Venovenous Bypass Circuit Research Articles

Venovenous bypass in liver transplantation: Exploring the benefits, efficacy, and safety.

Venovenous bypass (VVB) is a technique used in liver transplantation (LT) to maintain hemodynamic stability and abdominal organ perfusion and thereby improve patient outcomes. Despite its perceived benefits, VVB utilization has declined globally due to concerns related to heparinization, major bleeding and the need for expertise. Recent advancements, such as percutaneous cannulation techniques and improved extracorporeal technology have improved the safety of VVB in LT. This paper presents a modified VVB circuit with enhanced safety features. Cannulation plays a pivotal role in VVB establishment, with percutaneous methods increasingly favored. Studies demonstrate VVB's efficacy in improving patient outcomes with lower incidence of acute kidney injury and reduced operative time and blood loss, with no added morbidity or mortality. However, its routine use faces challenges, with alternative techniques gaining traction. Our experience highlights VVB's role in various clinical scenarios, including patients with high Model for End-Stage Liver Disease (MELD) scores, challenging surgical anatomy, portal vein thrombosis and pre-existing cardiovascular disease, emphasizing its safety and efficacy. Continued research is needed to optimize VVB techniques and ensure better outcomes for liver transplant recipients.

The AngioVac Device: Understanding the Failures on the Road to Success.

Current percutaneous thromboembolectomy techniques may obviate surgical intervention in high-risk patients with iliocaval thrombus or thrombus of the right side of the heart, but typically require thrombus fragmentation and thrombolysis with associated bleeding and thromboembolic complications. The AngioVac (Angiodynamics, Latham, NY USA) device uses a percutaneous venovenous bypass circuit to aspirate intact thrombus. A review of the literature was performed with regard to the AngioVac device to determine the factors correlating with successful thrombus extraction. A literature search was performed with regard to use of the AngioVac device using the PubMed database. A meta-analysis was not performed given the small size and lack of statistical analysis of the individual reports included. Twenty-three reports describing 57 procedures in 56 patients were analyzed. Indications for thrombectomy included iliocaval thrombus in 53% (30), thrombus of the right side of the heart, in 49% (28), pulmonary embolus in 14% (8), and upper extremity venous/Glenn shunt thrombosis in 7% (4). The complete success rate, defined as removal of all thrombus, was 75% (43), with an 11% (6) partial success rate. In 14% (8) of cases, minimal or no thrombus was retrieved. When analyzed by indication, iliocaval thrombus and thrombus of the right side of the heart demonstrated 87% (26) and 82% (23) complete success rates, respectively. Pulmonary embolus demonstrated a significantly lower success rate at 12.5% [1; (P < .001)]. Complications occurred in 12% (7), including six hematomas and one retroperitoneal bleed. The AngioVac device offers an excellent alternative to surgical thrombectomy for patients presenting with iliocaval or intracardiac thrombus, with success rates of more than 80%, although it seems that pulmonary emboli are less amenable. Appropriate patient selection can lead to improved outcomes. Larger numbers are needed to make more definite conclusions.

Factors Associated with Successful Thrombus Extraction with the AngioVac Device: An Institutional Experience

The AngioVac (AngioDynamics, Latham, NY) device utilizes a venovenous bypass circuit for percutaneous venous thrombectomy and has been applied in the setting of iliocaval thrombosis as well as right heart thrombus and pulmonary emboli. We describe our experience with the AngioVac device in 12 patients with a variety of indications with the goal of identifying factors correlating with successful thrombectomy. From August 2013 to June 2015, 12 patients underwent AngioVac percutaneous thrombectomy at our institution. Preoperative, intraoperative, and postoperative data were retrospectively analyzed. Indications for thrombectomy included iliocaval thrombosis in 33% (4), right heart thrombus in 42% (5), and pulmonary embolus in 25% (3). We experienced a 58% complete success rate. Partial success was achieved in 17%, and no thrombus was extracted in 25%. Iliocaval and right heart thrombi were the most amenable to AngioVac thrombectomy with 100% (4/4) and 60% (3/5) complete success rates, respectively. Pulmonary embolus was the least amenable to thrombectomy with a 33% partial success rate (1/3) and 67% failure rate (2/3). The AngioVac devices allow for percutaneous thrombectomy in the setting of iliocaval and right heart thrombus in patients for whom medical therapy fails or for those in whom surgical intervention is considered high risk. Pulmonary emboli are less amenable, likely due to limited steeribility of the device. Larger studies are needed to make more definitive conclusions, and newer iterations of the device will likely allow for improved outcomes.

Single Center Experience with the AngioVac Aspiration System.

The AngioVac catheter system is a mechanical suction device designed for removal of intravascular material using extracorporeal veno-venous bypass circuit. The purpose of this study is to present the outcomes in patients treated with the AngioVac aspiration system and to discuss its efficacy in different vascular beds. A retrospectively review was performed of seven patients treated with AngioVac between October 2013 and December 2014. In 6/7 cases, the AngioVac cannula was inserted percutaneously and the patient was placed on veno-venous bypass. In one of the cases, the cannula was inserted directly into the Fontan circuit after sternotomy and the patient was maintained on cardiopulmonary bypass. Thrombus location included iliocaval (2), SVC (1), pulmonary arteries (1), Fontan circuit and Glenn shunt with pulmonary artery extension (1), right atrium (1), and IVC with renal vein extension (1). The majority of thrombus (50-95%) was removed in 5/7 cases, and partial thrombus removal (<50%) was confirmed in 2/7 cases. Mean follow-up was 205 days (range 64-403 days). All patients were alive at latest follow-up. Minor complications included three neck hematomas in two total patients. No major complications occurred. AngioVac is a useful tool for acute thrombus removal in the large vessels. The setup and substantial cost may limit its application in straightforward cases. More studies are needed to establish the utility of AngioVac in treatment of intravascular and intracardiac material.

Use of Partial Venovenous Cardiopulmonary Bypass in Percutaneous Hepatic Perfusion for Patients with Diffuse, Isolated Liver Metastases: A Case Series

Diffuse isolated liver metastases are the dominant mode of tumor progression in a number of cancers and present a major treatment challenge for oncologists. An experimental treatment, percutaneous hepatic perfusion (PHP), utilizes partial venovenous cardiopulmonary bypass to allow administration of high-dose chemotherapy directly and solely to the liver with filtration of chemotherapeutic agents from the blood prior to its return to the systemic circulation, thereby minimizing toxic systemic effects. The following case series describes the management of 5 patients with metastatic melanoma undergoing serial PHPs. A single-center experience from a national multi-center random-assignment trial comparing PHP to best alternative care (BAC) in patients with diffuse melanoma liver metastases. A tertiary care hospital. Five patients with metastatic melanoma to the liver. Five patients underwent a total of fifteen PHPs using a venovenous bypass circuit with hemofiltration, receiving hepatic intra-arterial melphalan, 3 mg/kg of ideal body weight, for 30 minutes with a total of 60 minutes of hemofiltration. Five patients tolerated the procedure well with transient hemodynamic and metabolic changes. In patients with diffuse isolated liver metastases, PHP is a safe and well-tolerated procedure that can be performed more than once and is associated with marked anti-tumor activity in some patients.

Cannulation of a persistent left superior vena cava or a pericardiophrenic vein?

To the Editor, We read with interest the recently published case report by Schreiber et al., and in our view, the diagnosis of a persistent left superior vena cava (PLSVC) is unclear. The diagnosis appears to have been based on the features seen on the anterior chest x-ray and the findings at mini-sternotomy. The differential diagnosis of a cannula observed to be passing straight down from the left internal jugular vein to the mediastinum on an anterior chest x-ray would include both extravascular and intravascular placement with intravascular siting, including intra-arterial (aortic) and intravenous (left internal thoracic, pericardiophrenic, PLSVC, and left superior intercostal veins) siting. Features that may help differentiate between the various veins include the lateral arching of the superior intercostal vein near the aortic arch in the upper mediastinum before proceeding caudally, the lateral turning of the pericardiophrenic vein lower in the mediastinum along the left heart border, and the medial turning of the PLSVC near the left atrium. A simple way to demonstrate this is to repeat the anterior chest x-ray following the injection of intravenous contrast via the cannula to outline the vessel. Schummer recommends a lateral chest x-ray with injected contrast to help determine the position of the cannula where the lateral thoracic vein lies anteriorly passing to the chest wall, the pericardiophrenic vein and PLSVC lie centrally, while the superior intercostal vein lies more posterior. The mini-sternotomy did not define the lower limit of the cannulated vessel, but it did confirm its origin at the caudal junction of the left internal jugular vein and the left subclavian vein. However, all four of the abovementioned veins could arise from this site, with the pericardiophrenic vein and the PLSVC occupying similar positions in the upper mediastinum. Although the pericardiophrenic vein is usually a small vein in patients with portal hypertension (as is the case with liver transplant patients), it may be involved with gastroesophageal varices and portosystemic shunting causing enlargement. The authors reasoned that the hemodynamic instability with the institution of veno-venous bypass (VVB) and its reversibility on clamping the VVB circuit was due to blood loss into the left pleural cavity. However, blood loss sufficient to cause such a sudden change would presumably need volume resuscitation to restore hemodynamic stability. Furthermore, no overt damage to the cannulated vessel was observed, blood could be withdrawn easily from the cannula, and the patient was stable up to the institution of VVB. At the time, transesophageal echocardiography detected a large left pleural collection; however, the chest tube was not inserted until the completion of liver transplantation and only 1 L of dark blood was drained via the chest tube. Although it is true that a dilated coronary sinus may cause left ventricular inflow tract obstruction due to its proximity to the mitral valve, the coronary sinus was not dilated on the preoperative transthoracic echocardiography. An alternative explanation could be that the cannulated vessel was a dilated pericardiophrenic vein involved in portosystemic shunting, and during VVB, blood would flow down this vessel in a retrograde manner and would not be returned to the heart. This would have caused an immediate drop in venous return, which would have been immediately reversible on clamping the VVB circuit. Blood in the left pleural cavity may have originated from several sources, including the contralateral diaphragm during surgery. A. Verniquet, MD (&) R. Kakel, MD James Paton Memorial Hospital–Central Health, Gander, NL, Canada e-mail: andrewverniquet@hotmail.com

A Technique for Autologous Priming of the Veno-Venous Bypass Circuit during Liver Transplantation

Orthotopic liver transplantations (OLT) have been associated with significant blood loss and hemodilution, necessitating significant homologous blood component replacement. Increasing administration of homologous blood products has been found to be inversely related to patient and graft survival. Various methods to reduce the amount of blood products patients receive during OLT, such as antifibrinolytic therapy, thromboelastography-guided transfusion, phlebotomy, reduced central venous pressures intraoperatively, and the use of the veno-venous bypass (VVB) circuit, have been explored. The asanguineous priming volume of the VVB circuit increases the likelihood of the patient receiving homologous blood products due to hemodilution. It was reasoned that autologous priming of the VVB circuit in OLT surgery was a plausible adjunctive blood conservation technique given its application to the extracorporeal circuit during cardiac surgery. We describe our technique of modifying the VVB circuit for autologous priming. This technique adds minimal risk and a small amount of cost to the procedure, requires slightly more communication among members of the surgical team, and with proper sequencing, adds no additional length to the surgical procedure. It is recommended that this technique be considered for addition to the arsenal of blood conservation techniques when VVB is used during OLT.

Cavopulmonary Bypass to Facilitate Infrahepatic Vena Cava Gunshot Wound Repair

Traumatic injuries to the inferior vena cava continue to be associated with high mortality. The management of these injuries has been technically challenging and highly variable, often depending on factors that include the anatomic complexity and the severity of the insult. We report the first case in which a patient with massive exsanguination from an infrahepatic vena cava gunshot wound underwent successful repair with the aid of a novel variant active venovenous bypass circuit between the inferior vena cava and the pulmonary artery.

Does the Venovenous Bypass influence Coagulation Status in Living-Related Liver Transplantation?

Background: Venovenous bypass (VVB) in liver transplantation has been used to decrease the acute hemodynamic and metabolic changes during anhepatic periods. But, the use of VVB in patients undergoing liver transplantation is still under debate concerning its relative risks and benefits. Therefore, the aim of this study was to examine the influences of VVB on the coagulation status and the amount of transfusion in living-related liver transplantation. Methods: We conducted this retrospective study on 39 patients who underwent orthotopic living-related liver transplantation using the piggyback technique from March 2001 to April 2002. While 19 patients did not receive venovenous bypass, 20 patients received. We compared the two groups in terms of coagulation-related parameters (prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen and thromboelastograph), the amount of transfusion during intraoperative and post-operative 1day. We also compared the incidences of post-reperfusion syndrome in the two groups. Results: The group that underwent living-related liver transplantation with VVB required more packed red blood cell (p-RBC) transfusion than the other group without VVB from post-reperfusion untill the end of operation (P ＜ 0.05). This difference in the amount of p-RBC transfusion may be due to the blood remained in the VVB circuit at the termination of VVB. However, the two groups were similar in terms of coagulation-related parameters, the amount of other blood components, such as fresh frozen plasma, platelet concentrates, cryoprecipitate, total amount of transfusion during the 24 hours postoperatively, and the incidence of post-reperfusion syndrome. Conclusions: We conclude that the using of venovenous bypass in living-related liver transplantation did not influence coagulation status and the amount of transfusion perioperatively.

Percutaneous bypass cannulae can interfere with rapid infusion during liver transplantation

VENOVENOUS BYPASS (VVB) may be used during orthotopic liver transplantation (OLT) to maintain adequate preload when blood return to the heart is interrupted by cross-clamping of the inferior vena cava. Traditionally, when VVB is used, 1 drainage cannula is inserted via surgical cutdown into a femoral vein, and another is used to cannulate the portal vein directly. A centrifugal pump is used to aspirate venous blood from these sites and return it through a cannula inserted via surgical cutdown into an axillary vein. To avoid the complications of surgical cutdowns, percutaneous VVB has been used. 1 Tisone G Mercadante E Dauri M et al. Surgical versus percutaneous technique for veno-venous bypass during orthotopic liver transplantation: A prospective randomized study. Transplant Proc. 1999; 31: 3162-3163 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar , 2 Frenette L Cox J Singer D et al. Five years of experience with percutaneous cannula for establishing venous bypass access in orthotopic liver transplantation. Transplant Proc. 1996; 28: 2974-2977 PubMed Google Scholar , 3 Manas DM Gibbs P Talbot D et al. Use of percutaneously placed catheters for venovenous bypass in orthotopic liver transplantation. Transplantation. 1996; 62: 144-145 Crossref PubMed Scopus (3) Google Scholar , 4 Spiekermann BF Bogdonoff DL Hershey JE McLaughlin JD A method for percutaneous cannulation for veno-veno bypass during orthotopic liver transplantation. Anesth Analg. 1995; 80: 432-433 PubMed Google Scholar , 5 Scherer R Erhard J Giebler R et al. Percutaneous portofemoro-subclavian venovenous bypass during orthotopic liver transplantation. Transplantation. 1994; 57: 472-473 Crossref PubMed Google Scholar , 6 Scherer R Giebler R Schmutzler M et al. Effect of high shunt flows during portofemoro-subclavian venovenous bypass in human orthotopic liver transplantation. Transplant Proc. 1993; 25: 2591 PubMed Google Scholar , 7 Washburn WK Lewis WD Jenkins RL Percutaneous venovenous bypass in orthotopic liver transplantation. Liver Transpl Surg. 1995; 1: 377-382 Crossref PubMed Scopus (9) Google Scholar , 8 Ozaki CR Langnas AN Bynon JS et al. A percutaneous method for venovenous bypass in liver transplantation. Transplantation. 1994; 57: 472-473 Crossref PubMed Google Scholar , 9 Scherer R Giebler R Erhard J et al. A new method of veno-venous bypass during human orthotopic liver transplantation. Anaesthesia. 1994; 49: 398-402 Crossref PubMed Scopus (15) Google Scholar , 10 Johnson SR Marterre WF Alonso MH Hanto DW A percutaneous technique for venovenous bypass in orthotopic cadaver liver transplantation and comparison with the open technique. Liver Transpl Surg. 1996; 2: 354-361 Crossref PubMed Scopus (16) Google Scholar Although these reports all use at least 1 percutaneous cannula in the VVB circuit, they vary in their choice of cannulation sites, types and sizes of percutaneous cannulae, and VVB circuit configuration. The authors' VVB technique also varies from what has been reported. The authors routinely insert percutaneously a left femoral venous drainage cannula and a right internal jugular (RIJ) venous return cannula. The RIJ cannula serves a dual role as the major conduit for intravenous infusions from the rapid infusion system (RIS) (Haemonetics Corporation, Braintree, MA); this eliminates the need for additional large-bore intravenous access. In the following case, an unusually high VVB flow rate limited the maximal intravenous infusion rate of the RIS.

Antifibrinolytic Therapy and Pulmonary Thromboembolism During Orthotopic Liver Transplantation

To The Editor: We read with great interest the article by O’Connor et al. (1) regarding pulmonary thromboembolism during orthotopic liver transplantation (OLT). Also, we agree that antifibrinolytic drugs may play a role in unwanted clot formation during OLT; however, we feel some additional factors not mentioned in these case reports may have also contributed to what was observed intraoperatively. In Case 1, the patient did not exhibit a significant coagulopathy as evidenced by her preoperative laboratory data. In addition, no mention was made of obtaining a baseline intraoperative thromboelastogram at the start of OLT. Nevertheless, both fresh-frozen plasma and aprotinin were subsequently administered. Although we share the concern of the authors regarding the potential for blood loss during redo OLT, as in this case, empiric use of any antifibrinolytic agent without significant preexisting coagulopathy or evidence of fibrinolysis through coagulation monitoring may be difficult to justify knowing the potential for thrombotic complications. In Case 2, venovenous bypass (VVB) was used to facilitate removal of the recipient’s diseased liver. Again, the authors make no mention of obtaining a baseline thromboelastogram, although one can assume that with a prothrombin time of 28.4 s and moderate thrombocytopenia, the thromboelastogram would have been abnormal. Subsequently, large dose ε-aminocaproic acid therapy was initiated. In contrast to this, Kang (2) recommended using small dose ε-aminocaproic acid to treat demonstrable fibrinolysis and cautioned against its prophylactic use to avoid potential thrombotic complications. Of interest, this patient had a possible preexisting clot in the right internal jugular vein. With antifibrinolytic therapy combined with presumed fresh-frozen plasma and platelet administration for “persistent intraabdominal bleeding,” the potential for further clot propagation existed. Whether a preexisting clot extended itself into the right heart or was dislodged from the right internal jugular vein or innominate vein during VVB, one can only speculate. More importantly though, the authors do not mention whether once initiated, adequate VVB flow was established and maintained. Although VVB tubing is heparin bonded, in low flow states of <1 L/min, fibrin deposition within the VVB circuit is possible (3–4). This filamentous material can then migrate into the right heart and pulmonary circulation where further clot formation can occur. In the face of right heart dysfunction and increased central venous pressure secondary to an acute rise in pulmonary artery pressures because of thromboembolism, we doubt “normal” VVB flow could be maintained. Thus, a viscous cycle of clot formation, resulting in a low flow state during VVB, followed by additional clot formation, may have been established in this patient. Brian M. Parker MD Samuel A. Irefin MD

Antifibrinolytic Therapy and Pulmonary Thromboembolism During Orthotopic Liver Transplantation

In Response: We appreciate the interest expressed by Parker and Irefin in our recent publication. Regarding Case 1, they felt that our “empiric” use of aprotinin during orthotopic liver transplantation (OLT) was unjustified without documentation of a preexisting coagulopathy or evidence of ongoing fibrinolysis because of the potential for thrombotic complications. However, while we agree that monitoring of fibrinolysis is important during OLT, previous data have demonstrated the utility of prophylactic aprotinin therapy during OLT, presumably because of the underlying hemostatic abnormalities that characterize patients with end-stage liver disease and the propensity for fibrinolysis after allograft reperfusion (1–5). Although the efficacy of aprotinin in this setting is admittedly controversial, serious thrombotic complications were not observed in any of the published trials. Our approach in this case was thus consistent with the existing literature regarding aprotinin use during OLT. Additionally, Parker and Irefin also question the use of prophylactic ε-aminocaproic acid use during OLT as described in Case 2, again citing the potential for thrombotic complications. However, ε-aminocaproic acid is frequently used during OLT (6,7) and a review of the prevailing literature failed to reveal any significant thrombotic complications. Despite this paucity of data regarding the prothrombotic risk of antifibrinolytic drug use during OLT, we agree that aprotinin, together with other ill-defined factors favoring thrombosis, may increase the risk of serious thromboembolic events. This was the intended message of our report. Parker and Irefin note the possible etiologic role of the presumed clot in the right internal jugular vein. We did, however, pointedly acknowledge and discuss the potential role of this preoperative abnormality. They finally suggest that low flows during veno-venous bypass (VVB) may have precipitated fibrin deposition in the bypass circuit, which then migrated to the right heart. Although we cannot exclude activation of clotting within the VVB circuit, flows were always greater than 2 L/min before the hypotensive and hypoxemic event. After the onset of hemodynamic instability, the flows decreased, but the perfusion staff promptly and appropriately discontinued the VVB pump. The temporal sequence of events and the transesophageal echocardiographic findings strongly support the view that the low VVB flows were secondary to the massive pulmonary thromboembolism rather than a primary etiologic factor in its formation. We appreciate the insightful comments of Parker and Irefin regarding the role of coagulation monitoring during OLT as a guide to blood product replacement and the selective use of antifibrinolytic agents. Nonetheless, it remains our judgment that aprotinin use was justified on the basis of the known coagulation and fibrinolytic abnormalities characteristic of similar patients undergoing OLT (especially reoperative procedures) (1–5), the absence of documented or widely accepted serious thrombotic risks associated with aprotinin, the presence of data supporting its beneficial impact on fibrinolysis and transfusion requirements (1–5), and because of the ongoing clinical evidence of impaired hemostasis. In hindsight, we believe the similarity of these two events, the rarity of pulmonary embolism during OLT, and the reports of four other identical events associated with aprotinin use during OLT, all suggest a possible prothrombotic effect of aprotinin in certain patients undergoing OLT. Thus, it may be prudent to avoid aprotinin during OLT in the absence of demonstrable clinical or laboratory evidence of fibrinolysis because of the potential risk of life-threatening thromboembolic events. Christopher J. O’Connor MD Kenneth J. Tuman MD

Intravascular membrane oxygenator and carbon dioxide removal devices: a review of performance and improvements.

The first intravascular oxygenator and carbon dioxide (CO2) removal device (IVOX), conceived by Mortensen, was capable of removing 30% of CO2 production of an adult at normocapnia with a measurable reduction in ventilator requirements. Through studies of mathematical modeling, an ex vivo venovenous bypass circuit to model the human vena cava, animal models of severe smoke inhalation injury, and patients with acute respiratory failure, the practice of permissive hypercapnia has been established to enhance CO2 removal by IVOX. By allowing the blood pCO2 to rise gradually, the CO2 excretion by IVOX can be linearly increased in a 1:1 relationship. Experimental and clinical studies have shown that CO2 removal by IVOX can increase from 30 to 40 ml/min at a normal blood pCO2 to 80 to 90 ml/min at a pCO2 of 90 mm Hg. In addition, IVOX with permissive hypercapnia allows a significant reduction in minute ventilation and peak airway pressure. Active blood mixing to decrease the boundary layer resistance in the blood can significantly improve O2 transfer by up to 49% and CO2 removal by up to 35%. Design changes can also improve the performance of IVOX. Increased surface area with more fibers and enhanced mixing by increased fiber crimping in new prototypes of IVOX significantly increased CO2 removal. Other groups have used alternative designs to address the limited performance of intravascular gas exchange devices. With improved design and patient management, clinically meaningful gas exchange and reduction in mechanical ventilatory support may be achieved during treatment of severe respiratory failure.

Intravascular Gas Transfer

Single and double hollow fiber intravascular gas exchangers were evaluated in an extracorporeal veno-venous bypass circuit (right atrium to pulmonary artery) including a tubular blood chamber (mimicking caval veins with an inner diameter of 26 mm) for evaluation of the membrane surface area/host vessel diameter gas transfer relationships. Six bovine experiments (body wt: 68 ± 4 kg) with staged ex vivo blood flows of 1, 2, 3, and 4 L/min and a device oxygen inflow of 0, 3, and 6 L/min (0 or 3 L/min/device) were performed. Total oxygen transfer at a blood flow of 1 L/min was 33 ± 4 ml/min for a gas flow of 3 L/min (one device) vs 60 ± 25 ml/min for a gas flow of 6 L/min (two devices); at a blood flow of 2 L/min, the corresponding oxygen transfer was 46 ± 16 ml/min for a gas flow of 3 L/min vs 95 ± 44 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding oxygen transfer was 48 ± 24 ml/min for a gas flow of 3 L/min vs 92 ± 37 ml/min for a gas flow of 6 L/min (p < 0.01 for comparison of areas under the curves). Total carbon dioxide transfer at a blood flow of 1 L/min was 47 ± 18 ml/min for a gas flow of 3 L/min vs 104 ± 26 ml/min for a gas flow of 6 L/min; at a blood flow of 2 L/min, the corresponding carbon dioxide transfer was 59 ± 19 ml/min for a gas flow of 3 L/min vs 129 ± 39 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding carbon dioxide transfer was 60 ± 22 ml/min for a gas flow of 3 L/min vs 116 ± 49 ml/min for a gas flow of 6 L/min (p < 0.01). For the given setup, the blood flow/gas transfer relationship is non linear, and a plateau is achieved at a blood flow of 2.5 L/min for O2 and CO2. Doubling membrane surface area and consecutively sweeping gas flows result in doubling of gas transfers at all tested blood flows. However, increased membrane surface area and blood flow produce a higher pressure drop that in turn limits the fiber density that can be used clinically.

INTRAVASCULAR GAS TRANSFER

Single and double hollow fiber intravascular gas exchangers were evaluated in an extracorporeal veno-venous bypass circuit (right atrium to pulmonary artery) including a tubular blood chamber (mimicking caval veins with an inner diameter of 26 mm) for evaluation of the membrane surface area/host vessel diameter gas transfer relationships. Six bovine experiments (body wt: 68 +/- 4 kg) with staged ex vivo blood flows of 1, 2, 3, and 4 L/min and a device oxygen inflow of 0, 3, and 6 L/min (0 or 3 L/min/device) were performed. Total oxygen transfer at a blood flow of 1 L/min was 33 +/- 4 ml/ min for a gas flow of 3 L/min (one device) vs 60 +/- 25 ml/ min for a gas flow of 6 L/min (two devices); at a blood flow of 2 L/min, the corresponding oxygen transfer was 46 +/- 16 ml/min for a gas flow of 3 L/min vs 95 +/- 44 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding oxygen transfer was 48 +/- 24 ml/min for a gas flow of 3 L/ min vs 92 +/- 37 ml/min for a gas flow of 6 L/min (p < 0.01 for comparison of areas under the curves). Total carbon dioxide transfer at a blood flow of 1 L/min was 47 +/- 18 ml/min for a gas flow of 3 L/min vs 104 +/- 26 ml/min for a gas flow of 6 L/min; at a blood flow of 2 L/min, the corresponding carbon dioxide transfer was 59 +/- 19 ml/min for a gas flow of 3 L/ min vs 129 +/- 39 ml/min for a gas flow of 6 L/min; at a blood flow of 3 L/min, the corresponding carbon dioxide transfer was 60 +/- 22 ml/min for a gas flow of 3 L/min vs 116 +/- 49 ml/min for a gas flow of 6 L/min (p < 0.01). For the given setup, the blood flow/gas transfer relationship is non linear, and a plateau is achieved at a blood flow of 2.5 L/min for O2 and CO2. Doubling membrane surface area and consecutively sweeping gas flows result in doubling of gas transfers at all tested blood flows. However, increased membrane surface area and blood flow produce a higher pressure drop that in turn limits the fiber density that can be used clinically.

Development of a Membrane Oxygenator for Long-Term Respiratory Support and Its Experimental Evaluation in Prolonged ECMO

The authors developed a new membrane oxygenator (MO) for long-term respiratory support and evaluated its performance in animal experiments for as long as 336 hr. The MO, with a membrane area of 1.2 m2 and priming volume of 140 ml, is compact and designed to be interposed in a ventricular assist system (VAS) conduit. It is made with a novel hollow fiber membrane, in which micropores are blind-ended so that serum leakage can be prevented during prolonged use. The blood contacting surface of the MO is heparinized with a newly developed covalent bonding technique that ensures good thrombus resistance. In vivo evaluation with five adult goats was performed by installing the MO into a venoarterial or venovenous bypass circuit. No systemic anticoagulant therapy was used, except for a heparin-added fluid infusion to keep the pressure monitoring lines open (2-3 U/kg/hr). Throughout the experiments, no plasma leakage was observed, and gas transfer rates were maintained in a satisfactory range. Platelet counts did not decrease to less than 60% of levels before bypass, and hemolysis was negligible. The levels of coagulation parameters including fibrinogen, fibrin degradation products (FDP), antithrombin III (AT III), antiplasmin, prothrombin time (PT) and activated partial thromboplastic time (APTT) remained within physiologic ranges and relatively constant. At the end of the evaluation, no thrombus formation was noted in three of five MOs. These results suggest that this MO is a promising device for long-term respiratory support.

Intravascular Oxygenation

An extra corporeal venovenous bypass circuit (right atrium to pulmonary artery), including an intravascular gas exchanger in a blood chamber with a variable inner diameter, was developed for ex vivo evaluation of the host vessel diameter/intravascular oxygen transfer relationship. Three host vessel diameters mimicking different configurations of the caval axis were studied in three bovine experiments (body weight 82 +/- 3 kg). Blood flow was 3,000 ml/min and device oxygen inflow was 2,300 ml/min. Serial blood samples were taken for 26 mm, 23 mm, and 20 mm inner blood chamber diameters after hemodynamic stabilization before and after exposure of the circulating blood to the intravascular gas exchanger (sampling ports at blood chamber inlet and outlet). Measured oxygen saturation at the blood chamber inlet was 25.0 +/- 11.7% for the 26 mm diameter as compared to 31.7 +/- 12.6% for 23 mm, and 28.7 +/- 9.2% for 20 mm. At the outlet, the corresponding O2 saturations were 34.5 +/- 11.5% for 26 mm, 42.9 +/- 8.8% for 23 mm, and 43.2 +/- 6.2 for 20 mm. Total O2 transfer was 24.9 +/- 11.5 ml/min for 26 mm, 31.9 +/- 7.4 ml/min for 23 mm, and 35.9 +/- 12.2 ml/min for 20 mm (p < 0.05). Likewise, O2 transfer rate was 8.3 +/- 3.8 ml/L, 10.6 +/- 2.4 ml/L, and 12.0 +/- 4.0 ml/L (p < 0.05). Parallel analyses of total CO2 transfer and CO2 transfer rates provided less consistent findings. At 3 L/min, the pressure drop between the inlet and outlet of the blood chamber was 12 +/- 3 mmHg for 26 mm, 26 +/- 1 mmHg for 23 mm, and 38 +/- 2 mmHg for 20 mm diameters (p < 0.001). The authors conclude that oxygen transfer of a given intravascular gas exchanger appears to be indirectly proportional to the host vessel diameter. Increasing blood pressure gradient as a function of decreasing diameter has to be considered in clinical application.

Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors.

This prospective, nonrandomized trial evaluated a percutaneous isolated chemotherapy perfusion approach for treating advanced primary and metastatic liver tumors. Chemotherapy was administered via hepatic artery catheter and hepatic venous blood isolated by a novel percutaneous double-balloon inferior vena cava (IVC) catheter was passed through a detoxification/filtration cartridge in a venovenous bypass circuit. Among 23 patients enrolled onto the study, 58 procedures were performed on 21 patients. Twelve patients received dose escalations of fluorouracil (5-FU) (1,000 mg/m2 to 5,000 mg/m2), and nine received dose escalations of doxorubicin (50 mg/m2 to 120 mg/m2). Pharmacokinetic studies included drug accumulation in the liver, extraction by detoxification filters, systemic exposure, and alterations of half-life. Each patient received two treatments at 3-week intervals. Those showing stabilization or response received additional treatments. There was a direct relationship between dose and peak concentration of drug entering the hepatic veins. The system functioned efficiently throughout the dose range, with extraction efficiencies ranging from 64% to 91% (P < .001). The hepatic vein drug levels showed a sixfold increase in 5-FU with dose escalation from 1,000 to 5,000 mg/m2, and a twofold increase in dox with dose escalation from 50 to 120 mg/m2 (P < .001, filter-mediated drug extraction). The treatments were accomplished with only an overnight hospital stay and no mortality. The common procedure-related toxicity was transient hypotension (grade I to II), due to catecholamine depletion by the filter. Dose-limiting toxicity (leukopenia) was observed in patients receiving 5-FU at a dose of 5,000 mg/m2 and doxorubicin at a dose of 120 mg/m2. Significant tumor response (> 95% reduction) was obtained in two patients receiving doxorubicin at 90 mg/m2 and 120 mg/m2. The use of a double-balloon catheter to isolate and detoxify hepatic venous blood during intraarterial therapy is technically feasible, safe, and allows administration of large doses of intrahepatic chemotherapy at short intervals. This approach should allow new dose-intensification strategies to increase tumor responses in primary and metastatic liver tumors.

Intravascular Membrane Oxygenation and Carbon Dioxide Removal with IVOX: Can Improved Design and Permissive Hypercapnia Achieve Adequate Respiratory Support During Severe Respiratory Failure?

The intravenacaval oxygenator and carbon dioxide removal device (IVOX) conceived by Mortensen at CardioPulmonics is a diffusion-limited device capable of removing 30% of CO2 production of an adult at normocapnia with minimal reduction in ventilator requirements. Through mathematical modeling, an ex vivo venovenous bypass circuit to model the vena cava and animal models of severe smoke inhalation injury, the practice of permissive hypercapnia has been established to enhance CO2 removal by IVOX. By allowing the blood PCO2 to rise gradually, the CO2 excretion by IVOX can be linearly increased in a 1:1 relationship. Experimental and clinical studies have shown that CO2 removal by IVOX increased from 30-40 ml/min at normal blood PCO2 to 80-90 ml/min at PCO2 of 90 mm Hg. In addition, IVOX with permissive hypercapnia allowed a significant reduction in minute ventilation and peak airway pressure. Design changes could also improve the performance of IVOX. Increased surface area and mixing with more fibers and crimping in new prototypes of IVOX significantly increased CO2 removal and oxygen transfer. Active mixing in the blood to decrease the boundary layer resistance can further enhance gas exchange of IVOX. In conclusion, gas exchange by the current design of IVOX is limited, and improvements in design are needed for it to become a more clinically applicable device. Permissive hypercapnia can significantly enhance CO2 removal by IVOX as well as significantly reduce ventilator requirements.

Improved gas exchange performance of the intravascular oxygenator by active blood mixing.

The intravascular oxygenator and carbon dioxide removal device (IVOX; CardioPulmonics, Salt Lake City, UT) has been shown to perform 30% of the gas exchange in animals and patients with acute respiratory failure. Among the factors that limit gas exchange is the mass transfer resistance in the blood phase. To determine if a reduction in mass transfer resistance by mixing venous blood can enhance the O2 transfer and CO2 removal by IVOX, a right atrium-pulmonary artery venovenous bypass circuit was used in sheep to model the adult vena cava. A size 9 IVOX (894 fibers with 0.41 m2 surface area, n = 5) was incorporated in the bypass circuit and the blood flow controlled by a roller pump ranging from 1 to 4 l/min. An intra-aortic balloon was placed near the shaft of the IVOX and pulsated at the rate adjusted to best improve CO2 removal (100-120 bpm). O2 transfer and CO2 removal were measured with balloon pulsation on and off at different flow rates. Results showed that blood mixing by pulsation of the balloon caused a 25-49% increase in O2 transfer by IVOX, and this increase remained relatively constant throughout the full flow range. CO2 removal was also increased by up to 35%, but at flows between 3.5 and 4 l/min, the effect of mixing was diminished. It is concluded that reduction in the mass transfer resistance by blood mixing improves gas exchange. Because O2 is more diffusion limited, it is more dependent upon mixing of blood for gas exchange than CO2. More design improvements to incorporate active mixing may further enhance the gas exchange performance of IVOX.