Alain Rudiger

Mechanisms of sepsis-induced cardiac dysfunction

Objectives:To review mechanisms underlying sepsis-induced cardiac dysfunction in general and intrinsic myocardial depression in particular. Data Source:MEDLINE database. Data Synthesis:Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis. Due to the lack of a generally accepted definition and the absence of large epidemiologic studies, its frequency is uncertain. Echocardiographic studies suggest that 40% to 50% of patients with prolonged septic shock develop myocardial depression, as defined by a reduced ejection fraction. Sepsis-related changes in circulating volume and vessel tone inevitably affect cardiac performance. Although the coronary circulation during sepsis is maintained or even increased, alterations in the microcirculation are likely. Mitochondrial dysfunction, another feature of sepsis-induced organ dysfunction, will also place the cardiomyocytes at risk of adenosine triphosphate depletion. However, clinical studies have demonstrated that myocardial cell death is rare and that cardiac function is fully reversible in survivors. Hence, functional rather than structural changes seem to be responsible for intrinsic myocardial depression during sepsis. The underlying mechanisms include down-regulation of &bgr;-adrenergic receptors, depressed postreceptor signaling pathways, impaired calcium liberation from the sarcoplasmic reticulum, and impaired electromechanical coupling at the myofibrillar level. Most, if not all, of these changes are regulated by cytokines and nitric oxide. Conclusions:Integrative studies are needed to distinguish the hierarchy of the various mechanisms underlying septic cardiac dysfunction. As many of these changes are related to severe inflammation and not to infection per se, a better understanding of septic myocardial dysfunction may be usefully extended to other systemic inflammatory conditions encountered in the critically ill. Myocardial depression may be arguably viewed as an adaptive event by reducing energy expenditure in a situation when energy generation is limited, thereby preventing activation of cell death pathways and allowing the potential for full functional recovery.

Disruption of methylarginine metabolism impairs vascular homeostasis.

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure.

Objective:B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. Design:Prospective, clinical study. Setting:Academic medical intensive care unit (ICU). Patients:A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. Interventions:BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. Measurements and Main Results:We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13–1,300) and 6,526 (198–70,000) ng/L in patients with sepsis and 581 (6–1,300) and 4,300 (126–70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m2 (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. Conclusion:In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis-associated myocardial dysfunction.

Acute heart failure : Clinical presentation, one-year mortality and prognostic factors

Acute heart failure (HF) is a common but ill‐defined clinical entity. We describe patients hospitalised with acute HF in regard of clinical presentation, mortality, and risk factors for an unfavourable outcome.

Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology

Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV‐specific treatment approaches.

Cardioprotection, attenuated systemic inflammation, and survival benefit of β1-adrenoceptor blockade in severe sepsis in rats*

Objective: To explore the hypothesis that beta-1 adrenoreceptor blockade may be protective through the attenuation of sympathetic hyperactivity and catecholaminergic inflammatory effects on cardiac and hepatic function. Design: Prospective, randomized, controlled study. Setting: Animal laboratory in a university medical center. Subjects: Male adult Wistar rats. Interventions: Peripheral &bgr;1-adrenoceptor blockade through daily intraperitoneal injection (metoprolol, 100 mg·kg−1; atenolol, 6 mg·kg−1) or central nervous system &bgr;1-adrenoceptor blockade (intracerebroventricular metoprolol, 25 &mgr;g) to achieve ∼20% heart rate reduction in rats for 2 days before or after the induction of lethal endotoxemia, cecal ligation and puncture, or fecal peritonitis. Measurements and Main Results: Peripheral &bgr;1-adrenoceptor blockade established for 2 days before lethal endotoxemia markedly improved survival in both metoprolol-treated (n = 16; log rank test, p = .002) and atenolol-treated (n = 15; p = .03) rats. Overall mortality in cecal ligation and puncture was similar between metoprolol (40%; n = 10) and saline (50%; n = 10) pretreatment (p = .56), but the median time to death was increased by 33 hrs in metoprolol-treated rats (p = .03). Metoprolol pretreatment reduced hepatic expression of proinflammatory cytokines and lowered plasma interleukin-6 (both p < .05). Myocardial protein expression of interleukin-18 and monocyte chemoattractant protein-1, key mediators of cardiac dysfunction in sepsis, were also reduced (p < .05). Peripheral &bgr;1-adrenoceptor blockade commenced 6 hrs after lethal endotoxemia or fecal peritonitis did not improve survival. However, arterial blood pressure was preserved and left ventricular contractility restored similar to that found in nonseptic controls. Central nervous system &bgr;1-adrenoceptor blockade (metoprolol) did not reduce plasma cytokines or mortality, despite enhancing parasympathetic tone. Conclusions: Peripheral &bgr;1-adrenoceptor blockade offers anti-inflammatory and cardioprotective effects, with mortality reduction if commenced before a septic insult. Its role in sepsis should be explored further.

Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Experimental studies in a rat model of fecal peritonitis conducted by Michael Bauer and colleagues show that in this model, changes in liver function occur early in the development of sepsis, with potential implications for prognosis and development of new therapeutic approaches.

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.

Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

IntroductionLactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication.MethodsMulticentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 ± 0.20; lactate 18 ± 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available.ResultsOn day 1, VO2 was markedly depressed (67 ± 28 ml/min/m2) despite a normal CI (3.4 ± 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 ± 1.0 ml O2/100 ml) or without (2.5 ± 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32).ConclusionsVO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.

Transpulmonary thermodilution-derived cardiac function index identifies cardiac dysfunction in acute heart failure and septic patients: an observational study

IntroductionThere is limited clinical experience with the single-indicator transpulmonary thermodilution (pulse contour cardiac output, or PiCCO) technique in critically ill medical patients, particularly in those with acute heart failure (AHF). Therefore, we compared the cardiac function of patients with AHF or sepsis using the pulmonary artery catheter (PAC) and the PiCCO technology.MethodsThis retrospective observational study was conducted in the medical intensive care unit of a university hospital. Twelve patients with AHF and nine patients with severe sepsis or septic shock had four simultaneous hemodynamic measurements by PAC and PiCCO during a 24-hour observation period. Comparisons between groups were made with the use of the Mann-Whitney U test. Including all measurements, correlations between data pairs were established using linear regression analysis and are expressed as the square of Pearsons correlation coefficients (r2).ResultsCompared to septic patients, AHF patients had a significantly lower cardiac index, cardiac function index (CFI), global ejection fraction, mixed venous oxygen saturation (SmvO2) and pulmonary vascular permeability index, but higher pulmonary artery occlusion pressure. All patients with a CFI less than 4.5 per minute had an SmvO2 not greater than 70%. In both groups, the CFI correlated with the left ventricular stroke work index (sepsis: r2 = 0.30, P < 0.05; AHF: r2 = 0.23, P < 0.05) and cardiac power (sepsis: r2 = 0.39, P < 0.05; AHF: r2 = 0.45, P < 0.05).ConclusionsIn critically ill medical patients, assessment of cardiac function using transpulmonary thermodilution technique is an alternative to the PAC. A low CFI identifies cardiac dysfunction in both AHF and septic patients.