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

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Venovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow, and thermal gradients
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   2000;70:644-652  Ann Thorac Surg Zwischenberger Roger A. Vertrees, Akhil Bidani, Donald J. Deyo, Weike Tao and Joseph B.  and thermal gradientsVenovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow,  http://ats.ctsnetjournals.org/cgi/content/full/70/2/644on the World Wide Web at: The online version of this article, along with updated information and services, is located Print ISSN: 0003-4975; eISSN: 1552-6259. Southern Thoracic Surgical Association. Copyright © 2000 by The Society of Thoracic Surgeons. is the official journal of The Society of Thoracic Surgeons and the The Annals of Thoracic Surgery  by on May 29, 2013 ats.ctsnetjournals.orgDownloaded from   Venovenous Perfusion-Induced SystemicHyperthermia: Hemodynamics, Blood Flow, andThermal Gradients Roger A. Vertrees,  PhD  , Akhil Bidani,  MD, PhD  , Donald J. Deyo,  DVM  , Weike Tao,  MD  ,and Joseph B. Zwischenberger,  MD Division of Cardiothoracic Surgery, Department of Surgery, Pulmonary Division, Department of Medicine, and Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas Background . Thermal events during extracorporealvenovenous perfusion-induced systemic hyperthermia(VV-PISH) were studied and related to determination ofwhole-body and regional thermal isoeffect doses.  Methods . Swine (n    6, 77    4.5 kg) were heated to atarget temperature of 43°C for 120 minutes using VV-PISH. Colored microspheres were injected during pre-heat, heat induction, maintenance, cool down, and afterdecannulation. The esophageal, tympanic, rectal, pulmo-nary artery, bladder, bone marrow, kidney, brain, blood,lung, and airway temperatures were recorded continu-ously. The thermal dose, thermal exchange, metabolicheat production, heat loss to the environment, the changein body heat, and the thermal isoeffect dose were studiedat 15-minute intervals. Results . VV-PISH increased heart rate and cardiacoutput and caused a redistribution of blood flow favor-ing the thoracoabdominal organs. Greatest thermal ex-change occurred during the heating phase (total 2,162   143 kJ), metabolic heat production contributed in allphases (274    9 kJ), the greatest change in body heatoccurred during heating (1,310    309 kJ) with a totaldelivered thermal dose of 298  21 kJ, and the total wholebody thermal isoeffect dose at 100  5 minutes. Conclusions . VV-PISH is feasible, is capable of trans-ferring sufficient heat, causes a redistribution of bloodflow favoring the thoracoabdominal organs, and facili-tates calculation of whole-body and regional thermalisoeffect doses.(Ann Thorac Surg 2000;70:644–52)© 2000 by The Society of Thoracic Surgeons A ll known mammalian cells and tissues are thermo-sensitive as manifest by protein denaturation andtissue destruction at critically elevated temperatures. Fortemperatures less than the critical temperature (41°C to43°C), the outcome depends on the thermal dose (TD;degree of temperature elevation and duration of expo-sure) received and the type of cell or tissue involvedbecause of cell-specific thermosensitivity [1, 2]. Neoplas-tic as opposed to nonneoplastic cells and tissues areselectively more vulnerable to destruction by heat in thetherapeutic range [2, 3]. The possibility exists of exploit-ing this variable vulnerability and developing a treat-ment modality in which exogenously generated heatselectively destroys neoplastic tissue. Whole-body heat-ing via an extracorporeal circuit is an example of aheat-treatment modality for metastatic neoplasticdisease.Exogenously generated heat (hyperthermia) applied tothe body is currently used as a treatment for localized [4]and regional [5] therapy, and is under investigation as awhole-body therapy for metastatic neoplastic disease [6].We have developed an extracorporeal method of whole-body heating—venovenous perfusion-inducedsystemic hyperthermia (VV-PISH) with multiple-pointtemperature monitoring—that has ameliorated many of the adverse effects associated with therapeutic tempera-tures [7]. VV-PISH requires blood to be withdrawn through acannula in a central vein (superior vena cava), heatedexternally in an extracorporeal circuit heat exchanger,and reinfused back into the circulation through a cannulain another central vein (femoral). Thus, this configurationoffers the following advantages over arterial reinfusion:increased safety, elimination of reinfusion of heatedblood [8], and a more homogenous distribution of heatbecause of mixing with the cardiac output.Another aspect of VV-PISH—multiple-point tempera-ture monitoring for feedback temperature control—haseliminated uncertainty and revealed a more completepicture of whole-body hyperthermia. Thermal gradientsnormally exist within the core of homeotherms as theresult of an unequal distribution of heat [9]. Therefore,various organs and tissues heat at different rates makinga thermal map based on only a few temperatures sim-plistic at best, and more probably, dangerous. Extracor-poreal heat exchangers are capable of transferring largeamounts of thermal energy in a reliable and consistent Accepted for publication Feb 7, 2000.Address reprint requests to Dr Vertrees, Division of CardiothoracicSurgery, Department of Surgery, The University of Texas MedicalBranch, 301 University Blvd, Galveston, TX 77555-0528; e-mail:rvertree@utmb.edu. © 2000 by The Society of Thoracic Surgeons 0003-4975/00/$20.00Published by Elsevier Science Inc PII S0003-4975(00)01381-3  by on May 29, 2013 ats.ctsnetjournals.orgDownloaded from   manner. Target-tissue destruction as well as destructionof normal tissue is dependent on TD; therefore, accuratedetermination of end-organ TDs is critical in determiningthe safety and effectiveness of this intervention. Princi-pals of extracorporeal heat exchange can be applied to VV-PISH for determination of factors influencing ther-mal delivery to various end organs [10].This study had a threefold purpose: first, to develop alarge animal model of VV-PISH; second, to assess theeffectiveness of VV-PISH in inducing whole-body hyper-thermia; and finally, to develop reliable methods of thermal dosimetry. In this study, we showed that VV-PISH was effective at delivering a therapeutic TD homo-genously throughout the body of a large animal causinga redistribution of blood flow favoring the thoracoab-dominal organs. The methods used in this study areeffective in assessing target tissue thermal dosimetry. Material and Methods Animal Care and Use Committee approval was obtainedand all animals received humane care in compliance withthe “Guide for the Care and Use of Laboratory Animals”(National Institutes of Health publication 85-23, revised1985). Adult swine were heated by VV-PISH to a targettemperature of 43°C sustained for 120 minutes. Targettemperature was attained when the average body tem-perature (T B ) was equal to 43°C. The T B  was the mathe-matical average of the temperatures measured from bothauditory canals, rectal, bladder, pulmonary artery blood,and esophagus. Perfusion blood flow rate varied from 20mL    min  1   kg  1 when the T B  was less than 43°C to lessthan 5 mL    min  1   kg  1 when the T B  equaled 43°C.Fasted animals were sedated using 1 mL    50 kg  1 of 100 mg/mL Telazol (Fort Dodge Animal Health, FortDodge, 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 animalswere mechanically ventilated (Narxomed; North Ameri-can Dra¨ger, Telford, PA) to keep end-tidal CO 2  at 35 Torr,anesthesia was maintained during cannulation withisoflurane at 0.5% to 2.0% titrated to keep mean arterialpressure (MAP) at 60 to 80 Torr. After cannulation andbefore hyperthermia, isoflurane was discontinued (be-cause of its documented [11] vasodilatory affect); andanesthesia was maintained with fentanyl (20   g    h  1  kg  1 ) and diazepam (0.2 mg    h  1   kg  1 ). In addition,before and during hyperthermia, a bolus of 10   g    kg  1 of fentanyl and 0.1 mg    kg  1 diazepam was given viasyringe pump. Intravenous phenylephrine was titrated(0.5 to 2.0   g    kg  1   min  1 ) to maintain MAP more than50 Torr. Because phenylephrine was administered beforecollection of baseline data, any effect on end-organ bloodflow would be consistent for all measurements and atthese doses has minimal differential effect on end-organblood flow [12]. An 18-gauge femoral artery catheter wasinserted for monitoring arterial pressures and collectionof arterial blood samples. An online, O 2 -saturation-tipped probe/Swan-Ganz catheter (Opticath, Abbott,Mountain View, CA) was inserted through an internal jugular vein, and advanced into the pulmonary artery. A5F pigtail catheter was inserted through the left externalcarotid artery retrograde into the ascending aorta, acrossthe aortic valve and into the left ventricle, and was usedto measure intraventricular pressures and for injection of microspheres.Temperature probes were placed in the following lo-cations and temperatures recorded at 15-minute intervalsfrom two multiprobe 12-channel electrical thermistorthermometers (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 arterythrough a Swan-Ganz catheter (Model 3, Optimetrix,Abbott) connected to a cardiac output computer; bonemarrow (YSI 406, Cole-Parmer) through a Jam-Shidiintraosseous needle (Baxter Labs, Deerfield, IL); kidneythrough 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 burrhole; 4 cm into the lung parenchymal tissue (YSI 542,Cole-Parmer) through a minithoracotomy at the sixthintercostal space; and stomach by pneumatic injection of a telethermometer (HTI Technologies, St. Petersburg, FL)placed through a gastric tube. All skin incisions wereclosed in layers to provide stability to the temperatureprobe and normal homeostasis. Additionally, airwaytemperature (Electromedics, YSI 401x, Cole-Parmer),blood in and out of the animal (Model #4700, Electromed-ics), and room temperature (YSI 423, Cole-Parmer) wererecorded. All temperature probes were previously cali-brated to two points with standardized accuracy of   0.05C° for all. Room air was controlled thermostaticallyat 22°C; during hyperthermia, the inspired air was heatedto 41°C by a heater/humidifier (MR 730, Fisher andPaytel, Germany).Hyperthermia was induced by a self-contained heatingunit (iP Scientific, Minneapolis, MN) that uses a currentlyavailable heat exchanger (Electromedics) and a DeBakeyroller pump (3M/Sarns, Ann Arbor, MI) in an extracor-poreal circuit. The circuit was primed with 200 mL of asolution consisting of 1,000 mL of Plasmalyte A (BaxterLabs, 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 hadbeen added. A 200-mL bolus of the prime solution wasadministered intravenously to maintain the central ve-nous pressure (CVP) more than 11 Torr and the pulmo-nary artery pressure (PAP) more than 22 Torr. Anticoag-ulation was produced by the administration of porcineheparin (200 IU/kg bolus, Elkin-Simms, Cherry Hill, NJ),followed by a continuous systemic infusion to keep theactivated clotting time (ACT; Hemochron 400, Edison, NJ)greater than 400 seconds. To provide vascular access forhyperthermic perfusion, a 22F perfusion cannula wasinserted into the internal jugular vein and positionedproximal to the right atrium and an 18F cannula (Re-search Medical, Midvale, UT) positioned within the right645 Ann Thorac Surg VERTREES ET AL2000;70:644–52 PERFUSION-INDUCED SYSTEMIC HYPERTHERMIA  by on May 29, 2013 ats.ctsnetjournals.orgDownloaded from   femoral vein. Circuit orientation was a venovenous bloodpath with blood being withdrawn from the cannula in the jugular vein, passed into the circuit, heated, and thenreturned via the femoral vein. The initial 15 minutesconsisted of normothermic perfusion (baseline, 37°C)allowing the animal to equilibrate to the perfusion inter-vention. During the heating phase, the water-to-perfusate blood temperature gradient was less than orequal to 10C° with a maximum blood temperature of 47°C; blood flow rate was 20 mL    min  1   kg  1 . (OneCelsius degree [1C°] is a temperature interval [  T] of oneunit 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. Themaintenance interval was initiated when the T B  wasequal to the target temperature (43°C). The water tem-perature was reduced slowly to 45°C, and blood flowreduced slowly to 5 mL    min  1   kg  1 maintaining the T B at 43°C. During the cooling period, the water tempera-ture was reduced to 30°C and the blood flow increased to20 mL    min  1   kg  1 . When the T B  had returned to 37°C,perfusion was terminated, the perfusion cannulas re-moved, 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 micronpolystyrene microspheres (Interactive Medical Technol-ogies, Los Angeles, CA) were injected. Simultaneouslythe cardiac output was measured (n    3 to 5) by ther-modilution technique (Oximetric Swan-Ganz catheter inpulmonary artery). One color of the colored micro-spheres was injected at the following time points: (1)baseline, before connecting the animal to the pump; (2)heating, during induction of hyperthermia when theaverage core temperature reached 41°C; (3) maintenance,60 minutes after T B    43°C, halfway through the stablehyperthermic interval; (4) cooling, during cooling whenthe 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 nec-ropsy was performed and 5-g samples of organs weresent to Interactive Medical Technologies for analysis byspectrofluorometry. Organs/tissues sampled were brain(cerebrum, cerebellum, and hippocampus), heart (leftand right ventricles), liver, kidney (medulla and cortex),adrenal gland, digestive tract (stomach, duodenum, jeju-num, ileum, and colon), pancreas, skin, muscle, bonemarrow, and cervical lymph nodes.  Hemodynamic Variables The hemodynamic variables measured continuously dur-ing this experiment were heart rate, MAP, PAP, and CVP.Other directly measured variables recorded at 30-minuteintervals were cardiac output, venous oxygen saturation(S  V O 2 ), and left ventricular end diastolic pressure(LVEDP).The following calculated hemodynamic variables weredetermined every 30 minutes throughout the experimentby standard formulae: oxygen delivery, oxygen con-sumption, systemic vascular resistance, pulmonary vas-cular resistance, stroke volume index, right and leftventricular stroke work indices, cardiac work, and ratepressure product (RPP) [14]. Thermal Calculations Calculations were performed every 15 minutes. In thisexperimental system, the external heat source was theperfusion heat exchanger and the thermal gain wasdesignated as Q PISH . In the following analysis, a gain of heat by the animal was considered “positive” and a lossis considered “negative.” In general terms, the TD deliv-ered to the animal can be calculated from an overallthermal balance:TD  Q PISH  Q M  Q S  Q  V  Q U . (1)Thermal dose may also be expressed as the change inbody heat (Equation 6 below). In the above formula, Q M was the heat generated by metabolism, Q S  was the heatlost through body surface area, Q  V  was the heat lostduring mechanical ventilation, and Q U  was the heat lossthat occurred as a result of urinary excretion.Steady-state thermal exchange to the animal from theextracorporeal heat exchanger was estimated by an ap-plication of the Fick Principle.Q PISH  F    C b    TB O  TB I    t (2)where F is blood flow, C b  is the heat capacitance of theblood and is equal to 3.64 J    °C  1   g  1  , TB o  thetemperature of the blood leaving (B O ) the heat ex-changer, TB I  the temperature of the blood entering (B I ),and t is the time interval (minutes) at the elevatedtemperature.During the transient conditions of heating or cooling,Q PISH  was estimated from the following integralequation:Q PISH  C b  0t F    TB O  t   TB I  t    dt. (3)Here, C b  is the heat capacitance of the blood and is equalto 3.64 J    °C  1   g  1  , F    the blood flow, and TB O (t)   TB I (t) the difference in temperature between the bloodleaving and entering the heat exchanger during the timeinterval involved. Therefore, total Q PISH  was summedover the various periods (heating, maintenance, andcooling) of elevated temperatures.Metabolic heat production (Q M ) of the animal wasapproximated from whole-body oxygen consumption (V   O 2 ) by the equation:Q M   0t  V    O 2  dt (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 pro-cess) and is expected to underestimate Q M  by less than4% [15].646  VERTREES ET AL Ann Thorac SurgPERFUSION-INDUCED SYSTEMIC HYPERTHERMIA 2000;70:644–52  by on May 29, 2013 ats.ctsnetjournals.orgDownloaded from   Thermal exchange with the environment (Q E ) wasdifficult to measure accurately and included cutaneous,ventilatory, and urinary heat losses. In this experimentalmodel, 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 circuitat a maximum rate of heating).An indirect estimation of heat loss to the environmentwas obtained from the change in body heat by rearrange-ment of Eq (1) (TD  BH):Q E   BH  Q PISH  Q M  (5)The   BH of the animal was estimated by the method of Burton [16] and Ramanathan [17] as expressed in thefollowing equation:  BH    T B  c    m  (6)where   T B  is the variation in the average body temper-ature (taken as the nonweighted average of the changesin the two tympanics, rectal, esophageal, pulmonaryartery blood, and bladder temperatures),  c  is the meanspecific heat of the body (  3.474 J    °C  1   g  1 ) and  m  isthe mass of the body. Ventilatory heat exchanges (Q  V ) were minimal in thisexperimental model and ignored because the inspired airwas progressively warmed during heat induction to 41°Cand maintained at this temperature during the period of elevated temperature. The temperature of the inspiredair was then reduced (22°C) during the cooling. Urinaryheat exchange (Q U ) in this model was also minimal thusignored. The TD can be calculated from formula 1 as thesum of Q PISH  , Q M  , and Q E  and ignoring the effects of Q  V and Q U . Table 1. Effects of VV-PISH on Regional Blood Flow  Variable Base Line c Heating Maintenance Cooling Final  p Cerebrum 0.45  0.1 0.61  0.16 1.12  0.2 0.87  0.1 0.78  0.2 0.049 b Cerebellum 0.38  0.1 0.51  0.1 1.25  0.1 1.08  0.1 0.82  0.1   0.05 b Watershed 0.4  0.07 0.5  0.1 0.93  0.1 0.87  0.04 0.76  0.2   0.05 b Left ventricle 0.67  0.2 1.31  0.2 3.5  0.5 2.24  0.7 1.54  0.3   0.05 b Right ventricle 0.47  0.1 1.76  1.1 1.99  0.4 1.14  0.3 0.99  0.3 0.01 b Liver 0.29  0.1 0.805  0.3 1.14  0.3 0.41  0.3 0.30  0.2   0.05 b Spleen 0.59  0.3 2.12  0.3 3.25  1.2 0.79  0.3 0.73  0.3 0.01 b Kidney (cortex) 2.17  0.4 3.4  0.5 4.7  0.7 3.2  0.3 2.85  0.2 0.05Kidney (medulla) 0.9  0.3 1.17  0.3 2.08  0.8 1.4  0.3 1.3  0.2 0.009 b Adrenal 1.4  0.3 1.33  0.2 5.7  0.9 3.1  0.4 1.97  0.5 0.001 b Stomach 0.06  0.01 0.14  0.02 0.31  0.1 0.27  0.1 0.21  0.1   0.05 b Duodenum 0.13  0.03 0.25  0.02 1.26  0.3 0.68  0.1 0.47  0.1   0.05 b  Jejunum 0.18  0.03 0.32  0.06 1.8  0.4 1.3  0.2 1.05  0.2   0.05 b Ileum 0.17  0.04 0.29  0.05 0.79  0.2 0.81  0.2 0.63  0.1   0.05 b Colon 0.17  0.03 0.26  0.03 0.75  0.3 0.83  0.2 0.57  0.1   0.05 b Pancreas 0.07  0.01 0.32  0.04 1.04  0.2 0.45  0.1 0.4  0.05   0.05 b Skin 0.02  0.00 0.03  0.01 0.03  0.01 0.03  0.01 0.02  0.01 0.05Muscle 0.01  0.00 0.04  0.01 0.05  0.01 0.1  0.06 0.05  0.02 0.05Marrow 0.01  0.00 0.01  0.07 0.02  0.00 0.03  0.02 0.03  0.02 0.05Lymph 0.07  0.00 0.25  0.08 0.58  0.3 0.63  0.4 0.28  0.08 0.3 a Average  SEM over specific interval identified.  b Significant difference (ANOVA  p    0.05).  c Units of measure are mL    min  1   gram weightof tissue  1 . VV-PISH  venovenous perfusion-induced systemic hyperthermia. Table 2. Changes in Measured Hemodynamic Variables due to VV-PISH  Time (min)  p Baseline Heating Maintenance Cooling FinalHeat rate (80–120 bpm) 79  4 99  8 117  18 113  14 122  31 0.039 b Cardiac output (4–6 L/min) 4.2  1 4.6  1 6.6  2.1 4.8  1.3 4.1  0.5 0.038 b Mean arterial pressure (70–150 Torr) 84  7 104  6 79  7 68  9 72  10 0.015 b Central venous pressure (0–7 cm H 2 O) a 7  2 11  1 13  2 12  2 12  1 0.005 b Pulmonary artery pressure (15–20 Torr) 22  3 28  3 24  2 24  1 22  2 0.406 Venous blood oxygen saturation (60%–85%) 77  5 69  2 70  2 70  4 69  9 0.146Left ventricular end diastolic pressure 13  1 13  1 13  2 12  3 9  1 0.19 a Central venous pressure is maintained elevated by experimental design.  b Significant difference (ANOVA  p    0.05). VV-PISH  venovenous perfusion-induced systemic hyperthermia. 647 Ann Thorac Surg VERTREES ET AL2000;70:644–52 PERFUSION-INDUCED SYSTEMIC HYPERTHERMIA  by on May 29, 2013 ats.ctsnetjournals.orgDownloaded from 
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