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Ann Thorac Surg 2001;71:1524-1529
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Prophylactic use of pentoxifylline on inflammation in elderly cardiac surgery patients

Joachim Boldt, MDa, Christian Brosch, MDa, Andreas Lehmann, MDa, Günter Haisch, MDa, Johannes Lang, MDa, Frank Isgro, MDb

a Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
b Clinic of Cardiac Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

Accepted for publication December 21, 2000.

Address reprint requests to Dr Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany
e-mail: boldtj{at}gmx.net


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Inflammation plays a pivotal role in the pathogenesis of organ injury after cardiopulmonary bypass (CPB). Elderly patients appear to be especially prone to develop general inflammation. Use of pentoxifylline (PTX) before surgery may be a promising approach to minimize the negative effects of CPB in these patients.

Methods. In a prospective, randomized study, patients more than 80 years old undergoing aortocoronary artery bypass grafting received either PTX (n = 15) after induction of anesthesia (initial bolus of 300 mg followed by a continuous infusion of 1.5 mg · kg-1 · h-1 during the next 2 days) or saline as placebo (control group; n = 15). Polymorphonuclear neutrophil (PMN) elastase, C-reactive protein (CRP), and interleukins (IL-6, IL-8, IL-10) were measured from arterial blood samples before surgery (T0), at the end of surgery (T1), 5 hours after surgery (T2), and at the morning of the first (T3) and second (T4) postoperative day.

Results. Postoperatively, PTX-treated patients less often needed catecholamines and were extubated earlier than the control patients (p < 0.05). On the intensive care unit, cardiac index inceased more in the PTX-treated (from 1.95 ± 0.3 to 3.26 ± 0.4 L · min-1 · m-2) than in the control patients (from 1.89 ± 0.2 to 2.78 ± 0.3 L · min-1 · m-2). Increase in CRP and PMN-elastase was significantly higher in the untreated control than in the PTX patients. After CPB, IL-6, IL-8, and IL-10 increased in both groups showing a significantly higher increase in the untreated control patients (IL-8 control: from 11.3 ± 2.6 to 154.4 ± 57 pg/mL [T1]); IL-8 PTX: from 10.9 ± 2.7 to 71.8 ± 23 pg/mL [T1]).

Conclusions. In elderly cardiac surgery patients, use of PTX before surgery and continued after CPB resulted in less inflammatory response than in an untreated control group. The value of attenuating the inflammatory process by PTX on outcome in this patient population needs to be evaluated in further controlled studies.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
In spite of improvements in biomaterials, surgical techniques, and anesthesiologic management, cardiac surgery using cardiopulmonary bypass (CPB) may still be associated with profound changes throughout several organ systems resulting in the development of post-CPB organ dysfunction [1]. Many of these problems seem to be related to a generalized activation of inflammatory pathways [2, 3]. This activation results from stimulation of immune effector cells that subsequently synthesize and release potent mediators of inflammation, eg, different proinflammatory cytokines such as interleukin (IL)-6 or IL-8, as well as different antiinflammatory cytokines, eg, IL-10 [4].

Advanced age appears to be one of the possible factors that may predispose to post-CPB complications [5]. Elderly patients are at increased risk of perioperative morbidity and mortality secondary to their high incidence of coexisting diseases or to an overwhelming inflammatory response [5–7]. Compared with the younger patient, the margin of reserve for adaptation is reduced in the elderly and the damaging effects of CPB may be less tolerated.

Pharmacologic manipulation of whole-body inflammatory response associated with CPB has received some attention [8]. Several approaches to reduce the negative sequelae of CPB have been used including administration of drugs (eg, aprotinin, corticosteroids) or modification of CPB (eg, pulsatile blood flow) [3, 8–10]. Pentoxifylline (PTX), a methylxanthine derivative with rheologic and immunomodulatory effects [11–16], is another promising approach to attenuate the negative effects of CPB on postoperative organ function. The present study was designed to assess the influence of prophylactic use of PTX given before surgery on the inflammatory process in elderly patients undergoing cardiac surgery.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Thirty patients aged more than 80 years undergoing elective first-time coronary artery bypass surgery were enrolled into the study.

Written informed consent was obtained from all patients and the study was approved by the local ethics committee. Exclusion criteria were a myocardial infarction within 3 months before surgery, renal insufficiency (serum creatinine > 2.0 mg/dL), liver insufficiency (aspartate aminotransferase [ASA] > 40 U/L, alanine aminotransferase [ALA] > 40 U/L), severe coagulation disorders, noncontrolled diabetes mellitus, and use of antiinflammatory drugs (eg, corticosteroids). Preoperatively, the patients were randomized into two groups: group 1 (n = 15) received PTX immediately after induction of anesthesia at an initial bolus of 300 mg, followed by a continuous infusion of 1.5 mg · kg-1 · h-1 until the second postoperative day); group 2 (n = 15) received saline solution as placebo.

Anesthesia was induced and maintained by weight-related doses of sufentanil, midazolam, and pancuronium. CPB was carried out using a nonpulsatile roller pump, membrane oxygenators, and standard (nonheparinized) extracorporeal circuits. The circuit was primed with 1,000 mL Ringer‘s solution and 500 mL gelatin. The standard "high-dose" (Hammersmith) aprotinin regimen was used for all patients. Temperature was kept at mild hypothermia (esophageal temperature 30°C to 32°C) and a flow rate of 2.4 L · min-1 · m-2 was used. If necessary, Ringer’s solution was added to the circuit to maintain filling volume. When hemoglobin was less than 7 g/dL, packed red blood cells (PRBC) were given. During weaning off bypass, as much pump blood as necessary to keep pulmonary capillary wedge pressure (PCWP) more than 10 mm Hg but less than 14 mm Hg was infused. After termination of CPB, the residual blood remaining in the extracorporeal circuit was concentrated using a cell-saving device and the autologous blood was retransfused until the end of surgery. Shed mediastinal blood was not retransfused postoperatively. After surgery, all patients were transferred to the intensive care unit (ICU) and controlled mechanical ventilation was continued during the next 6 hours at least.

Extubation was performed when hemodynamics were stable for a half hour, temperature was more than 36°C, and the patient breathed spontaneously reaching adequate blood gases. Postoperatively, low-dose dopamine (3 µg · kg-1 · h-1) was administered to all patients.

Epinephrine was given when mean arterial blood pressure (MAP) was less than 60 mm Hg (8 kPa) and cardiac index (CI) was less than 2.00 L · min-1 · m-2 in spite of sufficient volume infusion (target for CI between 2.0 to 3.0 L · min-1 · m-2). Norepinephrine was administered when systemic vascular resistance (SVR) was less than 600 dyn · sec · cm-5 and MAP was less than 60 mm Hg (8 kPa; target for SVR 800 to 1000 dyne · sec · cm-5).

The patients’ management in the ICU was carried out by physicians who were not involved in the study and were blinded to the grouping. No steroids or nonsteroid antiinflammatory drugs were given throughout the investigation period. All patients received cefuroxime as antibiotic prophylaxis after induction of anesthesia and during the next 24 hours (3 x 1.5 g cefuroxime).

Measured variables and data points
Hemodynamic monitoring consisted of measuring heart rate (HR), MAP, pulmonary artery pressure (PAP), PCWP, central venous pressure (CVP), and cardiac output ([CO] using thermodilution technique). Derived hemodynamic parameters (SVR, pulmonary vascular resistance [PVR], and CI) were calculated from standard formulas. Oxygen consumption (VO2) and oxygen delivery (DO2) were calculated using a bed-sided monitoring system (Explorer, Baxter, Irvine, CA).

From arterial blood samples, IL-6, IL-8, and IL-10 were measured in duplicate using commercially available solid-phase two site chemiluminescent enzyme immunometric assays (Diagnostic Product Corporation, Los Angeles, CA). Normal values (measured in 20 healthy volunteers) for IL-6 was less than 5 pg/dL, for IL-8 less than 60 pg/mL, and for IL-10 2 to 24 pg/mL. Polymorphonuclear neutrophil (PMN) elastase immunoassay (Merck, Darmstadt, Germany; normal values 30 to 85 µg/L), acute phase protein C-reactive protein (CRP; normal values < 0.5 mg/dL), leukocyte count, and temperature were also documented. All measurements were performed after induction of anesthesia during hemodynamic steady state before PTX was given (base line values: TO), at the end of surgery (T1), 5 hours after surgery on the ICU (T2), and at the morning of the first (T3) and second (T4) postoperative day (POD).

Statistics
A power analysis determined that a sample size of 14 patients or more in each group would be adequate to detect a 50% difference in IL-10 between the two groups with a power of 80% at the p less than 0.05 level of significance. Statistical analysis were performed using software package SPSS/PC+ (V 4.0. SPSS, Inc, Chicago, IL). Data are presented as mean ± standard deviation (SD) unless otherwise indicated. A {chi}2 analysis with Fisher’s exact tests was used for categoric data if appropriate. A nonparametric test (Wilcoxon rank sum test) was used for variables not normally distributed. Serially measured variables were tested with analysis of variance (ANOVA) for repeated measurements to detect treatment or treatment time interaction. Then data were compared with the Friedman one-way ANOVA to detect changes in each group. Wilcoxon’s signed rank test was used post hoc to locate the changes. Changes among the groups at each data point were tested first with Kruskal-Wallis one-way ANOVA; if statistically significant changes were seen, the Mann-Whitney U test was post hoc used to locate the changes. A p value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Demographic and perioperative data were without significant differences (Table 1). Fewer PTX-treated patients than untreated control group patients needed catecholamines in the postoperative period, and PTX patients needed less time to be extubated than the control patients (p < 0.05). No side effects of PTX infusion were noticed throughout the entire study period.


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  		Table 1. Demographic Data and Data From the Perioperative Period

 
CI was higher after CPB than at base line in both groups (Table 2). CI increased significantly more in the PTX-treated group (from 1.95 ± 0.3 to 3.26 ± 0.4 L · min-1 · m-2) than in the untreated control group (from 1.89 ± 0.2 to 2.92 ± 0.3 L · min-1 · m-2). SVR decreased more in the PTX-treated than in the control patients, whereas DO2 increased significantly more in the PTX group than in the control group (Table 2).


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  		Table 2. Hemodynamic Changes in the Two Groups

 
PMN elastase increased signficantly more in the control patients (maximum 365 ± 39 µg/L end of surgery) than in the PTX-treated patients (maximum 214 ± 29 µg/L end of surgery; Fig 1).



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  		Fig 1. Changes in polymorphonuclear elastase (normal values 30 to 85 µg/L) and leukocyte count. Mean ± standard deviation (SD) is given. (ICU = intensive care unit; PTX = pentoxifylline; +p < 0.05 difference from baseline data; *p < 0.05 difference from the other group.)

 
Postoperative leukocyte count was also higher in the untreated control than in the PTX-treated patients (Fig 1). Starting from normal values at base line, CRP increased in both groups showing a significantly higher increase in the control patients (p < 0.05; Fig 2). CRP was highest at the end of the study period without showing any more differences between the two groups. No detectable IL-6 concentration was seen at baseline in both groups (Fig 2). After CPB, IL-6 was elevated in both groups with a significantly higher IL-6 level in the control (306 ± 86 pg/mL) than the PTX group (162 ± 45 pg/mL) until the end of the study period.



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  		Fig 2. Changes of C-reactive protein (CRP) and interleukin (IL)-6 (normal values < 5 pg/dL) and IL-8 (normal values: < 60 pg/mL). Mean ± standard deviation (SD) is given. (ICU = intensive care unit; PTX = pentoxifylline; +p < 0.05 difference from baseline data; *p < 0.05 difference from the other group.)

 
IL-8 plasma levels were normal at baseline but increased significantly after surgery until the first POD (Fig 3). This increase was significantly higher in the control group (from 11.3 ± 2.6 baseline to 154.4 ± 57 pg/mL end of surgery) than in the PTX-treated patients (from 10.9 ± 2.7 baseline to 71.8 ± 23 pg/mL end of surgery). IL-10 plasma levels were also within normal range at baseline in both groups (Fig 3). IL-10 increased more in the control (maximum 186 ± 28 pg/mL end of surgery) than in the PTX patients (maximum 106 ± 25 pg/mL end of surgery). At the end of the study IL-10 plasma levels have returned almost to baseline values in both groups.



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  		Fig 3. Changes of interleukin(IL)-8 (normal values < 60 pg/mL) and IL-10 (normal values 2 to 24 pg/mL). Mean ± standard deviation (SD) is given. (ICU = intensive care unit; PTX = pentoxifylline; +p < 0.05 difference from baseline data; *p < 0.05 difference from the other group.)

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
The definite mechanisms by which PTX exerts its beneficial effects are not fully known. Possible mechanisms include the blocking of the production and release of proinflammatory cytokines (eg, TNF-alpha, IL-6), attenuated LPS-induced leukocyte-endothelial adhesion/emigration and macromolecular extravasation, altered PMN chemotaxis, reduced superoxide production, improved microperfusion, and microbicidal activity [12, 17–20]. Additionally, PTX possesses vasodilator properties leading to improved microcirculatory blood flow [21, 22]. This effect may be of particular interest in cardiac surgery because altered microperfusion is often present in the pathophysiology of CBP-related organ failure. PTX also shows some bronchodilator effects. Aside from its effects on inflammation, beneficial effects on hemodynamics (eg, increase in CI) and ventilation (earlier extubation) may be related to these actions of PTX. The beneficial effects of PTX are partly thought to be attributable to inhibition of phosphodiesterase activity resulting in accumulation of the intracellular signaling molecule cAMP [23]. Antioxidant properties of the substance may be another explanation for the beneficial effects of PTX [24].

We have measured IL-6 plasma levels because it has been shown that IL-6 seems to be responsible for much of the morbidity associated with the inflammatory response to CPB [25]. It increases by 2 hours after initiation of CPB, peaks at 4 hours, and is still significantly elevated 24 hours after start of CPB [26]. IL-8 was measured because it plays a major role in bridging the humoral mediators with the cellular mediators of inflammation [25]. Finally, IL-10 a is potent antiinflamatory cytokine that may counteract the negative effects of the proinflammatory substance.

One major result of the present study was that the administration of PTX before surgery followed by continuous infusion during the next 48 hours resulted in fewer signs of inflammation showing lower leukocyte count, lower plasma levels of the acute phase protein CRP, a lower level of PMN elastase, and lower plasma levels of proinflammatory cytokines (IL-6, IL-8) than in an untreated control group. Plasma levels of the antiinflammatory cytokine IL-10 were also lower in the PTX patients, most likely due to attenuation of the inflammatory process by PTX. Hemodynamics were improved in the PTX-treated patients, they less often needed catecholamines, and they were extubated earlier than the untreated control patients. The lower need for catecholamines may also have contributed to less inflammatory response in the PTX-treated patients, because it is known that these substances may increase endotoxemia during CPB.

Our study was designed to assess the influence of PTX on the extent of inflammation after CPB but not on patients’ outcome. Although survival rate was slightly higher in the PTX-treated group (14 versus 12 patients), the patient population was much too small to draw definite conclusions with regard to outcome. Data on PTX and outcome are conflicting. In a rat model of subacute bacterial peritonitis, Nelson and associates [27] showed that treatment with PTX (5 mg/kg daily) resulted in an improved survival. In patients undergoing bone marrow transplantation, PTX (1,200, 1,600, or 2,000 mg given orally) was associated with a reduction in morbidity and mortality [28]. In septic patients infusion of PTX (5 mg/kg) resulted in a significant improvement in hemodynamics [29]. In spite of promising experimental and human studies on inflammation and ischemia/reperfusion, studies without beneficial effects of PTX have also been reported [30–32]. The used dose may be an important reason for these conflicting results [12]. We used 1.5 mg · kg-1 · h-1 of PTX which summed up to approximately 2,800 mg of PTX per day in each patient. Butler and coworkers [33] used an infusion of 1 mg/h of PTX only during surgery summing up to approximately 200 to 250 mg PTX. With this dose, PTX did not show beneficial effects on inflammation. Timing of PTX administration may be also of interest with regard to the conflicting data on the value of PTX. Prophylactic and continuous administration of PTX rather than using it only during or after the injury may be important. Early use of PTX before cardiac surgery (400 mg 1 week before surgery) resulted in attenuation of endothelial injury and permeability seen in CPB [34]. In an experimental endotoxic shock in animals, PTX has provided protection against the deleterious sequelae of endotoxemia when given before endotoxin [32]. In rats, PTX given before the operation improved tissue oxygenation after surgery [21].

Levi and colleagues [35] administered PTX (1.5 g over 3 hours) in chimpanzees before injection of endotoxin. TNF and IL-6 plasma levels were significantly elevated by endotoxin and this increase was significantly attenuated by PTX pretreatment.

Influence of PTX on inflammatory response in cardiac surgery patients has only been studied rarely. Other antiinflammatory manipulations including use of corticosteroids, acadesine/adenosine, and aprotinin have already been assessed, but not in elderly patients [4, 8]. In our study, all patients received aprotinin to reduce blood loss. Because aprotinin is considered to possess additional antiinflammatory properties [25], the beneficial effects of PTX and aprotinin may have been additive. It may also be assumed that the beneficial effects on inflammation would have been more obvious when aprotinin had not been used.

It is summarized that numereous proinflammatory and antiinflammatory substances are produced in response to CPB. Antiinflammatory approaches aimed at limiting production of one specific substance (eg, anti-TNF) must fail because the inflammatory process in cardiac surgery is very complex. The possible beneficial effects of PTX are more comprehensive including effects on the immune system, on hemodynamics, and on coagulation. In patients aged more than 80 years administration of PTX before surgery followed by continuous infusion resulted in less inflammatory response and improved hemodynamics. Whether this regimen will also result in improved organ function or even improved outcome needs further studies in larger patient population.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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