DE19531935A1 - Device for whole body hyperthermia treatment - Google Patents

Abstract

An apparatus for the hyperthermic treatment of the whole body comprising an artificial kidney as heat exchanger, temperature measurement probes upstream and downstream of the heater and a controller for the cascade control of blood temperature that uses the temperature at the catheter inlet as control variable. The apparatus is used to treat cancer diseases and infectious diseases such as HIV/AIDS or hepatitis B and C.

Description

The invention relates to a device for whole body hyperthermia treatment (WBH = whole body hyperthermia), which serves to overheat the entire body of a patient, whereby the blood out of the body, past a heat source and with the help of a Cascade control of blood temperature is returned to the body (extracorporeal Blood heating, ESH = extracorporeal systemic heating. The temperature is controlled via Measuring probes. Use cases are primarily cancer and infectious diseases (HIV infection / AIDS, hepatitis B and C).

Berlin surgeons (W. Busch, Barg. Naturk. Society. Preuss. Rhine. Westphal. 23 (1886) 22-30; P. Bruns, Post Clinical Surgery. 3 (1887) 443-446) made the observation that there was a complete remission of the tumor came when postoperative high fever occurred. Coley, a New York orthopedist, made the same observation and developed a bacterial toxin to produce high fever for tumor treatment (W.B. Coley, Post graduate 8 (1893) 278-286). The Viennese neurologist Julius Wagner von Jauregg treated for the first time in 1917 the neurolues successfully with fever therapy (malaria therapy). He was for this the Nobel Prize was awarded in 1927.

Although you learned very quickly, high body temperatures increased physically generate what was also easier to control, the hyperthermia treatment with the Triumphant advance of antibiotics, radio and chemotherapy an outsider existence.

It was only in the mid-1960s that she slowly came to the fore again. The reason for this was the pathophysiological knowledge that tumor cells, in contrast to healthy cells, are extremely thermolabile and on heat with pathological changes to their Membranes and cell organelles react, which ultimately leads to apoptosis (M.B. Yatvin, Int. J. Hyperthermia (1993), 2, 165-185). Tumor cells also speak under hyperthermia more on chemotherapy drugs, so the dosage with consideration for side effects can be reduced.

Numerous WBH processes have been described: water bath, paraffin bath, steam-saturated hot air, heated blankets, heated water blankets. It is disadvantageous in these Cases that the heat must be conducted from the outside in. The heat radiation has  first to overcome the skin barrier; further guide and adsorb the tissues, such as Adipose tissue, muscles or bones, differently, so that some types of tissue already may be disproportionately heated while the inside of the body is not yet Treatment temperature has reached. The WBH using ESH proved to be more advantageous here. Blood is the best vehicle for warmth. It distributes heat through the circuit evenly from the inside out into all tissues. The technique of extracorporeal Blood treatment is well known and safe from hemodialysis (H. Nakajima, Hyperthermic Oncologie 1988, Ed. T. Sugahara & M. Saito, 1989, VoI. 1, Taylor & Francis, 375-377; J. H. Lee ibid., Pp 385-387; M. Yokoyama ibid., VoI. 2, pp 511-512; U. Willnow, Dtsch. med. Wschr., 1989, Vol. 114, No. 6, 208-213). In all publications the upper temperature limit of 42 ° C to prevent irreparable damage to the To avoid central nervous system.

B. Spire provided the basic work for the treatment of HIV infection with hyperthermia 1985, who was able to show that HI viruses are killed 40% in vitro at 42 ° C (The Lancet, Jan 26, 1985, 188-189). M. B. Yatvin (Medical Hypotheses, 1988, 27, 163-165), S. Brenner (AIDS Res Hum Retrov, 1989, Feb 5 (1), 5-6) and H. Weatherbum (Brlt. J. Radiol., Sept 1989, Vol. 61, 862-863) discussed the possibility of therapy for HIV infection using hyperthermia. G. H. W. Wong (Proc. Natl. Acad. Sci. USA, Vol. 88, May 1988, 4372- 4376) showed in vitro that cells infected with HIV are also thermolabile and massive Apoptosis begins at 42 ° C. She also observed that cells surviving though Virus particle expressed, but no viable virus could be detected.

The first treated W.D. Logan and K. Alonso 1991 (Med-Oncol-Tumor Pharmacother. 1991; 8 (1): 45-7) and K. Alonso et al. 1992 (Proc-Annu-Meet-Am-Soc-Clin-Oncol. 11: A8 1992; Biomed pharmacother. 1992, 46 (1): 21-4) and 1993 successfully HIV positive in Stage AIDS with and without Kaposi's sarcoma with the help of whole body hyperthermia (proc Annu-Meet-Am-Soc-Clin-Oncol. 12: A10 1993). The blood is heated by means of ESH: The blood is led out of the body via double-barreled catheters past the heat source and returned to the body. Alonso has a heater in the Integrated coil through which the blood flows. The core temperature was measured via a measuring probe that is inserted into the esophagus up to the level of the heart. The regulation of Temperature was set manually after the thermometer was displayed.

Wilinow had used an artificial kidney as the heat exchanger (U. Willnow et al., DMW (Dtsch.med.Wschr. 114 (1989) 208-213): The temperature control is as with Alonso performed.  

A hyperthermia device using ESH describes the US (patent) 5354277: The blood is Passed out of the body via catheters and warmed to 42 ° C. As a heat exchanger a dialysis machine is also used. The temperature of the dialysis fluid is 48 ° C. The temperature is controlled via a tubular heat exchanger and a heated mattress.

Methods for extracorporeal blood treatment are the subject of numerous others Patents, e.g. B.

• - US 5074838, 4950225, 4908014, 4065264, 4705508 and EP 0371173: Die Temperature control takes place via heater and heat exchanger; also the blood various substances for the treatment of diseases are added.
• - According to US 4787883, in which a method of treating AIDS and cancer is described, the blood drawn is separated and led into two chambers, whereby red and white blood cells accumulate separately. Both chambers can be separated be heated.
• - A temperature control zone is described in the patents US 4479798 and DE 8 22 167 presented. The temperature is kept constant at 41.5 ° C and must not exceed 42.5 ° C climb. The temperature control zone can also be attached as a skin implant.
• - Roller pumps for blood transport are proposed in US 4692138.
• - The patent specification WO 89/03706 calls a hyperthermia device in which overheating should be prevented by means of induction heating.
• - A device for performing an extracorporeal hyperthermia treatment is in DE 38 17 603 shown. Then the blood is heated up to 47 ° C and before the Return to the body cooled down again. The temperature is controlled via two Switching thermostats with temperature sensors attached.
• - The patents DE 38 31 016, 3790764, 3431314, 3401492, 3137581 and EP 0465441 contains hyperthermia devices that use infrared or microwaves heating and regulating radiation. They are mainly used for brain tumor therapies or for Local hyperthermia (DE 40 20 714) used. Hyperthermia devices without extracorporeal Heating, the energy supply using an electrical field (U 5251645), electromagnetic waves (US 5231997), high-frequency circuits (DE 35 26 531 and DE 33 06 391) or ultrasound (US 5230334) is known.

Control circuits are in connection with the extracorporeal hyperthermia treatment has not been described so far.

The invention has for its object to develop a hyperthermia device, the one improved temperature control via probes. According to the  Task solved by an arrangement according to which there are several measuring probes in the bloodstream and a cascade control from several successive control loops trigger, the decisive control variable being the venous temperature at the inlet of the Is catheter.

The arrangement according to the invention consists in the combination of known and new or newly composed elements. It represents a new combination of known elements based on an artificial kidney (hemodialyzer); essential components of dialysis technology are also used. Fig. 1 shows schematically the structure used. A distinction is made between a blood circulation and a heating circuit. The heat exchanger is the dialyzer.

The hose system of the heating circuit is connected to the water side of the kidney. This - a closed - system is filled with electrolyte solution. A pump is conveyed the solution past the heater and back. In front and behind the heater are each Temperature probes attached.

The functioning of the blood circulation is that in the large draining jugular vein (internal vena jugular, right or left, but also subclavian or femoral vein, right or left) a double-barreled catheter is inserted. From dialysis treatment is known that this catheter, with a correspondingly sterile dressing, several weeks to May linger for a number of treatments over the same catheter is possible. In the device according to the invention, the blood is admitted to the Catheter tip, the outlet above the tip through the side of the catheter Holes. The blood is removed from the body via a roller pump (blood flow 350 ml / min) pumped through the heat exchanger and back into the body. Is against an air embolism the patient is secured by a bubble trap and an air trap (ultrasound). At the Blood outlet of the heat exchanger is a temperature probe, also at the inlet and outlet of the catheter.

The probe at the inlet senses the temperature of the blood with which it is pumped into the body becomes. This temperature can be selected, up to a maximum of 42.2 ° C. The crucial one The controlled variable is the venous temperature at the inlet of the catheter. With help, too a protective device, possibly causing an emergency shutdown of the heater: At 42.3 ° C the heater switches off after 20 seconds with an alarm tone, at 42.6 ° C the The heater is switched off immediately with an alarm tone.

The probe at the outlet shows the actual temperature of the body, which rises slowly. At Specification of a target temperature of 42 ° C in simple sedation of the patient 70 to 80 min reached, with intubation anesthesia (ITN) in 40 to 50 min. The time difference between sedation and ITN until the target temperature is reached, it follows that  when the patient is sedated, the room temperature can only be increased to 39 ° C during in ITN the breathing air is preheated sufficiently. After reaching the target temperature of The treatment time is 41.8 to 42 ° C for 2 hours. During the entire treatment period chemotherapy drugs can be administered. The water and electrolyte loss will continuously balanced, the energy loss through glucose.

It has been found that with the device according to the invention significant disadvantages of previous methods and devices can be avoided. So it works with help the temperature at the catheter inlet as a guide variable a cascade control Realize blood temperature so that a maximum temperature in the heat exchanger of 43.4 ° C is required and there is no need for a cooling system. High temperatures in the Heat exchangers are therefore not necessary, which means the possibility of coagulation of the Blood decreased. When treating tumors, there are high temperatures in the heat exchanger also not efficient, because the tumor has settled in the tissues and not freely in the blood swims along. The same applies to a virus infection, since the majority of the viruses are in the Tissue is localized - like the virus-infected cells, which ultimately have to be destroyed, since they are the place of replication (Wong, see above).

It also turned out that by directly measuring the temperatures at the inlet and The catheter outlet does not require probes in the esophagus and rectum can. The temperature at the inlet is predefined and is displayed directly. The outlet or Actual temperature corresponds exactly to the brain temperature, as by tympanothermometric Measurements could be demonstrated because the catheter is located in the internal vena iugularis. Overheating of the brain is hereby successfully prevented, since the between Existing temperature differences in the esophagus, rectum and brain were not included in the measurement come in.

It is also advantageous that standard systems from dialysis treatment without changes can be used, such as: single-use pump tubing arterial and venous, Disposable dialyzer as a heat exchanger, disposable pump hose for substitution solutions and Standard substitution solutions from dialysis treatment. The heating circuit can after Treatment can be disinfected wet (hydrogen peroxide, sodium hypochlorite).

The device for whole-body hyperthermia treatment according to the invention consists of an arrangement - based on an artificial kidney - with a hemodialyzer as a heat exchanger with blood pumps, heater and circulating pump, temperature sensors before and after the heater, a cascade control of the blood temperature, a control part of the temperature probe at the catheter inlet and a control device for cascade control of the blood temperature from a temperature control with the temperature at the catheter inlet as a reference variable ( FIG. 1). The heating circuit consists of a closed hose system connected to the water side of the kidney, which is filled with electrolyte solution. The blood circulation of the system is formed by a double-barreled catheter and the blood is pumped out of the body by roller pumps and pumped back into the body after passing through the heat exchanger.

The blood is admitted at the tip of the catheter and the outlet above the tip Holes on the side of the catheter. The probe at the inlet detects the blood temperature. The The probe at the outlet gives the actual temperature of the body rising during the treatment and the probe at the inlet restores the blood temperature generated in the heating system. The the decisive control variable is the venous temperature at the inlet of the catheter. About you is also a possibly necessary protective device, which as Emergency shutdown works, regulated.

The cascade control of the blood temperature consists of several successive control loops: a heating control, a kidney output control and a venous temperature control ( Fig. 2). The heating control receives its setpoint from the kidney output control (reproduction of the water temperature in the dialyzer) and the kidney output control receives its setpoint from the venous temperature control. This evaluates the venous temperature as a controlled variable, with the control loops being determined by the control deviation and the manipulated variable. The venous temperature control receives its setpoint from the outside, whereby the individual control loops calculate their respective manipulated variables from the control deviation, the setpoints directly and other physical variables that influence the controlled system.

The manipulated variables (control parameters and control procedures) of the kidney output and Vein temperature control can also be done through a higher-level adaptive Regulation or by automatically controlled and evaluated tests before Calculate treatment.

The device according to the invention is used to treat cancer or infectious diseases (HIV infections / AIDS, hepatitis B and C).

Fig. 1: Description of the arrangement

Fig. 2: Functional description

Reference numerals:
Ta arterial temperature
Th temperature heating output
Thr should set temperature heating
Tn kidney exit temperature
Tn is designed to target kidney exit temperature
Tr heating return temperature
Tv venous temperature
Tv should target venous temperature
^v BP blood pump speed

The invention will be explained in more detail with the aid of exemplary embodiments.

Embodiments

1. Description of the arrangement:

• - A four-way tap either leads the water circuit to external connections or closes it to a ring
• - a water pump fills / empties the water circuit, e.g. B. for sterilization or produces a circulation
• - a heater heats the water in the water circuit (control variable)
• - Deliver two temperature sensors Th (heating output) and Tr (heating return) Measured values for the heating control
• - A dialyzer serves as a heat exchanger between the water and blood circulation
• - A blood pump (peristaltic pump) creates a blood circulation
• - A temperature sensor Tv (venous temperature) provides a measured value for the Vein temperature control (controlled variable)
• - A temperature sensor Tn (kidney outlet temperature) provides a measured value for the Kidney exit control
• - a mechanical bubble trap collects air bubbles
• - An air trap (ultrasound) prevents air from entering the bloodstream
• - A hose clamp prevents blood circulation when air is detected
• - A temperature sensor Ta (arterial temperature) provides a measured value for information the treating staff

2. Functional description

The decisive variable (controlled variable) is the venous temperature, that is the temperature of the blood that is returned to the patient. It is ultimately influenced by  the heater (temperature increase) and by heat radiation in the individual Components of the arrangement (temperature reduction).

The closed water cycle supplies thermal energy to the dialyzer (Heat exchanger). This releases heat energy to the blood circulating in the bloodstream. In these processes, considerable dead times are to be expected, which the regulation on the Very difficult to maintain venous temperature.

The control consists of three successive control loops (one Cascade control; partly a mixture of control and regulation).

The innermost control loop is the heating control. The setpoint comes from the overriding kidney exit regulation; is regulated to a value that is the temperature reproduces the water in the dialyzer as well as possible (e.g. (Th + Tr)). The manipulated variable exists from a P and a D component, the D component to compensate for the inertia of the Heating serves:

x = Th _soll - (Th + Tr) / 2 (control deviation)
Y = P _* x + D _* x ′ (manipulated variable)

The second control loop is the kidney exit control. It provides the heating setpoint temperature for the subordinate "heating control" control loop as a manipulated variable. It receives its part as setpoint renal output target temperature Tn _will of the parent vein temperature control.

x = Th _soll - Tn (control deviation)
Y = P _* x + D _* x ′ + f (process) (manipulated variable)

The manipulated variable is composed of a P- and D component, calculated from the control deviation and a further portion, including calculated from the set value Th _{is intended} and other process parameters such. B. Circulation rate in the water and blood circulation together. The latter serves to prevent strong control vibrations due to the inertia of the system.

The control algorithm uses two parameter sets, depending on whether the control deviation is above a certain threshold (heating phase) or whether it is below (Fine control).

The third control loop is the venous temperature control. It provides the control variable Setpoint kidney temperature for the subordinate control loop "kidney output control". she evaluates the actual control variable "venous temperature":

x = Tv _should - Tv (deviation)
Y = P _* x + D _* x ′ + f (process) (manipulated variable)

The control variable is again composed of a P and a D component is calculated from the control deviation, and a further portion, including calculated from the setpoint Tv _should and other process parameters, as mentioned above, together. The latter is particularly important here, since a long and non-constant dead time makes regulation with the required control quality impossible. The control algorithm also uses two parameter sets here, depending on whether the control deviation is above a certain threshold (heating phase) or whether it is below (fine control).

The kidney outlet and venous temperature control for the calculation of the Process-dependent terms used for the manipulated variable can also be used by another overriding regulation can be determined. The dependencies can be either through longer observation of the control behavior (adaptive control) or by automatic controlled and evaluated trials can be calculated before the treatments.

Furthermore, an emergency shutdown is implemented which is dangerous for the patient Temperatures bring about a rapid cooling (see above).

Claims (10)

1. Device for whole body hyperthermia treatment, consisting of an arrangement in Based on an artificial kidney - hemodialyzer - as a heat exchanger with blood pumps, Heater and circulation pump, from temperature sensors before and after the heater, one Control unit for cascading the blood temperature with the temperature at the catheter inlet as a leader. 2. Apparatus according to claim 1, characterized in that the heating circuit from one to the Closed tubing connected to the water side of the kidney consists of Electrolyte solution is filled. 3. Apparatus according to claim 1, in which the blood circulation through a double-barreled catheter formed and the blood out of the body by roller pumps and after passing the Heat exchanger is pumped back into the body, characterized in that the Blood inlet at the tip of the catheter, the outlet above the tip through at the side Holes are made in the catheter and the probe at the inlet detects the blood temperature. 4. Apparatus according to claim 1 and 3, characterized in that the probe at the outlet actual temperature of the body during treatment and the probe at the inlet shows the blood temperature generated in the heating system. 5. Apparatus according to claim 1, 3 and 4, characterized in that the decisive one Control variable is the venous temperature at the inlet of the catheter, which is also about a Protection device may cause an emergency shutdown of the heater. 6. Apparatus according to claim 1, characterized in that the cascade control Blood temperature consists of several successive control loops, each by Control deviation and manipulated variable are defined. 7. Apparatus according to claim 1 and 6, characterized in that the control loops from one Heating control, from a kidney output control and from a Vein temperature control exist.   8. Apparatus according to claim 1, 6 and 7, characterized in that the heating control their setpoint from the kidney output control, the kidney output control their setpoint from the venous temperature control and the venous temperature control through their setpoint Receives specification from the outside, whereby the individual control loops select their respective manipulated variables the control deviation, the target values and other physical quantities, that affect the controlled system. 9. Apparatus according to claim 1 and 6 to 8, characterized in that the manipulated variables - Control parameters and control procedures - the kidney outlet and venous temperature control additionally by a higher-level adaptive control or by automatically controlled and evaluated trials are calculated before treatment. 10. Apparatus according to claim 1 to 9, characterized in that it is used to treat Cancer or infectious diseases, such as HIV / AIDS, hepatitis B and C, used becomes.