Quantitative assessment of a circulating depolarizing factor in shock.

Sustained depolarization of cell membranes and cellular edema are known to accompany various forms of circulatory shock and probably contribute to hypovolemia and cellular dysfunction. It has been proposed that a circulating protein is responsible for these effects. In the present study we have confirmed the existence of a circulating depolarizing factor (CDF) in hemorrhagic shock, burn shock, sepsis, and cardiopulmonary bypass. Plasma samples from pigs or sheep in shock were quantitatively assayed for depolarizing activity using a microelectrode method on rat diaphragm in vitro. The depolarizing effect of CDF in vitro was similar in magnitude to that of shock in situ. We conclude that CDF can entirely account for membrane depolarization during shock. The depolarizing effect of CDF was dose-dependent and saturable; it could be reversed by rinsing the diaphragm with Ringer's or control plasma. CDF activity was detectable in plasma within 5 min after a severe scald and gradually increased over the next 25 min. Resuscitation of hemorrhaged pigs, but not burned sheep, eliminated plasma CDF activity.

Perfusion technology in the hypothyroid patient.

Cardiopulmonary bypass may, by necessity, have to be performed in patients who are frankly hypothyroid. In treating five such patients, all of whom required coronary revascularization, it was noted that fluid balance during perfusion was considerably different than that in the normal population. In order to attempt to evaluate this difference, ten consecutive euthyroid patients having revascularization and the five hypothyroid patients were compared to correlate all fluid absorbed and excreted with the duration of bypass, the serum sodium, and subsequent weight gain. Fluid intake, urine output, and retained fluid were significantly elevated in the hypothyroid as compared to the euthyroid group, while serum sodium following operation was not significantly different. While there are considerable data indicating that hypothyroidism is associated with abnormal salt and water excretion, there is no information concerning the alterations which occur during cardiopulmonary bypass. The present study indicates that hypothyroidism is associated with significant diuresis (without administration of exogenous diuretic agents during cardiopulmonary bypass). The proposed explanation for this diuresis rests with the assumption that with cardiopulmonary bypass and appropriate fluid administration, the contracted blood volume in hypothyroid patients expands acutely and a diuresis results.

Gut mucosal ischemia during normothermic cardiopulmonary bypass results from blood flow redistribution and increased oxygen demand.

Impaired gut mucosal perfusion has been reported during cardiopulmonary bypass. To better define the adequacy of gut blood flow and oxygenation during cardiopulmonary bypass, we measured overall gut blood flow and ileal mucosal flow and their relationship to mucosal pH, mesenteric oxygen delivery and oxygen consumption in immature pigs (n = 8). Normothermic, noncross-clamped, right atrium-to-aorta cardiopulmonary bypass was maintained at 100 ml/kg per minute for 120 minutes. Animals were instrumented with an ultrasonic Doppler flow probe on the superior mesenteric artery, a mucosal laser Doppler flow probe in the ileum, and pH tonometers in the stomach, ileum, and rectum. Radioactive microspheres were injected before and at 5, 60, and 120 minutes of cardiopulmonary bypass for tissue blood flow measurements. Overall gut blood flow significantly increased during cardiopulmonary bypass as evidenced by increases in superior mesenteric arterial flow to 134.1% +/- 8.0%, 137.1% +/- 7.5%, 130.3% +/- 11.2%, and 130.2% +/- 12.7% of baseline values at 30, 60, 90, and 120 minutes of bypass, respectively. Conversely, ileal mucosal blood flow significantly decreased to 53.6% +/- 6.4%, 49.5% +/- 6.8%, 58.9% +/- 11.6%, and 47.8% +/- 10.0% of baseline values, respectively. Blood flow measured with microspheres was significantly increased to proximal portions of the gut, duodenum and jejunum, during cardiopulmonary bypass, whereas blood flow to distal portions, ileum and colon, was unchanged. Gut mucosal pH decreased progressively during cardiopulmonary bypass and paralleled the decrease in ileal mucosal blood flow. Mesenteric oxygen delivery decreased significantly from 67.0 +/- 10.0 ml/min per square meter at baseline to 42.4 +/- 4.6, 44.9 +/- 3.5, 46.0 +/- 3.6, and 42.9 +/- 3.9 ml/min per square meter at 30, 60, 90, and 120 minutes of bypass. Despite the decrease in mesenteric oxygen delivery, mesenteric oxygen consumption increased progressively from 10.8 +/- 1.4 ml/min per square meter at baseline to 13.4 +/- 1.2, 15.9 +/- 1.2, 16.7 +/- 1.4, and 16.6 +/- 1.54 ml/min per square meter, respectively. We conclude that gut mucosal ischemia during normothermic cardiopulmonary bypass results from a combination of redistribution of blood flow away from mucosa and an increased oxygen demand.

Platelet-rich plasma reduces postoperative blood loss after cardiopulmonary bypass.

To study the effect of plasma sequestration and reinfusion of platelet-rich plasma on blood loss after cardiopulmonary bypass, 18 patients undergoing heart operations were randomly selected either to have collected or not to have collected approximately 250 ml of platelet-rich plasma before initiating cardiopulmonary bypass with the use of the Haemonetics Plasma Saving System (Haemonetics Corporation, Braintree, Mass.). All patients had standardized anesthesia and cardiopulmonary bypass. After reversal of heparin, autologous platelet-rich plasma was reinfused in nine patients. Thrombocyte counts, hemoglobin, and hematocrit were calculated before, during, and after cardiopulmonary bypass, and 24 and 48 hours postoperatively. Blood loss and total number of transfusions were recorded. Although 9% of the total platelet volume was removed, there were no hemodynamic complications related to the use of the Haemonetics Plasma Saving System. In both groups, significant low levels of thrombocytes, hemoglobin, and hematocrit were seen after cardiopulmonary bypass. Platelet-rich plasma-reinfused patients had a significantly higher number of platelets after heparin reversal. They also had significantly less blood loss after the operation, necessitating 65% less banked blood products (p less than 0.05). We concluded that reinfusion of autologous platelet-rich plasma may serve as an effective and safe way to restore some of the hematologic derangements after cardiopulmonary bypass.

Preventive effect of Fluosol-DA for paraplegia encountered after surgical treatment of the thoracic aorta. Preliminary results in a dog model.

The effectiveness of Fluosol-DA (Green Cross Corporation, Osaka, Japan) on circulatory dynamics and neurologic outcome in dogs with ischemic spinal cord injury produced by aortic crossclamping was tested. The control group (receiving saline solution) had an elevated mean aortic proximal pressure (112.9 +/- 30.2 mm Hg versus 175.3 +/- 20.5 mm Hg, p greater than 0.05) and a drastic drop in mean distal aortic pressure (112.9 +/- 30.2 mm Hg versus 29.8 +/- 11.2 mm Hg, p less than 0.05). Although the same trend occurred in dogs treated prophylactically with Fluosol-DA, these changes were not statistically significant. However, there was a significant difference in mean distal aortic pressure during the ischemic phase between the two groups (58.9 +/- 16.0 mm Hg versus 29.8 +/- 11.2 mm Hg, p less than 0.05). Postoperatively all animals had mean arterial pressures within the normal range. All dogs in the control group were paraplegic (partial or complete); the treatment group had one dog with partial paraplegia. The difference between the mean neurologic scores of the two groups was of high statistical significance (3.7 +/- 0.5 versus 1.6 +/- 1.0, p less than 0.05). Our preliminary results show that prophylactic use of Fluosol-DA has favorable effects on hemodynamics and neurologic outcome in dogs with spinal cord ischemia produced by aortic crossclamping. The high propensity of the drug to carry oxygen and carbon dioxide and to provide nutritional support to the ischemic area with resultant improvement in local microcirculation and blood rheology are some speculative mechanisms advocated for these changes.

The time course of myocardial high-energy phosphate degradation during potassium cardioplegic arrest.

Myocardial high-energy phosphate and glucose-6-phosphate levels were determined in the in vivo pig heart model during ischemic arrest and reperfusion to determine the effectiveness of potassium cardioplegia in myocardial protection. Thirty-five pigs were divided into six experimental groups consisting of 2-hour normothermic arrest, 2-hour hypothemic arrest, 2-hour normothermic cardioplegic arrest, and 1-, 2-, and 3-hour hypothermic cardioplegic arrest. Myocardial biopsies from the left ventricle were obtained prior to arrest, every 30 minutes during the arrest interval, and at 30 and 60 minutes of reperfusion. The measurement of adenosine triphosphate and creatine phosphate showed that (1) cardioplegic arrest requires hypothermia to preserve high-energy phosphate levels in myocardial tissue; (2) hypothermia, while not completely protective alone, is more effective than potassium cardioplegia alone in providing myocardial preservation during 2-hour ischemic arrest; (3) the combination of potassium cardioplegia and hypothermia is additive in providing an effective means of maintaining myocardial high-energy phosphate stores during 1, 2, and 3 hours of ischemic arrest; (4) myocardial reperfusion does not allow a return to preischemic adenosine triphosphate (ATP) levels after 2 hours of arrest, except following hypothermic cardioplegia; and (5) extension of the duration of ischemic arrest to 3 hours using hypothermic cardioplegia prevents recovery of high-energy phosphate stores to preischemic levels during reperfusion. Optimal preservation can be achieved during 2 hours of ischemic arrest by using hypothermic potassium cardioplegia. The effects of myocardial reperfusion, however, prevent full ATP and creatine phosphate (CP) recovery following 3 hours of arrest. No other technique studied was as effective in providing myocardial preservation.

A technique of myocardial preservation perfusion.

We present a technique for administering cold cardioplegia that permits the pump technician to conveniently give the fluid. The method is comparable to that used in providing coronary perfusion for aortic valve procedures because it allows controlled volume flow and perfusion pressure. In addition, the technique is inherently safe from infusion of air bubbles.

Acute normovolemic red cell exchange for cardiopulmonary bypass in sickle cell disease.

A patient with sickle cell disease (hematocrit, 28.5%; hemoglobin S fraction, 79%), required mitral valve repair. Partial red cell removal and blood component sequestration with an autotransfusion device before cardiopulmonary bypass initially decreased the sickle red cell mass. This was followed by an acute one-volume whole blood exchange transfusion performed upon the initiation of cardiopulmonary bypass, resulting in a further reduction. Both techniques yielded fresh autologous plasma for use; sequestration yielded a platelet-pheresis product. Adequate postbypass hemostasis was demonstrated.

Oncogenic ras results in increased cell kill due to defective thermoprotection in lung cancer cells.

BACKGROUND: The survival response of normal cells to heat stress is an upregulation of heat shock proteins and ras protein activation. We hypothesized that in lung cancer cells the presence of oncogenic ras interferes with thermoprotective mechanisms resulting in cell death. METHODS: An equal number of lung tissue culture cells (normal and cancerous) were subjected to either heat stress and then recovery (43 degrees C for 180 minutes, 37 degrees C for 180 minutes) or recovery alone (37 degrees C for 360 minutes). End points were surviving number of cells, cell-death time course, heat shock protein (HSP70, HSC70, HSP27) expression before and after heat stress, and time course for HSP70 expression during heat stress and recovery. Heated cells were compared with unheated control cells, then this difference was compared between cell types. RESULTS: Heat stress in normal cells caused an 8% decrease in cell number versus a 78% +/- 5% decrease in cancer cells (p < 0.05). In normal cells, heat stress caused a 4.4-fold increase in HSP70, no change in HSC70, and a 1.7-fold increase in HSP27. In contrast, cancer cells initially contained significantly less HSP70 (p < 0.05), and there was a 27-fold increase in HSP70 and a 2-fold increase in HSC70 with no HSP27 detected (comparison significant, p < 0.05). HSP70 time course in normal cells showed that HSP70 increased 100-fold, reaching a vertex at 2 hours and remaining elevated for 24 hours; in cancer cells, HSP70 maximum expression (100-fold) peaked at 5 hours,,then decreased to slightly elevated at 24 hours. CONCLUSIONS: Cancer cells with oncogenic ras have defective thermoprotective mechanism(s) causing increased in vitro cell death, which provides an opportunity for thermal treatment of lung cancer.

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

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 (n = 6, 77+/-4.5 kg) were heated to a target temperature of 43 degrees 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.

Safety and efficacy of a heparin removal device: a prospective randomized preclinical outcomes study.

BACKGROUND: Systemic protamine sulfate for heparin reversal after cardiopulmonary bypass (CPB) is associated with uncommon, but life-threatening adverse reactions. METHODS: In a prospective randomized 3-day outcomes study, a heparin removal device (HRD) group (n = 12; 60-, 80-, 100-kg subgroups) was compared with a matched systemic Protamine group (Protamine; n = 6) for safety and efficacy using an adult swine model of CPB (60 minutes, 28 degrees C). RESULTS: HRD run time was 25 to 38 minutes depending on weight without complications. After HRD, heparin concentration decreased from 4.77 +/- 0.17 to 0.45 +/- 0.06 U/mL (activated clotting time [ACT] 776 +/- 83 to 180 +/- 12 seconds), and in Protamine, 3.94 +/- 0.63 to 0.13 +/- 0.02 U/mL (ACT 694 +/- 132 to 101 +/- 5 seconds) (p = 0.01 between groups, but no significant differences 60 minutes later). No significant difference between HRD and Protamine to 72 hours was seen in plasma-free hemoglobin C3a, heparin concentration, thromboelastogram index, platelet count, activated partial thromboplastin time, anti-thrombin III, fibrinogen, ACT, and tissue histology. CONCLUSIONS: In a prospective randomized outcomes study, HRD achieved predictable reversal of systemic heparinization after CPB with no difference in safety or outcomes compared with protamine.

Adverse effects of postoperative infusion of shed mediastinal blood.

BACKGROUND: Postoperative infusion of shed mediastinal blood has been used in an effort to decrease blood usage after cardiac operations. Recent experience has suggested that this practice may actually lead to a delayed increase in bleeding. METHODS: In a prospective, randomized study, 40 patients undergoing coronary artery bypass grafting with shed mediastinal blood collected in a cardiotomy reservoir were divided into two equal groups and studied during their first 4 hours in the intensive care unit. Shed mediastinal blood was directly infused in group I (n = 20), whereas in group II (n = 20), it was not. In group II, if a sufficient volume of red cells was present to allow processing (n = 5), washed red cells were infused. Variables studied before and after infusion were the amount of blood lost and infused, homologous blood transfused, complete blood count and differential, serum fibrinogen, fibrin split products, D-dimers, clotting factors, prothrombin time, activated partial thromboplastin time, thromboelastograms, plasma-free hemoglobin, complement factors C3 and C4, creatine kinase and its MB isoenzyme, and body temperature. RESULTS: After infusion of shed mediastinal blood, elevated levels of fibrin split products and D-dimers were found in significantly more patients in group I. The thromboelastogram index was normal in 76% of patients in group II but in only 12.5% in group I. Group I also had an increase in band neutrophils, a greater number of febrile patients, higher serum levels of creatine kinase, its MB isoenzyme, and plasma-free hemoglobin, and greater blood loss during hours 3, 4, and 5 in the intensive care unit. The volume of red cells in shed mediastinal blood (hematocrit, 9% to 10%) was small, resulting in clinically insignificant autotransfusion when infused directly, and insufficient for cell processing in most patients. CONCLUSIONS: These data support those in previous studies that direct infusion of shed mediastinal blood does not save substantial amounts of autologous red cells and can cause a delayed coagulopathy and other adverse effects that may be harmful to patients postoperatively.

Technique of controlled reperfusion of the transplanted lung in humans.

BACKGROUND: Reperfusion injury remains a significant and sometimes fatal problem in clinical lung transplantation. Controlled reperfusion of the transplanted lung using white cell-filtered, nutrient-enriched blood has been shown recently to significantly ameliorate reperfusion damage in a porcine model. We modified this experimental technique and applied it to human lung transplantation. METHODS: Approximately 1,500 mL of arterial blood was slowly collected in a cardiotomy reservoir during the lung implant, and mixed to make a 4:1 solution of blood:modified Buckberg perfusate. This solution was passed through a leukocyte filter and into the transplant pulmonary artery for 10 minutes, at a controlled rate (200 mL/min) and pressure (less than 20 mm Hg), immediately before removal of the vascular clamp. RESULTS: Five patients underwent lung transplantation (1 bilateral, 4 single lung) using this technique. All patients were ventilated on a 40% fraction of inspired oxygen within a few hours and extubated on or before the first postoperative day. CONCLUSIONS: Controlled reperfusion of the transplanted lung with white cell-filtered, nutrient-enriched blood has given excellent functional results in our small initial clinical series.

Percutaneous venovenous perfusion-induced systemic hyperthermia for advanced non-small cell lung cancer: initial clinical experience.

BACKGROUND: Venovenous perfusion-induced systemic hyperthermia raises core body temperature by extracorporeal heating of the blood. Five patients with advanced non-small cell lung carcinoma stage IV (4.4+/-1 months after initial diagnosis) received venovenous perfusion-induced systemic hyperthermia to 42.5 degrees C (core temperature) to assess technical and patient risks. METHODS: After general anesthesia and systemic heparinization (activated clotting time > 300 seconds), percutaneous cannulation of the right internal jugular vein (15F) for drainage and common femoral vein (15F) for reinfusion allowed extracorporeal flow rates up to 1,500 mL/min (20 mL x kg(-1) x min(-1)) with the ThermoChem System. This device uses charcoal-based sorbent for electrolyte homeostasis. Six monitored sites (rectal, bladder, tympanic x2, nasopharyngeal, and esophageal) determined average core temperature. RESULTS: All patients achieved a core target temperature of 42.5 degrees C for 2 hours. Electrolyte balance was maintained throughout hyperthermia (mean) in mmol/L: Na+, 136.2+/-2.2 mmol/L; K+, 4.0+/-0.3 mmol/L; Ca2+, 4.1+/-0.2 mg/dL; Mg2+, 1.9+/-0.1 mg/dL; PO4-, 4.5+/-0.9 mg/dL). Plasma cytokine concentration revealed significant heat-induced activation of proinflammatory and antiinflammatory cascades. All patients exhibited systemic vasodilation requiring norepinephrine infusion, 4 of 5 patients required vigorous diuresis, and 3 of 5 required intubation for 24 to 36 hours because of pulmonary edema or somnolence, with full recovery. Average length of hospital stay was 5.4 days. Serial tumor measurements (1 patient withdrew) revealed a decrease (64.5%+/-18%) in tumor size in 2 patients, no change in 1, and enlargement in 1, with no 30-day mortality. Median survival after hyperthermia treatment was 172 days (range, 40 to 271 days). CONCLUSIONS: Venovenous perfusion-induced systemic hyperthermia is feasible and provides the following potential advantages for better tumoricidal effect: (1) homogeneous heating, and (2) a higher sustained temperature.

Development of a human to murine orthotopic xenotransplanted lung cancer model.

The goal was to develop a clinically relevant animal model that could be used to assess the efficacy of therapeutic interventions in lung cancer. Two cell lines, noncancerous control (BEAS2-B, immortalized human bronchial-epithelial cell line) and cancerous (BZR-T33, H-ras transformed BEAS2-B) were implanted into nude (athymic) mice. Two groups (n = 10 each) received dorsoscapular subcutaneous injection of 10(6) cells from either cell line. BEAS2-B cells were nontumorigenic, whereas mice with BZR-T33 cells had tumors (9,510 +/- 4,307 mm3) confirmed by histology, and a significantly smaller body weight (BZR-T33, 28.5 +/- 0.49 vs. BEAS2-B, 30.7 +/- 0.75 g, p < .05). The next phase evaluated invasion/metastasis. Two groups (n = 10 each) received 10(6) cells from either cell line injected into tail veins. Animals receiving BZR-T33 cells had a smaller body weight, palpable lung masses (67%), obvious tail masses (44%), and average tumor burden (1,120 +/- 115 mm3), and histology revealed invasion of lung tissue and interstitial hemorrhage. In development of the orthotopic xenotransplanted model, mice (2 groups, n = 10 each) received 10(6) cells from either cell line implanted into the lungs through a tracheotomy. Animals with BZR-T33 cells did not survive past 59 days and had a smaller body weight, increased lung weight, lung masses (100%), and metastatic loci (30%). Magnetic resonance imaging (MRI) confirmed the presence of masses in intubated live mice, later confirmed by histology. In summary, the H-ras transfected cell line developed lung masses following tail-vein injection and endotracheal seeding. Evaluation by MRI allows for a comprehensive model with significant potential in the study of lung cancer.

A surgical approach to chronic aortomyoplasty in the goat model.

The left latissimus dorsi skeletal muscle of seven male goats was prepared and applied circumferentially to the descending aorta just below the subclavian artery. Stimulation of the neural pedicle of the latissimus dorsi was performed in an attempt to convert it to a fatigue-resistant cardiac-like muscle. Timing of the stimulus was in diastole. Biochemical assays established the conversion, and echocardiography demonstrated aortic compressions in the area of the muscle wrap. Although limited in numbers, the converted latissimus dorsi muscle in the extra-aortic position appears to provide diastolic augmentation.

Significant reduction in circuit pressure with modified plasma separation chamber for a heparin removal device.

The heparin removal device (HRD), using plasma separation and poly-L-lysine (PLL) affinity adsorption, has been shown to be an effective alternative to protamine after cardiopulmonary bypass (CPB). Previous designs of the HRD used standard Luer-Lok ((phi = 2.3 mm) port connections between the extracorporeal tubing and the plasma separation chambers, which resulted in excessively high circuit pressures (> 750 mm Hg) at an HRD flow of 1,400 ml/min. To reduce circuit pressures, we enlarged the connection ports to phi = 4.2 mm, keeping other circuit components and sorbent amounts unchanged. The modified circuit HRD was divided into the SMALL PORT group (phi = 2.3 mm, A = 4.15 mm2) and the LARGE PORT group (phi = 4.2 mm, A = 13.85 mm2) in adult swine (70+/-5 kg) given 300 U/kg heparin. A dual lumen cannula was inserted into the right atrium and connected to the HRD. Inlet pressure ranged from 749+/-42 to 795+/-57 mm Hg in the SMALL PORT group during the HRD run at 1,400 ml/min, whereas it ranged from 345+/-5 to 372+/-34 mm Hg in the LARGE PORT group (p < 0.01 between groups). Likewise, the chamber pressure ranged from 447+/-21 to 452+/-27 mm Hg in the SMALL PORT group and from 190+/-14 to 204+/-19 mm Hg in the LARGE PORT group (p < 0.01 between groups). There were no significant differences in ACT between groups. We conclude that enlarged chamber ports significantly lower circuit pressures for the HRD without changing heparin removal capability.

Parallel dialysis normalizes serum chemistries during venovenous perfusion induced hyperthermia.

Whole-body hyperthermia is currently under investigation as a method to treat systemic malignancies; however, available techniques induce a derangement in serum and urine chemistries. This study was done to determine whether veno-venous perfusion induced hyperthermia (vv-PISH) that incorporated a parallel dialysis system to control blood chemistries would eliminate these heat induced derangements. Adult female Yorkshire swine were divided into perfusion only (group P, n = 6, 62.8 +/- 2.5 kg), and perfusion with dialysis (group PD, n = 6, 63.8 +/- 4.3 kg). In both groups, hyperthermia was induced with a computer assisted jugular-to-femoral venovenous heat exchange/perfusion system primed with a balanced electrolyte solution, operating at 30 ml/min-1/kg-1, which used a thermal gradient induced by blood heated to a maximum of 48 degrees C and a perfusate-to-blood temperature gradient < 10 degrees C during heating. The target core temperature was 43 degrees C for 120 min as measured by the average of the rectal, bladder, esophageal, bilateral tympanic, and pulmonary artery temperatures. Including ramp-up and cool down, the total perfusion interval was 263 +/- 29 min in group P and 240 +/- 18 min in group PD (ns). Serum and urine chemistry values expressed as the mean value +/- SEM were compared before and after hyperthermia treatment. Variables include blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, magnesium, phosphorus, glucose, total protein, albumin, alkaline phosphatase (ALKP), creatinine kinase, aspartate aminotransferase, alanine aminotransferase (ALT), lactate dehydrogenase (LDH), plasma free hemoglobin, urine specific gravity, pH and urine creatinine. All variables remained within normal ranges for the PD group. In the P group, the following final values were outside the normal range: (normal range) creatinine 2.1 +/- 1 (0.4-1.4) mg/dl, Ca2+ 5.1 +/- 1 (6-13) mg/dl, Mg2+ .8 +/- 0.1 (1.2-10) mg/dl, ALKP 134 +/- 6 (34-122) U/L, ALT 69 +/- 3 (9-51) U/L, and LDH 1291 +/- 237 (300-600) U/L. We conclude that the significant changes in serum and urine chemistries associated with vv-PISH are normalized with the use of a parallel dialysis system and may decrease the incidence of electrolyte associated complications.

Induction of whole body hyperthemia with venovenous perfusion.

Whole body hyperthermia can be used for the treatment of metastatic cancer and human immunodeficiency virus infections. The therapeutic effects of hyperthermia are dependent upon the actual temperature of the target tissues. Therefore, homogeneous distribution of heat and precise control of temperature gradients is critical. To describe heat distribution during hyperthermia induced by venovenous perfusion, the authors used multiple channel temperature monitoring and a servo-regulated perfusion/heat exchange system. Young swine were randomly assigned to either a heated group (perfusion-induced hyperthermia, target core temperature at 43 degrees C, n = 6), or a control group (perfusion alone, target core temperature at 38 degrees C, n = 6). Blood was drained from the external jugular vein, heated with a computer assisted heat exchange system, and reinfused through the femoral vein at a flow of 10 ml/kg-1/min-1. Temperature probes in the esophagus, right and left tympanic canals, brain, pulmonary artery, arterial and venous blood, rectus spinae muscle, kidney, rectum, bone marrow, bladder, subcutaneous tissue, gluteus, and skin were simultaneously recorded. During the heat induction phase, the maximum water temperature was 54 degrees C, with a heating gradient of the blood (blood in-blood out) at 6 degrees C. The maximum temperature difference between tissues was 3.6 degrees C (kidney and esophagus) during heat induction, but decreased to 1.75 degrees C during maintenance. Bone marrow temperature was consistently 1-2 degrees C below the average core temperature of 43 degrees C throughout the experiment. The authors conclude that venovenous perfusion can predictably induce hyperthermia, but is associated with heterogenous temperature distribution among organs. Further studies are necessary to evaluate different perfusion and heating patterns to achieve homogenous hyperthermia.

Heparin clearance profiles after systemic anticoagulation using a heparin removal device system.

An extracorporeal heparin removal device system (HRDS) based on plasma separation and affinity adsorption has been developed to reduce the risks of protamine-related adverse reactions. The heparin clearance profile of the HRDS was characterized by the first-order exponential depletion. A mathematical model was established to predict the time to achieve 85% heparin removal for different body weights at 700 ml/min and 1400 ml/min extracorporeal HRDS blood flow. With an HRDS flow of 700 ml, 85% of total body heparin removal cannot be achieved within 30 min for subjects greater than 50 kg. With an HRDS flow of 1400 ml/min, 85% heparin removal can be achieved within 32 min for subjects larger than 90 kg. Such model predictions were validated in an adult swine (n = 10) model of 60-min, hypothermic (28 degrees C) cardiopulmonary bypass (CPB). Animals were given 300 U/kg intravenous heparin and 5000 U heparin in the circuit prime for initial heparinization, with subsequent heparin given to maintain activated clotting time above 450 sec. Immediately following CPB, plasma heparin concentration as determined by anti-factor Xa assays was 4.40 +/- 1.08 U/ml in the 700 ml/min group and 4.78 +/- 0.70 U/ml in the 1400 ml/min groups, respectively (p > 0.05). Target HRDS flow was 700 ml/min for animals below 75 kg and 1400 ml/min for animals above 75 kg. The mean body weight in the 1400 ml/min group (81.4 +/- 3.7 kg) was significantly higher than that in the 700 ml/min group (67.2 +/- 2.2 kg) (p < 0.05), with the actually achieved HRDS flow 658.5 +/- 20.8 and 1437.4 +/- 30.1 ml/min, respectively. During the HRDS run, plasma heparin concentration followed the predicted first-order exponential depletion (r2 = 0.97 for the 700 ml/min group and r2 = 0.99 for the 1400 ml/min group). In the 700 ml/min group, the time needed to achieve 85% heparin clearance was over 40 min, whereas in the 1400 ml/min group, this time was reduced to less than 30 min despite greater body weight. At 30 min on HRDS, the 700 ml/min group had 27.4 +/- 3.7% heparin left in the plasma, whereas the 1400 ml/min group had only 12.6 +/- 2.5% (p < 0.05). The authors conclude heparin clearance by the HRDS can be precisely predicted with the mathematical model of first-order exponential depletion. Increasing the HRDS flow can effectively reduce the time needed to achieve a targeted heparin removal.