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J Thorac Cardiovasc Surg 2000;119:501-505
© 2000 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

PULMONARY FUNCTION AFTER MODIFIED VENOVENOUS ULTRAFILTRATION IN INFANTS: A PROSPECTIVE, RANDOMIZED TRIAL

From the Department of Pediatrics, Division of Critical Care, University of North Carolina, Chapel Hill, NC^a; Department of Pediatrics, the Children’s Hospital, Boston, Mass^b; Department of Cardiothoracic Surgery, Wilford Hall Medical Center, Lackland Air Force Base, Tex^c; and Department of Anesthesia,^d and Department of Surgery,^e Children’s Hospital and Regional Medical Center, University of Washington School of Medicine, Seattle, Wash.

Address for reprints: Heather Keenan, MDCM, MPH, Department of Pediatrics, CB 7220, 7701 A 7th Floor, UNC Children’s Hospital, The University of North Carolina, Chapel Hill, NC 27599-7200 (E-mail: hkeenan{at}med.unc.edu ).

	Abstract

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Objective: We sought to examine the effects of modified venovenous ultrafiltration after cardiopulmonary bypass on pulmonary compliance in infants.
Methods: We prospectively enrolled 38 infants undergoing their first operation for congenital heart disease. Infants were randomized to receive 20 minutes of modified ultrafiltration after bypass or control. Static and dynamic compliance was measured after induction of anesthesia, before and immediately after filtration in the operating theater, 1 hour after return to the pediatric intensive care unit, and 24 hours after the operation. Length of time on the ventilator, inotropic requirements, and length of stay in the intensive care unit were recorded.
Results: Modified ultrafiltration produced a significant immediate improvement in dynamic (pre-ultrafiltration 2.5 ± 1.9 mL/cm H₂O to post-ultrafiltration 2.9 ± 2.7 mL/cm H₂O, P = .03) and static (pre-ultrafiltration 2.1 ± 0.9 mL/cm H₂O to post-ultrafiltration 2.9 ± 2.1 mL/cm H₂O, P = .04) compliance. However, there was no significant difference in the change in dynamic (P = .3) or static (P = .7) compliance in the ultrafiltration and control groups when compared before the operation, after the operation, and at 24 hours. There was no significant difference in the time to extubation between patients and control subjects (140 ± 91 hours vs 90 ± 58 hours) or the length of intensive care unit stay (10.0 ± 9.1 days vs 7.4 ± 5.7 days).
Conclusions: Modified ultrafiltration produces an improvement in pulmonary compliance after bypass in infants. However, these improvements are not sustained past the immediate post-ultrafiltration period and do not lead to a decreased length of intubation or intensive care unit stay.

	Introduction

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Cardiopulmonary bypass (CPB) is associated with an inflammatory response that results in tissue edema and organ dysfunction primarily involving the heart, lungs, kidneys, and brain. ¹ Chemical mediators, including cytokines, have been implicated in this proinflammatory state. Recently, modified ultrafiltration (MUF) has been used as a method to reduce circulating cytokines after CPB and decrease their undesirable side effects. ²

MUF is a process that removes water and low-molecular-weight substances under a hydrostatic pressure gradient. ³ It is carried out after weaning from CPB but before administration of protamine. ⁴ MUF has been shown to induce hemoconcentration, reduce bleeding, and decrease total body water in the pediatric patient. ⁵ The CPB-induced inflammatory state is thought to be greater in pediatric patients. ⁶ Infants are at special risk of an accentuated inflammatory response because of their size, hemodilution, prolonged bypass times, and complex operations requiring extreme degrees of hypothermia. ⁷

Clinically, pulmonary dysfunction may be the most common manifestation of the post-CPB inflammatory response. ⁸ This may adversely affect cardiopulmonary interactions after surgery, delaying extubation and discharge from the intensive care unit. Several investigators have shown that ultrafiltration produces immediate improvement in pulmonary function in children ⁹ and may lead to a shorter ventilatory course and possibly a shorter pediatric intensive care unit (PICU) stay. ^5,10 However, these studies have primarily concentrated on short-term outcomes or have included a broad range of patient ages and weights. This has made it difficult to assess the clinical effect of ultrafiltration on the high-risk infant population.

The purpose of this prospective, randomized controlled study was to compare postoperative pulmonary compliance in infants undergoing MUF after CPB to control post-CPB infants who did not undergo MUF. Patients were followed up to determine whether any improvement in pulmonary compliance persisted beyond the immediate postoperative period and whether this resulted in earlier extubation or discharge from the PICU.

	Methods

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This study was approved by the Institutional Review Board of Children’s Hospital and Medical Center (Seattle, Wash). A power analysis indicated that 15 patients would be needed in each group to show a 20% difference in pulmonary compliance by using a 2-sided significance level of 5% ( = .05) with power set at 80% (ß = .8). Patients less than 1 year of age who required CPB for a primary operation for congenital heart disease were eligible for the study. Infants with a pre-existing coagulation disorder, evidence of sepsis, or pre-existing pulmonary disease were excluded from the study. There were 157 patients less than 1 year of age who had open cardiac operations during the study period. Of this group, 43 families had consent requested, and 3 families refused consent. There were 31 patients ineligible for the study because of previous cardiac surgery; 23 patients were not eligible because of sepsis, coagulation disorders, or pre-existing lung disease. Seven patients did not have consent requested because the surgical case was very small (atrial septectomy). The remaining 53 patients were operated on as emergencies, second cases, or on the weekend; thus the laboratory was unable to accommodate cytokine specimens for the other arm of the study (not reported here). After written parental consent was obtained, infants were randomly assigned at the time of surgery to the MUF or control group. Randomization was performed by sealed envelopes prepared from a table of random numbers. Patients assigned to the MUF group underwent 20 minutes of filtration after separation from CPB. Venovenous ultrafiltration was performed as previously reported. ¹¹ Briefly, blood was drawn from the venous cannula in the inferior vena cava and returned after filtering into the superior vena cava. The ultrafilter used (Minntech HPH 400; Minntech Corporation, Minneapolis, Minn) filters particles of 65,000 d and less. Inotropic support, if any was provided, was adjusted before institution of the filtration. No adjustments of inotropic agents occurred while filtering. If transfusion was required during MUF, blood was transfused through the aortic cannula still in place. Then protamine was given to reverse heparin anticoagulation. Patients in the control group were separated from CPB, but heparin was not reversed for 20 minutes. Caregivers in the PICU were blinded to the patient’s filtration status.

All children were intubated with a cuffed endotracheal tube by the anesthesiologist, unless the child had an uncuffed endotracheal tube in place with no air leak around it. After induction of anesthesia but before surgical incision, baseline static and dynamic pulmonary compliance measurements were obtained for each child (baseline measurement). Repeat measures of compliance were obtained within the first hour after admission to the PICU (admission measurement) and then again at 24 hours after admission to the PICU (24-hour measurement). Children who underwent MUF had additional measurements of both static and dynamic compliance performed in the operating room after CPB immediately before and at completion of MUF.

Static and dynamic pulmonary compliance was measured by using a Ventrak model 1550 pediatric/neonatal pulmonary function machine (Novametrix Medical Systems, Inc, Wallingford, Conn) with the neonatal adapter. Measurements were performed during hand ventilation, with care taken to deliver the same tidal volume for each breath. Static compliance was calculated from the averaged measured plateau pressures and volumes of 3 breaths with good plateau wave forms. Dynamic compliance calculations were taken from the Ventrak machine during hand ventilation.

Additionally, demographic data, length of CPB, use of deep hypothermic circulatory arrest, complications, use of inotropic drugs, use of peritoneal dialysis catheters for alleviation of abdominal compression caused by edema (placed at the surgeon’s discretion), baseline and highest subsequent creatinine levels, change in weight at 24 hours, duration of intubation, and days in the PICU were recorded.

Statistical analysis was performed with the SPSS statistical package (SPSS Inc, Chicago, Ill). Comparisons between groups were made by using the Student t test. The Levene test for equality of variance was used to ensure equal variances between groups. Groups with unequal variances were compared by using the t test for groups with unequal variance. Comparisons within groups were made by using the t test for paired data and the repeated measures analysis of variance for comparisons of more than 2 groups. Nonparametric data were compared by using the Mann-Whitney test.

	Results

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Thirty-eight patients were enrolled in the study. In 4 patients (2 undergoing MUF and 2 control subjects) pulmonary compliance measurements were not obtained. Preoperative diagnoses are presented in Table I. The 2 groups were not appreciably different in age, weight, preoperative hematocrit levels, CPB time, duration of deep hypothermic circulatory arrest, or preoperative static or dynamic compliance (Table II). The MUF group showed a significant increase from post-CPB/pre-MUF to post-MUF hematocrit levels (21.7% ± 3.4% vs 31.6% ± 4.8%, P = .006). The mean amount of fluid filtered was 497 mL ± 155 mL (143 mL/kg ± 64 mL/kg). The control group also showed a small but significant rise in hematocrit value from post-CPB levels after transfusion from the CPB circuit (23.6% ± 4.2% vs 25.7% ± 5.0%, P = .01).

	Discussion

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The principal finding of this study is that MUF after CPB in infants did result in immediate improvements in both static and dynamic pulmonary compliance, but the effect was not sustained after admission to the PICU or 24 hours after the operation. Our findings concur with those reported by Meliones and colleagues, ⁹ who reported on a series of 11 patients in whom MUF after bypass contributed to an immediate improvement in dynamic pulmonary compliance compared with that found in control subjects. However, the study by Meliones and colleagues did not monitor patients beyond the immediate postoperative period, and thus it was not possible to know whether the improvement was sustained. MUF has been reported to contribute to a shorter duration of mechanical ventilation in children, suggesting a more sustained improvement. Naik and colleagues ⁵ found a respiratory benefit to MUF for a subgroup of patients, those who underwent low-flow, low-temperature CPB. This subgroup had a shorter ventilator course if they received MUF (mean, 2 days; range, 1-8 days) versus that of control patients (mean, 7 days; range, 4-14 days, P < .01). Unfortunately, in spite of randomization, the control patients were significantly smaller than the patients in the MUF group (4.2 vs 6.7 kg, P = .02) and overall had more complex operations, making it hard to separate these factors from the effects of MUF.

In our study no sustained pulmonary benefits of MUF could be demonstrated after the first hour or at 24 hours after the operation in the PICU. Also, both groups of children had similar needs for inotropic support and no significant difference in weight change between the preoperative period and postoperative day 1, suggesting ongoing capillary leak. These results are similar to those of Naik and colleagues, ⁵ who found improved hemodynamics immediately after MUF but did not find differences in 24-hour inotropic requirements or urine output.

Why are these improvements not sustained? A possible reason is that pulmonary compliance is affected both by excess fluid from the hemodilutional effect of bypass, as well as by the systemic inflammatory response. Ultrafiltration after bypass decreases total body water and removes inflammatory cytokines. However, the initiation of the systemic inflammatory response most likely occurs during rewarming. ¹² Therefore MUF starts after the inflammatory cascade has been activated. Thus it may be that the salutary effects of hemoconcentration and removal of water after bypass by MUF are unable to overcome the ongoing effects of capillary leak possibly caused by an activated ongoing inflammatory response.

It is also possible that no long-term positive effect of MUF was seen because of the technique of venovenous MUF, as opposed to arteriovenous MUF. The volume of ultrafiltrate removed in this study is similar to that reported in studies of arteriovenous MUF, as is the rise in hematocrit level, ¹³ and venovenous MUF has been shown to remove cytokines. However, because there have not been any direct studies done that compare the 2 techniques, one cannot rule out that these results are not obtained on the basis of type of ultrafiltration. Another limit of this study is that our intermediate outcome (pre-MUF to post-MUF compliance) was not adequately controlled. However, another study, which did examine both MUF and control groups immediately after CPB, found that MUF did improve compliance, whereas no favorable changes were observed in compliance in the control group. ⁹

The 2 clinical, randomized controlled trials in which there was significant pulmonary improvement after MUF did not use MUF alone. Journois and colleagues ¹⁴ compared an intervention group who underwent high-volume, zero-balance hemofiltration during rewarming plus post-CPB MUF to a control group who received post-CPB MUF alone. In this study the intervention group had a significantly shorter time to meet extubation criteria (11 vs 28 hours, P = .02). Bando and colleagues ¹⁵ studied 100 patients, including neonates and children. They compared dilutional ultrafiltration during CPB followed by MUF after CPB to a control group who underwent only conventional ultrafiltration during CPB. They found a significant decrease in duration of ventilatory support in the intervention group. When the subgroup of neonates was examined, the difference in need for ventilatory support was accentuated, with the intervention group requiring a markedly shorter duration of support (59.3 vs 242.1 hours, P < .001). Because neither of these 2 studies examined MUF alone but rather studied a combination of filtration during CPB and MUF, it is hard to attribute the ventilatory outcomes to MUF. Possibly the technique of dilutional filtration followed by MUF will prove to be the most optimal technique for shortening the need for ventilatory support in infants after CPB.

In conclusion, MUF has been shown to be a useful technique for the removal of excess fluids in infants after CPB. However, in this study MUF led only to short-term improvements in pulmonary compliance, which were not sustained and did not permit earlier extubation or discharge from the PICU.

	Footnotes

 
This work was done at Children’s Hospital and Regional Medical Center, University of Washington School of Medicine, Seattle, Wash.

	References

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