SUMMARY. Continuous renal replacement therapy (CRRT) is a relatively new therapeutic procedure which helps in the treatment of critically ill patients with renal failure as well as those without renal failure. CRRT effectively removes urea and creatinine and maintains a balanced milieu interieur and water balance. A role in the elimination of pro-inflammatory cytokines is also ascribed to this method. Most frequently venovenous haemofiltration and venovenous haemodiafiltration are used. The authors present their experience with the CRRT treatment of 40 patients in the Burn Centre Ostrava and with the results attained.
Die Behandlung mithilfe der kontinualen Eliminationsmethoden bei patienten mit Verbrennungstrauma
Hladik M., Tymonovä J., Zaoral T., Kadlcik M., Adämkovä M.
Die kontinualen Eliminationsmethoden (continuous renal replacement therapy - CCRT) stellen ein ziemlich neues Behandlungsverfahren dar, das in der Behandlung bei kritisch Erkrankten mit oder ohne Nierenversagen hilft. Das CCRT beseitigt wirksam Urea and Kreatinin, erhält eine ausgeglichene innere Umwelt and Wasserbilanz. Der CCRT wird auch die Rolle bei Elimination der entzündlichen Cytokinen anerkannt. Am meisten wird die venovenöse Hemofiltration and venovenose Hemodiafiltration benützt.
Die Autoren führen seine Erfahrungen mit Behandlung von 40 Patienten mithilfe der CCRT am Verbrennungszentrum in Ostrava and seine Ergebnisse ein.
Key words: continuous renal replacement therapy, renal and non-renal indications, systemic inflammatory response
The continuous development of medicine makes possible ever newer therapeutic and diagnostic procedures. Areas that develop very dynamically also include the treatment of critical conditions, concerned with the treatment of patients affected with multiple organ dysfunction syndrome (MODS) or their failure - multiple organ failure (MOF). Several medical disciplines participate in the solution of this problem in patients who are in serious or critical condition, in particular the disciplines of intensive care, surgery, nephrology, microbiology, radiology, biochemistry, immunology, haematology, and others, if necessary.
For a long time nephrologists were not included among the specialists engaged in problems of critical conditions. Till recently they were able to offer, when renal replacement therapy was necessary, only classical intermittent haemodialysis. During the last two decades, based on findings of changes that develop in severely afflicted patients, the sub-discipline, critical care nephrology, developed. The basic therapeutic procedure in this sphere is continuous renal replacement therapy (CRRT).
The history of CRRT is relatively short. Its beginning was in 1977 when Kramer, while introducing a catheter into the femoral vein before haemodialysis, accidentally inserted the catheter into the femoral artery. He realized the possibility of using the arteriovenous gradient for filtration of blood and fluid elimination. He replaced the excessive losses by continuous infusion of substituting solutions. He used for the method the term continuous arteriovenous haemofiltration (CAVH). This was the first step in CRRT.
Principle of action of CRRT and its implementation
The basic principle of action of CRRT is the elimination of inflammatory mediators, urea, creatinine and uraemic toxins from the organism. At the same time it makes possible the maintenance of a stable milieu interieur and water balance. It makes use of four physical principles: ultrafiltration, convection, diffusion and adsorption.
Inflammatory mediators (cytokines, thromboxane A2, leukotriens and prostaglandins) serve as regulatory agents of the defense response of the organism. They influence the growth, differentiation and mobility of immune cells and act directly on the causal, most frequently bacterial, agent. They function thus as activating and defense factors of inflammation and have the main role in localizing the inflammation and its elimination. They thus create conditions for repair of the affected organ. If, however, the inflammatory mediators extend beyond the focus (in the case of extensive multiple injuries, burns or septicaemia), generalization of the inflammatory response occurs, manifested clinically (hyperpyrexia, destabilization of the circulation, procoagulation activity, development of DIC, ARDS, renal and hepatic failure) and by laboratory indicators (leucocytosis, high CRP, high lactate, decline of albumin, decline of AT III, thrombocytopenia, acidosis, changes of biochemical parameters of the function of dif
ferent organs). Generalization of the inflammatory response thus leads to the systemic inflammatory response syndrome SIRS. Its consequence is usually MODS or possibly MOF.
CRRT has the capacity to eliminate inflammatory mediators, depending on the type of filter used, up to 30 000-50 000 daltons (D). The basic mediators and their molecular weights are given in Table 1.
To ensure adequate elimination of these mediators, urea and creatinine in the CRRT filtration system, the patient must be rinsed by at least 1.5-2 litres of substitution solution/1.73 m2 /hour. The composition of the solution depends on the state of the milieu interieur of the patient. Presently, arteriovenous methods, in which the heart is driven by an extracorporeal system, are practically not used. Almost exclusively venovenous methods are used with pumps with a venous access by means of double-lumen catheters.
A basic and complex problem of CRRT is the use of anticoagulation to maintain a functional extracorporeal system. So far there is no fully biocompatible material for extracorporeal circulation that does not induce blood coagulation and the formation of inflammatory mediators during the procedure. In order to prevent this undesirable phenomenon, depending on the patient's status and his coagulation status, several anticoagulation methods are used: a) anticoagulation by nonfractionated heparin (UFH), b) anticoagulation by low-molecular heparin (LMWH) and c) citrate anticoagulation by means of 4% sodium citrate.
<% createTable "Table I","Some mediators of SIRS/septicaemia",";Mediator ;Molecular weight (D)@;Thromboxane A2;352@;PAF;524@;Leukotriens ;600@;Complement 3a;10000@;Complement 5a ;11200@;Interleukin 1, 2 ;15000@;Tumor necrosis factor alpha ;17000@;Interleukin 6 ;25000@;Endotoxin ;100000","",4,300,true %>The most frequent modifications of CRRT
At present, venovenous continuous elimination methods are used almost exclusively. The most frequently used method is continuous venovenous haemofiltration (CVVH), in which the patient is rinsed with a substitution solution. This method is based on the physical principle of convection. While diuresis is maintained, the amount of supplied solution is equal to the amount of filtered liquid. If the patient does not pass urine, the system makes it possible to maintain the balance of the patient by filtering a larger volume of fluid than the volume of supplied solution.
Another continuous method is continuous
haemodiafiltration (CVVHDF). The method is based on the principle of convection supplemented by diffusion known from classical haemodialysis. CVVHDF is used in case if CVVH is not sufficient for maintaining urea and creatinine levels. The diffusion rate in CVVHDF is, however, many times lower than in classical intermittent haemodialysis, and thus the patient does not run the danger of disequilibration syndrome due to sudden and rapid changes of the milieu interieur. This method imitates very well the external excretory renal function.
<% immagine "Fig. 1","gr0000040.jpg","treatment of a patient in critical condition with burns.",230 %>
Indications of CRRT
During SIRS a modification of MODS and MOF develops and within their framework the kidney may or may not be affected. Also, in conditions without renal affection,CRRT is fully indicated for eliminating inflammatory mediators that damage other organs. Therefore, the indications for CRRT are divided into renal and non-renal. In MODS with renal failure, both indications are interconnected.
Renal indications
They are obvious from the term. The main indication is oliguric renal failure, in which it is possible to eliminate by CRRT fluid in renal hyperhydration and create more space for parenteral nutrition and drug administration. Balancing takes place as required evenly throughout 4 hours. At the same time a stable milieu interieur is maintained and urea, creatinine, uraemic toxins and cytokines are eliminated evenly.
Non-renal indications
This group comprises:
Disadvantages and complications of CRRT
In the indications for CRRT in critically ill patients, contraindications are not considered because methods are involved that can revert fatal disease .Before they are applied, however, it is necessary to consider and minimize possible disadvantages and complications:
From June 1996 till April 2000, the authors treated, using CRRT, 40 patients of the Burn Centre of the Faculty Hospital in Ostrava hospitalized in the intensive care unit. Age of patients in this group was 18-72 years, mean 47.2 The reason for admission was in all instances grade III burns covering 9 to 87 % of the body surface. In 16 patients (40 %) burns of the airways were also involved. Twenty-two patients (55 %) developed shock, which was in the majority of cases associated with sepsis and concurrent, otherwise refractory, hyperpyrexia and circulatory failure.
Ten patients (25 %) developed renal failure, 30 patients (75 %) were treated due to non-renal indications.
Patients who developed renal failure were first treated by intermittent haemodialysis. During onset of oliguria, CVVH and CVVHDF were started.
As to venous approaches, the authors used the right internal jugular vein eight times, four times the left internal jugular vein, ten times the right subclavian vein and eighteen times the femoral vein. Selection of the vascular approach was limited by the site of the burns. The authors used double-lumen catheters GamCath (Joka GmbH, Hechingen, Germany) with a diameter of 11 F and a length of 15 and 25 cm.
CVVH is implemented on an ADM 08 apparatus from the Fresenius Co., and for CVVHDF a Prisma Hospal apparatus is used. In CVVH on a ADM 08 apparatus, high-flux polysulphone capillaries are used and for the Prisma Hospal apparatus high-flux polyacrylonitrile AN 69 is, however considered a better elimination medium with greater biocompatibility. It is, however, also considerably more expensive. During the procedure we prefer predilution connection of the substitution solution and thus replace the filtered-off amount of fluid by supplying the substitution solution before the capillary. This prolongs the service life of the filter, but to a certain extent the effectiveness of haemofiltration is reduced. As the substitution and dialysis solution, Medisol is used, produced by Medites Pharma (Roznov pod Radhostem, CR). The composition is given in Table 2.
The type of solution was selected with regard to laboratory results, in particular the potassium blood level. Lactate serves as an alkalinization substitution in these solutions, and is transformed in the liver into bicarbonate. Therefore, patients with hepatic insufficiency or failure were given as substitution and dialysis solution saline or Ringer's solution and metabolic acidosis was corrected by bicarbonate.
The period of treatment by CRRT varied from 48 to 408 hours.The haemofilter was changed once in 24 to 48 hours.As an anticoagulant for the extracorporeal system, non-fractionated heparin was used in 12 patients, in 27 patients low-molecular heparin (Clexane) and in one patient citrate. The rate of the blood pump varied from 100 to 130 ml/min. The volume of the substitution solution was maintained at 1500-2000 ml/1.73 m2/h. The volume of ultrafiltration was adjusted according to the hydratation state of the patient, values of the central venous pressure, the amount of administered crystalloids and nutritive solutions and losses by diuresis, catheters and perspiration. During the procedure the haemogram, thrombocytes, ionogram, ALT,AST,urea, creatinine and ABB were checked at 6-12hour intervals. As to haemocoagulation examinations, at the mentioned intervals the following were performed: Quick's test, APTT, and thrombin time. Once a day fibrinogen was examined and as necessary the activity of antithrombin III.
From the total number of treated patients, 12 (30 %) survived and 28 (70 %) died. In three patients with an unstable circulation, CVVH was performed during extensive necrectomy and application of a xenotransplant. The large-volume haemofiltration stabilized the patients and made undisturbed general anaesthesia possible and reduced the risk of the procedure.
<% createTable "Table II","Composition of substitution and dialysis solution Medisol",";Name ;Na mmol/l;Cl mmol/l;Ca mmol/l;Mg mmol/l;K mmol/l;Lactate mmol/l;Glucose mmol/l;Osmolality mmol/l@;M 0;140;106,5;1,5;0,75;0;40;1;295@;M 02;140;106,5;1,5;0,75;2;40;1;296@;M 04;140;106,5;1,5;0,75;4;40;1;297","",4,300,true %>The hitherto widespread use of intermittent dialysis in patients in critical condition has revealed a number of pitfalls. They include circulatory instability and a marked drop in blood pressure during the procedure. This is due in particular to the elimination of a large volume of fluid during a brief time, but in hypotension the bicarbonate component of the dialysis solution also participates as well as the inadequate elimination of inflammatory mediators.
During intermittent haemodialysis, a rapid drop of intravascular urea occurs and after the procedure a shift of urea, depending on the concentration gradient, from extravascular spaces into the blood vessels. Therefore rapid re-equilibration occurs, and it is necessary to repeat haemodialysis as frequently as twice a day. Bellomo and Ronco compared two groups of critically ill patients with acute renal failure. The first group, which they treated by intermittent haemodialysis, had a median urea level of 35 mmol/1, while the group treated by CVVH had a median urea level of 23.4 mmol/l. To achieve
the same result, daily seven-hour haemodialysis would be necessary involving the risk of marked variability of the osmolality of the serum, a considerable drop of urea during the procedure and its subsequent rise.
Multiorgan failure involves a great risk for the patient. With failure of two organ systems the lethality is 30-40 %, with failure of three systems it is 60-70 %, and with failure of four systems 80-100 % of patients die. According to available data, CRRT reduces the mortality by 18 % to 28 %.
CRRT makes a controlled fluid balance possible, which may have a decisive effect on the improvement of a number of critical conditions. According to data in the literature and the authors' experience, a marked regression of pulmonary oedema and acute respiratory distress syndrome occurred in MODS/MOF during septic conditions. Standard intermittent haemodialysis is in these instances less effective due to its short-term action. The authors observed repeatedly, when attempting to eliminate a major volume of fluid by intermittent haemodialysis in oliganuric patients, severe hypotension that did not develop during CRRT. When ultrafiltration is discontinued during intermittent haemodialysis, an adequate amount of fluid is not eliminated and further infusion treatment leads to hyperhydration of the patient.
CRRT also make an adequate supply of nutrients possible by creating space for a greater turnover of protein nitrogen. An adequate protein supply (1.5-2 g/kg/day) has a favourable effect on the general condition of critically ill subjects, in particular by invigorating the respiratory muscles, and it promotes cell regeneration of renal tissue.
The results obtained in large groups confirmed that during properly conducted CRRT, disequilibration syndrome does not develop. In the group treated by the authors, disequilibration syndrome was not manifested clinically in any patient and a possible risk of its development was not found in laboratory examinations.
Nephrologists and specialists in intensive care agree that CRRT has a positive effect on the condition of critically ill patients. A controversial point remains the elimination of cytokines and the possible favourable consequences when they are eliminated from the circulation. With regard to the permeability of haemofilters, interleukins 1 and 2 and platelet activating factor should be eliminated directly and interleukin 6, tumour necrosis factor and endotoxins by adsorption onto the surface of the material of the haemofilter. So far there is no uniform view on their elimination by CRRT, and some authors have doubts about the elimination of mediators. At present two multicentre prospective studies are underway that should contribute towards the elucidation of these controversial problems.
J. Tymonovd Burn Center 17.listopadu 1790 708 52 Ostrava Czech Republic
" %>