Acute renal failure (ARF) developing after cardiac surgery substantially increases mortality rates. The analysis of our treatment results shows that about 2% of patients undergoing surgery require renal replacement therapy. The pathogenesis of ARF is complex; the fundamental problems involve toxaemia (endogenous and exogenous), metabolic disorders, sequels of ischemia-reperfusion syndrome, neurohormonal activation, generalized inflammatory reaction, and oxidative stress [1]. The processes mentioned are natural consequences of the surgical techniques used, therapy and coexisting diseases (extracorporeal circulation, diabetes, obesity, myocardial infections). The direct causes of renal ischemia in the perioperative period are low cardiac output syndrome, hypotension unrelated to cardiac function and renal artery thrombi.

Continuous renal replacement therapy (CRRT) requires anticoagulation to prevent clotting in the dialysis circuit, to protect the filter function and to avoid frequent changes of sets. Intensive anticoagulation in the early postoperative period or in severely ill patients with coagulopathy is likely to increase dangerously the bleeding. Bleedings were observed in 5-25% patients administered bedside replacement therapy with heparin [2]. The contraindications for heparin are history of heparin-induced thrombocytopenia, heparin allergy, intracranial haemorrhage within past 3 months, alimentary bleeding requiring blood transfusion (>2  red blood cell packs over past 3 months), extensive trauma, platelet count  <40 000 mm-3, coagulopathy (INR >2; PTT >60 sec; fibrinogen <1.0 g L-1) [3].

Blood coagulation cascade can be inhibited using regional citrates in the haemofiltration system. Citrates bind calcium decreasing its concentration in blood. The concentration of ionized calcium below 0.35 mmol L-1 prevents the development of thrombi (calcium is a cofactor in the clotting system, its deficiency inhibits the synthesis of thrombin) [4]. Citrates administered to the extracorporeal system are partially excreted with the dialysate by diffusion through the filter membrane. The molecular weight of a citrate is max. 300 Da and its small molecules diffuse easily through the filtration membrane to the dialysate [5]. The remaining portion of citrates passes to the bloodstream where it is converted to citric acid metabolized into bicarbonates in the liver, kidneys and muscles; three molecules of NaHCO3 are produced from each citrate molecule [6].

During therapy, the concentration of ionized calcium in the blood outside the system should range from 1.05 to 1.15 mmol L-1; to obtain such a concentration, calcium has to be continuously supplemented. The second source of ionized calcium in blood is metabolism of citrates, which pass from the extracorporeal system to the systemic circulation. Proper ionized calcium concentrations in blood prevent systemic coagulation abnormalities.  

Citrates for renal replacement therapy are contraindicated if the ionized calcium concentration in blood is <0.7 mmol L-1; pH > 7.6; sodium concentration > 160 mmol L-1 [3]. It is extremely difficult to use citrate anticoagulation in patients with liver failure due to possible accumulation of citrates and toxic effects of their high levels [7].

The present report describes continuous renal replacement therapy with regional citrate anticoagulation in three patients with acute postoperative renal failure and at risk of haemorrhage.

CASE REPORTS

Case 1. A 59-year-old female patient with extreme left ventricular failure of ischaemic origin and multi-organ insufficiency was qualified for artificial left ventricle implantation. The procedure was uneventful. In the early postoperative period, the patient developed respiratory failure of unknown aetiology. Bronchoscopy demonstrated the tumour in the trachea occluding periodically the lumen of the right bronchus. The patients required repeated bronchoscopies (the tumour removal, bronchial tree toilet), which was complicated by the bleeding from the bronchial tree mucosa; moreover, gastroscopy showed the presence of gastric tube-induced bleeding. Preoperative diarrhoeas persisted. The patient required parenteral feeding.

These complications led to acute renal failure, which overlapped the existing chronic renal insufficiency. On postoperative day 15, renal replacement therapy was used. Regional anticoagulation was decided due to coumarin (artificial left ventricle) administered and incidents of alimentary and pulmonary bleedings. The parameters were routinely set for a patient weighing< 60 kg at: blood flow 80 mL min-1; dialysate flow 1500 mL h-1, citrate dose 4 mmol L-1; ionized calcium dose 1.7 mmol L-1 [8]. During the therapy, doses of citrates and calcium were adjusted to concentrations of ionized calcium in the system and in patient`s blood according to the manufacturer’s recommendations.  The calcium levels were determined every 6 h. The volume of ultrafiltration was adjusted to the patient`s status. No electrolyte or acid-base balance abnormalities were observed. The therapy was successfully completed after 9 days. During renal replacement therapy, the filter was changed twice, as scheduled.

Case 2. A 38-year-old patient was hospitalized to treat the complex aortal valve defect and to undergo coronary stenting. In 2007, due to end-stage renal failure caused by glomerulitis, the patient underwent renal transplant. The transplanted kidney did not resume its function. The patient was chronically dialyzed since 1996. The Bentall procedure (implantation of valvular conduit) modified by Urbański (reconstruction of coronary sinuses) was performed under extracorporeal circulation. The mechanical aortic valve was implanted  and two coronary by-passes inserted. Due to low ejection fraction of the left ventricle, the patient required catecholamines. Despite routine management (dialysis on the day preceding surgery) and haemodiafiltration during extracorporeal circulation, renal replacement therapy had to be instituted immediately after surgery. The blood potassium concentration was high (high volume of cardioplegic fluid, red blood cells transfused). Haemodiafiltration with regional citrate anticoagulation was applied. The therapy was started at postoperative hour 4 and maintained for 37 hours. The parameters were set according to the manufacturer’s guidelines: blood flow 100 mL h-1, dialysate supply 2000 mL h-1 (body weight >60 kg) [8]. During the first 24 h after surgery, the drain blood loss was 1130 mL. On day 1, aspirin and dalteparine were administered. On day 2, citrates were changed to heparin (as scheduled) due to necessity to institute anticlotting therapy (artificial valve, epicardial stimulation). No metabolic alkalosis was observed during the therapy. The platelet count decreased by 60% compared to the baseline value, there were no features of bleeding or thrombosis. Due to persistent transudate, the pleural drains had to be maintained in place. On day 6, the patient left the postoperative ward in satisfactory general condition and haemodialysis was resumed.

Case 3. A 21-year-old patient with idiopathic pulmonary fibrosis was qualified for lung transplantation. The diseases was accompanied by right ventricular failure with features of severe pulmonary hypertension and chronic renal failure (240 mg of furosemide a day were needed). Both lungs were transplanted and tricuspid valvuloplasty carried out under extracorporeal circulation. In the early postoperative period, the patient developed ischemia-reperfusion trauma and infection, which were manifested by respiratory distress requiring prolonged ventilation and tracheostomy. The concentration of creatinine gradually increased (>300 µmol L-1); oliguria was observed. The decision was made to institute scheduled renal replacement therapy on postoperative day 16. The continuous heparin infusion induced pumonary bleeding. After two days, the therapy was restarted using citrate anticoagulation with the blood flow of 120 mL min-1 and dialysate volume of  2500 mL h-1 (body weight >90 kg) [8]. After three days of therapy, metabolic alkalosis developed with pH 7.55 and elevated bicarbonate concentration in blood. The blood flow was reduced to 80 mL min-1 yet without improvement. The dose of dialysate was increased to 3000 L h-1. Thanks to these actions, pH stopped to increase but metabolic parameters were not normalized. Renal replacement therapy was successfully discontinued after 6 days. The filter was changed twice, as scheduled. During citrate anticoagulation, no pulmonary bleeding was observed.

DISCUSSION

The complications of citrate anticoagulation include electrolyte disturbances, acidosis or alkalosis. Low concentrations of ionized calcium result in impaired contractility of the myocardium. Such abnormalities were earlier observed only under experimental conditions [9]. The recent studies demonstrate that low concentrations of ionized calcium occur in patients with liver failure; thus, the total calcium-ionized fraction ratio should be determined. [10]. Liver failure prevents the metabolism of citrates and the circulating calcium bound to them enters the total pool. The total calcium-ionized fraction ratio > 2.5 suggests increased supply of ionized calcium before its concentration dangerously decreases. In such cases, electrolyte concentration during therapy should be determined every 2 h. Limited citrate supply is not recommended as this management markedly increases the risk of coagulation of the system.

Regional anticoagulation may also induce hypernatraemia as the citrate used is a trisodium compound. The risk of hypernatraemia may be eliminated using low-sodium content dialysates. Low phosphate concentrations result from their lack in dialysis and substitutive fluids (haemofiltration). Phosphates are the elements of ATP; their deficiencies cause energy dysfunction of cells and lead to functional abnormalities of the heart and striated muscles or to hypodynamic respiratory insufficiency. During renal replacement therapy, determinations of their concentration in blood serum as well as of magnesium, which forms complexes with citrates diffused during dialysis, are obligatory.

Citrate anticoagulation may impair the acid-base balance. The excess of citrates, which does not permeate the dialysate, passes to the circulatory system where it is metabolized to bicarbonates. The excessive amounts of bicarbonates cause metabolic alkalosis, which requires interventions in about 50% of patients [5].

In general, patients undergoing renal replacement therapy develop metabolic acidosis; pH tends to increase after about 3 days of therapy. To avoid the excess of bases in blood, dialysates with low bicarbonate concentrations were introduced (20 mmol L-1). Alkalosis may be corrected in two ways. Firstly, the dialysate flow may be increased thus bigger amounts of citrates are eliminated with the dialysate. The clinical experiences show that an increase in dialysate flow by 20% is sufficient to correct the abnormalities [7]. It should be pointed out, however, that an increase in dialysate doses only due to metabolic abnormalities results in clinically ungrounded increases in therapy costs [5]. Another option is to reduce the blood flow (the citrate dose required for effective anticoagulation is proportional to the blood flow). Reduced blood flow determines the reduction in the citrate dose, which results in limitation of their passage to the bloodstream. The final and desirable effect is lowered number of bicarbonate molecules formed during citrate metabolism and lower pH of blood. 

Metabolic disturbances manifest themselves during 30-40 h after the onset of renal replacement therapy. If metabolic alkalosis develops, the blood flow should be reduced; once this fails, the dialysate flow should be increased. The dialysate flows up to 4 000 mL h-1 were successfully used [5, 7].

Regional anticoagulation markedly reduces the risk of bleeding during therapy. Patients, who did not receive heparin, required significantly lower doses of red blood cells than those receiving the drug in continuous infusions [11]. In patients without the risk of bleeding, the therapy with regional anticoagulation is safer than that with low-molecular-weight heparin [4]. Lower mortality rates were observed in patients receiving citrates to provide anticoagulation in the haemofiltration circuit [4].

Experiences gained during routine bedside renal replacement therapy in patients in the early postoperative period enable to perform safely and effectively the procedure of haemofiltration using regional citrate anticoagulation. This type of anticoagulation allows using renal replacement therapy also in patients with a high risk of bleeding. Once the concentration of ionized calcium in the system is maintained at 0.25-0.35 mmol L-1 and in the blood at 1.12-1.2 mmol L-1, the clotting in the haemofiltration circuit is not observed.

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REFERENCES

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2.    Oudemans-van Straaten HM, Wester JPJ, de Pont ACJ, Schetz MRC: Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med 2006; 134: 188-202.

3.    Kutsogiannis DJ, Gibney N, Stroller D, Gao J: Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 2005; 67: 2361-2367.

4.    Oudemans-vas Straaten HM, Bosman RJ, Koopmans M, van der Voort PHJ, Wester JPJ, van der Spoel JI, Dijksman LM, Zandstra DF: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37: 2-9.

5.    Kindgen-Milles D, Amman J, Kleinekofort W, Morgera S: Treatment of metabolic alkalosis during continuous renal replacement therapy with regional citrate anticoagulation. Int J Artif Org 2008; 31: 363-366.

6.    Monchi M, Berghamas D, Ledoux D, Canivet JL, Dubois B, Damas P: Citrate vs heparin for anticoagulation in continuous veno-venous haemofiltration: a prospective randomized study. Inten Care Med 2004; 30: 260-265.

7.    Morgera S, Schneider M, Slowinski T, Vargas-Hein O, Zuckermann-Becker H, Peters H, Kindgen-Milles D, Neumayer HH: A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid-base status. Crit Care Med 2009; 37: 2018-2024.

8.    Morgera S: Regional anticoagulation with multiFiltrate
Ci-Ca. Basic principles and clinical implementation. Fresenius Medical Care 2006.

9.    Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990; 38: 976-981.

10.    Meier-Kriesche HU, Gitomer J, Finkel K, DuBose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med 2001; 29: 748-752.

11.    Betjes MG, van Oosterom D, van Agteren M, van de Wetering J: Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding. J Nephrol 2007; 20: 602-608.

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Address:

*Ewa Kucewicz-Czech
Oddział Kliniczny Kardioanestezji i Intensywnej Terapii Śląskiego UM
ul. Szpitalna 2, 41-800 Zabrze
tel.: 0-32 3733724, tel./fax 0-32 273 27 31
e-mail: kardanest@sum.edu.pl

Received: 21.08.2009
Accepted: 21.09.2009