Severe sepsis and septic shock are among the most important causes of morbidity and mortality in patients admitted to the intensive care unit. The purpose of this review is to review current ...understanding of sepsis-induced cardiac dysfunction and discuss pertinent findings regarding its clinical presentation, underlying mechanisms of disease, and therapy.
Cardiac dysfunction in sepsis is characterized by decreased contractility, impaired ventricular response to fluid therapy, and in some patients ventricular dilatation. Current data support a complex underlying physiopathology with a host of potential pathways leading to myocardial depression. Circulating factors such as cytokines (TNF-alpha, IL-1beta), lysozyme c, endothelin-1 have direct inhibitory actions on myocyte contractility. Nitric oxide has a complex role in sepsis-induced cardiac dysfunction. Current data suggest a combination of deleterious and positive effects on the myocardium determined by the specific type of nitric oxide expressed. Recent studies have shown that mitochondrial dysfunction and apoptosis also play a role in the development of sepsis-induced cardiac dysfunction. Current treatment for sepsis-induced cardiac dysfunction is based on appropriate treatment for the infectious focus (antibiotics and source control) and hemodynamic support (fluids, vasopressors, and inotropes).
Cardiac dysfunction is common in patients with severe sepsis and septic shock. Current understanding of the underlying mechanisms responsible is rapidly evolving and future novel therapeutic targets may be soon available. Present therapy for sepsis-induced cardiac dysfunction is based on treatment of underlying sepsis with antibiotics and hemodynamic support.
Purpose
We set out to summarize the current knowledge on vasoactive drugs and their use in the management of shock to inform physicians’ practices.
Methods
This is a narrative review by a ...multidisciplinary, multinational—from six continents—panel of experts including physicians, a pharmacist, trialists, and scientists.
Results and conclusions
Vasoactive drugs are an essential part of shock management. Catecholamines are the most commonly used vasoactive agents in the intensive care unit, and among them norepinephrine is the first-line therapy in most clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine remains the first-line therapy. Vasoactive drugs have a narrow therapeutic spectrum and expose the patients to potentially lethal complications. Thus, these agents require precise therapeutic targets, close monitoring with titration to the minimal efficacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to their norepinephrine-sparing effects.
Myocardial dysfunction in sepsis may be associated with changes in left ventricular (LV) size. The goal of this study was to evaluate the impact of myocardial dysfunction and changes in LV diameter ...on hemodynamics and survival in a murine model of sepsis.
C57Bl/6 mice (N = 30) were used. Septic mice (n = 24) had cecal ligation and puncture (CLP) followed by fluid and antibiotic resuscitation and control mice (n = 6) received sham ligation. Echocardiography with a 30-mHz probe was performed at baseline and at frequent predefined time points after CLP. Stroke volume (SV), cardiac output (CO), LV internal diameter in diastole (LVIDd), and fractional shortening (FS) were measured. LV dilation was prospectively defined as an increase in LVIDd ≥ 5% from baseline values. Septic animals were classified as dilators or nondilators.
Among septic animals, 37% were dilators and 63% were nondilators. After CLP, SV and CO decreased early in both groups. With resuscitation, SV and CO improved to a greater extent in dilators than nondilators (for SV, 46.0 ± 8.2 vs 36.1 ± 12.7 μL at 24 h, P = .05; for CO, 20.4 ± 4.8 vs 14.8 ± 6.7 mL/min, P = .04). Survival at 72 h was significantly improved in dilators compared with nondilators (88% vs 40%, P = .01).
In a clinically relevant murine model of sepsis, animals with LV dilation had better cardiovascular performance and increased survival. Our results suggest that LV dilation is associated with improved SV and CO, a pattern resulting in greatly improved survival. These studies highlight the importance of diastolic function in septic shock.
Animal models of sepsis Zanotti-Cavazzoni, Sergio L; Goldfarb, Roy D
Critical care clinics,
10/2009, Letnik:
25, Številka:
4
Journal Article
Recenzirano
In this review, we start with a general discussion of relevant factors that can determine the validity of a sepsis animal model. We briefly review some of the currently used animal models of sepsis ...(small animal models and large animal models). We discuss the clinical relevance of animal models in sepsis research today and address potential reasons for the apparent underperformance of animal models in predicting therapeutic success of novel drugs in clinical trials.
Sepsis is associated with cardiovascular changes that may lead to development of tissue hypoperfusion. Early recognition of sepsis and tissue hypoperfusion is critical to implement appropriate ...hemodynamic support and prevent irreversible organ damage. End points for resuscitation need to be defined and invasive hemodynamic monitoring is usually required. Targets for hemodynamic optimization should include intravascular volume, blood pressure, and cardiac output. Therapeutic interventions aimed at optimizing hemodynamics in patients with sepsis include aggressive fluid resuscitation, the use of vasopressor agents, inotropic agents and in selected cases transfusions of blood products. This review will cover the most important aspects of hemodynamic optimization for treatment of sepsis induced tissue-hypoperfusion.
Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to ...provide clinical recommendations.
Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies.
Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis.
1) The jury opines that the term "targeted temperature management" replace "therapeutic hypothermia." 2) The jury opines that descriptors (e.g., "mild") be replaced with explicit targeted temperature management profiles. 3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome. 4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C-34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). 5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C-35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).
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 until <10% 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.
Rationale
Current murine models of sepsis do not account for the effects of aggressive fluid resuscitation on hemodynamics and mortality.
Objectives
Evaluate the impact of fluid resuscitation ...regimens on cardiovascular performance and survival in a murine model of sepsis.
Methods
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.
Measurements and main results
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 µL, and 26.8 ± 4.9 to 13.1 ± 5.8 ml/min; Intermediate: 52.1 ± 7.0 to 21.5 ± 6.6 µL, and 24.9 ± 4.1 to 11.9 ± 3.9 ml/min; Low: 54.0 ± 7.0 to 20.3 ± 5.6 µL, and 25.8 ± 4.0 to 11.3 ± 3.9 ml/min (
P
< 0.05 for all vs. baseline). With resuscitation there was a dose-dependent improvement in SV and CO (
P
< 0.05). At 24 h SV and CO were 44.0 ± 13.8 µL and 20.7 ± 8.5 ml/min in the High group, 39.8 ± 12.3 µL and 16.7 ± 6.5 ml/min in the Intermediate group, and 30.1 ± 12.4 µL 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 (
P
< 0.05).
Conclusions
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.
PDF
