Organ monitoring apparatus and method

Abstract

A container 1 is described for containing an ex vivo organ 4, having been removed from a donor and awaiting transplantation to a recipient. The organ 4 is provided with a controlled environment and at

Description

The present invention relates to the monitoring of organs in the field of organ transplantation. In this connection, organ transplantation is currently limited by ischaemic time, from the point of organ retrieval from the donor to the time of implanting into a recipient (host). In this regard, it is recognised that early organ rejection by the host is influenced in particular by preceding ischaemic organ damage. The level of ischaemia remains difficult to assess and often comes down to the experience of the transplant team based on their knowledge of the age of the donor; the extent of other injuries / disorders that the donor may have been subjected to such as blood loss or chest injury; any pharmacological treatments administered to resuscitate the donor to minimise subsequent organ damage; and, any advanced mechanical donor support to minimise subsequent organ damage e.g. Extracorporeal Membrane Oxygenation (ECMO) or Circulatory support. Not uncommonly, the general appearance of the organ prior to being inserted into the host still influences whether an organ is used or not. Organ transplantation is also very labour intensive and costly, since for years transplant teams have been on standby 24 hours a day to retrieve donor organs and then to implant them into a suitable host before the organ deteriorates. Not surprisingly, transplant teams are only willing to undertake this work for a few years given the impact it has on their own lives. To reduce ischaemic damage and to enable surgical teams to work in a more acceptable manner, ex-vivo organ support using machines are becoming increasingly popular since they can greatly extend the usable period for the organ by maintaining perfusion, while also permitting certain key biochemical and functional parameters to be measured on a regular basis to optimise organ perfusion. In this regard, normothermic and hypothermic organ perfusion is also topical and may have advantages for specific organs. In this respect, organs for transplantation generally include the heart, lungs, liver, kidney, pancreas, and small bowel, or combinations e.g. heart and lungs, pancreas and small bowel. Further, whilst there are machines available to support organs awaiting transplantation, this is still a relatively new field. For example, sophisticated machines do exist that primarily perfuse the organ awaiting transplantation with oxygen enriched blood while also monitoring biochemical markers such as oxygen, carbon dioxide, glucose, and lactate present within the arterial and venous blood present, circulated by the machine. Other functional parameters such as the volume of bile production or urine production can also be monitored for liver and kidney respectively and used as a surrogate measure of organ health. An object of the present invention is to provide an apparatus and method to alleviate problems with existing devices and methods associated with organ transplantation. According to the present invention there is provided apparatus for monitoring the condition of an ex-vivo organ, wherein the organ has been removed from a donor and is awaiting transplantation into a recipient; the apparatus comprising: a chamber for housing the organ in a controlled environment; and one or more probes for measuring pH associated with the organ. Optionally, one or more probes are configured to measure any one or more of organ tissue, bile, urine, pancreatic secretions, small bowel secretions associated with the specific organ respectively, or peritoneal fluid that is collectively produced by the intrabdominal organs. Optionally, the one or more probes are configured to monitor the pH of fluids produced by, ordraining from, different regions of the organ. Optionally, the organ may be any one or more of the liver, the kidney, the small bowel, the heart, lungs and pancreas. A plurality of probes may be provided to monitoring pH of different regions of the organ. In the case of the liver, the one or more probes may have separate elements for monitoring different regions of the liver’s biliary tree, the probe elements being provided up the common bile duct and into the hepatic ducts and smaller branches of the hepatic ducts within the left and right sides of the liver. Optionally, the apparatus further comprises a control device in communication with the one or more probes, the control device being configured to monitor pH measurements of the one or more probes. The control device may use the pH measurements in association with other parameters being measured, such as one or more of oxygen, glucose, CO2, lactate, pyruvate, and ions such as bicarbonate, potassium, calcium, magnesium and phosphate. Optionally, the control device is coupled to means for influencing the environment within the chamber, in reaction to the pH measurements of the probe, and optionally in association with one or more other parameters being measured selected from oxygen, glucose, CO2, lactate, pyruvate as well as key ions such as bicarbonate, potassium, calcium, magnesium and phosphate. In this regard, any one or more of oxygen, glucose, CO2, lactate, pyruvate, as well as key ions such as bicarbonate, potassium, calcium magnesium and phosphate can be supplied to the controlled environment at levels controlled by the control device in response to the measurements being taken. Optionally, the one or more probes are provided within the chamber in such a manner that measurements can be taken without disturbing the integrity of the controlled environment of the chamber. Optionally, the one or more probes are coupled to the exterior of the chamber by way of one or more of: a) one or more cables passing through one or more sealed apertures in the chamber; or b) a wireless connection, such as a Bluetooth (RTM) connection. Optionally, the apparatus is configured for continuous measurement. In this regard, the apparatus may be configured for measuring any one of organ tissue pH, the pH of arterial or venous blood, or the pH of other bodily liquids such as bile, urine, small bowel and pancreatic secretions or peritoneal fluid that is produced by the intraabdominal organs. In this respect, since pH (the inverse log to the base 10 of hydrogen ion concentration), is derived from the concentration of hydrogen ions present, it provides a highly accurate overview of acid-base balance, unlike attempting to derive pH levels through measuring the concentration of molecules such as lactate and pyruvate, with methods that have inherent errors and are not a true reflection of actual pH, far less acid-base balance. By measuring pH directly, using hydrogen ion concentration, this method assesses the overall effects of buffering systems that are naturally present within the organ or introduced along with machine support of the organ, or through the administration of drugs or other pharmaceutical agents. pH, if assessed continuously, is, by way of the present invention, considered invaluable to detect any suboptimal organ metabolic activity enabling intervention to maintain ideal organ function and extend the survival period of the organ prior to implantation. Optionally, a sterile Blue-tooth (RTM) transmitter is attached to a connector end of each of the one or more probes. The transmitter may optionally be separately powered using a sealed battery unit. Alternatively, the transmitter may be powered through adaptations within the organ support machine. Optionally, the apparatus may further comprise an alarm unit to provide an alert of undesirable pH measurements or levels. In this regard, alarm thresholds or limits may be set to trigger the alarm unit. For example, organ tissue ischaemia (pH approx. 7.0-7.2), urine (variable pH range that changes with kidney ischaemia), bile (usually alkaline - pH approx. 8.5, but can become less alkaline with liver ischaemia), pancreatic secretions (usually highly alkaline - pH approx. 12-14, but can become less alkaline with pancreas ischaemia), or possible small bowel secretions (variable pH range, but can become acidic with intestinal ischaemia). With respect to the intrabdominal organs that may become ischaemic, the peritoneal fluid will also become increasingly acidic. The alert may be any one or more of a visual, audible or vibration alert. Optionally, the apparatus further comprises a thermometer for assessing an accurate measure of organ tissue, blood, or body fluid temperature. In this way, the accuracy of pH readings, can be calibrated and improved, especially where hypothermic circulation or solely hypothermic organ storage is being used. Optionally, the apparatus further comprises means for altering conditions affecting the organ within the chamber, these including one or more of temperature, blood oxygenation, nutrient and buffer provision. According to a further aspect of the present invention, there is provided a method of monitoring an ex-vivo organ, the method comprising: placing the ex-vivo organ into a chamber having a controlled environment, coupling the organ or a part thereof to one or more probes configured to measure one or more pH values associated with the organ. Optionally, the one or more probes measure any one or more of organ tissue bile, urine, pancreatic secretions, small bowel secretions associated with the organ, or peritoneal fluid that is produced by the intraabdominal organs, or venous and arterial blood. Optionally, the one or more probes monitor the pH of fluids produced by different regions of the organ. Optionally, the organ any one or more of the liver, the kidney, the small bowel, the heart, lungs and pancreas. Where the organ is the liver, the one or more probes may have separate elements for monitoring different regions of the liver’s biliary tree, the probe elements being provided up the common bile duct and into the hepatic ducts and smaller branches of the hepatic ducts within the left and right sides of the liver. Where the organ is the kidney, the one or more probes may have separate elements for monitoring different regions of the kidney’s urinary drainage system, the probe elements being provided into different regions of the urinary collecting system that drain different regions of the kidney. Optionally, a control device is provided in communication with the one or more probes, the control device monitoring pH measurements of the one or more probes. The control device may use the pH measurements in association with other parameters being measured, such as one or more of oxygen, glucose, CO2, lactate, pyruvate as well as key ions such as bicarbonate, potassium, calcium, magnesium and phosphate. Optionally, the control device acts to influence the environment within the chamber in reaction to the pH measurements of the probe. Moreover, the control device may act to influence the environment within the chamber in reaction to the pH measurements in association with other parameters being measured, such as one or more of oxygen, glucose, CO2, lactate, pyruvate as well as key ions such as bicarbonate, potassium, calcium, magnesium and phosphate. Optionally, the one or more probes take pH measurements without disturbing the integrity of the controlled environment of the chamber. Optionally, the one or more probes are communicated with the control device by way of one or more of: a) one or more cables passing through one or more sealed apertures in the chamber; or b) a wireless connection, such as a Bluetooth (RTM) connection. Optionally, the one or more probes allow for continuous measurement. Optionally, the control activates an alarm unit to provide an alert in response to undesirable pH measurements or levels. In this regard, an alarm is activated when alarm thresholds or limits are reached or broken. Optionally, the method further comprises monitoring temperature within the chamber for assessing an accurate measure of organ, blood or body fluid temperature. In this way, the accuracy of pH readings, can be greatly improved, especially where hypothermic organ preservation methods are being used in isolation or in association with continuous perfusion methods. According to a further aspect of the present invention there is provided a method of monitoring the pH of organs, in the donor, prior to being harvested to assess suitability for transplantation. In this respect, the present invention may encompass monitoring the effects of donor support devices e.g. Extracorporeal Membrane Oxygenation (ECMO), Circulatory pumps, combinations, and the need for blood transfusions, drug intervention, and perfusion of nutrients and buffers to optimise / maintain organ function and acid-base balance prior to the organ being harvested and additionally, monitoring pH of organs after being transplanted into the recipient to detect signs of early rejection or the need for additional drug therapy, to enhance organ recovery and reduce the risk of rejection. According to a further aspect of the present invention there is provided apparatus for monitoring the condition of a transplantation organ, wherein the apparatus comprises: one or more probes for measuring pH associated with the organ. According to a further aspect of the present invention there is provided a method of monitoring the condition of a transplantation organ, the method comprising: coupling the organ or a part thereof to one or more probes configured to measure one or more pH values associated with the organ. Optionally, the method involves attaching pH probes to different regions of an organ. Optionally, the control device includes a processor and a memory, the memory storing environment condition profiles for optimising organ preservation, the processor tailoring the conditions applied to the organ in order to optimise organ preservation based on the probe measurements taken. Optionally, the control device has a learning function, in order to update the environment condition profiles, based on organ preservation success. An embodiment of the present invention will now be described by way of example and with reference to the attached drawings:- Figure 1 shows a schematic view of the apparatus of the present invention; and Figure 2 a representation of a process of the present invention. Figure 1 shows a chamber 1 which creates a controlled environment for an organ 4 to be transplanted. The organ is ex-vivo having been removed from a donor and not yet transplanted into a recipient. A number of probes 2 are provided within the chamber and are coupled to areas of the organ tissue and various fluids entering, exiting or being produced by the organ 4. A control device 3, in this case shown outside the chamber, is coupled to the probes. This can be by way of physical cables, passing through sealed apertures in the chamber, or by way of a wireless link such a Bluetooth (RTM). As shown the probes are configured to measure any one or more of bile, urine, pancreatic secretions, or small bowel secretions associated with the organ, or venous and arterial blood, in addition to the organ tissue, in this case the liver. The probes may have separate elements for monitoring different regions of the liver’s biliary tree, the probe elements being provided up the common bile duct and into the hepatic ducts and smaller branches within the left and right sides of the liver. The control device 3 is provided in communication with the one or more probes and is configured to monitor pH measurements of the one or more probes. The control device 3 is preferably configured to influence the environment within the chamber in reaction to the pH measurements of the probes 2. This could be to alter any one or more of the temperature, blood oxygenation level, nutrient infusion or buffer infusion, and the concentrations of other metabolites / molecules e.g. oxygen, CO2, glucose, lactate, pyruvate, and ions such as bicarbonate, potassium, magnesium, calcium and phosphate, etc. The control device optionally additionally influences the chamber environment in association with one or more other parameters being measured selected from oxygen, glucose, CO2, lactate, and pyruvate, and ions such as bicarbonate, potassium, magnesium, calcium and phosphate, etc. In this regard, any one or more of oxygen, glucose, CO2, lactate, pyruvate, as well as key ions such as bicarbonate, potassium, calcium, magnesium and phosphate can be supplied to the controlled environment at levels controlled by the control device 3 in response to the measurements being taken. Hence, in addition to the overall assessment of the organ when taken into consideration with pH, oxygen, glucose and the other parameters may also be considered as nutrients / treatment to maintain optimal organ function, that again may be used therapeutically as influenced by pH. In this regard, the control device may include a processor and a memory, the memory storing environment condition profiles for optimising organ preservation, the processor tailoring the conditions applied to the organ in order to optimise organ preservation based on the probe measurements taken. Optionally, the control device moreover has a learning function, in order to update the environment condition profiles, based on organ preservation success. In this connection, the apparatus is configured for continuous measurement. A sterile Blue-tooth (RTM) transmitter (not shown) may be attached to a connector end of each of the one or more probes. The transmitter may also optionally be separately powered using a sealed battery unit. Alternatively, the transmitter may be powered through adaptations within the organ support machine. As shown, the apparatus further comprises an alarm unit 5 to provide an alert of undesirable pH levels. In this regard, alarm thresholds or limits may be set to trigger the alarm unit. For example, organ tissue ischaemia (pH approx. 7.0-7.2), urine (variable pH range that changes with kidney ischaemia), bile (usually alkaline - pH approx. 8.5, but can become less alkaline with liver ischaemia), pancreatic secretions (usually highly alkaline - pH approx. 12-14, but can become less alkaline with pancreas ischaemia), or possible small bowel secretions (variable pH range, but can become acidic with intestinal ischaemia). With respect to the intraabdominal organs that may become ischaemic, the peritoneal fluid will also become increasingly acidic. The alert may be any one or more of a visual, audible or vibration alert. Optionally, the apparatus further comprises a thermometer (not shown) for assessing an accurate measure of organ, blood or body fluid temperature. In this way, the accuracy of pH readings, can be greatly improved, especially where hypothermic circulation is being used. Figure 2 shows a schematic of a method according to the present invention. At step 100 the ex-vivo organ is placed within the chamber for transport and wellbeing purposes until the point it is needed for the transplant operation. At step 200 one or more probes are attached to the organ at various locations as appropriate. At step 300, with the chamber sealed so that the environment there within can be maintained at optimal conditions, the readings from the one or more probes are continuously monitored with a view to optimising the condition of the organ. In this connection, if at step 400 readings from the one or more probes indicate undesirable pH levels are being measured, conditions within the chamber can be altered as appropriate, there being a feedback loop to step 300. The conditions within the chamber can in this respect be altered to take account of the pH measurements and the levels of other parameters may be taken into consideration in addition to or in the light of the measured pH levels. As shown in Figure 1, the probes are set up in this embodiment for monitoring the pH of the blood being introduced into the organ (arterial side) through the hepatic artery, with the blood flowing from the organ (venous side) through the inferior vena cava, the pH of the right and left lobes of the liver, and the pH of the bile. In this way, the apparatus can be used to monitor the pH of human and animal ex-vivo organs directly from the organ tissue itself or from the fluids that enter into, exit from, or are manufactured by the organ. In some embodiments, one or more probes could be used for monitoring pH of organs prior to being harvested to assess suitability for transplantation. Further the present invention may encompass monitoring the effects of donor support devices e.g. Extracorporeal Membrane Oxygenation (ECMO), Circulatory pumps, combinations, and the need for blood transfusions and drug intervention to optimise / maintain organ function and acid-base balance prior to the organ being harvested and pH monitoring of organs after being transplanted into the recipient to detect signs of rejection or the need for additional drug therapy to enhance organ recovery and reduce the risk of rejection. Organs that are considered relevant for the present invention comprise: 1. Heart - tissue, aortic root, coronary sinus. 2. Lungs - tissue, pulmonary vein (oxygen enriched blood), pulmonary artery (oxygen depleted blood) 3. Liver - tissue, hepatic artery, inferior vena cava, bile 4. Kidney - tissue, renal artery, renal vein, urine 5. Pancreas - tissue, pancreatic artery, pancreatic vein, pancreatic secretions 6. Small bowel - tissue, mesenteric artery, mesenteric vein, small bowel secretions 7. Organ combinations - heart and lungs; pancreas and small bowel 8. All intra-abdominal organs that become ischaemic will also make the peritoneal fluid more acidic. Therefore, peritoneal fluid pH concentration is also indicative of the level of intra-abdominal organ ischaemia irrespective of the cause. The apparatus of the present invention can further be used to conduct a comparison of pH changes measured from the organ tissue, fluids, arterial and venous blood simultaneously. Moreover, the apparatus of the present invention may be used to conduct a comparison of pH changes measured from the organ tissue, fluids made by the organ and arterial and venous blood in light of infused nutrients e.g. glucose, oxygen, buffers e.g. bicarbonate, ions such as potassium, calcium, magnesium and phosphate and drugs that are used to optimise organ function. Further, the apparatus of the present invention may be used to conduct a comparison of pH changes measured from the organ tissue, fluids, arterial and venous blood in-light of infused nutrients e.g. glucose, oxygen; buffers e.g. bicarbonate, that are required to maintain organ tissue, fluids, arterial and venous blood pH within a normal or acceptable range. Additionally, the apparatus of the present invention may be used to conduct a comparison of pH changes measured from organ tissues, fluids, arterial and venous blood in-light of intentional hypothermic organ storage. Such apparatus may also take into consideration other parameters in addition to pH. Finally, the apparatus of the present invention may be used to conduct a comparison of pH changes measured from organ, fluids, arterial and venous blood in-light of intentional hypothermic organ storage combined with machine perfusion. Such apparatus may take into consideration other parameters in addition to pH. Moreover, it will be appreciated that measuring pH directly from different parts of an organ can afford useful information. For example, in the heart the right side works essentially as a different pump from the left side of the heart, so that one side could be ischaemic, while the other side is not. Similarly, in the liver, the left and right lobes can also perform differently as they have different blood supplies via different arteries. In the kidney, the cortical region will be different from the collecting part of the kidney. As such, the present invention encompasses attaching probes to different regions of an organ for mining additional information. The present invention hence provides the opportunity to measure pH directly from more than one part of an organ, and moreover in real-time, for example measuring organ tissue as well as measuring pH directly from fluids produced by the organs, e.g. bile and urine, as well as venous and arterial blood, in real-time. It will be understood that the various aspects of the present invention can be practiced alone or in combination with one or more of the other aspects, as will be appreciated by those skilled in the relevant arts. The various aspects of the invention can optionally be provided in combination with one or more of the optional features of the other aspects of the invention. Also, optional features described in relation to one aspect can typically be combined alone or together with other features in different aspects of the invention. Any subject matter described in this specification can be combined with any other subject matter in the specification to form a novel combination. Various aspects of the invention are described in detail with reference to the accompanying figures. Still other aspects, features, and advantages of the present invention are readily apparent from the entire description thereof, including the figures, which illustrates a number of exemplary aspects and implementations. The invention is also capable of other and different examples and aspects, and its several details can be modified in various respects, all without departing from the scope of the present invention. Accordingly, each example herein should be understood to have broad application, and is meant to illustrate one possible way of carrying out the invention, without intending to suggest that the scope of this disclosure, including the claims, is limited to that example. Furthermore, the terminology and phraseology used herein is solely used for descriptive purposes and should not be construed as limiting in scope. In particular, unless otherwise stated, dimensions and numerical values included herein are presented as examples illustrating one possible aspect of the claimed subject matter, without limiting the disclosure to the particular dimensions or values recited. All numerical values in this disclosure are understood as being modified by "about". All singular forms of elements, or any other components described herein are understood to include plural forms thereof and vice versa. Language such as "including", "comprising", "having", "containing", or "involving" and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents, and additional subject matter not recited, and is not intended to exclude other additives, components, integers or steps. Likewise, the term "comprising" is considered synonymous with the terms "including" or "containing" for applicable legal purposes. Thus, throughout the specification and claims unless the context requires otherwise, the word “comprise” or variations thereof such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Any discussion of documents, acts, materials, devices, articles and the like is included in the specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention. In this disclosure, whenever a composition, an element or a group of elements is preceded with the transitional phrase "comprising", it is understood that we also contemplate the same composition, element or group of elements with transitional 5 phrases "consisting essentially of”, "consisting", "selected from the group of consisting of”, “including”, or "is" preceding the recitation of the composition, element or group of elements and vice versa. In this disclosure, the words “typically” or “optionally” are to be understood as being intended to indicate optional or nonessential features of the invention which are present in certain examples but which 10 can be omitted in others without departing from the scope of the invention. References to directional and positional descriptions such as upper and lower and directions e.g. “up”, “down” etc. are to be interpreted by a skilled reader in the context of the examples described to refer to the orientation of features shown in the 15 drawings, and are not to be interpreted as limiting the invention to the literal interpretation of the term, but instead should be as understood by the skilled addressee.

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