Anesth Analg 2000;91:270-275
© 2000 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Myocardial Dysfunction Associated with Proinflammatory Cytokines After Esophageal Resection
Kazuhiro Nakanishi, MD*,
Shinhiro Takeda, MD, PhD*,
Katsuyuki Terajima, MD*,
Teruo Takano, MD, PhD
, and
Ryo Ogawa, MD, PhD*
Departments of
*Anesthesiology and
Medicine, Nippon Medical School, Tokyo, Japan
Address correspondence and reprint requests to Shinhiro Takeda, MD, PhD, Department of Anesthesiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Address e-mail to shin/anesth{at}nms.ac.jp
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Abstract
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Proinflammatory cytokines have been implicated in mediating myocardial dysfunction associated with major surgery. We investigated the profile of proinflammatory cytokines and the association of cytokine levels with myocardial function after esophagectomy. We studied 12 patients who underwent subtotal esophagectomy. One patient died of multiple organ failure. This patient had the largest interleukin-6 (IL-6) level of all the subjects. IL-6 levels increased from 14.9 ± 8.7 pg/mL to 498.4 ± 294.3 pg/mL (P < 0.05) at 6 h postoperatively. Interleukin-8 (IL-8) levels also significantly increased postoperatively. Right ventricular ejection fraction (RVEF) decreased from 44% ± 1% to 36% ± 2% (P < 0.05) and 37% ± 2% (P < 0.05) at 6 h and 12 h postoperatively. Stroke volume index (SVI) decreased significantly at the end of operation and at 6 h and 12 h postoperatively. The changes of RVEF and SVI showed an independent negative correlation with the IL-6 level (r = -0.70, P < 0.001 and r = -0.62, P < 0.001, respectively). In contrast, the change of RVEF and SVI was not correlated with the IL-8 level. Esophagectomy is associated with transient depression of myocardial function. IL-6 may contribute to this postoperative myocardial dysfunction.
Implications: We examined the association between myocardial function and proinflammatory cytokines after esophagectomy. Interleukin-6 may be the cytokine that most sensitively reflects the postoperative myocardial dysfunction.
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Introduction
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An association between inflammation and myocardial dysfunction has been recognized for more than 50 years, and it remains a topic of continued investigation. The extent of this proinflammatory cytokine release is related to mortality and morbidity (1). Proinflammatory cytokines have been implicated in mediating myocardial dysfunction (2,3). Previous study has suggested that proinflammatory cytokines have significant cardiovascular activity by regulating nitric oxide homeostasis (4).
Major surgery is associated with a transient severe inflammatory response involving the release of proinflammatory cytokines (5) and leading to systemic inflammation, which may be accompanied by cytokine-induced myocardial ventricular dysfunction. Esophagectomy for esophageal carcinoma is one of the most invasive surgical procedures and is associated with a generalized systemic inflammatory response characterized by the activation of proinflammatory cytokines and other chemical mediators (6). This inflammatory response after esophagectomy may lead to the development of postoperative complications (7).
Right ventricular function is important in preventing left ventricular failure by ensuring delivery of the necessary preload required to preserve left ventricular output. Under normal conditions of right ventricular function, any increase in afterload is accompanied by a substantial decrease in right ventricular ejection fraction (RVEF) (8). Conversely, the right ventricle, which is a thin-walled and highly compliant chamber, appears to be less preload-dependent than the left ventricle. The right ventricle may be highly susceptible to cytokine-induced negative inotropic effects. The relationship between proinflammatory cytokines and myocardial function in patients undergoing esophagectomy has not yet been elucidated. We tested the hypothesis that proinflammatory cytokine levels increase after esophagectomy and that this increase is associated with postoperative myocardial, especially right ventricular, dysfunction.
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Methods
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This study was approved by our Committee on Human Subjects, and all patients gave informed consent. We studied 12 adults with squamous cell carcinoma of the thoracic esophagus without circulatory, respiratory, or associated metabolic diseases.
General anesthesia was induced with fentanyl (5 µg/kg), midazolam (0.2 mg/kg), and vecuronium (0.1 mg/kg) and was maintained by using fentanyl, sevoflurane, nitrous oxide, and oxygen. The patients’ lungs were mechanically ventilated with the tidal volume and respiratory rate adjusted to maintain normocapnia (PaCO2 35 to 40 mm Hg). All patients underwent subtotal esophagectomy via right thoracotomy, followed by reconstruction with a gastric tube in the chest or neck and three-field (thoracic, abdominal, and cervical) lymph node dissection. The patients were taken to the intensive care unit (ICU) after the operation, and received continuous sedation with fentanyl (1.5 µg · kg-1 · h-1) and midazolam (1–4 mg/h). In the ICU all of the patients were routinely ventilated (Servo ventilator 300; Siemens Elema, Solna, Sweden). The ventilatory mode was the pressure support mode with positive end-expiratory pressure. The patients were tracheally extubated on the third postoperative day, whenever rapid shallow respiration ceased, the PaO2 (mm Hg) reached 250, and the cough reflex returned. No patient received inotropic drugs during the study.
Systemic arterial pressure was monitored via a radial arterial catheter with an appropriate transducer. A four-lumen right ventricular ejection fraction catheter (model 431H-7.5F; Baxter Healthcare Corp., Edwards Div., Irvine, CA)TM was inserted via the femoral vein to assess cardiac function, and a special cardiac output computer (Edwards Laboratories, Santa Ana, CA)TM was used to make the necessary computations. The catheter was equipped with a fast-response (95 ms) thermistor, as well as two electrodes for intracardiac electrocardiogram recording. The proximal port of the catheter was positioned just above the tricuspid valve under guidance of the pressure wave form.
Hemodynamic variables and the plasma levels of interleukin-6 (IL-6), interleukin-8 (IL-8), epinephrine, and norepinephrine were measured after the induction of anesthesia (T0) as control value, at the end of the operation (T1) and at 6 h (T2), 12 h (T3), 24 h (T4), and 48 h (T5) postoperatively. There was a 30-min stabilization period before measurements. Because the ventilatory mode and positive end-expiratory pressure level affect the hemodynamic variables, postoperative hemodynamic variables were also measured with volume-controlled ventilation and zero end-expiratory pressure at the same ventilatory mode as in the control state after muscle relaxation was achieved with vecuronium (0.1 mg/kg). The following hemodynamic variables were obtained: heart rate, mean arterial pressure, pulmonary capillary wedge pressure (PCWP), right atrial pressure, mean pulmonary arterial pressure, cardiac index (CI), RVEF, stroke volume index (SVI), right ventricular end-diastolic volume index, and right ventricular end-systolic volume index. Cardiac output was measured by obtaining five comparable estimates with ice-cooled 5% dextrose (10 mL) during the cessation of ventilation. Hemodynamic measurements associated with a RVEF of <0.2 were excluded from data analysis because the accuracy of the technology at this level of cardiac function is unproven. No patient had a RVEF less than 0.2.
Blood samples were collected into chilled tubes that contained 4% EDTA. Samples were kept on ice and immediately centrifuged (3000 rpm for 20 min, at 4 °C), with plasma being stored at -70 °C until analysis. Plasma levels of IL-6 and IL-8 were measured with enzyme-linked immunosorbent assay kits (IL-6: Toray Fujibionics Inc, Tokyo, Japan; IL-8: R & D systems, Minneapolis, MN)TM. Lower limits of detection in these assays were less than 4 pg/mL for IL-6 and 3 pg/mL for IL-8. Plasma epinephrine and norepinephrine levels were assayed by using high-performance liquid chromatography. The reference ranges of plasma epinephrine and norepinephrine are less than 100 pg/mL and 100 pg/mL to 450 pg/mL, respectively.
Data were expressed as mean ± SEM. Statistical analysis was performed by using repeated-measures analysis of variance followed by Dunnet’s tests. Regression analysis was performed to examine the relationship between pairs of variables. For all statistical analyses performed, P < 0.05 was considered significant.
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Results
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The clinical data are summarized in Table 1. Two patients developed postoperative complications. One of the patients died 19 days after the surgery because of postoperative anastomotic leak, pneumonia, sepsis, and subsequent multiple organ failure. It is noteworthy that this patient had the highest IL-6 level of the study group, peaking 6 h postoperatively at 3710 pg/mL. The other patient with complications had postoperative pneumonia and subsequent respiratory failure, which required ventilator support for 12 days after the operation. Plasma IL-6, IL-8, epinephrine, and norepinephrine were measured as indicators of response to surgical injury. Plasma epinephrine levels were increased significantly at T1 and T2 (Table 2). Plasma norepinephrine levels showed a progressive increase being significantly elevated at T5 (Table 2). IL-6 and IL-8 levels were significantly increased at T2 and at T1, T2, and T3, respectively (Table 2).
RVEF decreased significantly at T2 and T3 (Table 3). SVI decreased significantly at T1, T2, and T3 (Table 3). The absolute RVEF and SVI were not correlated with the circulating levels of cytokines postoperatively. However, the change of RVEF (
RVEF = RVEF [Tn] - RVEF [T0], n = 1, 2, 3, 4, and 5) showed an independent negative correlation with IL-6 level (r = -0.70, P < 0.001) (Fig. 1). Also, the change of SVI (SVI = SVI [Tn] - SVI [T0], n = 1, 2, 3, 4, and 5) showed a negative correlation with the IL-6 level (r = -0.62, P < 0.001) (Fig. 2). In contrast, the changes of both RVEF and SVI were not correlated with the IL-8, epinephrine, or norepinephrine levels. There was a weak but significant negative correlation between the IL-6 level and systemic vascular resistance index (SVRI) (r = -0.25, P < 0.05). The IL-6 level was also correlated with right ventricular end-systolic volume index (r = 0.30, P < 0.05) and heart rate (r = 0.44, P < 0.001).
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Figure 1. The correlation of the change of right ventricular ejection fraction (RVEF) with interleukin-6 (IL-6) levels. The change of RVEF (RVEF = RVEF [Tn] - RVEF [T0], n = 1, 2, 3, 4, and 5) showed an independent negative correlation with IL-6 level (r = -0.70, P < 0.001). T0 = after the induction of anesthesia, T1 = at the end of the operation, T2 = at 6 h postoperatively, T3 = at 12 h postoperatively, T4 = at 24 h postoperatively, T5 = at 48 h postoperatively.
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Figure 2. The correlation of the change of stroke volume index (SVI) with interleukin-6 (IL-6) levels. The change of SVI (SVI = SVI [Tn] - SVI [T0], n = 1, 2, 3, 4, and 5) showed a negative correlation with the IL-6 level (r = -0.62, P < 0.001). T0 = after the induction of anesthesia, T1 = at the end of the operation, T2 = at 6 h postoperatively, T3 = at 12 h postoperatively, T4 = at 24 h postoperatively, T5 = at 48 h postoperatively.
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Discussion
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The increase of proinflammatory cytokines seemed to be reflected in a decline of ventricular contractility. We demonstrated that RVEF and SVI were transiently depressed in the early postoperative period, in association with an increase of IL-6 production. The changes of RVEF and SVI were significantly correlated with the circulating level of IL-6.
It was noteworthy that the change of RVEF, and not the absolute value, was the variable showing a correlation with IL-6 levels, suggesting that baseline right ventricular function was independent of circulating proinflammatory cytokines, whereas the decline of myocardial contractility was partly related to an increase of IL-6. The correlation between IL-6 levels and RVEF suggests that IL-6 may be one of the many variables that affect postoperative myocardial contractility, along with the load on the heart, sympathetic nervous activity, medications, and other acute phase reactants. The right ventricle is known to be sensitive to any increase in pulmonary artery pressure or pulmonary vascular resistance, and there is a negative correlation between RVEF and these variables (9). Six hours after surgery, we found the highest levels of IL-6. At this time, SVRI decreased and heart rate increased without a change in CI. We cannot refute the possibility that the parallel decrease in RVEF is induced by a cytokine-induced vasodilation mediated by an activation of cellular inhibiting G protein and inducible nitric oxide synthase. RVEF was, however, significantly depressed at 6 and 12 hours after surgery, although the pulmonary vascular resistance index and the load on the right ventricle remained consistent. Therefore, this reduced RVEF may imply a deterioration of right ventricular contractility.
In human and animal models of the systemic inflammatory response syndrome, four cytokines, which are tumor necrosis factor-
(TNF-), interleukin-1 (IL-1), IL-6, and IL-8, are released in a sequential manner, and produce an "inflammatory cascade." The appearance of serum IL-6 after surgery may be directly related to production of TNF- and IL-1 (10). IL-6 is synthesized by monocytes/macrophages, T-lymphocytes, fibroblasts, and endothelial cells after stimulation by TNF- and IL-1. Stein et al. (11) demonstrated that TNF- and IL-1ß have a direct negative inotropic effect on cardiac myocytes via induction of nitric oxide synthase. The direct negative inotropic effect of both TNF- and IL-1 may have contributed to the right ventricular dysfunction observed in our patients. However, TNF- and IL-1 were measured over a relatively short perioperative period, and the serum levels of both cytokines were not correlated with the clinical course (12). In contrast, the serum levels of IL-6, which is released in the second wave of the "cytokine cascade," seems to be a good indicator of activation of the inflammatory cascade, as well as a predictor of subsequent organ dysfunction and death (1,5,10). In the present study, IL-6 and IL-8 levels were significantly increased after esophagectomy. The changes of RVEF and SVI were, however, correlated with the IL-6 level only. These data suggested that elevation of the IL-6 level could predict a decrease in myocardial contractility. A relationship between the IL-6 response and the extent of surgical trauma has been reported (1,5). Cruickshank et al. (5) reported that more severe trauma was associated with a greater increase of serum IL-6 and a larger serum IL-6 concentration. Thus, an excessive and prolonged increase of the circulating IL-6 level is associated with both morbidity and mortality (1).
Stroke volume is influenced by physiological factors that alter preload, afterload, and contractility. In the present study, SVI decreased significantly after the operation, and the change of SVI was correlated with IL-6 level. Decreased stroke volume without a change in PCWP (preload) suggests either deteriorated inotropic function of the left ventricle or increased left ventricular afterload. RVEF also decreased without a change in right atrial pressure. As we did not measure ventricular stroke work, we cannot demonstrate directly that inotropic function of the right and left ventricle deteriorated after esophagectomy. However, large serum IL-6 levels have been demonstrated to impair cardiac function as a result of a negative inotropic effect (13). Significantly increased IL-6 levels have been found in patients with heart failure and are correlated with the prognosis (2). Hennein et al. (3) reported a direct relationship between the IL-6 level and the development of left ventricular wall dyskinesia in the postoperative period. Finkel et al. (13) clinically confirmed that the IL-6 levels in pulmonary venous effluent were dramatically increased immediately after aortocoronary bypass surgery, and they showed experimentally that the same concentrations of IL-6 could cause reversible myocardial depression in the human heart (4). Kinugawa et al. (14) demonstrated a nitric oxide-mediated negative inotropic effect of IL-6 in cultured chick ventricular myocytes. Therefore, the negative inotropic effect of IL-6 seems to depend on alteration of nitric oxide synthesis in the myocardium.
Plasma epinephrine and norepinephrine levels have long been used as indicators of cardiac adrenergic activity and generally increase in response to physical and psychological challenges. Norepinephrine is the variable that most sensitively reflects the severity of surgical stress (15). We have reported that plasma norepinephrine levels showed a progressive increase until the second postoperative day, even if glucocorticoids were given as an antiinflammatory drug before the operation to mitigate surgical stress for esophagectomy (16). We found an increase in CI accompanied by endogenous norepinephrine levels that increased continuously throughout the study. The increase in CI observed during our study was primarily caused by alterations in heart rate. The bulk of circulating norepinephrine seems to originate from sympathetic neurons rather than from the adrenal medulla (17). Enhanced sympathetic activity leads to an excessive increase in heart rate partly because cardiac contractility does not increase appropriately. Increases in heart rate increase myocardial oxygen consumption, potentially resulting in local myocardial ischemia. The continuous increase in plasma norepinephrine levels was paralleled by a decrease in SVRI. There was, however, no significant correlation between SVRI and either catecholamine levels. Moreover, there was a weak but significant negative correlation between the IL-6 level and SVRI. It has been suggested that this systemic vasodilatation associated with hyporesponsiveness to endogenous catecholamines may be induced by cytokines. In the present study, plasma norepinephrine levels showed a progressive increase after the operation, so the development of right ventricular dysfunction seemed to be independent of sympathetic activity.
The modified thermodilution technique we used was useful for detecting any change of right ventricular volume that occurred simultaneously with changes of preload used for postoperative management (18). Right ventricular end-diastolic volume index can now not only be measured but also routinely monitored at the bedside by this thermodilution technique, providing additional information about preload beyond measurement of PCWP in critically ill patients, especially those with pulmonary hypertension (19). This modified thermodilution technique, however, has some technical limitations. Measurements made by using this method underestimate the true cardiac output in patients with tricuspid regurgitation with hypervolemia (20). Judging from right atrial pressure data, clinically significant tricuspid regurgitation was absent in our patients. Spinale et al. (21) demonstrated that there was a strong correlation between thermodilution measurements and biplane ventriculographic measurements of RVEF, provided that hypovolemia was not present and that the thermistor was not too remote from the pulmonary valve. The accuracy of the thermodilution technique has been validated in comparisons to traditional radionuclide techniques (18,22,23), biplane angiography (24), and two-dimensional echocardiography (25). Of these techniques, thermodilution volumetric measurements are most applicable in the ICU. Radionuclide ventriculography, angiography, and echocardiography can be difficult and sometimes impossible to perform in the critically ill patient and, with the exception of echocardiography, cannot be used serially to guide therapy. The position of the thermodilution catheter was checked by pressure monitoring before cardiac output and RVEF measurements in our study. Therefore, we believe that our hemodynamic measurements obtained by using the thermodilution method were reliable.
Cytokine-mediated intimation, as a cause for myocardial dysfunction, has been implicated in cardiac surgery (3). Cardiopulmonary bypass has been proposed as a model for studying the inflammatory pathways involved in the systemic inflammatory response syndrome. Several investigators have demonstrated a negative inotropic effect of proinflammatory cytokines in this clinical setting (3,14). However, many variables, such as the load on the heart, the state and reversal of anticoagulation, intrinsic sympathetic function, inotrope therapy, the effectiveness of myocardial protection, and the surgical procedure performed on the heart, may affect postbypass myocardial function. Thus, it seems to be difficult to identify the variables that contribute most to postbypass myocardial dysfunction. Our results suggest that major surgery, such as esophagectomy, represents a more controlled and reproducible model for studying the relationship between the systemic inflammatory response and postoperative complications, particularly postoperative myocardial dysfunction.
We conclude that IL-6 may be the substance that most sensitively reflects postoperative right ventricular dysfunction.
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References
|
|---|
-
Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993;119:771–8.[Abstract/Free Full Text]
-
Tsutamoto T, Hisanaga T, Waga A, et al. Interleukin-6 production in peripheral circulation increases with the severity of heart failure and increase of plasma IL-6 level has an important role on the prognosis of patients with congestive heart failure [abstract]. Circulation 1996;94:495.
-
Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994;108:626–35.[Abstract/Free Full Text]
-
Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–9.[Abstract/Free Full Text]
-
Cruickshank AM, Fraser WD, Burn HJG, et al. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 1990;79:161–5.[Medline]
-
Ono S, Aosasa S, Mochizuki H. Effects of a protease inhibitor on reduction of surgical stress in esophagectomy. Am J Surg 1999;177:78–82.[Web of Science][Medline]
-
Katsuta T, Saito T, Shigemitsu Y, et al. Relation between tumor necrosis factor alpha and interleukin 1 beta producing capacity of peripheral monocytes and pulmonary complications following oesophagectomy. Br J Surg 1998;85:548–53.[Web of Science][Medline]
-
Weber KT, Janicki JS, Shroff S, et al. Contractile mechanisms and interaction of the right and left ventricles. Am J Cardiol 1981;47:686–95.[Web of Science][Medline]
-
Brent BN, Mahler D, Matthay RA, et al. Not-invasive diagnosis of pulmonary arterial hypertension in chronic obstructive pulmonary disease: right ventricular ejection fraction at rest. Am J Cardiol 1984;53:1349–53.[Web of Science][Medline]
-
Shalaby MR, Waage A, Aarden L, Espevik T. Endotoxin, tumor necrosis factor- and interleukin-1 induce interleukin-6 production in vivo. Clin Immunol Immunopathol 1989;53:488–98.[Web of Science][Medline]
-
Stein B, Frank P, Schmitz W, et al. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 1996;28:1631–9.[Web of Science][Medline]
-
Tompkins RG. The role of proinflammatory cytokines in inflammatory and metabolic responses. Ann Surg 1997;225:243–5.[Web of Science][Medline]
-
Finkel MS, Hoffman RA, Shen L, et al. Interleukin-6 as a mediator of stunned myocardium. Am J Cardiol 1993;71:1231–2.[Web of Science][Medline]
-
Kinugawa K, Takahashi T, Kohmoto O, et al. Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes. Circ Res 1994;75:285–95.[Abstract/Free Full Text]
-
Kopin IJ, Lake RC, Ziegler M. Plasma levels of norepinephrine. Ann Intern Med 1978;88:671–80.
-
Takeda S, Ogawa R, Nakanishi K, et al. The effect of preoperative high dose methylpredonisolone in attenuating the metabolic response after oesophageal resection. Eur J Surg 1997;163:511–7.[Web of Science][Medline]
-
Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436–44.[Web of Science][Medline]
-
Dhainaut JF, Brunet FB, Monsallier JF, et al. Bedside evaluation of right ventricular performance using a rapid computerized thermodilution method. Crit Care Med 1987;15:148–52.[Web of Science][Medline]
-
Diebel LN, Wilson RF, Tagett MG, et al. End-diastolic volume: a better indicator of preload in the critically ill. Arch Surg 1992;127:817–21.[Abstract/Free Full Text]
-
Hines R, Barash PG. Right ventricular failure. In: Kaplan JA, ed. Cardiac anesthesia. 2nd ed. Vol 1. New York: Grune and Stratton, 1987:995–1020.
-
Spinale FG, Smith AG, Carabbello BA, et al. Right ventricular function computed by thermodilution and ventriculography: a comparison of methods. J Thorac Cardiovasc Surg 1990;99:141–52.[Abstract]
-
Kay HR, Afshari M, Barash P, et al. Measurement of ejection fraction by thermal dilution techniques. J Surg Res 1983;34:337–46.[Web of Science][Medline]
-
Vincent JL, Thirion M, Brimioulle S, et al. Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter. Intensive Care Med 1986;123:33–8.
-
Urban P, Scheidegger D, Gabathuler J, et al. Thermodilution determination of right ventricular volume and ejection fraction: a comparison with biplane angiography. Crit Care Med 1987;15:652–5.[Web of Science][Medline]
-
Jardin F, Brun-Ney D, Hardy A, et al. Combined thermodilution and two-dimensional echocardiographic evaluation of right ventricular function during respiratory support with PEEP. Chest 1991;99:162–8.[Abstract/Free Full Text]
Accepted for publication May 3, 2000.
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Abstract
Introduction
