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Ann Thorac Surg 1996;62:1284-1288
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Low-Flow Cardiopulmonary Bypass Produces Greater Pulmonary Dysfunction Than Circulatory Arrest

Departments of Surgery and Pediatric Critical Care Medicine, Duke University Medical Center, Durham, North Carolina

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Deep hypothermic circulatory arrest (DHCA) is used during the repair of congenital heart disease in neonates. However, because of concern about neurologic injury after DHCA, there is increasing use of continuous deep hypothermic low-flow cardiopulmonary bypass (DHCPB). This study examines the effects of DHCPB versus DHCA on pulmonary dynamics in 1-week-old piglets (weight range, 2.5 to 3.5 kg).

Methods. Animals were placed on CPB (37°C) at 100 mL•kg^-1•min^-1, cooled to 18°C, and then assigned to one of two groups: DHCPB (n = 7), 25 to 50 mL•kg^-1•min^-1 DHCPB for 90 minutes; or DHCA (n = 8), DHCA for 90 minutes. Animals were rewarmed to 37°C, weaned from CPB, and observed for 30 minutes. Static pulmonary compliance and pulmonary vascular resistance index were assessed before CPB, 5 minutes after CPB, and 30 minutes after CPB.

Results. There was greater impairment of static pulmonary compliance after DHCPB compared with 90 minutes of DHCA. There was a trend toward higher pulmonary vascular resistance index in the DHCPB group; however, significance was not reached.

Conclusions. Deep hypothermic low flow cardiopulmonary bypass produces greater pulmonary dysfunction than DHCA, manifested by decreased static pulmonary compliance. If DHCPB is used in place of DHCA in congenital heart operations, close attention to ventilatory and fluid management is mandatory in the postoperative period to prevent further worsening of pulmonary dysfunction.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Deep hypothermic circulatory arrest (DHCA) and deep hypothermic continuous low-flow cardiopulmonary bypass (DHCPB) are often used for the repair of complex congenital heart defects in neonates. Traditionally, DHCA has been used for this purpose. Because of concerns about central nervous system dysfunction after the use of DHCA [1], however, DHCPB is being used increasingly. The use of DHCPB, however, may have injurious effects on other organs, including the pulmonary system.

Young age at operation (<2 years) and longer duration of cardiopulmonary bypass (CPB) are known risk factors for pulmonary dysfunction after cardiac operations [2]. Total body water is increased after CPB and may result in tissue edema and organ dysfunction. The increase in total body water is greatest in patients with low weight and younger age who undergo long periods of DHCPB [1, 3]. Postnatal changes in the shape, structure, and biochemical composition of the pulmonary endothelium are associated with an increase in permeability and susceptibility of the neonatal lung to the damaging effects of CPB [4]. Recent investigations have demonstrated increased neutrophil-endothelium interactions [5], alterations of endothelium-dependent pulmonary microvascular reactivity [6], increased pulmonary vascular resistance and lung water [7], and failure of endothelium-dependent pulmonary vasodilation [8] with the use of total CPB. Pulmonary function after DHCPB may be impaired from the prolonged exposure to the bypass circuit and the increased fluid accumulation inherent in the use of this technique. Postoperative pulmonary dysfunction may lead to increases in the duration of mechanical ventilation, intensive care unit time, hospital stay, and cost.

The few studies performed in neonates and infants that examined the effects of CPB on pulmonary function are difficult to interpret because of heterogeneous patient populations [9] and diverse CPB techniques [2, 10]. This study investigates the effects of DHCPB versus DHCA on pulmonary dynamics in a 1-week-old piglet model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Fifteen 1-week-old piglets weighing 2.5 to 3.5 kg were studied with approval of the institution's Animal Care and Use Committee and in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Animals were premedicated with intramuscular ketamine (20 mg/kg), intubated using a 3-mm cuffed endotracheal tube, and mechanically ventilated (Infant Ventilator; Sechrist Industries, Anaheim, CA). Methyprednisolone (40 mg/kg) was given intravenously. After a bolus of intravenous fentanyl (100 µg) and pancuronium (0.1 mg/kg), anesthesia was maintained with continuous fentanyl infusion (50 µg•kg^-1•h^-1). A femoral artery catheter was placed for measurement of mean arterial pressure and arterial blood sampling. A median sternotomy was performed, and an 8-mm ultrasonic flow probe (Transonic Systems, Ithaca, NY) was positioned around the main pulmonary artery for measurement of cardiac index. A left atrial and pulmonary artery catheters were inserted for measurement of left atrial pressure and pulmonary artery pressure. A temperature probe was placed in the nasopharynx.

A SensorMedics 2600 Pediatric Pulmonary Function Laboratory (Yorba Linda, CA) was used to assess static compliance (C_stat) and airway resistance (R_aw). The peak inspiratory pressure and positive end-expiratory pressure were kept constant at 24 cm H₂O and 2 cm H₂O, respectively, while C_stat was assessed. An occlusion valve with an attached pneumotach was inserted between the endotracheal tube and the ventilator. The ventilator was switched out of the circuit by closure of the valve at peak inspiratory pressure, with exhalation occurring through the pneumotach. At end exhalation, the piglet was switched back into the ventilatory circuit. The slope of the linear midportion of the computer-generated flow volume curve represented C_stat. We calculated C_stat from the measured delivered tidal volume/plateau pressure - positive end-expiratory pressure. A mean value of C_stat was calculated for a minimum of six breaths at each stage.

A Stöckert-Shiley (Irvine, CA) CAPS nonpulsatile roller pump and a COBE VP-CML (Denver, CO) membrane oxygenator with venous reservoir formed the CPB circuit. Circuit blood gases were monitored using a CDI-300 (CDI; 3M Healthcare, Irvine, CA) continuous in-line blood gas analyzer. Filters were not incorporated in the bypass circuit. The circuit was primed with fresh heparin-treated donor pig whole blood to maintain a hematocrit of 23% to 24%. After the animals were given heparin (500 U/kg), an 8F arterial cannula and a 14F venous cannula were inserted in the ascending aorta and right atrium, respectively, for initiation of CPB. Pharmacologic agents were not administered to control blood pressure during CPB. Sodium bicarbonate was given as necessary to maintain the base excess between -3 and 3 mmol/L. Alpha-stat blood gas management was used throughout the experiment. Ventilation was continued throughout CPB at a respiratory rate of 6 breaths/min, positive end-expiratory pressure of 2 cm H₂O, and concentration of inspired oxygen of 0.35 to prevent atelectasis.

Data collection was divided into three stages. After instrumentation, data were collected before CPB at 37°C (I). Animals were then placed on CPB at 100 mL•kg^-1 •min^-1 at 37°C and cooled by perfusion to 18°C over a 20-minute period. Animals were randomly assigned to one of two groups: DHCPB (n = 7), 90 minutes of DHCPB at 25 to 50 mL•kg^-1•min^-1; or DHCA (n = 8), 90 minutes of DHCA. Flow in the DHCPB group was adjusted to between 25 and 50 mL•kg^-1•min^-1 to maintain mean arterial pressure less than 50 mm Hg. After a rewarming period of 30 ± 1 minutes to 36°C, the animals were weaned from CPB, and data were collected 5 minutes after separation from CPB (II). The animals were observed, and data were collected again 30 minutes after separation from CPB (III).

We measured C_stat, R_aw, mean arterial pressure, cardiac index, left atrial pressure, pulmonary artery pressure, arterial blood gases, and hemoglobin concentration at each stage. A GEM-STAT Blood Gas/Electrolyte Monitor (Mallinckrodt, Ann Arbor, MI) was used to measure blood gases. The alveolar-arterial oxygen gradient (A-aDO₂) and pulmonary vascular resistance index (PVRI) were calculated at each stage as follows:

where CO = cardiac output; FiO₂ = concentration of inspired oxygen; LAP = left atrial pressure; PaCO₂ = partial pressure of carbon dioxide in arterial blood; PaO₂ = partial pressure of oxygen in arterial blood; and PAP = pulmonary artery pressure.

Data were analyzed using Student's paired t test to compare results within each group. The unpaired t test was used to compare results between groups. All results are expressed as mean ± standard error. Differences were considered significant if p was less than 0.025.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Pulmonary injury occurred after both DHCA and DHCPB, which worsened over time (ie, worse at stage III versus II). However, the injury was more severe after DHCPB, as assessed by C_stat. The duration of CPB was 61 ± 1 minutes and 147 ± 2 minutes for the DHCA and DHCPB groups, respectively.

Hemodynamic and arterial blood gas data are presented in Tables 1 and 2. In the DHCPB animals, mean arterial pressure decreased significantly at stage I compared with stage II, and left atrial pressure increased slightly but significantly in stages II and III compared with stage I. However, these changes were not believed to be of physiologic importance. The PAP increased significantly at stages II and III compared with stage I in the DHCPB animals and in the DHCA group.

View larger version (32K): [in this window] [in a new window]   Fig 1. . Static compliance (Cstat) measurements before cardiopulmonary bypass (CPB) and after CPB. Ninety minutes of deep hypothermic low-flow cardiopulmonary bypass (DHCPB) resulted in greater impairment of static compliance than 90 minutes of deep hypothermic circulatory arrest (DHCA). Data are shown as mean values ± standard error. Stages: I = before CPB; II = 5 minutes after CPB; III = 30 minutes after CPB. (*p < 0.025 vs deep hypothermic circulatory arrest; < 0.025 versus stage I.)

View larger version (30K): [in this window] [in a new window]   Fig 2. . Pulmonary vascular resistance index (PVRI) measurements before cardiopulmonary bypass (CPB) and after CPB. The index increased significantly 30 minutes after separation from CPB compared with baseline in the deep hypothermic circulatory arrest (DHCA) animals. There was a significant elevation in pulmonary vascular resistance in the deep hypothermic low-flow cardiopulmonary bypass (DHCPB) group 5 and 30 minutes after separation from CPB compared with baseline. Data are shown as mean values ± standard error. Stages: I = before CPB; II = 5 minutes after CPB; III = 30 minutes after CPB.(p < 0.025 versus stage I.)

View larger version (33K): [in this window] [in a new window]   Fig 3. . Alveolar-arterial oxygen gradient (A-aDO2) before cardiopulmonary bypass (CPB) and after CPB. The gradient increased after deep hypothermic circulatory arrest (DHCA) and deep hypothermic low-flow cardiopulmonary bypass (DHCPB) 5 and 30 minutes after separation from CPB; however, these changes were not statistically significant. Data are shown as mean values ± standard error. Stages: I = before CPB; II = 5 minutes after CPB; III = 30 minutes after CPB.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Recent investigations have demonstrated excellent survival and reduced postoperative morbidity from pulmonary hypertension when repair of congenital heart defects was performed during the first month of life [11, 12]. Both DHCA and DHCPB are used in the repair of congenital heart defects. Traditionally, DHCA has been preferred because of its simplicity, allowing the removal of cannulas during repair of heart defects. Currently, there is an increasing trend in congenital heart operations for earlier repair (less than 1 month of age) and the use of DHCPB in place of DHCA to prevent central nervous system morbidity and mortality [1]. A tradeoff may exist with the use of DHCPB: improving neurologic outcome at the expense of other organ dysfunction. Previous studies have compared the effects in neonates of DHCPB and DHCA on the brain. This study was conducted to examine the effects of DHCPB versus DHCA on pulmonary function using a 1-week-old piglet model.

In this neonatal CPB model, 90 minutes of DHCPB resulted in greater impairment of C_stat than 90 minutes of DHCA. The PVRI tended to be higher after DHCPB than after DHCA; however, significance was not reached. The A-aDO₂ increased above baseline after DHCA and DHCPB, with the greatest increase occurring after DHCPB. However, this increase in A-aDO₂ was not found to be statistically significant between or within groups, most likely because of the small number of animals in the study.

Possible mechanisms for the greater pulmonary dysfunction seen after the use DHCPB include: ischemia-reperfusion injury, complement activation, neutrophil activation, and postnatal developmental changes of the neonatal lung, which may increase the susceptibility to injury. Friedman and colleagues [7] demonstrated that lung water, pulmonary vascular resistance, and thromboxane levels were significantly higher in animals undergoing total CPB versus partial CPB. These investigations suggested that the lung injury seen after total CPB may result from an inflammatory response secondary to reperfusion after a period of pulmonary ischemia [7]. During nonpulsatile total CPB, the lungs receive only bronchial flow. An increased generation of constrictor prostaglandins by pulmonary microvessels has been associated with the use of total CPB [6]. These alterations in pulmonary microvascular reactivity after total CPB were believed to be associated with reduced pulmonary perfusion.

Exposure of the blood to foreign substances during CPB results in complement [13] and polymorphonuclear leukocyte activation, as well as loss of endothelial cell integrity [2, 14]. Complement activation and pulmonary endothelial ultrastructural changes have been correlated with the duration of CPB. The use of soluble human complement receptor 1, a complement activation inhibitor, has been found to attenuate pulmonary injury after CPB in pigs [15]. Neutrophil activation has been implicated as a possible mechanism of pulmonary injury after CPB. Leukocyte depletion has been shown to reduce free radical–mediated pulmonary injury [16] and pulmonary edema [17] in dogs after CPB. Markers of cytokine production, cytokine-upregulated endothelial ligands for neutrophil adhesion molecules, and neutrophil degranulation were shown to be increased in patients after CPB [95].

Mills and Haworth [4] demonstrated instability in the pulmonary endothelium associated with the changes that occur during the neonatal period in the structure, shape, and biochemical composition of the endothelial cell. This instability in the pulmonary endothelium makes the neonatal lung more vulnerable to the injurious systemic inflammatory effects of CPB. A failure of endothelium-dependent pulmonary vasodilation is associated with pulmonary endothelial damage induced by CPB in children [8]. Postoperative pulmonary endothelial dysfunction seen after CPB may be a mechanism of the pulmonary hypertension that occurs in children undergoing congenital heart operations.

The data from this study suggest that the greater pulmonary dysfunction seen after DHCPB as compared with DHCA may be a result of complement and neutrophil activation secondary to exposure of blood to the bypass circuit, rather than of ischemia-reperfusion injury. The duration and severity of lung ischemia were equal or greater in the DHCA group compared with the DHCPB animals. If lung ischemia were the primary mechanism for pulmonary injury, one would expect an equal or more impaired level of pulmonary dysfunction in the DHCA group. Wernovsky and associates [18] demonstrated a direct relation between fluid balance and the duration of CPB, with infants undergoing DHCPB requiring a significantly greater amount of fluid than those undergoing DHCA. Thus, one can hypothesize that the increased exposure to foreign material in the bypass circuit may lead to more complement- and leukocyte-mediated injury of the neonatal pulmonary endothelium in those animals undergoing 90 minutes of DHCPB.

There are several limitations to this study. This study did not examine the mechanisms of pulmonary injury that occurred after the two bypass strategies. The lungs were not examined histologically or on a molecular level. Further studies are needed to assess these acute changes in pulmonary dynamics on a molecular level.

In summary, this study demonstrates that 90 minutes of DHCPB produces greater pulmonary dysfunction than 90 minutes of DHCA. Because DHCPB will be used more frequently in the future to prevent central nervous system injury, the increased risk for pulmonary dysfunction in these patients must be appreciated and anticipated. If DHCPB is used in place of DHCA in congenital heart operations, close attention to ventilatory and fluid management is mandatory in the postoperative period to prevent further worsening of pulmonary dysfunction.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Presented at the Poster Session of the Thirty-first Annual Meeting of The Society of Thoracic Surgeons, Palm Springs, CA, Jan 30–Feb 1, 1995.

Address reprint requests to Dr Gaynor, Pediatric Cardiothoracic Surgery, Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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2. Kirklin JW, Barratt-Boyes BG. Cardiac surgery. 2nd ed. New York: Churchill Livingstone, 1993:210–5.
3. Maehara T, Novak RKH, Elliott MJ. Perioperative monitoring of total body water by bio-electrical impedance in children undergoing open heart surgery. Eur J Cardiothorac Surg 1991;5:258–65.[Abstract]
4. Mills AN, Haworth SG. Greater permeability of the neonatal lung. J Thorac Cardiovasc Surg 1991;101:909–16.[Abstract]
5. Menasche P, Peynet J, Lariviere J, et al. Does normothermia during cardiopulmonary bypass increase neutrophil-endothelium interactions? Circulation 1994;90(Part 2):275–9.
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13. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Pacifico AD, Chenoweth DE. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57.[Abstract]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Lynne A. Skaryak Andrew J. Lodge Paul M. Kirshbom Louis R. DiBernardo Ross M. Ungerleider Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Skaryak, L. A. Articles by Gaynor, J. W. Search for Related Content PubMed PubMed Citation Articles by Skaryak, L. A. Articles by Gaynor, J. W.