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J Thorac Cardiovasc Surg 2004;127:51-56
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Improved cerebral protection through replacement of residual intracavital air by carbon dioxide: A porcine model using diffusion-weighted magnetic resonance imaging

S. Martens, MDa,*, A. Theisen, DVMb, J. O. Balzer, MDc, M. Dietrich, MDa, K. Graubitz, MDa, M. Scherer, MDa, C. Schmitzc, M. Doss, MDa, A. Moritz, MD, PhDa

a Department for Thoracic and Cardiovascular Surgery,, University Hospital J. W. Goethe, Frankfurt am Main, Germany
b Central Research Facility,, University Hospital J. W. Goethe, Frankfurt am Main, Germany
c Department of Diagnostic and Interventional Radiology, University Hospital J. W. Goethe, Frankfurt am Main, Germany

Received for publication November 22, 2002; revisions received January 9, 2003; accepted for publication March 11, 2003.

* Address for reprints: Sven Martens, MD, Klinikum der J. W. Goethe-Universität Klinik für Thorax-Herz und thorakale Gefässchirurgie, Theodor Stern Kai 7, D-60529 Frankfurt am Main, Germany
martens.herz{at}gmx.de


   Abstract
Top
 Abstract
Material and methods
 Results
 Conclusions
 References
 
BACKGROUND: Major risk of central or peripheral organ damage is attributed to air embolism from incompletely de-aired cardiac chambers after cardiac operations. Replacement of air by carbon dioxide insufflation into the thoracic cavity is widely used. Diffusion-weighted magnetic resonance imaging of the brain detects ischemia within minutes after onset. The reversibility of ischemia in cerebral tissue after massive gaseous emboli has not yet been described.

METHODS: After selective catheterization of a common carotid artery in 15 pigs, boli of 1 mL/kg body weight of air (n = 5) or carbon dioxide (n = 5, "low dose") were applied. Five pigs received 2 mL/kg body weight of carbon dioxide ("high dose"). Diffusion-weighted magnetic resonance imaging of the brain was performed 2, 5, 10, 15, and 25 minutes after embolization.

RESULTS: All animals of the "air" group showed important circulatory reactions leading to death of 2 animals. In the whole group, diffusion-weighted magnetic resonance imaging revealed irreversible hyperintense signals in both hemispheres. In the low-dose group, no change in signal intensity was observed in 2 pigs, and 3 others showed reversible changes in signal intensity, without important circulatory reactions. In 3 animals of the high-dose group, hyperintense signals were reversible, but 2 others presented with bilateral, irreversible signals in diffusion-weighted magnetic resonance imaging, accompanied by minor circulatory reactions.

CONCLUSION: In contrast to the dramatic effect of air emboli, identical quantities of carbon dioxide injected into cerebral arteries of the pigs were not associated with major clinical symptoms. The early reversibility of ischemic reactions visualized in diffusion-weighted magnetic resonance imaging encourages the use of carbon dioxide insufflation as a protective method in cardiac surgery.

As reported in the literature, neurocognitive impairment has been observed in up to 88% of patients after cardiac surgery. The disturbances may be progressive and persistent.1 Introduction of air into the cardiopulmonary bypass circuit, resulting in gaseous microembolization, may contribute to postoperative cognitive impairment.2 Transcranial Doppler studies performed in cardiac procedures revealed large amounts of gaseous emboli during the first ejections of the heart after release of the aortic crossclamp, even after de-airing procedures have been carefully performed.3 With the advent of minimally invasive valve surgery through limited incisions, de-airing of cardiac chambers has become more difficult, and replacing air in the operative field by a more soluble gas has become a widely used technique. Carbon dioxide fills the thoracic cavity by gravity and replaces air if adequately insufflated.4

Webb and coworkers5 demonstrated a reduction of gas bubbles in cardiac chambers visualized by transesophageal echocardiography when carbon dioxide was insufflated into the operative field. However, even with carbon dioxide protection, residual gas bubbles in the cardiac chambers may dislodge to cerebral arteries. Gas emboli always remain in the arterial circulation until complete absorption.6 Because solubility of carbon dioxide is better than that of air, occlusion or blood flow disruption in cerebral arteries is thought to be diminished if air is effectively replaced by carbon dioxide. Differences regarding tissue damage caused by embolization of air or carbon dioxide have already been reported by Eguchi and coworkers7 in 1963. The aim of our present study was to visualize ischemic lesions in brain tissue resulting from embolization of air or carbon dioxide to cerebral vessels, focusing on a possible reversibility of the lesions.


   Material and methods
Top
 Abstract
 Material and methods
Results
 Conclusions
 References
 
Diffusion-weighted magnetic resonance imaging (DWI) was introduced in the early 1980s as a diagnostic method for early stroke detection. Cell swelling after ischemia in brain tissue leads to a reduction of the extracellular space, leading to restriction of proton spin movements. DWI sequences visualize ischemic regions as hyperintense signals, an enhancement of the signal intensity of 20% was found predictive for the evolving infarction size.8 Ischemic lesions are detected within minutes after onset of acute perfusion abnormalities with DWI, long before conventional T2- weighted MRI or computed tomography indicate ischemia.9 In the present study, the DWI sequences were performed with a 1.5-tesla magnetic resonance imager (Magnetom Symphonie Quantum, Siemens Inc., Germany).

Fifteen German landrace pigs (mean weight 37.7 ± 6.1 kg) were assigned to 3 groups: The "air" group received 1 mL/kg body weight (BW) of air as boli into the common carotid artery, in the low-dose group 1 mL/kg BW of carbon dioxide was applied, and a third, the high-dose group, received 2 mL/kg BW of carbon dioxide (each group: n = 5). All animals received humane care in compliance with the "Guide for the care and use of laboratory animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996. The study was approved (No. F 93/20) by the state government.

Anesthesia was induced with ketamine hydrochloride (10 mg/kg injected intramuscularly.), xylazine (1 mg/kg intramuscularly) and midazolam (1 mg/kg intramuscularly). After endotracheal intubation, anesthesia was maintained with midazolam (1 mg · kg-1 · h-1 intravenously) and buprenorphine (0.005-0.01 mg/kg intravenously), allowing for spontaneous breathing supported with oxygen (2-3 L/min). Vital functions were monitored with a pulse oxymeter and a finger clip sensor placed on the tail (OxyShuttle, Critikon Inc., Yorba Linda, Calif). After puncturing of the common femoral artery and introduction of a 6F introducer sheath, a 5F multipurpose diagnostic catheter (Cordis Inc, Miami, Fla) was placed in the left common carotid artery by the Seldinger technique under angiographic control. The animals were placed in the magnetic resonance system in the supine position. After positioning of the head in the head coil and appropriate fixation, the measurements were started using a standard head localizing sequence in 3 slice orientations. According to these initial measurements, positioning of the DWI sequences was performed (repetition time [TR] 220; echotime [TE] 139; Flip-Angle 90). DWI sequences were achieved (Figure 1) before (A), 2 minutes after (B), 5 minutes after (C), 10 minutes after (D), 15 minutes after (E), and 25 minutes after gas injection into the common carotid artery as a bolus. Vital parameters such as heart rate and oxygen saturation were monitored during and after gas application, if manual ventilation or inotropic drug application was mandatory for resuscitation, the next DWI sequence had to be delayed. In case of unsuccessful resuscitation, following DWI sequences were cancelled. After completion of the last sequence, the animals were put to death with intravenous injection of T61. DWI sequences were analyzed focusing on an increase of signal intensity (>20%) regarded as ischemic lesions, and location of lesions in one or both hemispheres of the brain.



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  		Figure 1. DWI sequences for the "air" group before (A), 2 minutes after (B), 5 minutes after (C), 10 minutes after (D), and 15 minutes after (E) gas injection. The sequence after 25 minutes had to be cancelled because of unsuccessful resuscitation. Five minutes after gas application, bilateral hyperintense signals were visible (C), gaining intensity in later sequences.

 

   Results
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 Abstract
 Material and methods
 Results
Conclusions
 References
 
Clinical reactions ranged from tachypnea in 2 animals receiving low-dose carbon dioxide to severe symptoms as bradycardia, apnea, and need for resuscitation due to cardiac arrest in pigs that were subject to air injection. These animals showed important circulatory reactions accompanied by generalized convulsions, leading to death of 2 pigs. DWI sequences revealed hyperintense signals in both hemispheres 5 minutes after air injection, only 1 animal did not show an increase of contralateral signal intensity. Because of unsuccessful resuscitation, the sequences remained uncompleted in 2 cases (see Figure 1, A-E). The clinical observations are described in Table 1, and results of DWI sequences are summarized in Table 2.


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  		TABLE 1. Clinical observations

 

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  		TABLE 2. Neuroradiologic results

 
In the low-dose group, no change in signal intensity was observed in 2 pigs, whereas 3 others showed reversible changes in signal intensity (see Figure 2, A-F), without important circulatory reactions. Tachypnea was observed in 2 pigs. In 3 pigs of the high-dose group, hyperintense signals were reversible, but 2 others presented with bilateral, irreversible signals in DWI (as demonstrated in Figure 3, A-F). Clinical reactions in this group varied from hyperventilation (1 pig) to apnea with need for manual ventilation accompanied by bradycardia in 1 animal. Even after application of high carbon dioxide quantities, 2 pigs showed no circulatory reactions. Generalized convulsions were not observed in this group; all animals survived.



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  		Figure 2. An example for the low-dose group (A-F). Two minutes after application, peripheral hyperintense signals occur (B), increasing in C and D, but completely reverting in E and F. The contralateral side remained unaffected.

 


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  		Figure 3. Results with high-dose application (A-F). As in the low-dose group, increase of signal intensity is already detected 2 minutes after application of gas (B), affecting the contralateral side (E).

 

   Conclusions
Top
 Abstract
 Material and methods
 Results
 Conclusions
References
 
Carbon dioxide is used to replace air in the operative field during cardiac procedures with the assumption that the more soluble carbon dioxide will reduce the amount and sequaele of gaseous emboli. Carbon dioxide may be resorbed already in the cardiac chambers, and so the amount of gas bubbles in the ascending aorta can be reduced as shown by an echocardiographic study.5 A protective effect may also result from quicker resorption of embolic bubbles obstructing a peripheral vessel, when they consist of a high concentration of carbon dioxide. After clinical studies on the efficiency of carbon dioxide insufflation to the thoracic cavity, 4,10 our group established a porcine model to demonstrate the sequelae of air or carbon dioxide emboli obstructing brain vessels. With diffusion-weighted MRI, ischemic regions of the brain can be visualized a few minutes after onset of ischemia.8,9

The gas quantities injected in our animal study largely exceed realistic amounts of air accidentally embolizing during cardiac surgery, but anatomic properties and the injection site necessitate these dosages in animal models. They are comparable to the gas quantities injected by Eguchi and coworkers.7 This group found extensive necrotic areas after air injection; after application of carbon dioxide only minor tissue damage was revealed by histologic examination. Disturbances in cognitive and motor functions of dogs were observed with carbon dioxide quantities exceeding 4 mL/kg. In the group that received air, half of the animals died with generalized convulsions after injection of 2 mL/kg.7 An increase of carbon dioxide partial pressure (PCO2) leads to increased cerebral blood flow through a decrease of vascular resistance. Cerebral autoregulation is impaired.11,12 In contrast to our results obtained with massive embolization, the reversible DWI signals (low-dose group and—in part—high-dose group) were always located in peripheral brain regions, possibly influenced by a loss of vascular tonus after carbon dioxide application. Dissolution of residual carbon dioxide in the capillary bed explains reversibility of ischemia in the low-dose group and 3 pigs of the high-dose group.

In our study, massive gas embolization led to occlusion of cerebral arteries with consecutive persistent impairment of organ perfusion, characterized by irreversible hyperintense signals located centrally in both hemispheres. Circulatory failure and generalized convulsions in the "air" group indicate a massive cerebral infarction. In DWI, bilateral hyperintense signals were visualized 5 minutes after gas application. The fact that tissue damage is also detected contralaterally to the side of injection can be explained by the extensive collateralization of the brain vasculature in pigs.13 In 2 animals of the high-dose group, the increase in signal intensity with bilateral extension was irreversible, thus indicating that excessive amounts of carbon dioxide may also cause long-lasting disruptions of organ perfusion. However, clinical and neuroradiologic changes after injection of carbon dioxide in high doses (100 mL in a 50-kg pig) were mild compared with those after air injections (in lower doses).

Regarding clinical observations and results of DWI, a possible contamination with air in both carbon dioxide groups has to be discussed. However, even with improved methods of carbon dioxide insufflation into the operative field, the carbon dioxide concentration approaches, but seldom reaches, 100%.4 Our animal model reproduces incomplete de-airing procedures of cardiac chambers and embolic accidents caused by air trapped in the arterial line of the cardiopulmonary bypass equipment, resulting in gaseous macroembolization and microembolization.

Massive embolization of carbon dioxide may cause clinical complications.14 The persistence of ischemic areas and circulatory reactions in our high-dose group confirm these reports. The use of carbon dioxide for digital subtraction angiography is limited to subphrenic application by most radiologists, because there is concern about possible stroke and disruption of the blood-brain barrier with excessive volume of the gas.15 Compared with the dramatic reactions provoked by injection of air, residual carbon dioxide in cerebral vessels causes minor sequelae, justifying efforts to replace intracavital air by carbon dioxide in cardiac surgery. Besides reduction of residual gas in cardiac chambers after de-airing, reversibility of vessel obstruction by carbon dioxide and consecutive reperfusion contribute to the protective effect of carbon dioxide insufflation into the thoracic cavity.


   References
Top
 Abstract
 Material and methods
 Results
 Conclusions
 References
 

  1. McKhann GM, Goldsborough LM, Borowicz MS, et al. Cognitive outcome after coronary artery bypass: a one-year prospective study. Ann Thorac Surg. 1997;63:510–515[Abstract/Free Full Text]
  2. Borger MA, Peniston CM, Weisel RD, Vasiliou M, Green REA, Feindl CM. Neuropsychologic impairment after coronary bypass surgery: effect of gaseous microemboli durino perfusionist interventions. J Thorac Cardiovasc Surg. 2001;121:743–749[Abstract/Free Full Text]
  3. van der Linden J, Casimir-Ahn H. When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann Thorac Surg. 1991;51:237–241[Abstract/Free Full Text]
  4. Martens S, Dietrich M, Doss M, Wimmer-Greinecker G, Moritz A. Optimal carbon dioxide application for organ protection in cardiac surgery. J Thorac Cardiovasc Surg. 2002;124:387–391[Abstract/Free Full Text]
  5. Webb WR, Harrison LH, Helmcke FR, et al. Carbon dioxide field flooding minimizes residual intracardiac air after open heart operations. Ann Thorac Surg. 1997;64:1489–1491[Abstract/Free Full Text]
  6. Branger AB, Eckmann DM. Theoretical and experimental intravascular gas embolism absorption dynamics. J Appl Physiol. 1999;87:1287–1295[Abstract/Free Full Text]
  7. Eguchi S, Sakurai Y, Yamaguchi A. The use of carbon dioxide gas to prevent air embolism during open heart surgery. Acta Med Biol. 1963;11(1):1–3
  8. Wittsack HJ, Ritzl A, Fink GR. MR imaging in acute stroke: Diffusion-weighted and perfusion imaging parameters for predicting infarct size. Radiology. 2002;222:397–403[Abstract/Free Full Text]
  9. Warach S. Use of diffusion and perfusion magnetic resonance imaging as a tool in acute stroke clinical trials. Curr Control Trials Cardiovasc Med. 2001;2:38–44
  10. Martens S, Dietrich M, Wals S, Steffen S, Wimmer-Greinecker G, Moritz A. Conventional carbon dioxide application does not reduce cerebral or myocardial damage in open heart surgery. Ann Thorac Surg. 2001;72:1940–1944[Abstract/Free Full Text]
  11. Williams DJ, Doolette DJ, Upton RN. Increased cerebral blood flow and cardiac output after cerebral arterial air embolism in sheep. Clin Exp Pharmacol Physiol. 2001;28:868–872[Medline]
  12. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:45–52[Abstract/Free Full Text]
  13. Sedlarik K, Endler S, Hindersin P, Weidenbach H. Experimentelle Thrombosen der A. carotis interna im Tierversuch als Voraussetzung für Modelstudien der akuten Hirnischämie. Zbl. Neurochirurgie. 1984;45:141–146
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