Chest相关的心功能不全

DOI 10.1378/chest.129.5.1349 2006;129;1349-1366Chest Micha Maeder, Thomas Fehr, Hans Rickli and Peter Ammann Troponins and Natriuretic Peptides CardiacDiagnostic and Prognostic Impact of :*Sepsis-Associated Myocardial Dysfunction http://chestjournal.chestpubs.org/content/129/5/1349.full.html services can be found online on the World Wide Web at: The online version of this article, along with updated information and 49.DC1.html http://chestjournal.chestpubs.org/content/suppl/2006/04/28/129.5.13 Supplemental material related to this article is available at: ISSN:0012-3692 )http://chestjournal.chestpubs.org/site/misc/reprints.xhtml( of the copyright holder. may be reproduced or distributed without the prior written permission Northbrook, IL 60062. All rights reserved. No part of this article or PDF by the American College of Chest Physicians, 3300 Dundee Road, 2006Physicians. It has been published monthly since 1935. Copyright is the official journal of the American College of ChestCHEST © 2006 American College of Chest Physicians by guest on September 7, 2010chestjournal.chestpubs.orgDownloaded from Sepsis-Associated Myocardial Dysfunction* Diagnostic and Prognostic Impact of Cardiac Troponins and Natriuretic Peptides Micha Maeder, MD; Thomas Fehr, MD; Hans Rickli, MD; and Peter Ammann, MD Myocardial dysfunction, which is characterized by transient biventricular impairment of intrinsic myocardial contractility, is a common complication in patients with sepsis. Left ventricular systolic dysfunction is reflected by a reduced left ventricular stroke work index or, less accurately, by an impaired left ventricular ejection fraction (LVEF). Early recognition of myocardial dysfunction is crucial for the administration of the most appropriate therapy. Cardiac troponins and natriuretic peptides are biomarkers that were previously introduced for diagnosis and risk stratification in patients with acute coronary syndrome and congestive heart failure, respectively. However, their prognostic and diagnostic impact in critically ill patients warrants definition. The elevation of cardiac troponin levels in patients with sepsis, severe sepsis, or septic shock has been shown to indicate left ventricular dysfunction and a poor prognosis. Troponin release in this population occurs in the absence of flow-limiting coronary artery disease, suggesting the presence of mechanisms other than thrombotic coronary artery occlusion, probably a transient loss in membrane integrity with subsequent troponin leakage or microvascular thrombotic injury. In contrast to the rather uniform results of studies dealing with cardiac troponins, the impact of raised B-type natriuretic peptide (BNP) levels in patients with sepsis is less clear. The relationship between BNP and both LVEF and left-sided filling pressures is weak, and data on the prognostic impact of high BNP levels in patients with sepsis are conflicting. Mechanisms other than left ventricular wall stress may contribute to BNP release, including right ventricular overload, catecholamine therapy, renal failure, diseases of the CNS, and cytokine up-regulation. Whereas cardiac troponins may be integrated into the monitoring of myocardial dysfunction in patients with severe sepsis or septic shock to identify those patients requiring early and aggressive supportive therapy, the routine use of BNP and other natriuretic peptides in this setting is discouraged at the moment. (CHEST 2006; 129:1349–1366) Key words: cardiac troponins; myocardial dysfunction; natriuretic peptides; sepsis; septic shock Abbreviations: ACS
acute coronary syndrome; ANP
A-type natriuretic peptide; APACHE
acute physiology and chronic health evaluation; BNP
B-type natriuretic peptide; CAD
coronary artery disease; CHF
congestive heart failure; cTnI
cardiac troponin I; cTnT
cardiac troponin T; E/A
ratio of early peak flow velocity to atrial peak flow velocity; LVEF
left ventricular ejection fraction; LVFAC
left ventricular fractional area contraction; LVSWI
left ventricular stroke work index; NT-proANP
N-terminal-pro-A-type natriuretic peptide; NT-proBNP
N-terminal pro-B-type natriuretic peptide; PAC
pulmonary artery catheter; PCWP
pulmonary capillary wedge pressure; S/D
ratio of systolic to diastolic pulmonary vein flow velocity; SIRS
systemic inflammatory response syndrome Learning Objectives: 1. Assess myocardial dysfunction in sepsis and early recognition for administration of optimal therapy. 2. Analyze the elevation of cardiac troponins in patients with sepsis, severe sepsis or septic shock. 3. Evaluate the relationship between BNP (B-type natriuretic peptide) and both left ventricular ejection fraction and left-sided filling pressures. D espite advances in therapy, sepsis causes 200,000 deaths per year in the United States, thus equaling the number of patients dying from myocardial infarction.1 Myocardial dysfunction is a common complication in patients with severe sepsis, and early recognition and aggressive supportive ther- CHEST Special Features www.chestjournal.org CHEST / 129 / 5 / MAY, 2006 1349 © 2006 American College of Chest Physicians by guest on September 7, 2010chestjournal.chestpubs.orgDownloaded from apy are mandatory as mortality in patients with septic shock is still high.2 The value of the use of pulmonary artery catheters (PACs) has come under scrutiny after studies3 have failed to prove a survival benefit for patients treated with PAC-guided therapy com- pared to those in whom PACs were not used. Nevertheless, information about cardiac perfor- mance is needed for the selection of the most appropriate catecholamine regimen after adequate fluid resuscitation.4 In the past few years, the follow- ing two groups of biomarkers have emerged as potential candidates for the evaluation and quantifi- cation of cardiac dysfunction in patients with sepsis: For instructions on obtaining CME credit, see page A-84 cardiac troponins; and natriuretic peptides.5–15 These biomarkers were initially introduced for use in diagnosis and risk stratification in patients with acute coronary syndrome (ACS)16 and congestive heart failure (CHF) respectively,17,18 but their spectrum of application is widening. The aim of the present review is to provide clinicians with a summary of the current evidence about the prognostic and diagnostic impact of cardiac troponins and natriuretic peptides in patients with sepsis-associated myocardial dys- function. The available data on cardiac troponins and natriuretic peptides and the possible underlying pathophysiologic mechanisms are discussed in the light of studies on these biomarkers in patients without sepsis. Definitions Sepsis has been defined as the presence of the systemic inflammatory response syndrome (SIRS) in response to a culture-proven infection.19 However, SIRS can result not only from infection, but also from a variety of conditions such as autoimmune disorders, vasculitis, thromboembolism, and burns, or after surgery. The severity of sepsis is graded according to the associated organ dysfunction and hemodynamic compromise. The original definitions have been revisited by a group of experts,20 but, apart from expanding the list of signs and symptoms of sepsis, no relevant changes have been made. In a recently published review, Annane and coworkers2 propose a very practical modification of the defini- tions including exact hemodynamic definitions of septic shock. It is important to recognize that the original definitions relied only on the degree of vasodilatation, whereas in the modification by both the International Sepsis Definition Conference20 and Annane et al2 myocardial depression defined as low cardiac index or echocardiographic evidence of cardiac dysfunction has been included in the defini- tion of severe sepsis (Table 1).2,20 Myocardial Dysfunction and Hemodynamic Assessment Prevalence Abnormalities of cardiac function are quite com- mon in patients with sepsis. The prevalence of this transient phenomenon critically depends on the population studied, the definition applied, and the time point during the course of the disease. Approx- imately 50% of patients with severe sepsis and septic shock seem to have any form of impairment of left ventricular systolic function.4,9 Pathomechanisms The phenomenon of myocardial depression is mediated by circulating depressant substances,21–24 which until now have been incompletely character- ized. Among those on a list of possible candidates, tumor necrosis factor- and interleukin-1 play a central role.21,22 In addition, interleukin-6 has been shown24 to be a key mediator of myocardial dysfunc- tion in children with meningococcal septic shock. A comprehensive discussion of the numerous pathways involved in the complex pathogenesis of sepsis is beyond the aim of the present clinically oriented review, but can be found elsewhere.23 Clinical Presentation and Hemodynamics The hemodynamic pattern in human septic shock is generally characterized by a hypercirculatory state in- cluding decreased systemic vascular resistance and a markedly increased cardiac index after adequate fluid resuscitation. Nevertheless, several studies have re- vealed clear evidence of intrinsic depressed left ven- tricular performance in patients with septic shock. The *From the Division of Cardiology (Drs. Maeder, Rickli, and Ammann), Department of Internal Medicine, Kantonsspital St. Gallen, Switzerland; and Transplantation Biology Research Cen- ter (Dr. Fehr), Massachusetts General Hospital/Harvard Medical School, Boston, MD. The following authors have indicated to The ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in this article: Micha Maeder, MD; Thomas Fehr, MD; Hans Rickli, MD; Peter Ammann, MD. Manuscript received August 9, 2005; revision accepted Decem- ber 9, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Micha Maeder, MD, Division of Cardiology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzer- land; e-mail: micha.maeder@bluewin.ch 1350 Special Features © 2006 American College of Chest Physicians by guest on September 7, 2010chestjournal.chestpubs.orgDownloaded from phenomenon of “myocardial depression” was first de- scribed by Parker and coworkers,25 who performed serial radionuclide ventriculograms in 20 patients with septic shock, 7 of whom died during their stay in the ICU. Ten of 13 survivors had a reversibly depressed left ventricular ejection fraction (LVEF) of  0.4, whereas none of the nonsurvivors had an LVEF of  0.4. Survivors had substantially increased left ventricular end-diastolic and end-systolic volumes, and, thus, pre- served stroke volumes despite impaired LVEF, whereas in nonsurvivors ventricular dimensions re- mained normal. Nonsurvivors had a lower mean sys- temic vascular resistance index than survivors. Mean stroke volume indexes did not differ between survivors and nonsurvivors.25 These changes normalized within 10 days after the onset of septic shock. The authors postulated that all patients with septic shock may developmyocardial depression, but nonsurvivors would have a lower systemic vascular resistance index than survivors. They concluded that the lower afterload may result in normal LVEF in nonsurvivors despite a re- duced myocardial contractility.25 Another study26 by the same group revealed that patients with septic shock, and even those with normotensive sepsis, have a markedly abnormal response in left ventricular stroke work index (LVSWI), which is a measure of external left ventricular work, to volume infusion, indicating that in patients with sepsis an impairment of intrinsic myocardial performance is present. In this study, how- ever, no outcome data are presented; therefore, it remains unknown whether there were any differences in LVSWI between survivors and nonsurvivors, and also whether the previous findings on the prognostic impact of LVEF and systemic vascular resistance index could be confirmed. Similar changes have been observed in the right ventricle (ie, dilatation and reduction of contractility, which are expressed as right ventricular stroke work index). In contrast to the left ventricular pattern, changes in right ventricular performance occurred in both survivors and nonsurvivors, but normalization was seen only in survivors.27 In accordance with the results of the study by Parker et al,25 some studies4,9 evaluating cardiac performance in patients with sepsis by echocardiography found an LVEF (using transthoracic echocardiography) or a left ventricular fractional area contraction (LVFAC) [using transesophageal echocardiography] of 50% in ap- proximately 50% of patients with severe sepsis and septic shock. However, the typical pattern of left ventricular dilation in combination with an impaired LVEF was found in only one study,9 whereas in another study4 ventricular dimensions were normal despite low LVEF. Many other studies did not report left ventricular dimensions. Very interesting data came from a comprehensive study28 employing both trans- esophageal echocardiography and invasive monitoring to assess systolic and diastolic left ventricular function in patients with septic shock. Based on an analysis of transmitral inflow and pulmonary vein flow patterns, patients were subdivided into the following three sub- sets: (1) ratio of early peak flow velocity to atrial peak flow velocity (E/A) of  1 and a ratio of systolic to diastolic pulmonary vein flow velocity (S/D) of 1; (2) E/A of 1 and S/D of 1; and (3) E/A of 1 and S/D of  1. By analysis of other hemodynamic variables derived from PAC and transesophageal echocardiogra- phy measurements, these three groups were character- ized as follows: (1) normal LVFAC, normal transmitral and pulmonary flow (ie, E/A of  1 and S/D  1), corresponding to normal systolic and diastolic left ventricular function; (2) normal LVFAC, abnormal pulmonary vein flow (ie, E/A of  1 and S/D of  1 [called pseudonormal transmitral inflow]), which has Table 1—Definitions of SIRS and Different Degrees of Severity of Sepsis2,19 Condition Description SIRS Two or more of the following conditions: temperature  38.5°C or  35.0°C; heart rate of  90 beats/min; respiratory rate of  20 breaths/min or Paco2 of  32 mm Hg; and WBC count of  12,000 cells/mL,  4,000 cells/mL, or  10% immature (band) forms Sepsis SIRS in response to documented infection (culture or Gram stain of blood, sputum, urine, or normally sterile body fluid positive for pathogenic microorganism; or focus of infection identified by visual inspection, eg, ruptured bowel with free air or bowel contents found in abdomen at surgery, wound with purulent discharge) Severe sepsis Sepsis and at least one of the following signs of organ hypoperfusion or organ dysfunction: areas of mottled skin; capillary refilling of
3 s; urinary output of  0.5 mL/kg for at least 1 h or renal replacement therapy; lactate  2 mmol/L; abrupt change in mental status or abnormal EEG findings; platelet count of  100,000 cells/mL or disseminated intravascular coagulation; acute lung injury/ARDS; and cardiac dysfunction (echocardiography) Septic shock Severe sepsis and one of the following conditions: systemic mean BP of  60 mm Hg ( 80 mm Hg if previous hypertension) after 20–30 mL/kg starch or 40–60 mL/kg serum saline solution, or PCWP between 12 and 20 mm Hg; and need for dopamine of  5 g/kg/min, or norepinephrine or epinephrine of  0.25 g/kg/min to maintain mean BP at  60 mm Hg (80 mm Hg if previous hypertension) Refractory septic shock Need for dopamine at  15 g/kg/min, or norepinephrine or epinephrine at  0.25 g/kg/min to maintain mean BP at  60 mm Hg (80 mm Hg if previous hypertension) www.chestjournal.org CHEST / 129 / 5 / MAY, 2006 1351 © 2006 American College of Chest Physicians by guest on September 7, 2010chestjournal.chestpubs.orgDownloaded from Table 2—Prospective Studies on Cardiac Troponin Levels in Critically Ill Adults Mainly Including Patients With Sepsis* Study Study Population (Age,† yr) Severity of Disease Assessment of LV Performance Troponin Positivity In-Hospital Mortality Relationships Among Cardiac Troponin Level, LV Performance, and Outcome Exclusion of Flow-Limiting CAD Fernandes et al5 10 pts with sepsis (30 6) APACHE II score: 25 11 PAC, TTE cTnI (cutoff, 0.6 g/L): 6/10 pts (60%) 4/10 pts (40%); cTnI, 3 pts All pts with LVEF  0.5 were cTnI; cardiac index and cTnI not related Not done Spies et al6 26 pts with sepsis (approximately 60) APACHE II: approximately 48 PAC cTnT (cutoff, 0.2 g/L): 18/26 pts (69%) cTnT, 15/18 pts (83%); cTnT—, 3/8 pts (37%) Higher mortality in cTnT pts (p
0.02) Not done Turner et al7 G1: 15 pts with septic shock (70; age range, 24–77); G2: 6 pts without sepsis, but receiving mechanical ventilation (61; age range, 24– 77) APACHE II score: G1, 24 (range, 3–39); G2, 14.5 (range, 8–23) PAC (except one pt) cTnI (cutoff, 0.4 g/L): G1, 12 of 15 pts (80%); G2, 1/6 pts (17%) G1, 4/15 pts (27%); G2, 0/6 pts; cTnI, 4/13 pts (31%); cTnI—, 0/8 pts Correlation minimum LVSWI and maximum cTnI level (r
0.72); correlation maximum vasopressor dose and maximum cTnI (r
0.55) Not done Arlati et al8 G1: 19 pts with severe sepsis or septic shock (56 4); G2: 12 pts with hypovolemic shock (71 4) Pao2/Fio2 ratio: G1, 198 21 mm Hg; G2, 270 42 mm Hg Not assessed; hypotension (MAP  90 mm Hg) graded as moderate (30– 60 min) or severe ( 60 min) cTnI (cutoff, 0.5 g/L): G1, 11/ 19 pts (58%); G2, 12/12 pts (100%) G1, 10/19 pts (53%); G2, 5/12 pts (42%) Correlation abnormal cTnI levels and duration of hypotension (Kendall , 0.48); weak correlation abnormal cTnI levels and outcome (r
0.28) Not done; 2 pts in G1 and 5 pts in G2 had a history of CAD, all of whom were cTnI; 4 pts from G1 and 1 pt from G2 had ECG evidence of MI Ver Elst et al9 46 pts with septic shock (66; IQR, 54–74) APACHE II score: 24 (IQR, 20–30) PAC; TEE: LV dysfunction defined as LVEDD  60 mm, LVEDV  120 mL, and LVFAC  0.4 cTnI (cutoff, 0.4 g/L): 23/46 pts (50%) cTnT (cutoff, 0.1 g/L): 16/ 45 pts (36%) 21/46 pts (46%) LV dysfunction in 78% of cTnI pts, but only in 9% of cTnI— pts (p 0.0001); correlation ICU admission APACHE II score and peak cTnI (r value, NA) and cTnT (r value, NA); correlation cTnI and LV dysfunction (r value, NA) Autopsy performed in 7 cTnI and 5 cTnI—pts; LV free wall rupture in 1 cTnI— pt, MI in 1 cTnI pt; no MI in 10 pts; contraction band necrosis in 3 cTnI pts and in 1 cTnI— pt Ammann et al10 G1: 20 pts with SIRS (n
3), sepsis (n
9), or septic shock (n
8) 66 8]; G2: age and sex- matched control subjects NA Not systematically assessed cTnI (cutoff, 0.1 g/L): G1, 17/ 20 pts (85%); G2, 0 G1, 6/20 pts (30%); G2, 0 pts; cTnI, 5/17 pts (29%); cTnI—, 1/9 pts (11%) Not assessed In 10/17 cTnI pts (59%) relevant CAD ruled out by autopsy, coronary angiography, or stress echocardiography 1352 Special Features © 2006 American College of Chest Physicians by guest on September 7, 2010chestjournal.chestpubs.orgDownloaded from been interpreted as isolated diastolic dysfunction; and (3) decreased LVFAC, abnormal transmitral and pul- monary vein flow pattern (ie, E/A of  1 and S/D of  1), whichmight be explained by diastolic dysfunction as a consequence of systolic dysfunction. The patients in the latter group were significantly older and had a higher mortality rate than those patients in the other two groups. There was no significant difference in systemic vascular resistance or LVSWI between the groups. This study is limited by a small number of patients, but, interestingly, it revealed that patients with lower LVFAC have worse outcome,28 which is contra- dictory to the results of the study by Parker et al,25 and that