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Ann Thorac Surg 2003;76:136-140
© 2003 The Society of Thoracic Surgeons


Original article: cardiovascular

Continuous ultrafiltration attenuates the pulmonary injury that follows open heart surgery with cardiopulmonary bypass

Huimin Huang, MDa*, Tingjun Yao, MDa, Wei Wang, MDa, Deming Zhu, MDa, Wei Zhang, MDa, Hong Chen, MDa, Weiding Fu, MDa

a Department of Cardiothoracic Surgery, Shanghai Children’s Medical Center, Xinhua Hospital, Shanghai Second Medical University, Shanghai, China

Accepted for publication February 4, 2003.

* Address reprint requests to Dr Huang, Department of Cardiothoracic Surgery, Children’s Medical Center, Xinhua Hospital, Shanghai Second Medical University, 1678, Dongfang Rd, Shanghai 200127, China.
e-mail: wenfeik{at}online.sh.cn


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Pulmonary injury after cardiac surgery is one of the complications of cardiopulmonary bypass. We evaluated the ultrafiltration technique in preventing and relieving the pulmonary injury that can follow open heart surgery with cardiopulmonary bypass (CPB).

METHODS: Thirty patients with congenital heart defects were divided into two groups. In the control group conventional cardiopulmonary bypass was used without ultrafiltration. In the treated group, in addition to the same cardiopulmonary bypass procedure, balanced ultrafiltration plus modified ultrafiltration was used throughout cardiopulmonary bypass. Pulmonary function, hematocrit, serum albumin, and some inflammatory mediators were measured.

RESULTS: Compared with measurements before anesthesia the pulmonary static compliance at 15 minutes and 6 hours post bypass had decreased by 27.8% and 34.0% in the control group versus 12.6% and 15.4% in the treated group, the airway resistance had increased by 38.0% and 45.2% in the control group versus 9.5% and 4.7% in the treated group, and the alveolar-arterial oxygen difference increased by 73.4% and 62.0% in the control group versus 52.1% and 35.9% in the treated group. Hemodilution from cardiopulmonary bypass caused the hematocrit and serum albumin to decrease by 35.8% and 32.8% in the control group versus 36.1% and 34.5% in the treated group at the termination of CPB. After 10 to 15 minutes modified ultrafiltration the hematocrit and serum albumin increased by 40.0% and 47.6%. At the termination of CPB the serum concentrations of interleukin-6, thromboxane B2, and endothelin-1 were increased by 160%, 265%, and 890% in the control group versus 103%, 208%, and 838% in the treated group compared with those before anesthesia.

CONCLUSIONS: The combined use of balanced ultrafiltration and modified ultrafiltration can effectively concentrate the blood, modify the increase of some harmful inflammatory mediators, attenuate the lung edema and inflammatory pulmonary injury, and mitigate the impairment of pulmonary function.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Pulmonary injury after cardiac surgery is one of the complications of cardiopulmonary bypass with a high incidence among infants and younger patients with severe pulmonary hypertension. The severity of pulmonary injury is determined by several factors and various methods have been proposed for prevention.

We report the effect of continuous ultrafiltration in moderating pulmonary injury during cardiopulmonary bypass.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Patients
The study protocol had been approved in advance by the ethics committee of the hospital. Thirty cases undergoing cardiopulmonary bypass were selected for the trial. Informed consent was obtained from the children’s parents. Congenital heart disease was diagnosed in all the patients. They were randomized into two groups: 15 patients served as control and the other 15 were assigned to continuous ultrafiltration treatment. Thirteen patients in each group had ventricular septal defects with moderate to severe pulmonary hypertension and 2 patients in each group had tetralogy of Fallot. The degree of pulmonary hypertension in the two groups was comparable. The mean age of the control group was 2.10 ± 1.10 years and the mean age of the treated group was 2.08 ± 1.13 years; the mean weight was 11.1 ± 1.9 kg for the control group and 10.1 ± 2.0 kg for the treated group. No statistical difference existed between the groups for either age or body weight.

Cardiopulmonary bypass
A membrane oxygenator (Minimax plus; Medtronic, Minneapolis, MN) and a roller pump (Sarns 8000; Sarns, 3M Health Care, Ann Arbor, MI) were used in the extracorporeal circuit for both groups, and a blood hemoconcentrator (Hemocor HPH 400; Minntech, Minneapolis, MN) was placed with the inlet connected to the arterial line and outlet to the venous line for the treated group. Perfusion flow was maintained at 100 to 120 mL/kg. Cold crystalloid cardioplegic solution was used for myocardial preservation. Systemic hypothermia (25°C to 28°C) was maintained during aortic crossclamping. After discontinuation of CPB in the control group or after modified ultrafiltration in the treated group, heparin was neutralized with protamine sulfate. Cardiopulmonary bypass lasted 45.3 ± 10.5 minutes in the control group and 48.7 ± 11.5 minutes in the treated group; aortic crossclamping duration was 34.3 minutes in the control group and 37.2 minutes in the treated group. No significant differences were found between the two groups for either bypass duration or crossclamping duration.

Continuous ultrafiltration was used in the treated group. At the beginning of CPB the hemoconcentrator was kept isolated by clamping the inlet line. After 3 to 5 minutes of bypass to reach perfusion stability the clamp was released and conventional ultrafiltration was begun. The blood flowed from the arterial line through the hemoconcentrator and the venous line into the venous reservoir. The flow rate of 5 to 10 mL · kg-1 · min-1 was controlled by an additional roller pump throughout the CPB. After weaning from bypass, ultrafiltration was switched to the modified method. The inlet of the venous reservoir was clamped and blood flowed from the aorta through the arterial line, the hemoconcentrator, and the venous line into the right atrium. The flow rate was kept at 15 to 20 mL · kg-1 · min-1 by the roller pump. During the modified ultrafiltration period blood from the venous reservoir was transfused to compensate for the lost water, keeping the arterial blood pressure above 60 mm Hg. The venous reservoir was kept primed by adding the crystalloid solution. The time of modified ultrafiltration was 10 to 15 minutes.

Blood samples and measurements
Blood samples were taken before induction of anesthesia (T1), before CPB (T2), 5 minutes after the start of CPB (T3), at the termination of CPB (T4), 15 minutes after CPB (just after the termination of modified ultrafiltration in the treated group, T5), and 6 hours after operation (T6). Interleukin-6 (IL-6), endothelin-1 (ET-1), thromboxane B2 (TXB2), hematocrit, serum albumin, and blood gases were measured.

Pulmonary variables
At the same times that blood was sampled (except for the T3 sample) pulmonary variables including peak pressure (Ppeak), pause pressure (Ppause), tidal volume (TV), respiratory frequency (F), and inspired oxygen fraction (Fio2) were recorded. Based on these and the blood gas analysis, pulmonary static compliance (Cstat), airway resistance (Raw), and alveolar-arterial oxygen difference (A-a DO2) were calculated.

Statistical analysis
Statistical analysis was performed with Student’s t test in all matched groups. All the results were expressed as mean ± standard error. A p value of less than 0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Effects of continuous ultrafiltration on pulmonary function
CSTAT
Before bypass no significant difference in pulmonary static compliance existed between the two groups. Fifteen minutes and 6 hours after bypass the pulmonary static compliance decreased by 27.8% and 34.0% in the control group versus 12.6% and 15.4% in the treated group. The differences are statistically significant (Table 1).


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Table 1. Effect of Continuous Ultrafiltration on Pulmonary Function

 
Raw
Before bypass the airway resistance for the two groups was almost the same. Fifteen minutes and 6 hours after bypass the airway resistance increased by 38.0% and 45.2% in the control group versus 9.5% and 4.7% in the treated group. The differences are statistically significant (Table 1).

A-aDO2
Before bypass no significant difference in A-a DO2 existed between the two groups. Fifteen minutes and 6 hours after bypass the A-aDO2 increased by 73.4% and 62.0% in the control group versus 52.1% and 35.9% in the treated group. The differences are statistically significant (Table 1).

Effects of continuous ultrafiltration on blood concentration
Hemodilution used in cardiopulmonary bypass caused the hematocrit and serum albumin to decrease by 35.8% and 32.8% in the control group and 36.1% and 34.5% in the treated group by the termination of CPB. After 10 to 15 minutes modified ultrafiltration the hematocrit and serum albumin increased by 40.0% and 47.6%, significantly higher than that of the control group (Table 2).


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Table 2. Effect of Continuous Ultrafiltration on Blood Concentration

 
Effects of continuous ultrafiltration on removal of harmful medium-size solutes
IL-6
The serum concentrations of IL-6 increased after anesthesia and during bypass in both groups but not to the same degree. At the termination of CPB the IL-6 concentration increased by 160% in the control group and 103% in the treated group compared with those before anesthesia. The difference was statistically significant. Similarly after bypass the concentration of IL-6 declined in both groups but the decrease in the treated group was greater than that of control group (Table 3). Moreover the concentrations of IL-6 in ultrafiltrates were almost the same as those in the serum taken at the same points (data not shown).


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Table 3. Effect of Continuous Ultrafiltration on Removal of Medium-Size Solutes

 
TXB2
Like IL-6 the serum concentrations of TXB2 increased after anesthesia and during bypass in both groups but the degree of the increment were also statistically different. At the termination of CPB the TXB2 concentration increased by 265% in the control group and 208% in the treated group compared with those before anesthesia. After bypass the concentration of TXB2 concentration declined in both groups at similar rates (Table 3). In the filtrates some TXB2 could be measured but unlike IL-6 the concentrate was much less than that in the serum selected at the same points (data not shown).

ET-1
The serum concentrations of ET-1 increased significantly after anesthesia and during CPB. No significant difference could be found between groups at any of the sample selection times (Table 3). In the filtrates the ET-1 could hardly be measured.

Clinical results
All the patients survived. The duration of postoperative mechanical ventilation was 9.3 hours in the control group and 8.7 hours in the treated group (p > 0.05). But the intensive care unit stay was 59.9 ± 18.6 hours in the control group versus 47.6 ± 13.2 hours in the treated group; the difference is statistically significant (p < 0.05).


    Comment
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
After CPB various degrees of pulmonary dysfunction occur that are manifested by lower pulmonary compliance, higher pulmonary resistance, and poor alveolar gas exchange. Sometimes severe acute pulmonary dysfunction will lead to death [1, 4]. Several factors may contribute to such pulmonary problems. Hemodilution makes serum albumin concentration and colloid osmotic pressure drop and the effective capillary filtration pressure to increase. That leads to the accumulation of the plasma water in the interstitial space, which will decrease pulmonary compliance and impair air exchange across the respiratory membrane. Additionally when the aorta and vena cava are cross-clamped, the lung is ischemic and metabolic products will accumulate in the interstitial fluid of the lung. After the cross-clamp is released the oxygenated blood will perfuse the lung again and produce oxygen free radicals, which lead to ischemic reperfusion damage of the lung. Furthermore the hypothermia, the contact of blood with the bypass circuit, and the hemodynamic changes will all promote the production and release of inflammatory mediators. That in turn causes a systemic inflammatory response that can cause further pulmonary damage [13].

Since the 1970s conventional ultrafiltration has been suggested as a means of reducing the fluid accumulation but it has not proved satisfactory in pediatric practice because of a relatively lower volume in the venous reservoir. A modified method was reported by Naik in 1991 [10]. The apparent advantages of modified ultrafiltration are that it is less limited by the level of fluid in the venous reservoir and more suitable for younger pediatric patients. Recently it has been found that, in addition to the effect of blood concentration, the ultrafiltration will remove some harmful medium-size inflammatory mediators and relieve the inflammatory response. Hence balanced ultrafiltration has been reported. By this method ultrafiltration is kept throughout CPB and harmful medium-size solutes are removed constantly. The crystalloid solution is added to maintain a safe volume level in the reservoir [59]. Evidently relieving fluid accumulation in the interstitial space of the lung and decreasing the systemic inflammatory response are valuable for the preservation of postoperative pulmonary function.

The effects of blood concentration and inflammatory mediator removal led us to consider the combined use of balanced ultrafiltration and modified ultrafiltration during pediatric cardiopulmonary bypass. We term it continuous ultrafiltration. By this method the ultrafiltration proceeded throughout almost all the CPB period, mainly removing the harmful inflammatory mediators produced during CPB. After weaning from CPB the patient was switched from balanced to modified ultrafiltration to further remove the harmful inflammatory mediators and also concentrate the blood.

The results of our research have demonstrated the preserving effect of continuous ultrafiltration on pulmonary function. First, pulmonary ventilation function was improved as shown by the increased pulmonary compliance and decreased airway resistance compared with those in the control group. Second, pulmonary air exchange was also improved after CPB as demonstrated by decreased A-aDO2 compared with that of the control group.

The preserving effects of continuous ultrafiltration on postoperative pulmonary function were attributed to its effects on concentration of blood and removal of inflammatory mediators. In this report hematocrit and serum albumin concentration in the treated group were 25.5% and 44.1% higher than those of control group after 10 to 15 minutes modified ultrafiltration, almost back to preoperative levels. Having a higher hematocrit and serum albumin maintained the oxygen supply and prevented interstitial edema of the lung. To determine the ability of ultrafiltration to remove harmful medium-size solutes produced in CPB we selectively measured IL-6, TXB2, and ET-1 at various points. Interleukin-6 is an important inflammatory factor and is closely associated with the systemic inflammatory response. Ultrafiltration clearly affected IL-6. After bypass the serum IL-6 concentration was much lower than that in control group and concentration in blood and filtrates were similar, showing that IL-6 can move through the hemoconcentrator membrane freely. During bypass platelets were activated and secreted TXA2, which has been proved harmful to lung function by increasing pulmonary blood vessel permeability. Because TXA2 is unstable in circulating blood we measured its metabolic product, TXB2. The TXB2 in the ultrafiltrate was much less than that in serum, showing that the removal rate of ultrafiltration was restricted. Of interest we also found that the serum TXB2 concentration in the treated group was much lower than that in the control group after bypass. That may be the result of less platelet activation and secretion owing to the removal of other inflammatory mediators. Endothelin-1 is another important factor and it increased significantly during CPB. It too may impair pulmonary function. Our results show that continuous ultrafiltration did not affect the ET-1 increase and concluded that ultrafiltration may not prevent pulmonary injury caused by ET-1.

In conclusion the combined use of balanced ultrafiltration and modified ultrafiltration can effectively concentrate the hemodiluted blood and remove some harmful inflammatory mediators. That in turn can reduce pulmonary edema and inflammatory pulmonary injury. The technique should beconsidered for pulmonary protection during CPB.


    Acknowledgments
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
This investigation was supported by grants from the Chinese National Natural Science Foundation.


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Butle J., Rocker G.M., Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-559.[Abstract]
  2. Hall R.I., Smith M.S., Rocker G., et al. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic and pharmacological considerations. Anesth Analg 1997;85:766-782.[Medline]
  3. Richter J.A., Meisner H., Tassani P., et al. Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 2000;69:77-83.[Abstract/Free Full Text]
  4. Maehara T., Novak I., Wyse R.K.H., et al. Perioperative monitoring of total body water by bioelectrical impedance in children undergoing open heart surgery. Eur J Cardiothorac Surg 1991;5:258-265.[Abstract]
  5. Jeffrey M.P., Peter B.M., Jerri L.M., et al. Effect of modified ultrafiltration on plasma thromboxane B2, leukotriene B4, and endothelin-1 in infants undergoing cardiopulmonary bypass. Ann Thorac Surg 1999;68:1369-1375.[Abstract/Free Full Text]
  6. Elliott M.J. Ultrafiltration and modified ultrafiltration in pediatric open heart surgery. Ann Thorac Surg 1993;56:1518-1522.[Abstract]
  7. Wang M.J., Chiu Hsu C.M., Wang C.M., et al. Efficacy of ultrafiltration in removing inflammatory mediators during pediatric cardiac operations. Ann Thorac Surg 1996;61:651-656.[Abstract/Free Full Text]
  8. Journpis D., Israel-Biet D., Pouard P., et al. High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965-976.[Medline]
  9. Nagashima M., Toshiharu S., Georg N. High-volume continuous hemofiltration during cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after deep hypothermic circulatory arrest. Circulation 1998;98:378-384.[Free Full Text]
  10. Naik S.K., Knight A., Elliott M.J. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion 1991;6:41-50.[Abstract/Free Full Text]



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