and heparin (like APC inhibiting coagulation) was less effective (12). Here APC reduced the increase in renal concentrations of proinflammatory cytokines and myeloperoxidase activity (indicative of the number of neutrophils), whereas the other interventions had no such effect. The concept that APC had anti-inflammatory effects in this model of ischemia-reperfusion was further supported by the observation that renal injury could also be prevented in rats that were severely leukocytopenic during the experiment (12). The study by Dr. Hoffmann and colleagues (4) has several limitations. First, endotoxin was used as a bolus challenge to induce a systemic inflammatory response; the host response to sepsis, as it occurs in the clinic, is likely much more complicated. Second, the APC preparation used was prepared from human plasma by methods that were not described in detail in the article. The biological activity may be different from recombinant human APC used in clinical practice. Although this interesting study will not halt the discussion about whether APC should be part of the standard of care of patients with sepsis, this investigation does provide valuable infor-
mation about the effect of APC on leukocyte-endothelial cell interaction during systemic inflammation. Tom van der Poll, MD Marcel Levi, MD Department of Internal Medicine, Academic Medical Center University of Amsterdam Amsterdam, The Netherlands
REFERENCES 1. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699 –709 2. Warren BL, Eid A, Singer P, et al: Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001; 286:1869 –1878 3. Abraham E, Reinhart K, Opal S, et al: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: A randomized controlled trial. JAMA 2003; 290:238 –247 4. Hoffmann JN, Vollmar B, Laschke MW, et al: Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit Care Med 2004; 32: 1011–1017 5. Esmon CT: The protein C pathway. Chest 2003; 124:26S–32S 6. Murakami K, Okajima K, Uchiba M, et al:
7.
8.
9.
10.
11.
12.
Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272: L197–L202 Taylor FB Jr, Chang A, Esmon CT, et al: Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79:918 –925 Levi M, Dorffler-Melly J, Reitsma PH, et al: Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein C-deficient mice. Blood 2003; 101:4823– 4827 Joyce DE, Gelbert L, Ciaccia A, et al: Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276:11199 –11203 White B, Schmidt M, Murphy C, et al: Activated protein C inhibits lipopolysaccharideinduced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 2000; 110:130 –134 Shibata M, Kumar SR, Amar A, et al: Antiinflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103:1799 –1805 Mizutani A, Okajima K, Uchiba M, et al: Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 2000; 95: 3781–3787
Right ventricular function and failure: Methods, models, and mechanisms*
T
he physiologic importance of the right ventricle has been underestimated in the past, but its essential role in a wide variety of conditions is becoming increasingly evident. In various forms of congenital heart disease, the right ventricle is directly or indirectly subjected to abnormal loading conditions (1), and consequently right ventricular function has been shown to be a major determinant of clinical outcome in these patients (2).
*See also p. 1035. Key Words: right ventricular function; ventricular failure; contractility; pressure overload; pressurevolume relation; single-beat elastance Copyright © 2004 by Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000121430.62987.A2
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The increasing number of children with (corrected) congenital cardiac malformations who are reaching adulthood leads to a large cohort of patients in which function (or dysfunction) of the right ventricle importantly determines their clinical status and prognosis. However, right ventricular function is also important in patients with acquired heart disease. For example, right ventricular dysfunction has an important independent bearing on prognosis in chronic obstructive pulmonary disease (3), and in patients with primary pulmonary hypertension, mortality rate was reported to be most closely associated with right ventricular hemodynamic function (4). Pulmonary thromboembolic disease and acute respiratory distress syndrome represent other cases
in which right ventricular function plays an essential role. In addition to rightsided valvular disease in which the right ventricle is obviously involved, the function of the right ventricle may also be relevant in left-sided valvular disease (5). In patients with mitral regurgitation, the attention is primarily focused on the left ventricle, but when the insufficiency is severe the right ventricle may also be affected and right ventricular function should be considered during clinical management and treatment (6). In a recent review, Goldstein (7) discussed the pathophysiology and management of right heart ischemia and indicated that the right ventricle appears to be relatively resistant to infarction and may recover even after prolonged occlusion. However, 1087
patients with inferior myocardial infarction who have right ventricular involvement are clearly at increased risk of death, shock, and arrhythmias (8, 9). Finally, a number of studies have provided evidence that right ventricular ejection fraction is an independent prognostic factor in patients with moderate to severe heart failure (10, 11). Accurate assessment of right ventricular function is difficult because the ventricle has a complex structure and physiology. In clinical practice, physicians are asking which measurements best reflect the various aspects of right ventricular function and how accurate those measurements are. Most proposed indexes require the measurement of right ventricular volumes or dimensions, but conventional imaging methods such as angiography, echocardiography, and radionuclide methods have important limitations due to the complex anatomical geometry of the right ventricle and its position in the thorax (12). Magnetic resonance imaging provides the noninvasive technique of choice for the evaluation of right ventricular function because of the high spatial resolution and its potential for three-dimensional imaging. Additional features such as flow quantification, wall thickness, and myocardial mass measurements add to the diagnostic power of this technique (13). However, the availability of magnetic resonance imaging is still limited and the technique is impractical in the operating room and the intensive care unit. Therefore, echocardiography remains indispensable in the clinical setting. Furthermore, recent developments including three-dimensional approaches and tissue-Doppler techniques (14) have increased the value of echocardiography for the assessment of right ventricular function. Despite the high clinical value of noninvasive imaging techniques, an important problem remains in that all of the derived indexes are more or less load dependent. This is a significant limitation because almost without exception, loading conditions are abnormal in right ventricular disease either as a primary cause of the disease or as a compensatory response. Furthermore, in many cases, important alterations in loading conditions occur during the disease process and/or as a result of treatment, which complicates the interpretation of right ventricular function indexes. A way to overcome these problems is by analyzing right ventricular function in terms of pressure1088
volume relationships, which provide relatively load-independent indexes of systolic and diastolic function (15). This approach has been proven to be valid and very useful not only for the left ventricle but also for the right ventricle (16 –19). Assessment of pressure-volume relationships typically involves simultaneous measurements of ventricular volume and pressure during a loading intervention. An elegant (but invasive) method, which is used as the gold standard to assess systolic and diastolic ventricular function in several recent articles (14, 20), is the conductance catheter method. A combined pressure-conductance catheter positioned in the right ventricle provides continuous, on-line pressure and volume signals. The required alteration in loading may be obtained, for example, by balloon occlusion of the vena cava inferior (21), volume infusions, leg tilting, or pharmacologic interventions. In this issue of Critical Care Medicine, Dr. Kerbaul and colleagues (22) investigate right ventricular function and pulmonary artery characteristics in an animal model of acute right ventricular failure. The model is based on studies by Greyson et al. (23) showing that a transient pressure overload may induce persistent right ventricular failure. Dr. Kerbaul and colleagues subjected dogs to a right ventricular pressure overload by gradually snaring the right and left pulmonary arteries up to a two-fold increase in right ventricular systolic pressure. The pulmonary artery constrictions were maintained for 90 mins, and measurements were subsequently obtained at 30, 60, and 90 mins after release. The authors tested the ability of dobutamine and norepinephrine to restore systemic arterial pressure and cardiac output and documented the effects on right ventricular function, pulmonary artery impedance, and ventricular-arterial coupling. The experiments in an untreated control group confirmed the persistent reduction in right ventricular function and ventricular-arterial uncoupling after pressure overload. The experiments in the treated groups show that dobutamine restored ventricular-arterial coupling and cardiac output better than norepinephrine, presumably because of its more pronounced inotropic effect. In this study, the authors aimed at evaluating drugs that are actually used in patients during right ventricular failure rather than investigating the underlying mechanisms; therefore, these mechanisms remain largely speculative.
An important factor may be that heart rate was lower than control in the norepinephrine group, whereas it was substantially higher in the dobutamine group. Positive effects of increased heart rate may partly explain the findings (24). An interesting finding in this study is that right ventricular contractility (endsystolic elastance) was only slightly depressed during the constriction period and sharply decreased after release of the constriction. Previous studies have shown that the right ventricle may actually improve its contractile state in response to an increased afterload (16). This mechanism, homeometric autoregulation, may have helped to maintain contractility during the constriction period. Some methodological limitations of the study should be mentioned. First, end-systolic elastance (slope of the endsystolic pressure-volume relation) was determined by a single-beat method previously developed by Sunagawa et al. (25) for the left ventricle. This method was previously tested in the right ventricle (26), but as mentioned by the authors it has not been validated in conditions of right ventricular failure. This may be important because studies in the left ventricle indicate that more advanced approaches are required to reliably estimate end-systolic elastance in the failing heart (27). Furthermore, absolute volume of the right ventricle was not measured, but rather volume changes were derived from integrated pulmonary artery flow. Thus, possible right ventricular dilation and parallel shifts of the end-systolic pressure-volume relationship could not be identified. Previous studies have reported that shifts of the end-systolic pressurevolume relationship may be more sensitive indicators of changes in systolic function than changes in the slope (28). Despite these limitations, the data presented by Dr. Kerbaul and colleagues convincingly demonstrate a clinically relevant example of right ventricular failure and provide important insights in the physiology of the right ventricle that may help to optimize therapeutic interventions. Paul Steendijk, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands
REFERENCES 1. Fogel MA, Rychik J: Right ventricular function in congenital heart disease: Pressure
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2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
and volume overload lesions. Prog Cardiovasc Dis 1998; 40:343–356 Graham TP Jr, Bernard YD, Mellen BG, et al: Long-term outcome in congenitally corrected transposition of the great arteries: A multi-institutional study. J Am Coll Cardiol 2000; 36:255–261 Burgess MI, Mogulkoc N, Bright-Thomas RJ, et al: Comparison of echocardiographic markers of right ventricular function in determining prognosis in chronic pulmonary disease. J Am Soc Echocardiogr 2002; 15: 633– 639 D’Alonzo GE, Barst RJ, Ayres SM, et al: Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343–349 Nagel E, Stuber M, Hess OM: Importance of the right ventricle in valvular heart disease. Eur Heart J 1996; 17:829 – 836 Borer JS, Hochreiter CA, Supino PG, et al: Importance of right ventricular performance measurement in selecting asymptomatic patients with mitral regurgitation for valve surgery. Adv Cardiol 2002; 39:144 –152 Goldstein JA: Pathophysiology and management of right heart ischemia. J Am Coll Cardiol 2002; 40:841– 853 Mehta SR, Eikelboom JW, Natarajan MK, et al: Impact of right ventricular involvement on mortality and morbidity in patients with inferior myocardial infarction. J Am Coll Cardiol 2001; 37:37– 43 Zehender M, Kasper W, Kauder E, et al: Eligibility for and benefit of thrombolytic therapy in inferior myocardial infarction: Focus on the prognostic importance of right ventricular infarction. J Am Coll Cardiol 1994; 24:362–369 de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998; 32:948 –954 Gavazzi A, Berzuini C, Campana C, et al:
12.
13.
14.
15.
16.
17.
18.
19.
Value of right ventricular ejection fraction in predicting short-term prognosis of patients with severe chronic heart failure. J Heart Lung Transplant 1997; 16:774 –785 Tulevski II, Romkes H, Dodge-Khatami A, et al: Quantitative assessment of the pressure and volume overloaded right ventricle: Imaging is a real challenge. Int J Cardiovasc Imaging 2002; 18:41–51 Rathi VK, Biederman RW: Imaging of ventricular function by cardiovascular magnetic resonance. Curr Cardiol Rep 2004; 6:55– 61 Vogel M, Derrick G, White PA, et al: Systemic ventricular function in patients with transposition of the great arteries after atrial repair: A tissue Doppler and conductance catheter study. J Am Coll Cardiol 2004; 43: 100 –106 Kass DA, Maughan WL, Guo ZM, et al: Comparative influence of load versus inotropic states on indexes of ventricular contractility: Experimental and theoretical analysis based on pressure-volume relationships. Circulation 1987; 76:1422–1436 De Vroomen M, Cardozo RH, Steendijk P, et al: Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb. Am J Physiol Heart Circ Physiol 2000; 278:H100 –H105 Brookes CI, White PA, Bishop AJ, et al: Validation of a new intraoperative technique to evaluate load-independent indices of right ventricular performance in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1998; 116:468 – 476 Leeuwenburgh BP, Steendijk P, Helbing WA, et al: Indexes of diastolic RV function: Load dependence and changes after chronic RV pressure overload in lambs. Am J Physiol Heart Circ Physiol 2002; 282: H1350 –H1358 Lopes Cardozo RH, Steendijk P, Baan J, et al: Right ventricular function in respiratory distress syndrome and subsequent partial liquid ventilation. Homeometric autoregulation in
20.
21.
22.
23.
24.
25.
26.
27.
28.
the right ventricle of the newborn animal. Am J Respir Crit Care Med 2000; 162: 374 –379 Leather HA, Segers P, Sun YY, et al: The limitations of preload-adjusted maximal power as an index of right ventricular contractility. Anesth Analg 2002; 95:798 – 804 Kass DA, Midei M, Graves W, et al: Use of a conductance (volume) catheter and transient inferior vena caval occlusion for rapid determination of pressure-volume relationships in man. Cathet Cardiovasc Diagn 1988; 15: 192–202 Kerbaul F, Rondelet B, Motte S, et al: Effects of norepinephrine and dobutamine on pressure load-induced right ventricular failure. Crit Care Med 2004; 32:1035–1040 Greyson C, Xu Y, Lu L, et al: Right ventricular pressure and dilation during pressure overload determine dysfunction after pressure overload. Am J Physiol Heart Circ Physiol 2000; 278:H1414 –H1420 Lancon JP, Pillet M, Gabrielle F, et al: Effects of atrial pacing on right ventricular contractility after coronary artery surgery. J Cardiothorac Vasc Anesth 1994; 8:536 –540 Sunagawa K, Yamada A, Senda Y, et al: Estimation of the hydromotive source pressure from ejecting beats of the left ventricle. IEEE Trans Biomed Eng 1980; 27:299 –305 Brimioulle S, Wauthy P, Ewalenko P, et al: Single-beat estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart Circ Physiol 2003; 284: H1625–H1630 Senzaki H, Chen CH, Kass DA: Single-beat estimation of end-systolic pressure-volume relation in humans. A new method with the potential for noninvasive application. Circulation 1996; 94:2497–2506 Steendijk P, Baan J Jr, van der Velde ET, et al: Effects of critical coronary stenosis on global systolic left ventricular function quantified by pressure-volume relations during dobutamine stress in the canine heart. J Am Coll Cardiol 1998; 32:816 – 828
Does improved oxygenation really imply increased benefit?*
A
cute respiratory distress syndrome (ARDS) is a heterogeneous disorder characterized by decreased lung compliance, nonhydrostatic pulmonary edema, and
*See also p. 1055. Key Words: acute respiratory distress syndrome; acute lung injury; prostacyclin; nitric oxide; pulmonary hypertension; outcome; oxygenation; pediatric Copyright © 2004 by Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000121431.64219.9A
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refractory hypoxemia. The pathogenesis of ARDS is believed to be a direct or indirect injury to the pulmonary epithelium and endothelium (1) and is associated with numerous pulmonary and nonpulmonary triggers. Although the traditionally published mortality rate for ARDS is high (40 – 60%), improvements in supportive care appear to have gradually decreased this rate (1–3). The exact explanation for the reduction in mortality rate remains uncertain but is unlikely to
be related to improved oxygenation in the acute management period. Intrinsic to the pathophysiology of ARDS is an elevation in pulmonary vascular resistance (PVR). The resultant pulmonary hypertension of ARDS has been associated with an imbalance in vasoactive mediators, severe regional hypoxic pulmonary vasoconstriction, thromboemboli secondary to disturbances in coagulation and fibrinolytic pathways, obliteration of the vascular bed, and im1089