APPARATUS FOR EXTRACORPOREAL BLOOD TREATMENT

Abstract

An apparatus for extracorporeal blood treatment is configured for detecting a disconnection between a connector (6a, 7a) for connection to a vascular access device (400) fixed to a patient (P) and the vascular access device (400) by: calculating a hydrostatic pressure difference (P.sub.H_patient) due to a difference in height between the vascular access device (400) and a pressure sensor (25, 26); calculating a section pressure drop (P.sub.line) due to a section of the blood circuit from the connector (6a, 7a) to the pressure sensor (25, 26); calculating a disconnection pressure (P.sub.disc) from the hydrostatic pressure difference (P.sub.H_patient) and the section pressure drop (P.sub.line); receiving a measured pressure (P) from the pressure sensor (25, 26); detecting a disconnection of the connector (6a, 7a) from the vascular access device (400) by comparing the measured pressure (P) with a pressure alarm threshold (P.sub.thresh) function of the disconnection pressure (P.sub.disc).

Claims

1-23. (canceled)

24. Apparatus for extracorporeal blood treatment comprising: a filtration unit; an extracorporeal blood circuit having a blood withdrawal line connected to an inlet of the filtration unit and a blood return line connected to an outlet of the filtration unit, said extracorporeal blood circuit configured to connect to a cardiovascular system of a patient; the extracorporeal blood circuit comprising at least one connector configured to connect to a vascular access device fixed to the patient; at least one pressure sensor configured to detect a pressure in at least one measurement location in the extracorporeal blood circuit; a blood pump configured to control flow of blood through the extracorporeal blood circuit; a control unit connected to the blood pump and to the at least one pressure sensor, the control unit configured to detect a disconnection between the at least one connector of the extracorporeal blood circuit and the vascular access device by: calculating a hydrostatic pressure difference due to a difference in height between the vascular access device and said at least one pressure sensor; calculating a section pressure drop due to a section of the blood circuit from the at least one connector to said at least one pressure sensor; calculating a disconnection pressure as an algebraic sum of the hydrostatic pressure difference and the section pressure drop; setting a pressure alarm threshold as a function of the disconnection pressure; wherein, during an extracorporeal blood treatment, the control unit is configured to: receive a measured pressure from the at least one pressure sensor; detect a disconnection of the least one connector from the vascular access device by comparing the measured pressure with the pressure alarm threshold.

25. The apparatus of claim 24, wherein the disconnection pressure is a constant along at least part of the extracorporeal blood treatment or wherein the control unit is configured to continuously update the disconnection pressure during at least part of the extracorporeal blood treatment.

26. The apparatus of claim 24, wherein the control unit is configured to calculate the hydrostatic pressure difference before starting the extracorporeal blood treatment.

27. The apparatus of claim 26, wherein the control unit is configured to calculate the hydrostatic pressure difference at least one time during the extracorporeal blood treatment.

28. The apparatus of claim 24, wherein the control unit is configured to calculate the section pressure drop before starting the extracorporeal blood treatment.

29. The apparatus of claim 28, wherein the control unit is configured to calculate the section pressure drop at least one time the extracorporeal blood treatment.

30. The apparatus of claim 28, wherein the control unit is configured to continuously update the section pressure drop during at least part of the extracorporeal blood treatment.

31. The apparatus of claim 24, wherein, to calculate the hydrostatic pressure difference, the control unit is configured to: stop the blood pump or keep the blood pump stopped to obtain a zero a blood flow rate; receive a static pressure from the at least one pressure sensor while the blood flow rate is zero; receive a patient central venous pressure; calculate the hydrostatic pressure difference as a difference between the static return pressure and the central venous pressure.

32. The apparatus of claim 31, wherein the patient central venous pressure is measured.

33. The apparatus of claim 31, wherein the patient central venous pressure is set as a default value.

34. The apparatus of claim 33, wherein the default value is between +800 Pa and +1600 Pa or is +1333 Pa.

35. The apparatus of claim 24, wherein, to calculate the section pressure drop, the control unit is configured to: receive a blood flow rate; receive or calculate a blood viscosity; receive or calculate a section pressure drop coefficient function of a geometry of the section of the blood circuit; calculate the section pressure drop as function of the blood flow rate, the blood viscosity, and said section pressure drop coefficient.

36. The apparatus of claim 35, wherein the section pressure drop coefficient is a constant.

37. The apparatus of claim 35, wherein the section pressure drop coefficient is given by the following equation: k.sub.line=(128L)/(d.sup.4); where L is a length of the section and d is an internal diameter of the section.

38. The apparatus of claim 35, wherein the control unit is configured to update the section pressure drop coefficient and the disconnection pressure during the extracorporeal blood treatment.

39. The apparatus of claim 31, wherein, to calculate the section pressure drop, the control unit is configured to: receive a blood flow rate; receive or calculate a blood viscosity; receive or calculate a section pressure drop coefficient function of a geometry of the section of the blood circuit; calculate the section pressure drop as function of the blood flow rate, the blood viscosity, and said section pressure drop coefficient, wherein an initial section pressure drop coefficient at a start of the extracorporeal blood treatment is given and is set as design section pressure drop coefficient, where L is a length of the section and d is an internal diameter of the section; update the section pressure drop coefficient and the disconnection pressure during the extracorporeal blood treatment, wherein, to update the section pressure drop coefficient during the extracorporeal blood treatment, the control unit is configured to: calculate an initial circuit pressure drop coefficient as k.sub.circ.sup.init=|(P.sub.initP.sub.Qb0)|/(Qb) and set it as reference circuit pressure drop coefficient; calculate an initial catheter pressure drop coefficient as k.sub.cath.sup.init=k.sub.circ.sup.initk.sub.line.sup.design and set it as reference catheter pressure drop coefficient; during the extracorporeal blood treatment, measure the pressure and calculate the circuit pressure drop coefficient as k.sub.circ=(PP.sub.Qb0)/(Qb); compare each calculated value of the circuit pressure drop coefficient to the reference circuit pressure drop coefficient and: if k.sub.circ is greater than k.sub.circ.sup.ref then the section pressure drop coefficient is updated as k.sub.line=k.sub.circk.sub.cath.sup.ref and the disconnection pressure is updated accordingly; if k.sub.circ is less than k.sub.circ.sup.ref then the section pressure drop coefficient remains unchanged and the disconnection pressure remains unchanged; the reference catheter pressure drop coefficient is updated as k.sub.cath.sup.ref=k.sub.circk.sub.line design, the reference circuit pressure drop coefficient is updated as k.sub.circ.sup.ref=k.sub.circ.

40. The apparatus of claim 39, wherein the initial section pressure drop coefficient at the start of the extracorporeal blood treatment is given by the following equation: k.sub.line.sup.init=(128L)/(d.sup.4).

41. The apparatus of claim 35, wherein the control unit is configured to: receive a blood hematocrit; calculate the blood viscosity from the blood hematocrit.

42. The apparatus of claim 41, wherein the control unit is configured to: receive a blood temperature and/or receive one of a protein concentration or albumin concentration; calculate the blood viscosity also from the blood temperature and/or one of the protein concentration or albumin concentration.

43. The apparatus of claim 24, wherein control unit is configured to set the pressure alarm threshold by: setting the pressure alarm threshold equal to the disconnection pressure; or setting the pressure alarm threshold equal to the disconnection pressure plus a safety margin; wherein the control unit is configured to send an alarm or a warning signal and/or stop the extracorporeal blood treatment when the pressure detected by the at least one pressure sensor in the at least one measurement location is outside a pressure range delimited by the pressure alarm threshold.

44. The apparatus of claim 24, wherein the at least one connector comprises a connector of the blood return line, wherein the at least one pressure sensor comprises a return pressure sensor configured to detect pressure at a measurement location in the blood return line, and wherein the control unit is configured to detect a disconnection between the connector of the blood return line and the vascular access device; wherein the hydrostatic pressure difference is a hydrostatic pressure difference in the blood return line due to a difference in height between the vascular access device and the return pressure sensor; wherein the section pressure drop is a section pressure drop in the blood return line due to a section of the blood return line from the connector of the blood return line to the return pressure sensor; wherein the disconnection pressure is a return disconnection pressure and is a sum of the hydrostatic pressure difference in the blood return line and the section pressure drop in the blood return line; wherein the pressure alarm threshold is a pressure alarm threshold of the blood return line and is set as a function of the return disconnection pressure; wherein the pressure detected at the measurement location in the blood return line is a measured return pressure from the return pressure sensor; wherein the control unit is configured to detect the disconnection between the connector of the blood return line and the vascular access device by comparing the measured return pressure with the pressure alarm threshold of the blood return line.

45. The apparatus of claim 44, wherein control unit is configured to set the pressure alarm threshold by: setting the pressure alarm threshold equal to the disconnection pressure; or setting the pressure alarm threshold equal to the disconnection pressure plus a safety margin; wherein the control unit is configured to send an alarm or a warning signal and/or stop the extracorporeal blood treatment when the measured return pressure is outside a pressure range delimited by the pressure alarm threshold or equal to or lower than the pressure alarm threshold.

46. The apparatus of claim 24, wherein the at least one connector comprises a connector of the blood withdrawal line, wherein the at least one pressure sensor comprises a withdrawal pressure sensor configured to detect pressure at a measurement location in the blood withdrawal line, and wherein the control unit is configured to detect a disconnection between the connector of the blood withdrawal line and the vascular access device; wherein the hydrostatic pressure difference is a hydrostatic pressure difference in the blood withdrawal line due to a difference in height between the vascular access device and the withdrawal pressure sensor; wherein the section pressure drop is a section pressure drop in the blood withdrawal line due to a section of the blood withdrawal line from the connector of the blood withdrawal line to the withdrawal pressure sensor; wherein the disconnection pressure is a withdrawal disconnection pressure and is a difference between the hydrostatic pressure difference in the blood withdrawal line and the section pressure drop in the blood withdrawal line; wherein the pressure alarm threshold is a pressure alarm threshold of the blood withdrawal line and is set as a function of the withdrawal disconnection pressure; wherein the pressure detected at the measurement location in the blood withdrawal line is a measured withdrawal pressure from the withdrawal pressure sensor; wherein the control unit is configured to detect the disconnection between the connector of the blood withdrawal line and the vascular access device by comparing the measured withdrawal pressure with the pressure alarm threshold of the blood withdrawal line.

47. The apparatus of claim 24, designed for continuous renal replacement therapies, Extra-Corporeal CO.sub.2 Removal, Hemo-Perfusion or Therapeutic Plasma Exchange.

Description

DESCRIPTION OF THE DRAWINGS

[0144] Aspects of the invention are shown in the attached drawings, which are provided by way of non-limiting examples, wherein:

[0145] FIG. 1 shows a schematic representation of an extracorporeal blood treatment apparatus;

[0146] FIG. 2 shows a schematic view in side elevation of the extracorporeal blood treatment apparatus of FIG. 1;

[0147] FIG. 3 shows an element of the extracorporeal blood treatment apparatus of FIGS. 1 and 2;

[0148] FIG. 4 is a flowchart showing a method of detecting disconnection events in an apparatus for extracorporeal blood treatment according to aspects of the invention;

[0149] FIGS. 5 and 6 represent a flowchart showing part of another method of detecting disconnection events in an apparatus for extracorporeal blood treatment according to aspects of the invention;

[0150] FIG. 7 is a flowchart showing another part of the method of FIGS. 5 and 6.

DETAILED DESCRIPTION

[0151] Extracorporeal blood treatment apparatus An apparatus 1 for extracorporeal blood treatment is schematically represented in FIG. 1. The apparatus 1 is a continuous renal replacement therapy (CRRT) apparatus for intensive care treatments, for instance configured to deliver various therapies, like CCVH, CVVHDF, CVVHD, SCUF.

[0152] The apparatus 1 comprises a treatment or filtration unit 2 having a primary chamber 3 and a secondary chamber 4 separated by a semi-permeable membrane 5. Depending upon the treatment, the semi-permeable membrane 5 of the filtration unit 2 may be selected to have different properties and performances. A blood circuit is coupled to the primary chamber 3 of the filtration unit 2. The blood circuit comprises a blood withdrawal line 6 connected to an inlet 3a of the primary chamber 3, a blood return line 7 connected to an outlet 3b of the primary chamber 3. The blood withdrawal line 6 and blood return line 7 are configured for connection to a cardiovascular system of a patient P.

[0153] In use, the blood withdrawal line 6 and the blood return line 7 are connected to a vascular access device 400 which is then placed in fluid communication with the patient P vascular system, such that blood may be withdrawn through the blood withdrawal line 6, flown through the primary chamber 3 and then returned to the patient's vascular system through the blood return line 7.

[0154] An air detector, not shown, and an air separator, such as a deaeration chamber 8, may be present on the blood return line 7. Moreover, a monitor valve 9 may be present on the blood return line 7, downstream the deaeration chamber 8. The blood flow through the blood circuit is controlled by a blood pump 10, for instance a peristaltic blood pump, acting either on the blood withdrawal line 6 or on the blood return line 7. The embodiment of FIG. 1 shows the blood pump 10 coupled to a pump section of the blood withdrawal line 6. A dialysis circuit is connected to the secondary chamber 4 of the filtration unit 2 and comprises a dialysis line 11 connected to an inlet 4a of the secondary chamber 4 and an effluent line 12 connected to an outlet 4b of the secondary chamber 4 and to a drain, not shown.

[0155] An effluent pump 13 is located on the effluent line 12 and is able to recall fluid from the second chamber 4. The dialysis line 11 is connected to a source 14, e.g. a bag or a preparation device, of fresh dialysis fluid and a dialysis pump 15 is located on the dialysis line 11 and is able to pump fluid to the second chamber 4.

[0156] The apparatus 1 further comprises an infusion circuit comprising at least one infusion line. The infusion circuit shown in the embodiment of FIG. 1 comprises a pre-blood pump line 16, a pre-infusion line 17 and a post-infusion line 18.

[0157] The pre-blood pump line 16 is connected to the blood withdrawal line 6 upstream of the blood pump 10 and to a first source 19 of infusion fluid, e.g. a bag. A pre-blood pump 20 is located on the pre-blood pump line 16 and is able to pump fluid from the first source 19 to the blood circuit.

[0158] The pre-infusion line 17 is connected to the blood withdrawal line 6 downstream of the blood pump 10 and upstream of the filtration unit 2 and to a second source 21 of infusion fluid, e.g. a bag. A pre-infusion pump 22 is located on the pre-infusion line 17 and is able to pump fluid from the second source 21 to the blood circuit.

[0159] The post-infusion line 18 is connected to the blood return line 7 downstream of the filtration unit 2 and to a third source 23 of infusion fluid, e.g. a bag. A post-infusion pump 24 is located on the post-infusion line 18 and is able to pump fluid from the third source 23 to the blood circuit.

[0160] The apparatus 1 may also comprise one or more auxiliary line/s, not shown, connected to the blood circuit and to a source of at least one compensation substance or of an anticoagulant, such as potassium or bicarbonate, and a pump or syringe configured to deliver a flow rate of the compensation substance, such as potassium or bicarbonate, etc.

[0161] A withdrawal pressure sensor 25 is configured to detect a pressure at a measurement location in the blood withdrawal line 6. A return pressure sensor 26 is configured to detect a pressure at a measurement location in the blood return line 7. The withdrawal pressure sensor 25 and the return pressure sensor 26 may comprise pressure pods in the blood withdrawal line 6 and blood return line 7. The return pressure sensor 26 may be operatively coupled to the deaeration chamber 8, as shown in FIG. 1.

[0162] A control unit 100 is connected and controls the blood pump 10, the dialysis pump 15, the effluent pump 13, the pre-blood pump 20, the pre-infusion pump 22 and the post-infusion pump 24 to regulate a blood flow rate Q.sub.b in the blood circuit, a dialysis flow rate crossing the dialysis line 11, an effluent flow rate crossing the effluent line 12, an infusion flow rate crossing the pre-blood pump line 16, an infusion flow rate crossing the pre-infusion line 17, an infusion flow rate crossing the post-infusion line 18. Through the control of the dialysis flow rate crossing the dialysis line 11 and/or of the effluent flow rate crossing the effluent line 12, the control unit 100 is also configured to control/regulate a filtration flow rate (through the control of the dialysis pump 15 and the effluent pump 13) in the filtration unit 2 and/or a patient fluid removal rate (also through the control of the pre-blood pump 20, the pre-infusion pump 22 and the post-infusion pump 24).

[0163] The control unit 100 is also connected to the withdrawal pressure sensor 25 and to the return pressure sensor 26 to receive signals correlated to pressure values from these sensors 25, 26. The withdrawal pressure sensor 25 and the return pressure sensor 26 provide to the control unit 100 signals correlated to pressure in the extracorporeal blood circuit.

[0164] The control unit 100 may be an electronic control unit comprising at least a CPU, a memory and input/output devices. The control unit 100 comprises or is connected to an interface 110 configured to display data and/or allow a user to input data. For instance, the interface comprises a display, e.g. a touch screen, and/or buttons or a keyboard.

[0165] The apparatus 1 may comprise a treatment machine 200 and an integrated disposable set configured to be coupled to the treatment machine 200. The outline of the treatment machine 200 is represented schematically in FIG. 2.

[0166] The treatment machine 200 comprises the cited blood pump 10, effluent pump 13, dialysis pump 15, pre-blood pump 20, pre-infusion pump 22, post-infusion pump 24, control unit 100 with the interface 110, flow rate sensors.

[0167] The treatment machine 200 may comprise also the withdrawal pressure sensor 25 and the return pressure sensor 26 or the withdrawal pressure sensor 25 and the return pressure sensor 25 may be part of the integrated disposable set. The treatment machine 200 comprises also all the other elements and/or devices configured to receive and hold parts of the integrated disposable set.

[0168] The integrated disposable set comprises the treatment or filtration unit 2, the blood circuit, the effluent line 12, the dialysis line 11, the infusion lines 16, 17, 18, which are grouped together.

[0169] When the integrated disposable set is mounted on the treatment machine 200, the withdrawal pressure sensor 25 and the return pressure sensor 26 or the measurement locations of the withdrawal pressure sensor 25 and return pressure sensor 26 are in fixed positions on a frame 300 of the treatment machine 200 and at predefined heights above the ground.

[0170] A section 27 of the blood withdrawal line 6 develops from the withdrawal pressure sensor 25 on the treatment machine 200 to the vascular access device 400 and to the patient P undergoing treatment. A section 28 of the blood return line 7 develops from the return pressure sensor 26 on the treatment machine 200 to the vascular access device 400 and to the patient P.

[0171] As shown in FIG. 2, the patient P undergoing treatment is lying on a bed 29 and the vascular access device 400 is placed at a height which may be different from a height of the withdrawal pressure sensor 25 and of the return pressure sensor 26 and may vary with respect to both the heights of the withdrawal pressure sensor 25 and return pressure sensor 26, since the bed height is typically adjustable.

Vascular Access Device

[0172] The vascular access device 400 shown in FIG. 3 is central double lumen venous catheter (CVC) which is configured to be placed in a large central vein of the patient P, for instance in the neck (internal jugular vein).

[0173] The vascular access device 400 comprises a withdrawal section 30 delimiting a withdrawal lumen and a return section 31 delimiting a return lumen. Distal portions of the withdrawal section 30 and return section 31 are provided respectively with a distal tip 32 of the withdrawal section 30 and a distal tip 33 of the return section. The distal portions of the withdrawal section 30 and return section 31 are paired and configured to be placed inside the large central vein. Proximal portions of the withdrawal section 30 and return section 31 are split and configured to remain outside the patient body.

[0174] The proximal portions are provided respectively with a withdrawal port 34 and a return port 35. The withdrawal port 34 is connected or configured to be connected to a connector 6a of the blood withdrawal line 6 and the return port 35 is connected or configured to be connected to a connector 7a of the blood return line 7, as shown in FIG. 3, and allow to connect the extracorporeal blood circuit to the vascular system of the patient P.

Detection of Disconnection Events

[0175] According to a method of detecting disconnection events in an apparatus for extracorporeal blood treatment, the control unit 100 is configured and/or programmed for detecting a disconnection between the withdrawal port 34 and the connector 6a of the blood withdrawal line 6 and/or between the return port 35 and the connector 7a of the blood return line 7 while the patient P is undergoing an extracorporeal blood treatment. When a disconnection event is detected, the control unit 100 is configured and/or programmed for sending an alarm or a warning signal and/or stopping the extracorporeal blood treatment.

Disconnection of Return Line

[0176] During treatment (i.e. when the blood pump 10 is running), the return pressure P.sub.ret at the measurement location of the return pressure sensor 26 is given by the following equation:

[00001]$\begin{array}{cc}{P}_{\mathrm{ret}}=P_{\mathrm{offset\_ret}}+P_{\mathrm{ret\_cath}}+P_{\mathrm{ret\_line}}& \mathrm{Eq}.1)\end{array}$

wherein [0177] P.sub.offset_ret=P.sub.ret_Qb0 is the pressure when there is no blood flow rate (Qb=0); [0178] P.sub.ret_cath is the pressure drop in the return section 31 of the vascular access device 400; [0179] P.sub.ret_line is the pressure drop in the section 28 of the blood return line 7 from the connector 7a of the blood return line 7 to the return pressure sensor 26.

[0180] The return pressure at the measurement location P.sub.ret_Qb0 when there is no blood flow rate (Qb=0) is given by the following equation:

[00002]$\begin{array}{cc}{P}_{\mathrm{offset\_ret}}=P_{\mathrm{ret\_Qb}0}=P_{\mathrm{venous}}+P_{\mathrm{Hret\_patient}}& \mathrm{Eq}.2)\end{array}$

wherein [0181] P.sub.venous is a patient central venous pressure; [0182] P.sub.Hret_patient is a hydrostatic pressure difference in the blood return line 7 due to a difference in height H.sub.ret between the vascular access device 400 and the return pressure sensor 26.

[0183] Indeed, in the case of zero blood flow rate, there is no pressure drop along the blood circuit and only hydrostatic pressure as well as patient central venous pressure define the offset pressure.

[0184] Therefore equation 1 becomes:

[00003]$\begin{array}{cc}{P}_{\mathrm{ret}}=P_{\mathrm{venous}}+P_{\mathrm{Hret\_patient}}+P_{\mathrm{ret\_cath}}+P_{\mathrm{ret\_line}}& \mathrm{Eq}.1^{})\end{array}$

[0185] In case of disconnection between the connector 7a of the blood return line 7 and the return port 35 of the vascular access device 400, the return pressure at the measurement location (the return disconnection pressure P.sub.ret_disc) is given by the following equation:

[00004]$\begin{array}{cc}{P}_{\mathrm{ret\_disc}}=P_{\mathrm{Hret\_patient}}+P_{\mathrm{ret\_line}}& \mathrm{Eq}.3)\end{array}$

because, if the connector 7a is disconnected from the return port 35, the return pressure at the measurement location is not affected by the patient central venous pressure P.sub.venous and by the pressure drop P.sub.ret_cath in the return section of the vascular access device 400.

Example 1 (FIG. 4)

[0186] In view of equations 1), 1), 2) and 3) above, in order to detect the disconnection of the blood return line 7, before starting the blood treatment and after the patient has been connected, while the blood pump 10, the effluent pump 13, the dialysis pump 15, the pre-blood pump 20, the pre-infusion pump 22 and the post-infusion pump 24 are stopped and the blood flow rate is zero (Qb0), the control unit 100 is configured for performing the following steps: [0187] measuring the return pressure P.sub.ret_Qb0 at the measurement location; [0188] receiving the patient central venous pressure P.sub.venous; and [0189] calculating the hydrostatic pressure difference P.sub.Hret_patient in the blood return line 7 starting from equation 2) as:

[00005]$\begin{array}{cc}{P}_{\mathrm{Hret\_patient}}=P_{\mathrm{ret\_Qb}0}-P_{venous}& \mathrm{Eq}.4)\end{array}$

[0190] In equation 4), the central venous pressure P.sub.venous may be set as a default value, for instance between +6 mmHg and +12 mmHg, e.g. of +10 mmHg, because typical values are reported in the 6-12 mmHg range. The central venous pressure P.sub.venous may also be measured and entered into the control unit 100 through a query to the operator/medical staff.

[0191] After starting the blood treatment, the control unit 100 is configured for performing the following steps: [0192] receiving the blood flow rate Qb (e.g. 200 ml/min); [0193] receiving a blood viscosity (e.g. 3 mPa s); [0194] receiving a length L.sub.ret (e.g. 2.2 m) and an internal diameter d.sub.ret (e.g. 4.5 mm) of the section 28 of the blood return line 7; [0195] calculating a section pressure drop coefficient of the blood return line k.sub.ret_line through the following equation:

[00006]$\begin{array}{cc}{k}_{\mathrm{ret\_line}}=\left(128L_{\mathrm{ret}}\right)/\left(d_{\mathrm{ret}}^4\right)\left(e.g.0.0277\mathrm{mmHg}/\left(m1/\min \right)/\left(\mathrm{mPa}s\right)\right)& \mathrm{Eq}.5)\end{array}$ [0196] calculating the pressure drop P.sub.ret_line in the section 28 of the blood return line 7 through the following equation:

[00007]$\begin{array}{cc}{P}_{\mathrm{ret\_line}}=k_{\mathrm{ret\_line}}\mathrm{Qb}\left(e.g.17\mathrm{mmHg}\right)& \mathrm{Eq}.6)\end{array}$ [0197] calculating the return disconnection pressure P.sub.ret_disc through equation 3 (e.g. 2 mmHg assuming P.sub.venous=10 and P.sub.ret_Qb0=5 mmHg); [0198] setting a pressure alarm threshold P.sub.ret_thresh of the blood return line 7 as:

[00008]$\begin{array}{cc}{P}_{\mathrm{ret\_thresh}}=P_{\mathrm{ret\_disc}}+P_{\mathrm{ret\_safety}}\left(\mathrm{safety}\mathrm{margin}\right)\left(e.g.12\mathrm{mmHg}\mathrm{assuming}a\mathrm{safety}\mathrm{margin}\mathrm{of}10\mathrm{mmHg}\right)& \mathrm{Eq}.7)\end{array}$

[0199] Once the pressure alarm threshold P.sub.ret_thresh has been calculated, the control unit 100 is configured for performing the following steps: [0200] receiving the measured return pressure P.sub.ret and comparing with the pressure alarm threshold P.sub.ret_thresh of the blood return line 7 (with a second or a few seconds frequency); [0201] sending the alarm or the warning signal and/or stopping the extracorporeal blood treatment if the measured return pressure P.sub.ret is equal to or lower than the pressure alarm threshold P.sub.ret_thresh.

[0202] If P.sub.ret>P.sub.ret_thresh no disconnection of the blood return line 7;

[0203] If P.sub.ret<=P.sub.ret_thresh disconnection of the blood return line 7.

[0204] In this Example 1, the section pressure drop coefficient k.sub.ret_line of the blood return line 7 is a constant along the extracorporeal blood treatment. If the blood flow rate Qb and the blood viscosity remain unchanged, also the pressure drop P.sub.ret_line calculated through equation 6) remains unchanged even if the calculation is repeated.

[0205] The hydrostatic pressure difference P.sub.Hret_patient may change due to changes of bed height and/or of patient position. Therefore, the calculation of the hydrostatic pressure difference P.sub.Hret_patient, which is performed before starting the blood treatment through equation 4), is repeated every 6 to 12 hours along the treatment and each time a change in bed height and/or patient position is reported.

[0206] In order to repeat the measurements of the return pressure P.sub.ret_Qb0 and the calculation of the hydrostatic pressure difference P.sub.Hret_patient, the pumps (the blood pump 10, the effluent pump 13, the dialysis pump 15, the pre-blood pump 20, the pre-infusion pump 22 and the post-infusion pump 24) are stopped and the static pressure P.sub.Qb0 is measured when becoming stable.

[0207] Then, the return disconnection pressure P.sub.ret_disc and the pressure alarm threshold P.sub.ret_thresh are updated accordingly. The safety margin P.sub.ret_safety may be e.g. 10 mmHg or may be also set to zero, such that the pressure alarm threshold P.sub.ret_thresh of the blood return line 7 is equal to the return disconnection pressure P.sub.ret_disc.

Example 2 (FIGS. 5, 6 and 7)

[0208] According to Example 2, the section pressure drop coefficient k.sub.ret_line of the blood return line 7 and consequently also the pressure drop P.sub.ret_line in the section 28 of the blood return line 7, the return disconnection pressure P.sub.ret_disc and the pressure alarm threshold P.sub.ret_thresh are continuously updated during the extracorporeal blood treatment (e.g. every 1 to 10 minutes). This example 2 allows to take into account the presence of clotting in the blood return line 7, since the catheter pressure drop coefficient k.sub.ret_cath and the section pressure drop coefficient k.sub.ret_line of the blood return line 7 may change along treatment further to clotting problems.

[0209] At the start of the extracorporeal blood treatment, the control unit 100 is configured for performing the following steps: [0210] receiving the blood flow rate Qb (e.g. 150 ml/min); [0211] receiving the blood viscosity (e.g. 3.0 mPa s); [0212] receiving the length L.sub.ret (e.g. 246 cm) and the internal diameter d.sub.ret (e.g. 4.55 mm) of the section 28 of the blood return line 7; [0213] calculating an initial section pressure drop coefficient k.sub.ret_line.sup.init of the blood return line 7 through the following equation (the same as Eq.5; indeed when initiating blood circulation with a new disposable set, it is safe to assume that no clot is present in the blood return line; in this situation the initial section pressure drop coefficient is provided by Eq. 5):

[00009]$\begin{array}{cc}{k}_{\mathrm{ret\_line}}^{\mathrm{init}}=\left(128L_{\mathrm{ret}}\right)/\left(d_{\mathrm{ret}}^4\right)\left(e.g.0.031\mathrm{mmHg}/\left(m1/\min \right)/\left(\mathrm{mPa}s\right)\right)& \mathrm{Eq}.8)\end{array}$ [0214] calculating P.sub.ret_line.sup.init=k.sub.ret_line.sup.initQb (e.g. 14 mmHg); [0215] calculating P.sub.ret_disc.sup.init=P.sub.Hret_patient+P.sub.ret_line.sup.init (e.g. 0 mmHg); [0216] calculating P.sub.ret_thresh.sup.init=P.sub.ret_disc.sup.init+P.sub.ret_safety (e.g. +10 mmHg); [0217] setting the initial section pressure drop coefficient k.sub.ret_line.sup.init as design section pressure drop coefficient of the blood return line: k.sub.ret_line.sup.init=k.sub.ret_line.sup.design; [0218] calculating an initial circuit pressure drop coefficient k.sub.ret_circ.sup.init of the blood return line 7 through the following equation:

[00010]$\begin{array}{cc}{k}_{\mathrm{ret\_circ}}^{\mathrm{init}}=\left(P_{\mathrm{ret}}^{\mathrm{init}}-P_{\mathrm{Qb}0}\right)/\left(\mathrm{Qb}\right)\left(e.g.0.142\mathrm{mmHg}/\left(m1/\min \right)/\left(\mathrm{mPa}s\right)\right)& \mathrm{Eq}.9)\end{array}$ [0219] setting the initial circuit pressure drop coefficient k.sub.ret_circ.sup.init as reference circuit pressure drop coefficient k.sub.ret_circ.sup.ref of the blood return line 7; [0220] calculating an initial catheter pressure drop coefficient k.sub.ret_cath.sup.init of the blood return line 7 through the following equation:

[00011]$\begin{array}{cc}{k}_{\mathrm{ret}\_\mathrm{cath}}^{\mathrm{init}}=k_{\mathrm{ret\_circ}}^{\mathrm{init}}-k_{\mathrm{ret\_line}}^{\mathrm{design}}\left(e.g.0.111\mathrm{mm}\mathrm{Gh}/\left(\mathrm{ml}/\min \right)/\left(\mathrm{mPa}s\right)\right))& \mathrm{Eq}.10)\end{array}$ [0221] setting the initial catheter pressure drop coefficient k.sub.ret_cath.sup.init as reference catheter pressure drop coefficient k.sub.ret_cath.sup.ref of the blood return line 7.

[0222] The circuit pressure drop coefficient k.sub.ret_circ of the blood return line 7 is the coefficient related to the pressure drop due both to the return section 31 of the vascular access device 400 and to the section 28 of the blood return line 7 from the connector 7a of the blood return line 7 to the return pressure sensor 26. In other embodiments, the initial section pressure drop coefficient of the blood return line k.sub.ret_line.sup.init at the start of the extracorporeal blood treatment may also be derived from experimental measurements (measurements (in the scenario where the system may identify the return line configuration, either unique or in relation to the set type).

[0223] During the extracorporeal blood treatment, the control unit 100 is configured for performing the following steps: [0224] measuring the pressure return line P.sub.ret; [0225] calculating the circuit pressure drop coefficient k.sub.ret_circ of the blood return line 7 through the following equation:

[00012]$\begin{array}{cc}{k}_{\mathrm{ret}\_\mathrm{circ}}=\left(P_{\mathrm{ret}}-P_{\mathrm{Qb}0}\right)/\left(\mathrm{Qb}\right)& \mathrm{Eq}.11)\end{array}$ [0226] comparing each new value of the circuit pressure drop coefficient k.sub.ret_circ of the blood return line 7 to the reference circuit pressure drop coefficient k.sub.ret_circ.sup.ref of the blood return line 7; and then
if k.sub.ret_circ is greater than k.sub.ret_circ.sup.ref, then the section pressure drop coefficient k.sub.ret_line of the blood return line 7 is updated as

[00013]$\begin{array}{cc}{k}_{\mathrm{ret}\_\mathrm{line}}=k_{\mathrm{ret}\_\mathrm{circ}}-k_{\mathrm{ret}\_\mathrm{cath}}^{\mathrm{ref}}& \mathrm{Eq}.12)\end{array}$

and the return disconnection pressure P.sub.ret_disc is updated accordingly through equations 6, 3 and 7;
if k.sub.ret_circ is less than or equal to k.sub.ret_circ.sup.ref, then the section pressure drop coefficient k.sub.ret_line of the blood return line 7 remains unchanged and also the return disconnection pressure P.sub.ret_disc remains unchanged while the reference catheter pressure drop coefficient k.sub.ret_cath.sup.ref of the blood return line 7 is updated design and the reference circuit as k.sub.ret_cath.sup.ref=k.sub.ret_circk.sub.ret_line pressure drop coefficient k.sub.ret_circ.sup.ref of the blood return line 7 is updated as k.sub.ret_circ.sup.ref=k.sub.ret_circ.

[0227] In the situation where k.sub.ret_circ is less than k.sub.ret_circ.sup.ref, the circuit pressure drop coefficient k.sub.ret_circ of the blood return line 7 is lower than ever documented since the start of the treatment. This means that the catheter pressure drop was initially overestimated, expectedly because of some clotting that has resolved over time, assuming that the section pressure drop coefficient k.sub.ret_line of the blood return line 7 cannot decrease below its initial value.

[0228] The procedure of FIGS. 5 and 6 is repeated with a period in the range of minutes, e.g. 1 to 10 minutes, while the control procedure of FIG. 7, corresponding to the last part of the method of Example 1 shown in FIG. 4, is repeated with a period in the range of seconds or less, e.g. 0.2 to 2 seconds.

[0229] The following Table 1 is an example of evolution of the pressure return line P.sub.ret over time and related computed pressure drop coefficients and alarm threshold obtained starting from the above illustrative values between brackets of this example 2.

TABLE-US-00002 TABLE 1 Time Qb P.sub.ret k.sub.ret.sub..sub.circ k.sub.ret.sub..sub.line k.sub.ret.sub..sub.circ.sup.ref k.sub.ret.sub..sub.cath.sup.ref P.sub.ret.sub..sub.thresh min ml/min mmHg mmHg/(ml/min)/(mPa s) mmHg 0 150 58 0.142 0.031 0.142 0.111 +10 10.sup. 150 60 0.147 0.036 0.142 0.111 +12 20.sup. 150 59 0.144 0.033 0.142 0.111 +11 26.sup.(1) 200 81 0.145 0.034 0.142 0.111 +30 30.sup. 200 83 0.148 0.037 0.142 0.111 +32 40.sup.(2) 200 96 0.170 0.059 0.142 0.111 +45 50.sup.(2) 200 101 0.178 0.067 0.142 0.111 +50 60.sup.(2) 200 103 0.182 0.070 0.142 0.111 +52 70.sup.(3) 200 88 0.157 0.045 0.142 0.111 +37 80.sup.(3) 200 82 0.147 0.039 0.142 0.111 +34 90.sup.(3) 200 77 0.138 0.031 0.138 0.107 +29 100 200 81 0.145 0.038 0.138 0.107 +33 .sup.(1)blood flow rate change at time 26 min (values a few seconds after the flow change) .sup.(2)simulation of some clotting in the return circuit .sup.(3)recovery from clotting

[0230] Once the pressure alarm threshold P.sub.ret_thresh has been calculated, the control unit 100 is configured for performing the following steps: [0231] receiving the measured return pressure P.sub.ret and comparing with the pressure alarm threshold P.sub.ret_thresh of the blood return line 7 (with a second or a few seconds frequency); [0232] sending the alarm or the warning signal and/or stopping the extracorporeal blood treatment if the measured return pressure P.sub.ret is equal to or lower than the pressure alarm threshold P.sub.ret_thresh.

Example 3

[0233] Example 3 may be a variant embodiment of Example 1 or of Example 2 wherein the blood viscosity is calculated by the control unit 100.

[0234] The control unit 100 is configured for receiving a blood hematocrit Hct and a blood temperature T and for calculating the blood viscosity through the following equation:

[00014]$\begin{array}{cc}=e^{\left(1,8/T\right)5,54}{e}^{2,3\left(\mathrm{Hct}/100\right)}& \mathrm{Eq}.13)\end{array}$

[0235] The hematocrit Hct and the blood temperature T may be entered by an operator in the control unit through the interface 110 or may be measured by sensors operatively connected to the control unit 100 and automatically transmitted to the control unit 100. For instance, an optical sensor may be used to measure hematocrit Htc.

Disconnection of Withdrawal Line

[0236] The following equations pertaining to the blood withdrawal line 6 are similar to those related to the return line 7.

[00015]$\begin{array}{cc}{P}_{\mathrm{with}}=P_{\mathrm{offset}\_\mathrm{with}}-P_{\mathrm{with}\_\mathrm{cath}}-P_{\mathrm{with}\_\mathrm{line}}\left(\mathrm{see}\mathrm{Eq}.1\right)& \mathrm{Eq}.14)\end{array}$$\begin{array}{cc}{P}_{\mathrm{offset}\_\mathrm{with}}=P_{\mathrm{with}\_\mathrm{Qb}0}=P_{\mathrm{venous}}+P_{\mathrm{Hwith}\_\mathrm{patient}}\left(\mathrm{see}\mathrm{Eq}.2\right)& \mathrm{Eq}.15)\end{array}$$\begin{array}{cc}& \mathrm{Eq}.16)\end{array}$$P_{\mathrm{with}}=P_{\mathrm{venous}}+P_{\mathrm{Hwith}\_\mathrm{patient}}-P_{\mathrm{with}\_\mathrm{cath}}-P_{\mathrm{with}\_\mathrm{line}}\left(\mathrm{see}\mathrm{Eq}.1^{}\right)$$\begin{array}{cc}{P}_{\mathrm{with}\_\mathrm{disc}}=P_{\mathrm{Hwith}\_\mathrm{patient}}-P_{\mathrm{with}\_\mathrm{line}}\left(\mathrm{see}\mathrm{Eq}.3\right)& \mathrm{Eq}.17)\end{array}$

wherein [0237] P.sub.with: measured withdrawal pressure from the withdrawal pressure sensor 25; [0238] P.sub.with_Qb0: withdrawal pressure at the measurement location when there is no blood flow rate (Qb=0); [0239] P.sub.Hwith_patient: hydrostatic pressure difference in the blood withdrawal line 6 due to a difference in height between the vascular access device 400 and the withdrawal pressure sensor 25; [0240] P.sub.with_cath: pressure drop in the withdrawal section 30 of the vascular access device 400; [0241] P.sub.with_line: section pressure drop in the blood withdrawal line 6 due to the section 27 of the blood withdrawal line 6 from the connector 6a of the blood withdrawal line 6 to the withdrawal pressure sensor 25; [0242] P.sub.with_disc: withdrawal disconnection pressure.

[0243] Equation 17 is used to calculate the withdrawal disconnection pressure immediately after a disconnection event.

[0244] Differently, since after disconnection of the withdrawal line 6 the blood pump 10 sucks air and the withdrawal line 6 is emptied of blood and filled with air, after an amount of time (e.g. 1 s to 2 s) the withdrawal disconnection pressure P.sub.with_disc may be considered negligible and set to zero (P.sub.with_disc=0).

Example 4

[0245] Example 4 is analogous to Example 1. In order to detect the disconnection of the blood withdrawal line 6, before starting the blood treatment, while the blood pump 10, the effluent pump 13, the dialysis pump 15, the pre-blood pump 20, the pre-infusion pump 22 and the post-infusion pump 24 are stopped and the blood flow rate is zero (Qb0), the control unit 100 is configured for performing the following steps: [0246] measuring the withdrawal pressure P.sub.with_Qb0 at the measurement location; [0247] receiving the patient central venous pressure P.sub.venous; and [0248] calculating the hydrostatic pressure difference PH.sub.with patient in the blood withdrawal line 6 starting from equation 15) as:

[00016]$\begin{array}{cc}{P}_{\mathrm{Hwith}\_\mathrm{patient}}=P_{\mathrm{with}\_\mathrm{Qb}0}-P_{\mathrm{venous}}& \mathrm{Eq}.18)\end{array}$

[0249] After starting the blood treatment, the control unit 100 is configured for performing the following steps: [0250] receiving the blood flow rate Qb; [0251] receiving the blood viscosity (which may be calculated as disclosed in Example 3); [0252] receiving a length L.sub.with and an internal diameter d.sub.with of the section 27 of the blood withdrawal line 6; [0253] calculating a section pressure drop coefficient of the blood withdrawal line k.sub.with_line through the following equation:

[00017]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{line}}=\left(128L_{\mathrm{with}}\right)/\left(d_{\mathrm{with}}^4\right)\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.5\right)& \mathrm{Eq}.19)\end{array}$ [0254] calculating the pressure drop P.sub.with_line in the section 27 of the blood withdrawal line 6 through the following equation:

[00018]$\begin{array}{cc}{P}_{\mathrm{with}\_\mathrm{line}}=k_{\mathrm{with}\_\mathrm{line}}\mathrm{Qb}\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.6\right)& \mathrm{Eq}.20)\end{array}$ [0255] calculating the withdrawal disconnection pressure P.sub.with_disc immediately after disconnection through equation 17; [0256] setting a pressure alarm threshold P.sub.with_thresh of the blood withdrawal line 6 as:

[00019]$\begin{array}{cc}{P}_{\mathrm{with}\_\mathrm{thresh}}=P_{\mathrm{with}\_\mathrm{disc}}-P_{\mathrm{with}\_\mathrm{safety}}\left(\mathrm{safety}\mathrm{margin}\right)& \mathrm{Eq}.21)\end{array}$ [0257] receiving the measured return pressure P.sub.with and comparing with the pressure alarm threshold P.sub.with_thresh of the blood withdrawal line 6; [0258] sending the alarm or the warning signal and/or stopping the extracorporeal blood treatment if the measured withdrawal pressure P.sub.with is equal to or greater than the pressure alarm threshold P.sub.with_thresh.

[0259] If P.sub.with<P.sub.with_thresh no disconnection of the blood withdrawal line 6;

[0260] If P.sub.with>=P.sub.with_thresh disconnection of the blood withdrawal line 6.

Example 5

[0261] Example 5 is analogous to Example 2. According to Example 5, the section pressure drop coefficient k.sub.with_line of the blood withdrawal line 6 and consequently also the pressure drop P.sub.with_line in the section 27 of the blood withdrawal line 6, the withdrawal disconnection pressure P.sub.with_disc and the pressure alarm threshold P.sub.with_thresh are continuously updated during the extracorporeal blood treatment.

[0262] At the start of the extracorporeal blood treatment, an initial section pressure drop coefficient k.sub.with_line.sup.init of the blood withdrawal line 6 is calculated through the following equation (same as Eq.19):

[00020]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{line}}^{\mathrm{init}}=\left(128L_{\mathrm{with}}\right)/\left(d_{\mathrm{with}}^4\right)& \mathrm{Eq}.22)\end{array}$

[0263] The initial section pressure drop coefficient k.sub.with_line.sup.init is set as design section pressure drop coefficient k.sub.with_line.sup.design of the blood withdrawal line 6.

[0264] An initial circuit pressure drop coefficient k.sub.with_circ.sup.init of the blood withdrawal line 7 is calculated through the following equation:

[00021]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{circ}}^{\mathrm{init}}=\left(P_{\mathrm{Qb}0}-P_{\mathrm{with}}^{\mathrm{init}}\right)/\left(\mathrm{Qb}\right)\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.9\right)& \mathrm{Eq}.23)\end{array}$

[0265] The initial circuit pressure drop coefficient k.sub.with_circ.sup.init is set as reference circuit pressure drop coefficient k.sub.with_circ.sup.ref of the blood withdrawal line 6.

[0266] An initial catheter pressure drop coefficient k.sub.with_cath.sup.init of the blood withdrawal line 6 through the following equation:

[00022]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{cath}}^{\mathrm{init}}=k_{\mathrm{with}\_\mathrm{circ}}^{\mathrm{init}}-k_{\mathrm{with}\_\mathrm{line}}^{\mathrm{design}}\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.10\right)& \mathrm{Eq}.24)\end{array}$

[0267] The initial catheter pressure drop coefficient k.sub.with_cath.sup.init is set as reference catheter pressure drop coefficient k.sub.with_cath.sup.ref of the blood withdrawal line 6.

[0268] During the extracorporeal blood treatment, the control unit 100 measures the pressure withdrawal line P.sub.with and calculates the circuit pressure drop coefficient k.sub.with_circ of the blood withdrawal line 6 through the following equation:

[00023]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{circ}}=\left(P_{\mathrm{Qb}0}-P_{\mathrm{with}}\right)/\left(\mathrm{Qb}\right)\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.11\right)& \mathrm{Eq}.25)\end{array}$

[0269] Each new value of the circuit pressure drop coefficient k.sub.with_circ of the blood withdrawal line 6 is compared to the reference circuit pressure drop coefficient k.sub.with_circ.sup.ref of the blood withdrawal line 6; and then:

if k.sub.with_circ is greater than k.sub.with_circ.sup.ref, then the section pressure drop coefficient k.sub.with_line of the blood withdrawal line 6 is updated as

[00024]$\begin{array}{cc}{k}_{\mathrm{with}\_\mathrm{line}}=k_{\mathrm{with}\_\mathrm{circ}}-k_{\mathrm{with}\_\mathrm{cath}}^{\mathrm{ref}}\left(\mathrm{analogous}\mathrm{to}\mathrm{Eq}.12\right)& \mathrm{Eq}.26)\end{array}$

and the withdrawal disconnection pressure P.sub.with_disc is updated accordingly through equations 20, 17 and 21;
if k.sub.with_circ is less than k.sub.with_circ.sup.ref, then the section pressure drop coefficient k.sub.with_line of the blood withdrawal line 6 remains unchanged and also the withdrawal disconnection pressure P.sub.with_disc remains unchanged while the reference catheter pressure drop coefficient k.sub.with_cath.sup.ref of the blood withdrawal line 6 is updated as k.sub.with_cath.sup.ref=k.sub.with_circk.sub.with_line.sup.design and the reference circuit pressure drop coefficient k.sub.with_circ.sup.ref of the blood withdrawal line 6 is updated as k.sub.with_circ.sup.ref=k.sub.with_circ.

Example 6

[0270] According to Examples 2 and 5, a consistency check of the circuit pressure drop coefficient k.sub.ret_circ of the blood return line 7 or of the circuit pressure drop coefficient k.sub.with_circ of the blood withdrawal line 7 may also be performed. Equations and computation steps at start and during therapy are unchanged. For instance, referring to Example 2, where the access device 400 (catheter) type is identified and its pressure drop coefficient known (k.sub.ret_cath.sup.design), the previous algorithm of Example 2 may be slightly tuned. The change consists in an additional check for consistency of the return circuit (or catheter) pressure drop coefficient through the following equation.

[00025]$\begin{array}{cc}{k}_{\mathrm{ret}\_\mathrm{circ}}>k_{\mathrm{ret}\_\mathrm{cath}}^{\mathrm{design}}+k_{\mathrm{ret}\_\mathrm{line}}^{\mathrm{design}}& \mathrm{Eq}.27)\end{array}$

[0271] In case above equation is not verified-within the accuracy limits of the measurements-this may drive a confirmation of the catheter type as well as suspicion of return pressure malfunction if the same outcome occurs after repetition of the measuring sequence.

[0272] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover modifications included within the scope of the appended claims.