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J Thorac Cardiovasc Surg 2003;125:625-632
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
From the Division of Cardiovascular Surgery, University of California at Los Angeles Medical Center, Los Angeles, Calif, and The Heart Institute for Children, Hope Children's Hospital, Oak Lawn, Ill.
Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.
Received for publication May 16, 2001. Revisions requested July 18, 2001; revisions received Sept 19, 2001. Accepted for publication Oct 2, 2001. Address for reprints: Bradley S. Allen, MD, The Heart Institute for Children, Hope Children's Hospital, 4440 West 95th St, Oak Lawn, IL 60453 (E-mail: bradallen{at}thic.com).
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAppendix: DiscussionReferences |
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Reperfusion injury produces functional, metabolic, and structural alterations following reintroduction of blood after temporary ischemia.
1-4 This damage after reperfusion is exaggerated when reperfusion takes place in an uncontrolled manner with unmodified (normal) blood. 1,2 If the ischemia is prolonged, this can result in cellular damage, with impairment of end-organ function and an increase in morbidity and mortality. The cardiac surgeon is in the unique position to counteract this manner of reperfusion damage because the conditions of reperfusion and the composition of the reperfusate are under his or her direct control. Initial cardiac studies showed substantial injury reduction by modifying (controlling) the method of reperfusion after myocardial ischemia. 1,2,5,6 Subsequently, similar underlying principles of controlled reperfusion were also found to limit reperfusion damage in the lung, kidney, and skeletal muscle. 7-12
These focal studies made it clear that the principles of controlled reperfusion can be applied to the entire body. Global damage can result during efforts to repair certain congenital defects, as well as during adult cardiac surgery, because an interval of circulatory arrest may be needed to expedite surgical repair. 13,14 If CPB is restarted in an uncontrolled fashion with unmodified blood, as is the usual clinical practice, the potential exists for a global reperfusion injury to occur in every organ. Such an injury would explain why generalized edema and multiple organ impairment are common after deep hypothermic circulatory arrest (DHCA). 13-15 Studies in individual organs (heart, lung, kidney, and skeletal muscle), however, have shown that the fate of ischemic tissue is determined more by the method of reperfusion than by the duration of ischemia itself. 1,2,5-12 It may therefore be possible to limit this global reperfusion injury after DHCA by applying the principles of controlled reperfusion pioneered in individual organs.
The aims of this study were to determine whether a global reperfusion injury occurs after DHCA and whether this injury could be avoided with controlled reperfusion by modifying the pump prime during the period of circulatory arrest to produce a modified global reperfusate.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAppendix: DiscussionReferences |
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The femoral artery and vein were cannulated to monitor arterial pressure for blood gas determinations and for intravenous infusions. After systemic heparinization (3 mg/kg), a thin-walled 18F to 20F, 52-cm-long venous cannula (Baxter Healthcare Corp, Irvine, Calif) was inserted into the femoral vein to the level of the right atrium, and a 14F to 16F thin-walled cannula was inserted into the femoral artery. A second 18F to 20F short venous cannula was placed into the right external jugular vein, and a Swan-Ganz catheter (Baxter) was placed into the pulmonary artery through the internal jugular vein to measure cardiac output. Arterial blood gases, electrolytes, and hemoglobin levels (Blood Gas System 288; Ciba Corning, Midfield, Mass) were measured every 15 to 30 minutes to ensure optimal levels. A heating-cooling blanket was placed below the pig, and a second pad was placed on the abdomen to maintain a constant core temperature of 37°C to 38°C when warm and 19°C during circulatory arrest. The cardiopulmonary bypass (CPB) circuit was heparinized, primed with packed red cells from donor pigs, and made normocalcemic. The hematocrit value was adjusted to 25% to 35% with donor blood and Plasmalyte solution (Baxter). A Baxter Univox Membrane Oxygenator (Baxter) was used, and the systemic flow rate was adjusted to approximately 100 to 125 mg · kg-1 · min-1 at full flow to maintain a continuously monitored aortic root pressure of 50 to 70 mm Hg.
Experimental protocol
All animals were started on CPB with a fraction of inspired oxygen (FiO2) of 100%, cooled to 19°C by using the alpha-stat strategy, and separated into 3 experimental groups. In 5 pigs CPB was continued without ischemia (control animals), whereas the other 10 animals underwent 90 minutes of DHCA. After DHCA, bypass was restarted at a pressure of 20 to 30 mm Hg and slowly increased to 50 to 70 mm Hg. All pigs were then rewarmed to 36°C or 37°C. The heart was defibrillated as needed at 25°C, and all animals were started on 10 µg · kg-1 · min-1 dopamine once the core temperature reached 35°C. Dopamine was then either increased or weaned to keep systolic arterial pressure greater than 70 mm Hg and was discontinued only when arterial pressure was maintained at greater than 70 mm Hg for 5 minutes. Hemodynamic and pulmonary measurements were obtained before (baseline) and 60 minutes after CPB. Biochemical measurements were made before CPB (baseline), at 15 minutes of rewarming (conjugated dienes [CD] and endothelin-1), and 4 hours after CPB was discontinued (creatine kinase [CK] and aspartate aminotransferase [AST]). After the hemodynamic measurements, protamine was given, and all cannulas were removed. Bleeding was controlled, the vessels were repaired, and all wounds were closed. The animals were then allowed to regain consciousness, were extubated, and underwent neurologic assessment approximately 4 hours later (6 hours after CPB). Fentanyl (0.2-0.3 µg/kg) was given as needed for postoperative pain but was held for at least 2 hours before the neurologic evaluation. The animals were then killed with 30 mg/kg phenobarbital and potassium chloride.
Experimental groups
Control animals
Five pigs were cooled (19°C) and rewarmed by using the alpha-stat strategy and an FIO2 of 100%, without any ischemia or period of circulatory arrest.
DHCA
After cooling to 19°C with the alpha-stat strategy and an FIO2 of 100%, the other 10 pigs underwent 90 minutes of DHCA and were reperfused by using either the unmodified blood prime or a modified global reperfusate.
Unmodified CPB prime
CPB was reinstituted in 5 pigs without altering the pump blood bypass prime, oxygen concentration (100%), or pH strategy (alpha-stat), and the animals were rewarmed. This simulates the usual clinical practice.
Modified CPB prime
In the other 5 animals, the CPB prime was modified during the period of circulatory arrest to make a modified global reperfusate (Table 1). This included adding citrate to reduce the ionized calcium concentration to 0.2 to 0.5 µg/dL and magnesium sulfate to increase the ionized magnesium concentration to 2 to 4 mEq/L, reducing the oxygen tension (PO2) to 80 to 100 mm Hg (normoxic strategy) and changing to a pH-stat management for the first 10 minutes of reperfusion, and adding a sodium-hydrogen ion exchange inhibitor (HOE 642, 5 mg/kg) and mannitol (12.5 g). The bypass prime was also leukocyte depleted by circulating the blood prime through 3 parallel conditioned blood reperfusion application (CoBRA) filters (Pall B-1328 filter; Pall Corporation, East Hills, NY) for 20 minutes during DHCA and an LG-6 high-flow leukocyte-depleting filter (Pall Corp, East Hills, NY) placed in the arterial line to continue white blood cell (WBC) removal during the entire period of rewarming.
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7,10,12,16,17 Dopamine requirements are expressed as the total dose each animal received and calculated as the summation of the dose per minute multiplied by the total number of minutes at each dose.
Oxygenation
To assess pulmonary alveolar damage, the PO2 was obtained on 100% oxygen before (baseline) and 1 hour after CPB by using a tidal volume of 12 to 15 mL/kg, and the ventilator rate was adjusted to maintain a PCO2 of 36 to 44 mm Hg. Postoperative values are expressed as a percentage change from baseline, with each pig acting as its own control.
Conjugated dienes
CD, which are a marker of oxidant-mediated lipid peroxidation, were determined as previously described and expressed as the absorbance at a wave length of 240 nm/0.5 mL plasma. 16,17
CK and AST
Cellular injury was determined by measuring CK and AST activity with the UV-spectrophotometric method (Sigma Chemical Co, St Louis, Mo) and expressed as units per milliliter of plasma.
Endothelin-1
Vascular injury was determined by measuring endothelin levels with an Enzyme Immunometric Assay (ACE EIA Kit; Cayman Chemical Co, Ann Arbor, Mich) and expressed as picograms per milliliter of plasma.
Neurologic injury
Neurologic assessment was performed in all animals approximately 4 hours after wounds were closed, and the animals were extubated (6 hours after bypass). An adaption of neurologic deficit scoring described elsewhere was used, and a summary of the variables assessed are listed in Table 2. 18 In neurologic deficit scoring, 5 general components of the neurologic examination are evaluated, and a score of 100 is assigned to each category. A total score of 500 indicates brain death, whereas a score of 0 is normal. Neurologic deficit scoring was not blinded but was always agreed on by 2 members of the laboratory team. All animals were also kept under close supervision for any clinical evidence of seizure activity.
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Results |
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Biochemical measurement
No increased CD or endothelin-1 efflux occurred in control (nonischemic) pigs or those undergoing DHCA with a modified reperfusate. Likewise, there was only a small increase in AST and a moderate increase in CK levels, indicating little tissue damage. In contrast, pigs undergoing DHCA with an unmodified reperfusate sustained a significant oxidant and vascular injury, with a marked increase in CD and endothelin-1 production. In addition, there was a substantial increase in both AST and CK levels, signifying significant tissue injury.
WBC count
The prebypass total WBC count was 5.5 ± 0.7 x 103 cells/mm3, which was not statistically different between groups. The WBC count was reduced with CPB to 3.5 ± 0.4 x 103 cells/mm3 by the end of cooling but was once again not significantly different between groups. However, in pigs receiving modified reperfusion, the WBC count decreased to 0.2 ± 0.1 x 103 cells/mm3 after filtering the bypass prime through the CoBRA filters. Five minutes after rewarming, the WBC count increased to only 1.6 ± 0.6 x 103 cells/mm3 in the leukocyte-depleted pigs, whereas the WBC count increased to 4.5 ± 0.9 x 103 cells/mm3 in the unfiltered nonischemic (control) and DHCA animals receiving an unmodified reperfusate. Four hours after bypass was discontinued, the WBC remained slightly lower in pigs receiving a modified reperfusate with leukocyte depletion (6.3 ± 1.1 x 103 cells/mm3) compared with that seen in control and unmodified pigs (7.9 ± 1.4 x 103 cells/mm3), but this was not statistically different (P > .2) and was higher than prebypass levels in all groups.
Neurologic function
In nonischemic (control) pigs postoperative neurologic function was almost completely normal, with minimal impairment (Figure 3
). However, pigs receiving an unmodified reperfusate after circulatory arrest had severe neurologic impairment, indicating substantial neurologic damage. They all had a severely depressed level of consciousness and were unable to stand or walk. In addition, 2 of 5 animals experienced generalized tonic clonic seizure activity. In contrast, the neurologic injury was substantially reduced in pigs receiving a modified reperfusate, resulting in significantly less neurologic impairment and no postoperative seizure activity. These pigs only had mild alterations in their levels of consciousness and were usually able to stand and walk.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAppendix: DiscussionReferences |
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13-15,19,20 Our study confirmed that DHCA, followed by normal blood reperfusion (uncontrolled), produces vascular, tissue, and neurologic damage, with cardiac and pulmonary dysfunction. In contrast, controlled reperfusion with a modified reperfusate limits the formation of oxygen-derived free radicals, resulting in preservation of vascular, cardiac, pulmonary, and neurologic function.
We and others have shown that negative consequences of unmodified blood can be substantially avoided in isolated studies of the heart, lung, kidney, and skeletal muscle by controlling the initial period of reperfusion. 1,2,5-12 Our global results are consistent with prior observations of the effects of controlled reperfusion in isolated organs. Controlled reperfusion has not previously been studied globally or locally in the brain. This study indicates that the principles of controlled reperfusion are effective in the brain because the neurologic score was significantly improved with a modified reperfusate, and no pig had seizures. A potential drawback is that we did not examine the brain histologically or look at biochemical markers of brain injury (ie, S-100 protein or neuron-specific enolase). Neurologic deficit scoring, however, directly correlates with pathologic, as well as biochemical, markers of injury. 18,20-22 A similar correlation has also been seen with the production of oxygen-derived free radicals, which were substantially reduced with controlled reperfusion.
A second potential limitation is that the observation period was limited, with a neurologic assessment only performed 6 hours after bypass. However, leukocyte depletion alone has been shown to significantly reduce neurologic damage after DHCA in animals observed for up to 7 days. 22 Moreover, these investigations used a Pall LG-6 filter, which is relatively inefficient. In contrast, by using more efficient filters (as was done in the present study), as well as by modifying the constituents of the solution, vastly improved results in individual organs have been shown. 2,4,7,11,12,23,24 We therefore believe that even in the absence of biochemical or histologic data, our findings confirm that controlled reperfusion significantly reduces neurologic injury. However, future studies will be needed to more precisely define the role of controlled reperfusion in limiting neurologic damage.
Each modification of the bypass prime was based on the principles established in individual organs. 1,2,4,7,10,12 Calcium is one of the primary mediators of the reperfusion injury and may be the common pathway leading to cellular death. 2,25 Reperfusion hypocalcemia was modulated in several ways. Citrate was added to directly reduce the ionized calcium levels. Magnesium levels were increased to both reduce intracellular calcium levels by inhibiting calcium entry across cellular membranes and to displace calcium from binding sites of the sarcolemmal membrane. 4,26 Postischemic calcium entry is further limited because magnesium prevents the influx of sodium, which, during reperfusion, is exchanged for calcium. This Na+/H+ exchange mechanism was also addressed by providing a (HOE 642) sodium hydrogen ion exchange inhibitor. Ischemia and hypoxia produce intracellular acidosis from anaerobic glycolysis. The sodium hydrogen ion antiporter becomes activated in an attempt to correct this acidosis, leading to sodium overload. 27,28 This sodium overload results in an intracellular calcium overload with reperfusion because sodium is exchanged for calcium. Exchange inhibitors, such as HOE 642, selectively block this antiporter, paradoxically preserving the intracellular acidosis but avoiding intracellular hypercalcemia and its associated injury. 27,28
The pH of the reperfusate was changed to pH-stat through the initial period of reperfusion to further limit sodium hydrogen ion exchange and calcium deposition by means of the same mechanism. Mannitol was added to reduce edema and may also be beneficial because it is a potential oxygen radical scavenger. 2 The specific benefits of individual components is unknown because these factors interact. Each component was found to be important in individual organs, and for this reason, we applied these individual principles in an integrated way in constructing the global modified solution used in this study. 1,2,4
Although WBCs are involved mainly in the maintenance of the immune system, under certain pathologic conditions of altered physiology, they may cause damage to myocardial, pulmonary, or vascular tissue. 4,7,23,24 Leukocyte depletion is a readily available method that allows the surgeon to safely minimize the harmful effects of neutrophils, without risking side effects of pharmacologic interventions aimed at altering leukocyte function or preventing the free radical injury through the use of exogenous oxygen radical scavengers. WBCs have a variety of deleterious effects. 4,7,23,24,29 Under conditions of hypoxemia or ischemia, vascular endothelium expresses sites that bind neutrophils on reperfusion. Once bound, the neutrophil may be activated by several different mechanisms. The bound, activated neutrophil is then involved in pathways that contribute to cellular injury in addition to releasing substances that are chemotactic for other neutrophils and macrophages, resulting in an amplification of the inflammatory response. Although WBCs can injure tissue by means of several mechanisms, numerous studies have demonstrated that the production of oxygen radicals is probably the major factor responsible for cellular damage. 4,7,12,23,24,29 This explains the reduction in oxygen-derived free radical formation (lower CD) in pigs receiving leukocyte depletion, as well as the reduction in vascular damage (decreased endothelin-1), because activated WBCs cannot bind to the vascular endothelium if they are removed.
Leukocyte depletion was accomplished by using 2 different types of filters. First, a CoBRA filter was used during circulatory arrest to completely leukocyte deplete the bypass prime. The CoBRA filter is extremely efficient and removes greater than 99% of WBCs in a single pass. 30 It also attenuates the membrane attack complex, which can damage membranes directly. However, the CoBRA filter can only accommodate flows of up to 150 mL/min and becomes fully saturated after 500 to 750 mL of blood. We therefore, used 3 CoBRA filters in parallel to completely leukocyte deplete the prime. We strongly believe blood in the bypass prime should always be completely leukocyte depleted because oxygen-derived free radical formation is greatest with the initial reintroduction of oxygen and blood during reperfusion. 7,23,24,29 An LG-6 filter was placed in the arterial line to continue the beneficial effects of leukocyte depletion. This filter can accommodate flows of up to 6 L/min for 1 to 2 hours before becoming saturated. It is less efficient in removing WBCs and instead removes neutrophils slowly over time. It also does not attenuate the membrane attack complex. The LG-6 filter, however, removes a significant number of WBCs at lower flow rates (1-2 L/min) because WBC removal is flow dependent. Therefore, an LG-6 filter is still very effective at reducing leukocytes in infants and small children. Use of inefficient WBC filters, coupled with leukocyte depletion during times that are less critical, probably explains why some investigators have failed to demonstrate a clinical advantage with WBC filtration, despite overwhelming experimental evidence to their benefit. 7,12,23,24 Clearly, a more efficient in-line arterial filter that substantially reduces leukocyte counts in a single pass over the entire bypass run would be ideal. However, until such filters are commercially available, clinical improvement will probably only be seen when WBC filters are used in a specific manner and directed at distinct events.
The management of blood pH during CPB remains a source of controversy and a subject of considerable recent clinical and laboratory investigations. Surgeons have sometimes taken adversarial approaches to pH management during DHCA, advocating either pH-stat or alpha-stat exclusively. Each strategy has its own advantage, and they may be integrated. 13,14,19-22,31 pH-stat results in cerebral vasodilatation with more homogeneous brain perfusion, as well as more rapid cooling and rewarming. However, by leaving the cell in an acidic environment, pH-stat inhibits cellular metabolism during ischemia. An alternative may be pH-stat during cooling, followed by alpha-stat before circulatory arrest to delay evolving acidosis during ischemia. In contrast, alpha-stat causes cerebral vasoconstriction and reduced cerebral perfusion, leading to longer cooling and rewarming times. This may be particularly detrimental in the setting of increased pulmonary collaterals that compete for blood flow when perfusion pressure is fixed by CPB flow rate. The more alkaline pH of alpha-stat reduces pulmonary resistance and increases cerebral resistance, thereby increasing competition for blood flow between the cerebral and the pulmonary circulation. However, maintaining a more alkaline environment by means of late alpha-stat can help preserve and optimize enzymatic function in the face of ischemia. Therefore, a combined approach takes advantage of the strength while minimizing the weakness of each strategy.
We used an alpha-stat strategy in this study because it is commonly used in numerous institutions and is probably superior during the period of circulatory arrest because it preserves cellular metabolism during ischemia. 13,14,19,20,22,31 A pH-stat strategy was used in the modified reperfusion group for the first 10 minutes of reperfusion to limit sodium hydrogen ion exchange and calcium deposition. Although pH-stat is probably also the optimal method for cooling and rewarming, it was only used for the first 10 minutes of rewarming to limit the differences between experimental groups. However, we believe that the ideal approach would be to integrate these 2 strategies by using pH-stat for longer intervals of cooling, rewarming, and reperfusion and to use alpha-stat just before the period of circulatory arrest. This may mimic hyperventilation before apnea, a helpful strategy.
A similar adversarial approach has occurred with oxygen strategy. Hyperoxia substantially increases an oxygen-mediated injury after hypoxia or ischemia. 16,17,23,29 In contrast, maintaining normoxia (PO2 of 80-100 mm Hg), rather than hyperoxia, during the initiation of CPB can substantially reduce oxidant damage and decrease the extent of tissue injury. 16,23 These benefits coincide with the PO2-dependent nature of the injury because free radical production and myocyte injury after reoxygenation or reperfusion of isolated heart preparations are proportional to PO2. 16,23 In clinical practice, hyperoxic bypass is performed routinely but likely never needed because a PO2 value of greater than 100 to 150 mm Hg confirms only a negligible increase in oxygen content and has been associated with an impairment in peripheral perfusion. 23,32 The only exception is during a period of DHCA, when high oxygen levels have been shown to improve neuroprotection. 19,33 However, these same studies found that initiating CPB after DHCA with a normoxic strategy significantly reduced formation of oxygen-derived free radicals. Therefore, as with pH strategy, an integrated approach making use of both normoxic and hyperoxic management probably provides the optimal therapy. This may provide balance through hyperoxia before arrest (DHCA) to raise cerebral PO2 levels and slow depletion during ischemia: a preischemic preconditioning mechanism. Conversely, normoxic reperfusion can limit oxidant injury because flow is ensured by the CBP circuit.
Pigs in this study underwent 90 minutes of DHCA, which is significantly longer than what is commonly used in the clinical setting. However, these were normal, unstressed pigs. In contrast, most patients with cardiovascular disease are stressed by a variety of factors (ie, hypoxia, ischemia, acidosis, or pressure-volume overload) that may make them substantially less tolerant to the ischemic insult of DHCA. A similar evolution may occur in adults subjected to circulatory arrest (ie, aortic aneurysm procedures).
Even with a shorter period of circulatory arrest, any injury is unacceptable in the brain, which is extremely sensitive to ischemia and reperfusion. In addition, when combined with other necessary interventions (ie, cardioplegic arrest or prolonged CPB), a shorter period of circulatory arrest may still adversely affect the postoperative function in less susceptible organs.
Controlled reperfusion is not just changing the reperfusate but also the conditions of reperfusion. 1,2,10 A lower initial reperfusion pressure (20-30 mm Hg) has been shown to reduce cellular damage in the heart, lung, and brain. 2,4,10,14 When given before ischemia (pretreatment), numerous substances have also been found to lessen the reperfusion injury. For instance, sodium hydrogen ion exchange inhibitors (HOE 642) are much more effective if given before ischemia. 27,28 In a sense, 100% oxygen is a pretreatment because it leaves the cell in an environment for maximal energy production and reduces the damage during ischemia. Using the same low perfusion pressure in both groups and, with the exception of 100% oxygen, avoiding pretreatment allowed us to examine the effects of the global reperfusate, without other compounding variables. However, lower initial pressure and pretreatment are both important adjuncts in limiting reperfusion damage and should always be used in concert with a modified reperfusate.
In conclusion, this study confirms that a reperfusion injury occurs after DHCA and demonstrates that it can be significantly avoided by controlling the initial period of reperfusion with a global modified prime. Incorporating this modality will allow surgeons to reduce the damage after DHCA, leading to a significant reduction in morbidity and mortality and improved patient outcome.
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Appendix: Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAppendix: DiscussionReferences |
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Dr Allen. I am often asked this question when I talk about our cardioplegic (reperfusate) solution, which is the basis for this approach. The answer is, every component is important. White cell filtration probably results in the biggest improvement, but every component makes a difference. Each acts in a specific way to limit the reperfusion injury. It is like asking what is the most important instrument in an orchestra. The answer is the one that is missing.
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Acknowledgments |
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References |
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