Validation of real-time continuous perfusion measurement.

Perfusion, the rate at which blood in tissue is replenished at the capillary level, is a primary factor in the transport of heat, drugs, oxygen and nutrients. While there have been many measurement techniques proposed, most do not lend themselves to routine, continuous and real-time use. A minimally invasive probe, called the thermal diffusion probe (TDP), which uses a self-heated thermistor to measure absolute perfusion continuously and in real time, was validated at low flows with the microsphere technique. In 27 rabbits, simultaneous TDP measurements were made in liver from 0 to 60 ml min-1 100 g-1. The TDP perfusion correlated well with the microspheres (R2 = 0.898) and the agreement between techniques is very good with a slope close to unity (0.921) and an intercept close to zero (0.566 ml min-1 100 g-1). Variability between the two techniques was primarily due to the sampling error from the microsphere 'snap shot' of periodic blood flow when compared with the continuous TDP perfusion measurement. The ability to quantify local perfusion continuously and in real time may have a profound impact on patient management in a number of clinical areas such as organ transplantation, neurosurgery, oncology and others, in which quantitative knowledge of perfusion is of value.

Thermodiffusion for continuous quantification of hepatic microcirculation--validation and potential in liver transplantation.

Hepatic microcirculation is a main determinant of reperfusion injury and graft quality in liver transplantation. Methods available for the quantification of hepatic microcirculation are indirect, are invasive, or preclude postoperative application. The aim of this study was the validation of thermodiffusion in a new modification allowing long-term use in the clinical setting. In six pigs Doppler flowmeters were positioned around the hepatic artery and portal vein for the measurement of total liver blood flow. Liver perfusion was quantified by thermodiffusion and compared to H(2) clearance as an established technique under baseline conditions, during different degrees of portal venous obstruction and during occlusion of the hepatic artery. Thermodiffusion measurements were recorded for five days postoperatively followed by histological evaluation of the hepatic puncture site. Perfusion data obtained by thermodiffusion were significantly correlated to H(2) clearance (r = 0.94, P < 0. 001) and to liver blood flow (r = 0.9, P < 0.05). The agreement between thermodiffusion and H(2) clearance was excellent (mean difference -2.1 ml/100 g/min; limits of agreement -12.5 and 8.3 ml/100 g/min). Occlusion of the portal vein or hepatic artery was immediately detected by thermodiffusion, indicating a decrease of perfusion by 64 +/- 7% or 27 +/- 5% of baseline, respectively. Perfusion values at baseline and during vascular occlusion were reproducible during the entire observation period. Histological changes of the liver tissue adjacent to the thermodiffusion probes were minute and did not influence long-term measurements. In vivo validation proved that enhanced thermodiffusion is a minimally invasive technique for the continuous, real-time quantification of hepatic microcirculation. Changes in liver perfusion can be safely detected over several days postoperatively. The implication for liver transplantation has led to the clinical application of thermodiffusion.

A miniature MOSFET radiation dosimeter probe.

Prototype miniature dosimeter probes have been designed, built, and characterized employing a small, radiation sensitive metal oxide semiconductor field effect transistor (MOSFET) chip to measure, in vivo, the total accumulated dose and dose rate as a function of time after internal administration of long range beta particle radiolabeled antibodies and in external high energy photon and electron beams. The MOSFET detector is mounted on a long narrow alumina substrate to facilitate electrical connection. The MOSFET, alumina substrate, and lead wires are inserted into a 16 gauge flexineedle, which, in turn, may be inserted into tissue. The radiation dosimeter probe has overall dimensions of 1.6 mm diam and 3.5 cm length. The MOSFET probe signals are read, stored, and analyzed using an automated data collection and analysis system. Initially, we have characterized the probe's response to long range beta particle emission from 90Y sources in solution and to high energy photon and electron beams from linear accelerators. Since the prototype has a finite substrate thickness, the angular dependence has been studied using beta particle emission from a 90Sr source. Temperature dependence and signal drift have been characterized and may be corrected for. Measurements made in spherical volumes containing 90Y with diameters less than the maximum electron range, to simulate anticipated geometries in animal models, agree well with Berger point kernel and EGS4 Monte Carlo calculations. The results from the prototype probes lead to design requirements for detection of shorter range beta particles used in radioimmunotherapy and lower photon energies used in brachytherapy.

Thermal diffusion probe and instrument system for tissue blood flow measurements: validation in phantoms and in vivo organs.

A minimally invasive probe and instrument system for real-time measurements of temperature, thermal conductivity and tissue blood flow has been designed for research and clinical use. The essence of the probe is a thermistor, located at the tip of catheters or glass and steel needles, and operating in transient self-heated mode at constant temperature increment. Thermal conductivity and tissue blood flow are determined by use of a coupled tissue-probe thermal model. The effects of temporal baseline temperature shifts are minimized by a novel, automatic, analog compensation circuit. Very short heating periods (3 s) and cooling periods (12 s) provided near-continuous measurements (4/min). Calibration experiments performed in media of known thermal conductivity exhibit a linear response with respect to thermal conductivity. In vitro experiments performed in isolated perfused dog liver preparations are presented to evaluate this instrument system. In vivo experiments performed in cat brain, dog liver, and human tumor demonstrate the ability of this instrument system to perform physiologically valid measurements (comparison inter-subjects and intra-subjects). The minimally invasive probes (0.8 mm OD) are capable of long term measurements (several months), with minimal tissue reactions (0.3 mm around the probe).

Thermal model for the local microwave hyperthermia treatment of benign prostatic hyperplasia.

A system for the noninvasive localized, hyperthermia treatment of benign prostatic hyperplasia was investigated. The system uses a microwave transrectal antenna with a water cooled jacket to achieve localized hyperthermia. The purpose of this study is to model the temperature rise in the prostate and in the surrounding tissue during treatment. The SAR distribution for the transrectal probe is measured in a muscle tissue equivalent phantom. The SAR information is used with a finite element solution of the bioheat transfer equation to give the temperature rise during the treatment. Also the finite element solution is further used to determine the effect of the microwave power, the cooling fluid temperature and the blood perfusion on the tissue temperature rise. The results of the solution are compared to temperature measurements in a canine protocol. It was found that the maximum temperature rise in the tissue during treatment is 44 degrees C at a depth of 2 cm from the rectal mucosa.

Effect of facial cooling on mucosal blood flow in the mouth in humans.

1. To determine the effects of facial cooling on intraoral thermal events, we placed a thermal conductivity sensor on the buccal surface of the left cheek in six normal and six asthmatic subjects. Room temperature and cold stimuli were then applied to the integument surface of both sides of the face while mucosal surface temperature and thermal conductivity, as an index of blood flow, were recorded. 2. The room temperature challenge had no effect. Application of the cold stimulus to the exterior of the left cheek caused a monotonic decrease in temperature in the mouth in all subjects and was associated with a change in thermal conductivity in which blood flow increased and then fell to baseline despite a continued drop in temperature. These responses were purely local in that cooling of the right side of the face did not change the temperature or blood flow on the left side. No differences were noted between the asthmatic and normal subjects. 3. The data indicate that lowering the temperature of the skin of the face produces significant alterations in the thermal environment within the mouth. With facial cooling, buccal temperature falls and mucosal blood supply transiently rises. This effect appears to be a purely local thermally mediated event. Facial pressure and cutaneous reflexes do not play a role. The above changes may contribute to the conditioning of inspired air during oral breathing.

Limitations and significance of thermal washout data obtained during microwave and ultrasound hyperthermia.

It is common in clinical hyperthermia to calculate an 'effective blood flow' by neglecting tissue thermal conduction and fitting thermal washout data to a simple, perfusion-dominated exponential model. We have applied this approach to characterize thermal dissipative mechanisms in patients treated at the Harvard-MIT Hyperthermia Center, by analysing thermal washout curves which were obtained during treatment sessions by momentarily interrupting the applied heating. Unfortunately, these measurements of 'effective blood flow' in patient sessions have given inconsistent results. These inconsistencies arise from uncertainties inherent in the clinical situation: the actual thermal boundary conditions and the spatiotemporal characteristics of the heating field. To quantify these observations a Green's function solution to the tissue bioheat equation has been derived, to enable temperature fields produced by various heating geometries to be easily calculated. This has been applied to the analysis of temperature decay curves following local energy deposition representative of ultrasound and microwave hyperthermia therapy devices. These results show that thermal washout data are as dependent on patient- and session-specific parameters as on tissue properties and perfusion. For measurements of effective blood flow following ultrasonic heating, errors are dependent on the measurement position within the heated volume, heating geometry, and duration of heating prior to the decay; for microwave heating, results are dependent on the position of the measurement point within the heated field, the heating frequency, and the surface boundary conditions, whether heated, cooled, or insulated. Thus, any effective tissue property calculated without correctly modelling the heating geometry, boundary conditions and initial conditions will be of a qualitative rather than quantitative nature, and may lead to erroneous and misleading conclusions concerning tissue and tumour response.

Infrared fibers for radiometer thermometry in hypothermia and hyperthermia treatment.

Hypothermia is a condition which results from prolonged exposure to a cold environment. Rapid and efficient heating is needed to rewarm the patient from 32-35 degrees C to normal body temperature. Hyperthermia in cancer treatment involves heating malignant tumors to 42.5-43.0 degrees C for an extended period (e.g., 30 min) in an attempt to obtain remission. Microwave or radio frequency heating is often used for rewarming in hypothermia or for temperature elevation in hyperthermia treatment. One severe problem with such heating is the accurate measurement and control of temperature in the presence of a strong electromagnetic field. For this purpose, we have developed a fiberoptic radiometer system which is based on a nonmetallic, infrared fiber probe, which can operate either in contact or noncontact mode. In preliminary investigations, the radiometer worked well in a strong microwave or radiofrequency field, with an accuracy of +/- 0.5 degrees C. This fiberoptic thermometer was used to control the surface temperature of objects within +/- 2 degrees C.

Indirect assessment of mucosal surface temperatures in the airways: theory and tests.

We developed and tested a method, based on conduction heat transfer analysis, to infer airway mucosal temperatures from airstream temperature-time profiles during breath-hold maneuvers. The method assumes that radial conduction of heat from the mucosal wall to inspired air dominates heat exchange during a breath-hold maneuver and uses a simplified conservation of energy analysis to extrapolate wall temperatures from air temperature vs. time profiles. Validation studies were performed by simultaneously measuring air and wall temperatures by use of a retractable basket probe in the upper airways of human volunteers and intrathoracic airways of paralyzed intubated dogs during breath holding. In both protocols, a good correlation was demonstrated between directly measured wall temperatures and those calculated from adjacent airstream temperature vs. time profiles during a breath hold. We then calculated intrathoracic bronchial wall temperatures from breath-hold airstream temperature-time profiles recorded in normal human subjects after cold air hyperpnea at 30 and 80 l/min. The calculations show airway wall temperatures in the upper intrathoracic airways that are below core body temperature during hyperpnea of frigid air and upper thoracic airways that are cooler than more peripheral airways. The data suggest that the magnitude of local intrathoracic heat/water flux is not represented by heat/water loss measurements at the airway opening. Both the magnitude and locus of heat transport during cold gas hyperventilation vary with changes in inspired gas temperature and minute ventilation; both may be important determinants of airway responses.

Ligament and tendon oxygenation measurements using polarographic oxygen sensors.

This pilot study was designed to investigate a new flexible polarographic oxygen sensor for intraarticular oxygen tissue tension monitoring, as a first step in designing a combined simultaneous oxygen and perfusion monitor. The tendoachilles in the sheep provided the initial testing model, which was followed by in vivo testing in the human knee. In the animal model, the tendoachilles was perforated by a single needle through which the new flexible multichannel polarographic oxygen sensor probe was passed. Variations in blood and oxygen delivery to the hindlimb were then produced by tourniquet and fraction of inspired oxygen (FiO2) changes. The oxygen sensors appropriately recorded current variations proportional to the hypothesized oxygen delivery. In the human model, the anterior cruciate ligament (ACL) in five human knees was exposed during routine total knee replacement surgery and stripped of the fat pad and synovial attachments. The probe was inserted into the substance of the ligament from distal to proximal. Oxygen measurements were taken with the tourniquet elevated and then inflated, in an effort to evaluate the response of the oxygen sensors and to establish the degree of oxygenation that the bone blood supply provides to the ACL. In the sheep, 100% of the time (13 of 13 events), the current changed appropriately to a change in the FiO2. Ninety-four percent of the time (17 of 18 events), the current changed appropriately to a tourniquet change. In the human ACL, the probe was 83% sensitive (5 of 6 events) to a tourniquet change. The FiO2 changes were inconclusive owing to an insufficient amount of time allowed for tissue perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermal mapping of the airways in humans.

To characterize the intrathoracic thermal events that occur during breathing in humans, we developed a flexible probe (OD 1.4 mm) containing multiple thermistors evenly spaced over 30.2 cm, that could be inserted into the tracheobronchial tree with a fiberoptic bronchoscope. With this device we simultaneously recorded the airstream temperature at six points from the trachea to beyond the subsegmental bronchi in six normal subjects while they breathed ambient and frigid air at multiple levels of ventilation (VE). During quiet breathing of room air the average temperature ranged from 32.0 +/- 0.05 degrees C in the upper trachea to 35.5 +/- 0.3 degrees C in the subsegmental bronchi. As ventilation was increased, the temperature along the airways progressively decreased, and at a VE of 100+ 1/min the temperature at the above two sites fell to 29.2 +/- 0.5 and 33.9 +/- 0.8 degrees C, respectively. Interval points were intermediate between these extremes. With cold air, the changes were considerably more profound. During quiet breathing, local temperatures approximated those recorded in the maximum VE room-air trial, and at maximum VE, the temperatures in the proximal and distal airways were 20.5 +/- 0.6 and 31.6 +/- 1.2 degrees C, respectively. During expiration, the temperature along the airways progressively decreased as the air flowed from the periphery of the lung to the mouth: the more the cooling during inspiration, the lower the temperature during expiration. These data demonstrate that in the course of conditioning inspired air the intrathoracic and intrapulmonic airways undergo profound thermal changes that extend well into the periphery of the lung.

Influence of cromolyn sodium on airway temperature in normal subjects.

It is well established that cromolyn sodium attenuates the bronchoconstriction induced by airway cooling in both normal and asthmatic subjects. To determine whether this protection derives from a modification of the thermal events that transpire during the conditioning of inspired air, we first recorded the effect of cromolyn on the bronchoconstrictor response to hyperventilation with frigid air in 7 normal subjects. On a separate occasion, we imposed the same thermal burden and measured the temperature at multiple sites within the airways before and after pretreatment with cromolyn. The first cold air challenge produced a significant decrease in forced expiratory volume in one second (FEV1) of 5.5 +/- 0.9% (SEM) and these changes were significantly reduced by cromolyn (FEV1 = 2.8 +/- 0.9%; p less than 0.05). In concert with the improvement in mechanics, the temperatures (T) within the trachea (tr) and the anterior segment of the right lower lobe (AS-RLL) were significantly higher after cromolyn (Ttr = 1.3 +/- 0.2 degrees C; p less than 0.01; TAS-RLL = 1.0 +/- 0.4 degrees C; p = 0.05), and there was a direct positive relationship between the mechanical protection offered by the drug and the increase in airway temperature (Spearman's rank correlation coefficient = 0.83; p = 0.05). These data suggest that cromolyn modifies respiratory heat exchange in such a fashion as to limit airway cooling. The mechanism of this action is not presently known but may reflect a direct or indirect influence on the bronchial vasculature.

An isolated rat liver model for the evaluation of thermal techniques to quantify perfusion.

An isolated, thermally regulated, perfused rat liver model system is presented. The model was developed to evaluate thermal methods to quantify perfusion in small volumes of tissue. The surgically isolated rat liver is perfused with an isothermal oxygenated Krebs-Ringer bicarbonate buffer solution via the cannulated portal vein. A constant-pressure head variable-resistance scheme is utilized to control the total flow to the liver. Total flow is quantified by hepatic vein collection. The spatial distribution of perfusion within the liver is determined using two independent methods. In the first method, radio-labelled microspheres are injected into the portal vein, and the regional flow distribution is determined from the relative radioactivity of each section of tissue. In the second method, the tissue is thermally perturbed, and the time constant of the tissue temperature recovery is measured. The regional distribution is determined from the relative time constants of each section of tissue. Both methods require the measurement of total liver flow to determine the absolute perfusion at each point. Results obtained by the two methods were well correlated (0.973). The rat liver system offers a stable, controllable, and measurable perfusion model for the evaluation of new perfusion measurement techniques.

The simultaneous measurement of thermal conductivity, thermal diffusivity, and perfusion in small volumes of tissue.

An improved technique is presented for the "in-vivo" determination of thermal conductivity, thermal diffusivity, and perfusion using a self-heated spherical thermistor probe. In the presence of flow, solution of the time-dependent, probe-tissue coupled thermal model allows the measurement of "effective" thermal conductivity and "effective" thermal diffusivity, which represent the thermal properties of the perfused tissue. Perfusion can be quantified from both "effective" thermal properties. In the presence of flow, it has been shown that the transient power responses does not follow t-1/2 as has been previously assumed. An isolated rat liver preparation has been developed validate the measurement technique. Radioactive microspheres are used to determine the true perfusion from the total collected hepatic vein flow. Experimental data demonstrates the ability to quantify perfusion in small volumes of tissue.

Heat transfer mechanisms and thermal dosimetry.

The heat transfer mechanisms that led to the development of the bioheat equation are reviewed. Thermal modeling and analytical judgments which must be made in application of the equation are noted. Temperature profiles that result from solution of the equation with a simple spherical model are considered with particular emphasis on the influence of thermal conductivity and perfusion. Thermal conductivity values of a host of both normal and tumor tissues are discussed. The importance of adequate macroscopic thermal dosimetry to the evaluation of the ultimate promise of hyperthermia is observed. Experience in the quantification of temperature, thermal conductivity, thermal diffusivity, and perfusion from a single, minimally invasive measurement in small volumes of tissue with the thermal diffusion probe is presented.