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J Thorac Cardiovasc Surg 1999;117:1166-1171
© 1999 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

OXYGENATION STRATEGY AND NEUROLOGIC DAMAGE AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST. I. GASEOUS MICROEMBOLI

Georg Nollert, MD, Mitsugi Nagashima, MD, Jan Bucerius, MD, Toshiharu Shin'oka, MD, Richard A. Jonas, MD

From the Department of Cardiac Surgery, Children's Hospital, and the Department of Surgery, Harvard Medical School, Boston, Mass.

Supported by a Habilitandenstipendium of the Deutsche Forschungsgemeinschaft NO344/1-1 (G.N.).

Received for publication Aug 28, 1998. Revisions requested Oct 30, 1998. Revisions received Feb 2, 1999. Accepted for publication Feb 19, 1999. Address for reprints: Richard A. Jonas, MD, Department of Cardiac Surgery, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Objectives: Recent studies suggest that myocardial reperfusion injury is exacerbated by free radicals when pure oxygen is used during cardiopulmonary bypass. Partial replacement of the oxygenator gas mixture with nitrogen, however, such as has already been adopted clinically in many centers, could increase the risk of gaseous nitrogen microembolus formation and therefore of brain damage because of the low solubility of nitrogen, particularly under conditions of hypothermia.
Methods: Ten 7- to 10-kg piglets were cooled for 30 minutes to 15°C on cardiopulmonary bypass and then rewarmed for 40 minutes to 37°C. In 5 piglets cardiopulmonary bypass was normoxic and in 5 it was hyperoxic. In each group 3 bubble oxygenators without arterial filters and 2 membrane oxygenators with filters were used. Cerebral microemboli were monitored continuously by carotid Doppler ultrasonography (8 MHz) and intermittently by fluorescence retinography.
Results: Embolus count was greater with lower rectal temperature (P < .001), use of a bubble oxygenator (P < .001), and lower oxygen concentration (P = .021) but was not affected by the temperature gradient between blood and body during cooling or rewarming.
Conclusions: Gaseous microemboli are increased with normoxic perfusion, but this is only important if a bubble oxygenator without a filter is used. (J Thorac Cardiovasc Surg 1999; 117:1166-71)


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In the early years of oxygenator technology pure oxygen was used as a safety measure to ensure sufficient blood oxygenation. Recent experimental and clinical data, however, suggest that the hyperoxygenation achieved with modern oxygenators during reperfusion aggravates ischemia-reperfusion injury through generation of oxygen free radicals, particularly in the heart.Go Go 1-3 Normoxic cardiopulmonary bypass (CPB) has therefore been advocated and is now part of clinical practice in many centers. In normoxic CPB oxygen is replaced by nitrogen. Because nitrogen is less soluble than oxygen, we speculated that normoxic CPB might increase gaseous microemboliGo 4 and reduce brain oxygen supply, with the potential to overwhelm any beneficial effects against reoxygenation injury. The aim of this study was therefore to investigate the effects of normoxic and of hyperoxic CPB on neurologic outcome in a piglet model of prolonged deep hypothermic circulatory arrest. In the first phase of the study the influence of normoxia on the number of gaseous emboli passing to the brain was investigated. Cerebral oxygenation and brain injury were assessed in the second phase.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experimental preparation
Yorkshire piglets weighing 7.2 to 10.2 kg (mean 8.6 kg) were anesthetized with 15 to 20 mg/kg intramuscularly injected ketamine and intubated with a 5-mm cuffed endotracheal tube. The animals were ventilated with a pressure-controlled ventilator (Healthdyne model 105; Respironics, Inc, Pittsburgh, Pa) with a peak inspiratory pressure of 25 cm H2O and an inspired oxygen fraction (FIO2) of 0.3 (normoxic group) or 1.0 (hyperoxic group) at a rate of 12 breaths/min. After an intravenous bolus of 25 µg/kg fentanyl and 0.5 mg/kg pancuronium bromide, anesthesia was maintained by continuous infusion of 20 to 40 µg · kg–1 · h–1 fentanyl and 0.2 mg · kg –1 · h–1 pancuronium bromide throughout the entire experiment. Esophageal and rectal temperatures were recorded continuously. The left femoral artery was cannulated for arterial blood pressure monitoring and blood gas sampling. After exposure of the left internal jugular vein, a catheter was placed in the jugular bulb to allow blood withdrawal. The chest was opened by a median sternotomy. After systemic heparinization (300 IU/kg heparin), a 10F arterial cannula (Medtronic DLP, Grand Rapids, Mich) and 24F venous cannula (USCI Division, C.R. Bard Inc, Billerica, Mass) were inserted into the ascending aorta and the right atrium, respectively.

All animals received humane care in compliance with the "Principles of Laboratory Animal Care," formulated for the National Society for Medical Research, and the "Guide for the Care and Use of Laboratory Animals," prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).

CPB technique. The CPB circuit consisted of a roller pump (Cardiovascular Instrument Corp, Wakefield, Mass), sterile tubing (OLSON Medical Sales Inc, Ashland, Mass), and either a membrane oxygenator (VPCML plus; COBE Cardiovascular, Inc, Arvada, Colo) with 40-µm arterial filter (pediatric extracorporeal blood filter; Pall Biomedical, Inc, Fajardo, PR) or a bubble oxygenator (Bentley Bio2; Baxter Healthcare Corporation CardioVascular Group, Irvine, Calif) without any arterial filter system. The pump prime consisted of a balanced electrolyte solution and freshly drawn heparinized blood to achieve a hematocrit between 20% and 25% during CPB. The prime was dosed with 25 mg/kg cefazolin sodium, 30 mg/kg methylprednisolone sodium succinate, 0.25 µg/kg furosemide, and 10 mL sodium bicarbonate. Full bypass flow was set at 100 mL · kg–1 · min–1. The animal was immediately cooled to an esophageal temperature of 15°C during 30 minutes according to alpha-stat strategy, which was selected to avoid the complexity of blending 3 gases in the laboratory setting and because of its current widespread clinical use. Ventilation was stopped after the establishment of CPB. After 30 minutes of cooling, 0.25 mg/kg furosemide, 0.5 g/kg mannitol, and 10 mL sodium bicarbonate were administered into the pump. The animal was then rewarmed to a temperature of 37°C during 40 minutes. The heart was defibrillated as necessary at 25°C. Fresh whole blood was transfused into the pump as required to increase the hematocrit to a range of 20% to 25% during rewarming.

Data collection
Doppler ultrasonography. An 8-MHz continuous-wave probe placed directly over the right common carotid artery was connected to a TCD monitor (MedaSonics CDS; Nicolet Biomedical Inc, Madison, Wis) and both the acoustic and video signals were recorded continuously on tape during CPB. Criteria for emboli were a sudden and sharp increase of the visual signal of more than 30% (Fig. 1) and a high pitched sound similar to chirping or whistling.Go 4 Quantification of emboli by this method is limited to approximately 150 emboli/min, because the signals cannot be discriminated at higher embolic rates. Higher counts of emboli were therefore arbitrarily recorded as 150 emboli/min, as previously suggested,Go 4 although embolus counts might have exceeded 500 emboli/min at low temperatures.



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  		Fig. 1 Monitoring of emboli during CPB by Doppler ultrasonography. An 8-MHz continuous-wave Doppler flow probe was placed over right common carotid artery. The x-axis shows time frame of 6 seconds. A, Typical flow pattern during CPB in piglet operated on with membrane oxygenator and 40-µm arterial filter. B-D, Increasing numbers of emboli during cooling in pig operated on with bubble oxygenator without filter. Emboli are characterized visually by a sharp increase of more than 30% of signal. Blood foam containing massive amounts of gas bubbles were injected at end of experiment. E, Onset of this massive air embolism. F, Peak of embolism.

 
Retinal angiography. Retinography of the left eye was performed with a fundus camera (APC; Nikon Corporation, Tokyo, Japan) and intravenous injection of 0.3 mL fluorescent dye (AK-Fluor 10%; Akorn Ophthalmics, Buffalo Grove, Ill). The signal was recorded with a professional videocassette recorder (VCR VO5600; Sony Corporation, Tokyo, Japan) and digitized for later analyses.

Blood gas values and biochemical analyses. Arterial and venous (jugular bulb) blood gas values, including electrolyte, glucose, and lactate levels, were measured (Nova 900; Nova Biomedical, Waltham, Mass) at baseline, 5 minutes after start of CPB, every 10 minutes during CPB, 30 minutes after the end of CPB, and at the end of the experiment.

Experimental groups
In 5 piglets CPB was normoxic (FIO 2 20%-40%) and in 5 it was hyperoxic (FIO 2 100%). In each group bubble oxygenators without arterial filters were used for 3 animals and membrane oxygenators with 40-µm filters were used for 2 animals. At the end of the experiment in each group gas bubbles were directly injected into the aortic cannula to validate the methods used for embolus detection.

Statistical analysis
All results were expressed as mean and standard error of the mean. The Student t test was used to compare absolute quantitative values between the groups. To assess differences between time points within groups the paired t test was used, and if applicable the results were corrected for multiple testing according to the method of Bonferroni. Correlation coefficients were calculated according to the method of Pearson for continuous data; Spearman coefficients were calculated for discrete data. Multiple stepwise linear regression was performed by the backward elimination method with an entry criterion of P < .10 and a criterion of P < .05 for being kept in the model. Statistical analyses were facilitated with the help of SPSS statistical software (version 7.0 for Windows; SPSS Inc, Chicago, Ill).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Doppler ultrasonography
Embolus counts increased during cooling (Fig. 1Go; Table I) and decreased during rewarming with both types of oxygenator. They were significantly lower at every time point during CPB with membrane oxygenators with filters than with bubble oxygenators without filters (P < .001).


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  		Table I. Embolus counts in the carotid artery
 
Multiple regression analysis revealed that embolus count correlated with lower rectal temperature (P < .001), type of oxygenator (greater with bubble oxygenators than with membrane oxygenators, P < .001) and PaO 2 (lower in hyperoxia group, P = .021, r = 0.788 for the model). Temperature gradients between blood and body showed no significant influence (P = .344). The embolus count at all times correlated positively with the lactate level (r = 0.3, P = .006).

Retinography
Retinography was feasible in all animals and demonstrated delayed filling of retinal vessels 5 minutes after rewarming. Gaseous emboli could not be detected retrospectively by discontinuous retinography (Fig. 2). Retinography demonstrated only temporary obstruction of retinal vessels after injection of massive air bubbles, with complete reopening within 2 minutes (Fig. 2, GoE-G).



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  		Fig. 2 Retinography during CPB. Fundus of pig is shown by conventional retinography (A). Fluorescent retinography of left eye was performed by venous injection of dye before aortic cannulation (B), 5 minutes after start of rewarming (C), and at end of rewarming (D). At end of experiment blood foam mixed with dye was injected into aortic cannula. E, Fundus before injection. F, Immediately after injection retinal vessels become obstructed. One minute later (G) all vessels opened up again.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Partially replacing oxygen in the oxygenator gas mixture with 70% to 80% nitrogen during hypothermia may reduce reoxygenation injury, but it increases the gaseous microembolic load to the brain if bubble oxygenators are used. This has been demonstrated in at least 1 previous study.Go 4 Nitrogen is much less soluble in blood than is oxygen, especially during hypothermia. Therefore there was a strong correlation between lower temperature and microembolus count, an association that was most significant for rectal temperature in our multiple regression model. Interestingly, temperature gradients during both cooling and rewarming had no influence on the number of emboli, although traditional perfusion dogma emphasizes an important role for the temperature gradient in causing gaseous microemboli. If conventional wisdom were accurate one would anticipate that the effect would be magnified with the addition of nitrogen. However, temperature gradients were not important either with or without nitrogen during either cooling or rewarming.Go 5

Further support for the concept that the gaseous microemboli detected in the carotid artery were not generated by gas coming out of solution because of rapid warming, either of the cold oxygenator blood during cooling or of the pig's cold arterial blood during rewarming, is provided by the observation that simply replacing a bubble oxygenator with a membrane oxygenator resulted in almost complete elimination of the microemboli. Perhaps gas coming out of solution could be important more distally in the arterial tree. The transducer used to detect microemboli in the common carotid artery was less than 10 cm from the arterial cannulation site in the ascending aorta. Assuming a flow velocity of more than 30 cm/s in the ascending aorta, bovine trunk, and carotid artery, warming and bubble formation would have to take place within 0.3 second.Go 6 There was no indication by retinography, however, that gaseous microemboli had an important role in permanently occluding small vessels more distally.

Retinography in fact proved to be remarkably insensitive in detecting gaseous microemboli. We were fortunate to be able to work with persons highly skilled in this technique and with state-of-the-art equipment from the Joslin Diabetes Center. We were therefore surprised when we were unable to demonstrate embolic vascular occlusions despite recording carotid microembolus counts greater than 500 emboli/min. This observation led us to conclude each study with the injection of a large amount of air directly into the aortic cannula, which revealed that the gaseous emboli caused obstruction of the retinal vessels for only a few seconds. Presumably the longer lasting occlusions of retinal vessels seen in previously reported clinical studiesGo 7 were caused by fat or by atherosclerotic particulate emboli. This is not to say that transient gaseous emboli are benign. Previous studies have shown that they can cause endothelial dysfunction, with leukocyte and platelet adhesion leading to eventual capillary obstruction.Go 8 In support of this observation is the correlation that we observed between lactate level and the carotid artery embolus count.

The brain is subjected to several possible sources of injury during correction of congenital cardiac anomalies. During circulatory arrest ischemia itself and the subsequent reperfusion can lead to brain injury caused by calcium influx; the neurotoxicity of excitatory neurotransmitters such as dopamine, glutamate, and aspartate; and lipid peroxidation caused by free radicals.Go 9 High oxygen pressures during reperfusion may aggravate reperfusion injury by increased formation of free radicals. For example, nitric oxide transformation to the cytotoxic peroxynitrite or hydroxyl radicals is more likely in the presence of high oxygen pressures.Go 10 CPB with F IO2 of 1.0 results in oxygen pressures of 400 mm Hg and greater. Ihnken and associatesGo 1 have reported higher lipid oxygenation, increased nitric oxide formation, and worse cardiac contractility after hypoxia and ischemia-reperfusion of immature canine hearts with hyperoxic management of CPB than with normoxic management. Laboratory studies elsewhere also have demonstrated beneficial effects for the brain of normoxic reperfusion with respect to hyperoxic reperfusion after ischemia. Reoxygenation with FIO 2 0.2 reduced oxygen radical–mediated injury of neurons and resulted in better recovery of dopamine metabolism than did reoxygenation with 100% oxygen after hypoxiaGo Go 11,12 and ischemiaGo 13 in pigs and rabbits. Graded postischemic reperfusion by increasing arterial FIO2 levels during 30 minutes from 0.1 to 0.21 showed further protective effects for neurons as long as 2 days after the operation.Go 14

Clinical studies comparing hyperoxic and normoxic management of CPB in cyanotic children have also revealed higher oxygen free radical damage after reperfusion, as assessed by products of lipid peroxidation.Go Go 2,3 However, these studies have not assessed the potential for greater hypoxic injury or injury related to increased gaseous microemboli. Many cardiac surgery centers have nevertheless changed during the last 5 years from hyperoxic to normoxic management of CPB, even though direct clinical benefit has not been demonstrated by any prospective trials.

If membrane oxygenators are used in conjunction with arterial line filters, normoxic oxygenation during CPB does not increase the number of gaseous cerebral microemboli. Bubble oxygenators without an arterial line filter should not be used for normoxic CPB. Traditional concepts regarding temperature gradients and risk of gaseous microemboli should be reexamined.


   Acknowledgments
 
We thank Mark Cioffi, Pascal Gebeyan, and Christine Rader, from the Department of Cardiac Surgery, and Gene Walter, from the Department of Neurology, for technical support during the operations. Assistance with data analysis by David Zuraowski, PhD, statistician, Department of Biostatistics, and Frank Perron, PhD, Joslin Diabetes Center, is greatly appreciated. We also acknowledge the assistance of Allen Clermont, MS, and Sven Bursell, PhD, from the Joslin Diabetes Center for assistance with retinography and Laverne Gugino, MD, for his assistance with carotid Doppler studies. We thank Laura Young for preparation of the manuscript.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Ihnken K, Morita K, Buckberg GD, Shermann MP, Young HH. Studies of hypoxemic/reoxygenation injury: without aortic clamping. III. Comparison of the magnitude of damage by hypoxemia/reoxygenation versus ischemia reperfusion. J Thorac Cardiovasc Surg 1995;110:1182-9.
  2. Bolling KS, Halldorsson A, Allen BS, Rahman S, Wang T, Kronon M, et al. Prevention of the hypoxic reoxygenation injury with the use of a leukocyte-depleting filter. J Thorac Cardiovasc Surg 1997;113:1081-9. [Abstract/Free Full Text]
  3. Allen BS, Rahman S, Ilbawi MN, Kronon M, Bolling KS, Halldorsson AO, et al. Detrimental effects of cardiopulmonary bypass in cyanotic infants: preventing the reoxygenation injury. Ann Thorac Surg 1997;64:1381-7.[Abstract/Free Full Text]
  4. Johnston WE, Stump DA, DeWitt DS, Vinten-Johansen J, O'Steen WK, James RL, et al. Significance of gaseous microemboli in the cerebral circulation during cardiopulmonary bypass in dogs. Circulation 1993;88:II319-29.
  5. Geissler HJ, Allen SJ, Mehlhorn U, Davis KL, de Vivie ER, Kurusz M, et al. Cooling gradients and formation of gaseous microemboli with cardiopulmonary bypass: an echocardiographic study. Ann Thorac Surg 1997;64:100-4.[Abstract/Free Full Text]
  6. Dexter F, Hindman BJ, Marshall JS. Estimate of the maximum absorption rate of microscopic arterial air emboli after entry into the arterial circulation during cardiac surgery. Perfusion 1996;11:445-50. [Abstract/Free Full Text]
  7. Blauth CI, Arnold VA, Schulenburg WE, McCartney AC, Taylor KM. Cerebral microembolism during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1988;95:668-76.[Abstract]
  8. Persson LI, Johansson BB, Hansson HA. Ultrastructural studies on blood-brain barrier dysfunction after cerebral air embolism in the rat. Acta Neuropathol (Berl) 1978;44:53-6.[Medline]
  9. Kjellmer I. Mechanisms of perinatal brain damage. Ann Med 1991;23:675-9.[Medline]
  10. Cazevieille C, Muller A, Meynier F, Bonne C. Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury. Free Radic Biol Med 1993;14:389-95.[Medline]
  11. Goplerud JM, Kim S, Delivoria-Papadopoulos M. The effect of post-asphyxial reoxygenation with 21% vs. 100% oxygen on Na+,K(+)-ATPase activity in striatum of newborn piglets. Brain Res 1995;696:161-4. [Medline]
  12. Halsey JH Jr, Conger KA, Garcia JH, Sarvary E. The contribution of reoxygenation to ischemic brain damage. J Cereb Blood Flow Metab 1991;11:994-1000.[Medline]
  13. Huang CC, Yonetani M, Lajevardi N, Delivoria-Papadopoulos M, Wilson DF, Pastuszko A. Comparison of postasphyxial resuscitation with 100% and 21% oxygen on cortical oxygen pressure and striatal metabolism in newborn pigs. J Neurochem 1995;64:292-8.[Medline]
  14. Feráková A, Halát G, Marala M, Lukáová N, Marala J. Graded postischemic reoxygenation reduces lipid peroxidation and reperfusion injury in the rabbit spinal cord. Brain Res 1992;593:159-67.[Medline]



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