Application of a heparin removal device in patients with known protamine hypersensitivity.
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Anticoagulants↗
Biomedical subjects
R L Brunston
Publications and source records attributed to R L Brunston.
Extracorporeal heparin adsorption following cardiopulmonary bypass with a heparin removal device--an alternative to protamine.
OBJECTIVES: To evaluate the therapeutic efficacy and applicability of a heparin removal device (HRD) based on plasma separation and poly-L-lysine (PLL) affinity adsorption as an alternative to protamine in reversing systemic heparinization following cardiopulmonary bypass (CPB). DESIGN: A prospective study. SETTING: University research laboratory. SUBJECTS: Adult female swine (n=7). INTERVENTIONS: Female Yorkshire swine (n=7, 67.3+/-3.5 [SEM] kg) were subjected to 60 mins of right atrium-to-aortic, hypothermic (28 degrees C) CPB. After weaning from CPB, the right atrium was recannulated with a two-stage, dual-lumen cannula which was connected to an HRD via extracorporeal circulation. Blood flow was drained at 1431.2+/-25.4 mL/min from the inferior vena cava, through the plasma separation chamber of the HRD (where heparin was bound to PLL), and reinfused into the right atrium. The HRD run time was determined by a previously established mathematical model of first-order exponential depletion. MEASUREMENTS AND MAIN RESULTS: Heart rate, mean arterial pressure, pulmonary arterial pressure, central venous pressure, kaolin and celite activated clotting time (ACT), activated partial thromboplastin time (APTT), heparin concentration, and plasma free hemoglobin were obtained before, during, and after the use of the HRD. Pre-CPB ACT was 167+/-89 secs (kaolin) and 99+/-7 secs (celite), and APTT was 34+/-5 secs. The HRD run time averaged 27.4 +/-1.5 mins targeted to remove 90% total body heparin. Use of the HRD was not associated with any adverse hemodynamic reactions or increases in plasma free hemoglobin. The heparin concentration immediately following CPB was 4.85+/-0.24 units/mL, with ACT >1000 secs and APTT >150 secs in all animals. During heparin removal, total body heparin content followed first-order exponential depletion kinetics. At the end of the HRD run, heparin concentration decreased to 0.51+/-0.09 units/mL, with kaolin ACT returning to 177+/-22 secs, celite ACT returning to 179+/-17 secs, and APTT returning to 27+/-3 secs (p > .05 vs. pre-CPB baseline for all variables). CONCLUSIONS: The HRD is capable of reversal of anticoagulation following CPB without significant blood cell damage or changes in hemodynamics. The HRD, therefore, can serve as an alternative to achieve heparin clearance in clinical situations where use of protamine may be contraindicated.
Adsorption↗
Total arteriovenous CO2 removal: simplifying extracorporeal support for respiratory failure.
BACKGROUND: To reduce the complexity, complications, and cost of conventional extracorporeal membrane oxygenation, we have developed a technique of simplified arteriovenous extracorporeal CO2 removal (AVCO2R) with a low-resistance membrane gas exchanger for total CO2 removal to provide lung rest in the setting of severe respiratory failure. METHODS: We initially used AVCO2R in healthy animals to quantify the gas exchange capabilities of the system and establish ventilator management protocols for the subsequent studies of AVCO2R in a large animal model of respiratory failure secondary to a severe smoke inhalation injury. RESULTS: In healthy sheep the maximum spontaneous arteriovenous flow ranged from 1,350 to 1,500 mL/min, whereas CO2 removal plateaued at a blood flow of approximately 1,000 mL/min in which 112 +/- 3 mL/min CO2 was removed, allowing an 84% reduction in the minute ventilation of from 6.9 +/- 0.8 L/min to 1.1 +/- 0.4 L/min (p < 0.01) without triggering hypercapnia. A subsequent reduction in extracorporeal flow at a reduced minute volume led to the development of hypercapnia only if it decreased to less than 500 mL/min. We also applied AVCO2R in mechanically ventilated sheep with a severe smoke inhalation injury and removed 95% (111 +/- 4 mL/min) of the total CO2 production. This allowed the minute ventilation to be reduced by 95% and the peak inspiratory pressures by 52% (both p < 0.05) over 6 hours and produced no adverse hemodynamic effects. The partial pressure of arterial oxygen was maintained above 100 mm Hg at a maximally reduced minute volume. The mean AVCO2R flow was 1,213 +/- 29 mL/min, averaging 27% +/- 1% of the cardiac output. CONCLUSIONS: We conclude that AVCO2R in a simple arteriovenous shunt is a less complicated technique than extracorporeal membrane oxygenation and is capable of total CO2 removal that allows a significant reduction in the minute ventilation and peak airway pressure during severe respiratory failure.
Animals↗
Prolonged hemodynamic stability during arteriovenous carbon dioxide removal for severe respiratory failure.
OBJECTIVE: The effects of prolonged arteriovenous carbon dioxide removal on hemodynamics during severe respiratory failure were evaluated in adult sheep with severe smoke inhalation injury. METHODS: Adult female sheep (n = 6,33.8 +/- 5.2 kg) were subjected to intratracheal cotton severe smoke insufflation to a mean carboxyhemoglobin level of 83% +/- 3%. Twenty-four hours after injury, a low-resistance 2.5 m2 membrane oxygenator was placed in a carotid-to-jugular pumpless arteriovenous shunt at unrestricted flow to allow complete carbon dioxide removal and reductions in ventilator support. Animals remained conscious, and heart rate, cardiac output, mean arterial pressure, and pulmonary arterial pressure were measured at baseline, after injury, and daily during support with the arteriovenous carbon dioxide removal circuit for 7 days. RESULTS: All animals survived the study period. Carbon dioxide removal ranged from 99.7 +/- 13.7 to 152.2 +/- 16.2 ml/min, and five (83%) of the six animals were successfully weaned from the ventilator before day 7. During full support with the arteriovenous carbon dioxide removal circuit, shunt flow ranged from 1.24 +/- 0.06 to 1.43 +/- 0.08 L/min and accounted for 20.1% +/- 1.4% to 25.9% +/- 2.4% of cardiac output. No statistically significant changes in heart rate, cardiac output, mean arterial pressure, or pulmonary artery pressure were demonstrated over the study course despite the extracorporeal shunt flow. CONCLUSIONS: Arteriovenous carbon dioxide removal as a simplified means of extracorporeal gas exchange support is relatively safe without adverse hemodynamic effects or complications.
Animals↗
Significant reduction in minute ventilation and peak inspiratory pressures with arteriovenous CO2 removal during severe respiratory failure.
OBJECTIVES: To quantify CO2 removal using an extracorporeal low-resistance membrane gas exchanger placed in an arteriovenous shunt and evaluate its effects on the reduction of ventilatory volumes and airway pressures during severe respiratory failure induced by smoke inhalation injury. DESIGN: Prospective study. SETTING: Research laboratory. SUBJECTS: Adult female sheep (n = 5). INTERVENTIONS: Animals were instrumented with femoral and pulmonary arterial catheters and underwent an LD50 cotton smoke inhalation injury via a tracheostomy under halothane anesthesia. Twenty-four hours after smoke inhalation injury, the animals were reanesthetized and systemically heparinized for cannulation of the left carotid and common jugular vein to construct a simple arteriovenous shunt. A membrane gas exchanger was interposed within the arteriovenous shunt, and blood flow produced by the arteriovenous pressure gradient was unrestricted at the time of complete recovery from anesthesia. CO2 removal by the gas exchanger was measured as the product of the sweep gas flow (FIO2 of 1.0 at 2.5 to 3.0 L/min) and the exhaust CO2 content measured with an inline capnometer. CO2 removed by the animal's lungs was determined by the expired gas CO2 content in a Douglas bag. We made stepwise, 20% reductions in ventilator support hourly. We first reduced the tidal volume to achieve a peak inspiratory pressure of < 30 cm H2O, and then we reduced the respiratory rate while maintaining normocapnia. PaO2 was maintained by adjusting the FIO2 and the level of positive end-expiratory pressure. MEASUREMENTS AND MAIN RESULTS: Mean blood flow through the arteriovenous shunt ranged from 1154 +/- 82 mL/min (25% cardiac output) to 1277 +/- 38 mL/min (29% cardiac output) over the 6-hr study period. The pressure gradient across the gas exchanger was always < 10 mm Hg. Maximum arteriovenous CO2 removal was 102.0 +/- 9.5 mL/min (96% of total CO2 production), allowing minute ventilation to be reduced from 10.3 +/- 1.4 L/min (baseline) to 0.5 +/- 0.0 L/min at 6 hrs of arteriovenous CO2 removal while maintaining normocapnia. Similarly, peak inspiratory pressure decreased from 40.8 +/- 2.1 to 19.7 +/- 7.5 cm H2O. PaO2 was maintained at > 100 torr (> 13.3 kPa) at maximally reduced ventilator support. Mean arterial pressure and cardiac output did not change significantly as a result of arteriovenous shunting. CONCLUSIONS: Extracorporeal CO2 removal using a low-resistance gas exchanger in a simple arteriovenous shunt allows significant reduction in minute ventilation and peak inspiratory pressure without hypercapnia or the complex circuitry and monitoring required for conventional extracorporeal membrane oxygenation. Arteriovenous CO2 removal can be applied as an easy and cost-effective treatment to minimize ventilator-induced barotrauma and volutrauma during severe respiratory failure.
Acute Disease↗
Therapeutic hyperthermia.
Those diseases that medicines do not cure, are cured by the knife, and those diseases that the knife cannot cure are cured by fire. And those diseases that fire does not cure are to be reckoned wholly incurable.
HIV Infections↗
Comparison of two topical collagen-based hemostatic sponges during cardiothoracic procedures.
The need for topical hemostasis during cardiothoracic procedures continues to fuel the development of additional hemostatic products with a focus on minimizing cost and increasing efficacy. The efficacy of a recently approved collagen-based topical hemostatic agent (Hemostagene, Coletica, S.A., Lyon, France) was tested in a prospective randomized trial of 60 consecutive patients undergoing cardiothoracic surgical procedures. Comparisons to a control collagen sponge (Helistat, Integra Life Sciences, Inc., Plainsboro, NJ) were made and hemostasis was considered successful if bleeding was controlled in 10 min or less. We employed a unique hemorrhage grading scale to more closely assess the relative effectiveness of these different topical agents. Overall, Hemostagene and Helistat achieved a successful hemostasis rate of 75% and 77%, respectively, with no statistically significant difference. The Hemostagene sponge was deemed easier to handle when compared to control. During the study, neither of the products was associated with complications attributable to the topical sponge. In conclusion, Hemostagene had improved handling characteristics yet was equal to Helistat at topical hemostasis, adding an alternative to the topical hemostatic market.
Blood Coagulation↗
Determination of low blood flow limits for arteriovenous carbon dioxide removal.
Arteriovenous carbon dioxide removal (AVCO2R) has been shown to achieve total carbon dioxide (CO2) exchange. To determine optimal blood and gas flow parameters that can provide maximal gas exchange and evaluate the utility of AVCO2R at reduced blood flow, the authors used a low resistance membrane gas exchanger within an arteriovenous shunt in mechanically ventilated sheep. Adult female sheep (n = 5) were anesthetized and underwent placement of the gas exchange device in a simple arteriovenous shunt created between the carotid artery and common jugular vein. CO2 removal was determined as the product of the sweep gas flow (100% oxygen) and its exhaust CO2 content. Gas and blood flow were varied independently, and incremental reductions in minute ventilation (MV) were made while maintaining normocapnia. At maximally reduced ventilator settings, stepwise reductions in blood flow were made to determine the resultant changes in arterial PaCO2 at a sweep gas flow of 3 L/min. CO2 removal increased proportionally to blood flow to a maximum of 1,417 +/- 26 ml/min (19% of cardiac output) and gas flow to 3 L/min. Normal PaO2 and PaCO2 could be maintained with minimal ventilator support (MV = 16% baseline MV) at a blood flow of 500 ml/min or higher. At these maximally reduced ventilator settings, moderate hypercapnia (PaCO2 < or = 75 mmHg) resulted only when blood flow was decreased to below 500 ml/min. Optimizing AVCO2R blood and gas flow maximizes CO2 removal and allows a significant reduction in minute ventilation. In cases of severely limited blood flow, lung rest can still be realized at moderate hypercapnia. At flow rates achievable by percutaneous access, extracorporeal AVCO2R can be used to achieve lung rest during mechanical ventilation.
Adult↗
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.
Animals↗
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.
Animals↗
High flow/low resistance cannulas for percutaneous arteriovenous carbon dioxide removal.
Percutaneous cannulas with low resistance are necessary for arteriovenous carbon dioxide removal (AVCO2R) to allow highest flow at lowest pressure to maximize CO2 removal. Commercially available arterial (A) and venous (V) percutaneous cannulas (8-18 Fr) were tested for pressure/flow characteristics under conditions that simulated percutaneous AVCO2R at clinically pertinent flow rates between 200-1000 ml/min to obtain the M number previously described by Delius, et al. The Bio-Medicus (Bio-Medicus, Grand Rapids, MI) 17F A, Research Medical, Inc (RMI) (Model FEM II, Research Medical, Inc., Midvale, UT) 16F A, and RMI 18F V cannulas exhibited the lowest M numbers that correlated with low resistance to flow. The four most clinically favorable arterial cannulas (8, 10, 12, and 14 Fr), coupled with a venous cannula four French sizes larger, were used in an AVCO2R circuit in adult sheep (n = 3) at varying mean arterial pressures (MAP) between 65-105 mmHg. The 8, 10, 12, and 14 Fr arterial cannulas allowed an arteriovenous flow of 208 +/- 72, 530 +/- 37, 848 +/- 66, and 944 +/- 96 ml/min, respectively, at a MAP of 65 mmHg. An increase in MAP to 105 mmHg was associated with approximately a 41, 30, 32, and 27% increment in blood flow, respectively. In summary, an arterial percutaneous cannula of 10 Fr or larger will allow AVCO2R blood flow greater than 500 ml/min, as previously shown by Brunston et al. to achieve total CO2 removal without incurring hypercapnia.
Adult↗
Organ blood flow during arteriovenous carbon dioxide removal.
Animal models of arteriovenous carbon dioxide removal (AVCO2R) have achieved lung rest during treatment of severe respiratory failure, with total CO2 removal at arteriovenous shunt flow rates of 10% to 25% of cardiac output (CO). Previously, no statistically significant changes were reported in heart rate, cardiac output, mean arterial pressure, or pulmonary arterial pressure during prolonged (7 days) AVCO2R with shunt flows to 25% of CO. In this study, to determine the effect of various shunt levels on organ blood flow, colored microspheres were used in a conscious ovine model of AVCO2R. A low resistance 2.5 m2 oxygenator was placed in a simple carotid-to-jugular arteriovenous circuit. The AVCO2R flow (Qb) was incrementally increased to 5%, 10%, 15%, 20%, and 25% of baseline CO. After equilibration, colored microspheres were injected into a left atrial catheter while reference blood was withdrawn from an arterial line at a constant rate. Organ blood flow obtained by measuring microspheres in the tissues, showed approximately a 10-20% decrease at a 5% shunt, but remained relatively unchanged thereafter at up to a 25% shunt, and was well tolerated without hemodynamic sequelae or evidence of end organ ischemia. It was concluded that AVCO2R can achieve lung rest during respiratory failure at flow rates of 10-25% CO, with a resultant mild decrease in critical organ blood flow that appears well tolerated.
Adult↗
Efficacy of a heparin removal device in comparison with protamine after hypothermic cardiopulmonary bypass.
To reduce the risks of protamine reactions after cardiopulmonary bypass (CPB), a heparin removal device (HRD) with plasma separation and poly-L-lysine (PLL) affinity adsorption was developed. To compare the efficacy of HRD with that of protamine, blood coagulation variables were evaluated in a swine model of CPB. Female Yorkshire swine were randomly divided into the HRD group (n = 6, weight 79.7 +/- 7.0 kg) and the protamine group (n = 6, weight 79.3 +/- 6.8 kg), and subjected to 60 min of right atrium-to-aortic, hypothermic (28 degrees C) CPB. After weaning from CPB, the right atrium was recannulated with a two-stage, dual lumen cannula in the HRD group. Blood flow was drained from the inferior vena cava, through the plasma separation chamber of the HRD where heparin was bound to PLL, and re-infused into the right atrium. The HRD run time was determined by an established mathematical model of first-order exponential depletion targeted to 90% heparin removal. In the protamine group, protamine was given in a 100 U heparin to 1 mg protamine ratio after CPB in a slow intravenous infusion. Hemodynamics, activated clotting time (ACT), activated partial thromboplastin time (APTT), and heparin concentration were obtained before, every 5 min during, and after the use of the HRD or before and after protamine administration, and 1 and 3 hours after HRD or protamine. Heparin concentration immediately after CPB was 4.90 +/- 0.19 U/ml in the HRD group and 3.94 +/- 0.63 U/ml in the protamine group, respectively (p > 0.05 between groups). The ACT was 994 +/- 7 sec in the HRD group and 768 +/- 55 sec in the protamine group, and APTT was greater than 150 sec in both groups (p > 0.05 between groups). In the HRD group, the HRD run time was determined to be 31.5 +/- 2.4 min for the targeted 90% heparin removal, and the plasma heparin concentration followed first-order depletion kinetics. In the protamine group, the full dose of protamine was administered over 15 min. Immediately after the HRD run or protamine administration, plasma heparin concentration decreased to 0.48 +/- 0.09 U/ml in the HRD group and 0.13 +/- 0.02 U/ml in the protamine group (p < 0.01 between groups); likewise, ACT decreased to 188 +/- 25 sec in the HRD group and 101 +/- 5 in the protamine group (p < 0.01 between groups). The APTT was not significantly different between the groups at any time during the experiment. Plasma heparin concentration and ACT were not significantly different three hours after the HRD run or protamine administration. The authors conclude that the HRD is capable of predictable reversal of systemic heparinization after CPB, and is an alternative to achieve heparin clearance in subjects who may develop adverse reactions to protamine.
Animals↗