Development of a Pulsatile Flow-Generating Circulatory Assist Device (K-Beat) For Use with Veno-Arterial Extracorporeal Membrane Oxygenation in a Pig Model Study.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) preserves the life of heart failure patients by providing an adequate oxygen supply and blood flow to vital organs. For patients with severe cardiogenic shock secondary to acute myocardial infarction or acute myocarditis, V-A ECMO is commonly used as the first choice among cardiac circulatory support devices. While V-A ECMO generates circulatory flow using a centrifugal pump, the provision of pulsatile flow is difficult. We previously reported our development of a new circulatory flow assist device (K-beat) for cardiac management with pulsatile flow. To obtain more efficient pulsatile assist flow (diastolic augmentation), an electrocardiogram (ECG)-analyzing device that can detect R waves and T waves increases the assist flow selectively in the diastole phase by controlling (opening and closing) the magnetic valve of the tamper. Here, we describe the first use of the K-beat on a large animal in combination with a clinical device. In addition, the diastolic augmentation effect of the K-beat as a circulatory flow assist device was examined in a pig V-A ECMO model. The K-beat was stopped every 60 minutes for a period of a few minutes, and blood pressure waveforms in the pulsatile and non-pulsatile phases were checked. This experiment showed that stable V-A ECMO could be achieved and that hemodynamics were managed in all animals. The pulsatile flow was provided in synchrony with the ECG in all cases. A diastolic augmentation waveform of femoral arterial pressure was confirmed in the pulsatile phase. K-beat could be useful in patients with severe heart failure.

A novel small animal extracorporeal circulation model for studying pathophysiology of cardiopulmonary bypass.

Extracorporeal circulation (ECC) is indispensable for cardiac surgery. Despite the fact that ECCcauses damage to blood components and is non-physiologic, its pathophysiology has not been fully elucidated. This is because difficulty in clinical research and animal experiments keeps the knowledge insufficient. Therefore, it is desirable to have a miniature ECC model for small animals, which enables repetitive experiments, to study the mechanism of pathophysiological changes during ECC. We developed a miniature ECC system and applied it to the rat. We measured changes in hemodynamics, blood gases and hemoglobin (Hb) concentration, serum cytokines (TNF-α, IL-6, IL-10), biochemical markers (LDH, AST, ALT), and the wet-to-dry weight (W/D) ratio of the lung for assessing whether the rat ECC model is comparable to the human ECC. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride), and roller pump. Priming volume of this system is only 8 ml. Rats (400-450 g) were divided into the SHAM group (n = 7) and the ECC group (n = 7). Blood samples were collected before, 60 and 120 min after initiation of ECC. During ECC, blood pressure and Hb were maintained around 80 mmHg and 10 g/dL, respectively. The levels of the inflammatory and biochemical markers and the W/D ratio were significantly elevated in the ECC group, indicating some organ damages and systemic inflammatory responses during ECC. We successfully established the ECC for the rat. This miniature ECC model could be a useful approach for studying the mechanism of pathophysiology during ECC and basic assessment of the ECC devices.

Investigation of the biological effects of artificial perfusion using rat extracorporeal circulation model.

Extracorporeal circulation (ECC) is indispensable for cardiac surgery. Since difficulty in clinical research keeps the knowledge insufficient, it is desirable to have a miniature ECC system for small animals. We aimed to establish a miniature ECC system and apply the system to the rat for investigating biochemical changes. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride) and roller pump. Priming volume of this system is only 15 ml. Rats were divided into the SHAM group and the ECC group. ECC pump flow was initiated and maintained at 70 ml/kg/min. We measured the serum cytokine levels of tumor necrosis factor-a, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) before, 60, and 120 min after the initiation of ECC. In addition, we measured the wet-to-dry weight (W/D) ratio of the left lung tissues. During ECC, blood pressure and Hb were maintained around 80 mmHg and 10g/dl, the serum cytokine levels and biochemical markers were significantly elevated in the ECC group compared with the SHAM group. The W/D ratio increased significantly more in the ECC group compared with that in the SHAM group. These data suggest that ECC promotes organ damages and systemic inflammatory response. This rat ECC model is considered to be equivalent to the already established human ECC and useful for studying the mechanism of pathophysiological changes during artificial perfusion.

Insufflation of hydrogen gas restrains the inflammatory response of cardiopulmonary bypass in a rat model.

Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H2) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H2 on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H2 group in which H2 was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-α, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H2 group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H2 group. We suggest that H2 insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation.

Suppressive effect of phosphodiesterase type 4 inhibition on systemic inflammatory responses after cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) induces excessive production of endogenous proinflammatory mediators such as cytokines and elastase, which are responsible for the subsequent development of systemic inflammatory response syndrome (SIRS). In this study, we investigated the protective effect of rolipram against SIRS after CPB. Rats were divided into three groups (n = 5 in each): control (C), rolipram (R), and sham (S). Rats in groups C and R underwent CPB for 60 min followed by 60 min of observation, while those in group S were observed for 120 min without CPB. In group R, 40 microg/kg/min of rolipram was intravenously administered throughout the experiment. CD11b expression on neutrophils was analyzed using flow cytometry. Serum concentrations of tissue necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), macrophage inflammatory protein 2 (MIP-2), and elastase were also determined. CD11b expression at the end of the experiment was unchanged from the initial value in group R, whereas that in group C increased to almost double, and that in group S also showed a slight increase (P < 0.01). Serum TNF-alpha levels in groups R and S were lower than those observed in group C (P < 0.05). Serum IL-1beta and MIP-2 levels in groups C and R tended to be higher than those in group S, although the difference was not statistically significant. Regarding elastase, group R showed a significantly lower value than group C and a higher value than group S (P < 0.05). Phosphodiesterase type 4 inhibition seems to suppress CPB-induced SIRS through the regulation of proinflammatory mediators in this rat model.

Early experience with low-prime (99 ml) extracorporeal membrane oxygenation support in children.

Quick setup is mandatory for cardiopulmonary resuscitation using an extracorporeal membrane oxygenation (ECMO) assist device. Our conventional ECMO circuit for pediatric patients consists of a centrifugal pump (CX-HP) and membrane oxygenator (CX10H). Because of the large priming volume (260 ml), the circuit had to be primed with donor blood and required 30 minutes for setup. We started to use a low-prime ECMO with small centrifugal pump (HPM-15) and membrane oxygenator (MENOX Alpha Cube) for induction of ECMO beginning in 2000. The priming volume of this low-prime circuit is only 99 ml. The circuit can be primed without donor blood, even in the small patient, and requires only 10 minutes to set up. We review our experiences with cardiopulmonary resuscitation for sudden cardiopulmonary collapse in pediatric patients, including postcardiotomy patients. From 1997 to 2000, 23 patients underwent ECMO support with a conventional circuit (group A). From 2000 to 2004, we used low-prime circuit for induction of ECMO in 12 patients (group B). After the induction of ECMO with low-prime circuit, ECMO was converted to conventional heparin-bonded circuit for the longer support. The results suggested that the quick induction of ECMO with low-prime circuit has significant advantages in cardiopulmonary support in pediatric patients.

Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model.

OBJECTIVES: Cardiopulmonary bypass (CPB) induces systemic inflammatory response with neutrophil activation and subsequent lung dysfunction. Rolipram, a selective phosphodiesterase type 4 inhibitor, blocks the decrease in levels of cyclic adenosine monophosphate associated with neutrophil activation. Here, we tested the protective effect of rolipram on CPB-induced lung injury in the rat. METHODS: Rats were divided into three groups: control (C), rolipram (R) and sham (S). In the C and R groups, animals underwent CPB at a flow rate of 60 ml/kg per min for 60 min followed by another 60-min observation, whereas the S group rats were sustained for 120 min only with median sternotomy and the placement of cannulae for CPB. Rolipram (40 microg/kg per min) was administered to the R group rats by continuous intravenous infusion from 10 min before the establishment of CPB to the end of the experiment. RESULTS: The R and S groups showed significantly higher mean arterial oxygen pressure and lower mean lung wet-to-dry weight ratio compared with those observed in the C group (R: 489+/-44 or S: 527+/-55 vs. C: 287+/-185, and R: 5.0+/-0.4 or S: 4.7+/-0.3 vs. C: 5.9+/-0.5, respectively; (P < 0.01). Although CD11b expression levels on circulating neutrophils in the C group doubled after CPB, those in the R and S groups remained almost the same (P = 0.0008). Intrapulmonary tumor necrosis factor-alpha concentrations (pg/microg protein) in the C group tended to be higher than those observed in the R and S groups (R: 5.2+/-2.1, S: 5.0+/-2.1 and C: 8.9+/-5.4; R vs. C: P = 0.09 and S vs. C: P = 0.08). Pathological study of lungs revealed that more alveolar hemorrhage and neutrophil accumulation were observed in the C group compared to the R and S groups. CONCLUSIONS: These results suggest that rolipram prevents acute lung injury via the inhibition of neutrophil activation during and after CPB in this setting of a rat model.

[Successful management after cardiopulmonary bypass without administration of protamine in a patient with severe food allergy--beneficial result with the use of heparin-coated bypass circuit].

We experienced the anesthetic management for cardiac surgery without the administration of protamine in a patient with severe food allergy. The patient, a 15-year-old boy, who had been avoiding many kinds of food including fish due to severe food allergy, received a correction of ventricular septal defect under cardiopulmonary bypass (CPB). To detect intraoperative drugs, including protamine, which might induce allergic reaction, we performed intradermal tests and prick tests. We used heparin-coated bypass circuit to minimize the amount of heparin necessary for anticoagulation during CPB. After CPB, hemostasis was achieved without the administration of protamine, and the patient received neither transfusion nor blood product throughout the perioperative period. Avoidance of protamine is advisable if the patient is allergic to food especially fish. The use of heparin-coated bypass circuit should be considered to establish hemostasis without protamine after CPB and to reduce blood products.