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Ann Thorac Surg 2003;75:S729-S734
© 2003 The Society of Thoracic Surgeons
a Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, Oregon, USA
* Address reprint requests to Dr Ungerleider, Doernbecher Children’s Hospital, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code L353, Portland, OR 97201, USA.
e-mail: ungerlei{at}ohsu.edu
Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.
Abstract
The use of cardiopulmonary bypass is still necessary for the repair of many congenital cardiac defects. However, exposure to cardiopulmonary bypass can still lead to major morbidity and sometimes mortality, especially in neonates and infants, despite a perfect surgical repair. Various research-based strategies have been used to minimize some of the complications related to cardiopulmonary bypass, including the systemic inflammatory response, hemodilution, and transfusion requirement. This overview provides some of the strategies that we use in our practice in applying cardiopulmonary bypass in the repair of congenital cardiac defects in neonates and infants.
The current trend in pediatric cardiac surgery has been the emphasis of early complete repair of congenital heart defects before the heart and the patient undergo deleterious adaptation to the abnormal physiology. As a result, many repairs of complex congenital cardiac defects occur during the neonatal period. Innovative techniques for the repair of many defects allow reconstruction of normal anatomy and physiology, resulting in excellent outcome in most patients. However, major morbidity can still occur despite a perfect repair as a result of exposure to cardiopulmonary bypass (CPB), which is necessary to perform these operations.
The conduct of CPB during the repair of complex congenital cardiac defects often subjects these tiny patients to wide ranges of physiologic variables, including temperature, blood viscosity, pH, pressure, and flow. The deleterious effects of CPB in neonates are often more pronounced than those seen in larger pediatric or adult patients. This is due to their immature tissue and organ function in the first few months of life and the tremendous disparity between the CPB circuit size and the patient. Often, the bypass circuit volumes are 200% to 300% greater than the patient’s circulating blood volume. In addition, there is a substantial inflammatory reaction that accompanies exposure to the foreign surface area of the CPB circuit, and the ramifications of this reaction can create significant challenges to fluid and hemodynamic management in the postoperative period. Although the solutions to these problems are not completely available, there are practical methods that can be employed to temper some of the potentially deleterious effects of CPB without having to compromise the ability to conduct a safe and technically superb operation [1].
Various strategies can be used to decrease the morbidity from CPB during the prebypass, bypass, and postbypass periods. The aim of this overview is not to provide an exhaustive list of possible interventions, but rather to catalog those protocols that we found useful in our practice at Oregon Health & Science University.
Prebypass
The first step in reducing CPB-related morbidity is to be able to identify patients who are at increased risk. Neonates who have ductal-dependent heart defects with high pulmonary blood flow (interrupted aortic arch, hypoplastic left heart syndrome [HLHS], double-outlet right ventricle [DORV] with subpulmonary ventricular septal defect [VSD], and coarctation) or cyanosis with high pulmonary blood flow (transposition of the great arteries [TGA] with or without ventricualr septal disease [VSD], truncus arteriosus, aorto-pulmonary window) seem to comprise a high-risk group for post-CPB edema and pulmonary dysfunction. Furthermore, infants who are septic, who have depressed ventricular function, who have multiple congenital problems in addition to their cardiac defect, or who are small (< 1,800 g) present an increased risk for CPB. Ironically, many of these patients have defects that require surgical intervention in the neonatal period, and it may be that neonates, in general, comprise a high-risk group of patients. It is our policy to consider any patient who requires CPB in the first month of life as a high-risk patient. Recognizing these patients being at increased risk will allow initiation of interventions before surgery to decrease potential CPB-related complications.
One of the potential complications as a result of exposure to CPB is a substantial systemic inflammatory response leading to capillary leakage, profound soft tissue edema, and end-organ dysfunction. The exact mechanism of this process is not well understood, but leukocytes, especially neutrophils in particular, are partly responsible for this process. Clinical and experimental studies in both adults and infants have shown that leukocyte filtration during CPB can ameliorate some of the inflammatory reaction associated with CPB [2–4]. However, our results of using leukocyte filters to remove white blood cells during CPB have been inconsistent. Therefore, we utilize the strategy of premedicating all neonates with high-dose steroid before CPB to decrease the ability of white blood cells to synthesize inflammatory mediators during CPB. We administer intravenous methylprednisolone at 10 mg/kg 8 hours and again 2 hours before surgery. Recent data from our laboratory demonstrate a significant decrease in post-CPB fluid gain and improvement in pulmonary compliance and pulmonary vascular resistance in animals premedicated with this steroid regimen compared with controls that either did not receive steroids or that were first exposed to steroids in the pump prime [5]. Results with patients receiving this pretreatment have also been extremely encouraging [6–9]. These infants required less additional volume during CPB, have less postoperative edema, and have a generally more expeditious postoperative convalescence. The use of steroid pretreatment may have an important role in protecting neonates from the inflammatory component of CPB that can lead to serious fluid management problems after surgery.
Bypass
Similar efforts to blunt the systemic inflammatory response to CPB are continued during the bypass period. Methylprednisolone is routinely added to the extracorporeal circuit prime. Leukocyte-reduced blood is used to prime the bypass circuit in order to decrease any possible donor-versus-host reaction. Many pediatric cardiac surgery centers [10] are now administering Aprotinin as an intravenous infusion to neonates and infant patients before initiation of CPB and continuing the infusion through the duration of the bypass. Aprotinin may reduce the inflammatory response to CPB [11–13] in addition to its effect on postoperative bleeding [14, 15]. However, the optimal dosing regimen of Aprotinin in pediatric cardiac surgery is still unclear. Because of varying prime volumes and the inverse relationship between the patient’s small blood volume and the large circuit prime, a higher dosing regimen may be necessary to achieve effective plasma concentrations of Aprotinin to inhibit kallikrein and contact activation. Our protocol to calculate Aprotinin dosing is based on body surface area; therefore, we use the following dosing regimen: 240 mg/m2 (1.7 x 106 KIU/m2) bolus infusion at the beginning of the operation and a similar dose in the extracorporeal circuit prime, followed by a continuous infusion of 56 mg/m2/h (4 x 105 KIU/m2/h) throughout the procedure [16]. Our indications in the past for using Aprotinin included patients who have liver dysfunction, have coagulation abnormalities, are at risk of significant postoperative bleeding, or require reoperation. We have begun using Aprotinin more routinely in all of our patients who will be undergoing deep hypothermic circulatory arrest (DHCA), neonates who require complex cardiac repairs, and particularly in those whom we anticipate postoperative use of either ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO). Our preliminary impression is that the addition of Aprotinin has had a beneficial effect on outcome.
CPB circuitry
One of the ways to decrease the deleterious effect of CPB is to minimize the amount of exposure to the CPB circuit by keeping the duration on CPB as short as possible and limiting the amount of artificial surface area to which blood must be exposed. Miniaturization of the CPB circuit using biocompatible-coated circuits and oxygenators and using vacuum-assisted venous drainage (VAVD) are just a few methods for decreasing blood contact with nonbiological surfaces of the CPB circuit. Special coated circuits are now available that are supposed to mitigate some of the systemic inflammatory response to CPB. However, the challenge has been in providing coated surfaces for oxygenators that improve the blood/surface interface without altering their gas exchange performance. Common strategies to reduce circuit size include decreasing the overall length and diameter of tubing used, optimizing the pump orientation in relationship to the surgical table, and employing VAVD. Even elimination of some components of the extracorporeal circuit, such as arterial line filters and in-line blood cardioplegia, may be practiced at times. We commonly use -inch arterial line and -inch venous lines in patients up to 7 kg with the aid of VAVD. Although VAVD is convenient and advantageous in pediatric perfusion, it is important to be aware of some of the risks and complications that have been reported. We, however, have not experienced any of the reported complications associated with VAVD thus far [17–20]. With VAVD, it is theoretically not necessary to prime the venous side of the circuit, although we do not recommend such practice. By optimizing both the length and diameter of tubing and the proximity of the pump and oxygenator to the patient, we rarely have the need to regulate the vacuum to greater than 10 to 12 mm Hg. In addition, monitoring both the positive and negative pressures helps improve the overall safety of utilizing VAVD.
Another advantage of circuit miniaturization is smaller priming volumes, which will result in less hemodilution. This, along with the use of asanguinous prime, may eliminate the need for blood transfusion and the risk of transfusion-related complications. Currently, we are able to repair congenital cardiac defects in patients as small as 5 to 6 kg without the need for any blood transfusion. However, they must have an adequate hematocrit at the start of their operation and they must be able to tolerate anemia during their postoperative convalescent period. In these patients, we do not use blood to prime the CPB circuit. The arterial line filter is eliminated and myocardial protection is provided by crystalloid cardioplegia. We use -inch internal diameter tubing for both the arterial and the venous lines, and VAVD is essential to ensure adequate venous drainage. With this technique, we are able to decrease our priming volume to approximately 240 mL. In addition, all patients undergo modified ultrafiltration at the conclusion of bypass. As advances in circuit design enable us to routinely achieve prime volumes less than 200 mL, it may be possible to extend asanguinous CPB to even smaller patients. Nevertheless, ultimately, the ability to avoid transfusion will still relate, in part, to the patient’s postoperative hemodynamic requirement.
Hemostasis/anticoagulation
Neonates and infants are at greater risk for bleeding diatheses after cardiac surgery due to their lower circulating volume of antithrombin III (ATIII) compared with the adult population, decreased von Willebrand factor, and reduced platelet aggregation. Furthermore, neonates with cyanotic heart defects have further impairment with hemostasis due to polycythemia, thrombocytopenia, abnormal platelet functions, decreased levels of factors V, VII, and VIII, and an increase in fibrinolyis [21, 22]. Anticoagulation, however, is a critical necessity during CPB. Providing an antithrombotic versus an anticoagulant environment on CPB is challenging in neonates and infants when hemodilution and hypothermia can also influence the clotting mechanism. An empirical loading dose of heparin at 300 to 400 U/kg is usually used, and maintaining the activated clotting time (ACT) greater than 480 seconds has been the gold standard for measuring adequate anticoagulation on bypass. However, neonates have a much greater variation of response to heparin administration and can show either a greater resistance or sensitivity to heparin [23–25]. This may be due to varying levels of circulating ATIII, and, it is our belief that congenital ATIII deficiencies are under-reported. Rather than using a fixed dose protocol of heparin in neonates and infants, it may be more prudent to evaluate each patient’s individual response to heparin by measuring heparin concentration and adjusting it throughout the course of CPB. We currently monitor heparin concentration along with corresponding ACTs, and believe that using these two assays in concert has been successful in helping us provide optimal anticoagulation.
Although optimal anticoagulation during bypass is crucial, the risk of heparin exposure as an anticoagulant cannot be overlooked. Complications of heparin exposure can range from massive postoperative bleeding to heparin-induced thrombocytopenia and thrombosis (HITT). The reported incidence of HITT in adults varies between 5% and 28% of patients receiving heparin [21, 22]. Although it is well recognized in adults, HITT is frequently overlooked in neonates and infants. We have now documented the development of HITT in 3 neonates after undergoing cardiac surgery. Patients with HITT can present a formidable challenge when they need cardiac surgery and the use of CPB. Two alternative anticoagulants used in adults undergoing CPB are danaparoid and argatroban. The relatively short half-life of argatroban (39 to 51 minutes), its lack of renal toxicity, its predictable dose-response, and because its effect can be monitored by ACTs and partial thromboplastin time (PTT) make it an attractive alternative to heparin [26]. Our protocol for dosing argatroban is 250-µg/kg intravenous bolus followed by an intravenous infusion of 15 µg/kg/min. This will elevate the ACT to approximately between 300 and 400 seconds. However, the experience of using argatroban or other alternative anticoagulants instead of heparin as an anticoagulant on CPB is very limited.
Deep hypothermic circulatory arrest
In recent years, there has been a movement towards avoidance of using DHCA as one of the perfusion strategies employed during repair of cardiac defects in neonates and infants. Improvements in circuit technology along with advances in cannula and vent design have made it easier and safer to employ bicaval cannulation and continuous hypothermic low-flow perfusion to tiny patients. Concurrent improvements in myocardial protection have allowed prolonged periods of myocardial ischemia during moderate hypothermia with successful outcomes. The impact of these advances is that the simple strategy of rapidly cooling a patient to 18°C using a single venous cannula, turning off the pump for the entire repair even when the period of DHCA extends beyond 45 to 60 minutes, and then rewarming the patient on CPB have been replaced with alternative, albeit more complex, methods that avoid the use of any periods of DHCA. Although it is indeed possible to provide continuous CPB to almost any patient, the question of which strategy is best is not yet determined. Numerous experimental studies have clearly demonstrated that the brain is not adequately protected by the methods of DHCA as they were utilized in the 1980s and early 1990s [27–33]. Despite the successful cardiac outcomes that were being achieved, patients were probably being neurologically injured by the strategy of DHCA in the format it was offered. However, continuous hypothermic low-flow perfusion exposes patients to prolonged duration of CPB, and the consequences of prolonged CPB exposure have an enormous impact on postoperative convalescence. The complexity of the circuitry required in some cases can hinder exposure and the ability to perform a high-quality operation. Furthermore, there is a growing body of data that continuous hypothermic low-flow CPB might lead to more soft tissue edema, diminished pulmonary function [34, 35], substantial cerebral edema [7, 36], and damage to neuronal golgi apparatus [37]. Experimental data suggest that there is some acute neurologic metabolic injury after prolonged exposure to continuous hypothermic low-flow CPB that is not apparent if the brain is exposed to short durations of DHCA [36]. Substantial research has been performed over the past 15 years regarding how to more safely apply the strategy of DHCA [1]. This research has led to several modifications for applying DHCA, such as: (1) prebypass treatment with steroids and aprotinin [7, 11]; (2) hyperoxygenation before the initiation of DHCA [38]; (3) adequate duration of cooling (
20 minutes) [27, 29, 39] to ensure more uniform and homogeneous brain protection; (4) maintenance of higher hematocrits during the cooling phase; (5) using pH stat blood gas management strategy [40–42] during the cooling phase, especially for "high-risk" patients (eg, those with aorto-pulmonary collaterals or those with preoperative cyanosis) [13, 43]; (6) limiting the duration of DHCA exposure by providing intermittent cerebral perfusion for 1 to 2 minutes at 15- to 20-minute intervals [36] (this technique virtually eliminates the detrimental ischemic effects of DHCA while avoiding the disadvantages of continuous low-flow perfusion); (7) the use of modified ultrafiltration after CPB [44]; and (8) attention to postoperative cerebral "energetics" because this is a time that much cerebral injury can occur [45]. This latter area includes techniques such as limiting hyperthermia and providing adequate cardiac output (by using inotropic agents, leaving the sternum "open," or using ECMO or VAD) to ensure adequate cerebral oxygen delivery, especially for patients who remain cyanotic after surgery (eg, those with mixing lesions). Modifications in the technique of applying DHCA have made DHCA one of the tools for some high-risk patients and can improve the outcomes for these patients. It is essential for surgeons to understand the risks and benefits of the various strategies available and to learn how to use them all in the most appropriate manner.
Ultrafiltration
Despite current changes to the CPB circuitry and efforts toward optimizing CPB strategies, neonates and infants constitute a group who may exhibit excessive fluid accumulation during their exposure to CPB. Efforts have been directed at removal of fluid from these patients during or immediately after CPB. Removal of fluid during CPB (conventional ultrafiltration) is difficult in neonates because removal of any fluid from a miniaturized circuit requires replacement to maintain adequate reservoir levels, and often times, the results with conventional ultrafiltration are inconsistent [46–49]. The technique of zero-balance ultrafiltration (Z-BUF) during CPB may be another useful method in the removal of fluid and possibly harmful activated inflammatory mediators. This method involves an isovolumetric exchange of fluid, typically Normasol, congruent with the amount of ultrafiltrate removed. Z-BUF has been reported to reduce postoperative blood loss, decrease time to extubation, and remove a significant amount of circulating tissue necrosis factor, interleukin-10, myeloperoxidase, and C3a [50] The most effective form of ultrafiltration appears to be the method as described by Elliott and Naik [47, 51]. This is referred to as modified ultrafiltration (MUF) because it is performed after the completion of CPB. Using variations of this technique, it is possible to remove from the patient 500 to 750 mL of fluid that is rich in inflammatory mediators. This leads to improvements in pulmonary, cardiac, and cerebral function [44, 46, 52–55]. Modified ultrafiltrarion (MUF) appears to be very beneficial for neonates and tiny infants, and clearly results in elevation of the hematocrit and generalized acute improvement in pulmonary and cardiac function [46, 47, 52, 55].
Postbypass
Once separated from the CPB circuit, the patient may continue to demonstrate capillary leakage and accumulate excessive soft tissue fluid for 24 to 36 hours. The extent of this may relate to hemodynamic factors, such as their underlying defect and type of repair, as well as to their cardiac function. Factors that can result in continued fluid accumulation are elevation of the central venous pressures (CVPs) (as is sometimes seen after neonatal repair of tetralogy of Fallot), reduced cardiac output (with consequent reduced renal blood flow), or the need for high ventilatory pressures (which will raise CVP and reduce venous return to the heart). Several ways to reduce fluid accumulation in this acute convalescent phase include: (1) leaving a foramen defect open in patients who may have decreased right ventricular compliance so that they can shunt right-to-left and maintain cardiac output and normal CVP at the expense of mild systemic oxygen desaturation; (2) judicious use of inotropic agents in lieu of continual and excessive volume replacement during the first 24 to 36 hours postoperatively; and (3) leaving the sternum open to prevent excessive increases in pulmonary pressures in selected patients. Some groups recommend the routine placement of peritoneal dialysis catheters in their patients at the time of surgery, but we have not done this and have no experience with its effectiveness. In unusual circumstances, infants with extremely elevated CVP and persistent fluid accumulation may benefit from a short period of ECMO support. This will lower CVP and help mobilize sequestered fluid while allowing the cardiac compliance and function to recover.
In an effort to determine whether there are any standards in CPB practice patterns for neonates, members of the Congenital Heart Surgeons Society (CHSS) were surveyed regarding their preferred CPB design and strategies for typical 3-kg neonates undergoing correction of cardiac defects (such as VSD, TGA, or HLHS). The survey included 31 questions and was sent to all CHSS members and several prominent congenital heart surgeon non-CHSS members in the US and Canada (n = 52). Thirty-one responses were received. There has been a movement towards using -inch arterial lines in 46% of programs, but towards using -inch venous lines in only 6% of programs. Seventy-six percent and 60% of practices utilize routine preoperative steroids and aprotinin, respectively, as a means to reduce the systemic inflammatory response. Perfusion flow rates for neonates have been increased from the conventional 100 mL/kg/min up to 150 to 200 mL/kg/min by 86% of practices, and some (56%) practices have shifted to the use of pH stat cooling. Despite claims that continuous hypothermic low-flow perfusion might be superior to deep hypothermic circulatory arrest (DHCA), two-thirds of practices still use DHCA as a viable strategy, although 23% have adopted the technique of intermittent perfusion to limit duration of DHCA exposure, and 79% cool for at least 20 minutes before commencing DHCA. MUF is used by 70% of practices. These results demonstrate that: (1) extreme variability still exists in the neonatal CPB practice patterns employed by experienced and dedicated congenital heart surgeons, and (2) CPB strategies have changed for some practices (but not all) in ways that reflect current contributions to the scientific literature. It is difficult to define a "standard of care" versus variability of preference in neonatal CPB technique [56].
Comment
In general, cardiac surgeons in the 21st century can apply far more sophisticated CPB strategies than what they may have been exposed to during their training. The field has been research driven, and many techniques have developed from an evidence-based format. Despite the huge amount of information available regarding infant CPB, there is still much room for improvement. Surgical techniques have undergone evolution to where we are capable of providing anatomic repair or optimal palliation to most infants. The next horizon for significant improvement of surgical outcomes will be reached as we learn how to better optimize the response of the patient to the CPB that is used during repair of cardiac defects.
References
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