Lack of renoprotective effect of theophylline during aortocoronary bypass surgery

Bernhard K. Krämer1,, Jürgen Preuner2, Andreas Ebenburger2, Michael Kaiser2, Ulrich Bergner3, Christoph Eilles3, Martin C. Kammerl1, Günter A. J. Riegger1 and Dietrich E. Birnbaum2

1 Klinik und Poliklinik für Innere Medizin II, 2 Klinik und Poliklinik für Herz-, Thorax- und Herznahe Gefäßchirurgie and 3 Abteilung für Nuklearmedizin, University of Regensburg, Regensburg, Germany



   Abstract
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 Abstract
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 Subjects and methods
 Results
 Discussion
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Background. The incidence of acute renal failure (ARF) after cardiac surgery remains high, despite improvements in surgical techniques and perioperative care, and is associated with an inacceptably high mortality. The adenosine receptor antagonist theophylline has been shown to confer some benefit in experimental and clinical ARF due to ischaemia, contrast media and various nephrotoxic agents.

Methods. In a double-blind, randomized, placebo-controlled trial, the effectiveness of theophylline for prevention of renal impairment after elective coronary artery bypass grafting (CABG) was evaluated. Fifty-six patients with normal renal function received a bolus of 4 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h theophylline (n=28) or isotonic saline (n=28) for up to 96 h. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery, and the glomerular filtration rate (GFR) ([51Cr]EDTA-clearance) was determined preoperatively, and at days 1, 3 and 5 after surgery.

Results. Serum creatinine and GFR were the same in both groups. The number of patients with increases of serum creatinine >=0.4 mg/dl were five in the theophylline group and four in the placebo group. Volumes of infused fluid and urine volumes were not different between groups, both ranging from ~7.5 to 8 l during the first 24 h after surgery. The number of patients with termination of study medication due to presumed side effects was not different between placebo and theophylline groups.

Conclusions. Theophylline administration for renal protection after CABG appears to be ineffective in a pilot study in well-hydrated patients. However, the statistical power of our study was not sufficient to exclude a possible protective effect of theophylline. The present study demonstrated the feasability of a larger trial with theophylline or one of the new specific adenosine A1 receptor antagonists in the setting of ARF after cardiac surgery.

Keywords: acute renal failure; adenosine A1 antagonist; cardiac surgery; glomerular filtration rate; renal function



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The incidence of dialysis-requiring acute renal failure (ARF) following cardiac surgery depends on the patient population, ranging from <1% to 3% in recent cohorts [13]. Important perioperative risk factors for development of ARF comprise age, severity of underlying cardiac and vascular disease, pre-existing renal failure, diabetes mellitus and prolonged cardiopulmonary bypass time [14]. In the largest study to date, comprising 43 642 patients, Chertow et al. [2] analysed factors that were associated with ARF: decreased preoperative creatinine clearance, valvular surgery, intra-aortic balloon pump use, prior heart surgery, NYHA class IV, ejection fraction <35%, pulmonary rales, peripheral vascular disease, chronic obstructive pulmonary disease, and elevated systolic blood pressure in patients undergoing coronary artery bypass grafting (CABG). Despite improvements in dialysis machines/membranes and techniques, and supportive therapy, mortality of dialysis-dependent ARF remains high, in the range of up to 28–68% in recent cohorts [14,6].

Based on animal experiments, it has been suggested that adenosine A1 receptor agonism may mediate the haemodynamic changes that occur in renal damage induced by ischaemia and that theophylline may prevent this impairment of renal function [79]. In addition, theophylline has been shown to prevent radiocontrast-induced reduction in glomerular filtration rate (GFR) in three studies including 39, 93 and 58 patients undergoing various radiological examinations with administration of radiocontrast media [1012]. Finally, in critically ill neonates acute renal insufficiency could be markedly ameliorated by theophylline [13].

Therefore, the aim of the present study was to investigate the effects of the adenosine receptor antagonist theophylline on renal function in the cardiac surgery setting. This pilot study further aimed to elucidate the feasability of a larger, double-blind, randomized study with the use of theophylline vs saline perioperatively during cardiac surgery, using repeated measurements of GFR ([51Cr]EDTA clearance) and serum creatinine.



   Subjects and methods
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 Subjects and methods
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Patients
The protocol was approved by the institutional review board/ethical committee of the Medical Faculty of the University of Regensburg. All patients gave written, informed consent. Fifty-nine patients scheduled for elective CABG with extracorporal circulation were prospectively enrolled in this study. Exclusion criteria were a history of allergic reaction to theophylline, asthma bronchiale treated with theophylline, heart failure (ejection fraction <50%), baseline serum creatinine >1.3 mg/dl, and impairment of liver function. Three patients had to be excluded from this study due to: (i) (unscheduled) minimal-invasive surgery without the use of extracorporal circulation; (ii) the need for theophylline administration due to bronchospasm; and (iii) insufficient documentation of administration of the study drug in one patient each.

Study protocol
Patients undergoing CABG were randomized to receive theophylline (0.5 h before and up until 96 h after surgery at a dose of 0.25 mg/kg/h, after an initial bolus of 4 mg/kg was given during the 30 min immediately following initiation of general anaesthesia) or saline in a double-blind manner (Figure 1Go). The long duration of study medication was chosen in order to avoid overlooking the late beneficial effects of theophylline during the postoperative period. The treating anaesthesiologist or cardiac surgeon could stop the study medication if presumed side effects (e.g. arrhythmias, seizures) were thought to result. Serum creatinine was measured daily for 7 days (1 day before surgery, and at 6 h and on days 1–5 after surgery) and GFR ([51Cr]EDTA-clearance) was estimated four times (before surgery, and on days 1, 3 and 5 after surgery) (Figure 1Go). Plasma theophylline concentrations were measured in parallel with serum creatinine at all postoperative time points only.



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Fig. 1.  Study protocol showing theophylline dosing and assessment of renal function.

 

Methods
GFR was measured using the [51Cr]EDTA clearance method: heparinized blood samples were drawn before and at 15 min intervals during the first hour, and at 30 min intervals during hours 2–4 after injection of 3 MBq [51Cr]EDTA. Plasma samples were measured using a {gamma} counter. GFR was estimated using a two compartment model (modified from reference [14]). Serum creatinine was measured using standard laboratory techniques. Theophylline plasma concentrations were estimated using a commercially available competitive enzymoimmunoassay (Cedia® Theophylline II; Roche Pharmaceuticals, Mannheim, Germany).

Cardiac surgery
General anaesthesia was standardized using fentanyl, etomidate and pancuronium for induction, and isoflurane and fentanyl for maintenance. Myocardial revascularization was done using extracorporal circulation. The heart–lung machine (Stöckert, München, Germany) was prefilled with 1.5 l Ringer lactate solution+0.25 l mannitol solution and 5000 IU heparin. Cardioplegic solution (1800 ml; Custodiol®, Köhler Chemie, Alsbach, Germany) was injected via the aortic root immediately after aortic cross-clamping. Local hypothermia during surgery was achieved using 4°C cold electrolyte solution (Ionosteril®; Fresenius, Bad Homburg, Germany). Blood losses during surgery were recovered with a cell saver and re-transfused.

Statistics
The null hypothesis was that there would be no significant difference between the treatment and the placebo group. Variables were analysed with the Mann–Whitney U-test for comparison of area under curves of serum creatinine, for example, with Fisher's exact test with Bonferroni correction for multiple comparisons, or with student's t-test where appropriate. Data are given as mean±standard deviation. A P value <0.05 was considered statistically significant.



   Results
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 Results
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Patient characteristics
Fifty-six patients (28 patients each in the theophylline and saline groups) were evaluated in this trial. Age, sex distribution, minimal body temperature during extracorporal circulation, time of ischaemia (aortic cross-clamping) and time of reperfusion are given in Table 1Go. There was no significant difference between groups for any of these parameters. Study medication was given for 4 days in 13 patients of the theophylline group and in 10 patients of the saline group. Study medication was terminated prematurely by the treating physicians (anaesthesiologist, cardiac surgeon) in the remaining 33 patients, mainly on the day of surgery or the day after. The time of termination of study medication is given in Figure 2Go. Study medication was terminated mainly due to tachyarrhythmias (12 patients in the theophylline group and 15 in the saline group). In the remaining six patients, study medication was stopped for miscellaneous reasons: (i) withdrawal of consent (n=2); (ii) surgery due to ileus (n=1); and (iii) discontinuation by the treating physician on the peripheral ward (n=3).


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Table 1. Patient characteristics of patients randomized to theophylline or NaCl treatment

 


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Fig. 2.  Termination of study medication during the day of surgery or days 1–4 post-operation.

 
Due to the high number of study-medication terminations, the data were analysed in two ways: first, all patients in each group were analysed since they had all received at least one theophylline/saline bolus and at least 0.5 h of infusion of the respective medication (‘intention to treat’ analysis). Secondly, all patients in each group that had received study medication until at least day 2 after surgery were analysed separately (‘efficacy’ analysis).

No patient in this study died. Severe adverse events occurred in one patient in the theophylline group (ileus, see above) and in no patients in the NaCl group. The former event was classified as unrelated to study medication.

Serum creatinine and GFR
Serum creatinine for all patients included in the study and for patients treated until at least day 2 post-surgery were analysed separately. Mean serum creatinine ranged from ~0.8 mg/dl throughout the study and was not affected by theophylline, neither in all patients nor in the subgroup of patients treated at least until day 2. GFR in both treatment groups and its analysis are given in Figure 3Go. GFRs were not different between the theophylline and saline groups at any given time point. The number of patients with a decrease of >10% or >30% of GFR from baseline was six and four in the saline group, and seven and three in the theophylline group, respectively. Also, analysis of the whole patient group or of subgroups did not appear to affect these results. Increases in serum creatinine of >=0.5 mg/dl from baseline were observed in one patient in the theophylline group and two patients in the NaCl group, and increases of >=0.4 mg/dl were observed in five patients in the theophylline group and four patients in the NaCl group. No patients needed dialysis or developed other clinical signs of ARF.



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Fig. 3.  GFR ([51Cr]EDTA clearance) in all patients in the trial (A, NaCl group; B, theophylline group) and of patients that received study medication at least until the day 2 post-operation (C, NaCl group; D, theophylline group).

 

Fluid intake/output
Fluid intake and urine excretion during the first 48 h after surgery were ~10 l in both the theophylline and NaCl groups. Both fluid administration and urinary output ranged between ~5 l and 7.5–8 l during the first 12 and 24 h after surgery, independent of the study medication. High levels of fluid administration are part of the postoperative treatment standard in our Department of Cardiac Surgery. Daily furosemide dose and duration of administration did not differ between the theophylline and saline group. The same holds true for dopamine, dobutamine and i.v. nitroglycerin. Serum potassium levels also did not differ between groups and were not associated with arrythmias or other side effects.

Blood pressure and heart rate
Systolic and diastolic blood pressures ranged from approximately 135/75 mmHg throughout the trial and did not differ between the theophylline and placebo group. Heart rate ranged from ~100 b.p.m. and again appeared to be unaffected by treatment with theophylline in comparison with saline.

Plasma theophylline concentrations
Plasma theophylline concentrations reached nearly 6 mg/l after only 6 h and remained, on average, in the region of 7.1±0.5 mg/l for the remaining time.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study demonstrates that prophylactic treatment of well balanced patients undergoing CABG with the non-selective adenosine receptor antagonist theophylline does not appear to have a beneficial effect on renal function. Specifically, mean daily serum creatinine was unchanged up to 5 days after surgery, both in the theophylline and the saline group, and the number of patients with an increase in postoperative serum creatinine was identical in both groups. Furthermore, measurements of GFR at days 1, 3 and 5 post-operation were not different from baseline GFR.

Our study is in contrast to the study of Erley et al. [10], which demonstrated the prevention of a decline in GFR after radiocontrast with theophylline. However, in this study GFR was already measured during the first 4 h after radiocontrast administration, and serum creatinine tended to decrease both in the theophylline and placebo group by 0.1–0.2 mg/dl 4 h after radiocontrast application; serum creatinine measured on the following days are not given [10]. Therefore, it is possible that we have not been able to detect subtle and early changes in GFR (and a potential effect of theophylline) due to the design of our study; however, clinically relevant changes in renal function should have been picked up.

Another important confounder of susceptibility to ARF is the amount of fluid intake (hydration) before, during and after the renal insult [15]. In our study, all patients received large amounts of fluid during and after aortocoronary bypass grafting, thereby probably ameliorating renal damage and blunting the potential treatment effects of theophylline. In a follow-up study by Erley et al. to their previous report [10], they were unable to demonstrate an effect of radiocontrast application in 64 well hydrated patients on serum creatinine and creatinine clearance during the 3 days after radiocontrast, both in the placebo and theophylline group [16].

Moreover, the patients in our study had a rather low risk of postoperative renal impairment [15], thus lowering the probability of being able to observe ARF and a potential treatment effect. However, due to the pilot character of our study, recruiting high-risk patients with higher morbidity/mortality was considered inadequate. Furthermore, our study, with its rather small number of (low-risk) patients, did not have the statistical power to demonstrate moderate treatment effects of theophylline.

Another issue is dose and duration of theophylline administration. The i.v. bolus of theophylline used in our study was slightly less than that used by Erley et al. [10] (4 vs 5 mg/kg body weight); in our study, however, a continuous infusion of theophylline was also given for 4 days. The plasma theophylline concentrations reached in our study were in the same range as those achieved by Erley et al. [10], and are considered therapeutic for the treatment of asthma bronchiale, for example [17]. Since pharmacokinetics of theophylline during CABG are not well known and because liver function might be affected by the surgical procedure itself, we tried to avoid toxic concentrations of theophylline by aiming at the lower therapeutic dose range [17].

Concomitant medication could also be of relevance to the results of our study. However, both patient groups were well balanced with regard to the use of concomitant medication such as furosemide and dopamine.

ARF after CABG may, in contrast to radiocontrast-induced ARF, not be responsive to theophylline treatment.

Another important result of our study is the issue of feasability of a larger study with theophylline in patients undergoing cardiac surgery. The number of patients, where withdrawal of study medication was considered necessary by the treating physician, was not different between the theophylline and the saline group. Cardiac arrhythmias, blood pressure and heart rate were also unaffected by theophylline treatment. A study with a larger number of patients would therefore appear feasible with regard to safety, blinding and handling of study procedures.

Recently, specific adenosine A1 receptor antagonists have been shown to prevent or ameliorate experimental ARF. In various models of established ARF in rats, adenosine A1 receptor antagonist proved to be a more potent diuretic than thiazides or loop diuretics [18]. A diuretic effect of adenosine A1 receptor antagonists has also been shown in patients with chronic renal failure, and in cirrhotic patients with ascites [19,20]. Therefore, a trial using adenosine A1 receptor antagonists (with a more favourable side-effect profile than theophylline) for prevention of ARF in (high-risk) patients undergoing cardiac surgery could prove to be an attractive option for further study.



   Acknowledgments
 
We acknowledge the helpful comments of Prof. F. Kokot (Katowice, Poland), and of Dr C. Erley and Prof. H. Osswald (Tübingen, Germany). Special thanks go to T. Wondrak and M. Thierauf, without whom this study would not have been possible. This study was supported by a grant from former Hoechst AG (now Aventis), which covered the costs of patient insurance. Braun-Melsungen covered the cost of study medication.



   Notes
 
Correspondence and offprint requests to: Dr B. K. Krämer, Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany. Email: bernhard.kraemer{at}klinik.uni\|[hyphen]\|regensburg.de Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 3. 2.01
Accepted in revised form: 11.12.01