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Ann Thorac Surg 2000;70:644-652
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

Venovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow, and thermal gradients

Roger A. Vertrees, PhDa, Akhil Bidani, MD, PhDb, Donald J. Deyo, DVMc, Weike Tao, MDc, Joseph B. Zwischenberger, MDa,b

a Division of Cardiothoracic Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, USA
b Pulmonary Division, Department of Medicine, The University of Texas Medical Branch, Galveston, Texas, USA
c Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA

Address reprint requests to Dr Vertrees, Division of Cardiothoracic Surgery, Department of Surgery, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0528
e-mail: rvertree{at}utmb.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Thermal events during extracorporeal venovenous perfusion-induced systemic hyperthermia (VV-PISH) were studied and related to determination of whole-body and regional thermal isoeffect doses.

Methods. Swine ( , 77 ± 4.5 kg) were heated to a target temperature of 43°C for 120 minutes using VV-PISH. Colored microspheres were injected during preheat, heat induction, maintenance, cool down, and after decannulation. The esophageal, tympanic, rectal, pulmonary artery, bladder, bone marrow, kidney, brain, blood, lung, and airway temperatures were recorded continuously. The thermal dose, thermal exchange, metabolic heat production, heat loss to the environment, the change in body heat, and the thermal isoeffect dose were studied at 15-minute intervals.

Results. VV-PISH increased heart rate and cardiac output and caused a redistribution of blood flow favoring the thoracoabdominal organs. Greatest thermal exchange occurred during the heating phase (total 2,162 ± 143 kJ), metabolic heat production contributed in all phases (274 ± 9 kJ), the greatest change in body heat occurred during heating (1,310 ± 309 kJ) with a total delivered thermal dose of 298 ± 21 kJ, and the total whole body thermal isoeffect dose at 100 ± 5 minutes.

Conclusions. VV-PISH is feasible, is capable of transferring sufficient heat, causes a redistribution of blood flow favoring the thoracoabdominal organs, and facilitates calculation of whole-body and regional thermal isoeffect doses.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
All known mammalian cells and tissues are thermosensitive as manifest by protein denaturation and tissue destruction at critically elevated temperatures. For temperatures less than the critical temperature (41°C to 43°C), the outcome depends on the thermal dose (TD; degree of temperature elevation and duration of exposure) received and the type of cell or tissue involved because of cell-specific thermosensitivity [1, 2]. Neoplastic as opposed to nonneoplastic cells and tissues are selectively more vulnerable to destruction by heat in the therapeutic range [2, 3]. The possibility exists of exploiting this variable vulnerability and developing a treatment modality in which exogenously generated heat selectively destroys neoplastic tissue. Whole-body heating via an extracorporeal circuit is an example of a heat-treatment modality for metastatic neoplastic disease.

Exogenously generated heat (hyperthermia) applied to the body is currently used as a treatment for localized [4] and regional [5] therapy, and is under investigation as a whole-body therapy for metastatic neoplastic disease [6]. We have developed an extracorporeal method of whole-body heating—venovenous perfusion-induced systemic hyperthermia (VV-PISH) with multiple-point temperature monitoring—that has ameliorated many of the adverse effects associated with therapeutic temperatures [7].

VV-PISH requires blood to be withdrawn through a cannula in a central vein (superior vena cava), heated externally in an extracorporeal circuit heat exchanger, and reinfused back into the circulation through a cannula in another central vein (femoral). Thus, this configuration offers the following advantages over arterial reinfusion: increased safety, elimination of reinfusion of heated blood [8], and a more homogenous distribution of heat because of mixing with the cardiac output.

Another aspect of VV-PISH—multiple-point temperature monitoring for feedback temperature control—has eliminated uncertainty and revealed a more complete picture of whole-body hyperthermia. Thermal gradients normally exist within the core of homeotherms as the result of an unequal distribution of heat [9]. Therefore, various organs and tissues heat at different rates making a thermal map based on only a few temperatures simplistic at best, and more probably, dangerous. Extracorporeal heat exchangers are capable of transferring large amounts of thermal energy in a reliable and consistent manner. Target-tissue destruction as well as destruction of normal tissue is dependent on TD; therefore, accurate determination of end-organ TDs is critical in determining the safety and effectiveness of this intervention. Principals of extracorporeal heat exchange can be applied to VV-PISH for determination of factors influencing thermal delivery to various end organs [10].

This study had a threefold purpose: first, to develop a large animal model of VV-PISH; second, to assess the effectiveness of VV-PISH in inducing whole-body hyperthermia; and finally, to develop reliable methods of thermal dosimetry. In this study, we showed that VV-PISH was effective at delivering a therapeutic TD homogenously throughout the body of a large animal causing a redistribution of blood flow favoring the thoracoabdominal organs. The methods used in this study are effective in assessing target tissue thermal dosimetry.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Animal Care and Use Committee approval was obtained and all animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 85-23, revised 1985). Adult swine were heated by VV-PISH to a target temperature of 43°C sustained for 120 minutes. Target temperature was attained when the average body temperature (TB) was equal to 43°C. The TB was the mathematical average of the temperatures measured from both auditory canals, rectal, bladder, pulmonary artery blood, and esophagus. Perfusion blood flow rate varied from 20 mL · min-1 · kg-1 when the TB was less than 43°C to less than 5 mL · min-1 · kg-1 when the TB equaled 43°C.

Fasted animals were sedated using 1 mL · 50 kg-1 of 100 mg/mL Telazol (Fort Dodge Animal Health, Fort Dodge, IA) (50 mg · mL-1 tiletamine, 50 mg · mL-1 zolazepam), 50 mg · mL-1 xylazine, and 50 mg · mL-1 ketamine. Mask induction with 4% isoflurane, 50:50 air:oxygen, preceded endotracheal intubation. The animals were mechanically ventilated (Narxomed; North American Dräger, Telford, PA) to keep end-tidal CO2 at 35 Torr, anesthesia was maintained during cannulation with isoflurane at 0.5% to 2.0% titrated to keep mean arterial pressure (MAP) at 60 to 80 Torr. After cannulation and before hyperthermia, isoflurane was discontinued (because of its documented [11] vasodilatory affect); and anesthesia was maintained with fentanyl (20 µg · h-1 · kg-1) and diazepam (0.2 mg · h-1 · kg-1). In addition, before and during hyperthermia, a bolus of 10 µg · kg-1 of fentanyl and 0.1 mg · kg-1 diazepam was given via syringe pump. Intravenous phenylephrine was titrated (0.5 to 2.0 µg · kg-1 · min-1) to maintain MAP more than 50 Torr. Because phenylephrine was administered before collection of baseline data, any effect on end-organ blood flow would be consistent for all measurements and at these doses has minimal differential effect on end-organ blood flow [12]. An 18-gauge femoral artery catheter was inserted for monitoring arterial pressures and collection of arterial blood samples. An online, O2-saturation-tipped probe/Swan-Ganz catheter (Opticath, Abbott, Mountain View, CA) was inserted through an internal jugular vein, and advanced into the pulmonary artery. A 5F pigtail catheter was inserted through the left external carotid artery retrograde into the ascending aorta, across the aortic valve and into the left ventricle, and was used to measure intraventricular pressures and for injection of microspheres.

Temperature probes were placed in the following locations and temperatures recorded at 15-minute intervals from two multiprobe 12-channel electrical thermistor thermometers (Cole-Parmer, Niles, IL): midesophagus (YSI 401, Cole-Parmer), right and left auditory canals, deep (10 cm) and superficial (4 cm) rectal (Electromedics, Englewood, CO), and bladder (8F Foley, Electromedics). Other temperatures monitored were pulmonary artery through a Swan-Ganz catheter (Model 3, Optimetrix, Abbott) connected to a cardiac output computer; bone marrow (YSI 406, Cole-Parmer) through a Jam-Shidi intraosseous needle (Baxter Labs, Deerfield, IL); kidney through a small flank incision 3 cm deep into the cortex (YSI 542, Cole-Parmer); brain (YSI 542, Cole-Parmer) 3.0 cm deep into the right temporal lobe through a burr hole; 4 cm into the lung parenchymal tissue (YSI 542, Cole-Parmer) through a minithoracotomy at the sixth intercostal space; and stomach by pneumatic injection of a telethermometer (HTI Technologies, St. Petersburg, FL) placed through a gastric tube. All skin incisions were closed in layers to provide stability to the temperature probe and normal homeostasis. Additionally, airway temperature (Electromedics, YSI 401x, Cole-Parmer), blood in and out of the animal (Model #4700, Electromedics), and room temperature (YSI 423, Cole-Parmer) were recorded. All temperature probes were previously calibrated to two points with standardized accuracy of ± 0.05C° for all. Room air was controlled thermostatically at 22°C; during hyperthermia, the inspired air was heated to 41°C by a heater/humidifier (MR 730, Fisher and Paytel, Germany).

Hyperthermia was induced by a self-contained heating unit (iP Scientific, Minneapolis, MN) that uses a currently available heat exchanger (Electromedics) and a DeBakey roller pump (3M/Sarns, Ann Arbor, MI) in an extracorporeal circuit. The circuit was primed with 200 mL of a solution consisting of 1,000 mL of Plasmalyte A (Baxter Labs, Deerfield, IL), to which 6.25 g of mannitol, 10 mL of 50% dextrose, 25 mEq sodium bicarbonate, 250 mg of calcium chloride, and 1 mg · kg-1 of 2% lidocaine had been added. A 200-mL bolus of the prime solution was administered intravenously to maintain the central venous pressure (CVP) more than 11 Torr and the pulmonary artery pressure (PAP) more than 22 Torr. Anticoagulation was produced by the administration of porcine heparin (200 IU/kg bolus, Elkin-Simms, Cherry Hill, NJ), followed by a continuous systemic infusion to keep the activated clotting time (ACT; Hemochron 400, Edison, NJ) greater than 400 seconds. To provide vascular access for hyperthermic perfusion, a 22F perfusion cannula was inserted into the internal jugular vein and positioned proximal to the right atrium and an 18F cannula (Research Medical, Midvale, UT) positioned within the right femoral vein. Circuit orientation was a venovenous blood path with blood being withdrawn from the cannula in the jugular vein, passed into the circuit, heated, and then returned via the femoral vein. The initial 15 minutes consisted of normothermic perfusion (baseline, 37°C) allowing the animal to equilibrate to the perfusion intervention. During the heating phase, the water-to-perfusate blood temperature gradient was less than or equal to 10C° with a maximum blood temperature of 47°C; blood flow rate was 20 mL · min-1 · kg-1. (One Celsius degree [1C°] is a temperature interval [{Delta}T] of one unit measured on a Celsius scale. One degree Celsius [1°C] is a specific temperature reading [T°] on that scale [29].) The maximum water temperature was 54°C. The maintenance interval was initiated when the TB was equal to the target temperature (43°C). The water temperature was reduced slowly to 45°C, and blood flow reduced slowly to 5 mL · min-1 · kg-1 maintaining the TB at 43°C. During the cooling period, the water temperature was reduced to 30°C and the blood flow increased to 20 mL · min-1 · kg-1. When the TB had returned to 37°C, perfusion was terminated, the perfusion cannulas removed, and anticoagulation reversed with protamine (ACT = baseline ± 10%)—the final period.

Organ blood flow
This technique has been described previously [13]. Briefly, at each of five time points, 5.2 million 15 micron polystyrene microspheres (Interactive Medical Technologies, Los Angeles, CA) were injected. Simultaneously the cardiac output was measured ( ) by thermodilution technique (Oximetric Swan-Ganz catheter in pulmonary artery). One color of the colored microspheres was injected at the following time points: (1) baseline, before connecting the animal to the pump; (2) heating, during induction of hyperthermia when the average core temperature reached 41°C; (3) maintenance, 60 minutes after , halfway through the stable hyperthermic interval; (4) cooling, during cooling when the average core temperature was 41°C; and (5) final, 37°C, after disconnection from the pump and reversal of the anticoagulation. Following the experiment, a necropsy was performed and 5-g samples of organs were sent to Interactive Medical Technologies for analysis by spectrofluorometry. Organs/tissues sampled were brain (cerebrum, cerebellum, and hippocampus), heart (left and right ventricles), liver, kidney (medulla and cortex), adrenal gland, digestive tract (stomach, duodenum, jejunum, ileum, and colon), pancreas, skin, muscle, bone marrow, and cervical lymph nodes.

Hemodynamic variables
The hemodynamic variables measured continuously during this experiment were heart rate, MAP, PAP, and CVP. Other directly measured variables recorded at 30-minute intervals were cardiac output, venous oxygen saturation (SVO2), and left ventricular end diastolic pressure (LVEDP).

The following calculated hemodynamic variables were determined every 30 minutes throughout the experiment by standard formulae: oxygen delivery, oxygen consumption, systemic vascular resistance, pulmonary vascular resistance, stroke volume index, right and left ventricular stroke work indices, cardiac work, and rate pressure product (RPP) [14].

Thermal calculations
Calculations were performed every 15 minutes. In this experimental system, the external heat source was the perfusion heat exchanger and the thermal gain was designated as QPISH. In the following analysis, a gain of heat by the animal was considered "positive" and a loss is considered "negative." In general terms, the TD delivered to the animal can be calculated from an overall thermal balance:

((1))
Thermal dose may also be expressed as the change in body heat (Equation 6 below). In the above formula, QM was the heat generated by metabolism, QS was the heat lost through body surface area, QV was the heat lost during mechanical ventilation, and QU was the heat loss that occurred as a result of urinary excretion.

Steady-state thermal exchange to the animal from the extracorporeal heat exchanger was estimated by an application of the Fick Principle.

((2))
where F is blood flow, Cb is the heat capacitance of the blood and is equal to 3.64 J · °C-1 · g-1, TBo the temperature of the blood leaving (BO) the heat exchanger, TBI the temperature of the blood entering (BI), and t is the time interval (minutes) at the elevated temperature.

During the transient conditions of heating or cooling, QPISH was estimated from the following integral equation:

((3))
Here, Cb is the heat capacitance of the blood and is equal to 3.64 J · °C-1 · g-1, , and TBO(t) - TBI(t) the difference in temperature between the blood leaving and entering the heat exchanger during the time interval involved. Therefore, total QPISH was summed over the various periods (heating, maintenance, and cooling) of elevated temperatures.

Metabolic heat production (QM) of the animal was approximated from whole-body oxygen consumption (V · O2) by the equation:

((4))
where 20.7 kJ was the heat equivalent of 1 L of oxygen, and t is the duration of the study interval. Equation (4) ignores anaerobic metabolism (an exothermic process) and is expected to underestimate QM by less than 4% [15].

Thermal exchange with the environment (QE) was difficult to measure accurately and included cutaneous, ventilatory, and urinary heat losses. In this experimental model, additional heat was lost through the exposure of blood in the extracorporeal circuit to the environment; however, this heat loss was minimal (4.2 kJ in our circuit at a maximum rate of heating).

An indirect estimation of heat loss to the environment was obtained from the change in body heat by rearrangement of Eq (1) (TD = {Delta}BH):

((5))
The {Delta}BH of the animal was estimated by the method of Burton [16] and Ramanathan [17] as expressed in the following equation:

((6))
where {Delta}TB is the variation in the average body temperature (taken as the nonweighted average of the changes in the two tympanics, rectal, esophageal, pulmonary artery blood, and bladder temperatures), c is the mean specific heat of the body (=3.474 J · °C-1 · g-1) and m is the mass of the body.

Ventilatory heat exchanges (QV) were minimal in this experimental model and ignored because the inspired air was progressively warmed during heat induction to 41°C and maintained at this temperature during the period of elevated temperature. The temperature of the inspired air was then reduced (22°C) during the cooling. Urinary heat exchange (QU) in this model was also minimal thus ignored. The TD can be calculated from formula 1 as the sum of QPISH, QM, and QE and ignoring the effects of QV and QU.

The thermal isoeffect dose (TID) concept equates different heating protocols for different times at different temperatures to equivalent minutes at 43°C (EM43) [18]. In this manner, TID allows for direct comparison of TD delivered between various protocols, or various end organs within protocols. During periods of temperature variation, that is, induction of either heating or cooling, there was a therapeutic effect although it was limited. Therefore, the total heat dose delivered was the sum of all of these intervals. The total dose delivered was the equivalent minutes at 43°C (EM43), expressed by the following equation:

((7))
where T is the average temperature during {Delta}t, and R, the duration of heating [19]. A thermal isoeffect dosage was calculated for the head, chest, abdomen, bone marrow, and blood in this experimental system.

Data are expressed and graphed as mean ± standard error and analyzed by SigmaPlot and SigmaStat (Jandel Scientific, San Rafael, CA). Intragroup comparisons were made using one-way analysis of variance (ANOVA). Significance differences were accepted when p was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
All animals survived the experimental period. Adult Yorkshire swine ( ) weighed an average of 77 ± 4.5 kg, and had a body surface area of 1.33 ± 0.036 m2. The swine required an average of 60 ± 5.7 minutes of heating (rate of core temperature increase of 0.096C° · min-1 to reach a TB (average body temperature) of 43°C. Temperature was maintained for 120 minutes; cooling to normal temperatures required 45 ± 4.0 minutes for a total perfusion time of 255 ± 9.7 minutes. The initial temperatures for the animals were documented to be lower than what is normal for resting swine. This mild hypothermia (35.6°C ± 0.1°C) resulted from the relatively long period of time required for induction of anesthesia, insertion of intravascular lines, temperature probes, and perfusion cannulas, which required up to 3 hours of anesthesia. During this preparation period, no attempt was made to maintain the animal’s temperature at normal values. There was a 15% reduction in hematocrit and no significant change in plasma free hemoglobin (data not shown) associated with VV-PISH. At completion of the experiment and in accordance with established guidelines animals were subjected to euthanasia.

Table 1 displays all measured sites of regional blood flow during baseline, heating, maintenance, cooling, and final phases of VV-PISH. Overall, the blood flow to each region/organ increased almost immediately during the heating phase, reached the highest flow during the maintenance phase then returned to prehyperthermia levels during the cooling and final periods. Exceptions included the following: colon (highest blood flow during the cooling phase) and cortex of the kidney (highest blood flow during maintenance). Other notable exceptions were: the brain (cerebrum, cerebellum, and hippocampus), all parts of which displayed an increase in blood flow during heating that remained significantly elevated through the cool down phase; and the bone marrow, skin, and skeletal muscle, which show no increase in blood flow.


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  		Table 1. Effects of VV-PISH on Regional Blood Flow

 
The effect of hyperthermia on the measured hemodynamic variables (Table 2) shows that an increase in heart rate (38%) and cardiac output (173%) occurred during the heating phase. Present also is a larger increase in heart rate (57%) and cardiac output (203%) during the maintenance period; a decrease back to baseline values for both variables occurred during the 45 minutes of cooling. Mean arterial blood pressure showed an initial increase during heating that returned to base line for the rest of the experiment. The CVP was maintained at elevated values by experimental design.


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  		Table 2. Changes in Measured Hemodynamic Variables due to VV-PISH

 
Table 3 shows the results for the calculated hemodynamic variables. There was a significant decrease in oxygen delivery throughout the experiment, which is associated with the reduced hematocrit of VV-PISH. There was a significant treatment related increase in the cardiac index. Also seen was a significant increase in the RPP during heating that returned to base line values by the end of the experiment.


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  		Table 3. Changes in Calculated Hemodynamic Variables due to VV-PISH

 
Results of the dynamics of the thermal exchanges (QPISH) between swine and the VV-PISH circuit during the five phases of this experiment are that the largest quantity of heat gain occurred during the heating phase (2,162 ± 143 kJ), and the largest quantity of heat loss occurred during cooling (-526 ± 382 kJ). A total of 3,351 ± 320 kJ (heating + maintenance phases) of heat was transferred to the animals’ blood from the heat exchanger in the VV-PISH circuit. The temperature increased uniformly throughout the swine (slope of thermal-dose curve, 0.082 ± 0.011C° · min-1) except for a significantly increased slope in the kidney (0.094° ± 0.01C° · min-1, p < 0.05) and a significantly decreased slope (p < 0.05) in both bone marrow (0.070 ± 0.01C° · min-1) and skeletal muscle (0.058 ± 0.02C° · min-1). The slope of the curve for the blood exiting the heat exchanger (0.162 ± 0.02C° · min-1) was nearly two times the mean slope for the group.

Table 4 shows the average temperatures in tissues of this swine during the experiment. During heating, the highest temperature was found in the blood exiting the heat exchanger. Once in the body, the heated blood mixed with the normally circulating venous blood, producing the next hottest measured temperature—pulmonary artery blood. The bone marrow and the skeletal muscle had the lowest measured temperatures. During the maintenance phase, the highest temperature was found in the lung. Other temperatures averaged over the interval that exceeded 43°C were kidney and both auditory canals. Temperatures were returned to normal levels during the cooling period, induced by reducing the temperature of the circuit blood to 30°C.


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  		Table 4. Temperature in Tissue of a Heated Swine

 
In Table 5 , the metabolic heat production QM increased during heating (125 ± 5 kJ). Overall, 363 ± 12 kJ of metabolic heat was produced. Heat loss to the environment, QE, was greatest during heating (-2,043 ± 173 kJ) and continued to be a significant contributor during maintenance (-1,206 ± 106 kJ). The total TD delivered to the body (also considered the therapeutic dose), which excludes the cooling phase, was 280 ± 21 kJ. The gain in body heat of the animal was 355 ± 45 kJ.


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  		Table 5. Summary of Swine Thermal Dynamics

 
Table 6 displays the results of TID calculations for specific regions within the body and the body as a whole. The total body TID for the 255 ± 9.7 minutes of perfusion was 100 ± 5 minutes (EM43). The largest TID delivered occurred in the blood during the heating phase (817 ± 173, EM43). The thoracic cavity also received a large portion of its TID during the heating phase. During the maintenance phase the whole body, cranial vault, and the bone marrow received a majority of their TIDs. During the cooling phase, the cranial vault, and abdomen received large portions of their TIDs. The smallest TID delivered was to the bone marrow (45.8 ± 17, EM43).


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  		Table 6. Thermal Isoeffect Dose (TID) per Body Region

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Our study had three major objectives: (1) to develop a swine model of VV-PISH, (2) to assess the effectiveness of VV-PISH in inducing whole-body hyperthermia, and (3) to develop reliable techniques of thermal dosimetry. This report used quantitative methods to study thermal delivery in which whole-body heating was accomplished with a VV-PISH circuit. VV-PISH as measured by these techniques provides consistent and predictable amounts of heat transferred resulting in a homogenous temperature throughout the large animal model.

In humans [20] and mimicked in swine [7], hyperthermia has been reported to have disruptive effects on cardiovascular performance. Rowell [21] documented a CVP (preload) that approaches zero during hyperthermia representing an uncompensated increase in peripheral vascular compliance. Such a change in vascular compliance (ie, an increase in cutaneous blood flow) would in effect reduce central volume, cardiac filling pressures, and cardiac stroke volume requiring an associated increase in heart rate if cardiac output is to be maintained [21]. Koga and Maeta [22] showed that the intrinsic heart rate of the heated human heart with sympathetic and parasympathetic blockade rises 7.1 beats · min-1 · °C-1, and that the cardiac output tends to increase 50% to 75% at temperatures of more than 40°C. Additional cardiovascular alterations resulting from hyperthermia include a reduced MAP (afterload) and an increase in stroke volume (left ventricular stroke work index) calculated as 7 mL · 100 mL-1 · min-1 [21, 23].

Another homeostatic alteration attributed to hyperthermia is redistribution of blood flow away from the visceral organs. Methods of inducing hyperthermia other than VV-PISH cause a significantly reduced blood flow to the visceral organs and an increased blood flow to skin and peripheral tissue [24]. These methods apply a thermal gradient to the peripheral tissues that results in vascular dilation (increased vascular compliance at the site) thus a diversion of blood flow away from the visceral organs [9]. Because end organs heat because of blood flow, these methods of heating may indeed induce therapeutic levels in peripheral tissues and not in visceral tissue.

The other problem addressed by this study was the lack of currently available methods of determining how much heat is distributed and accumulated throughout the body. The TD is the product of the temperature (degree of elevation) and duration (length of time) and is the result of how much heat is developed, delivered, transferred, and absorbed by the end-organ tissue. These thermodynamic relationships are dynamic and dependent on many factors [25]. Because end-organ blood flow is altered by hyperthermia, it is expected that these thermodynamic relationships will also. Extension of the equations for determining these thermodynamic relationships, developed from extracorporeal perfusion, and application of the quantitative methods of Henle and Roti Roti [26] to VV-PISH showed that this method is capable of delivering significant amounts of heat.

The present study, by design, maintained the preload at normal to elevated levels as measured by the CVP and PAP. First, because of the use of vigorous hydration directed by measured variables of preload and cardiac output before and during the heating phases, hypohydration (preload) and tachycardia were avoided. Secondly, the use of phenylephrine prevented a significant reduction in the MAP (afterload). Additionally, manipulation of the anesthetic regimen was aimed at maintaining an adequate circulating volume without overloading the animal and therefore consisted of agents selected to avoid both vasodilatation and hypohydration during the hyperthermia treatment.

The circuit selected was percutaneous venovenous, which is most efficient for heat transfer, minimally invasive, and by itself does not alter cardiac output or end-organ blood flow [27]. In our model, hyperthermia was induced through blood heated in an extracorporeal circuit that was returned to, and mixed with, the animal’s central venous volume. Therefore, heating was accomplished through distribution of the heated blood by the cardiac output.

During VV-PISH the quantity of heat developed is controlled by the temperature of the water in the circulating water bath. As heating begins, heat transfer through the heat exchanger to the animal’s blood (QPISH) creates elevated blood temperatures. The water temperature reaches a peak of 54°C, the blood 46.7°C at the beginning of heating. The efficiency of this heat exchanger is sufficient to produce blood temperatures at which extensive damage to the formed elements can occur; this damage can be avoided by limiting the residence time of the blood within the heat exchanger (increasing the flow rate through the heat exchanger). In this manner, large quantities of heat can be delivered to the body without damage to the blood.

VV-PISH introduces the hottest blood into the vena cava, resulting in a 7C° elevation of the right atrial temperature. This degree of temperature elevation should result in an increase in the heart rate of 49.7 beats · min-1 [23], however the heart rate in our model increased by only 20 beats · min-1. Our model showed an increased MAP associated with the induction of hyperthermia, which returned to normal values during the maintenance period. The RPP was the only other index of myocardial performance to reveal a significant change over the course of the experiment; however, this value returned to baseline by the end of the experiment.

Our data suggest that when using VV-PISH the thermal gradient is applied most efficiently to the visceral, cranial, and thoracic organs and less efficiently to the peripheral tissues of skeletal muscle and bone marrow. In this model, all organs in which temperatures were measured received significant TDs. The initial thermal gradient disappeared during the treatment interval. Our microsphere data reveal that VV-PISH did not heat in a manner similar to other methods. In fact, we showed a redistribution of blood flow that favored the thoracoabdominal organs over the peripheral tissue, the result of which was the homogenous heating of the body to target temperatures well within defined therapeutic limits.

A study by Oleson and colleagues [28] showed that an EM43 of 2.1 accumulated over several hyperthermia exposures was required to double the complete response rate from 15% for radiation alone to 30% for hyperthermia and radiation. A median cumulative EM43 of 5.4 occurred in those patients manifesting necrosis. They conclude that for a phase III trial, a cumulative EM43 of about 25 in soft tissue sarcomas is necessary. In our study with a one-time TD generated by VV-PISH and multipoint temperature monitoring, the TD delivered to these animals was 320 ± 32 kJ. The 255 minutes of VV-PISH resulted in a TID of 100 ± 5 minutes at 43°C ( ).

Our study addresses some of the impediments to the application of clinical whole-body hyperthermia by determining relationships between end-organ temperatures and effects on end-organ blood flow during VV-PISH. A critique of our study is that our measurements were from tissue and end organs that would support tumor growth and not values measured in tumors themselves. The therapeutic effect of heat results from the temperature within the tumor and depends to a large degree on the individual tumor involved. Our data showed that the thoracic EM43 during VV-PISH was 209 ± 82 minutes, almost eight times that recommended by Oleson and coworkers [28]. This fact coupled with the knowledge that lung cancers are thermosensitive [6] helped guide us in our decision to select the lung as the target tissue for our first clinical study. The development of VV-PISH and multipoint monitoring has resulted in significant progress toward clinical implementation of whole-body perfusion hyperthermia.


   Acknowledgments
 
We thank Eileen Figueroa and Karen Martin and Steve Schuenke for the preparation of this manuscript. This research was funded in part by the American Society of Extracorporeal Technology Grant 1995.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Harmon B.V., Corder A.M., Collins R.J., et al. Cell death induced in a murine mastocytoma by 42–47 degrees C heating in vitro. Int J Radiat Biol 1990;58:845-858.[Medline]
  2. Brown S.L., Hunt J.W., Hill R.P. Differential thermal sensitivity of tumour and normal tissue microvascular response during hyperthermia. Int J Hyperthermia 1992;8:501-514.[Medline]
  3. Armour E.P., McEachern D., Wang Z., Corry P.M., Martinez A. Sensitivity of human cells to mild hyperthermia. Cancer Res 1993;53:2740-2744.[Abstract/Free Full Text]
  4. Shidnia H., Hornback N., Ford G., Shen R.N. Clinical experience with hyperthermia in conjunction with radiation therapy. Oncology 1993;50:353-361.[Medline]
  5. Edwards M.J., Soong S.J., Boddie A.W., Balch C.M., McBride C.M. Isolated limb perfusion for localized melanoma of the extremity. A matched comparison of wide local excision with isolated limb perfusion and wide local excision alone. Arch Surg 1990;125:317-321.[Abstract/Free Full Text]
  6. Parks L.C., Minaberry D., Smith D.P., Neely W.A. Treatment of far-advanced bronchogenic carcinoma by extracorporeally induced systemic hyperthermia. J Thorac Cardiovasc Surg 1979;78:883-892.[Medline]
  7. Vertrees R.A., Tao W., Pencil S.D., Sites J.P., Althoff D.P., Zwischenberger J.B. Induction of whole body hyperthermia with venovenous perfusion. ASAIO J 1996;42:250-254.[Medline]
  8. Vertrees R.A., Deyo D.J., Tao W., Brunston R.L., Zwischenberger J.B. Parallel dialysis normalizes serum chemistries during veno-venous perfusion-induced hyperthermia. ASAIO J 1997;43:M806-M811.[Medline]
  9. Dickson J.A., McKenzie A., McLeod K. Temperature gradients in pigs during whole-body hyperthermia at 42 degrees C. J Appl Physiol 1979;47:712-717.[Abstract/Free Full Text]
  10. Shanks C.A., Wade L.D., Meyer R., Wilkinson C.J. Changes of body temperature and heat in cardiac surgical patients. Anaesth Intensive Care 1985;13:12-17.[Medline]
  11. Stevens W.C., Cromwell T.H., Halsey M.J., Eger E.I., Shakespeare T., Bain W.H. The cardiovascular effects of a new inhalation anesthetic, forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971;35:76-89.[Medline]
  12. O’Dwyer C., Woodson L.C., Conroy B.P., et al. Regional perfusion abnormalities with phenylephrine during normothermic bypass. Ann Thorac Surg 1997;63:728-735.[Abstract/Free Full Text]
  13. Hakkinen J.P., Miller M.W., Smith A.H., Knight D.R. Measurement of organ blood flow with coloured microspheres in the rat. Cardiovasc Res 1995;29:74-79.[Medline]
  14. Sprung C.L., Rackow E.C., Claas F.H. Direct measurements and derived calculations using the pulmonary artery catheter. In: Sprung C.L., ed. The pulmonary artery catheter. University Park, MI: University Park Press, 1983:105-140.
  15. Davis F.M., Parimelazhagan K.N., Harris E.A. Thermal balance during cardiopulmonary bypass with moderate hypothermia in man. Br J Anaesth 1977;49:1127-1132.[Abstract/Free Full Text]
  16. Burton A.C. Human calorimetry. II. The average temperature of the tissues of the body. J Nutrition 1935;9:261-280.
  17. Ramanathan N.L. A new weighting system for mean surface temperature of the human body. J Appl Physiol 1964;19:531-533.[Abstract/Free Full Text]
  18. Dewey W.C. Arrhenius relationships from the molecule and cell to the clinic. Int J Hyperthermia 1994;10:457-483.[Medline]
  19. Sapareto S.A., Dewey W.C. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys 1984;10:787-800.[Medline]
  20. Tonnesen A.S., Marnock C., Bull J.M., Morgenweck C.J., Fallon K.D. Sweating, hemodynamic responses, and thermal equilibration during hyperthermia in humans. J Appl Physiol 1987;62:1596-1602.[Abstract/Free Full Text]
  21. Rowell L.B. Cardiovascular aspects of human thermoregulation. Circ Res 1983;52:367-379.[Medline]
  22. Koga S., Maeta M. Extracorporeally induced total-body hyperthermia for disseminated cancer. Adv Exp Med Biol 1990;267:177-188.[Medline]
  23. Bull J.M., Lees D.E., Schuette W.H., Smith R., Glatstein E., DeVita V.T., Jr Immunological and physiological responses to whole-body hyperthermia. Natl Cancer Inst Monogr 1982;61:177-181.
  24. Song C.W., Rhee J.G., Levitt S.H. Blood flow in normal tissues and tumors during hyperthermia. J Natl Cancer Inst 1980;64:119-124.
  25. Sapareto S.A. A workshop on thermal dose in cancer therapy. Int J Hyperthermia 1987;3:289-290.[Medline]
  26. Henle K.J., Roti Roti J.L. Time-temperature conversions in biological applications of hyperthermia. Radiat Res 1980;82:138-145.[Medline]
  27. Cornish J.D., Clark R.H. Principles, and practice of venovenous extracorporeal membrane oxygenation. In: Zwischenberger J.B., Bartlett R.H., eds. ECMO extracorporeal cardiopulmonary support in critical care. Ann Arbor, MI: Extracorporeal Life Support Organization, 1995:87-110.
  28. Oleson J.R., Samulski T.V., Leopold K.A., et al. Sensitivity of hyperthermia trial outcomes to temperature and time. Int J Radiat Oncol Biol Phys 1993;25:289-297.[Medline]
  29. Halliday D., Resnick R. Temperature. In: Halliday D., Resnick R., eds. Physics. New York: John Wiley & Sons, 1966:524-544.
Accepted for publication February 7, 2000.




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