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This study sought to define the 2-dimensional and Doppler echocardiographic hemodynamics associated with each Society for Cardiovascular Angiography and Interventions (SCAI) stage, and to determine their association with mortality.The SCAI shock stages classification stratifies mortality risk in cardiac intensive care unit (CICU) patients, but the echocardiographic and hemodynamic parameters that define these SCAI shock stages are unknown.Unique CICU patients admitted from 2007 to 2015 who had a transthoracic echocardiogram within 1 day of CICU admission were included. Echocardiographic variables were evaluated as a function of SCAI shock stage. Multivariable logistic regression determined the association between echocardiographic parameters with adjusted hospital mortality.We included 5,453 patients with a median age of 69.3 years (interquartile range: 58.2 to 79.0 years) (37% women), and a median left ventricular ejection fraction (LVEF) of 50% (interquartile range: 35% to 61%). Higher SCAI shock stages were associated with lower LVEF and worse systemic hemodynamics. Hospital mortality was higher in patients with LVEF 40%, cardiac index 1.8 l/min/mNoninvasive 2-dimensional and Doppler echocardiographic parameters correlate with the SCAI shock stages and improve risk stratification for hospital mortality in CICU patients. Low stroke volume index and high E/e' ratio demonstrated the strongest association with hospital mortality.

Aim:This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients.Methods:A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered.Structure:Chest pain is a frequent cause for emergency department visits in the United States. The “2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain” provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated, and shared decision-making with patients is recommended.

Scientific statements and publications have recommended the use of vasoconstrictors as the first-line pharmacologic choice for most cases of cardiogenic shock (CS), without the abundance of strong clinical evidence. One challenge of guidelines is that the way recommendations are stated can potentially lead to oversimplification of complex situations. Except for acute coronary syndrome with CS, in which maintenance of coronary perfusion pressure seems logical prior to revascularization, physiologic consequences of increasing afterload by use of vasoconstrictors should be analyzed. Changing the CS conceptual frame, emphasizing inflammation and other vasodilating consequences of prolonged CS, mixes causes and consequences. Moreover, the considerable interpatient differences regarding the initial cause of CS and subsequent consequences on both macro- and microcirculation, argue for a dynamic, step-by-step, personalized therapeutic strategy. In CS, vasoconstrictors should be used only after a reasoning process, a review of other possible options, and then should be titrated to reach a reasonable pressure target, while checking cardiac output and organ perfusion.

Sepsis is the life-threatening organ dysfunction caused by a dysregulated host response to infection and is the leading cause of death in intensive care units. Cardiac dysfunction caused by sepsis, usually termed sepsis-induced cardiomyopathy, is common and has long been a subject of interest. In this Review, we explore the definition, epidemiology, diagnosis and pathophysiology of septic cardiomyopathy, with an emphasis on how best to interpret this condition in the clinical context. Advances in diagnostic techniques have increased the sensitivity of detection of myocardial abnormalities but have posed challenges in linking those abnormalities to therapeutic strategies and relevant clinical outcomes. Sophisticated methodologies have elucidated various pathophysiological mechanisms but the extent to which these are adaptive responses is yet to be definitively answered. Although the indications for monitoring and treating septic cardiomyopathy are clinical and directed towards restoring tissue perfusion, a better understanding of the course and implications of septic cardiomyopathy can help to optimize interventions and improve clinical outcomes.

Patients admitted to the cardiac intensive care unit (CICU) are often in shock and require hemodynamic support. Identifying and addressing the pathophysiology mechanisms operating in an individual patient is crucial to achieving a successful outcome, while initiating circulatory support therapy to restore adequate tissue perfusion. Vasopressors and inotropes are the cornerstone of supportive medical therapy for shock, in addition to fluid resuscitation when indicated. Timely initiation of optimal vasopressor and inotrope therapy is essential for patients with shock, with the ultimate goals of restoring effective tissue perfusion in order to normalize cellular metabolism. Use of vasoactive agents for hemodynamic support of patients with shock should take both arterial pressure and tissue perfusion into account when choosing therapeutic interventions. For most patients with shock, including cardiogenic or septic shock, norepinephrine (NE) is an appropriate choice as a first-line vasopressor titrated to achieve an adequate arterial pressure due to a lower risk of adverse events than other catecholamine vasopressors. If tissue and organ perfusion remain inadequate, an inotrope such as dobutamine may be added to increase cardiac output to a sufficient level that meets tissue demand. Low doses of epinephrine or dopamine may be used for inotropic support, but high doses of these drugs carry an excessive risk of adverse events when used for vasopressor support and should be avoided. When NE alone is inadequate to achieve an adequate arterial pressure, addition of a noncatecholamine vasopressor such as vasopressin or angiotensin-II is reasonable, in addition to rescue therapies that may improve vasopressor responsiveness. In this review, we discuss the pharmacology and evidence-based use of vasopressor and inotrope drugs in critically ill patients, with a focus on the CICU population.

Objective: Menopause may augment age-dependent increases in arterial stiffness, with black women having greater progression in midlife compared with white women. We sought to determine whether and when women experience changes in arterial stiffness relative to the final menstrual period (FMP) and whether these changes differ between black and white midlife women. Approach and Results: We evaluated 339 participants from the SWAN (Study of Women’s Health Across the Nation) Heart Ancillary study (Study of Women’s Health Across the Nation). Women had ≤2 carotid-femoral pulse-wave velocity (cfPWV) exams over a mean±SD of 2.3±0.5 years of follow-up. Annual percentage changes in cfPWV were estimated in 3 time segments relative to FMP and compared using piecewise linear mixed-effects models. At baseline, women were 51.1±2.8 years of age and 36% black. Annual percentage change (95% CI) in cfPWV varied by time segments: 0.9% (−0.6% to 2.3%) for >1 year before FMP, 7.5% (4.1% to 11.1%) within 1 year of FMP, and −1.0% (−2.8% to 0.8%) for >1 year after FMP. Annual percentage change in cfPWV within 1 year of FMP was significantly greater than the other 2 time segments; P P for interaction, 0.04. Conclusions: The interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, FACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair [‡‡][1] Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD

Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for

Background: Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units. Methods: The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions. Results: Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%–50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%–100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use. Conclusions: There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity.

Background The outcome of cardiogenic shock complicating myocardial infarction has not appreciably changed in the last 30 years despite the development of various percutaneous mechanical circulatory support options. It is clear that there are varying degrees of cardiogenic shock but there is no robust classification scheme to categorize this disease state. Methods A multidisciplinary group of experts convened by the Society for Cardiovascular Angiography and Interventions was assembled to derive a proposed classification schema for cardiogenic shock. Representatives from cardiology (interventional, advanced heart failure, noninvasive), emergency medicine, critical care, and cardiac nursing all collaborated to develop the proposed schema. Results A system describing stages of cardiogenic shock from A to E was developed. Stage A is "at risk" for cardiogenic shock, stage B is "beginning" shock, stage C is "classic" cardiogenic shock, stage D is "deteriorating", and E is "extremis". The difference between stages B and C is the presence of hypoperfusion which is present in stages C and higher. Stage D implies that the initial set of interventions chosen have not restored stability and adequate perfusion despite at least 30 minutes of observation and stage E is the patient in extremis, highly unstable, often with cardiovascular collapse. Conclusion This proposed classification system is simple, clinically applicable across the care spectrum from pre-hospital providers to intensive care staff but will require future validation studies to assess its utility and potential prognostic implications.

Background Clinical investigations of shock in cardiac intensive care units (CICUs) have primarily focused on acute myocardial infarction (AMI) complicated by cardiogenic shock (AMICS). Few studies have evaluated the full spectrum of shock in contemporary CICUs. Methods and Results The Critical Care Cardiology Trials Network is a multicenter network of advanced CICUs in North America. Anytime between September 2017 and September 2018, each center (n=16) contributed a 2-month snap-shot of all consecutive medical admissions to the CICU. Data were submitted to the central coordinating center (TIMI Study Group, Boston, MA). Shock was defined as sustained systolic blood pressure P P Conclusions The epidemiology of shock in contemporary advanced CICUs is varied, and AMICS now represents less than one-third of all CS. Despite advanced therapies, mortality in CS and mixed shock remains high. Investigation of management strategies and new therapies to treat shock in the CICU should take this epidemiology into account.

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

To ensure that guidelines reflect current knowledge, available treatment options, and optimum medical care, existing clinical practice guideline recommendations are modified and new recommendations are added in response to new data, medications or devices. To keep pace with evolving evidence, the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guidelines (“Task Force”) has issued this focused update to revise guideline recommendations on the basis of recently published data. This update is not based on a complete literature review from the date of previous guideline publications, but it has been subject to rigorous, multilevel review and approval, similar to the full guidelines. For specific focused update criteria and additional methodological details, please see the ACC/AHA guideline methodology manual.1 ### Modernization In response to published reports from the Institute of Medicine2,3 and ACC/AHA mandates,4–7 processes have changed leading to adoption of a “knowledge byte” format. This entails delineation of recommendations addressing specific clinical questions, followed by concise text, with hyperlinks to supportive evidence. This approach better accommodates time constraints on busy clinicians, facilitates easier access to recommendations via electronic search engines and other evolving technology (eg, smart phone apps), and supports the evolution of guidelines as “living documents” that can be …

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Jeffrey L. Anderson, MD, FACC, FAHA, Immediate Past Chair [∗∗][1] Nancy M. Albert, PhD, RN, FAHA[∗∗][1] Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD

A 76-year-old woman loses a close friend. Several hours later, she has chest pain, diaphoresis, and shortness of breath. She presents to the emergency department, where an ECG shows deep T wave inversion across the precordium. Cardiac troponin is elevated. This presentation is classic for myocardial ischemia and for stress cardiomyopathy. Recognition of stress cardiomyopathy, and its distinction from acute coronary syndrome (ACS), is crucial for the clinician, since their pathophysiology and treatment are quite different. Stress cardiomyopathy is an acute reversible syndrome with characteristic wall motion abnormalities, consisting of apical hypokinesis or dyskinesis with sparing of the basal ventricular segments. Although the final outcome is generally good, early in their clinical course, patientsmay have cardiogenic shock (4 %), malignant ventricular arrhythmias (1–2 %), and death (1–1.5 %) [1]. Stress cardiomyopathy can complicate other conditions in the ICU, notably including subarachnoid hemorrhage. Patients with these more complex presentations often present clinical challenges. This manuscript aims to increase understanding of the identification and pathophysiology of stress cardiomyopathy to help practitioners manage this interesting syndrome.

Cardiovascular disease risk increases in women after the menopausal transition; why this inflection point occurs remains uncertain. We aimed to characterize the influence of menopause on vascular aging by prospective assessment of change in indexes of subclinical atherosclerosis across the menopausal transition. We evaluated 411 healthy women from SWAN Heart, an ancillary study of SWAN (Study of Women's Health Across the Nation), for subclinical atherosclerosis at baseline and again after an average of 2.3 years. Carotid intima-media thickness and aortic pulse wave velocity were measured by ultrasound. Coronary artery calcium scores were obtained by computed tomography. Women were grouped by menopausal status as premenopausal, postmenopausal, or having undergone the transition during follow-up. Analyses of changes were adjusted for age at baseline and time between scans. Mean age at baseline was 51 ± 3 years; 93 (23%) subjects transitioned to menopause (Pre-Post), 147 (36%) remained premenopausal (Pre-Pre), while 171 (41%) were postmenopausal at baseline (Post-Post). Blood pressure readings did not differ between groups with similar increase noted in carotid intima-media thickness and log coronary artery calcium + 1 from baseline to follow-up. Change in aortic pulse wave velocity from baseline to follow-up was higher in Pre-Post (121 ± 23 cm/s) compared with Pre-Pre (38 ± 250 cm/s, p = 0.029) and Post-Post (41 ± 228 cm/s, p = 0.045). In conclusion, changes in aortic stiffness were more sensitive measures of perimenopausal vascular aging than morphologic indexes of subclinical atherosclerosis in women undergoing the menopausal transition. Serial assessment of such changes could potentially elucidate mechanisms of disease and identify women to target for aggressive lifestyle risk factor modification.

The liver and heart are closely related in health and in disease; the liver receives 25 to 30% of total cardiac output via the hepatic artery, and the portal vein. Liver disease can result from right-sided heart failure, with manifestations ranging from mild reversible liver injury to hepatic fibrosis, and, in its most severe form, cardiac cirrhosis. On the other end of the spectrum, advanced liver disease can manifest itself as a hyperdynamic state with decreased vascular resistance, but with concomitant cardiac dysfunction that is termed cirrhotic cardiomyopathy. The degree of cardiac derangement correlates with the degree of liver dysfunction, and may lead to other disease processes such as hepatorenal syndrome and hepatic encephalopathy. Prompt recognition and treatment of the underlying cause of acute decompensation is the only definitive therapy for this devastating disease process.

Objective: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." Design: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods: The panel consisted of five sections: hemodynamics infection adjunctive therapies metabolic and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. Results: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Conclusions: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality. © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sepsis treatment guidelines recommend macrocirculatory hemodynamic optimization; however, microcirculatory dysfunction is integral to sepsis pathogenesis. We aimed to test the hypothesis that following macrocirculatory optimization, inhaled nitric oxide would improve microcirculation in patients with sepsis and that improved microcirculation would improve lactate clearance and multiple organ dysfunction.Randomized, sham-controlled clinical trial.Single urban academic medical center.Adult patients with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L.After achievement of macrocirculatory resuscitation goals, we randomized patients to 6 hours of inhaled nitric oxide (40 ppm) or sham inhaled nitric oxide administration. We administered study drug via a specialized delivery device that concealed treatment allocation so that investigators and clinical staff remained blinded.We performed sidestream dark-field videomicroscopy of the sublingual microcirculation prior to and 2 hours after study drug initiation. The primary outcome measure was the change in microcirculatory flow index. Secondary outcomes were lactate clearance and change in Sequential Organ Failure Assessment score. We enrolled 50 patients (28 of 50 [56%] requiring vasopressor agents; 15 of 50 [30%] died). Although inhaled nitric oxide significantly raised plasma nitrite levels, it did not improve microcirculatory flow, lactate clearance, or organ dysfunction. In contrast to previous studies conducted during the earliest phase of resuscitation, we found no association between changes in microcirculatory flow and lactate clearance or organ dysfunction.Following macrocirculatory optimization, inhaled nitric oxide at 40 ppm did not augment microcirculatory perfusion in patients with sepsis. Further, we found no association between microcirculatory perfusion and multiple organ dysfunction after initial resuscitation.

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

In the cirrhotic liver, distortion of the normal liver architecture is caused by structural and vascular changes. Portal hypertension is often associated with a hyperdynamic circulatory syndrome in which cardiac output and heart rate are increased and systemic vascular resistance is decreased. The release of several vasoactive substances is the primary factor involved in the reduction of mesenteric arterial resistance, resulting in sodium and water retention with eventual formation of ascites. Management of these patients with acute cardiac dysfunction often requires invasive hemodynamic monitoring in an intensive care unit setting to tailor decisions regarding use of fluids and vasopressors.

The medical profession should play a central role in evaluating the evidence related to drugs, devices, and procedures for the detection, management, and prevention of disease. When properly applied, expert analysis of available data on the benefits and risks of these therapies and procedures can

Cardiovascular system failure is commonly faced by the intensivist. Heart failure can occur due to a host of predisposing cardiac disorders or as secondary effects of systemic illness. When the heart is unable to provide an adequate cardiac output to maintain adequate tissue perfusion, cardiogenic shock ensues. Without prompt diagnosis and appropriate management, these patients have significant morbidity and mortality, with in-hospital mortality approaching 60% for all age groups. Accurate and rapid identification of cardiogenic shock as a medical emergency, with expeditious implementation of appropriate therapy, can lead to improved clinical outcomes. In this review, we discuss optimal strategies for diagnosis and monitoring of cardiogenic shock. We discuss the diverse therapeutic strategies employed for cardiogenic shock, including pharmacological (e.g., vasoactive agents, fibrinolytic agents), mechanical (e.g., intraaortic balloon pumps, left ventricular assist devices, percutaneous coronary intervention [PCI]), and surgical approaches such as coronary artery bypass graft (CABG), valvular repair or replacement (e.g., for acute mitral regurgitation, ventricular septal rupture, or free wall rupture).

OBJECTIVE The aim of this study was to examine whether obesity modifies the effects of endogenous steroid sex hormones on arterial calcification in women at midlife. METHODS Associations between estradiol, testosterone, sex hormone-binding globulin, and free androgen index and the presence and extent of coronary and aortic calcification were evaluated in 187 obese (body mass index, ≥30 kg/m) and 281 nonobese (body mass index

The ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. In sepsis, both global and regional perfusion must be considered. In addition, mediators of sepsis can perturb cellular metabolism, leading to inadequate use of oxygen and other nutrients despite adequate perfusion; one would not expect organ dysfunction mediated by such abnormalities to be corrected by hemodynamic therapy. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that is particularly pertinent with respect to vasoactive agents. Both arterial pressure and tissue perfusion must be taken into account when choosing therapeutic interventions and the efficacy of hemodynamic therapy should be assessed by monitoring a combination of clinical and hemodynamic parameters. It is relatively easy to raise blood pressure, but somewhat harder to raise cardiac output in septic patients. How to optimize regional blood and microcirculatory blood flow remains uncertain. Specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle. The practice parameters were intended to emphasize the importance of such an approach so as to provide a foundation for the rational choice of vasoactive agents in the context of evolving monitoring techniques and therapeutic approaches.

The Dynamic Assessment and Referral System for Substance Abuse (DARSSA) conducts a computerized substance abuse assessment; prints personalized summary reports that include tailored substance abuse treatment referral lists; and, for individuals who provide authorization, automatically faxes their contact information to a “best match” substance abuse treatment provider (dynamic referral). After piloting the program and resolving problems that were noted, we enrolled a sample of 85 medical patients. The DARSSA identified 48 (56%) participants who were risky substance users, many of whom had not been identified during their routine medical assessment. Mean satisfaction scores for all domains ranged between “Good” to “Excellent” across patients, nurses, doctors, and substance abuse treatment providers The median completion time was 13 minutes. Of the 48 risky substance using participants, 20 (42%) chose to receive a dynamic referral. The DARSSA provides a user-friendly, desirable service for patients and providers. It has the potential to improve identification of substance abuse in medical settings and to provide referrals that would not routinely be provided. Future studies are planned to establish its efficacy at promoting treatment initiation and abstinence.

Current murine models of sepsis do not account for the effects of aggressive fluid resuscitation on hemodynamics and mortality.Evaluate the impact of fluid resuscitation regimens on cardiovascular performance and survival in a murine model of sepsis.Mice (n = 90) were made septic by cecal ligation and puncture (CLP), and received antibiotics plus Low, Intermediate, or High fluid resuscitation regimens. Stroke volume (SV), cardiac output (CO), and fractional shortening (FS) were measured by echocardiography at predefined time points.Baseline echocardiographic measurements were similar in all groups. After CLP, SV and CO decreased early in all groups; High: 57.2 +/- 9.2 to 23.9 +/- 7.2 microL, and 26.8 +/- 4.9 to 13.1 +/- 5.8 ml/min; Intermediate: 52.1 +/- 7.0 to 21.5 +/- 6.6 microL, and 24.9 +/- 4.1 to 11.9 +/- 3.9 ml/min; Low: 54.0 +/- 7.0 to 20.3 +/- 5.6 microL, and 25.8 +/- 4.0 to 11.3 +/- 3.9 ml/min (P0.05 for all vs. baseline). With resuscitation there was a dose-dependent improvement in SV and CO (P0.05). At 24 h SV and CO were 44.0 +/- 13.8 microL and 20.7 +/- 8.5 ml/min in the High group, 39.8 +/- 12.3 microL and 16.7 +/- 6.5 ml/min in the Intermediate group, and 30.1 +/- 12.4 microL and 14.0 +/- 7.2 ml/min in the Low group. Survival was improved in the High fluid group (75%) compared to the Intermediate (58%) and the Low (35%) resuscitation groups (P0.05).In this model, as in human sepsis, the intensity of fluid resuscitation modulates hemodynamic response and mortality. Incorporation of early and aggressive fluid resuscitation can significantly enhances the clinical relevance of murine models of sepsis.

Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: (1) the central role of the microcirculation in the pathophysiology of sepsis; (2) new translational research techniques of in vivo videomicroscopy for assessment of microcirculatory flow in human subjects; (3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; (4) the potential role of novel agents to "rescue" the microcirculation in sepsis; (5) current challenges facing this emerging field of clinical investigation; and (6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis), and we present the scientific rationale for clinical trials of exogenous nitric oxide administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy.

To determine the utility of an initial serum lactate measurement for identifying high risk of death in patients with infection. Post-hoc analysis of a prospectively compiled registry in an urban academic hospital. Patients with (a) a primary or secondary diagnosis of infection and (b) lactate measurement who were admitted over the 18 months following hospital-wide implementation of the Surviving Sepsis Campaign guideline for lactate measurement in patients with infection and possible severe sepsis. There were 1,177 unique patients, with an in-hospital mortality of 19%. Outcome measures included acute-phase (≤ 3 days) death and in-hospital death. We defined lactate ranges a priori (low, 0.0–2.0; intermediate, 2.1–3.9; high, 4.0 mmol/l or above)—and tested for linear associations with mortality by one-way analysis of variance. We determined sensitivity/specificity, odds ratios, and likelihood ratios for a lactate ≥ 4.0 mmol/l and performed a Bayesian analysis to determine its impact on a full range (0.01–0.99) of hypothetical pretest probability estimates for death. In-hospital mortality was 15%, 25%, and 38% in low, intermediate, and high lactate groups, respectively. Acute-phase deaths and in-hospital deaths increased linearly with lactate. An initial lactate ≥ 4.0 mmol/l was associated with sixfold higher odds of acute-phase death; however, a lactate level less than 4 mmol/l had little impact on probability of death. When broadly implemented in routine practice, measurement of lactate in patients with infection and possible sepsis can affect assessment of mortality risk. Specifically, an initial lactate ≥ 4.0 mmol/l substantiallyincreases the probability of acute-phase death.

Background Physical inactivity and obesity increase the risk for hypertension, and both are more prevalent in African-American than Caucasian women. Regular physical activity serves as an important intervention for reducing cardiovascular risk, yet the ideal physical activity profile to meet the needs of young, sedentary African-American women remains unclear. We performed a randomized, parallel, single-blind study to examine the effect of lifestyle physical activity (LPA) on blood pressure indices in sedentary African-American women aged 18 to 45 years with prehypertension or untreated stage 1 hypertension. Methods The primary intervention was an 8-week individualized, home-based program in which women randomized to Exercise (n = 14) were instructed to engage in lifestyle-compatible physical activity (eg, walking, stair climbing) for 10 minutes, 3 times a day, 5 days a week, at a prescribed heart rate corresponding to an intensity of 50% to 60% heart rate reserve. Women in the No Exercise group (n = 10) continued with their usual daily activities. Mean changes in cuff, ambulatory, and pressure load indices were compared using paired t tests, and physical activity adherence was expressed as percentages. Results Women in the Exercise group had a significant reduction in systolic blood pressure (-6.4 mm Hg, P = .036), a decrease in diastolic blood pressure status to the prehypertensive level (90.8 vs 87.4 mm Hg), and greater reductions in nighttime pressure load compared with the No Exercise group. Adherence to LPA was exceedingly high by all measures (65%-98%) and correlated with change in systolic blood pressure (r = -0.620, P = .024). Conclusion The accumulation of LPA reduced cuff, ambulatory, and pressure load. The accumulation of LPA appears well tolerated and feasible in this sample of young African-American women, demonstrated by the overall high adherence rates. Given the excess burden of pressure-related clinical sequelae among African Americans and the strong correlation between pressure load and target organ damage, LPA may represent a practical and effective strategy in this population.

Depressive disorders have been associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis has not been well described, particularly in women and minorities. The relation between repeated episodes of high depressive symptoms and coronary calcium (CAC) is unknown in women at midlife when depression is common. Participants in the Study of Women's Health Across the Nation Heart study were assessed annually for depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D scale]) over 5 years before CAC assessment and classified as high (CES-D ≥16) or not. CAC, measured by computed tomography, was analyzed as a categorical variable using cumulative logit partial proportional odds models. In these middle-aged women free of CVD and diabetes (194 black, 334 white), high depressive symptoms over 5 years were common; 19% had 1, 9% had 2, and 11% experienced ≥3 episodes. CAC was low; 54% had no CAC, 25% had scores from 0 to 10, and 21% had CAC ≥10 Agatston score. After adjusting for CVD risk factors, women with ≥3 episodes were twice as likely to have significant CAC (≥10 Agatston units) than women with no depressive episodes (odds ratio 2.20, 95% confidence interval 1.13 to 4.28, p = 0.020) with no difference by race. Women with 1 or 2 episodes did not differ from women with no episodes. In conclusion, in healthy women aged 46 to 59 years without clinical CVD or diabetes, persistent depressive symptoms were significantly associated with elevated CAC scores, suggesting that they are more likely to have pathophysiological and behavioral effects on the development of subclinical CVD than does a single episode of elevated depressive symptoms.

This article reviews current concepts about the diagnosis and acute management of postoperative arrhythmias. A systematic approach to diagnosis of arrhythmias and evaluation of predisposing factors is presented, followed by consideration of common bradyarrhythmias and tachyarrhythmias in the postoperative setting. Postoperative arrhythmias are common and represent a major source of morbidity after surgical procedures, both cardiac and noncardiac. Postoperative dysrhythmias are most likely to occur in patients with structural heart disease. The initiating factor for an arrhythmia following surgery is usually a transient insult such as hypoxemia, cardiac ischemia, catecholamine excess, or electrolyte abnormality. Management includes correction of these imbalances and, if clinically indicated, medical therapy directed at the arrhythmia itself.

Purpose The goal of modern therapy of acute myocardial infarction is twofold: to achieve rapid reperfusion of ischemic myocardium and to decrease subsequent remodeling, which can have deleterious effects on ventricular function and prognosis. The current paradigm for treatment of most patients with acute coronary syndromes is the consideration of an 'early invasive' strategy. Recent findings Studies published this year have reinforced the importance of early reperfusion, solidified the evidence for early institution of aggressive adjunctive treatment, and added newer therapies to the existing armamentarium. This review evaluates published data from the past year encompassing advancements in percutaneous coronary intervention, drug-eluting stents, glycoprotein IIb/IIIa antagonists, thienopyridines, HMG-CoA reductase inhibitors, aldosterone blockade, low-molecular-weight heparins, direct thrombin inhibitors, implantable cardioverter-defibrillators, and beta-blockade in the treatment of acute coronary syndrome and ST-segment elevation myocardial infarction. In addition to patency of the epicardial coronary arteries, the role of the microvascular has become an area of recent interest. Summary As novel modalities and approaches are put to the test of clinical trials, evidence-based therapies may help to lessen the adverse effects of myocardial ischemia and reduce future cardiovascular events.

Studies of sepsis in humans are difficult because the seriousness of the disease mandates immediate intervention and because the heterogeneity of patient presentations imposes substantial limitations on clinical trials. Thus, animal models have been used extensively to explore the pathogenesis of sepsis and to generate preclinical data for therapeutic interventions. Translation of findings in these models into therapeutic strategies has been difficult, in part because of limitations in preclinical models and in part to imperfect understanding of the pathophysiology of sepsis. It is important to use an animal model that reproduces the relevant physiologic parameters present in patients with septic shock. Mouse models are particularly useful for the dissection of molecular mechanisms of disease because of the proliferation of transgenic strains. We have developed a murine model of sepsis with fluid resuscitation and antibiotic treatment that reproduces the timing and degree of mortality seen in patients with septic shock. Using continuous micromanometric pressure monitoring and assessment of hemodynamics by echocardiography, we have shown that this model reproduces the hyperdynamic state with hypotension seen in clinical sepsis. The use of transgenic technology in appropriate murine models is exciting because of its potential to permit significant strides in our understanding of the molecular mechanisms of sepsis, multiple organ system failure, and other diseases. The use of reproducible and clinically relevant mouse models of shock is essential for delineation of pathogenetic mechanisms and for initial testing of potential therapeutic strategies.

In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for vasopressor and inotropic support in septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis.The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee.The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591.An arterial catheter should be placed as soon as possible in patients with septic shock. Vasopressors are indicated to maintain mean arterial pressure of65 mm Hg, both during and following adequate fluid resuscitation. Norepinephrine or dopamine are the vasopressors of choice in the treatment of septic shock. Norepinephrine may be combined with dobutamine when cardiac output is being measured. Epinephrine, phenylephrine, and vasopressin are not recommended as first-line agents in the treatment of septic shock. Vasopressin may be considered for salvage therapy. Low-dose dopamine is not recommended for the purpose of renal protection. Dobutamine is recommended as the agent of choice to increase cardiac output but should not be used for the purpose of increasing cardiac output above physiologic levels.

To provide the American College of Critical Care Medicine with updated guidelines for hemodynamic support of adult patients with sepsis.Publications relevant to hemodynamic support of septic patients were obtained from the medical literature, supplemented by the expertise and experience of members of an international task force convened from the membership of the Society of Critical Care Medicine.Both human studies and relevant animal studies were considered.The experts articles reviewed the literature and classified the strength of evidence of human studies according to study design and scientific value. Recommendations were drafted and graded levels based on an evidence-based rating system described in the text. The recommendations were debated, and the task force chairman modified the document until10% of the experts disagreed with the recommendations.An organized approach to the hemodynamic support of sepsis was formulated. The fundamental principle is that clinicians using hemodynamic therapies should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis by monitoring a combination of variables of global and regional perfusion. Using this approach, specific recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic in adult patients were promulgated.

Alveolar epithelial β-adrenergic receptor (βAR) activation accelerates active Na + transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no β 1 - or β 2 -adrenergic receptors (β 1 AR −/− /β 2 AR −/− ) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that βAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with β 1 - but not β 2 -adrenergic receptors to β 1 AR −/− /β 2 AR −/− mice indicates that the β 2 AR mediates the bulk of β-adrenergic-sensitive alveolar active Na + transport. To test the necessity of βAR signaling in acute lung injury, β 1 AR −/− /β 2 AR −/− , β 1 AR +/+ /β 2 AR −/− , and β 1 AR +/+ /β 2 AR +/+ mice were exposed to 100% oxygen for up to 204 hours. β 1 AR −/− /β 2 AR −/− and β 1 AR +/+ /β 2 AR −/− mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of β 2 -adrenergic receptor (β 2 AR) function into the alveolar epithelium of β 1 AR −/− /β 2 AR −/− and β 1 AR +/+ /β 2 AR −/− mice normalized distal lung β 2 AR function, alveolar epithelial active Na + transport, and survival from hyperoxia. These findings indicate that βAR signaling may not be necessary for basal AFC, and that β 2 AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.

Cardiogenic shock complicates about 5% to 8% of all admissions for acute myocardial infarction, and despite advancement in treatment over the past 50 years, mortality remains unacceptably high. Management with vasoactive agents after revascularization can have its limitations and thus mechanical circulatory support is often initiated. Intra-aortic balloon pumps (IABPs) are the devices most commonly used worldwide. IABPs appeared to improve mortality when used along with fibrinolytic therapy but may not when used along with percutaneous coronary interventions. Extracorporeal membrane oxygenation (ECMO) is utilized in the setting of worsening tissue perfusion despite inotropes and IABP utilization. Although retrospective studies show some mortality benefit, randomized prospective studies have not yet demonstrated ECMO to be advantageous either with or without IABP. Percutaneous left ventricular assist devices such as TandemHeart® and Impella are easier to institute than ECMO and are better for hemodynamics compared with the IABP but also have not yet shown a mortality benefit. More randomized studies are needed to define the most appropriate role of the various mechanical support devices in cardiogenic shock.

Postoperative arrhythmias are common and represent a major source of morbidity after both cardiac and noncardiac surgical procedures. Postoperative dysrhythmias are most likely to occur in patients with structural heart disease. The initiating factor for an arrhythmia in a given patient after surgery is usually a transient insult, such as hypoxemia, cardiac ischemia, catecholamine excess, or electrolyte abnormality. Management includes correction of these imbalances and medical therapy directed at the arrhythmia itself. The physiologic impact of arrhythmias depends on arrhythmia duration, ventricular response rate, and underlying cardiac function. Similarly, urgency and type of treatment is determined by the physiologic impact of the arrhythmia, as well as by underlying clinical status. The purpose of this review is to provide current concepts of diagnosis and acute management of arrhythmias after noncardiac surgery. A systematic approach to arrhythmia diagnosis and evaluation of predisposing factors is presented, followed by consideration of specific bradyarrhythmias and tachyarrhythmias in the postoperative setting.

Excess production of nitric oxide (NO) has been implicated in hypotension and blood flow abnormalities in sepsis, but NO is also an important inhibitor of leukocyte rolling and adhesion. Leukocyte adhesion is increased in sepsis despite elevated NO production. We hypothesized that inhibition of NO synthase (NOS) could increase leukocyte adhesion in sepsis.Prospective animal study.Experimental animal laboratory.Twenty-five male rats, anesthetized with ketamine and acepromazine.Topical superfusion of the nonselective NOS inhibitor N(G)-monomethyl-L-arginine (NMA) on skeletal muscle postcapillary venules.Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Leukocyte rolling and adhesion were measured in cremasteric postcapillary venules of septic and control rats using in vivo videomicroscopy. The effects of NOS inhibition on leukocyte rolling and adhesion were also measured. After a stable baseline was reached, 1 microM of the nonselective NOS inhibitor NMA was suffused topically followed by physiologic buffer. The effects of L-arginine on leukocyte rolling and adhesion were also measured, both before and after suffusion of NMA. Leukocyte rolling and adhesion was increased in septic rats as compared with controls (control 5.5+/-0.9 rolling cells/min, 1.0+/-0.3 adherent cells/min; septic 13.7+/-2.0 rolling cells/min, 3.1+/-0.6 adherent cells/min; p.001), and NOS inhibition further increased leukocyte rolling and adhesion in both septic and control rats (control 14.0+/-1.7 rolling cells/min, 2.8+/-0.5 adherent cells/min; septic 25+/-2.1 rolling cells/min, 5.4+/-0.5 adherent cells/min; both p.001 vs. baseline). Prior suffusion of excess L-arginine prevented the increase in leukocyte adhesion with NMA in septic rats (2.6+/-0.4 adherent cells/min vs. 3.0+/-0.6 adherent cells/min; n = 3; p.05). When administered after NMA, excess L-arginine partially reversed leukocyte adhesion in septic rats (5.4+/-0.7 adherent cells/min, with NMA vs. 4.3+/-0.7 adherent cells/min, after L-arginine; n = 5; p.05). Venular shear did not differ between septic and control rats (600+/-109 (sec(-1)) vs. 620+/-37 (sec(-1)); p.05).Although NOS inhibition may ameliorate hypotension in sepsis, such therapy may be deleterious by increasing leukocyte adhesion.

Abstract —Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 μm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) ( P 50 200±56 nmol/L) compared with WT and iNOS-deficient shams (16±4 and 13±6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35±13 nmol/L, P

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.