Modeling of heat transfer in whole-body hyperthermia

The therapeutic application of whole-body hyperthermia, whereby the body temperature is for a short time raised to 43–44°C is currently considered quite promising. However, body temperature above 42°C also raises the risks associated with hemodynamic instability and arrhythmia. A model of heat transfer is built to improve the efficacy and safety of the immersion-convection technique of whole-body hyperthermia. The model takes into account the changes in skin blood flow and the dynamics of heart rate depending on body temperature. It adequately reflects the processes of heating in the organism and can be used to calculate the heat distribution in the body.     

Mathematical apparatus of the circuit theory in modeling of heat transfer upon extreme heating of an organism

The mathematical model of heat transfer in whole-body hyperthermia, developed earlier by the author, has been refined using the mathematical apparatus of the circuit theory. The model can be used to calculate the temperature of each organ, which would increase the efficacy and safety of the immersion-convection technique of whole-body hyperthermia.     

Improved preferential tumor hyperthermia with regional heating and systemic blood cooling: a balanced heat transfer method

Absorption of power in large body volumes can occur with some approaches used for hyperthermia treatment of cancer. A systemic heat absorption rate exceeding the heat dissipation rate can lead to systemic temperature elevation that limits the magnitude and duration of application of power and hence the degree of preferential tumor temperature rise. We describe a hyperthermia approach consisting of regional electromagnetic power absorption and extracorporeal blood cooling with regulation of both systemic heat absorption and dissipation rates ("balanced heat transfer"). A test of this approach in five dogs with nonperfused tumor models demonstrated intratumoral temperatures greater than 42 degrees C, while systemic temperature remained at 33 degrees C and visceral temperatures within the heated region equilibrated between 33 and 42 degrees C. Solutions of the bioheat transfer equation were obtained for a simplified model with a tumor perfusion rate lower than surrounding normal tissue perfusion rate. In this model, the use of arterial blood temperatures less than 37 degrees C allowed higher power densities to be used, for given normal tissue temperatures, than when arterial temperature was greater than or equal to 37 degrees C. As a result, higher intratumoral temperatures were predicted. Control of arterial blood temperature using extracorporeal cooling may thus (1) limit systemic temperature rise produced by regional heating devices and (2) offer a means of improving intratumoral temperature elevations.     

Effects of hyperthermia on fetal and maternal plasma prostaglandin concentrations and uterine activity in sheep

The exposure of pregnant sheep to high ambient temperatures (43 degrees C) for 8 hours, sufficient to significantly elevate maternal and fetal body temperature +2.0 degrees C (p less than 0.001) and +1.9 degrees C (p less than 0.001) respectively, resulted in significant increases in PGE2 plasma concentrations in both the maternal and fetal circulations. Plasma PGF2 alpha concentrations were significantly raised in the fetal circulation but not the maternal during hyperthermia. The increase in prostaglandin concentrations were correlated with the magnitude of the increase in maternal and fetal body temperature. Uterine activity also increased during hyperthermia, probably as a result of the increase in prostaglandin concentrations. We propose that increased synthesis and release of prostaglandins from the uterus and/or placenta is an adaptive response to hyperthermia, and may protect the fetus from the consequences of heat stress.     

Regional hyperthermia by magnetic induction in a beagle dog model: analysis of thermal dosimetry

We have investigated magnetic induction heating techniques for achieving normal tissue hyperthermia in a beagle dog model to clarify the physics and physiology of "regional heating," to develop an animal model of regional heating in humans, and to develop a method of rapid regional heating in dogs for a normal visceral tissue toxicity study. Heating was done with a concentric coil or a coaxial pair of coils applied to the abdominal region, and with or without surface cooling blankets in each case. Thermometers were placed at multiple visceral and subcutaneous sites including an intraarterial thermocouple at the aortic arch level. With either electrode arrangement and no surface cooling, whole-body hyperthermia ( WBH ) at 42 degrees C was produced within 30 to 55 min with 250 W applied power; the 42 degrees C state could be maintained with 40 to 60 W of power. Thermal gradients in these cases reflected nonuniform power deposition superimposed upon arterial temperature elevation. With surface cooling blankets added, systemic heating was significantly reduced, and temperature gradients again reflected the nonuniform power deposition. Regional heating in a dog produces WBH unless sufficient surface cooling is used to provide a heat dissipation rate balancing the heat absorption rate; this latter case best models the use of inductive techniques in humans. The coaxial pair of coils, without surface cooling, produced rapid WBH and the visceral temperature maximum and minimum were within Tesoph + 0.21 degrees C and Tesoph - 0.07 degrees C, respectively (95% confidence index; Tesoph = esophageal temperature). This is an appropriate technique for the proposed toxicity study.     

An animal model of life-threatening hyperthermia during infancy.

A mathematical model of heat balance in human infants suggests that it may be possible for severe hyperthermia to develop if an infant is unable to remove his blankets in response to overheating (thermal entrapment). This hypothesis was tested in an animal model of weanling piglets. Ten piglets were warmed in a radiant heater to rectal temperature of 41 degrees C to simulate a fever. Animals in the experimental and control groups were removed from the heater and covered with ordinary infant blankets (to a thickness of approximately 3 cm). Endogenously produced heat caused the animals to warm to 42 degrees C. At this point, the control animals were uncovered. They rapidly cooled to normal body temperature. Animals in the experimental group remained covered until they expired from hyperthermia at 43.9 +/- 0.7 degrees C (SD) after 96 +/- 43 (SD) min. These data show that lethal hyperthermia may result from thermal entrapment. This finding may help clarify the role that hyperthermia may play in illnesses such as hemorrhagic shock and encephalopathy syndrome and some cases of sudden infant death syndrome.     

Sensitivity of mice to systemic hyperthermia: effect of ascites tumor cell transplants

The effect of a transplantation of mastocytoma cells in the abdominal cavity on the sensitivity of mice to a systemic hyperthermia was studied. The systemic hyperthermia was induced by exposing whole-body of animals to 2,450 MHz waves under anesthesia. Core body temperature was raised up to 42.0 +/- 0.2 degrees C in 15 min and maintained constant at the temperature for variable length of time. Thermosensitivity of animal was expressed with LD50, 42 degrees which was the length of heating time at the temperature of 42 degrees C lethal for 50% of the animals examined. The transplants were mastocytoma FMA3 cells. They were transplanted at a dose of 10(5) cells per mouse. The LD50, 42 degrees observed 3, 12 hrs, 1, 2, 3 and 6 days after the transplantation was 33, 23, 17, 24 and 35 min, respectively. In mice without tumor it was 43 min.     

Hyperthermia and neural tube defects of the curly-tail mouse

The mutant gene curly-tail produces neural tube defects (NTD) in 60% of mice, predominantly at the caudal end of the neural tube. Only 1% of individuals have exencephaly. Pregnant curly-tail mice and C57BL mice which are not genetically pre-disposed to NTD, were subjected to various regimes of hyperthermia on day 8 or on day 9 or on day 10 of gestation. Normal body temperature was around 36.8 degrees C, but it was found to be extremely labile in response to heat exposure. It was significantly raised for 15 min of a 20-min exposure period, and, after removal from the heat, it dropped rapidly. In C57BL mice, heat treatment produced exencephaly alone and in only 3% of mice. In curly-tail mice, none of the heat-treatment regimes had any consistent effect on the incidence of posterior NTD but produced specifically exencephaly. The incidence was increased slightly at an environmental temperature of 37 degrees C when the body temperature was 4.01 degrees C; at an ambient temperature of 43 degrees C and a body temperature of 42 degrees C, the incidence of exencephaly was 20%. Exencephaly was produced by two periods of 20 min heat exposures 7 hr apart or a single exposure of 1 hr, especially on day 8 of gestation, but not by a single 20 min exposure. It is concluded that these experiments, performed in a mutant predisposed to lesions especially at the caudal end of the neural tube, demonstrate the specificity of hyperthermia for affecting closure of the cranial neural folds.     

Heat loss from the human head during exercise

Evaporative and convective heat loss from head skin and expired air were measured in four male subjects at rest and during incremental exercise at 5, 15, and 25 degrees C ambient temperature (Ta) to verify whether the head can function as a heat sink for selective brain cooling. The heat losses were measured with an open-circuit method. At rest the heat loss from head skin and expired air decreased with increasing Ta from 69 +/- 5 and 37 +/- 18 (SE) W (5 degrees C) to 44 +/- 25 and 26 +/- 7 W (25 degrees C). At a work load of 150 W the heat loss tended to increase with increasing Ta: 119 +/- 21 (head skin) and 82 +/- 5 W (respiratory tract) at 5 degrees C Ta to 132 +/- 27 and 103 +/- 12 W at 25 degrees C Ta. Heat loss was always higher from the head surface than from the respiratory tract. The heat losses, separately and together (total), were highly correlated to the increasing esophageal temperature at 15 and 25 degrees C Ta. At 5 degrees C Ta on correlation occurred. The results showed that the heat loss from the head was larger than the heat brought to the brain by the arterial blood during hyperthermia, estimated to be 45 W per 1 degree C increase above normal temperature, plus the heat produced by the brain, estimated to be up to 20 W. The total heat to be lost is therefore approximately 65 W during a mild hyperthermia (+1 degrees C) if brain temperature is to remain constant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temperature regulation in the unrestrained rabbit during exposure to 600 MHz radiofrequency radiation

Six male New Zealand white rabbits were individually exposed to 600 MHz radiofrequency (RF) radiation for 90 min in a waveguide exposure system at an ambient temperature (Ta) of 20 or 30 degrees C. Immediately after exposure, the rabbit was removed from the exposure chamber and its colonic and ear skin temperatures were quickly measured. The whole-body specific absorption rate (SAR) required to increase colonic and ear skin temperature was determined. At a Ta of 20 degrees C the threshold SAR for elevating colonic and ear skin temperature was 0.64 and 0.26 W/kg, respectively. At a Ta of 30 degrees C the threshold SARs were slightly less than at 20 degrees C, with values of 0.26 W/kg for elevating colonic temperature and 0.19 W/kg for elevating ear skin temperature. The relationship between heat load and elevation in deep body temperature shown in this study at 600 MHz is similar to past studies which employed much higher frequencies of RF radiation (2450-2884 MHz). On the other hand, comparison of these data with studies on exercise-induced heat production and thermoregulation in the rabbit suggest that the relationship between heat gain and elevation in body temperature in exercise and from exposure to RF radiation may differ considerably. When combined with other studies, it was shown that the logarithm of the SAR required for a 1.0 degree C elevation in deep body temperature of the rabbit, rat, hamster, and mouse was inversely related to the logarithm of body mass. The results of this study are consistent with the conclusion that body mass strongly influences thermoregulatory sensitivity of the aforementioned laboratory mammals during exposure to RF radiation.     

Influence of body temperature on the development of fatigue during prolonged exercise in the heat.

We investigated whether fatigue during prolonged exercise in uncompensable hot environments occurred at the same critical level of hyperthermia when the initial value and the rate of increase in body temperature are altered. To examine the effect of initial body temperature [esophageal temperature (Tes) = 35.9 +/- 0.2, 37.4 +/- 0. 1, or 38.2 +/- 0.1 (SE) degrees C induced by 30 min of water immersion], seven cyclists (maximal O2 uptake = 5.1 +/- 0.1 l/min) performed three randomly assigned bouts of cycle ergometer exercise (60% maximal O2 uptake) in the heat (40 degrees C) until volitional exhaustion. To determine the influence of rate of heat storage (0.10 vs. 0.05 degrees C/min induced by a water-perfused jacket), four cyclists performed two additional exercise bouts, starting with Tes of 37.0 degrees C. Despite different initial temperatures, all subjects fatigued at an identical level of hyperthermia (Tes = 40. 1-40.2 degrees C, muscle temperature = 40.7-40.9 degrees C, skin temperature = 37.0-37.2 degrees C) and cardiovascular strain (heart rate = 196-198 beats/min, cardiac output = 19.9-20.8 l/min). Time to exhaustion was inversely related to the initial body temperature: 63 +/- 3, 46 +/- 3, and 28 +/- 2 min with initial Tes of approximately 36, 37, and 38 degrees C, respectively (all P < 0.05). Similarly, with different rates of heat storage, all subjects reached exhaustion at similar Tes and muscle temperature (40.1-40.3 and 40. 7-40.9 degrees C, respectively), but with significantly different skin temperature (38.4 +/- 0.4 vs. 35.6 +/- 0.2 degrees C during high vs. low rate of heat storage, respectively, P < 0.05). Time to exhaustion was significantly shorter at the high than at the lower rate of heat storage (31 +/- 4 vs. 56 +/- 11 min, respectively, P < 0.05). Increases in heart rate and reductions in stroke volume paralleled the rise in core temperature (36-40 degrees C), with skin blood flow plateauing at Tes of approximately 38 degrees C. These results demonstrate that high internal body temperature per se causes fatigue in trained subjects during prolonged exercise in uncompensable hot environments. Furthermore, time to exhaustion in hot environments is inversely related to the initial temperature and directly related to the rate of heat storage.     

Alterations in alpha-adrenergic and muscarinic cholinergic receptor binding in rat brain following nonionizing radiation

Microwave radiation produces hyperthermia. The mammalian thermoregulatory system defends against changes in temperature by mobilizing diverse control mechanisms. Neurotransmitters play a major role in eliciting thermoregulatory responses. The involvement of adrenergic and muscarinic cholinergic receptors was investigated in radiation-induced hyperthermia. Rats were subjected to radiation at 700 MHz frequency and 15 mW/cm2 power density and the body temperature was raised by 2.5 degrees C. Of six brain regions investigated only the hypothalamus showed significant changes in receptor states, confirming its pivotal role in thermoregulation. Adrenergic receptors, studied by [3H]clonidine binding, showed a 36% decrease in binding following radiation after a 2.5 degrees C increase in body temperature, suggesting a mechanism to facilitate norepinephrine release. Norepinephrine may be speculated to maintain thermal homeostasis by activating heat dissipation. Muscarinic cholinergic receptors, studied by [3H]quinuclidinyl benzilate binding, showed a 65% increase in binding at the onset of radiation. This may be attributed to the release of acetylcholine in the hypothalamus in response to heat cumulation. The continued elevated binding during the period of cooling after radiation was shut off may suggest the existence of an extra-hypothalamic heat-loss pathway.     

Effect of high temperature on the direct cortical response]

Acute experiments were conducted on anesthetized cats placed in a thermochamber at a temperature of 45 degrees C. The direct cortical response in suprasylvian convolution of the cortex during hyperthermia and after the restoration of the thermal homeostasis was studied. It was revealed that hyperthermia caused primary inhibition at a temperature of 40 degrees C and above it, and even complete disappearance of the slow negative potential; above 43 degrees C there was found a gradual depression of the dendrite potential. Restoration of body normothermia following high hyperthermia was accompanied by an insignificant tendency to normalization of the slow negative potential parameters. Analysis of the dendrite potential changes on coupled stimuli testified to the fact that high temperature had a preponderant influence on the presynaptic elements of the cortical axodendrite synapses. On the basis of differential action of heat on the component composition of the direct cortical response a conclusion was drawn on the differences in the sensitivity of functionally different cells of the cortex during hyperthermia.     

Effects of apomorphine on thermoregulatory responses of rats to different ambient temperatures.

Either systemic or central administration of apomorphine produced dose-related decreases in rectal temperature at ambient temperatures (Ta) of 8 and 22 degrees C in rats. At Ta = 8 degrees C, the hypothermia was brought about by a decrease in metabolic rate (M). At Ta = 22 degrees C, the hypothermia was due to an increase in mean skin temperature, an increase in respiratory evaporative heat loss (Eres) and a decrease in M. This increased mean skin temperature was due to increased tail and foot skin temperatures. However, at Ta = 29 degrees C, apomorphine produced increased rectal temperatures due to increased M and decreased Eres. Moreover, the apomorphine-induced hypothermia or hyperthermia was antagonized by either haloperidol or 6-hydroxydopamine, but not by 5,6-dihydroxytryptamine. The data indicate that apomorphine acts on dopamine neurons within brain, with both pre- and post-synaptic sites of action, to influence body temperature.     

Enhancement of DMBA induced mammary tumours by intermittent whole body hyperthermia (42 degrees C)

Wistar Female rats bearing DMBA induced mammary tumours were subjected to whole body hyperthermia 42 degrees C dry heat exposure for 15 minutes daily for 6 weeks. The control group was maintained at a room temperature of 25 degrees C. Hyperthermia induced significant growth stimulation of breast tumour compared to the controls. Plasma estradiol was slightly decreased while total T4 and TSH values remained unchanged in heat stressed rats. Plasma prolactin was significantly increased together with enhanced synthetic activity of pituitary prolactin cells. It is concluded that heat acting as stressor accelerates breast tumor growth, probably by influencing synthesis of prolactin. Therefore the hormone dependency of tumours should be considered before hyperthermia is used as an anticancer modality.     

A Three-Dimensional Finite Element Analysis of Heat Transfer in the Forearm

The finite element method was used to analyze heat transfer within a section of the forearm while exposed to different ambient conditions and with different metabolic states. The three-dimensional model accounts for the different material properties of bone, muscle and blood and incorporates a single artery-vein pair for counter-current heat exchange. The geometry of the model was developed from anatomical cross-sectional images of the forearm. The model was used to determine the effects or rest vs. exercise, free vs. forced surface convection and 0 degrees C vs. -20 degrees C external temperatures. The results of the model were compared to experimental data and the model exhibits qualitatively correct behaviour. This model can be used to study hyperthermia, burns and cryogenic freezing of tissue.     

Effect of low ambient temperature on protein turnover and heat production in chicks

1. Effect of low ambient temperature on protein turnover in the liver and whole body was investigated in chicks together with the contribution of protein synthesis to the total heat production. 2. Both protein synthesis and degradation in the whole body were increased, the latter to a larger extent, at low ambient temperature (LT, 22 degrees C) compared with adequate temperature (AT, 30 degrees C). Liver protein synthesis was not significantly altered by the temperature treatment. 3. The total heat production of LT group was as high as 160% of the AT group. 4. The increased heat production due to enhanced whole-body protein synthesis accounted for only 1.4% of the heat increment in thermogenesis at low ambient temperature, suggesting that protein synthesis would contribute little, if any, to cold-induced thermogenesis in chicks.     

A mathematical model of life-threatening hyperthermia during infancy.

A mathematical model was created to test the hypothesis that a partially covered febrile infant may develop potentially lethal temperature elevation. Infants may be at special risk to develop hyperthermia because, unlike older children, infants may not be able to remove blankets in response to temperature elevation. The model compared heat production (MTsk) with heat loss (Qtot). The difference between these terms is the excess energy (E): MTsk - Qtot = E. In most situations the simulated infant transfers heat to the environment as rapidly as it is produced (E less than 0), so hyperthermia does not result. In some situations, heat production exceeds heat loss (E greater than 0), causing progressive warming. The time was calculated for the simulated infant to progress from 41 to 43.4 degrees C (defined as a lethal end point). In certain circumstances, this may occur in less than 90 min. An infant at high risk of hyperthermia may not appear to be covered by a conspicuous excess of insulation (less than or equal to 3.5 cm may be sufficient). In many situations, heat loss is more closely determined by exposed body surface area than by blanket thickness. These findings have important implications for understanding the antecedents of hyperthermia in infants and may help in understanding the role of hyperthermia in certain pediatric illnesses.     

Temperature difference between the body core and arterial blood supplied to the brain during hyperthermia or hypothermia in humans

 A vascular heat transfer model is developed to simulate temperature decay along the carotid arteries in humans, and thus, to evaluate temperature differences between the body core and arterial blood supplied to the brain. Included are several factors, including the local blood perfusion rate, blood vessel bifurcation in the neck, and blood vessel pairs on both sides of the neck. The potential for cooling blood in the carotid artery by countercurrent heat exchange with the jugular veins and by radial heat conduction to the neck surface was estimated. Cooling along the common and internal carotid arteries was calculated to be up to 0.87 °C during hyperthermia by high environmental temperatures or muscular exercise. This model was also used to evaluate the feasibility of lowering the brain temperature effectively by placing ice pads on the neck and head surface or by wearing cooling garments during hypothermia treatment for brain injury or other medical conditions. It was found that a 1.1 °C temperature drop along the carotid arteries is possible when the neck surface is cooled to 0 °C. Thus, the body core temperature may not be a good indication of the brain temperature during hyperthermia or hypothermia. Received: 10 January 2002 / Accepted: 7 May 2002 This research was supported by a UMBC Summer Faculty Fellowship.