol (10-6 M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10-5 M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10-2 M) or Ang 1-7 (10-9 M) before experimentation with phenylephrine, propofol, and A779. RESULTS: Propofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1-7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1-7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect. CONCLUSIONS: Mas receptor activation by Ang 1-7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors.

A Ten-Year Analysis of Recent National Institutes of Health Funding for Anesthesiology Research in United States Medical Schools.

OBJECTIVES: The characteristics of recent National Institutes of Health (NIH) grant funding to anesthesiology researchers in United States (US) medical schools have not been systematically quantified. NIH funding to cardiac anesthesiologists has also not been estimated. The author conducted an internet-based analysis of NIH awards to anesthesiology researchers from 2011-2020 to identify the types, duration of funding, and amount of grants, and the terminal degree(s), faculty rank, gender, board certification status, and type of appointment of the grant recipients including those with an interest in cardiac anesthesiology. DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: NIH grants recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: NIH grant recipients affiliated with anesthesiology departments were identified from the Blue Ridge Institute for Medical Research website. The number of grants, years of support, and total amount of funding were quantified for research project grants (R series), mentored career development awards (K series), and other grants (U and P series) using NIH Research Portfolio Online Reporting Tools. The terminal degree(s), faculty rank, gender, and type of appointment of grant recipients were identified using department web pages. American Board of Anesthesiology (ABA) certification, National Board of Echocardiography Advanced Perioperative Transesophageal Echocardiography (TEE) certification, and previous or current Foundation for Anesthesia Education and Research (FAER) awards to NIH grant recipients were obtained from each organization's website. A total of 532 researchers received 1250 grants with 3844 cumulative years of funding amounting to $1,676,482,440. R series grants accounted for three-quarters of all funding. PhDs were awarded more than one-half of NIH grants. MDs had lower median numbers of projects, R01 grants, and total R series grants than their colleagues with PhD or MD PhD degrees, but MDs received more K awards. One hundred ninety-eight MD and MD PhD NIH grant recipients were ABA diplomates. These physician-scientists received 26.0% and 53.1% of R and K series grants, respectively. Thirty physician-scientists also held TEE certification; these individuals with an interest in cardiac anesthesiology were awarded 4.8% of all NIH grants. Full Professors were awarded more than three-quarters of R grants and amassed more than $1.3 billion in funding, whereas assistant and associate professors received the majority of K series grants. Male investigators received greater median R grants but fewer median K awards than female researchers. One hundred-fifteen previous or current holders of FAER grants were identified; these individuals earned a total of 240 NIH awards totaling $357.7 million. CONCLUSION: PhDs, Professors, and male researchers receive the majority of R01 and other R series grants to anesthesiology departments at US medical schools. Physician-scientists, including those interested in cardiac anesthesiology, are awarded a minority of R series grants. FAER continues to provide an important stimulus for subsequent NIH funding of physician-scientists in anesthesiology.

A two-circuit strategy for intraoperative extracorporeal support during single lung transplantation in a patient bridged with venovenous extracorporeal membrane oxygenation.

Venovenous extracorporeal membrane oxygenation is increasingly used as a bridging strategy in decompensating patients awaiting lung transplantation. Various approaches for continuing support intraoperatively have been previously described. A two-circuit strategy that uses the in situ venovenous extracorporeal membrane oxygenation circuit supplemented with peripheral cardiopulmonary bypass allows for diversion of native cardiac output away from the transplanted lung as well as seamless continuation of venovenous extracorporeal membrane oxygenation postoperatively.

Gradually Progressive Dyspnea and Exercise Intolerance in an Otherwise Active Middle-Aged Woman: Why Was the Presentation of Congenital Heart Disease Delayed?

Patients with congenital heart disease (CHD) increasingly are surviving into adulthood. In the United States alone, there are more than one million adult patients living with CHD with the number increasing about 5% each year. With more than 85% of infants with CHD surviving into adulthood with their disease, encounters with these patients in the operating room for cardiac and noncardiac operative procedures is becoming more commonplace. Most of these patients receive corrective surgery early in life, although some may live with uncorrected CHD with no-to-relatively mild symptoms and present at a later time in life with symptoms of heart failure or pulmonary hypertension. The authors present an adult patient with uncorrected CHD presenting with late onset of heart failure symptoms. The authors also review the patient's complex congenital heart lesion, transesophageal echocardiography findings, and intraoperative management.

Heart Failure With Preserved Ejection Fraction: A Comprehensive Review and Update of Diagnosis, Pathophysiology, Treatment, and Perioperative Implications.

Almost three-quarters of all heart failure patients who are older than 65 have heart failure with preserved ejection fraction (HFpEF). The proportion and hospitalization rate of patients with HFpEF are increasing steadily relative to patients in whom heart failure occurs as result of reduced ejection fraction. The predominance of the HFpEF phenotype most likely is explained by the prevalence of medical conditions associated with an aging population. A multitude of age-related, medical, and lifestyle risk factors for HFpEF have been identified as potential causes for the sustained low-grade proinflammatory state that accelerates disease progression. Profound left ventricular (LV) systolic and diastolic stiffening, elevated LV filling pressures, reduced arterial compliance, left atrial hypertension, pulmonary venous congestion, and microvascular dysfunction characterize HFpEF, but pulmonary arterial hypertension, right ventricular dilation and dysfunction, and atrial fibrillation also frequently occur. These cardiovascular features make patients with HFpEF exquisitely sensitive to the development of hypotension in response to acute declines in LV preload or afterload that may occur during or after surgery. With the exception of symptom mitigation, lifestyle modifications, and rigorous control of comorbid conditions, few long-term treatment options exist for these unfortunate individuals. Patients with HFpEF present for surgery on a regular basis, and anesthesiologists need to be familiar with this heterogeneous and complex clinical syndrome to provide successful care. In this article, the authors review the diagnosis, pathophysiology, and treatment of HFpEF and also discuss its perioperative implications.

Recombinant activated factor VII for hemostasis in patients undergoing complex ascending aortic surgery: A single-center, single-surgeon retrospective analysis.

BACKGROUND: Use of recombinant activated factor VII (rFVIIa) to achieve hemostasis during cardiac surgery continues to be debated, as support for its efficacy and safety has not been consistent. We examined our experience with rFVIIa for achieving hemostasis in high-risk patients undergoing complex ascending aortic surgery. METHODS: We reviewed patients who underwent complex ascending aortic surgery performed by a single surgeon (C. K. R.) from August 2014 to February 2019. Outcomes of patients who received rFVIIa were compared with those who did not. RESULTS: Of 59 consecutive patients, 20 patients (33.9%) received rFVIIa, whereas 39 (66.1%) did not. Median dose was 45.4 mcg/kg. rFVIIa was administered intraoperatively to 95% of patients who received it. Most patients underwent combined aortic valve, ascending aorta, and aortic arch surgery (80.0% vs. 64.1%, p = .52). Patients receiving rFVIIa had longer mean cross clamp times (212 vs. 173 min, p = .03) and received a greater median number of intraoperative blood products (18.5 vs. 12.0, p < .001). The number of patients who needed postoperative products (75.0% vs. 60.5%, p = .39), the median number of blood products transfused postoperatively (2 vs. 2, p = .40), and chest tube output (1138 vs. 805 ml, p = .17) were similar between groups. In-hospital mortality was similar between groups (10.0% vs. 10.3%, p = 1.00). Incidences of postoperative stroke (10.0% vs. 13.5%, p = 1.00) and thromboembolic events (10.0% vs. 13.5%, p = 1.00) were similar. CONCLUSIONS: Administration of rFVIIa intraoperatively for refractory bleeding during complex ascending aortic surgery provided hemostasis without greater in-hospital mortality or a higher risk of stroke and thromboembolic events.

Superior vena cava syndrome during veno-venous extracorporeal membrane oxygenation for COVID-19.

Superior vena cava (SVC) syndrome is typically associated with malignant tumors obstructing the SVC, but as many as 40% of cases have other etiologies. SVC obstruction was previously described during veno-venous extracorporeal membrane oxygenation therapy (VV ECMO) in children. In this report, we describe a woman with adult respiratory distress syndrome resulting from infection with coronavirus-19 who developed SVC syndrome during VV ECMO. A dual-lumen ECMO cannula was inserted in the right internal jugular vein, but insufficient ECMO circuit flow, upper body edema, and signs of hypovolemic shock were observed. This clinical picture resolved when the right internal jugular vein was decannulated in favor of bilateral femoral venous cannulae. Our report demonstrates that timely recognition of clinical signs and symptoms led to the appropriate diagnosis of an uncommon ECMO complication.

Titration of sevoflurane anesthesia to optimize the time to regain airway reflexes in patients undergoing elective surgery: A randomized clinical trial comparing desflurane and sevoflurane anesthesia.

BACKGROUND: Desflurane has adverse environmental effects, but has clinical advantages to speed emergence and return of protective airway reflexes compared with sevoflurane. We hypothesized that weaning of the inspired sevoflurane during the final 15 minutes of surgery would eliminate differences in airway reflex recovery between these agents. METHODS: After obtaining IRB approval and informed consent, 40 patients undergoing elective surgery (≥1-hour) randomly received desflurane or sevoflurane. Patients swallowed 20 mL of water without drooling or coughing, and then received sedation and PONV pre-medication. Anesthesia was induced using propofol and fentanyl and maintained with desflurane or sevoflurane through a laryngeal mask airway maintaining a bispectral index of 45-50 and 50-60 during the final 15 minutes before surgery end. Cardiorespiratory variables and age-adjusted minimal alveolar concentration were recorded. The duration between anesthetic discontinuation and first appropriate response to command was measured; the laryngeal mask airway was removed. Two minutes after responding to command, patients were positioned semi-upright and attempted to swallow water. If successful swallowing was not achieved, the test was repeated every 4 minutes after each failure until successful swallowing was achieved. RESULTS: Average anesthetic concentration and bispectral index was similar in patients receiving desflurane vs sevoflurane. Response times after discontinuation of anesthetics were similar. There were no differences in the recovery of swallowing ability between desflurane and sevoflurane groups. CONCLUSION: Weaning of sevoflurane during the final 15 minutes of surgery eliminates clinical advantages of the more rapid return of airway reflexes with desflurane.

The Physiology of Oxygen Transport by the Cardiovascular System: Evolution of Knowledge.

The heart, vascular system, and red blood cells play fundamental roles in O2 transport. The fascinating research history that led to the current understanding of the physiology of O2 transport began in ancient Egypt in 3000 BC, when it was postulated that the heart was a pump serving a system of distributing vessels. Over 4 millennia elapsed before William Harvey (1578-1657) made the revolutionary discovery of blood circulation, but it was not until the 20th century that a lucid and integrative picture of O2 transport finally emerged. This review describes major research achievements contributing to this evolution of knowledge. These achievements include the discovery of the systemic and pulmonary circulations, hemoglobin within red blood cells and its ability to bind O2, and diffusion of O2 from the capillary as the final step in its delivery to tissue. The authors also describe the classic studies that provided the initial description of the basic regulatory mechanisms governing heart function (Frank-Starling law) and the flow of blood through blood vessels (Poiseuille's law). The importance of technical advances, such as the pulmonary artery catheter, the blood gas analyzer and oximeter, and the radioactive microsphere technique to measure the regional blood flow in facilitating O2 transport-related research, is recognized. The authors describe how religious and cultural constraints, as well as superstition-based medical traditions, at times impeded experimentation and the acquisition of knowledge related to O2 transport.

Predisposing and Precipitating Factors Associated With Postoperative Delirium in Patients Undergoing Cardiac Surgery at a Veterans Affairs Medical Center: A Pilot Retrospective Analysis.

OBJECTIVE: Patients treated at Veterans Affairs (VA) medical centers are in poorer health, experience more medical and psychiatric conditions, and make greater use of medical resources than do patients in the general population. In the present pilot study, the authors examined their recent experience at a VA medical center to determine the incidence and risk factors associated with the development of postoperative delirium in VA patients after cardiac surgery and hypothesized that the risk factors for postoperative delirium after cardiac surgery are different between VA and non-VA patients. DESIGN: Retrospective cohort study. SETTING: Clement J. Zablocki Veterans Affairs Medical Center. PARTICIPANTS: The study comprised 250 consecutive patients undergoing cardiac surgery from July 2014 to March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, coexisting diseases, and medications were obtained from the VA electronic medical record. The European System for Cardiac Operative Evaluation II mortality risk index was calculated for each patient. The type and duration of the procedure and the duration of bypass were recorded. Intraoperative crystalloid, colloid, cell saver, and blood product volumes were compiled. Progress notes and International Classification of Diseases, Tenth Revision, Clinical Modification codes were searched for documentation of postoperative delirium. Thirty-eight patients (15.2%) developed postoperative delirium. Stepwise logistic regression analysis demonstrated that the European System for Cardiac Operative Evaluation II mortality risk index (odds ratio [OR] 1.036, 95% confidence interval [CI] [1.003-1.070]; p = 0.0344), congestive heart failure (OR 2.223 [95% CI 1.046-4.722]; p = 0.0377), pre-existing cognitive impairment (OR 5.147 [95% CI 1.994-13.28]; p = 0.0007), and the presence of a neuropsychiatric disorder (OR 2.015 [95% CI 1.004-4.043]; p = 0.0487) were predisposing factors associated with higher odds of postoperative delirium. The duration of surgery; transfusion of blood products (including packed red blood cells, fresh frozen plasma, and platelets); the durations of mechanical ventilation and conscious sedation (using either propofol or dexmedetomidine); and the length of intensive care unit stay were precipitating factors associated with higher odds of postoperative delirium. CONCLUSIONS: The results demonstrate that congestive heart failure, pre-existing cognitive impairment, and the presence of a neuropsychiatric disorder are predisposing risk factors for postoperative delirium after cardiac surgery in VA patients, whereas the duration of surgery, transfusion of blood products, durations of mechanical ventilation and conscious sedation, and length of intensive care unit stay are precipitating factors for postoperative delirium. These findings in VA patients generally are similar to those observed in the civilian population despite the differences between these cohorts.

Characteristics associated with Publication of Randomized Controlled Trials in the Journal of Cardiothoracic and Vascular Anesthesia: A 15-Year Analysis, 2004-2018.

Randomized controlled trials (RCTs) provide important data to guide clinical decisions. Publication bias may limit the applicability of RCTs because many clinical investigators prefer to submit and journals more selectively accept studies with positive results. The authors tested the hypothesis that positive RCTs published in the Journal of Cardiothoracic and Vascular Anesthesia were more likely to be associated with factors known to predict publication of positive versus negative RCTs in other journals. This observational study was an internet analysis of all issues of Journal of Cardiothoracic and Vascular Anesthesia from 2004-2018. Each issue was searched to identify human RCTs. The numbers of centers and enrolled patients in each RCT were tabulated. The corresponding author determined the country of origin (United States v international). A trial was "positive" or "negative" based on rejection or confirmation of the null hypothesis, respectively, for the primary outcome variable or the majority of measured outcomes if a primary outcome was not identified. The presence or absence of a hypothesis, randomization methodology, sample size calculation, and blinded research design was recorded. Registration in a public database, Consolidated Statements of Reporting Trials (CONSORT) guideline compliance, and the source of funding also were determined. The number of citations for each RCT was determined by using Google Scholar; the citation rate was calculated as the ratio of the number of total citations and the duration in years since the trial's original publication. A total of 296 RCTs were identified, of which 58.8% reported positive results. Most RCTs were single center, relatively small, and international in origin. Total citations/RCT decreased over time, but citations/year did not. The percentage of RCTs that identified a randomization method, were registered, or followed CONSORT guidelines increased in a time-dependent manner. No differences in any factors associated with publication of RCTs were observed when positive and negative trials were compared. The Journal of Cardiothoracic and Vascular Anesthesia publishes more positive than negative RCTs, but factors that have been previously associated with RCT publication in other journals were similar between groups.

Progressive Increase in Scholarly Productivity of New American Board of Anesthesiology Diplomates From 2006 to 2016: A Bibliometric Analysis.

BACKGROUND: Improving research productivity is a common goal in academic anesthesiology. Initiatives to enhance scholarly productivity in anesthesiology were proposed more than a decade ago as a result of emphasis on clinical work. We hypothesized that American Board of Anesthesiology diplomates certified from 2006 to 2016 would be progressively more likely to have published at least once during this time period. METHODS: A complete list of 17,332 new diplomates was obtained from the American Board of Anesthesiology for the years 2006 to 2016. These names were queried using PubMed, and the number of publications up to and including the diplomate's year of primary certification was recorded. Descriptive statistics and logistic regression analysis were used to analyze the association of the year of primary certification and whether a diplomate had published at least once. RESULTS: The percentage of American Board of Anesthesiology diplomates with ≥1 publication at the time of primary certification increased from 14.9% to 29.3% from 2006 to 2016. The mean number of publications per diplomate more than doubled from 0.31 to 0.79. Logistic regression analysis revealed the year of primary certification as significantly associated with having ≥1 publication (P < .001). Using 2006 as the reference year, odds of having published at least once were higher in the years 2010 to 2016, with the highest odds ratio of having a article published occurring in 2016: 2.359 (confidence interval, 1.978-2.812; P < .001). CONCLUSIONS: Publications by new diplomates of the American Board of Anesthesiology have increased between 2006 and 2016. Whether the observed increase in publications could reflect efforts to stimulate interest in academic objectives during training remains to be proven.

Gender Differences in Authorship in the Journal of Cardiothoracic and Vascular Anesthesia: A 28-Year Analysis of Publications Originating From the United States, 1990-2017.

OBJECTIVE: Gender-based differences in scholarship among cardiothoracic anesthesiologists have not been studied. The authors examined the gender distribution of authorship of original research articles, case reports, review articles, and editorials in the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) originating from the United States during four 3-year intervals to determine temporal changes in productivity of women in cardiothoracic anesthesiology. The authors tested the hypothesis that scholarly output of women has increased progressively in JCVA over time concomitant with greater participation in first, last, and corresponding author roles. DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: Authors of research articles, case reports, review articles, and editorials published in JCVA in 1990-92, 1999-2001, 2008-10, and 2015-17. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The gender of each author was determined by inspection of the first name. If gender could not be established easily, the author's institutional website was examined or an internet search using the Google search engine was conducted. First, last, and corresponding authors as well as coauthors were noted for each article. A total of 1,195 publications with 4,982 authors (1,032 women; 20.7%) were examined. Gender was identified positively in 98.5% of authors. Women were first, last, and corresponding authors on 22.4%, 10.3%, and 14.6% of publications, respectively. The percentage of women who were authors increased from 12.1% in 1990-92 to 20.9% in 1999-2001 (p < 0.05), but plateaued in 2008 to 2010 (22.3%) and 2015 to 2017 (22.9%). Greater percentages of women were first authors (26.2%), senior authors (11.8%), and corresponding authors (16.6%) in 2015 to 2017 compared with 1990 to 1992 (9.6%, 7.0%, and 8.7%, respectively; p < 0.05 for each). The contributions of women to research articles and case reports were primarily responsible for these observed increases, although women also made a substantial impact with review articles in 2015 to 2017. The percentage of publications that included at least 1 female author in any capacity increased in a time-dependent manner (p < 0.05) from 31.0% (1990-1992) to 74.4% (2015-2017). The proportion of female first or last authors (35.0%) appearing in JCVA during 2015 to 2017 was modestly higher than the current percentage of female cardiothoracic anesthesiologists practicing in departments with accredited fellowship programs (29.1%). CONCLUSION: The results indicate that scholarly output of women rose in JCVA over time, but gains in productivity have plateaued more recently. These findings are encouraging, but women continue to be underrepresented in corresponding and last author roles.

Gender Composition and Trends of Journal of Cardiothoracic and Vascular Anesthesia Editorial Board Membership: A 33-Year Analysis, 1987-2019.

OBJECTIVE: Gender disparities in editorial board composition exist in the vast majority of specialties including anesthesiology. If a similar lack of gender parity exists in cardiothoracic anesthesiology is unknown. The authors examined the gender composition and trends of the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) editorial board from the initial year of its publication (1987) to 2019. The authors tested the hypothesis that the proportion of women serving on the JCVA editorial board has steadily increased over the journal's history, but women are underrepresented compared with the percentage of those currently practicing academic cardiothoracic anesthesia in the United States (US). DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: All members of the JCVA editorial board, 1987-2019. INTERVENTIONS: The JCVA editor-in-chief, the associate editor-in-chief, associate editors, section editors, and general editors on the board were extracted from the masthead of a single issue from each calendar year. The years were divided into quartiles (1987-1995, 1996-2003, 2004-2011, and 2012-2019) to collect representative samples of editorial board composition for analysis. MEASUREMENTS AND MAIN RESULTS: A total of 2,797 members of the JCVA editorial board were positively identified (2,477 [88.6%] men; 310 [11.1%] women); 10 (0.3%) editors could not be identified. Four hundred and fourteen associate and section editors were recorded (men 360 [87.0%], women 54 [13.0%]). There were also 2,353 general editors (2,087 [88.7%] men; 256 [10.9%] women). The total number of JCVA board members, associate and section editors, and general editors progressively increased from 1987 to 1995 to 2012 to 2019. The percentage of women serving on the editorial board increased from 2.5% to 15.8%. Increases in the proportion of female general editors from 2.9% to 16.2% were responsible for this overall increase. A gender gap between the percentage of female first authors (data obtained from a previous publication) and editorial board members was observed in each quartile. Editorial board composition was also different than last author distribution in 1987 to 1995 and 2012 to 2019, but not the other 2 time periods. CONCLUSIONS: The results demonstrate that the proportion of women serving on the JCVA editorial board has steadily increased over the journal's history. Nevertheless, women continue to be underrepresented on the JCVA board compared with the percentage of US female academic cardiothoracic anesthesiologists, and gender gaps between first and last authorship and board composition also persist.

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

BACKGROUND: Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. METHODS: The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. FINDINGS: Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. INTERPRETATION: A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. FUNDING: National Institutes of Health and Cancer Center Support.

Right Ventricular Perfusion: Physiology and Clinical Implications.

Regulation of blood flow to the right ventricle differs significantly from that to the left ventricle. The right ventricle develops a lower systolic pressure than the left ventricle, resulting in reduced extravascular compressive forces and myocardial oxygen demand. Right ventricular perfusion has eight major characteristics that distinguish it from left ventricular perfusion: (1) appreciable perfusion throughout the entire cardiac cycle; (2) reduced myocardial oxygen uptake, blood flow, and oxygen extraction; (3) an oxygen extraction reserve that can be recruited to at least partially offset a reduction in coronary blood flow; (4) less effective pressure-flow autoregulation; (5) the ability to downregulate its metabolic demand during coronary hypoperfusion and thereby maintain contractile function and energy stores; (6) a transmurally uniform reduction in myocardial perfusion in the presence of a hemodynamically significant epicardial coronary stenosis; (7) extensive collateral connections from the left coronary circulation; and (8) possible retrograde perfusion from the right ventricular cavity through the Thebesian veins. These differences promote the maintenance of right ventricular oxygen supply-demand balance and provide relative resistance to ischemia-induced contractile dysfunction and infarction, but they may be compromised during acute or chronic increases in right ventricle afterload resulting from pulmonary arterial hypertension. Contractile function of the thin-walled right ventricle is exquisitely sensitive to afterload. Acute increases in pulmonary arterial pressure reduce right ventricular stroke volume and, if sufficiently large and prolonged, result in right ventricular failure. Right ventricular ischemia plays a prominent role in these effects. The risk of right ventricular ischemia is also heightened during chronic elevations in right ventricular afterload because microvascular growth fails to match myocyte hypertrophy and because microvascular dysfunction is present. The right coronary circulation is more sensitive than the left to α-adrenergic-mediated constriction, which may contribute to its greater propensity for coronary vasospasm. This characteristic of the right coronary circulation may increase its vulnerability to coronary vasoconstriction and impaired right ventricular perfusion during administration of α-adrenergic receptor agonists.