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J Am Coll Cardiol, 2007; 49:606-607, doi:10.1016/j.jacc.2006.11.007 (Published online 19 January 2007).
© 2007 by the American College of Cardiology Foundation
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PRECLINICAL STUDY: EDITORIAL COMMENT

A Cool Heart Protected From Infarction

Clinical Translation of Breathing Chilled Liquids*

Wilbur Y.W. Lew, MD, FACC{dagger},*

{dagger} Cardiology Section 111A, Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California, San Diego, San Diego, California

* Reprint requests and correspondence: Dr. Wilbur Lew, Cardiology Section 111A, Department of Medicine, Veterans Affairs San Diego Healthcare System, University of California, San Diego, San Diego, California 92161. (Email: wlew{at}ucsd.edu).

Myocardial hypothermia effectively reduces infarct size in animal models (1–3), particularly when initiated early, rapidly, and maintained for the duration of ischemia. It has been difficult to translate this to the clinical setting because the methods used to induce hypothermia (e.g., cardiac surface cooling, arteriovenous extracorporeal heat exchangers, and peritoneal cooling) are impractical for rapid implementation with proven safety.


   Therapeutic Hypothermia
Top
 Therapeutic Hypothermia
Liquid Ventilation
 Clinical Applications
 References
 
External cold packs and mattresses have been used to induce hypothermia and improve neurologic outcomes in patients resuscitated after cardiac arrest with ventricular fibrillation in randomized, controlled trials (4,5). Core body temperatures were lowered to 32°C to 34°C over 2 to 4 h and maintained for 18 to 24 h without cardiac arrhythmias, increasing cardiac enzymes, or major adverse events. Endovascular cooling is another safe method for therapeutic hypothermia in survivors of cardiac arrest (6). An endovascular cooling catheter positioned in the inferior vena cava cools local circulating blood to lower systemic temperatures by 1.2°C/h.

Endovascular cooling has been performed safely in patients with acute myocardial infarction undergoing percutaneous coronary interventions (PCI) (7,8). Core temperatures were lowered to 34°C over 1 h, and hypothermia maintained for 3 h without significant arrhythmias or hemodynamic compromise. Shivering, which causes sympathetic activation that may exacerbate ischemia, was prevented by external warming and pharmacologic agents (buspirone and meperidine). These studies were not powered to determine if hypothermia reduced infarct size.

Although hypothermia induced over one or more hours is neuroprotective after cardiac arrest (4,5) and is safe in acute myocardial infarction (7,8), more rapid means for inducing hypothermia may be required to observe the marked cardioprotective effects achieved in preclinical studies. In this issue of the Journal, Tissier et al. (9) induced hypothermia in rabbits using liquid ventilation with cooled perfluorocarbon solutions to decrease left atrial temperature to 32°C within 5 min. Hypothermia reduced infarct size after ischemia-reperfusion by 90%. Hypothermia during reperfusion was ineffective. This study is appealing for clinical translation because of the rapidity of inducing hypothermia and the clinical safety of liquid ventilation (10,11).


   Liquid Ventilation
Top
 Therapeutic Hypothermia
 Liquid Ventilation
Clinical Applications
 References
 
Liquid ventilation utilizes the unique properties of perfluorocarbons (PFCs), which are stable and inert compounds with low surface tension that dissolve a large amount of respiratory gases at atmospheric pressure and body temperature (10,11). The high gas solubility of oxygen and carbon dioxide and low surface tension permit effective gas exchange.

Liquid ventilation provides thermal control of the central circulation and has been used for therapeutic hyperthermia and hypothermia, primarily in preclinical studies (11). The sole use of PFCs for gas exchange (tidal or total liquid ventilation) provides more efficient thermal exchange and stability than partial liquid ventilation, a hybrid technique where the lungs are filled to functional residual capacity with PFCs with tidal volumes of gas superimposed.

Over the last decade, liquid ventilation has been used to treat preterm neonatal and pediatric patients with acute lung injury and adults with acute respiratory distress syndrome (ARDS) in phase II/III clinical trials (10,11). Partial liquid ventilation caused only mild, self-limited adverse events including hypoxia, respiratory acidosis, and bradycardia in a randomized, controlled study with 90 ARDS patients (12). In a randomized controlled trial with 311 adult patients with ARDS, partial liquid ventilation was safe but lacked efficacy, with a failure to improve 28-day mortality or ventilator-free days (13). Adverse events including bradycardia, arrhythmia, and cardiac arrest, did not differ between groups, but there was a higher incidence of pneumothorax, hypoxia, and hypotension in patients treated with partial liquid ventilation compared with conventional mechanical ventilation (13). Hypoxia and hypotension were related to transient interruptions of ventilatory support for additional dosing of PFCs. Thus, partial liquid ventilation with PFCs is well tolerated and safe. There has been limited clinical experience with tidal liquid perfusion.


   Clinical Applications
Top
 Therapeutic Hypothermia
 Liquid Ventilation
 Clinical Applications
References
 
Liquid ventilation can induce cardiac hypothermia within minutes, which may effectively limit infarct size. The efficiency of inducing hypothermia is comparable to extracorporeal blood heat exchangers and greater than with endovascular cooling. However, the requirement for intubation and mechanical ventilation with chilled PFCs may delay definitive therapy with primary PCI, and thus limit its applicability in acute coronary syndromes or ST-segment elevation myocardial infarction. It is difficult to obtain a detailed medical history after a patient is intubated, which is a consequential limitation in this setting. However, in clinical scenarios where PCI is not immediately contemplated or available, liquid ventilation may be useful for limiting infarct size.

In patients with atherosclerotic vascular disease undergoing high-risk surgery, myocardial ischemia may occur as a complication that is not amenable to immediate coronary revascularization. Postoperative myocardial infarction occurs in 12% to 14% of men with stable coronary artery disease after elective major vascular surgery, regardless of whether or not they undergo coronary revascularization before surgery (14). Liquid ventilation can be applied readily in patients who are already intubated and mechanically ventilated. Hypothermia may limit infarct size from myocardial ischemia until the patient has stabilized and recovered from the stress and ischemic triggers associated with surgery and anesthesia. Similarly, in patients with myocardial ischemia due to profound blood loss or hypovolemia with hypotension, therapeutic hypothermia with liquid ventilation may limit infarct size during recovery after the underlying cause for acute myocardial ischemia is treated. Finally, liquid ventilation may be used to induce hypothermia within minutes in patients resuscitated after cardiac arrest to limit infarct size. These cardioprotective effects may be additive to the neuroprotection observed when hypothermia is induced over hours (4,5).

Potential problems with liquid ventilation include pneumothorax, transient hypotension, and hypoxia (13). The PFCs are radio-opaque and interfere with radiographic imaging, which can mask underlying pulmonary problems. Liquid ventilation is safe compared with conventional mechanical ventilation in ARDS (12,13), but in this setting ventilatory support is required to treat pulmonary abnormalities (e.g., pulmonary edema, inflammation, loss of surfactant, decreased lung compliance, etc.) that cause a high mortality. In the normal lung, liquid ventilation may worsen gas exchange by creating ventilation/perfusion mismatches and disturbing normal lung mechanics (10). Potential complications can be minimized by using liquid ventilation to rapidly induce cardiac hypothermia during the critical early hours of myocardial ischemia, and then implement (slower) nonventilatory methods to maintain hypothermia. The risks of brief ventilatory support with PFCs may be acceptable in view of the high risks associated with myocardial infarction and clear benefits derived from reducing infarct size.

In summary, liquid ventilation is a novel approach for rapidly inducing cardiac hypothermia with cardioprotective effects. Liquid ventilation with PFCs has been safely used in humans in clinical trials. This method may provide an opportunity to translate the benefits of cardiac hypothermia, which have been well documented in preclinical studies, to the clinical setting to limit infarct size in patients with myocardial ischemia.


   Footnotes
 
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. Back


   References
Top
 Therapeutic Hypothermia
 Liquid Ventilation
 Clinical Applications
 References
 

  1. Hale SL, Kloner RA. Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia Am J Physiol 1997;273:H220-H227.
  2. Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol 1998;93:372-383.[CrossRef][ISI][Medline]
  3. Dae MW, Gao DW, Sessler DI, et al. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs Am J Physiol Heart Circ Physiol 2002;282:H1584-H1591.[Abstract/Free Full Text]
  4. The Hypothermia After Cardiac Arrest Study Group Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest N Engl J Med 2002;346:549-556.[Abstract/Free Full Text]
  5. Bernard SA, Gray TW, Buist, MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia N Engl J Med 2002;346:557-563.[Abstract/Free Full Text]
  6. Holzer M, Mullner M, Sterz F, et al. Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach Stroke 2006;37:1792-1797.[Abstract/Free Full Text]
  7. Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction J Am Coll Cardiol 2002;40:1928-1934.[Abstract/Free Full Text]
  8. Kandzari DE, Chu A, Brodie BR, et al. Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study) Am J Cardiol 2004;93:636-639.[CrossRef][ISI][Medline]
  9. Tissier R, Hamanaka K, Kuno A, Parker JC, Cohen MV, Downey JM. Total liquid ventilation provides ultra-fast cardioprotective cooling J Am Coll Cardiol 2007;49:601-605.[Abstract/Free Full Text]
  10. Kaisers U, Kelly KP, Busch T. Liquid ventilation Br J Anaesth 2003;91:143-151.[Free Full Text]
  11. Wolfson MR, Shaffer TH. Pulmonary applications of perfluorochemical liquids: ventilation and beyond Paediatr Respir Rev 2005;6:117-127.[CrossRef][Medline]
  12. Hirschl RB, Croce M, Gore D, et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome Am J Respir Crit Care Med 2002;165:781-787.[Abstract/Free Full Text]
  13. Kacmarek RM, Wiedemann HP, Lavin PT, et al. Partial liquid ventilation in adult patients with acute respiratory distress syndrome Am J Respir Crit Care Med 2006;173:882-889.[Abstract/Free Full Text]
  14. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery N Engl J Med 2004;351:2795-2804.[Abstract/Free Full Text]

Related articles in JACC:

Total Liquid Ventilation Provides Ultra-Fast Cardioprotective Cooling
Renaud Tissier, Kazutoshi Hamanaka, Atsushi Kuno, James C. Parker, Michael V. Cohen, and James M. Downey
JACC 2007 49: 601-605. [Abstract] [Full Text]  




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