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Eur J Cardiothorac Surg 2007;32:83-89. doi:10.1016/j.ejcts.2007.04.011
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
a Department of Anaesthesiology, University of Luebeck, Luebeck, Germany
b Department of Anaesthesiology, Catholic Hospital Association Weser-Egge, Höxter, Germany
c Department of Cardiac Surgery, University of Luebeck, Luebeck, Germany
Received 2 January 2007; received in revised form 31 March 2007; accepted 3 April 2007.
* Corresponding author. Address: Department of Anaesthesiology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel.: +49 451 500 4057; fax: +49 451 500 3407. (Email: Hermannheinze{at}ngi.de).
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Abstract |
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 Top Abstract 1. Background2. Patients and methods3. Results4. DiscussionReferences |
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(TNF) and C-reactive protein (CRP) were measured after the induction of anaesthesia (pre-CPB) and after weaning from CPB (post-CPB), 1 h after the admission to the intensive care unit (ICU) and on the morning of the first postoperative day (1 POD), respectively. In addition, ventilation time and the high dependency unit time, i.e. the time till transferral to a peripheral ward, were documented. Results: Patients in the PTX group had lower TNF values (6.3 ng ml–1 (4/8.2) vs 9.1 ng ml–1 (6.5/13.7)) (median (25%/75%), p
= 0.021), lower systolic (28 ± 7 mmHg vs 35 ± 9 mmHg, mean ± SD, p
= 0.011) and mean pulmonary artery pressures (21 ± 5 vs 26 ± 6 mmHg, p
= 0.017) after admission to the ICU than control patients. Haemodynamics and pulmonary function parameters did not differ. There was a trend towards earlier weaning from the respirator in the PTX group (10.0 ± 3.5 h) (min/max: 4/16; confidence interval (ConF): 1.8 h) than the control group (12.3 ± 4.2 h) (min/max: 5–24; ConI: 2.4 h) (p
= 0.077). Patients treated with PTX could be transferred to a peripheral ward about 24 h earlier than control patients (95 ± 35 h, min/max: 32/190 h; ConI: 17 h; 119 ± 29 h, min/max: 66/165 h; ConI: 16 h) respectively; p
= 0.037). Conclusion(s): A single dose of PTX prior to CPB was able to reduce plasma levels of TNF. In this descriptive study, there was a trend towards reduced duration of ventilation and the high dependency unit time, i.e. the time till transferral to a peripheral ward was shortened.
Key Words: Cardiopulmonary bypass • Cardiac surgery • Systemic inflammatory response • Pentoxifylline • Lung
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1. Background |
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TopAbstract1. Background2. Patients and methods3. Results4. DiscussionReferences |
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Different strategies have been undertaken to reduce the inflammatory response and thereby improve pulmonary function following CPB, e.g. administration of anti-inflammatory drugs as steroids or protease inhibitors [1,8]. Pentoxifylline (PTX), a methylxanthine derivate, inhibits non-specifically the phosphodiesterase activity resulting in an accumulation of the intracellular signaling molecule cyclic adenosin monophosphat (cAMP) [9,10]. This leads to inhibition of production and release of various cytokines, e.g. tumour necrosis factor (TNF) [11,12]. In addition, PTX seems to have haemorrheological activity and improves peripheral vascular circulation [9,10]. Because of these beneficial rheological and anti-inflammatory properties, PTX has been shown to attenuate the endothelial injury and permeability and the overall inflammatory response following CPB [13–17]. Effects on surrogate parameters, such as reduced cytokines or improved haemodynamics, are important results. But in times of reduced financial resources, the question of shorter duration of ventilation and faster discharge to the peripheral ward becomes more important. Beside less intensive, i.e. cheaper patient care, the number of operations per day may be increased. Some investigation using PTX showed promising results concerning this topic [18,19].
However, as different time and dosage regimes of PTX have been used, a definitive recommendation of its administration is lacking. Primary endpoint of this randomized, placebo controlled study was the effect of a single dose of PTX given before CPB in the high dependency unit time, i.e. the time till transferral to a peripheral ward. Secondary endpoints were the effects on postoperative inflammatory response, pulmonary function and ventilation time.
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2. Patients and methods |
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TopAbstract1. Background2. Patients and methods3. Results4. DiscussionReferences |
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By using a computerized random number generator, patients were prospectively randomized into two groups: group PTX (n = 20) received a bolus of 5 mg kg–1 PTX immediately after induction of anaesthesia; the control group (CTR) (n = 20) received saline solution as placebo. One patient in the control group was excluded from further analysis because of lack of pulmonary artery catheter-related data.
2.1 Anaesthesia and surgical technique
Premedication, induction and maintenance of anaesthesia were standardized. For premedication, each patient received 1 mg flunitrazepam per os. Anaesthesia was induced with etomidate (0.2–0.3 mg kg–1), sufentanil (0.5–0.7 µg kg–1) and pancuronium (0.1 mg kg–1) and maintained with continuous infusions of propofol (2–6 mg kg–1
h–1) and sufentanil (0.5–1.25 µg kg–1
h–1). Patients were mechanically ventilated with a tidal volume of 8–10 ml kg–1 predicted body weight in a volume controlled mode. Frequency was adjusted to achieve arterial normocapnia. The positive end-expiratory pressure was set to 5 mbar, I:E ratio of 1:2.
Additionally, to standard monitoring with a three-lead electrocardiogram, a transcutaneous oxygen sensor, a radial arterial and a central venous line, all patients were equipped before surgery with a pulmonary artery catheter for continuous determination of pulmonary artery pressures, automated semicontinuous measurement of cardiac output (CO)/cardiac index (CI) and continuous measurement of mixed venous oxygen saturation (SvO2) (Vigilance®, Edwards Lifescience, Irvine, USA).
All patients underwent standard open heart surgery with non-pulsatile cardiopulmonary bypass in moderate hypothermia (nasopharyngeal temperature: 32 °C; membrane oxygenator Hilite; Medos, Stolberg, Germany; roller pump: Stöckert, München, Germany). The pump was primed with 1430 ml Ringer's solution, 250 ml mannitol 20%, 500 ml albumin 5% and 20 ml sodium bicarbonate 8.4%.
After median sternotomy and harvesting of the saphaneous vein grafts, patients were fully heparinized (300 IU kg–1). Aortic and two-stage venous cannulation was used and after cross-clamping, the heart was arrested using antegrade cold blood cardioplegia which was repeated every 20 min. During CPB, the mean arterial pressure (MAP) was maintained at 60–80 mmHg. Noradrenaline was administered, if necessary.
After surgery, all patients were transferred to the intensive care unit for postoperative therapy. All patients were mechanically ventilated with biphasic airway pressure or pressure support ventilation as long as clinically appropriate. Pressures were adjusted to deliver a tidal volume of 8–10 ml kg–1 body weight and positive end-expiratory pressure (PEEP) was set to 5 mbar. Patients were sedated with continuous infusion of propofol and intermittent boli of piritramid or pethidin. Extubation was performed when haemodynamics were stable for half an hour, temperature was more than 36 °C, and the patients breathed spontaneously reaching adequate blood gases and were cooperative. Fluid management was adjusted to achieve and maintain a central venous pressure (CVP) between 8 and 12 mmHg. Volume replacement was performed with Ringer's solution and gelatine polysuccinate, as appropriate. Haematocrit was maintained above 0.27 by transfusion of packed red cells. Adrenaline was administered on a first line basis, if cardiac index was <2.5 l min–1 m–2. Noradrenaline was administered, if mean arterial pressure was <65 mmHg despite cardiac index >2.5 l min–1 m–2. Vasodilators (urapidil, sodium nitroprusside) were given, if MAP > 90 mmHg.
Patients were transferred from the intensive care unit (ICU) to the intermediate care unit (IMC) when they met the following criteria: extubated, SpO2 higher than 94% with oxygen insufflation up to 6 l min–1, stable haemodynamics with only minor doses of inotropes, i.e. adrenaline less than 0.05 µg kg–1 min–1, dobutamine 5 µg kg–1 min–1 and 0.3 µg kg–1 min–1.
Patients were discharged from the IMC to a peripheral ward if the following criteria were achieved: cooperative, SpO2 higher than 90% without oxygen insufflation, no ventricular arrhythmia, no tachycardia, no chest tubes, urine output above 0.5 ml kg–1 h–1, no inotropes or vasopressors and no signs of ischaemia on electrocardiogram. On the peripheral ward, there were no possibilities for oxygen insufflation and continuous monitoring of haemodynamics such as measurements of blood pressures or electrocardiogram. ICU time plus IMC time was defined as high dependency unit (HDU) time.
2.2 Haemodynamic measurement
Haemodynamic measurements (mean arterial pressure, cardiac index, mixed-venous oxygen saturation, central venous pressure, systolic pulmonary artery pressure (SPAP), mean pulmonary artery pressure (MPAP), pulmonary capillary occlusion pressure (PAOP)) were obtained. Pulmonary vascular resistance index (PVRI) was calculated as 79.92 x (MPAP–PCWP) x CI–1.
2.3 Laboratory measurement
From arterial blood samples, serum creatinine concentration, leucocyte count and C-reactive protein values were measured (standard laboratory technique). Creatinine clearance was calculated using the Cockkroft–Gault formula.
2.4 Pulmonary function measurement
Static compliance was calculated as tidal volume (V
t)/(plateau pressure–positive end-expiratory pressure).
Blood samples were drawn for the determination of arterial and mixed venous oxygen (paO2) and carbon dioxide (paCO2) tension (ABL 505 blood gas analyzer, Radiometer, Copenhagen, Denmark).
The alveolar–arterial pO2 difference (AaDO2) was calculated using the alveolar gas equation, assuming a respiratory quotient (RQ) of 0.8.
Shunt fraction (Q
s/Q
t) was calculated as
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All measurements were taken when the patient was anaesthetized in the supine position.
2.5 Cytokine measurement
Blood was withdrawn from the radial catheter and collected in different phlebotomy tubes containing ethylene diamine tetraacetic acid. Platelet poor plasma was prepared by centrifuging at 3600 rounds per minute for 15 min. The plasma was stored in polypropylene tubes at –73 °C until use. TNF was measured in duplicate using an ultrasensitive enzyme-linked immunosorbent assay (Human TNF UltraSensitive, Biosource International, Camarillo California, USA).
All measurements were performed after the induction of anaesthesia (pre-CPB), after weaning from ECC (post-CPB), after admittance to the ICU and in the morning of the first postoperative day (1 POD). In addition, duration of mechanical ventilation and length of ICU and intermediate care unit stay were documented.
The patients’ management in the ICU and IMC was carried out by physicians who were not involved in the study and were blinded to the grouping. No other anti-inflammatory drugs were given throughout the investigation period.
2.6 Statistical analysis
The size of the groups was estimated with reference to previous studies [15,19]. A power analysis determined that a sample size of 19 patients in each group would be adequate to detect a 25% difference in ventilation time between the two groups with a power of 80% at p
< 0.05 level of significance. Normal distribution was tested using the Kolmogorov–Smirnov test. A 
2 analysis was used for categoric data. Differences between groups were studied using the Student's t-test or Mann–Whitney U-test for independent continuous variables when appropriate. Analysis of variance for repeated measures was used to determine differences between the two groups over the study period. Post-hoc a t-test for paired variables was used to locate the differences in comparison with baseline data, and changes among the groups at each data point were tested using the Student's t-test. Non-parametrical tests (Friedman, Wilcoxon) were used for non-normally distributed data. A p
< 0.05 was considered as statistically significant, and a p
< 0.10 as in tendency significant. Data are presented as mean ± standard deviation (M ± SD) or median (25%/75%) when appropriate. Because of multiple comparisons, the data analysis is descriptive [20]. According to this, the term ‘significant’ (used for p
< 0.05) is given as a description of group differences.
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3. Results |
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TopAbstract1. Background2. Patients and methods3. Results4. DiscussionReferences |
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is shown in Fig. 1
. Patients in group PTX showed lower values after admittance to the ICU (6.3 ng ml–1 (4/8.2)) than the control patients (9.1 ng ml–1 (6.5/13.7)) (median (quartiles); p
= 0.021). Values for creatinin, creatinin clearance, leucocytes and C reactive protein (CRP) showed no differences between groups (Table 4
).
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There was a trend towards earlier weaning from the respirator in the PTX group (10.0 ± 3.5 h) (min/max: 4/16; confidence interval: 1.8 h) than the control group (12.3 ± 4.2 h) (min/max: 5–24; ConI: 2.4 h) (p = 0.077). Patients treated with PTX could be transferred to a peripheral ward about 24 h earlier than the control patients (95 ± 35 h, min/max: 32/190 h; ConI: 17 h; 119 ± 29 h, min/max: 66/165 h; ConI: 16 h, respectively; p = 0.037) (Figs. 2 and 3 ).
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4. Discussion |
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TopAbstract1. Background2. Patients and methods3. Results4. DiscussionReferences |
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CPB results in an activation of various inflammatory pathways [3]. Multiple activated cell types release proinflammatory cytokines, and this leads to a systemic inflammatory response and may ultimately result in multiple organ failure [3]. As the lung is one of the organs most often affected, different degrees of pulmonary dysfunction, ranging from subclinical functional changes to acute respiratory distress syndrome (ARDS), are quite common [7].
Although the definite mechanisms by which PTX exerts its known beneficial effects are not fully understood, the blocking of the production and release of TNF and others may be some of them [10,21]. It has been suggested that TNF may contribute to myocardial dysfunction and haemodynamic instability following CPB [22], and higher plasma levels of TNF have been shown to be associated with less favourable outcomes [23]. Different dosage regime of PTX showed reduced circulating and tissue-bounded inflammatory cytokines, especially TNF [16,17,24,25]. Therefore, we have measured plasma levels of TNF as a parameter of inflammatory response after CPB. An attenuation of inflammation may have protective effects on different tissues, e.g. the lung. Turkoz et al. [13] showed that PTX greatly minimized leucocyte sequestration in the lung after CPB. Tsang et al. [14] could demonstrate that PTX may attenuate the endothelial injury and permeability seen in CPB and may thus reduce pulmonary dysfunction. In addition, Hoffmann et al. [18] could reduce the duration of mechanical ventilation in patients who underwent major cardio-thoracic surgery by adding PTX to standard supportive treatment, showing protective pulmonary effects of PTX treatment. This is consistent with our data. We could show a reduction of circulating TNF after admittance to the ICU. In addition, patients treated with PTX showed improved markers of pulmonary dysfunction, i.e. a reduced PVR and lower pulmonary arterial pressures and a trend towards shorter mechanical ventilation time. Improved pulmonary haemodynamics may play an important role as myocardial dysfunction is frequent after CPB because of stunning [26] and therefore pulmonary hypertension may contribute to right heart insufficiency due to increased right ventricular afterload.
Conflicting results concerning improved organ function after PTX administration exist [13–15,19,27,28]. Besides different underlying circumstances (e.g. septic vs non-septic patients), the time and duration of PTX administration may play a major role. Butler et al. [27] could not show any beneficial effect on lung function with an intraoperative PTX dose of 1 mg kg–1 h–1 in patients undergoing cardiac surgery. In another study, a priming dose of 1 mg kg–1 followed by an intraoperative infusion of 1 mg kg–1 h–1 was not able to show beneficial effects on renal function [28]. Pretreatment with 400 mg per day for 1 week demonstrated a mild reduction in CPB-associated endothelial injury and permeability but showed no clinically relevant advantage [14]. Oral administration of 400 mg for 3 days, and following anaesthetic induction, infusion of 300 mg PTX inhibited the postoperative increase in PVR and greatly minimized leucocyte sequestration in the lungs due to CPB. But again, no clinically relevant benefit could be achieved [13]. In contrast, Boldt et al. [15] could reduce the inflammatory response in elderly cardiac surgery patients with a loading dose of 300 mg PTX followed by a continuous infusion of 1.5 mg kg–1 h–1 until the 2 POD. Another study by the same group showed an attenuated deterioration of endothelial, renal and liver function with the same dosing regime [19].
As a long-term infusion of PTX may lead to abdominal discomfort with nausea and vomiting in up to 40% of the patients [29], we studied, if a single dose of PTX before CPB without a continuous infusion could also effectively reduce the inflammatory response. That this stands true can be seen by the reduced levels of TNF. Moreover, this dosing regime was able to show clinical benefits by reducing the high dependency unit time. PTX group patients could be transferred to a peripheral ward 24 h earlier than CTR patients. In our institution's peripheral ward, there does not exist any means for continuous ECG monitoring and no device for oxygen insufflation. Therefore, for safety reasons patients are only transferred if they show stable haemodynamics without tachycardia and there is no need for oxygen insufflation. This may explain the long duration of 4–5 days till transferral. Unfortunately, data acquisition ended in the morning of the first POD and therefore we could not report the exact reason for the late transferral of the patients. Most studies investigating the effect of PTX in cardiac surgery do not report time till transferral to a peripheral ward. Hoffmann et al. showed reduced ICU-time, but they only included patients at risk for developing MOF, so their data cannot be compared with our data.
This effect can hardly be explained by the beneficial effects of PTX on one organ, e.g. the lungs. We could demonstrate minor positive effects on lung function parameters or global haemodynamics, but no effects on renal function or less sensitive markers of inflammation such as leucocyte count or CRP. Data on effects of PTX on renal function are conflicting. One study showed no effect on creatinine levels or markers of tubular function [28], whereas Hoffmann et al. [18] demonstrated fewer days on haemofiltration. In addition, Boldt et al. [19] showed an attenuated deterioration of renal function, as measured with -1-microglobulin, a sensitive marker for the early phase of renal failure, but no differences in creatinine levels. We could not demonstrate any difference in creatine levels or creatinin clearance between groups, but if more sensitive markers of renal function would have reacted differently, must be left speculative.
As a phophodiesterase inhibitor, PTX has vasodilatory activity. We could not demonstrate any differences between the two groups concerning global haemodynamics, but the higher number of patients needing noradrenaline after weaning from CPB may be due to this fact. Nevertheless, PTX can be regarded as a safe drug. There were no differences in the use of catecholamines after admittance to the ICU and moreover, in the morning of the 1 POD more CTR-patients needed inotropic and vasoconstrictive support. This is consistent with other studies [13,15,25]. Use of inotropes as adrenaline have been associated with lactic acidosis and hyperglycaemia after CPB [30]. Whether the catecholamine sparing effect of PTX demonstrated by us and other groups [15,19] contributes to the improved outcome should be studied further.
There are limitations of our study. As stated above, PTX interacts with various parameters of the inflammatory cascades. We only measured TNF, thus we cannot say, if our dosing regime was able to efficiently reduce other markers of inflammation. In addition, because the inflammatory response to CPB is multifactorial, one pharmacological intervention alone is very unlikely to produce overall beneficial effects. In the studies by Boldt et al. [15,19] – in contrast to ours – the high dose (Hammersmith) aprotinin regime was used in all patients. Whether this influenced the results must be left for speculation. To our knowledge, there does not exist any data specifically investigating the effects of PTX in combination with other drugs, which have shown to inhibit inflammatory pathways, e.g. steroids or aprotinin on the inflammatory response following CPB. Further studies should address this issue.
The study was not designed to investigate effects of PTX on mortality. Consistent with other investigations we could demonstrate beneficial effects of PTX on organ function and morbidity, but to draw definite conclusions concerning outcome, much larger patient populations have to be studied.
In addition, future studies should focus on special patient populations, as PTX may have more positive effects on more ill patients. Effects of PTX on clinical relevant measures have only been demonstrated in special patient groups. Hoffmann et al. studied patients at risk for SIRS after major cardio-thoracic surgery. These patients developed less often a MODS with reduced duration of mechanical ventilation, haemofiltration and intensive care unit stay [18]. Boldt et al. [19] showed shorter mechanical ventilation time and improved organ function in elderly cardiac surgery patients, a group of patients often showing comorbidities and limited functional reserve of several organs. We excluded patients with recent myocardial infarction and renal and liver insufficiencies. In addition, our patients were younger and showed higher LVEF values than those by Boldt et al. [15,19]. Thus, we cannot say if the results would have been different in more ill patients. Unfortunately, our study population is much too small for a subgroup analysis to find out which patient group could benefit most by PTX treatment.
In conclusion, we have shown in this descriptive study in cardiac surgery patients scheduled for coronary artery bypass surgery that a single dose of PTX of 5 mg kg–1 given before CPB is able to attenuate the inflammatory response. Moreover, with this dosing regime there was a trend towards reduced duration of ventilation and the high dependency unit time, i.e. the time till referral to a peripheral ward was shortened.
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Footnotes |
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References |
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TopAbstract1. Background2. Patients and methods3. Results4. DiscussionReferences |
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) represent group pentoxifylline (PTX), solid circles (\#9679;) represent control group (CTR); ICU: intensive care unit; IMC: intermediate care unit; pre-CPB: after induction of anaesthesia; post-CPB: after weaning from cardiopulmonary bypass; ICU: after admittance to the Intensive care unit; 1 POD: morning of the first postoperative day; p: Mann–Whitney-U-test. Results are shown as median (quartiles).
