Randomized Trial of the Terumo Capiox® FX05 Oxygenator with Integral Arterial Filter versus Terumo Capiox® Baby RX05 and Terumo Capiox® AF02 Arterial Filter in Infants Undergoing Cardiopulmonary Bypass

Abstract

The purpose of this clinical trial was to evaluate the effect of the Terumo Capiox® FX05 oxygenator with integrated arterial filter during cardiopulmonary bypass (CPB) compared with the Terumo Capiox® RX05 Baby RX and arterial filter on inflammatory mediators and blood product utilization. Forty patients weighing less than 10 kg who underwent congenital heart surgery utilizing cardiopulmonary bypass were randomized into either oxygenator group. The endpoints included measuring inflammatory markers at six different time points (preoperative baseline, CPB circuit being primed, 15 minutes after CPB initiation, status post protamine administration, prior to transport to intensive care unit, and within 12 to 24 hours post surgery), blood product utilization, extubation time, and days until discharge. The inflammatory mediators showed no significant differences between oxygenators at any time points. However, looking at the inflammatory mediators of both the FX and RX groups combined, a statistically significant difference was seen in interleukin (IL)-6 at 12/24 hour post surgery (p < .001) versus baseline and all other time points. IL-8 at status post protamine (p < .001) and 12/24 hours post surgery (p < .001) demonstrated significant differences versus all other time points, and IL-10 at status post protamine (p < .001) and prior to leaving the operating room (p < .001) were statistically different compared to all other time points. Cardiopulmonary bypass stimulates the systemic inflammatory response through various components of the extracorporeal system. This investigation did not find significant differences in cytokines interferon-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p70, tumor necrosis factor (TNF)-α, and TNF-β when comparing these two oxygenators. It is well known that various mechanisms contribute to the levels of cytokines circulating in a patient’s blood volume and many manipulations throughout cardiac surgery have the ability to demonstrate anti-inflammatory interventions. Further investigation is needed as to how modification of the extracorporeal circuit may minimize increases in inflammatory mediators.

Cardiopulmonary bypass (CPB) has been used successfully since 1953 and is often necessary for surgical repair and palliation of congenital heart defects in infants and children (1,2). Despite advances in the surgical management of children with congenital heart disease, post-CPB syndrome continues to lead to significant morbidity and (3). Although this syndrome can occur in any age group, it tends to be more severe in neonates, leading to prolonged ventilation, coagulopathy, cardiac failure, and increased mortality (1,2). Many of these deleterious effects of CPB are secondary to the exposure of blood to nonendothelial surfaces in the bypass circuit, which initiates a systemic inflammatory response, cardiac and pulmonary dysfunction, capillary leak, and generalized edema (1,2). Although multifactorial, post-CPB syndrome is largely due to activation of complement and the inflammatory cascade (4).

The particular type of bypass circuit design and the individual components selected can dramatically change the clinical outcome of a patient (1). Oxygenators in particular have undergone significant modifications with considerable improvement in performance. The use of one oxygenator versus another continues to be debated in many institutions and within the perfusion community. Terumo Cardiovascular Systems Corporation has recently released a new line of oxygenators, the Terumo Capiox® FX05 (Ann Arbor, MI) with integral arterial filter which is U.S. Food and Drug Administration approved for use. In contrast to the Terumo Capiox® RX05 Baby RX (Ann Arbor, MI), which utilizes a separate arterial filter, the FX incorporates an arterial filter inside the oxygenator, thus eliminating substantial priming volume (roughly 75–100 mL) as well as the surface area of both the tubing and a separate arterial filter. These changes have noticeably reduced the amount of surface area associated with foreign surface exposure, potentially reducing inflammation to the circulating blood (1).

Despite many advances, CPB for infants continues to have the potential to produce significant morbidity and mortality. With its pro-inflammatory effects, CPB adversely affects several organ systems. There continues to be significant gaps in our knowledge of how to decrease these effects. Continual investigation of modifications to the bypass circuit itself has the potential to decrease inflammation, improve organ function, and ultimately improve morbidity in this patient group. The purpose of this clinical trial was to evaluate the effect of the Terumo Capiox® FX05 oxygenator with integrated arterial filter during CPB compared to the Terumo Capiox® RX05 Baby RX and arterial filter on inflammatory mediators and blood product utilization.

MATERIALS AND METHODS

Patients

After receiving Institutional Review Board approval #4826 and obtaining informed parental consent, enrollment of patients began in June 2010 and ended in December 2010 at Children’s National Medical Center. The eligibility criteria included patients identified to have congenital heart disease requiring surgical repair on cardiopulmonary bypass and infants weighing less than 10 kg (Table 1). The exclusion criteria included significant left ventricular dysfunction (shortening fraction < 20%) or end organ insufficiency (as indicated by a blood urea nitrogen greater than 20, creatinine greater than 1, aspartate aminotransferase greater than 70, or alanine aminotransferase greater than 50), any known blood coagulation disorder, and any known ongoing infectious process that would affect inflammatory markers.

Table 1.

Preoperative characteristics.

	FX Group (n = 20)	RX Group (n = 20)	p value
Weight, kg	5.3 ± 1.7	5.5 ± 1.5	.68
BSA	.28 ± .07	.30 ± .07	.41
Diagnosis			.90
Septal defects	6	7
TOF	4	4
HLHS	3	3
DORV	3	3
D-TGA	3	1
Down syndrome	1	1
Williams	0	1

BSA, body surface area; TOF, tetralogy of fallot; HLHS, hypoplastic left heart syndrome; DORV, double outlet right ventricle; D-TGA, dextrotransposition of the great arteries.

Study Design

Participating infants were randomly assigned to either the Terumo Capiox® FX05 oxygenator or Terumo Capiox® Baby RX oxygenator and external Terumo Capiox® AF-02 filter (Ann Arbor, MI). Randomization was determined using simple random sampling with a 1:1 allocation ratio. Power analysis indicated that 20 patients randomly assigned to each oxygenator group would provide 80% power to detect moderate effect sizes (.80 or larger) between the groups with respect to median levels of each cytokine as well as postoperative outcomes using a Mann-Whitney U test (version 7.0, nQuery Advisor, Statistical Solutions, Saugus, MA). Due to obvious visual differences between the two oxygenators, the perfusionist operating the CPB could not be blinded to oxygenator selection. However, all other investigators, including anesthesiologist, surgeon, and other caregivers, were blinded to study group.

Methods

Anesthesia:

All patients had a standard anesthetic for this patient population. This included intravenous induction with Fentanyl 20 mcg/kg and Rocuronium .2 mg/kg. Maintenance of anesthesia included Fentanyl bolus doses as deemed necessary at the discretion of the anesthesiologist, with a goal of 50 mcg/kg of Fentanyl for the case.

CPB Technique:

The CPB circuit was set up using the same standard current institutional protocol employing the Century Heart Lung Machine (Salyer PRN Biomedical, St. Louis, MO). The only difference in circuit design was dependent on which oxygenator was used and in both setups the tubing was coated with SMART (Sorin Group, Arvada, CO) coating. There were no changes made to the circuit when using the current Terumo Capiox® Baby RX oxygenator and Terumo Capiox® AF-02 filter. When using the Terumo Capiox® FX05 oxygenator with integral filter, the oxygenator’s height was adjusted allowing for closer proximity to the arterial pump boot allowing for 5 inches of tubing to be cut from the outlet of the reservoir and 5 inches of tubing to be cut from the inlet to the oxygenator. Additionally, the external filter tubing set was eliminated, as there was no need for an arterial filter bypass loop. The table lines were connected directly to the oxygenator and the built-in pressure port was used for both the arterial line pressure and the CDI 500 manifold shunt line (Terumo, Ann Arbor, MI).

The circuit was CO₂ flushed, primed with Plasma-Lyte A (Baxter, Deerfield, IL) and de-aired using the same standard protocol as currently implemented. The addition of up to 1 unit of fresh frozen plasma (FFP) and 1 unit of red blood cells (RBC) was used for both circuit designs to obtain a hematocrit of 30% at initiation. The pump prime drugs added were the same for either system used, after as much of the Plasma-Lyte A priming fluid as possible had been removed into a waste bag or by the use of a hemoconcentrator (Hemocor HPH® 400, Minntech, Minneapolis, MN). The drugs consist of heparin 1200 units, ∼15 meq sodium bicarbonate, furosemide .25 mg/kg, mannitol .5 mg/kg, and if the patient was to be cooled to 15–20°C or was less than 1 week of age, methylprednisolone 10 mg/kg. After the pH and CO₂ had been normalized and the circuit blood prime had been warmed to 37 degrees, a blood gas sample was drawn along with a 1 mL sample for testing inflammatory mediators in the pump prior to initiation of CPB.

Once the patient was heparinized with 2 mg/kg and successfully cannulated, CPB was initiated with pH-stat strategy and 100% FiO₂. After initiation, the patient was cooled to the desired temperature. If the desired patient temperature was 25 degrees or less ice was placed around the patient’s head and .2 mg/Kg of phentolamine was given.

During the cooling phase of CPB, perfusion flow rates were maintained at a cardiac index of 2.4. Once the patient was at the desired temperature, the flow rate was to be maintained at a cardiac index of 1.6 or low flow rate stated by surgeon.

While maintaining a hematocrit of 30% on CPB, the use of the hemoconcentrator was used whenever extra volume was present. If additional volume was needed to maintain a stable reservoir level or maintain a hematocrit of 30%, volume replacement was either the FFP and/or RBC from the remaining volume of the units used to prime the circuit or additional units of RBCs.

Once the rewarming phase of the patient began, pump flow rates were increased to a cardiac index of 2.4 along with hemoconcentration of any additional volume that could be removed. If the patient was cooled to 25 degrees or less, an additional dose of phentolamine .2 mg/kg was given.

If the cross clamp was used, once removed, magnesium sulfate of 25 mg/kg was given to the patient. If the patient was fibrillated, once defibrillated, 25 mg/kg magnesium was given to the patient. After the patient’s temperature reached 30 degrees, the calcium level was corrected with calcium gluconate. After CPB, blood products, including red blood cells, platelets, and cryoprecipitate were administered as needed by the anesthesiologist to control bleeding and maintain a hematocrit of 30%as per standard of care.

Sample Collection:

Six samples were taken to measure inflammatory mediators: baseline (prior to skin incision), pump prime, 15 minutes after initiation of CPB, status post Protamine administration, prior to transport to intensive care unit (ICU), and 12–24 hours post surgery. Blood samples were drawn into sterile Vacutainer tubes and were immediately centrifuged for 15 minutes (4000 rpm) and stored at −80°C until assayed. Analysis was performed with the FlowCytomix Human Th1/Th2 11plex Kit (Bender MedSystems, Vienna, Austria) as defined in the manufacturer’s directions. The following markers were measured: cytokines interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p70, tumor necrosis factor (TNF)-α, and TNF-β. For each sample, a minimum of 50 uL was needed. This system was available for use at Children’s National Medical Center through the National Center for Medical Rehabilitation Research. The daily blood usage, chest tube drainage, and the time to extubation readiness were collected from the patient’s chart, along with discharge time in days postoperatively.

Statistical Analysis

Student’s t tests were used to compare mean values between FX and RX oxygenator groups for normally distributed data including body weight, body surface area, perfusion time, cross-clamp time, and blood products during perfusion and in the operating room (OR). Percentages of the various diagnoses were compared using the chi-squared test. Skewed data including the 11 cytokine variables at each of the time points, time to extubation and discharge, hours in ICU, chest tube drainage, and total perfusion requirements of the two groups were compared by the nonparametric Mann-Whitney U test and summarized using medians and interquartile ranges (25th to 75th percentiles) (5). Since cytokine variables were measured at different time points for each patient, a repeated measures analysis of variance was applied to assess 1) group differences at each time point and 2) changes from baseline in each inflammatory marker for the combined study population of 40 patients since no group differences were detected (6). The F-test was used to determine whether median levels for the set of cytokines at each time point were elevated or decreased compared to baseline with box-and-whisker plots used to describe the results (i.e., medians and interquartile ranges) with error bars denoting the 2.5% and 97.5% values. Two-tailed p < .05 were considered statistically significant. Analysis of the data was performed using the SPSS software package (version 18.0, SPSS Inc./IBM, Chicago, IL).

RESULTS

Perioperative characteristics in Table 1 showed no significant differences in body weight, body surface area, and diagnosis. Intraoperative conditions in Table 2 also showed no significant differences in total CPB time, total cross clamp time, RBCs during perfusion, or in the operating room. Postoperative outcomes in Table 3 also showed no significant differences in days until extubation, days in ICU, days until discharge, chest tube drainage, or total RBCs. Although not statistically significant, there was a fairly consistent trend with the use of the FX oxygenator, specifically with less transfusion totals (p < .07). There were no hospital deaths in either group.

Table 2.

Intraoperative conditions.

	FX Group (n = 20)	RX Group (n = 20)	p value
Total perfusion time	94 ± 39	83 ± 32	.30
Cross-clamp time	42 ± 30	32 ± 29	.26
During Perfusion
RBC	291 ± 90	347 ± 154	.17
FFP	277 ± 28	274 ± 54	.85
Operating Room
RBC	100 ± 116	115 ± 133	.69
Cryo	15 ± 12	22 ± 13	.07
Platelets	68 ± 46	84 ± 45	.28

Data are mean ± SD with times in minutes, otherwise mL. Groups were compared by the Student’s t test.

Table 3.

Postoperative outcomes.

	FX Group (n = 20)	RX Group (n = 20)	p value
Hours until extubate	21 (11–125)	23 (9–31)	.96
Hours in ICU	50 (44–245)	73 (33–151)	.72
Hours until discharge	167 (122–356)	130 (116–232)	.25
Chest tube output, mL	208 (140–306)	276 (200–309)	.39

Data are medians (interquartile range) with groups compared by the Mann-Whitney U test.

The inflammatory mediators showed no significant differences between oxygenators at any time points. However, looking at the inflammatory mediators of both the FX and RX groups combined, a statistically significant difference was seen in IL-6 at 12/24 hour post surgery (p < .001) versus baseline and all other time points. IL-8 at status post protamine (p < .001) and 12/24 hours post surgery (p < .001) demonstrated significant differences versus all other time points, and IL-10 at status post protamine (p < .001) and prior to leaving the OR (p < .001) were statistically different compared to all other time points (Table 4).

Table 4.

Changes in cytokines (n = 40).

Cytokine (pg/mL)	Baseline	Pump Prime	15 Minutes CPB	Status Post Protamine	Prior to Leave OR	12/24 Hour Post
IFN-γ	0 (0–5.2)	0 (0–1.5)	0 (0–3.5)	0 (0–2.3)	0 (0–3.8)	0 (0–.3)
IL-1β	.8 (0–6.0)	.6 (0–4.6)	1.5 (0–4.7)	1.7 (0–8.8)	5.2 (.1–11.5)	1.6 (0–9.1)
IL-2	7.6 (.2–25.5)	.7 (0–9.1)	2.7 (0–17.0)	2.0 (0–10.7)	6.9 (0–27.8)	4.1 (0–13.3)
IL-4	0 (0–6.5)	0 (0–1.1)	2.4 (0–13.6)	0 (0–1.5)	0 (0–9.6)	0 (0–5.0)
IL-5	6.4 (1.2–12.5)	1.8 (0–5.9)	6.7 (.2–14.0)	5.2 (0–10.3)	7.3 (.2–13.6)	7.7 (0–12.1)
IL-6	.1 (0–1.8)	.1 (0–1.3)	.5 (0–2.7)	2.6 (0–7.6)	25.9 (7.1–40.9)	131.8* (56.0–281.8)
IL-8	15.2 (5.8–31.6)	3.4 (0–14.2)	13.8 (7.6–26.4)	56.3* (30.8–124.4)	76.7* (48.0–176.6)	68.5* (47.8–120.7)
IL-10	3.2 (.5–10.3)	0.4 (0–4.6)	3.9 (0–10.1)	120.5* (31.0–195.3)	105.4* (31.1–183.2)	8.8 (.7–22.9)
IL-12	0 (0–0)	0 (0–0)	0 (0–0)	0 (0–0)	0 (0–0)	0 (0–0)
TNF-alpha	0 (0–7.8)	0 (0–7.6)	0 (0–8.1)	0 (0–9.6)	0 (0–8.6)	0 (0–7.6)
TNF-beta	0 (0–3.9)	0 (0–1.5)	0 (0–3.5)	0 (0–3.5)	0 (0–5.3)	0 (0–4.1)

Data are medians (interquartile range).

^*Statistically significant: IL-6: 12/24 hour post versus other time points; IL-8: status post protamine, prior to leave OR and 12/24 hour post versus other time points; IL-10: status post protamine and prior to leave OR versus other time points.

Figure 1 shows the difference in oxygenators graphically when analyzing median cytokine levels (FX Oxygenator - RX Oxygenator). The bar on the left represents a higher cytokine level for the RX oxygenator; if the bar is to the right that represents a higher cytokine level for the FX oxygenator. Although there were slight differences in cytokine levels (pg/mL), no statistical significance differences were noticed.

Figure 1.

Differences of median values between oxygenators (positive or negative) for each of the 11 cytokines at each time point.

DISCUSSION

Children’s Hospital in Omaha, NE compared the newly released Terumo Capiox® FX05 Oxygenator with the Terumo Capiox® Baby RX Oxygenator and demonstrated that the oxygenator performance of the Terumo Capiox® FX versus the RX were comparable in terms of gas exchange, pressure drop, and heat exchange coefficient. An additional benefit of the FX05 was the reduction of CPB prime volume and surface area due to the integrated arterial filter, allowing for a significant decrease in donor blood exposure in patients greater than 4 kg without compromising patient safety (7). In another study, Preston and colleagues demonstrated that the FX oxygenator simplified the arterial limb of the CPB circuit, thereby reducing the amount of tubing and prime volume, as well as the hemodilution effect that was seen (8). Gomez et al. confirmed these findings and postulated that this reduction in surface exposure and prime volume could decrease the inflammatory response and further blood product exposure (9).

In this prospective randomized clinical trial comparing two oxygenators during cardiopulmonary support in infants weighing less than 10 kg, there was no significant difference between oxygenators with respect to inflammatory mediators during bypass and 12/24 hours post operatively. Furthermore, post operative outcome measures, specifically hours to extubation, hours in the ICU, hours to discharge, and chest tube output, did not demonstrate a significant difference. While not statistically significant, it can be noted in Table 2, the use of the Terumo Capiox® FX oxygenator by perfusion allowed for less exposure to donor red blood cells. It has been well documented that transfusion of blood products has been linked to increased infection in critically ill patients and this donor exposure could promote significant changes in cell-mediated immunity (10–12).

CPB causes an inflammatory reaction through several different processes. Some known triggers include the surgical trauma itself, blood contact with the surfaces of the extracorporeal circuit, endotoxemia, and ischemia-reperfusion injury (4). The complement system is triggered to form proinflammatory cytokines such as TNF-α and interleukin-6. These cytokines depress myocardial contractile function through a negative inotropic effect that prevents calcium-induced calcium release from the sarcoplasmic reticulum (13). Specifically, TNF-a, has also been shown to increase systemic and pulmonary vascular permeability to increase lung water content and impair oxygenation (14). Its release with CPB also causes glomerular fibrin deposition and vasoconstriction to reduce glomerular filtration rate (15). Pulmonary dysfunction is also evident post-CPB. The inflammatory response, as well as mechanical factors, result in reduced compliance, reduced functional residual capacity, and an increased A-a gradient (16). Leukocytes cause capillary-alveolar membrane injury and microvascular dysfunction leading to increased pulmonary vascular resistance.

Studying neonates undergoing the arterial switch operation, Hovels-Gurich and colleagues demonstrated that patients with myocardial dysfunction postoperatively had elevated levels of IL-6 immediately after CPB and had significantly higher levels 4 hours after the operation compared to patients without cardiac dysfunction (17). Another study concluded that accelerated IL-6 expression correlated with worse postoperative mortality and could be used as a predictor of outcome (18). Following therapeutic interventions on bypass, IL-6 levels have correlated with outcome measures as well (19,20). While our study did not measure cardiac dysfunction or find a correlation with outcomes measures, IL-6 did increase significantly from baseline to 12/24 hour post operatively (F = 16.09, p < .001) as shown in Figure 1. Likewise, IL-8 increased significantly at the following time points: after protamine administration, prior to leaving the operating room, and at 12/24 hours post surgery (Figure 2).

Figure 2.

Changes in IL-6 (pg/mL) at each time point * = p value < .001.

Allan and colleagues found both IL-6 and IL-8 had a positive correlation with aortic cross-clamp time and circulatory arrest, and negatively correlated with the lowest temperature on bypass. They further stated that higher concentrations were associated with longer ICU stays (21). Although Figures 2 and 3 show an elevation in these cytokines, we did not find significance with regards to the outcomes measures we evaluated.

Figure 3.

Changes in IL-8 (pg/mL) at each time point, * = p value < .001.

Our results showed an elevation in the anti-inflammatory cytokine IL-10 after administration of protamine and before leaving the OR, although IL-10 returned near baseline after 12/24 hours post surgery (F = 12.96, p < .001). Seghaye and colleagues noticed a rise similar to Figure 4 and concluded that interleukin-10 may have a protective role by down-regulating cytokine release during and after cardiopulmonary bypass as they found correlation with the degree of hypothermia (22,23).

Figure 4.

Changes in IL-10 (pg/mL) at each time point, * = p value < .001.

CONCLUSION

Cardiopulmonary bypass stimulates the systemic inflammatory response through various components of the extracorporeal system. This investigation did not find significant differences in cytokines when comparing these two oxygenators. Looking specifically at the cytokines across both patient groups, IL-6, IL-8, and IL-10 demonstrated significant increases from baseline levels, although no correlation with regards to the outcomes measures measured in our study could be found. It is well known that various mechanisms contribute to the levels of cytokines circulating in a patient’s blood volume and many manipulations throughout cardiac surgery have the ability to demonstrate anti-inflammatory interventions. These interventions include, but are not limited to, length of time on bypass, aortic cross-clamp, circuit coatings, hemoconcentration, and steroids (23,24). These interventions may have placed a role in the minimal cytokine differences seen during this study, as Table 5 represents. One limitation of the study was individual variability between perfusion staff regarding blood component transfusion both on CPB and post-CPB as well as anesthesia and ICU staff postoperatively which could have affected our results. However, the patients were randomized between groups appropriately with respect to the perfusionist and anesthesiologist, which should not overly impact one study population relative to the other. Further investigation is needed as to how modification of the extracorporeal circuit may minimize increases in inflammatory mediators.

Table 5.

Changes in cytokines from baseline for each oxygenator group (FX, RX).

Cytokine	Pump Prime	15 minutes CPB	Status Post Protamine	Prior to Leave OR	12/24 Hour Post
IFN-γ	0, −2	0, −2	0, −2	0, −2	0, −2
IL-1β	0, −2	0, 0	1, 0	5, 3	1, 0
IL-2	−8, −2	−7, −1	−8, 1	−8, 9	−6, 2
IL-4	0, 0	2, 3	0, 0	0, 2	0, 0
IL-5	−2, −7	−1, 1	−1, −3	2, 0	1, 1
IL-6	0, 0	1, 0	3, 1	30, 14	113, 158
IL-8	−8, −15	1, −3	49, 35	60, 62	53, 57
IL-10	−2, −3	2, 0	139, 85	102, 104	6, 5
IL-12	0, 0	0, 0	0, 0	0, 0	0, 0
TNF-alpha	0, 0	1, 0	−1, 0	1, 1	0, 0
TNF-beta	0, 0	0, 0	0, 0	0, 0	0, 0

Values represent changes in median levels (pg/mL).