Extracorporeal blood therapy device

Abstract

The CRRT device comprises a filtration unit (2), a blood circuit (17), a blood pump (21), a dialysate line (13), and one or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring respective solutions to the blood, a fluid source for each of the one or more lines, the solutions including at least one buffer in the form of bicarbonate or a bicarbonate precursor. A control unit (12) receives a patient prescription and is configured to determine a parameter indicative of the steady-state acid-base balance of the blood of the patient who is to receive CRRT blood therapy, the parameter being determined as a function of the concentration of the buffer in the fluid source and as a function of the patient's estimated or calculated systemic steady-state concentration of bicarbonate and / or bicarbonate precursor.

Description

[Technical field]

[0001] The present invention relates to a device for extracorporeal blood treatment and a method for controlling an extracorporeal blood treatment device. More particularly, the present invention is applicable in the context of Continuous Renal Replacement Therapy (CRRT) with or without anticoagulation, e.g. CRRT with or without systemic anticoagulation (e.g. heparin) / CRRT with or without local anticoagulation (e.g. citrate). In particular, the present invention may be advantageously used to administer regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). Furthermore, the device of the present invention may be used to administer extracorporeal CO via extracorporeal blood circulation as an alternative or supplement to mechanical ventilation. 2 Removal or ECCO 2 Using R to efficiently CO 2 The compounds may be advantageously used in CRRT treatments to remove [Background technology]

[0002] The kidneys perform many functions, including the removal of water, the excretion of catabolic products (or waste products from metabolism, e.g., urea and creatinine), the regulation of blood electrolyte concentrations (e.g., sodium, potassium, magnesium, calcium, bicarbonate, phosphate, chloride), and the regulation of the body's acid / base balance (especially through the removal of weak acids and the production of ammonium salts). In individuals who have lost the use of their kidneys (either temporarily or permanently), these excretory and regulatory mechanisms no longer function, so the body accumulates water and waste products from metabolism, exhibiting electrolyte excess and, generally, acidosis, with a downward shifting plasma pH below 7.35 (blood pH normally varies within a narrow range of 7.35-7.45). As mentioned, to overcome renal dysfunction, blood is traditionally treated by extracorporeal circulation via a semipermeable membrane (dialyzer) that circulates the patient's blood on one side of the membrane, and an exchanger that circulates a dialysate, consisting of the major electrolytes in blood similar to that of a healthy individual, on the other side. Moreover, a pressure difference occurs between the two compartments of the dialyzer, which are separated by a semipermeable membrane, as a result of which part of the plasma fluid passes through the membrane by ultrafiltration into the compartment containing the dialysate. Blood processing carried out in the dialyzer in terms of waste products from metabolism and electrolytes is due to two mechanisms of molecular transport through the membrane. On the one hand, molecules move from the liquid in which they are more concentrated to the liquid in which they are less concentrated. This is diffusion transport. On the other hand, certain catabolic products and certain electrolytes are entrained by the plasma fluid passing through the membrane under the influence of the pressure difference created between the two compartments of the exchanger. This is convective transport. Three of the above functions of the kidney, namely water removal, excretion of catabolic products and regulation of the electrolyte concentration of the blood, are therefore carried out in conventional blood treatment devices by a combination of dialysis and hemofiltration (this combination is called hemodiafiltration). With regard to the regulation of the acid / base balance in the body, the approach adopted to overcome renal failure is to act on the mechanism by which the acid / base balance in the body is regulated, this mechanism consisting of the buffer system of the blood, the main one of which contains carbonic acid, as a weak acid, associated with its alkaline salt, bicarbonate. This is why, to correct the acidosis in a patient with renal failure, it is administered to the person via the vascular route, together with bicarbonate, directly or indirectly during a hemodialysis session.In the field of renal treatment, continuous renal replacement therapy (CRRT) is widely used in critically ill patients with acute kidney injury, and extracorporeal blood anticoagulation is required to maintain the patency of the circuit. In recent decades, different anticoagulation strategies have been used in clinical practice, with heparin being the most commonly used anticoagulant. Heparin has the advantages of low cost, easy monitoring, and simple reversal, but it may increase bleeding. In addition, it has the risk of heparin-induced thrombocytopenia type II, which may result in life-threatening complications. Regional citrate anticoagulation (RCA), first introduced into clinical use in the early 1980s, is recommended as the most suitable form of CRRT local circuit anticoagulation and has been used safely even in patients with severe liver dysfunction. However, citrate infusion in critically ill patients affects various metabolic systems that may lead to metabolic alkalosis, hypocalcemia, and citrate overload / toxicity. These potential obstacles may be partially resolved by careful monitoring, adherence to treatment protocols, and monitoring by staff trained in clinical practice. Despite the importance of the above, citrate anticoagulation has become the preferred anticoagulation option for continuous renal replacement therapy (CRRT) because it minimizes the patient's bleeding risk (local anticoagulation) and increases extracorporeal blood circuit life. Although RCA has some limitations regarding compatibility with "large" blood rates, this is not an issue in CRRT, where efficiency is primarily driven by the rate of fluid exchange and the majority of therapy is delivered at blood rates below 200 ml / min. On the other hand, ECCO. 2 The efficiency of RCA therapy is more or less proportional to the blood rate, with blood rates in the range of 350-450 ml / min typically prescribed. These large blood rates are obviously incompatible with the typical RCA prescriptions used in CRRT (citrate dose of 3.0 mmol / L of blood) due to the large amount of citrate infused into the patient (citrate load) and associated effects. The effects of a high patient citrate load include metabolic alkalosis and citrate accumulation / hypocalcemia. The fast metabolism of the citrate infused into the patient is part of the key mechanism for successful RCA. Citrate metabolism produces energy as well as bicarbonate and CO2.2 While producing bicarbonate, it releases complex calcium. In situations where large amounts of citrate are infused into a patient, large amounts of bicarbonate are produced, to the point where metabolic alkalosis is produced. Citrate accumulation is consistent with a scenario in which systemic citrate concentrations increase significantly. It can develop in two situations: when a "normal" citrate load is combined with poor citrate metabolism, and when a "normal" citrate metabolism is combined with a large citrate load. The first scenario is more likely to lead to metabolic acidosis, due to the low rate of bicarbonate production from citrate. The second scenario is more likely to lead to metabolic acidosis, particularly in the setting of ECCO. 2 It should be considered with regard to CRRT treatment in the R-RCA context. The consequence of citrate accumulation is the need to increase the total calcium concentration in order to keep the (systemic) ionized calcium within the physiological range. This is achieved by increasing the calcium infusion rate. This is a temporary issue during the initiation of treatment, since a safe steady state is reached after stabilization of the systemic citrate concentration (6-8 hours). However, stopping treatment can lead to episodes of hypercalcemia (as citrate is metabolized and complex-bound calcium is released). In clinical practice, citrate accumulation is diagnosed via monitoring the systemic total to ionized calcium ratio (a ratio >2.5 indicating possible citrate accumulation). Thus, while local anticoagulation may highly mitigate the adverse effects of heparin, RCA requires adequate monitoring of the acid-base balance of the patient's blood, significantly increasing the risk of alkalosis. Furthermore, ECCO 2 In R therapy, ECCO 2 Due to the conflicting requirements of the R and RCA modalities, RCA cannot be implemented satisfactorily. ECCO 2 In R, CO 2 The removal performance is directly related to blood velocity with the removal rate increasing strongly with blood flow. Under the current CRRT operating conditions of moderate fluid exchange rates (approximately 30 ml / kg / h), high blood rates are not possible because they would lead to excessive citrate infusion (via blood return) into the patient, which could lead to both metabolic alkalosis and hypocalcemia. Thus, the current ECCO 2 The design of R and RCA-CRRT was designed to provide satisfactory CO2 delivery, given that CRRT with RCA is rarely performed safely at blood rates above 200 ml / min in available commercial CRRT systems. 2 It drives conflicting requirements on blood velocity making delivery of clearance (greater than 50 ml / min clearance) impossible.

[0003] EP 0678301 concerns an artificial kidney for intensive care, especially adapted for the treatment of persons suffering from temporary renal failure following accidents or surgical operations. As revealed in the prior art documents, in addition to purifying plasma waste products (e.g. urea) and removing excess water, the kidney plays an important role in maintaining the acid-base balance of the blood. The main problem according to document EP 0678301 is that the concentration of bicarbonate in the patient's blood hardly ever corresponds exactly to the desired concentration, since the final concentration of bicarbonate in the blood depends on the concentration of bicarbonate in the perfusate or dialysate, their respective rates and on the rate of the patient's blood through the membrane exchanger. EP 0678301 describes a blood treatment device comprising a dialyzer with two chambers separated by a membrane. A dialysate container (not containing any bicarbonate) is connected to a fluid pump via a tube that passes through the second chamber of the dialyzer. An electromagnetic clamp is provided for connecting the container either to the dialyzer or to the blood circuit. A bubble trap is provided in the return line of the blood circuit. The bubble trap is connected to an infusion vessel containing a solution of bicarbonate. According to EP0678301, regardless of the type of therapy delivered to the patient by any of the formulas, the speed of the dialysis fluid pump Q OUT Circulation pump speed Q as a function of HCO3 is controlled. Q HCO3 =Q OUT * [HCO 3 ]DES / [HCO 3 ] SOL or by the following formula: Q HCO3 =Cl * [HCO 3 ] DES / [HCO 3 ] SOL Q HCO3 is the speed of the circulation pump, Q OUT is the speed of the dialysis fluid pump Q OUT That is, [HCO3] DES is the desired concentration of bicarbonate in the patient's blood; [HCO3] SOL is the concentration of the fluid in the container, Cl is the dialyzer clearance of bicarbonate.

[0004] In particular, this prior art is directed to properly regulating the acid-base balance of a patient's blood by using specific control of post-infusion of bicarbonate solution based on clearance / dialysate rate that works exclusively for the following dialysis machine configurations: HF with post-dilution and HD(F) with post-dilution. Thus, the problem of proper acid-base management in configurations where citrate is infused before the blood pump (e.g., regional anticoagulation systems) and / or where a bicarbonate-containing solution is pre-infused remains unsolved.

[0005] With regard to adapting to a particular patient's condition, the protocol may include guidelines (not far from systematic) for adjusting the citrate infusion or dialysate / substitution fluid rates if patient monitoring data evidence problems with alkalosis or acidosis. These guidelines, when they exist, appear to be largely empirical. There are some literature reports on the infusion of a bicarbonate "bolus" in case of acidosis. Some published protocols are derived from some upstream model, but no parameters representative of the buffer equilibrium expected from the treatment are explicitly available, regardless of which "original" protocol parameters are used, or even after these have been further adjusted to patient monitoring data. Summary of the Invention

[0006] It is an object of the present invention to provide an extracorporeal blood treatment device which is able to mitigate or ameliorate at least one of the disadvantages of the prior art.

[0007] In particular, it is the object of this embodiment to enable acid-balance control / management, and the system is also designed to alter the buffer balance of the extracorporeal blood circuit in an easy and controlled manner.

[0008] A further goal is to increase the safety of RCA prescribing by alerting the operator when prescribing at significant risk of patient alkalosis or acidosis, particularly in ICU settings where the prescriber may not be an expert in dialysis, and / or when initiating RCA.

[0009] Some embodiments make RCA prescription easier / safer for "abnormal" sized patients where standard prescriptions may not be applicable.

[0010] A further object of some of the described embodiments is to provide a method for treating CRRT+ECCO using local anticoagulation during CRRT treatment. 2To provide an extracorporeal blood treatment device configured to safely enable ECCO R treatment and / or extracorporeal blood treatment, i.e. 2 The goal is to have access to dialysis machines capable of providing R therapy and CRRT therapy using regional anticoagulation, particularly RCA.

[0011] A subsidiary goal is to have available an extracorporeal blood treatment device configured to maintain buffer balance within acceptable limits even in configurations operating the system at high blood velocities.

[0012] At least one of the above objects is achieved by an apparatus and corresponding method as claimed in one or more of the appended claims, taken alone or in any combination.

[0013] According to a first independent aspect of the present invention, an extracorporeal blood treatment device, in particular a continuous renal replacement therapy (CRRT) device, comprises: a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5); a blood circuit (17) configured for connection to a patient's cardiovascular system, the blood circuit having a blood withdrawal line (6) connected to an inlet of the primary chamber (3) and a blood return line (7) connected to an outlet of the primary chamber (3); a blood pump (21) for circulating blood in the blood circuit (17); a dialysate line (13) connected to the outlet of the secondary chamber (4); One or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring each solution into the bloodstream; at least one fluid source of solution for each of the one or more lines, the solution comprising at least one buffer in the form of bicarbonate or a bicarbonate precursor; a control unit (12) configured to receive a patient prescription including parameters for setting up a CRRT blood therapy; The control unit (12) A parameter indicative of the steady-state acid-base balance of the blood of the patient who is to undergo CRRT blood therapy (J buffer _ load / BW), the parameter being determined as a function of the concentration of the buffer in the fluid source and as a function of the estimated or calculated patient's systemic steady state concentration of bicarbonate and / or bicarbonate precursors; or A parameter indicative of the steady-state bicarbonate concentration of the blood of the patient who is to undergo the CRRT blood treatment (Cp HCO3 _ pat ), the parameters being a function of the concentration of the buffer in the fluid source, and the estimated or calculated net buffer load (J), which is indicative of the steady-state acid-base balance of the blood of the patient. buffer _ load / BW) The method is further configured as follows.

[0014] In a further independent aspect, there is provided a method for determining a parameter indicative of a steady state bicarbonate concentration of blood in a patient having to undergo CRRT blood therapy, the method being for an extracorporeal blood treatment device, in particular a continuous renal replacement therapy (CRRT) device, the extracorporeal blood treatment device comprising: a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5); a blood circuit (17) configured for connection to a patient's cardiovascular system, the blood circuit having a blood withdrawal line (6) connected to an inlet of the primary chamber (3) and a blood return line (7) connected to an outlet of the primary chamber (3); a blood pump (21) for circulating blood in the blood circuit (17); a dialysate line (13) connected to the outlet of the secondary chamber (4); One or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring each solution into the bloodstream; at least one fluid source of solution for each of the one or more lines, the solution comprising at least one buffer in the form of bicarbonate or a bicarbonate precursor; A control unit (12). The method comprises: Receiving a patient prescription containing parameters for setting up CRRT blood therapy and a parameter indicative of the steady-state bicarbonate concentration of blood in the patient who is to receive CRRT blood therapy (J buffer _ load and determining a parameter (i.e., a function of the concentration of the buffer in the fluid source and of the estimated or calculated patient's systemic steady state concentration of bicarbonate and / or bicarbonate precursors), the steps being performed by a controller.

[0015] In a further independent embodiment, a parameter indicative of the steady-state bicarbonate concentration of blood in a patient who is to undergo CRRT blood therapy (Cp HCO3 _ pat The present invention provides a method for determining a blood flow rate of an extracorporeal blood treatment device, in particular a continuous renal replacement therapy (CRRT) device, the method comprising: a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5); a blood circuit (17) configured for connection to a patient's cardiovascular system, the blood circuit having a blood withdrawal line (6) connected to an inlet of the primary chamber (3) and a blood return line (7) connected to an outlet of the primary chamber (3); a blood pump (21) for circulating blood in the blood circuit (17); a dialysate line (13) connected to the outlet of the secondary chamber (4); One or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring each solution into the bloodstream; at least one fluid source of solution for each of the one or more lines, the solution comprising at least one buffer in the form of bicarbonate or a bicarbonate precursor; A control unit (12). The method comprises: Receiving a patient prescription containing parameters for setting up CRRT blood therapy and a parameter indicative of the steady-state bicarbonate concentration of blood in a patient who is to receive CRRT blood therapy (Cp HCO3 _ pat ), wherein the parameter is determined as a function of the concentration of the buffer in the fluid source and as a function of the estimated or calculated patient's systemic steady state concentration of bicarbonate and / or bicarbonate precursors, steps performed by a controller.

[0016] According to any one of the previous aspects, in a second aspect, a parameter indicative of the steady-state acid-base balance of blood of a patient undergoing CRRT treatment (J buffer _ load / BW) is a parametric function of the net buffer load (NBL) in a patient predicted at steady state, specifically the net buffer load (nNBL) in a patient predicted at steady state, more specifically: TIFF0007657218000001.tif13145

[0017] According to the previous embodiment, in a third embodiment, the net buffer load (NBL) is normalized to the patient's body weight (BW).

[0018] According to any one of the previous aspects, in a fourth aspect, the bicarbonate precursor comprises a citrate, a lactate and / or an acetate.

[0019] According to any of the previous aspects, in a fifth aspect, the at least one fluid source of solution includes a solution bag connected to an end of a line for infusing solution into the blood.

[0020] According to any of the previous aspects, in a sixth aspect, the one or more lines (8; 51; 58; 63; 74) for injecting the respective solution into the blood comprise an infusion line (63) for injecting a substitution fluid containing bicarbonate or a bicarbonate precursor into the blood, in particular for injecting said substitution fluid directly into the blood circuit (17). Preferably, the substitution fluid contains bicarbonate.

[0021] According to any of the previous aspects, in a seventh aspect the device comprises a substitution fluid bag (64) connected to the end of said infusion line (63) for infusing a solution containing bicarbonate into the blood.

[0022] According to the previous two embodiments, in an eighth embodiment, the infusion line (63) is connected to the blood return line (7) for post-infusion of the solution containing bicarbonate, in particular the infusion line (63) comprises a pre-infusion branch (67) and a post-infusion branch (69) to allow infusion both upstream and downstream of the filtration unit (2).

[0023] According to any one of the previous three aspects, in a ninth aspect, the infusion line (63) is connected to the blood collection line (6) for pre-infusion of the solution containing bicarbonate, in particular the infusion line (63) comprises a pre-infusion branch (67) and a post-infusion branch (69) to enable infusion both upstream and downstream of the filtration unit (2).

[0024] According to any one of the previous four aspects, in a tenth aspect, the substitution fluid infusion rate (Q rep The system includes an infusion pump (65) operating on the infusion line (63) to determine a blood pressure (Pp) of the blood.

[0025] According to some of the previous embodiments, in an eleventh embodiment, the one or more lines (8; 51; 58; 63; 74) for injecting the respective solution into the blood comprise a supply line (8) for injecting a dialysis solution containing bicarbonate directly into the blood circuit (17), in particular via an infusion branch (58).

[0026] According to the previous embodiment, in a twelfth embodiment, the device comprises a dialysate bag (64) connected to the end of the supply line (8) for injecting a bicarbonate-containing solution into the filtration unit (2) and / or into the blood circuit (17).

[0027] According to the previous two embodiments, in a thirteenth embodiment, the injection branch (58) is connected to the blood return line (7) for post-injection of the solution containing bicarbonate, and in particular the supply line (8) includes an intake branch (57) for directing fluid into the second chamber of the filtration unit.

[0028] According to any of the previous three aspects, in a fourteenth aspect, the device operates on the supply line (8) to regulate the dialysate flow rate (Q d The dialysis fluid pump (25) determines the flow rate of the dialysis fluid.

[0029] According to any of the previous aspects, in a fifteenth aspect, said one or more lines (8; 51; 58; 63; 74) for infusing respective solutions into blood comprises an ion exchange infusion line (74) for infusing an ion balance solution comprising calcium into said blood.

[0030] According to the previous embodiment, in a sixteenth embodiment, the device includes a syringe connected to an end of an ion balance solution bag (11) or an ion exchange infusion line (74) for injecting ion balance solution into the patient or into the blood circuit (17).

[0031] According to any of the previous three aspects, in a seventeenth aspect, the device is configured to adjust the ion balance solution injection rate (Q ca The system includes an ion exchange pump / syringe (75) operating on the ion exchange inlet line (74) to determine the ion exchange concentration (Ic) of the ion exchange solution.

[0032] According to any of the previous aspects, in a seventeenth second aspect, the device comprises a container of a systemic anticoagulant (e.g., heparin) and an infusion line connected to the container of the systemic anticoagulant and to the blood circuit (17), in particular upstream of the filtration unit (2), for infusing the systemic anticoagulant into the extracorporeal blood.

[0033] According to any of the previous aspects, in an eighteenth aspect, said one or more lines (8; 51; 58; 63; 74) for injecting respective solutions into the blood comprise an anticoagulant line (51) for injecting an anticoagulant solution containing citrate and optionally containing citric acid directly into the blood circuit (17).

[0034] According to the previous embodiment, in a nineteenth embodiment, the device comprises an anticoagulant solution bag (10) connected to the end of an anticoagulant line (51) for injecting a solution containing citrate and, optionally, citric acid into the blood circuit (17).

[0035] According to either of the previous two aspects, in a twentieth aspect, the anticoagulant line (51) is connected to the blood circuit (17) upstream of the blood pump (21), which operates on the blood withdrawal line (6).

[0036] According to any one of the previous three aspects, in a twenty-first aspect, the device is configured to control the anticoagulant infusion rate (Q cit The system includes an anticoagulant pump (54) operating on the anticoagulant line (51) to determine the amount of coagulation fluid (20) that is in the blood.

[0037] According to any one of the previous aspects, in a twenty-second aspect, the control unit (12) is configured to control the parameter (J buffer _ load / BW) The bicarbonate precursor, in particular citrate (J met _ cit ) and / or lactic acid (J met _ lact Estimation of the amount of bicarbonate produced per unit time from the metabolism of Bicarbonate balance from the CRRT blood therapy delivered in terms of amount per unit time (J HCO3 _ bal ), Lactate balance from said CRRT blood therapy delivered in terms of amount per unit time; Acid injection from citric acid contained in said fluid source in terms of amount per unit time (J H+ ), The decision will be based on one or more of, and in particular three of, the following:

[0038] According to the previous aspect, in a twenty-third aspect, the control unit (12) controls the metabolism of a precursor in the form of bicarbonate (J met _ cit ;J lact ), the bicarbonate infusion (J HCO3 _ bal ), the predefined net buffer load (J buffer _ load ), and the acid injection (J H+ ), in particular the acid injection (J H+ ) is a negative term accounting for the patient's loss of buffering.

[0039] According to the previous aspect, in a twenty-fourth aspect, the control unit (12) controls the parameter (J) indicative of a steady-state acid-base balance of the blood of the patient. buffer _ load / BW) is determined as follows: Alternatively, when lactate balance is also taken into consideration, the control unit (12) controls the parameter (J buffer _ load / BW) is determined as follows: TIFF0007657218000003.tif13145

[0040] According to any one of the previous aspects, in a twenty-fifth aspect, the control unit (12) controls the amount of acid (J) from, for example, citric acid contained in the fluid source in terms of the amount per unit time. H+ ) based on the parameter (J) indicative of the steady-state acid-base balance of the blood of the patient. buffer _ load / BW) (or the parameter (Cp HCO3 _ pat ) and the acid injection (J H+ ) is the citric acid concentration (C citric _ pbp ) and the acid injection rate (Q cit ), in particular the acid injection (J H+ ) is the infusion rate of citric acid (Q cit ) multiplied by the citric acid concentration (C citric _ pbp ) times

[0041] According to any one of the previous aspects, in a twenty-sixth aspect, the control unit (12) is configured to control the metabolism (J) of the citrate injected into the patient. met _ cit ) based on an estimate of the amount of bicarbonate produced per unit time from the blood glucose level, the parameter (J) indicative of the steady-state acid-base balance of the blood of the patient. buffer _ load / BW) (or the parameter (Cp HCO3 _ pat ) and in particular, determining that said metabolism of a citrate load results in 3 moles of bicarbonate per mole of citrate at steady state, i.e. TIFF0007657218000004.tif7145

[0042] According to the previous aspect, in a 27th aspect, the control unit (12) calculates the amount of the bicarbonate generated from the metabolism of citrate per unit time, and in particular, the control unit calculates the patient's citrate metabolic clearance (K cit _ met ) as a function of citrate loading (Jcit _ load ) and in particular the metabolic clearance is determined based on, for example, a direct proportionality to the patient's body weight (BW), for example, as follows: TIFF0007657218000005.tif13145The patient's metabolic clearance of citrate is measured as [ml / min] and body weight (BW) is measured as [kg].

[0043] According to either of the previous two aspects, in the twenty-eighth aspect, the amount of bicarbonate produced from the metabolism of citrate per unit time, in particular the control unit is citrate clearance (K cit ) as a function of the citrate loading (J cit _ load ), in particular the control unit (12) calculates one or more rates, in particular one or more dialysate rates (Q d ), plasma water velocity (Qpw inlet ), ultrafiltration rate (Q fil ) as a function of one or more of cit ) to determine

[0044] According to the previous embodiment, in a twenty-ninth embodiment, the control unit (12) controls the sieving coefficient for citrate (SC) as a function of the filtration unit (2) intended for CRRT treatment. cit ) and / or the diffusion mass transfer resistance of citrate (K 0 A cit The citrate clearance (K) was calculated as a function of the ratio of the filtration unit surface area to the cit ) to determine

[0045] According to either of the previous two aspects, in a thirtieth aspect, the control unit 12 calculates the citrate clearance (K cit ) to determine TIFF0007657218000006.tif56145The above notations are included in the glossary.

[0046] According to any one of the previous five aspects, in a thirty-first aspect, the control unit (12) is configured to control the plasma water velocity (Qpw) at the filtration unit inlet and / or the plasma velocity (Qp). inlet ) as a function of the amount of bicarbonate produced per unit time from the metabolism of citrate (J met _ cit ), and in particular, the control unit (12) calculates the plasma water velocity (Qpw) at the inlet of the filtration unit according to the following formula: inlet ) to determine TIFF0007657218000007.tif7145The above notations are included in the glossary.

[0047] According to any of the previous six aspects, in a thirty-second aspect, the control unit (12) calculates the amount of the bicarbonate generated from the metabolism of citrate per unit time, and in particular, the control unit calculates a citrate dosage (D cit ) and blood velocity (Q b ) as a function of D cit Q b or the anticoagulant line (51) and the total citrate concentration (C cit _ pbp ) citrate velocity (Q cit ), i.e., Q cit C citpbp Alternatively, the citrate loading (J cit _ load ) to calculate

[0048] According to any of the previous seven aspects, in a thirty-third aspect, the control unit (12) calculates the amount of bicarbonate produced per unit time from the metabolism of citrate according to the following formula: TIFF0007657218000008.tif25145

[0049] According to any of the previous eight aspects, in the thirty-third second aspect, the control unit (12) controls citrate (J) according to the following formula: met _ cit ) to calculate the amount of bicarbonate produced per unit time from the metabolism of TIFF0007657218000009.tif13145The patient's systemic concentration is assumed to be zero.

[0050] According to any one of the previous aspects, in a thirty-fourth aspect, the control unit (12) is configured to control the bicarbonate balance (J) from the CRRT blood therapy delivered in terms of amount per unit time. HCO3 _ bal ) based on the parameter (J) indicative of the steady-state acid-base balance of the blood of the patient. buffer _ load Determine the bicarbonate balance (J / BW) and in particular the bicarbonate balance (J HCO3 _ bal ) is the infusion rate (J) from the dialysate and / or the substitution fluid. HCO3 _ inf ) and the bicarbonate removal to the dialysis fluid (J HCO3 _ dial ) is the difference between

[0051] According to the previous aspect, in a 35th aspect, the control unit (12) controls the bicarbonate balance (J HCO3 _ bal ) is the velocity of the replacement liquid (Q rep ) and bicarbonate concentration (C HCO3 _ rep ), i.e. Q rep C HCO3 _ rep Calculate as a function of .

[0052] According to any one of the previous two aspects, in a 36th aspect, the control unit (12) controls the bicarbonate clearance (K HCO3 ) as a function of bicarbonate balance (J HCO3 _ bal ), and in particular the control unit (12) calculates one or more rates, in particular one or more dialysate rates (Q d ), blood velocity (Qbw inlet ), the ultrafiltration rate of the filtration unit (2) (Q fil ) as a function of the bicarbonate clearance (K HCO3 ) to determine

[0053] According to the previous embodiment, in a 37th embodiment, the control unit (12) controls the sieving coefficient for bicarbonate (SC) as a function of the filtration unit (2) intended for CRRT treatment. HCO3 ) and / or the diffusion mass transfer resistance of the filtration unit surface area to bicarbonate (S / RT HCO3 ) as a function of the ratio of the bicarbonate clearance (K HCO3 ) to calculate

[0054] According to either of the previous two aspects, in a thirty-eighth aspect, the control unit (12) is configured to determine the bicarbonate clearance according to the following relationship: The TIFF0007657218000010.tif66153 notation is included in the glossary.

[0055] According to any of the previous five aspects, in a thirty-ninth aspect, the control unit (12) is configured to control the blood velocity (Qbw) at the filtration unit inlet and / or blood flow rate (Qbw inlet ) as a function of bicarbonate balance (J HCO3 _ bal ), and in particular, the control unit (12) is configured to calculate the blood velocity (Qbw) at the filter inlet according to the following formula: inlet ) to determine TIFF0007657218000011.tif13158The above notations are included in the glossary.

[0056] According to any of the previous five aspects, in a fortieth aspect, the control unit (12) controls the bicarbonate balance (J HCO3 _ bal ) was calculated by the bicarbonate plasma water concentration (Cpw HCO3 _ inlet ), especially the bicarbonate plasma water concentration at the filter inlet (Cpw HCO3 _ inlet ) and the bicarbonate concentration of the dialysis fluid (C HCO3 _ d ) as a function of the difference between

[0057] According to any of the previous six aspects, in a forty-first aspect, the control unit (12) controls the bicarbonate concentration (C HCO3 _ d ) as a function of the bicarbonate plasma water concentration at the filter inlet (Cpw HCO3 _ inlet ) and the bicarbonate concentration of the dialysis fluid (C HCO3 _ d ) as a function of the difference between the bicarbonate balance (J HCO3 _ bal ) to calculate

[0058] According to either of the previous two aspects, in a forty-second aspect, the control unit (12) controls the bicarbonate plasma water concentration (Cpw HCO3 _ inlet ) and blood velocity (Q bw ), blood velocity at the filter inlet (Q inlet ), the rate before the replacement fluid injection (Q rep _ pre ) as a function of flow rate, including one or more of the following: HCO3_pre ) and the bicarbonate concentration (Cp HCO3_pat ) as a function of

[0059] According to any one of the previous eight aspects, in a forty-third aspect, the control unit (12) controls the ultrafiltration rate (Q fil ) and bicarbonate concentration of the dialysis fluid (C HCO3_d ), i.e., Q fil C HCO3_d The bicarbonate balance (J HCO3 _ bal ) to calculate

[0060] According to any of the previous nine aspects, in a forty-fourth aspect, the control unit (12) calculates the bicarbonate balance (J) according to the following formula: HCO3 _ bal ) TIFF0007657218000012.tif32145

[0061] According to any of the previous aspects, in a forty-fifth aspect, the control unit (12) is configured to calculate lactate balance (J) from the delivered CRRT blood therapy in terms of amount per unit time. lact _ bal ) based on the parameter (J) indicative of the steady-state acid-base balance of the patient's blood. buffer _ load / BW) (or a parameter indicative of the patient's steady-state bicarbonate concentration in the blood (Cp HCO3 _ pat ) and in particular the lactate balance (J lact _ bal ) is the lactate infusion rate (J lact _ inf ) and lactate removal into the dialysate (J lact _ dial ) is the difference between

[0062] According to any of the previous aspects, in a 46th aspect, the control unit (12) controls the substitution fluid flow rate (Q rep ) and lactate concentration (C lact _ rep ), i.e., Q rep C lact _ rep Lactate balance (J lact _ bal ) to calculate

[0063] According to either of the previous two aspects, in a 47th aspect, the control unit (12) controls lactate clearance (K lact ) as a function of lactate balance (J lact _ bal ), and in particular, the control unit (12) calculates the dialysate flow rate (Q d ), blood velocity (Qbw inlet ), ultrafiltration rate (Q fil ) as a function of one or more flow rates, including one or more of lact ) to determine

[0064] According to the previous embodiment, in the forty-eighth embodiment, the control unit (12) is configured to calculate the sieving coefficient for lactate (SC) as a function of the filtration unit (2) intended for CRRT treatment. lact ) and / or the diffusion mass transfer resistance for lactate (S / RT lact ) as a function of the ratio of the filtration unit surface area to the lactate clearance (K lact ) to calculate

[0065] According to either of the previous two aspects, in a 49th aspect, the control unit (12) is configured to determine the lactate clearance according to the following relationship: TIFF0007657218000013.tif66158The above notations are included in the glossary.

[0066] According to any of the previous five aspects, in a 50th aspect, the control unit (12) is configured to control the blood velocity (Qbw) at the filtration unit inlet and / or blood flow rate (Qbw inlet ) as a function of lactate balance (J lact _ bal ) and in particular, the control unit (12) calculates the blood velocity (Qbw) at the filter inlet according to the following formula: inlet ) to determine TIFF0007657218000014.tif13158The above notations are included in the glossary.

[0067] According to any one of the previous six aspects, in a fifty-first aspect, the control unit (12) is configured to control the lactate plasma water concentration (Cpw lact _ inlet ) as a function of the lactate plasma water concentration at the filter inlet (Cpw lact _ inlet ) and lactate concentration in the dialysate (C lact _ d ) as a function of the difference between lactate balance (J lact _ bal ) is calculated.

[0068] According to any one of the previous seven aspects, in a fifty-second aspect, the control unit (12) controls the lactate concentration (C lact _ d ) as a function of the lactate plasma water concentration at the filter inlet (Cpw lact _ inlet ) and dialysate lactate concentration (C lact _ d ) as a function of the difference between lactate balance (J lact _ bal ) is calculated.

[0069] According to either of the previous two aspects, in a fifty-third aspect, the control unit (12) controls the lactate plasma water concentration (Cpw lact _ inlet ) is the blood velocity (Qbw), the blood water velocity at the filter inlet (Qbw_ inlet ) and pre-infusion rate of substitution fluid (Q rep _ pre ) and / or the lactate concentration of the replacement fluid (C lact _ rep ) and the patient's plasma lactate concentration (Cp lact _ rep ) as a function of lactate concentration including one or more of:

[0070] According to any one of the previous eight aspects, in a fifty-fourth aspect, the control unit (12) controls the ultrafiltration rate (Q fil ) and dialysate lactate concentration (C lact _ d ), i.e., Q fil C lact _ d Lactate balance (J lact _ bal ) is calculated.

[0071] According to any one of the previous nine aspects, in a fifty-fifth aspect, the control unit (12) calculates the lactate balance (J) according to the following formula: lact _ bal) is calculated. TIFF0007657218000015.tif24130

[0072] According to any of the previous aspects, in a fifty-sixth aspect, the control unit (12) controls the parameter indicative of a steady-state acid-base balance of the blood of the patient (or a steady-state bicarbonate concentration (Cp HCO3 _ pat ) to a threshold, and if the threshold is an upper threshold, the control unit (12) generates an alert if the parameter is higher than the upper threshold, and if the threshold is a lower threshold, the control unit (12) generates an alert if the parameter is lower than the lower threshold.

[0073] According to the previous aspect, in a fifty-seventh aspect, if the parameter exceeds the threshold value, the control unit (12) is configured to issue the alert and maintain the input patient prescription, or issue the alert and reject the input patient prescription; In particular, when the input prescription is rejected, the control unit (12) Reinstate a previously valid patient prescription, or automatically shifting one or more parameters of said patient prescription, such as blood rate and / or citrate dosage, to proposed values ​​defining a new valid patient prescription; It is further structured as follows.

[0074] According to any of the previous two aspects, in a fifty-eighth aspect, assuming a steady state patient bicarbonate concentration, in particular a target setting equal to 25 mmol, the threshold value includes an upper threshold value comprised in particular between 0.25 and 0.5 mmol / h / kg, in particular a first upper threshold (nNBL1) comprised between 0.25 and 0.35 mmol / h / kg, for example said first threshold (nNBL1) being about 0.3 mmol / h / kg; and / or The second upper threshold (nNBL2) is comprised between 0.35 and 0.5 mmol / h / kg, more particularly between 0.4 and 0.45 mmol / h / kg, for example said second threshold (nNBL2) is about 0.4 mmol / h / kg.

[0075] According to any of the previous three aspects, in a fifty-ninth aspect, the threshold value includes a lower threshold value comprised between 0 and 0.2 mmol / h / kg, in particular the lower threshold value (nNBL2) is about 0.1 mmol / h / kg, and the control unit (12) is further configured to issue and warn and / or block the input prescription when the parameter is lower than the lower threshold value.

[0076] According to any of the previous aspects, in a sixtieth aspect, the control unit (12) is configured to compare a parameter indicative of steady state acid-base balance in the patient's blood with a first upper threshold (nNBL1) and / or with a second upper threshold (nNBL2) higher than the first upper threshold (nNBL1), and if said parameter is higher than the first upper threshold (nNBL1) and lower than the second upper threshold (nNBL2), the control unit (12) is configured to issue a warning, and in particular if the input patient prescription remains acceptable and the parameter is higher than the second upper threshold (nNBL2), the control unit (12) is configured to reject the input patient prescription.

[0077] According to any of the previous aspects, in a sixty-first aspect, the control unit (12) is configured to determine a parameter indicative of a steady-state acid-base balance of the patient's blood (or determine a parameter indicative of a steady-state bicarbonate concentration of the patient's blood) prior to initiating CRRT blood therapy.

[0078] According to any of the previous aspects, in a sixty-second aspect, the control unit (12) receives prescription parameters for the patient and determines a parameter indicative of the steady-state acid-base balance of the patient's blood (or the steady-state bicarbonate concentration (CpHCO3 _ pat ) determining a parameter indicative of the

[0079] According to any of the previous aspects, in a 63rd aspect, the control unit (12) controls the blood flow rate (Q b ), the dialysate flow rate (Q d ), the patient fluid removal rate (Q wl ), and the dialysate rate (Q dial ) and in particular the control unit (12) controls the blood flow rate (Q b ), the dialysate velocity (Q d ) and the patient's fluid removal rate (Q wl ) to receive patient prescription parameters including:

[0080] According to any of the previous aspects, in a 64th aspect, the control unit (12) The rate of displacement (Q rep ), i.e. the total rate of substitution fluid injected into the pre- and post-filtration unit (2) and the pre- or post-injection ratio of substitution fluid (PRE%), or The post-infusion rate of substitution fluid (Q post ) and / or pre-infusion rate of substitution fluid (Q pre ), The patient prescription parameters include:

[0081] According to any of the previous aspects, in a sixty-fifth aspect, the control unit (12) is configured to receive patient prescription parameters including a calcium compensation parameter (CaComp), i.e., a relative dosage of calcium infusion to compensate for estimated calcium losses in the dialysate expressed as a percentage.

[0082] In a sixty-sixth aspect according to any of the previous aspects, the control unit (12) is configured to determine a parameter indicative of steady-state acid-base balance of the patient's blood, ignoring the effect of lactate.

[0083] According to any of the previous aspects, in a 67th aspect, the control unit (12) controls the patient's plasma bicarbonate concentration (Cp HCO3 _ pat ) wherein said constant value is, for example, 25 mM, to determine a parameter indicative of the steady-state acid-base balance of the patient's blood.

[0084] According to any of the previous aspects, in a sixty-seventh aspect, the control unit (12) is configured to calculate a parameter (Cp) indicative of a steady-state bicarbonate concentration of the patient's blood that imposes a constant value on a normalized net buffer load (NBL) for the patient at steady state. HCO3 _ pat ) wherein the constant value is, for example, 0.1 mmol / h / kg.

[0085] According to any of the previous aspects, in a 68th aspect, the control unit (12) controls the patient's plasma lactate concentration (Cp lact ) to determine a parameter indicative of the steady-state acid-base balance of the patient's blood (or a parameter indicative of the steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ) wherein the constant value is, for example, 1.5 mM.

[0086] According to any of the previous aspects, in a sixty-ninth aspect, the parameter indicative of the steady state acid-base balance of the patient's blood is the patient's plasma bicarbonate concentration (Cp HCO3 _ pat ) is the expected net buffer loading balance at steady state, stabilized at a set constant value, e.g., 25 mM.

[0087] According to any of the previous aspects, in a seventieth aspect, the control unit (12) receives a fixed value estimated for the patient's systemic steady state bicarbonate concentration, in particular 25 mM.

[0088] According to any of the previous aspects, in a seventy-first aspect, the control unit (12) receives an estimated fixed value for the patient's whole body steady state bicarbonate precursor concentration, in particular lactate, optionally the estimated fixed value is 1.5 mM.

[0089] According to any of the previous aspects, in a 72nd aspect, the device comprises a dialysate supply line (8) connected to the inlet of the secondary chamber (4).

[0090] According to any of the previous aspects, in a seventy-third aspect, the device comprises a CO2 inlet (46a) and a blood outlet (46b) connected to a blood circuit (17). 2 The gas exchanger (46) for removal of blood is included, and the gas exchanger (46) is connected to the blood circuit (17) in series with the filtration unit (2).

[0091] According to any of the previous aspects, in a seventy-fourth aspect, the control unit (12) is configured to control, in particular, the blood velocity (Q b ) based on the citrate infusion rate (Q cit )

[0092] According to any of the previous embodiments, in a seventy-fifth embodiment, the source of local anticoagulant (10) comprises a citrate salt, in particular trisodium citrate, and optionally citric acid.

[0093] According to the 73rd embodiment or any of the previous embodiments, in a 76th embodiment, the gas exchanger (46) has a blood chamber and a gas chamber separated by a membrane, the gas exchanger includes a gas inlet (52) and a gas outlet (53) in fluid communication with the gas chamber, and the blood inlet (46a) and blood outlet (46b) are in fluid communication with the blood chamber.

[0094] According to the previous embodiment, in the seventy-seventh embodiment, the gas exchanger (46) is located upstream of the filtration unit (2) connected and fluidly communicated with the blood withdrawal line (6), or the gas exchanger (46) is located downstream of the filtration unit (2) connected and fluidly communicated with the blood return line (7).

[0095] In a seventy-eighth embodiment, according to any of the previous embodiments, the apparatus includes a source of dialysate for supplying fluid to the dialysate supply line, the dialysate being substantially free of calcium ions.

[0096] According to any of the previous aspects, in a 79th aspect the apparatus includes a source of dialysis fluid comprising a buffer for supplying the fluid to the dialysate supply line, the buffer concentration of the dialysis fluid being comprised between 0 and 50 mmol / l, particularly between 10 mmol / l and 40 mmol / l.

[0097] According to any of the previous 1 to 78 aspects, in an 80th aspect, the apparatus includes a source of dialysate for supplying fluid to the dialysate supply line, the dialysate being substantially free of buffer.

[0098] According to any one of the previous aspects, in an eightieth second aspect the device comprises a substitution fluid bag (64) containing a buffer, the buffer concentration of the substitution fluid being comprised between 0 and 1000 mmol / l, in particular between 100 mmol / l and 200 mmol / l, optionally in combination with a buffer-free dialysis fluid and / or other substitution fluids containing no buffer, in particular between 50 mmol / l and 100 mmol / l, optionally in combination with a low buffer content (e.g. <25 mmol / l) of the dialysis fluid and / or a low buffer content (e.g. <25 mmol / l) of other substitution fluids, said one or more lines (8; 51; 58; 63; 74) for injecting the respective solution into the blood comprise an infusion line (63) connected to the substitution fluid bag (64) for injecting the substitution fluid into the blood.

[0099] According to any of the previous aspects, in an eightieth third aspect the apparatus comprises a substitution fluid bag (64) containing substitution fluid, the substitution fluid being substantially free of buffer, and one or more lines (8; 51; 58; 63; 74) for infusing the respective solutions into the blood comprise an infusion line (63) connected to the substitution fluid bag (64) for infusing the substitution fluid into the blood.

[0100] According to any one of the previous aspects, in an eightieth fourth aspect the buffer comprises (and is optional) bicarbonate.

[0101] According to any of the previous aspects, in an eighty-first aspect, the apparatus includes a dialysis pump (25) operating on a dialysate supply line (8) and a controller (12) operatively connected to the dialysis pump (25), the controller controlling the dialysate flow rate (Q d The dialysis pump (25) is configured to drive the dialysis pump (25) to generate a blood flow.

[0102] According to any of the previous aspects, in an eighty-second aspect, the apparatus includes a dialysate pump (26) operating on a dialysate line (13) and a controller (12) operatively connected to the dialysate pump (26), the controller controlling the dialysate rate (Q dial The dialysate pump (26) is configured to drive the dialysate pump (26) to generate a dialysate solution.

[0103] According to any of the previous aspects, in an 83rd aspect, the control unit (12) is operatively connected to an anticoagulant pump (10) to deliver an anticoagulant to the blood, the anticoagulant comprising citrate and the anticoagulant dosage comprised between 1.5 mmol / l and 6 mmol / l, particularly in the range of 2 mmol / l to 4 mmol / l, and more particularly about 3 mmol / l.

[0104] According to any one of the previous aspects, in an 84th aspect, the control unit (12) is configured to control a parameter indicative of a steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ), more specifically, the bicarbonate loss in the dialysate (J HCO3 _dial )of, The bicarbonate precursors injected into the patient, especially citrate (J met _ cit ) and / or lactate (J met _ lact Estimation of the amount of bicarbonate produced per unit time from the metabolism of Bicarbonate infusion from CRRT blood therapy delivered in terms of volume per unit time (J HCO3 _ inf ), Lactate balance from CRRT blood therapy delivered in terms of volume per unit time (J lact _ bal ), Predefined net buffer loads (J) selected, e.g., between 0 and 0.35 mmol / h / kg, especially 0.1 mmol / h / kg buffer _ load ), Acid injection from citric acid contained in the fluid source in terms of amount per unit time (J H+ ), The decision will be based on one or more of the following, but in particular on four:

[0105] According to the previous aspect, in an 85th aspect, the control unit (12) controls the metabolism of a precursor (J) in the form of bicarbonate. met _ cit ;J lact ), bicarbonate infusion (J HCO3 _ bal ), the predefined net buffer load (J buffer _ load ), and acid injection (J H+ ) is used to estimate the steady-state bicarbonate concentration of the patient's blood, based on the algebraic sum of the HCO3 _ pat ), and more detailed bicarbonate losses in the dialysate (J HCO3 _ dial ) and, in particular, the acid injection (J H+ ) is a negative term providing the patient's buffer loss.

[0106] According to any one of the previous aspects, in an 86th aspect, the control unit (12) controls the volume fraction of plasma (Fp) and / or the blood velocity (Q bw ), and in particular as a function of their ratio, a parameter (Cp HCO3 _ pat ) to determine

[0107] According to any one of the previous aspects, in an 87th aspect, the control unit (12) controls the replacement liquid / rate (Q rep _ pre ) and / or the bicarbonate concentration of the replacement fluid (C HCO3 _ rep ), and in particular the parameter that indicates the steady-state bicarbonate concentration of the patient's blood as a function of their products (Cp HCO3 _ pat ) to determine

[0108] According to any one of the previous aspects, in an 88th aspect, the control unit (12) is configured to control a parameter indicative of a steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ) was calculated by dividing the plasma bicarbonate concentration at the filter inlet (Cpw HCO3 _ inlet ) and / or the blood velocity at the inlet (Q inlet ), particularly as a function of their products.

[0109] According to any one of the previous aspects, in an eighty-ninth aspect, the control unit (12) controls the dialysate velocity (Q d ) and / or bicarbonate concentration (C HCO3 _ dial ) as a function of plasma water bicarbonate concentration at the filter inlet (Cpw HCO3 _ inlet ) to determine

[0110] According to any one of the previous aspects, in a 90th aspect, the control unit (12) is configured to control a parameter indicative of a steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat) is the ultrafiltration rate (Q fil ) and / or the bicarbonate concentration (C HCO3 _ dial ) as a function of

[0111] According to any one of the previous aspects, in a 91st aspect, the control unit (12) is configured to control the bicarbonate loss (J) to the dialysis fluid. HCO3 _ eff ) is a parameter that indicates the steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ) to determine

[0112] According to any one of the previous aspects, in a 92nd aspect, the control unit (12) controls bicarbonate clearance (K HCO3 ) is a parameter that indicates the steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ) to determine

[0113] According to any one of the previous aspects, in a 93rd aspect, the control unit (12) controls the bicarbonate concentration (C HCO3 _ dial ), and the dialysate rate (Q d ) and / or bicarbonate concentration of the dialysis fluid (Cp HCO3 _ dial ) and / or the ultrafiltration rate (Q fil ) and / or bicarbonate loss to the dialysate (J HCO3 _ eff ) and / or bicarbonate clearance (K HCO3 ) is a parameter that indicates the steady-state bicarbonate concentration of the patient's blood (Cp HCO3 _ pat ) to determine

[0114] Further features and advantages of the invention will become better apparent from the following detailed description of some embodiments of the invention, illustrated by way of non-limiting examples in the figures of the accompanying drawings, in which: [Brief description of the drawings]

[0115] The description continues below with reference to the accompanying drawings, which are provided as non-limiting examples. [Figure 1] FIG. 1 illustrates diagrammatically an extracorporeal blood treatment device particularly, but not exclusively, suitable for intensive care (such as CRRT). [Diagram 2] Figure 2 shows a schematic representation of mass transfer rates of interest during CRRT treatment with regional anticoagulation (RCA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0116] As mentioned above, extracorporeal blood therapy (dialysis) is used for patients with sudden loss of kidney function, referred to as acute renal failure, or slowly deteriorating kidney function, referred to as stage 5 chronic kidney disease (or end-stage renal disease). In the following description, some embodiments of the extracorporeal blood therapy device will first be described as being primarily (but not exclusively) suitable or designed for intensive care. Risk control measures, primarily taken to reduce the risk of developing metabolic alkalosis / acidosis in the patient, will be described thereafter and, as will be apparent from the following description, may be implemented in any of the described embodiments.

[0117] definition Unless otherwise defined, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art.

[0118] The term "downstream" refers to the position of a first component in a flow path relative to a second component, such that during normal operation, fluid passes through the second component before the first component. The first component is said to be "downstream" of the second component, while the second component is "upstream" of the first component. Figure 1 shows the direction of fluid circulation (indicated by reference 200) during normal operation of the device 1.

[0119] We define "dialysate" as the process fluid introduced into the second chamber of the filtration unit 2. The dialysate is prepared online or pre-packaged in sterile bags.

[0120] We define "dialysate" as the fluid from the outlet from the second chamber of the filtration unit 2. The dialysate is the spent dialysis fluid, which comprises uremic toxins removed from the blood, and includes ultrafiltrate.

[0121] We define a "local anticoagulant" as a substance that, once mixed with the extracorporeal blood, substantially prevents blood clotting within the extracorporeal blood circuit and is rapidly metabolized by the patient, thus avoiding systemic anticoagulation.

[0122] We define the "net buffer load" during extracorporeal blood treatment (e.g., CRRT) as a combination of bicarbonate generated from the metabolism of bicarbonate precursors such as citrate and / or lactate infused into the patient (J met _ cit ;J met _ lact ), extracorporeal blood therapy (J HCO3 _ bal ), and, if necessary, the acid infusion, for example from the citrate content of the anticoagulant solution. From a mathematical point of view, the general definition of net buffer load (mmol / h) used below is: TIFF0007657218000016.tif7145

[0123] We define "citrate dose" as the infusion rate of citrate per liter of blood treatment (mmol / L blood).

[0124] We define a patient's "citrate load" as the rate (mmol / h) at which citrate is returned to the patient. TIFF0007657218000017.tif7145

[0125] We define "bicarbonate balance" as the net rate of infusion or loss of bicarbonate in extracorporeal blood therapy that is equal to the difference between the infusion rate from the dialysate and / or substitution fluid and the rate of bicarbonate removal into the dialysate. TIFF0007657218000018.tif10155

[0126] We define "calcium compensation" (or calcium compensation parameter) as the relative dose of calcium infusion to compensate for the estimated calcium loss in the dialysate, expressed as a percentage.

[0127] We are "K 0 A” is defined as the mass transfer area coefficient of the filtration unit, and K 0 is the clearance at infinite blood and dialysate velocities, and A is the filtration unit surface area. 0 A" is specific to a given solute and will therefore vary depending on the particular solute under consideration. As used herein, the term "citrate" means that the component is in the form of a salt of citric acid, such as the sodium, magnesium, calcium, or potassium salts thereof. Citric acid (C 6 H 8 O 7 ) is deprotonated stepwise, so "citrate" is citrate (C 6 H 5 O 7 3- ), hydrogen citrate (C 6 H 6 O 7 2- ) and dihydrogen citrate (C 6 H 7 O 7- Includes all different forms of the

[0128] The term "citrate" or "total citrate" means the total amount of citric acid and any of its salts, such as sodium, magnesium, calcium, or potassium.

[0129] The term "buffer" refers to bicarbonate or a bicarbonate precursor such as lactate, citrate or acetate.

[0130] Glossary TIFF0007657218000019.tif192145TIFF0007657218000020.tif89145

[0131] Velocity formula The following velocity equations represent the relationships between the velocities used in the detailed description that follows.

[0132] Plasma water velocity is a function of blood flow velocity as follows: TIFF0007657218000021.tif7145

[0133] Blood water velocity is a function of blood flow velocity as follows: TIFF0007657218000022.tif7145

[0134] The ultrafiltration rate in the filtration unit is as follows: TIFF0007657218000023.tif7145

[0135] The pre-infusion rates of substitution fluid are as follows: TIFF0007657218000024.tif7145

[0136] The dialysate rates are as follows: TIFF0007657218000025.tif7145

[0137] Extracorporeal blood treatment device, especially for CRRT treatment With reference to FIG. 1, the numeral 1 refers globally to an extracorporeal blood treatment device, in particular for intensive care. The device according to FIG. 1 is especially designed for continuous renal replacement therapy (CRRT). The CRRT system is configured to provide a very specific treatment designed for patients in acute disease states and for patients with temporary total loss of renal function. In contrast to chronic patients, acute patients experience temporary total loss of renal function, typically during recovery from a contemporaneous severe injury state or surgery. Thus, acute patients are often extremely debilitated and typically are not in a condition to receive regular dialysis treatment, which may further deteriorate their condition and lead to serious and potentially life-threatening complications. Under the described circumstances, the CRRT system is especially designed to treat patients individually who exhibit very poor health, without causing deviations of the patient's blood-related vital parameters from ideal or near-ideal values ​​and without inducing further stress on the patient's body. Within the scope of this document, the CRRT system is therefore essentially characterized by one or more of the following features: CRRT includes renal replacement therapy and refers to an adjuvant therapy aimed primarily at promoting continuous fluid removal in patients with diuretic resistance or acute renal failure. Thus, CRRT systems essentially require continuous net fluid removal from the patient. In other words, CRRT systems require a fluid balance control system, such as a weight loss control system, configured to generate a continuous net weight loss rate (as opposed to simply controlling parameters to allow for a desired target weight loss to be achieved as is typically seen in chronic patient care). Additionally, acute patients experience extravascular fluid overload, which cannot be safely removed in the short term (e.g., within a few hours of chronic treatment) without causing potentially severe consequences (e.g., hypovolemic shock, arrhythmias, hypoxemia, hypoventilation, etc.). Thus, CRRT systems must essentially include much more precise control of system parameters, especially rates, to ensure that the required low rates of both blood circulation extracorporeally and treatment fluid (infused into the extracorporeal circuit or diffused through the dialyzer) are used.Furthermore, CRRT treatment is performed continuously (e.g., for days or weeks with no / minimal interruptions). Thus, treatment settings in CRRT are based on rate settings rather than settings related to some specific treatment time (which is unknown since acute patients may require treatment for an unknown amount of time). Thus, the operation of the CRRT system cannot be based on some predefined absolute weight loss to be achieved, but rather on a precisely controlled fluid balance in the patient, which requires continuous adjustments to many operating parameters that must be controlled and maintained during the entire (and a priori unknown) treatment time based on a set weight loss rate. In addition, CRRT renal replacement therapy replaces kidney function for a relatively long period of time, and thus the CRRT system further requires at least one fresh fluid in a combination of fresh dialysate exchange in the dialyzer (to remove undesirable substances from the blood and add desired substances to the blood by diffusion) and / or ultrafiltration (to remove undesirable substances from the blood and add desired substances to the blood by convection).

[0138] For at least the reasons stated above, CRRT systems The weight loss rate can be set. Continuously remove excess fluid according to a set weight loss rate, Operate continuously at relatively low speeds compatible with CRRT; and Balancing the ionic balance by implementing appropriate dialysis procedures and / or by continuously delivering replacement fluid at a controlled rate; It is necessary to demonstrate the specific technical features that enable

[0139] The device 1 of FIG. 1 comprises an extracorporeal blood circuit 17, which takes blood, for example from a patient P, by means of a catheter introduced into a vein or artery of said patient and takes said blood, for example continuously, through a blood withdrawal line 6 into the filtration unit 2. The blood passes through the primary chamber of the filtration unit 2 and through a blood return line 7, the treated blood is returned to the patient. In the example of FIG. 1, a connection with an anticoagulant line 51 is provided immediately downstream from the blood withdrawal zone of the blood withdrawal line 6. In particular, the device comprises a source of local anticoagulant 10, such as a secondary fluid container or bag, for supplying at least the anticoagulant line 51, and it is possible to control the fluid flow in said line by introducing the local anticoagulant directly into the blood by means of a direct connection to the blood withdrawal line 6, by using a corresponding means for conveying the fluid, including, in the example shown, an anticoagulant pump 54, for example a peristaltic pump. After defining the direction of the fluid (blood) circulation 200 (during normal use of the device) from the blood withdrawal line 6 towards the filtration unit 2 and from the latter through the blood return line 7 towards the patient P, a known blood pressure sensor 48, not described in further detail, is placed immediately downstream of the anticoagulant line 51. The blood circuit 17 comprises a means for transporting the fluid, i.e. in this particular case at least a suitable blood velocity Q in the circuit. b The blood pump 21 is generally a peristaltic pump. 2 A gas exchanger 46 may be connected to the blood circuit for removing CO. The gas exchanger 46 receives extracorporeal blood and removes CO from the blood. 2 The gas exchanger 46 is in fluid communication with the blood circuit 17 to remove excess blood and return blood to the blood circuit at a downstream point. Although FIG. 1 shows the gas exchanger 46 located upstream of the filtration unit 2, the gas exchanger may alternatively be located downstream of the filtration unit along the direction of blood circulation. The direction of blood circulation during normal use of the device is along the direction of blood flow with a blood velocity Q b 1 with arrows also indicating the direction. The gas exchanger 46 is connected in series with the filtration unit 2 and is located downstream of the injection point 50 through which the local anticoagulant solution is delivered to the extracorporeal blood. The gas exchanger 46 comprises a blood chamber and a membrane permeable to gases, in particular CO2 The gas exchanger has a gas chamber separated by a gas inlet that can be connected to a gas source, such as a medical gas supply system in a hospital, to receive pressurized air or oxygen, and a gas exchanger that can be connected to a gas inlet that can be connected to a gas source, such as a medical gas supply system in a hospital, to receive CO from the extracorporeal blood. 2 and a gas outlet in fluid communication with the gas chamber for exhausting the removed depleted gas. The blood inlet and blood outlet place the extracorporeal blood circuit 17 in fluid communication with the gas exchanger blood chamber.

[0140] The blood then passes another pressure sensor 49 that controls the correct flow in the blood circuit. After passing through the primary chamber of the filtration unit 2, where the proper exchange of substances, molecules and fluids takes place by means of a semipermeable membrane, the treated blood passes first through an air separator 19, commonly known as a "bubble trap", designed to ensure the detection and removal of air bubbles present in the blood, before entering the blood return line 7. The treated blood coming out of the air separator 19 then passes a bubble sensor 55 that checks that there is no formation of said danger in the treated blood that must be reintroduced into the patient's blood circulation. Immediately downstream from the bubble sensor 55, a safety valve 20 (or venous clamp) is installed, which in case of an alarm is able to block the blood flow towards the patient. In particular, if the bubble sensor 55 detects the presence of an anomaly in the blood flow, the device through the safety valve 20 will be able to immediately block the passage of blood to avoid any consequences for the patient. Downstream from the safety valve 20, the treated blood is then returned to the patient P undergoing treatment. The extracorporeal blood treatment device of Figure 1 includes a dialysate circuit 32, which also includes at least a dialysate supply line 8 leading to the filtration unit 2, and a dialysate line 13 leading from the filtration unit. A primary fluid container, defining at least a dialysate source 14, is designed to supply the supply line 8 of the dialysate circuit 32 (which should generally consist of one or more bags containing a suitable dialysate). Supply line 8 carries dialysate from the bags at a dialysate rate Q d1 comprises at least a means for transporting fluid, such as a dialysate pump 25 (in the embodiment of FIG. 1, a peristaltic pump) for controlling the flow rate and for defining the direction 200 of the dialysate circulation. Downstream from the dialysate pump 25 in the direction of circulation 200 there is a branch 56 which divides the dialysate supply line 8 into an intake branch 57 and an infusion branch 58. In particular, the infusion branch 58 is connected to the blood return line 7 of the blood circuit 17. In other words, by means of said infusion branch 58 it is possible to obtain a direct infusion in the blood line 17 with the contents of the primary fluid container. Conversely, the intake branch 57 conveys the fluid directly to the filtration unit 2, in particular to the secondary chamber of said unit. The dialysate circuit 32 further comprises a selection means 59 for determining the percentage of fluid flow in the infusion branch 58 and in the intake branch 57. Said selection means 59 are generally installed near the branches 56 and they can be located between a first operating condition, allowing the passage of fluid in the intake branch 57 and blocking the passage in the infusion branch 58, and a second operating condition, allowing the passage of fluid in the infusion branch 58 and blocking the passage in the intake branch 57. In other words, said selection means 59 may consist of a valve element acting on the dialysate circuit 32 by alternatively blocking the passage of fluid in either branch. Alternatively, a suitable selector can be provided that allows a priori to establish the amount of fluid that must pass through both branches simultaneously. It would also be possible to vary the percentage of fluid in either branch of a pre-established therapy as a function of time. The dialysate passing through the intake branch 57 enters the secondary chamber of the filtration unit 2. In particular, the primary chamber through which the blood flows is separated from the secondary chamber through which the dialysate flows by means of a semi-permeable membrane, which ensures proper passage of dangerous substances / molecules and liquids from the blood to the dialysate, mainly by means of convection and diffusion processes, and also ensures the passage of substances / molecules from the dialysate to the blood, through the same principles. The dialysate then enters the dialysate line 13 and passes a suitable dialysate pressure sensor 60.A means for transporting fluid, for example velocity Q in the dialysate line 13 in the fluid circuit 32. dial A dialysate pump 26 is provided which controls the flow rate of the dialysate, said pump typically being a peristaltic pump. The fluid to be removed then passes through a blood detector 61 and is conveyed to a collection container or bag 62. The hydraulic circuit of the device according to FIG. 1 includes at least another infusion line 63 for supplying fluid to the blood return line 7 of the blood circuit 17. In particular, the infusion fluid is taken from at least an auxiliary container 64 and is supplied at a rate Q rep An infusion pump 65 (in the example a peristaltic pump) that controls the total substitution fluid rate is fed directly to the blood return line 7 of the blood circuit 17 through a means for transporting fluid. In particular, the infusion fluid is taken from at least an auxiliary container 64 and is fed at a rate Q rep- an infusion pump 65 (in the example a peristaltic pump) which controls the total substitution rate is fed directly to the return blood line 7 of the blood circuit 17 through a means for transporting the fluid. In particular, the infusion fluid is introduced directly into the air separator 19. As can also be deduced, the infusion branch 58 of the dialysate circuit 32 and the infusion line 63 have a common end length 66 which directs the fluid into the blood circuit 17. Said intake end length 66 is arranged downstream from the infusion pump 65 in relation to the direction of infusion and conveys the fluid directly to the air separator 19. Furthermore, with reference to the diagram of FIG. 1, the infusion line 63 comprises at least a pre-infusion branch 67 connected to the withdrawal line 6 of the blood circuit 17. More particularly, downstream from the infusion pump 65 in relation to the direction of infusion there is an infusion branch 68 which branches the infusion line 63 upwards into a pre-infusion branch 67 and a post-infusion branch 69. The pre-infusion branch 67 conveys in particular the fluid taken from the bag 64 with respect to the direction of blood circulation from the blood pump 21 to the blood withdrawal line 6 of the blood circuit 17 downstream and to the downstream gas exchanger 46. Conversely, the post-infusion branch 69 is directly connected to the common end length 66. The infusion line 63 further comprises selection means 70 for determining the percentage of the fluid velocity sent to the post-infusion branch 69 and to the pre-infusion branch 67. The selection means 70 arranged close to the branches 68 can be switched between at least a first operating condition in which they allow the passage of the fluid in the pre-infusion branch 67 and block the passage in the post-infusion branch 69 and at least a second operating condition in which they allow the passage of the fluid in the post-infusion branch 69 and block the passage in the pre-infusion branch 67. Obviously, as in the case of the selection means 59 present on the dialysate circuit 32, the other selection means 70 could also determine the percentage of the fluid that must pass to each of the two branches and possibly vary it in time according to the planned therapy. Furthermore, the selection means 59 and the further selection means 70 will generally, but not necessarily, be of the same nature. The device comprises means 71 for determining at least the weight of the primary fluid container 14, and / or of the auxiliary fluid container 64, and / or of the local anticoagulant container 10, and / or of the collection container 62.In particular, said means 71 include weight sensors, for example respective scales A, B, C, D and E (for example an independent sensor at least for each fluid bag associated with the device). In particular, there are at least four of said scales, each pair being independent of the other, each measuring the weight of a respective bag. It is then noted that the control unit or CPU 12 operates on the blood circuit 17, in particular on the pressure sensor 48 for reading pressure values, on the blood pump 21, on the gas exchanger 46, on the other pressure sensor 49 and on the device for detecting the presence of air bubbles 55, and on the respective safety valve 20. The control unit 12 can also control the dialysate circuit 32, in particular inputting the data detected by the scales A, B, C, D and (possibly E) regarding the weight of the bag 14, acting on the pump 25, on the selection means 59, on the pressure sensor 60, then on the dialysate pump 26, and finally receiving the data detected by the scale A, whose function is to determine the weight of the collection container 62. The control unit 12 will also act on the infusion line 63, checking the weight of the auxiliary container 64 (checked by scale C), and will be able to control both the infusion pump 65 and the other selection means 70. The control unit 12 must also act on the anticoagulant line 51, detecting the weight of the anticoagulant fluid container 10 by means of scale B, and appropriately controlling the anticoagulant pump 54 according to the procedure to be performed, as will be explained in detail below. As is evident, a local anticoagulation system is implemented in the device 1 of FIG. 1 in order to provide limited anticoagulation in the extracorporeal blood circuit 17. The local anticoagulation system is explained in detail in the respective description paragraph. However, the device of FIG. 1 may alternatively (or additionally) be provided with a systemic anticoagulation system, such as a syringe pump for injecting heparin downstream of the blood pump 21. In fact, the algorithm of the embodiment of the invention described in the following detailed description works both in a CRRT treatment configuration with RCA and in a CRRT treatment configuration with systemic (or no) anticoagulation therapy without RCA.

[0141] Local anticoagulation system The local anticoagulation system includes a source of local anticoagulant 10, e.g., a container or bag containing a substance that has at least an anticoagulant effect. For example, citrate can be pure sodium citrate (Na 3 It is used for blood anticoagulation applications in the form of sodium citrate or a mixture of sodium citrate and citric acid. Alternatively, pure citric acid can be used as an anticoagulant. Indeed, citrate has a high affinity for calcium in complexing, and several steps of the coagulation cascade depend on blood (ionized) calcium. An appropriate reduction in the ionized calcium concentration in the presence of citrate inactivates the coagulation cascade.

[0142] Normal plasma contains approximately 1.1-1.3 mmol / l ionized calcium, 0.1-0.2 mmol / l complexed calcium and 0.9-1.2 mmol / l protein-bound calcium. To obtain an adequate anticoagulant effect, a general guideline is to adjust the citrate volume / dosage to reach an ionized calcium concentration of 0.20-0.35 mmol / l in the extracorporeal blood circuit after citrate infusion. Plasma citrated for anticoagulant use contains (as a mean value) approximately 0.3 mmol / l ionized calcium and 0.5 mmol / l complexed calcium (mainly Ca 3 Citrate 2) 1.8 mmol / l and protein-bound calcium 0.2 mmol / l. During RCA, the strength of anticoagulation can be adjusted via the amount of citrate injected. The ionized calcium concentration of the post-filtration unit is commonly used as the main parameter (target in the range of 0.20-0.35 mmol / l) and is measured, for example, with a blood gas analyzer. The local anticoagulation system is arranged to deliver a local anticoagulant to a delivery point 50 in the extracorporeal blood circuit 17. To obtain a complete anticoagulation of the extracorporeal blood circuit 17, it is preferred to administer the citrate injection close to the access end of the blood withdrawal line 6. Typically, the delivery point 50 is located upstream of the blood pump 21, but it is not excluded, however, that the delivery point 50 is located in the blood withdrawal line 6 downstream of the blood pump. Alternatively, or in combination, the citrate delivery point 50 may be the inlet of the filtration unit 2. In this latter configuration, the dialysate contains a sufficient amount of citrate to achieve an ionized calcium level of the order of 0.25-0.35 mmol / l in the blood circuit downstream of the dialyzer. Citrate may be added to the treatment fluid flowing along the supply line 8, using a corresponding concentrate bag / container, if the dialysate is prepared online, as in current devices for chronic treatment. Alternatively, especially for CRRT devices, the source 14 of dialysis fluid is a container / bag containing the appropriate citrate concentration or content. Commercially available citrate solutions are generally packaged in respective plastic bags (source 10) and may be divided between physiological and concentrated solutions. Physiological citrate solutions are solutions with a sodium concentration of about 140 mmol / l, e.g. Baxter PrismoCitrate 10 / 2 (with 10 mmol / l sodium citrate and 2 mmol / l citric acid) and Baxter RegioCit 18 / 0 (with 18 mmol / l sodium citrate). Concentrated citrate solutions are, for example, ACD-A (Anticoagulant Citrate Dextrose Solution) from Biomet: a mixture of sodium citrate (75 mmol / l), citric acid (38 mmol / l) and glucose, and Citrate 4% from Fresenius (citrate 136 mmol / l).

[0143] When citrate is injected into the blood collection line 6 close to the patient's vascular access, the blood pump speed is automatically adjusted to take the operator-set blood rate from the access site (blood pump speed = k*(Q b +Q cit ), where Q b is the set blood velocity - desired at the access site, and Q cit is the citrate infusion rate).

[0144] The amount of citrate is determined by the "Citrate Dose" parameter (D citrate ) and is the amount of citrate per liter of blood treatment (mmol / l blood). Notably, the citrate dosage does not match the citrate concentration in the diluted blood reaching the filtration unit. The concept is rather to provide an amount of citrate proportional to the amount of calcium being chelated. The settings for the citrate pump 54 are as follows: TIFF0007657218000026.tif2584, where Q cit is the infusion rate of citrate, Q b is the set blood velocity, D citrate is the dose of citrate, and [citrate] PBP is the citrate concentration in the source of anticoagulant.

[0145] Citrate infusions are delivered at doses aimed at maintaining ionized calcium levels around 0.25-0.35 mmol / L in the blood circuit downstream of the dialyzer. Typically, citrate doses fall within the range of 1.5-6.0 mmol / L of blood. The most common range is 2-4 mmol / L of blood. A citrate dose of 3.0 mmol / L of blood follows guidelines.

[0146] The ionized calcium and citrate complexes are rather small molecules and move easily through the filtration unit 2. The rate of loss depends essentially on the velocity, the filter efficiency for small molecules and the solute concentration. While about half of the total calcium is not available for mass transfer during standard anticoagulation therapy (because it is protein-bound), about 90% of the total calcium becomes available during citrate anticoagulation. Thus, citrate regional anticoagulation in combination with the use of calcium-free dialysis and / or substitution fluids means a large calcium loss to the dialysate. Extracorporeal blood therapy with RCA requires calcium infusion to balance the calcium loss to the dialysate. During RCA, calcium infusion is adjusted to keep the patient's systemic ionized calcium in the normal range (e.g., 1.0-1.2 mmol / l).

[0147] The local anticoagulation system of the device 1 thus includes a source of ionic balancing fluid 11, which is reinfused in the blood either in the blood return line 7, particularly in close proximity to the venous vascular access, or directly into the patient P (infusion into a central catheter is recommended). The ionic balancing fluid 11, e.g., a syringe, container or bag, is supplied with an appropriate ionic replacement fluid infusion rate Q caion exchange infusion line 74 and corresponding ion exchange pump 75 for driving the delivery of calcium to the patient P. FIG. 1 shows line 74 infusing directly to the patient P. Of course, line 74 could alternatively infuse directly into the blood return line 7, possibly closer to the venous access. In particular, auxiliary container 64 of FIG. 1 could be used (alternatively or in combination) to keep the blood return line 7 ion-balanced. In the latter example, pre-infusion branch 67 would remain closed and unused to avoid calcium infusion upstream of filtration unit 2. In the example of FIG. 1, a syringe pump (not shown) that is typically used to deliver heparin could alternatively be used to deliver an ion-balancing solution directly to the patient or alternatively to the blood return line. The ion-balancing solution would include ionized (concentrated) calcium, the infusion of which would be performed to restore the patient's systemic ionized calcium to normal levels. In particular, the ion-balancing solution could also include ionized magnesium, the infusion of which would be performed to restore the patient's systemic ionized magnesium to normal levels, since magnesium removal in the dialysate is also increased during RCA. The ion exchange infusion rate Q ca may be adjusted based on the determined patient's blood ionized calcium concentration, or automatic control may be implemented as described in patent publication US8668825B2.

[0148] In implementation, the ionic balance rate is kept proportional to the estimated rate of calcium loss in the dialysate, which is calculated by the device controller, for example, via the formula: TIFF0007657218000027.tif13145 Where CaComp is the calcium compensation parameter, Q ca is the ionic equilibrium liquid velocity (ml / h), and J ca is the estimated calcium loss in the dialysate (mmol / h), [Ca] is the calcium concentration in the ionic balance solution (mmol / l), and Q rep is the replacement fluid rate (ml / h) and [Ca rep [0.01] is the calcium concentration (mmol / l) of the substitution fluid after dilution. Calcium compensation is a user-controllable setting and can generally be set by the operator in the range of 5%-200%.

[0149] In particular, the above formula takes into account the presence of calcium-containing post-substitution fluid. If no calcium is present in the post-substitution fluid (or no post-substitution fluid is used), the second term in the formula should be ignored (equal to zero).

[0150] Indeed, as regards dialysis fluids (and substitution fluids), they are generally calcium-free to prevent the transfer of ionized calcium into the blood. Furthermore, the dialysis and / or substitution fluids are adapted for buffer content due to citrate metabolism and, in the case of the use of concentrated citrate solutions (hypertonic solutions), for sodium.

[0151] As for the buffering agent, RCA has a complex effect on the acid-base balance due to the significant proportion of citrate returned to the patient (citrate is metabolized to bicarbonate), which will be analyzed in the next section and the risk control mitigation action will be explained in detail. In fact, the blood returned to the patient contains a significant concentration of citrate-calcium complexes. These complexes are (rapidly) metabolized in the liver, skeletal muscles and kidneys, releasing calcium into the bloodstream and thus preventing systemic anticoagulation from occurring, and citrate metabolism produces bicarbonate (HCO for 1 mol of citrate). 3- 3 mol).

[0152] In contrast, the dialysate may be buffer-free, e.g. bicarbonate-free. Buffer from a source / container / bag 64 may be pumped into the blood return line 7 via suitable buffer supply lines 63, 69, 66 and corresponding buffer pump 65. Alternatively or in combination, to allow additional acid-balance control, the device 1 may be designed to vary the buffer balance of the extracorporeal blood circuit in an easy and controlled way through the possibility of setting the dialysate (low) buffer concentration and / or using source bags 14, 64 with different buffer concentrations, e.g., for bicarbonate, in the range of 15-25 mmol / l (and up to 40 mmol / l and / or down to 0 mmol / l).

[0153] As mentioned before, citrate accumulation in patients can correlate with hypocalcemia, metabolic acidosis (poor metabolism leading to reduced bicarbonate production) or metabolic alkalosis (excessive bicarbonate production following a high citrate load). As citrate measurements are not commonly available in hospitals, the ratio of total calcium to ionized calcium is used as an index, i.e. values ​​below 2.5 are considered normal (normal < 2.0) and values ​​above 2.5 indicate a low ionized calcium concentration with respect to total calcium, possibly due to the presence of significant systemic concentrations of citrate. However, this monitoring is not recommended, especially in patients with RCA+ECCO. 2 This is considered an insufficient measure, especially in treatments involving the associated risk of acid / base imbalances in RCAs with "high" rates such as R, or certain SCUF treatments. Additional Risk Control Mitigations (RCMs) identified below should be implemented as follows:

[0154] The additional Risk Control Mitigations (RCMs) identified below are: New alarms based on high citrate load, or more accurately, net buffer load, applicable to all RCA formulations; a new prescription boundary based on a second (higher) level of the same net buffer loading parameter; We request that the following be implemented:

[0155] The next sections provide further implementation details for the latter two RCMs.

[0156] Risk Control Mitigation Risk Control Mitigation (RCM) procedures are specifically activated for Net Buffer Load Monitoring. Net buffer load control is performed for all prescriptions of CRRT and specifically for RCA and CRRT+ECCO. 2For combination prescriptions of R, it is implemented in a general way. These new RCMs are not expected to be activated in known and conventional CRRT prescriptions, but this may not be true for SCUF cases where they may (relevantly) warn or prevent insufficient prescription (e.g. due to excessive blood flow). The following embodiment involves making available a parameter that characterizes the CRRT prescription (e.g. with RCA) in terms of acid-base (or buffer) balance. With this parameter, the prescriber obtains quantitative information on the intensity of the treatment in terms of increase or decrease of net patient buffer (bicarbonate). As mentioned before, this parameter is of particular interest in complex cases of citrate anticoagulation, while it is also relevant for any extracorporeal dialysis therapy (run systemically or without anticoagulation). Based on one or more predefined thresholds (set by the manufacturer or customization), the treatment system can trigger a warning if the prescription corresponds to a risk of alkalosis (excessive buffer increase) or acidosis (insufficient buffer increase or net loss). Absolute limits that prevent the implementation of excessive prescriptions can also be considered.

[0157] Definition of Buffer Load Extracorporeal treatment (J buffer _ load ) the net buffer loading is Citrate infused to the patient and / or lactate infused to the patient (J met _ lact ) metabolism (J met _ cit ), more commonly from the metabolism of bicarbonate precursors; Extracorporeal blood therapy (JBL) can be performed with a net loss or net gain for the patient. HCO3 _ bal ) bicarbonate equilibrium, Anticoagulant solution (J H+ ) citric acid content etc. from acid injection, It is defined as a combination of one or more of the following:

[0158] From a mathematical standpoint, the general definition of net buffer loading is: TIFF0007657218000028.tif7145 (Formula 1)

[0159] By convention, the net buffer load is positive if the extracorporeal blood therapy provides the patient with a net gain of buffer / bicarbonate, and negative in the case of a loss of buffer.

[0160] From a physiological standpoint, extracorporeal blood therapy is expected to provide the patient with a net buffer gain in terms of the balance of metabolic production of protons (protein metabolism). However, in scenarios where a patient begins treatment in the setting of (severe) metabolic alkalosis, a net buffer loss may be desirable.

[0161] The buffer equilibrium parameters are: the rate at which citrate is infused into the patient (citrate load); The balance of bicarbonate and other buffers (e.g. lactate), Assumptions regarding citrate metabolism (1 mole of citrate metabolized by 3 moles of bicarbonate), Assumptions regarding the patient's systemic concentrations of citrate, bicarbonate, and other buffers (which can be fixed or calculated from other submodels); The model is derived from one or more of the following:

[0162] The calculated buffer balance will not match the current buffer balance of the CRRT administration regimen (which would require specific knowledge of the current patient level of citrate and bicarbonate), but will match the expected (normalized) net buffer load at steady state when the patient's bicarbonate stabilizes at, for example, 25 mM.

[0163] Acid-base steady state is established slowly, with measurable changes typically present after 24 hours, and 2 days appears as a reasonable minimum to consider acid-base status as having been reached in the context of CRRT.

[0164] In the framework of buffer equilibrium analysis presented here, the question is when a steady state of acid-base balance is reached. The patient's systemic citrate concentration is stable across the systemic compartments, thus leading to a constant citrate load and bicarbonate production. The patient's bicarbonate concentration is determined by the metabolic proton production rate G H+ The net buffer load balance is stable across the whole body compartments.

[0165] Citrate loading Citrate load is defined as the net infusion rate of citrate into the patient, which is determined by the pre-blood pump (PBP) circuit (J cit _ PBP ) and the citrate infusion rate from the dialysate (J cit _ dial ) in the blood circuit. See Figure 2 Citrate infusion and citrate loss by the dialyzer / dialysate.

[0166] From a mathematical standpoint, the citrate load of a patient is defined as follows: TIFF0007657218000029.tif7145 (Formula 2)

[0167] The calculation of citrate infusion is as follows: cit ), it can be expressed in two ways.

[0168] From a mathematical standpoint, the citrate infusion rate is defined as follows: TIFF0007657218000030.tif7145 (Formula 3)

[0169] In this approach, citric acid and citrate forms are considered in the same manner.

[0170] The amount of citrate removed from the dialysate is determined by the amount of citrate-calcium complex (K cit) and the citrate concentration (in plasma water) at the filter inlet. From a mathematical standpoint, the definition of citrate removal into the dialysate is: TIFF0007657218000031.tif7145 (Formula 4)

[0171] Citrate loading (major variant) Assumptions for modeling citrate mass transfer in the extracorporeal blood circuit include the assumptions that citrate is distributed in the plasma (and not in red blood cells), that the citrate clearance of the CRRT filter is also calculated based on the citrate concentration in the plasma water for mass transfer calculations, that it takes into account the patient's citrate metabolism and non-zero steady-state citrate concentration at the time of blood access, and that the patient's citrate clearance is proportional to body weight.

[0172] The plasma water velocity at the filter inlet is defined as follows: TIFF0007657218000032.tif7145 (Formula 12)

[0173] The formula for calculating citrate clearance in CRRT with non-zero dialysate and filtration rates (Equation 13) is: TIFF0007657218000033.tif49145 (Formula 13)

[0174] It should be noted that the citrate mass transfer parameters used in the above removal calculations are known and are constants depending on the dialyzer selected.

[0175] For example, the following table shows the Prismaflex set of values ​​that were used: TIFF0007657218000034.tif29145

[0176] During RCA treatment, some citrate accumulates in the patient, so the citrate concentration at the blood access is never zero. This accumulation should be taken into account to avoid a bias of about 10% (in the case of neglect). The citrate metabolic rate (K cit _ met ), which can vary widely and with final estimates significantly biased. However, it would be appropriate to consider the "minimal" accumulation that occurs in patients with "normal" citrate metabolism.

[0177] In contrast, the patient's citrate concentration at steady state is calculated assuming a typical metabolic clearance value of 700 ml / min (from the literature). Although not stated in the literature, it is assumed that the patient's citrate clearance is proportional to body weight.

[0178] The expression for the patient's systemic citrate concentration at steady state is: TIFF0007657218000035.tif13145 (Formula 14)

[0179] Based on the above, an estimate of the patient's citrate metabolic clearance (ml / min) is: TIFF0007657218000036.tif13145 (Formula 15)

[0180] The expression of the citrate plasma water concentration at the filter inlet is: TIFF0007657218000037.tif7145 (Formula 16)

[0181] The combination of Equation 2, Equation 4, Equation 14 and Equation 16 above eliminates the citrate concentration parameter and allows for the expression of a patient's citrate burden as a function of rate and clearance. TIFF0007657218000038.tif25145 (Formula 17)

[0182] Citrate Loading (Simplified Modification) According to the major variants mentioned above, the patient's systemic citrate concentration (Cp cit _ pat ) is taken into account and extrapolated through equations 14 and 15. This choice leads to equation 17 reported for citrate loading above.

[0183] A simpler alternative to this formulation is to ignore the change in the patient's systemic citrate concentration and consider it to be a constant, e.g., zero. Equations 14 and 15 consequently cannot be used following this alternative. If the patient's systemic citrate concentration is assumed to be zero (Equations 16 and 17 change to the following Equations 16' and 17'): TIFF0007657218000039.tif7145(Formula 16') TIFF0007657218000040.tif13145(Formula 17')

[0184] Bicarbonate balance in extracorporeal blood circuits Bicarbonate balance is defined as the net infusion or loss rate of bicarbonate in extracorporeal blood therapy, which is determined by the amount of bicarbonate in the dialysate and / or substitution fluid (JF). HCO3 _ inf ) and bicarbonate removal rate into the dialysis fluid (J HCO3 _ dial ), see Figure 2.

[0185] The bicarbonate balance rate is defined as follows: TIFF0007657218000041.tif7145 (Formula 5)

[0186] The hypothesis for modeling bicarbonate mass transfer in the extracorporeal blood circuit is that bicarbonate is distributed in plasma and red blood cells, and the bicarbonate concentration at the blood access, Cp HCO3 _ pat is fixed (e.g., equal to 25 mM), and of course a different (fixed) value for the bicarbonate concentration at the blood access may be used.

[0187] Other assumptions include that the PBP citrate solution does not contain bicarbonate (the reverse would be the case, but the bicarbonate content / concentration would be taken into account in the bicarbonate balance), that CRRT filtration unit bicarbonate clearance is the same as urea clearance, and that bicarbonate removal in the dialysate is calculated according to a formula similar to that which takes into account the bicarbonate concentration in the plasma water for citrate and mass transfer calculations.

[0188] Calculation of the bicarbonate infusion rate is based on knowledge of the fluid composition (ie, known bicarbonate concentration). TIFF0007657218000042.tif7145 (Formula 6)

[0189] The fluid composition (i.e., bicarbonate concentration and / or replacement fluid formula) may be entered by a physician (upon request from the dialysis machine) or read through a reader on the dialysis machine, for example by associating a product name with its bicarbonate content / concentration.

[0190] The equations for bicarbonate removal into the dialysate are very similar to those for citrate, but they differ in that they take into account the presence of bicarbonate in the dialysate and the mass transfer parameter (K 0 A) and the fact that a fixed value is taken into account for the patient's total body bicarbonate. Obviously, if citrate is present in the dialysate, the corresponding citrate load / balance can take into account such dialysate citrate concentration, similar to the corresponding formulas for citrate and the following shown for bicarbonate:

[0191] The definition of bicarbonate removal into the dialysate is as follows: TIFF0007657218000043.tif7145 (Formula 7)

[0192] In contrast to citrate, bicarbonate moves readily between red blood cells and plasma, and thus, the total blood water velocity is taken into account in the calculation of mass transfer to the dialysate. Furthermore, the CRRT filter diffusion mass transfer coefficient for bicarbonate is taken to be the same as for urea based on their respective molecular weights (61 vs. 60 g / mol). The sieving coefficient is taken to be 1.

[0193] Considering a constant physiological value of bicarbonate at blood access, the blood water velocity at the filter inlet is defined as: TIFF0007657218000044.tif13164 (Formula 18)

[0194] The equations for calculating bicarbonate clearance in CRRT, where the rates of dialysate and filtration are nonzero, are similar to those for citrate, but for the reasons mentioned above, the mass transfer coefficients SC and K 0 A is different, and the velocity considered in the blood flow circuit is the plasma water velocity (Q pw ) instead of total blood velocity (Q bw ).

[0195] The formula for calculating citrate clearance in CRRT with non-zero dialysate and filtration rates (Equation 19) is: TIFF0007657218000045.tif49145 (Formula 19)

[0196] It is noted that the bicarbonate mass transfer parameters used in the above removal rate calculations are known and constant depending on the dialyzer selected.

[0197] For example, the following table shows the Prismaflex set of values ​​that were used: TIFF0007657218000046.tif29145

[0198] The plasma water concentration at the filter inlet is derived from the following set of equations: TIFF0007657218000047.tif22145 (Formula 20)

[0199] From the above equation, the expression for bicarbonate plasma water concentration at the filter inlet is: TIFF0007657218000048.tif19145 (Formula 21)

[0200] Lactate balance in the extracorporeal blood circuit (optional) Lactate balance is defined as the rate of net lactate infusion or loss in extracorporeal blood therapy, which is determined by the amount of dialysis fluid and / or substitution fluid (JF). lact _ inf ) and the infusion rate of the dialysate (J lact _ dial ) corresponds to the difference between the lactate removal rate to

[0201] Lactate can be used as an alternative buffer to bicarbonate with the advantage of obtaining a more stable solution. Lactate-based dialysates are well known in dialysis, for example, it is used in the home dialysis version of the System One device from NxStage. In addition, lactate is also present in a certain number of bicarbonate solutions, in the form of lactate, to control the pH and solution stability. This is the case for Baxter Hemosol / PrismaSol CRRT solution, which has 3 mM lactate. Similar to citrate, lactate is rapidly metabolized to bicarbonate when infused into the patient, at a conversion rate of 1 mole per citrate. Lactate can be modeled in a very similar way to bicarbonate, assuming that the patient's steady-state plasma lactate concentration is about 1.5 mM.

[0202] Lactate clearance may be assumed to be identical to urea clearance, even though the lactate molecular weight is approximately twice that of urea (112 vs. 60 g / mol). However, in the context of CRRT, where rate is the primary limiting factor, the clearance estimation error is minimal. Of course, more accurate estimates can be used, e.g., K 0 Using the dependence of the output on the absolute molecular weight of A (i.e., the known K of urea, creatinine, vitamin B12, inulin 0 A to K 0A_lactate can be derived). The assumptions of the model of lactate mass transfer in the extracorporeal blood circuit include the assumption that lactate is distributed in plasma and red blood cells and that the CRRT filtration unit lactate clearance is identical to urea clearance. Furthermore, we assume that the patient's steady-state plasma lactate concentration at the time of blood access is fixed at 1.5 mM. The lactate mass balance in the extracorporeal blood circuit is calculated with a formula similar to that for bicarbonate, taking into account the metabolism of the lactate load, which leads to one mole of bicarbonate per mole of lactate.

[0203] The mass transfer equation for lactate is: The lactate balance rate is defined as: TIFF0007657218000049.tif7145 (Formula 22)

[0204] Calculation of lactate infusion rate is based on knowledge of the fluid composition (ie, known lactate concentration). TIFF0007657218000050.tif7145 (Formula 23)

[0205] The fluid composition (i.e., lactate concentration and / or substitution fluid prescription) is entered by the physician or read, for example, through a reader on the dialysis machine. The definition of lactate removal into the dialysate is as follows: TIFF0007657218000051.tif7145 (Formula 24)

[0206] Lactate moves readily between red blood cells and plasma, and thus, whole blood is considered in the calculation of mass transfer to the dialysate. Furthermore, the CRRT filter diffusion mass transfer coefficient for bicarbonate is the same as for urea; the sieving coefficient is taken as 1.

[0207] Lactate Clearance (K lact ) is bicarbonate clearance (K HCO3 ) and therefore the controller calculates it in a similar manner to the same equation shown above. The expression for lactate plasma water concentration at the filter inlet is: TIFF0007657218000052.tif19145 (Formula 25)

[0208] Net Patient Buffer Load Obtaining the relationship between the citrate infusion rate into the patient (i.e., citrate load) and bicarbonate production is necessary to obtain the net patient buffer load. To achieve this goal, hypotheses regarding the metabolism of citrate include the following assumptions: metabolism of the citrate load leads to 3 moles of bicarbonate per mole of citrate, and the net buffer load (NBL) can be reduced by the infusion rate of an acid such as citric acid. The expression for bicarbonate production from citrate metabolism (at steady state) is: TIFF0007657218000053.tif7145 (Formula 8)

[0209] The expression in reference to the acid injection rate is as follows: TIFF0007657218000054.tif7145 (Formula 9)

[0210] The combination of Equation 1, Equation 8 and Equation 9 leads to an expression for the net buffer loading as a function of citrate loading and bicarbonate balance. TIFF0007657218000055.tif7145 (Formula 10)

[0211] J citrate _ load The expression for is given in Equation 17, while J HCO3 _ bal Note that the complete expression for is derived from Equation 5, Equation 6, Equation 7, Equation 19, and Equation 21. From a therapeutic perspective, the net buffer load is calculated by subtracting the protons (H + ) Production amount G H+ The literature gives a typical G of about 1 mmol / day / kg, 0.04 mmol / h / kg. H+ However, the production of protons from metabolism is highly dependent on protein catabolism.

[0212] If lactate is taken into account (optionally), the expression for net buffer load as a function of citrate load, lactate balance and bicarbonate balance is: TIFF0007657218000056.tif7145 (Formula 26)

[0213] Prescription Boundaries The control unit of the device for extracorporeal blood therapy calculates and monitors a parameter indicative of the steady-state acid-base (or buffer) balance in the blood of the patient who is to receive CRRT blood therapy. By calculating and monitoring (and displaying) this parameter, the prescriber obtains quantitative information regarding the intensity of the therapy in terms of net patient buffer (bicarbonate) gain or loss. This parameter is used in combination with citrate anticoagulation and ECCO 2 Of particular interest in complex cases of combined citrate anticoagulation, it is also relevant for any extracorporeal dialysis therapy (run with systemic or no anticoagulation). More specifically, the control unit 12 determines the net buffer load, particularly at machine set-up (i.e., before CRRT treatment is started). Even more specifically, the control unit controls the normalized net buffer load (nNBL) to prevent prescriptions likely to induce alkalosis and / or acidosis in the patient.

[0214] The normalized net buffer loading (nNBL) is defined as follows: TIFF0007657218000057.tif13145 (Formula 11)

[0215] The nNBL was chosen as an indicator parameter of the acid-base balance level at steady state and is expressed as the buffer infusion rate per unit time and per kg of patient (mmol / h / kg).

[0216] A review of published clinical data on CRRT with RCA at steady state shows good correlation of this nNBL parameter with both steady-state patient bicarbonate and base excess. Therefore, instead of using the (normalized) net buffer load as defined above, the buffer balance parameter can be expressed as the steady-state bicarbonate concentration once a "default" value of normalized net buffer load (nNBL) is assumed.

[0217] In the above embodiment, the nNBL is adjusted to the bicarbonate level expected by the patient (e.g., 25 mM → nNBL 25 ) corresponds to the buffer equilibrium value when nNBL 25 When G coincides with the rate of proton production (G), steady state is reached and the patient is at the assumed HCO 3 The level stabilizes at 25 mM. 25 If is greater than the amount of proton production, nNBL Ceq The patient's bicarbonate will increase to a point where Ceq is consistent with the current proton production. 25 G H+ If lower, the patient's bicarbonate will stabilize at a value lower than the assumed level.

[0218] Steady-state HCO 3 Variation with Indicator If a (desired / target) nNBL level has been selected, the patient's bicarbonate concentration (Cp HCO3 _ pat ) can be used as an indicator parameter of steady-state acid-base balance. In this scenario, the previous formulas may be rearranged to express the patient's steady-state bicarbonate concentration as a function of a given nNBL level, e.g., nNBL0=0.1 mmol / h / kg. The citrate formulas, i.e., formulas 2-4, 12-17, 16' and 17', remain unchanged. Differently, the bicarbonate formula requires some rearrangement. More specifically, the expression of the patient's bicarbonate at steady state (rearrangement of formula 20) is as follows: TIFF0007657218000058.tif13145 (Formula 27)

[0219] The expression for plasma water bicarbonate concentration at the filter inlet (rearrangement of Equation 7) is: TIFF0007657218000059.tif13145 (Formula 28)

[0220] The expression for bicarbonate loss to effluent (from Equations 1 and 5) is: TIFF0007657218000060.tif7145 (Formula 29)

[0221] Select / set nNBL0 and J buffer _ load The relationship between is as follows: TIFF0007657218000061.tif7145 (Formula 30)

[0222] J from formula 30, from formula 9, from formula 8 and formula 17 or 17', and from formula 6 buffer _ load is entered into Equation 29. The latter is then combined with Equation 28 so that all terms in this composite expression are known. Finally, Cpw is calculated to derive an expression for the known / measured variable that will allow the control unit 12 to determine the parameter to be controlled, the steady state patient bicarbonate value versus an appropriate threshold. HCO3 _ inlet is introduced into Eq. 27.

[0223] As can be seen, this solution provides a surrogate parameter, i.e., steady state patient bicarbonate concentration (which is a parameter indicative of the steady state acid-base balance in the blood of a patient who is to undergo CRRT blood therapy), with respect to the normalized buffer loading parameter, allowing the control unit 12 to verify that proper acid-base balance is maintained during CRRT therapy.

[0224] Monitoring to avoid alkalosis The normalized net buffer load is (optionally) monitored with respect to two different thresholds, nNBL1 and nNBL2, i.e., a first level (first threshold) that triggers a warning prompting a reminder regarding the risk of metabolic alkalosis and a second level (second threshold) at which prescription becomes impossible. As a matter of fact, the new RCM should not generate unnecessary alerts in the context of the current daily CRRT-RCA prescription, while on the other hand, it must prevent unsafe drifts.

[0225] When following the prescription, the normalized net buffer load is included between the first and second nNBL thresholds (nNBL1 < nNBL < nNBL2), and an alert or warning of high buffer load is provided to the user. In this scenario, the prescription may be accepted, but the control unit initiates two actions, i.e., a warning / alert message is provided (e.g., displayed) to inform about the high citrate / buffer load and the risk of patient alkalosis, and a periodic anticoagulation checkpoint reminder of the current prescription risk of alkalosis is provided so that the user is regularly informed about the potential problem of alkalosis. When following the prescription, if the normalized net buffer load is higher than the second nNBL threshold (nNBL > nNBL2), the control unit of the device blocks the setting "in real time" by adding the above criteria to the other existing prescription boundaries. In some cases, it is acceptable to manage this situation with an alarm (such as a message) indicating that the prescription is rejected due to excessive buffer / citrate load. While the last (confirmed) setting is rejected, it may be necessary to restore a valid prescription when closing the alarm. Two possible options (configured for the control unit to implement) are as follows. Option 1: Restore the previous (valid) prescription, or Option 2: Automatically shift the citrate dosage (and / or blood flow rate) downward to redefine the "valid" prescription.

[0226] Threshold Net buffer load quantifies the balance between the citrate load consistent with buffer gain and buffer loss (primarily bicarbonate, secondarily lactate) associated with CRRT treatment.

[0227] Although the net buffer loading data is calculated for a fixed patient bicarbonate level of 25 mM, the actual buffer loss is directly dependent on the patient's bicarbonate level. If the patient's bicarbonate is below 25 mM, the bicarbonate loss is low and the actual buffer load is high. If the patient's bicarbonate is increased above 25 mM, the bicarbonate loss is high and the actual buffer loading is low.

[0228] At steady state, the net buffer load is the net H from metabolism. + It is assumed that the patient's needs for balancing production are met. According to the literature, a typical H + The production rate is approximately 1 mmol / day / kg, or 0.04 mmol / h / kg, and is highly dependent on protein catabolism. This is because during CRRT, the net buffer load is H + This means that the patient's bicarbonate / acid-base balance is expected to stabilize at a point where it is equal to the amount of bicarbonate produced. Thus, an ideal RCA protocol may be defined as one that provides a normalized net buffer load of +0.04 mmol / h / kg to reach a plasma bicarbonate of 25 mM at steady state. However, a 1 mmol H + In the scenario of a hypermetabolizing patient producing > 0.04 mmol / h / kg / day, the above protocol would stabilize the patient at < 25 mM bicarbonate. Stabilizing this same patient at 25 mM bicarbonate would require a protocol associated with a net buffer load of > +0.04 mmol / h / kg.

[0229] Due to the limited intensity of CRRT therapy, an exponential stabilization profile of acid-base balance over time is expected, but it would rather operate with a CRRT protocol consistent with a steady state of “alkalosis” in order to more rapidly correct the general acidotic state at the start of treatment (several papers reported the development of alkalosis after more than 2 days of treatment).

[0230] Based on literature analysis, assuming a target set of steady-state patient bicarbonate concentrations equal to 24-26 mmol / l, especially 25 mmol / l, the initial normalized net buffer load threshold should be between 0.25-0.35 mmol / h / kg. In particular, the first threshold should be approximately 0.3 mmol / h / kg.

[0231] Normalized net buffer loading values ​​of less than 0.3 mmol / h / kg include all recommended protocols and most of the reviewed RCA studies. This threshold coincides with the patient's acid-base steady-state value at the upper end of the "normal" range, in accordance with the correlation observed between nNBL and the patient's bicarbonate or base excess.

[0232] The second alarm threshold (nNBL2) is intended to block any prescription above this value. Thus, the selection of an appropriate value is more important than the nNBL1 threshold. Based on alkalosis case reports in the literature and field data, the second normalized net buffer load threshold should be 0.35-0.5 mmol / h / kg. In particular, the second threshold should be about 0.4-0.45 mmol / h / kg. Preferably, the selected value is about 0.4 mmol / h / kg.

[0233] At a normalized NBL of 0.40 mmol / h / kg, the expected steady state for bicarbonate and base excess is approximately 33 mM and +6.5 mM, respectively, which is already considered excessive. However, if applied for a limited period of time, for example to rapidly correct a strongly acidotic state, a higher nNBL prescription may not pose a significant risk. For this reason, it may not be wise to set the nNBL2 threshold too low.

[0234] Due to the limited "strength" of CRRT, and the fact that it typically takes 24-48 hours or more to develop (or correct) an acid-base disturbance, it may be possible to tolerate high nNBL prescriptions (i.e., higher than nNBL2) for short periods of time (e.g., several hours). The duration of tolerance for high nNBL (i.e., above the second threshold) prescriptions may be correlated to the difference between normalized buffer loading and the second threshold, with longer distances resulting in shorter tolerance times.

[0235] Monitoring to avoid acidosis Also, the normalized NBL can be monitored to avoid prescriptions that may lead to metabolic acidosis.

[0236] In this situation, again, one or two thresholds may be set to provide an alert and / or cut off prescription. For example, the threshold may be set between 0 and -0.2 mmol / h / kg. Specifically, the threshold may be about -0.1 mmol / h / kg.

Claims

1. 1. A continuous renal replacement therapy (CRRT) device comprising: a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5); a blood circuit (17) having a blood withdrawal line (6) connected to an inlet of the primary chamber (3) and a blood return line (7) connected to an outlet of the primary chamber (3), the blood circuit (17) being adapted for connection to a patient's cardiovascular system; a blood pump (21) for circulating blood in the blood circuit (17); a dialysate line (13) connected to the outlet of the secondary chamber (4); one or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring each solution into the blood; at least one fluid source of solution for each of the one or more lines, the solution comprising at least one buffer in the form of bicarbonate or a bicarbonate precursor; a control unit (12) configured to receive a patient prescription including parameters for setting up a CRRT blood therapy; The control unit (12) determining a parameter indicative of the steady-state acid-base balance of the blood of the patient who must undergo CRRT blood therapy, wherein the parameter is the patient's predicted net buffer load (NBL) at steady state or the patient's predicted normalized net buffer load (nNBL) at steady state, and is determined as a function of the concentration of the buffer in the fluid source and as a function of the patient's estimated or calculated systemic steady-state concentration of bicarbonate and / or bicarbonate precursors; or determining a parameter indicative of a steady state bicarbonate concentration of the blood of the patient who must receive the CRRT blood therapy, wherein the parameter is the steady state bicarbonate concentration of the patient assuming a default value of the normalized net buffer load (nNBL) and is determined as a function of the concentration of the buffer in the fluid source and as a function of an estimated or calculated net buffer load indicative of the steady state acid-base balance of the blood of the patient; The net buffer load (NBL) during extracorporeal blood therapy is the sum of bicarbonate generated from metabolism of bicarbonate precursors and bicarbonate balance (JHCO3_bal) from the extracorporeal blood therapy, and the normalized net buffer load (nNBL) is normalized to the patient's body weight (BW); further comprising: Continuous Renal Replacement Therapy (CRRT) device.

2. The one or more lines (8; 51; 58; 63; 74) for infusing the respective solution into the blood comprise an infusion line (63) for infusing into the blood a substitution fluid containing bicarbonate or a bicarbonate precursor, the device being adapted to provide a substitution fluid infusion rate (Q rep a substitution fluid bag (64) connected to the end of the infusion line (63) for infusing a solution containing bicarbonate into the blood, the infusion line (63) being connected to the blood return line (7) for post-infusion of the solution containing bicarbonate, 2. The apparatus of claim 1.

3. The one or more lines (8; 51; 58; 63; 74) for injecting respective solutions into the blood include an anticoagulant line (51) for injecting an anticoagulant solution directly into the blood circuit (17), the device being operable to provide an anticoagulant injection rate (Q cit an anticoagulant pump (54) operating on the anticoagulant line (51) to determine the blood flow rate (P) of the blood circuit (17), and an anticoagulant solution bag (10) connected to the end of the anticoagulant line (51) for injecting a solution containing citrate into the blood circuit (17), the anticoagulant line (51) being connected to the blood collection line (6); 3. Apparatus according to claim 1 or 2.

4. The control unit (12) controls the parameter (J) indicative of the steady-state acid-base balance of the blood of the patient. buffer _ load / BW) The bicarbonate precursor injected into the patient is citrate (J met _ cit ) and / or lactate (J met _ lact an estimate of the amount of bicarbonate produced per unit time from metabolism of said bicarbonate precursor, Bicarbonate balance from the CRRT blood therapy delivered in terms of amount per unit time (J HCO3 _ bal ), Lactate balance from the CRRT blood therapy delivered in terms of amount per unit time (J lact _ bal ), Acid injection from the citric acid contained in the fluid source in terms of amount per unit time (J H+ ), The decision is based on three or more of the following:

4. Apparatus according to any one of claims 1 to 3.

5. The control unit (12) controls the parameter (J buffer _ load / BW) is determined as follows: Alternatively, when lactate balance is also taken into account, the control unit (12) may select the parameter (J buffer _ load / BW) is determined as follows:

5. The apparatus of claim 4.

6. The bicarbonate precursor may be the citrate and / or lactate (J met _ cit ;J met _ lact ) 6. Apparatus according to claim 4 or 5.

7. The bicarbonate balance (J HCO3 _ bal ) is the net loss or gain of bicarbonate in the patient; 7. Apparatus according to any one of claims 4 to 6.

8. The acid injection contains citric acid; 8. Apparatus according to any one of claims 4 to 7.

9. The control unit (12) controls the metabolism (J met _ cit ) based on an estimate of the amount of bicarbonate produced per unit time from the patient's blood, the parameter (Cp HCO3 _ pat ) and the metabolism of the citrate load results in 3 moles of bicarbonate per mole of citrate at steady state, That is, 9. Apparatus according to any one of claims 1 to 8.

10. The control unit (12) controls the parameter (Cp HCO3 _ pat ) wherein the constant value is 0.1 mmol / h / kg; 10. Apparatus according to any one of claims 1 to 9.

11. The control unit (12) controls the parameter (Cp HCO3 _ pat )of, an estimate of the amount of bicarbonate per unit time produced from metabolism of the bicarbonate precursor infused into the patient; Bicarbonate infusion from the CRRT blood therapy in terms of amount delivered per unit time (J HCO3 _ inf ), Lactate balance from the CRRT blood therapy delivered in terms of amount per unit time (J lact _ bal ), Predefined net buffer loads (J) selected between 0 and 0.35 mmol / h / kg buffer _ load ), Acid injection from the citric acid contained in the fluid source in terms of amount per unit time (J H+ ), The decision is based on four or more of the following:

11. Apparatus according to any one of claims 1 to 10.

12. The control unit (12) controls the metabolism of a precursor in the form of bicarbonate (J met _ cit ;J lact ), the bicarbonate infusion (J HCO3 _ bal ), the predefined net buffer load (J buffer _ load ), and the acid injection (J H+ ) based on an algebraic sum of the parameter (Cp HCO3 _ pat ) and the acid injection (J H+ ) is a negative term providing the loss of buffer for the patient; 12. The apparatus of claim 11.

13. The control unit (12) controls the amount of acid injection (J) contained in the fluid source in terms of the amount per unit time. H+ ) based on the parameter (J buffer _ load / BW) and the acid injection (J H+ ) is the concentration of acid (C citric _ pbp ) and the acid injection rate (Q cit ) and 13. Apparatus according to any one of claims 1 to 12.

14. The control unit (12) controls the citrate (J met _ cit The parameter (J) indicative of the steady-state acid-base balance of the blood of the patient is based on an estimate of the amount of bicarbonate produced per unit time from the metabolism of buffer _ load / BW) and said metabolism of a citrate load leads to 3 moles of bicarbonate per mole of citrate at steady state, where That is, 14. Apparatus according to any one of claims 1 to 13.

15. The control unit (12) calculates the amount of bicarbonate produced from the metabolism of citrate per unit time, and the control unit (12) calculates the patient's citrate metabolic clearance (K cit _ met Citrate loading (J) as a function of cit _ load ) and the patient's citrate metabolic clearance is directly proportional to the patient's body weight (BW) and is determined as follows:

15. The apparatus of claim 14.

16. The control unit (12) calculates the amount of the bicarbonate produced from the metabolism of citrate per unit time, and the control unit (12) determines the citrate load (J cit _ load ) as a function of citrate clearance (K cit ), and the control unit (12) calculates the dialysate rate (Q d ), plasma water velocity (Qpw inlet ), the ultrafiltration rate (Q fil ) as a function of flow rate, including one or more of cit ) and the control unit (12) determines the citrate clearance (K cit ) to determine 16. Apparatus according to claim 14 or 15.

17. The control unit (12) calculates the amount of bicarbonate produced from the metabolism of citrate per unit time, and the control unit (12) calculates the citrate dosage (D cit ) and blood velocity (Q b ) as a function of D cit Q b In accordance with, or The citrate rate (Q cit ) and total citrate concentration (C cit _ pbp ) as a function of Q cit ・C citpbp According to Alternatively, the citrate load (J cit _ load ) to calculate 17. Apparatus according to any one of claims 14 to 16.

18. The control unit (12) calculates the amount of bicarbonate produced from the metabolism of citrate per unit time, and the control unit (12) calculates the amount of bicarbonate produced from the metabolism of citrate per unit time according to the following formula: or if the patient's systemic citrate concentration is assumed to be zero, according to the following formula: The citrate loading (J cit _ load ) to calculate 18. Apparatus according to any one of claims 14 to 17.

19. The control unit (12) measures the bicarbonate balance (J) from the CRRT blood therapy delivered in terms of amount per unit time. HCO3 _ bal ) based on the parameter (J buffer _ load / BW) and the bicarbonate balance (J HCO3 _ bal ) is the infusion rate (J) from the dialysis fluid and / or the substitution fluid. HCO3 _ inf ) and bicarbonate removal into the dialysis fluid (J HCO3 _ dial ), which is the difference between 3. The apparatus of claim 2.

20. The control unit (12) HCO3 _ bal )of, The replacement liquid velocity (Q rep ) and bicarbonate concentration (C HCO3 _ rep ) based on Q rep ・C HCO3 _ rep As a function of Bicarbonate plasma water concentration at the filter inlet (Cpw HCO3 _ inlet ) and the bicarbonate concentration of the dialysis fluid (C HCO3 _ d ) the difference between The ultrafiltration rate (Q fil ) and the bicarbonate concentration of the dialysis fluid (C HCO3 _ d ), Bicarbonate Clearance (K HCO3 ), the control unit (12) controls the dialysate flow rate (Q d ), blood velocity (Qbw inlet ), the ultrafiltration rate (Q fil ) as a function of flow rate, including one or more of HCO3 ) and the control unit (12) determines the bicarbonate clearance (K) as a function of the filtration unit (2) intended for CRRT therapy. HCO3 ) to calculate as a function of one or more of:

20. The apparatus of claim 19.

21. the control unit (12) is configured to compare the parameter indicative of the steady state acid-base balance of the patient's blood with a threshold value, and if the threshold value is an upper threshold value, the control unit (12) generates an alert if the parameter is higher than the upper threshold value, and if the threshold value is a lower threshold value, the control unit (12) generates an alert if the parameter is lower than the lower threshold value, and if the parameter exceeds the threshold value, the control unit (12) is configured to issue the alert and maintain the entered patient prescription or issue the alert and reject the entered patient prescription, If the input prescription is rejected, the control unit (12) Reinstate a previously valid patient prescription, or automatically shifting one or more parameters of said patient prescription to proposed values ​​defining a new valid patient prescription; [0023] 21. Apparatus according to any one of claims 1 to 20.

22. Assuming that the patient's bicarbonate concentration target at steady state is comprised between 24 mmol / l and 26 mmol / l, said thresholds include an upper threshold comprised between 0.25 and 0.5 mmol / h / kg; a first upper threshold (nNBL1) comprised between 0.25 and 0.35 mmol / h / kg; and / or The second upper threshold (nNBL2) is comprised between 0.35 and 0.5 mmol / h / kg; and the threshold value includes a lower threshold value configured between 0 and -0.2 mmol / h / kg, and the control unit (12) is further configured to issue a warning and / or block the input prescription when the parameter is lower than the lower threshold value.

22. The apparatus of claim 21.

23. A source of dialysate for supplying fluid to a dialysate supply line, the dialysate being substantially free of buffer; A substitution fluid bag (64) containing a substitution fluid having a buffer, the substitution fluid having a buffer concentration comprised between 0 and 1000 mmol / l, said one or more lines (8; 51; 58; 63; 74) for injecting respective solutions into the blood comprise an infusion line (63) connected to said substitution fluid bag (64) for injecting said substitution fluid into said blood, the infusion line (63) is a post-infusion line for infusing the buffer into the blood circuit (17) downstream of the filtration unit (2), and the buffer comprises or is bicarbonate; 23. Apparatus according to any one of claims 1 to 22.

24. The control unit (12) is configured to receive the prescription parameters of the patient and determine the parameters indicating the steady-state acid-base balance of the blood of the patient based on one or more of the prescription parameters or on parameters directly derived from the prescription parameters, and the control unit (12) controls the blood speed (Q b ) of the blood circuit (17), the dialysis fluid speed (Q d ) of the dialysis fluid in the dialysis fluid supply line (8), and the fluid removal speed (Q wl ) of the patient to be removed from the patient, and is configured to receive a prescription for the patient, 24. Apparatus according to any one of claims 1 to 23.

25. 1. A continuous renal replacement therapy (CRRT) device comprising: a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5); a blood circuit (17) having a blood withdrawal line (6) connected to an inlet of the primary chamber (3) and a blood return line (7) connected to an outlet of the primary chamber (3), the blood circuit being adapted for connection to a cardiovascular system of a patient; a blood pump (21) for circulating blood in the blood circuit (17); a dialysate line (13) connected to the outlet of the secondary chamber (4); one or more lines (8; 51; 57; 58; 63; 69; 67; 74) for transferring each solution into the blood; at least one fluid source of solution for each of the one or more lines, the solution including at least one buffer in the form of bicarbonate or a bicarbonate precursor; a control unit (12) configured to receive a patient prescription including parameters for setting up a CRRT blood therapy; The control unit (12) determining a parameter indicative of the steady state acid-base balance of the blood of the patient who must receive CRRT blood therapy, wherein the parameter is the patient's predicted net buffer load (NBL) at steady state or the patient's predicted normalized net buffer load (nNBL) at steady state, and is determined as a function of the concentration of the buffer in the fluid source and as a function of the patient's estimated or calculated systemic steady state concentration of bicarbonate and / or bicarbonate precursors; The net buffer load during extracorporeal blood therapy is the sum of the bicarbonate produced in the patient from the metabolism of the bicarbonate precursors, including citrate, and the bicarbonate balance (J HCO3 _ bal ) is the sum of The control unit (12) determines a parameter (J buffer_load / BW) indicating a steady-state acid-base balance of the blood of the patient by the following formula: or Alternatively, when considering acid infusion, the control unit (12) determines the parameter (J buffer_load / BW) indicative of the steady-state acid-base balance of the blood of the patient according to the following formula: or Alternatively, when lactate balance is also taken into account, the control unit (12) determines the parameter (J buffer_load / BW) indicative of the steady-state acid-base balance of the blood of the patient according to the following formula: or where n is the normalized net buffer loading; NBL is the net buffer load; J buffer_load is the net buffer load; J met_cit is the amount of bicarbonate produced per unit time from the metabolism of citrate infused into the patient; JHCO3_bal is the bicarbonate balance from the CRRT blood therapy delivered in terms of amount per unit time; J H+ is the acid injection from the citric acid contained in the fluid source in terms of amount per unit time; J met_lact is the lactate balance from the CRRT blood therapy delivered in terms of amount per unit time; BW is the patient's weight CRRT device.

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