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Right ventricular (RV) dysfunction is a commonly considered cause of a low cardiac output in critically ill patients. Its management can be difficult and requires an understanding of how the RV limits cardiac output. We explain that RV stroke output is caught between the passive elastance of the RV walls during diastolic filling and the active elastance produced by the RV in systole. These two elastances limit RV filling and stroke volume, and consequently limit left ventricular (LV) stroke volume. We emphasize use of the term RV limitation and argue that limitation of RV filling is the primary pathophysiological process by which the RV causes hemodynamic instability. Importantly, RV limitation even can be present when RV function is normal. We use the term RV dysfunction to indicate that RV end-systolic elastance is depressed or diastolic elastance is increased. When RV dysfunction is present, RV limitation occurs at lower pulmonary valve opening pressures and lower stroke volume, but stroke volume and cardiac output still can be maintained until there RV filling i limited. We use the term RV failure to indicate the condition in which RV output is insufficient for tissue needs. We discuss the physiological underpinnings of these terms and implications for clinical management.

The hydrogen ion concentration ([H+]) in intracellular cytoplasmic fluid (ICF) must be maintained in a narrow range in all species for normal protein functions. Thus, mechanisms regulating ICF are of fundamental biological importance. Studies on the regulation of ICF [H+] have been hampered by use of pH notation, failure to consider the roles played by differences in the concentration of strong ions (strong ion difference, SID), the conservation of mass, the principle of electrical neutrality, and that [H+] and bicarbonate ions [HCO3−] are dependent variables. This argument is based on the late Peter Stewart’s physical–chemical analysis of [H+] regulation reported in this journal nearly forty years ago (Stewart. 1983. Can. J. Physiol. Pharmacol. 61: 1444–1461. Doi: 10.1139/y83-207 ). We start by outlining the principles of Stewart’s analysis and then provide a general understanding of its significance for regulation of ICF [H+]. The system may initially appear complex, but it becomes evident that changes in SID dominate regulation of [H+]. The primary strong ions are Na+, K+, and Cl−, and a few organic strong anions. The second independent variable, partial pressure of carbon dioxide (PCO2), can easily be assessed. The third independent variable, the activity of intracellular weak acids ([Atot]), is much more complex but largely plays a modifying role. Attention to these principles will potentially provide new insights into ICF pH regulation.

Purpose Reduction of right ventricular (RV) function after cardiac surgery has been shown to impact outcomes. Conventional indices for right ventricular dysfunction are validated using transthoracic echocardiogram (TTE) which has limited use compared to transesophageal echocardiogram (TEE) in the perioperative settings. The aim of this study was to assess the agreement of RV systolic function assessment with TEE compared to TTE and assess the association of echocardiographic parameter with hemodynamic indices of RV dysfunction. Method This was a single center prospective observational study in an academic institution. Fifty adult patients undergoing elective cardiac surgery were included. TTE, TEE and stroke volume measurements pre-cardiopulmonary bypass (CPB) and post-CPB were performed. The variables of interest were anatomical M-mode tricuspid annular plane systolic excursion (AMM-TAPSE), fractional area change (FAC), tricuspid annular velocity (S’) and myocardial performance index (MPI). Results FAC and AMM-TAPSE measured at the mid-esophageal 4 chamber view had substantial agreement with the TTE acquired parameters (Lin’s concordance correlation coefficient (CCC) = 0.76, 95%CI 0.59-0.86 and CCC = 0.85, 95%CI 0.76-0.91). S’ was significantly underestimated by TEE (CCC = 0.07, 95%CI -0.04-0.19) and MPI showed moderate agreement (CCC = 0.45 95%CI 0.19-0.65). Despite the significant changes in echocardiographic parameters, there were no corresponding changes in stroke volume (SV) or pulmonary artery pulsatility index at the post-CPB period. Conclusions TEE acquired FAC and AMM-TAPSE had substantial agreement with pre-operative TTE values and no significant differences between the pre-CPB and post-CPB period. Systolic RV echocardiographic parameters decreased post-CPB but this was not accompanied by significant hemodynamic changes.

This chapter uses an analytic approach to the factors limiting maximal aerobic exercise. A person’s maximal aerobic work is determined by their maximal oxygen consumption (VO2max). Cardiac output is the dominant determinant of VO2 and thus the primary determinant of population differences in VO2max. Furthermore, cardiac output is the product of heart rate and stroke volume and maximum heart rate is determined solely by a person’s age. Thus, maximum stroke volume is the major factor for physiological differences in aerobic performance. Stroke output must be matched by stroke volume return, which is determined by the mechanical properties of the systemic circulation. These are primarily the compliances of each vascular region and the resistances between them. I first discuss the physiological principles controlling cardiac output and venous return. Emphasis is placed on the importance of the distribution of blood flow between the parallel compliances of muscle and splanchnic beds as described by August Krogh in 1912. I then present observations from a computational modeling study on the mechanical factors that must change to reach known maximum cardiac outputs during aerobic exercise. A key element that comes out of the analysis is the role of the muscle pump in achieving high cardiac outputs.

Function of the right ventricle (RV) often is underappreciated because it produces such a small force compared to the left ventricle (LV). It also has a more complex shape and it is harder to image on echocardiography than the LV. These traits make it more difficult to evaluate. However, in the steady state, the RV must put out the same volume per minute as the LV, and the LV only can pump out what the RV gives it. Unlike the LV, which has the primary role of creating normal systolic pressure in the 120 mmHg range, the primary role of the RV is to keep right atrial pressure low and allow the return of blood from its upstream venous reservoir. The RV also has evolved to pump blood through a low resistance which allows for low pulmonary arterial pressures that protect the delicate alveoli. The limit of diastolic filling of the RV sets the limit of the stroke volume for the heart as a whole. This limit of RV filling often becomes an important factor in the management of critically ill patients.

Changes in heart rate are a major regulator of normal cardiac output, and thus a key component of adaptations in the cardiovascular system. The direct regulation of heart rate at the cellular level has evolved with a complex system of processes that regulate the currents across the cardiac membranes. These set spontaneous cyclic activation and lengths of the action potential which determine the lengths of systole and diastole. This cyclic nature of cardiac output creates important limitations on the circulation because it sets the time available for filling and the time available for ejection. These limits affect the maximum possible outputs from the heart and can lead to pathological processes. Heart rate is regulated by intrinsic processes in the membranes of the pacemaker of the heart (sinoatrial node), the conducting system of the heart, and neural and humoral regulating factors. Heart rate normally increases in proportion to what is called the relative workload but also can be altered by many factors not directly related to metabolic needs. The interplay of all these factors need to be considered by critical care physicians managing patients at the bedside.

The general cause of sepsis is by definition known. Sepsis is the body’s response to an invading pathogen. The basic pathological problem also is evident and that is an inability for bodily systems to maintain normal oxidative metabolism either because of a failure to adequately deliver the oxygen or to use it. However, the specific physiological mechanisms that cause these failures still are not well understood. This chapter begins with a description of the basic phenomenology of the sepsis syndrome. The discussion is largely based on controlled studies in healthy humans and septic animal models. The physiological processes that must be occurring to account for the hemodynamics observed in patients are then analyzed. Next, current theoretical explanations of what processes are occurring at the cellular level are reviewed. This chapter emphasizes the early stages of vascular collapse in sepsis. An underlying hypothesis is that early stabilization of tissue perfusion can prevent the vicious cycle produced by ongoing tissue damage. The therapeutic choices for managing the septic patient are covered in Part B.

All living organisms have tight regulation of the concentration of hydrogen ion ([H+]), or in its more familiar form, pH. This is necessary because of the unique effect of densely charged H+ ion on all structures of water-based solution which is the basic solvent for living organisms. We will mostly use the term [H+] in this chapter because it emphasizes its very low concentration relative to other elements in biological solutions. It also behaves fairly linearly in biological solutions. Assessment of [H+] has traditionally been done by considering [H+] and bicarbonate (HCO3−) as independent variables and their relationship to the partial pressure of carbon dioxide (PCO2). This relationship can be used to describe the changes in [H+] in biological solutions with the help of some empiric equations, and it is part of the approach presented in this chapter. However, it does not explain the physical–chemical processes involved and thus does not give a pathophysiological understanding. A proper physical–chemical analysis requires understanding the role of the true three independent variables. These are the difference in concentrations between strong positive and strong negative ions, which is called the strong ion difference ([SID]), PCO2, and the concentration of weak acids. These three factors determine the [H+] and [HCO3−] which are actually dependent variables. When combined with measurement of base excess, assessment of these three factors can be readily used to determine the mechanisms of altered pH in biological based solutions.

This chapter examines a cornerstone of critical care medicine: the measurement and monitoring of cardiac output (CO). A key focus is placed on the relevance of CO and clinical decision-making in intensive care setting. The concepts of normalization of CO to body size and fundamentals such as the Fick principle are discussed. Expanding upon these core concepts, indicator dilution methods and thermodilution techniques with their general concepts and sources of variability are explored and applied to clinical practice. The indirect Fick method is then outlined and its clinical applications. With the evolution of critical care medicine, emphasis has been placed on ability to measure CO by using a minimally invasive approach. Pulse contour analysis and the technology available to monitor CO such as Vigileo-FloTrac system, LiDCO plus system, and PiCCO system are reviewed; their clinical relevance is outlined. Echocardiographic techniques (transesophageal and transthoracic) of estimating CO have been described. The chapter concludes with analysis of methods to assess changes in thoracic volume and their relation to CO: thoracic bioimpedance and thoracocardiography.

Use of mechanical devices to support the heart and circulation in patients in cardiogenic shock is increasing. Dramatic results have been seen in patients in extremis, but observational cohort studies, as well as randomized trials, have not shown long-term outcome benefits to date. This is partly because the studies have been inadequately powered, but also because it still is not clear on how best to use these devices, when to use them, and in whom. This chapter will emphasize the physiological implications of the current clinical approaches. There are four basic strategies with these devices. The oldest approach is reduction of left ventricular (LV) afterload and augmentation of coronary perfusion with an intra-aortic balloon (IABP) pump. The second is to improve LV emptying by pumping blood forward; the pump can be inserted percutaneously or surgically directly onto the LV. The third is to withdraw blood from the left atrium and return it to the aorta. The fourth is to totally bypass the heart and lungs with the use of extracorporeal mechanical membrane oxygenation (ECMO). Each of these approaches has its own physiological implications and limitations, which govern their effective application. Finally, the right ventricular (RV) limitation and dysfunction add another important component to management decisions because the left side only can pump out what the right side gives it, and when filling of the RV is limited, a left-sided device cannot increase forward flow unless it relieves the right-sided limitation.

We begin this introduction to Cardiopulmonary Monitoring: Basic Physiology, Tools, and Bedside Management with a statement of bias. We love physiology. It is why we are intensivists. Physiology is at the core of our approach to management of our critically ill patients, and managing critically ill patients provides continuous feedback for our understanding of physiological processes. It is for this reason that physiological considerations are the central part of this book.

Shock is a state in which cardiac output is inadequate for tissue needs. In cardiogenic shock, the primary problem most often is failure of the left ventricle (LV) to adequately pump out returning blood. The majority of cases are associated with acute myocardial ischemia. Outcomes from cardiogenic shock have been improved by early aggressive therapy and, in particular, early revascularization procedures. However, as people live longer, and with many chronic conditions, non-acute acute ischemic causes of cardiogenic shock are increasing and require different therapeutic approaches. This chapter will review the epidemiology and classification of patients with cardiogenic shock. It emphasizes the physiological process involved in the failure of the LV to provide adequate flow to tissues and how best to deal with this disordered physiology. Key underlying principles are that flow to the tissues is what counts and not arterial pressure, the heart only can pump out what it gets back, and, unfortunately, there are only a limited numbers of ways to maintain organ function in cardiogenic shock. It also needs to be emphasized that earlier identification and treatment of shock can improve outcome. Cardiogenic shock continues to have a high mortality. Hopefully, a deeper understanding of the disordered process and what is physiologically achievable will help improve outcomes.

A critical step when monitoring cardiopulmonary interactions is ensuring that measured values are accurate and precise. This chapter deals with vascular pressure measurements. These are more prone to measurement errors than respiratory pressure measurements because gas measurements are not influenced by the force of gravity. With current technologies, vascular pressures can be measured with great precision, but the “blind box” of electronic monitors also can result in artifactual values that seemingly look real. Primary goals of vascular pressure measurements are to determine the force distending vessel walls because this gives an indication of the effective volume in the system and, second, the pressure difference between compartments because this determines blood flow. When using standard fluid-filled catheters as part of the measuring system, three factors always must be considered: zeroing, leveling, and calibrating. Changes in the intrathoracic pressure surrounding the heart and blood vessels in the chest add another element that can lead to faulty interpretations of the pressures in this region. The goal of this chapter is to review these principles and to indicate some important common errors in measurement.

The primary problem in sepsis is the invasion of the body by an infecting agent. Thus, the primary therapy needs to be directed at dealing with clearing the infection by use of antimicrobial agents and source control. However, at the onset of the syndrome, patients often present with life threatening failure of the cardiac and respiratory systems and require immediate support. It has become increasingly evident that the rapid onset of support improves outcomes. Loss of stressed vascular volume because of loss of vascular tone or because of increased capillary filtration need to be dealt with urgently with volume resuscitation. Early use of vasopressors, particularly norepinephrine, is important for restoring vascular tone and improving cardiac function. Adequate oxygenation needs to be maintained and there should be a low threshold for the use of mechanical ventilation because of the consequences of respiratory distress on the vascular system and because respiratory failure can occur quickly. The further details of the acute management of the patient in septic shock are the subject to this chapter.

Respiratory muscles are an important link between the cardiovascular and the respiratory systems. The circulation needs to supply the respiratory muscle with the blood flow that delivers O2 and other nutrients to the tissues and removes wastes. On the other hand, respiratory muscles are necessary to maintain ventilation, which provides the blood with O2 and clears the CO2 which are essential for cardiac function as well as the tissues of the rest of the body. The interaction between these two systems becomes important in the critically ill patient because failure of the cardiovascular system can limit blood flow to the working respiratory muscles and cause them to fail, and failure of the respiratory system leads to inadequate oxygenation and CO2 clearance and results in cardiac failure. Patterns of breathing, as well as afferent signals from the respiratory muscles, also can alter cardiovascular function. These interactions are reviewed in this chapter.

The heart sits between the lungs and blood must pass from the right heart to the left heart by traversing the lungs. Thus, interactions between the heart and lungs are a central part of managing critically ill patients. This becomes especially important when patients are mechanically ventilated because “nonphysiological” actions are added to the normal state. This chapter reviews key elements of these interactions and the implications for patient management. The primary principles are that the interactions are largely based on the actions of ventilation changing the environment (i.e., reference system) of the heart relative to the rest of body so that the actions of the cardiac function and return function are dissociated. The primary factor is the change in pleural pressure and its effect on right heart filling and left heart emptying. A second major factor is the creation of non-zone III conditions in the lung and its effect on right heart ejection. Factors on the cardiac side include volume status, heart rate, systemic blood pressure, and the contractile states of both the right and left ventricles.

Proper use of fluids requires consideration of the basic physiology of fluids in the body. This includes consideration of the following questions. What does water do? What is the importance of elements such as Na+, Cl−, and K+ in bodily solutions? What determines how water and electrolytes distribute between the plasma space, interstitial space, and intracellular space? What is the role of colloids, and in particular, albumin? What happens when different types of fluids are infused intravenously? This chapter emphasizes the physiological role of fluids, principles behind the movement and distribution of water and it solutes, and the characteristics of different kinds of commonly infused fluids.

Blood pressure is one of the most commonly monitored values in managing critically ill and non-critically ill patients. In the critically ill it is the major value used by clinicians to adjust fluid use, inotropic, and vasopressor therapy. Proper use of blood pressure measurements requires first an understanding of factors that affect the reliability of what actually is measured. Next, one needs to understand the physics that determine the measured values; this includes the role of elastic, kinetic, and gravitational energy. Finally, it is important to understand the role of arterial pressure and how this relates to the distribution of resistances with the consequent distribution of flow. A paradoxical basic point that needs to be emphasized is that pressure does not indicate flow, but rather the total cardiac output and resistances determined the arterial pressure. However, regional flows depend upon the arterial pressure, the local resistance, and how that local resistance relates to resistances in other vascular beds. Finally, normal organ function ultimately depends upon adequate blood flow and not pressure.

The volume contained in the circulation stretches the elastic walls of all of its components and creates a pressure that exist even without a beating heart. Only a proportion of the total blood volume produces pressure; that volume is called stressed volume and the pressure it produces is called mean circulatory filling pressure (MCFP). The rest of the blood volume just wrinkles the vessels but does not produce a pressure and is called unstressed volume. Under steady state conditions, stressed volume and MCFP are constant. When the system is opened to the surrounding atmospheric pressure, MCFP can transiently create flow without cardiac contractions. Volume in the circulation is distributed based on the elastance (or its inverse, compliance) of each compartment. The heart acts by rhythmically increasing its elastance. On each beat, this displaces a volume bolus into the rest of the circulation. However, in the steady state, the same volume must return to the heart during diastole so that only the equivalent of stroke volume is added per beat to the circulation. The distribution of volume under flow conditions is determined by pressure-flow and pressure-volume characteristics of the each compartment. The steady state cardiac output is determined by the interaction of a function that determines the emptying of the heart, that is, Starling’s law, and a function that determines the return of blood to heart, that is, Guyton’s venous return function. Directional changes in cardiac output and right atrial pressure at the intersection of the two functions can be used to infer a dominant change in cardiac function, return function, or both. Finally, the limits of function and return function determine the limits of how much blood can flow around the circulation.

Unlike organic electrolytes, elements in the blood, such as sodium (Na+) and chloride (Cl−), cannot be metabolized and their concentrations thus are dependent upon absorption and excretion. The concentration of Cl− is on average 40 meq/L less than the concentration of Na+ and this is an important determinant of hydrogen ion (H+) concentration in blood (i.e., pH). Increasing Cl− concentration produces acidemia and potentially affects renal, gastrointestinal, immune, and coagulation functions. There, thus, has been increasing interest in the use of intravenous solutions that have lower Cl− concentrations. These solutions require anions besides Cl− to “balance” the charge from Na+. The major anions are bicarbonate, lactate, acetate, and gluconate. The physiological actions of these electrolytes have been well described but the evidence of a clinical benefit is very limited. Three large observational studies demonstrated potential benefits of low Cl− solutions on renal function. There also has been suggestions of benefits for hospital survival and reduction of infections. This was not supported by the recent only reasonable-sized randomized clinical trial to test causality. However, the amount of fluid given was not large and the population was generally at low risk, thus limiting the power of the study to detect harm. Thus, the question remains unanswered in patients who are at higher risk. It is unlikely that a pragmatic trial will be helpful and future studies will need to target subjects who are expected to receive large volumes of resuscitations fluid and who have risk factors that may make them less able to handle large Cl− loads, such as diabetics, subjects with large extracellular volume, recent intravenous contrast, periods of hypotension, and use of catecholamines. More specific endpoints besides renal function also need to be considered such as gastrointestinal function, rate of infections, red cell survival, and coagulation. Based on current evidence, survival studies would likely require very large sample sizes with subjects at increased risk.

Based primarily on the rational that adequate diastolic pressure is needed to maintain sufficient coronary blood for myocardial needs, diastolic pressure has been proposed as a treatment target for patients in shock. To date, clinical evidence supporting this is limited to observational data. Key points are that what is important for tissues is flow not pressure; the coronary circulation has very large flow reserves and can maintain flow with a low pressure; raising arterial pressure by only increasing vascular resistance does not alter tissue perfusion and could even increase myocardial oxygen demand. Targeting diastolic pressure can lead to over use of vasopressors, which studies have associated with worse outcome. Pressor management in shock should include assessment of indicators of tissue perfusion and changes in flow if possible.

Endocardial endothelial cells (EECs) constitute an important component of the heart. These cells form a monolayer that covers the cavities of the right (EECRs) and left (EECLs) ventricles. They play an important role in cardiac excitation–contraction coupling via their secretion of cardioactive factors such as neuropeptide Y (NPY). They also contribute to cardiac pathology such as arrhythmia, hypertrophy, and heart failure. Differences between EECRs and EECLs contribute to tuning of circulating factors at the entry and exit of the ventricles. NPY, via activation of its receptors, modulates the excitation–secretion coupling of EECs, thus, indirectly modulating cardiac function and remodeling.

To analyze mechanical adaptations that must occur in the cardiovascular system to reach the high cardiac outputs known to occur at peak aerobic performance, we adapted a computational model of the circulation by adding a second parallel venous compartment as proposed by August Krogh in 1912. One venous compartment has a large compliance and slow time constant of emptying; it is representative of the splanchnic circulation. The other has a low compliance and fast time constant of emptying and is representative of muscle beds. Fractional distribution between the two compartments is an important determinant of cardiac output. Parameters in the model were based on values from animal and human studies normalized to a 70 kg male. The baseline cardiac output was set at 5 L/min, and we aimed for 25 L/min at peak exercise with a fractional flow to the peripheral-muscle region of 90%. Finally, we added the equivalent of a muscle pump. Adjustments in circuit and cardiac parameters alone increased cardiac output to only 15.6 L/min because volume accumulated in the muscle compartment and limited a higher cardiac output. Addition of muscle contractions decompressed the muscle region and allowed cardiac output to increase to 23.4 L/min. The pulsatility of blood flow imposes important constraints on the adaptations of cardiac and circulatory functions because it fixes the times for filling and emptying. Flow is further limited by the limits of cardiac filling on each beat. Muscle contractions play a key role by decompressing volume that would otherwise accumulate in the muscle vasculature and by decreasing the time for stroke return to the right ventricle. NEW & NOTEWORTHY We used a computational model of the circulation and previous human and animal data to model mechanical changes in the heart and circulation that are needed to reach the known high cardiac output at peak aerobic exercise. Key points are that time constants of drainage of circulatory compartments put limits on peak flow in a pulsatile system. Muscle contractions increase the rate of return to the heart and by doing so prevent accumulation of volume in the muscle compartment and greatly increase circulatory capacity.

CVP represents the equilibrium value of the cardiac function and return functions in the circulation. Thus, changes in CVP give an indication of the status of these two determinants of overall blood flow. This chapter reviews the physiology behind this statement, critical factors for making the measurement, and potential pitfalls with the use of the CVP. An approach is presented that can be used to combine measurements of CVP with measurements of cardiac output or surrogates of blood flow to guide treatment options in patients with depressed circulatory function.

In shock, hypotension may contribute to inadequate oxygen delivery, organ failure and death. We conducted the Optimal Vasopressor Titration (OVATION) pilot trial to inform the design of a larger trial examining the effect of lower versus higher mean arterial pressure (MAP) targets for vasopressor therapy in shock. We randomly assigned critically ill patients who were presumed to suffer from vasodilatory shock regardless of admission diagnosis to a lower (60–65 mmHg) versus a higher (75–80 mmHg) MAP target. The primary objective was to measure the separation in MAP between groups. We also recorded days with protocol deviations, enrolment rate, cardiac arrhythmias and mortality for prespecified subgroups. A total of 118 patients were enrolled from 11 centres (2.3 patients/site/month of screening). The between-group separation in MAP was 9 mmHg (95 % CI 7–11). In the lower and higher MAP groups, we observed deviations on 12 versus 8 % of all days on vasopressors (p = 0.059). Risks of cardiac arrhythmias (20 versus 36 %, p = 0.07) and hospital mortality (30 versus 33 %, p = 0.84) were not different between lower and higher MAP arms. Among patients aged 75 years or older, a lower MAP target was associated with reduced hospital mortality (13 versus 60 %, p = 0.03) but not in younger patients. This pilot study supports the feasibility of a large trial comparing lower versus higher MAP targets for shock. Further research may help delineate the reasons for vasopressor dosing in excess of prescribed targets and how individual patient characteristics modify the response to vasopressor therapy.

Following national and regional recommendations, intravenous lipid emulsion (ILE) has become established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, although evidence of efficacy is limited to animal studies and human case reports. A collaborative lipid emulsion workgroup was therefore established by the American Academy of Clinical Toxicology to review the evidence on the effect of ILE for LA toxicity.We performed a systematic review of the literature published through 15 December 2014. Relevant articles were determined based on pre-defined inclusion and exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity and studies that did not address antidotal use of ILE were excluded.We included 113 studies and reports. Of these, 76 were human and 38 animal studies. One publication included both a human case report and an animal study. Human studies included one randomized controlled crossover trial involving 16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILE versus saline. There was one case series and 73 case reports of ILE use in the context of toxicity (83 patients) including CNS depression or agitation (n = 45, 54%), seizures (n = 49, 59%), hypotension, hypertension, EKG changes, arrhythmias (n = 39, 47%), cardiac arrest (n = 18, 22%), cardiopulmonary resuscitation, and/or requirement for endotracheal intubation and/or mechanical ventilation (n = 35, 42%). There were 81 (98%) survivors including 63 (76%) with no reported sequelae from the LA poisoning or ILE, although the presence or absence of sequelae was not reported in 15 (18%) cases. Animal studies included 29 randomized controlled studies, three observational studies, five case series, and one case report; bupivacaine was used in 29 of these reports (76%). Of 14 controlled experiments in animals, eight showed improved survival or time to return of spontaneous circulation and five no benefit of ILE versus saline or non-ILE treatments. Combining ILE with epinephrine improved survival in five of the six controlled animal experiments that studied this intervention. The studies were heterogeneous in the formulations and doses of ILE used as well as the doses of LA. The body of the literature identified by this systematic review yielded only a very low quality of evidence.ILE appears to be effective for reversal of cardiovascular or neurological features in some cases of LA toxicity, but there is currently no convincing evidence showing that ILE is more effective than vasopressors or to indicate which treatment should be instituted as first line therapy in severe LA toxicity.

Our recent work showed that neuropeptide Y-induced secretion of endothelin-1 (ET-1) in left and right human ventricular endocardial endothelial cells (hLEECs or hREECs respectively) via the activation of neuropeptide Y2 or Y5 receptors depending on the cell type. The aim of this study was to verify whether hLEECs or hREECs secretion of ET-1 induced by NPY is due, in part, to the activation of ETA and/or ETB receptors by the secreted ET-1. Using the technique of indirect immunofluorescence coupled to real 3-D confocal microscopy, as well as ELISA, our results show that in hREECs, the NPY-induced release of ET-1 seems to be due, in part, to the activation of both ETA and ETB receptors. On the other hand, in hLEECs, ETA and ETB receptors do not contribute to the ET-1 released by NPY. Therefore, our results suggest that the NPY-induced release of ET-1 in EECRs is due to NPY receptor activation and the subsequent activation of the ETA and ETB receptors by the released ET-1. However, the release of ET-1 by NPY in hLEECs is mainly due to NPY receptor activation. Furthermore, this secretory process of ET-1 is different between the right and left ventricular cells and highlights the important tuning roles that right and left ventricular EECs possess as well as their contribution to the physiological and pathophysiological states of the underlying heart muscle.

Measurement of arterial pressure is one of the most basic elements of patient management. Arterial pressure is determined by the volume ejected by the heart into the arteries, the elastance of the walls of the arteries, and the rate at which the blood flows out of the arteries. This review will discuss the three forces that determine the pressure in a vessel: elastic, kinetic, and gravitational energy. Emphasis will be placed on the importance of the distribution of arterial resistances, the elastance of the walls of the large vessels, and critical closing pressures in small arteries and arterioles. Regulation of arterial pressure occurs through changes in cardiac output and changes in vascular resistance, but these two controlled variables can sometimes be in conflict.

INTRODUCTION: This is a state-of-the-art article of the diagnostic process, etiologies and management of acute right ventricular (RV) failure in critically ill patients. It is based on a large review of previously published articles in the field, as well as the expertise of the authors.RESULTS: The authors propose the ten key points and directions for future research in the field. RV failure (RVF) is frequent in the ICU, magnified by the frequent need for positive pressure ventilation. While no universal definition of RVF is accepted, we propose that RVF may be defined as a state in which the right ventricle is unable to meet the demands for blood flow without excessive use of the Frank-Starling mechanism (i.e. increase in stroke volume associated with increased preload). Both echocardiography and hemodynamic monitoring play a central role in the evaluation of RVF in the ICU. Management of RVF includes treatment of the causes, respiratory optimization and hemodynamic support. The administration of fluids is potentially deleterious and unlikely to lead to improvement in cardiac output in the majority of cases. Vasopressors are needed in the setting of shock to restore the systemic pressure and avoid RV ischemia; inotropic drug or inodilator therapies may also be needed. In the most severe cases, recent mechanical circulatory support devices are proposed to unload the RV and improve organ perfusion CONCLUSION: RV function evaluation is key in the critically-ill patients for hemodynamic management, as fluid optimization, vasopressor strategy and respiratory support. RV failure may be diagnosed by the association of different devices and parameters, while echocardiography is crucial.

The incidence of delayed graft function in patients undergoing kidney transplantation remains significant. Optimal fluid therapy has been shown to decrease delayed graft function after renal transplantation. Traditionally, the perioperative volume infusion regimen in this patient population has been guided by central venous pressure as an estimation of the patient’s volume status and mean arterial pressure, but this is based on sparse evidence from mostly retrospective observational studies. Excessive volume infusion to the point of no further fluid responsiveness can damage the endothelial glycocalyx and is no longer considered to be the best approach. However, achievement of adequate flow to maintain sufficient tissue perfusion without maximization of cardiac filling remains a challenge. Novel minimally invasive technologies seem to reliably assess volume responsiveness, heart function and perfusion adequacy. Prospective comparative clinical studies are required to better understand the use of dynamic analyses of flow parameters for adequate fluid management in kidney transplant recipients. We review perioperative fluid assessment techniques and discuss conventional and novel monitoring strategies in the kidney transplant recipient.

Critical care physicians frequently try to manipulate the preload of the heart to optimize cardiac function. There is, however, still debate as to what actually indicates the preload of the heart.Although central venous pressure (CVP) is commonly used to estimate cardiac filling, it is often argued that it is a poor indicator of preload. This is likely true if one does not understand what preload is, principles of measurement with fluid filled systems, the effect of respiratory efforts on the measurement, the physiological determinants of CVP, and finally which point on the tracing to use as the estimate of the preload of the heart. When these are considered, however, the value of the CVP at the base of the 'c' wave gives a good indication of cardiac preload and a value which can be followed.When properly measured CVP can be a useful guide to the filling status of the right ventricle. CVP is especially useful when followed over time and combined with a measurement of cardiac output. Importantly, preload is only one of the factors determining cardiac output and it must be integrated into a comprehensive approach that takes into account changes in cardiac function and the return of blood to the heart. Finally, the specific value of preload does not indicate volume responsiveness.

Sepsis is associated with an increase in reactive oxygen species (ROS), however, the precise role of ROS in the septic process remains unknown. We hypothesized that treatment with EUK-134 (manganese-3-methoxy N,N'-bis(salicyclidene)ethylene-diamine chloride), a compound with superoxide dismutase and catalase activity, attenuates the vascular manifestations of sepsis in vivo. Pigs were instrumented to measure cardiac output and blood flow in renal, superior mesenteric and femoral arteries, and portal vein. Animals were treated with saline (control), lipopolysaccharide (LPS, 10 µg·kg−1·h−1), EUK-134, or EUK-134 plus LPS. Results show that an LPS-induced increase in pulmonary artery pressure (PAP) as well as a trend towards lower blood pressure (BP) were both attenuated by EUK-134. Renal blood flow decreased with LPS whereas superior mesenteric, portal and femoral flows did not change. Importantly, EUK-134 decreased the LPS-induced fall in renal blood flow and this was associated with a corresponding decrease in LPS-induced protein nitrotyrosinylation in the kidney. PO2, pH, base excess and systemic vascular resistance fell with LPS and were unaltered by EUK-134. EUK-134 also had no effect on LPS-associated increase in CO. Interestingly, EUK-134 alone resulted in higher CO, BP, PAP, mean circulatory filling pressure, and portal flow than controls. Taken together, these data support a protective role for EUK-134 in the renal circulation in sepsis.

The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2–4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 μg) QD via Respimat®, formoterol 12 μg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 μg, 883 received olodaterol 10 μg, 885 received placebos, and 460 received formoterol 12 μg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 μg (marketed and registered dose) and 10 μg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.