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Ann Thorac Surg 2007;83:1923
© 2007 The Society of Thoracic Surgeons

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Correspondence

Reply

Department of Anesthesiology, Duke University Medical Center, Box 3094, DUMC, Durham, NC 27710

(Email: hill0012{at}mc.duke.edu).

To the Editor:

We welcome the opportunity to address concerns raised by Dr Mattrey [1] regarding our investigation into cerebral physiology of cardiac surgical patients receiving perfluorocarbon (PFC) emulsion [2]. Due to an increased incidence of stroke in the treatment group compared with the control group, a phase III trial of a perfluorocarbon emulsion (AF0144) used to augment intraoperative hemodilution was halted after approximately 400 patients were enrolled. This increase in stroke rate was not observed in the phase II dose escalation trial [3]. In an attempt to explain the unexpected findings of the larger study, we analyzed ancillary data related to cerebral physiology from the smaller trial and found that cerebral blood flow as well as high-intensity transcranial Doppler signals (HITS) were significantly elevated in patients receiving high-dose AF0144 compared with controls. These findings suggest a possible explanation for the increased stoke rate in patients receiving AF0144 in the phase III trial. Increased cerebral flow (CBF) in treated patients may have resulted in an increased delivery of embolic material generated during the surgical procedure.

Dr Mattrey [1] suggests that HITS measured in the phase II trial represent artifact from the presence of a perfluorocarbon emulsion in the vasculature rather than true emboli. Although perfluorocarbons are effective as sonographic contrast agents, these agents produce a generalized increase in echogenicity of the vasculature, enhancing the image. Transcranial Doppler measures high intensity signals that deviate significantly from baseline for a brief period of time and correspond to microembolic material in laboratory models and clinical settings. In the phase II trial data used in our analysis, these HITS were defined according to consensus guidelines as signals that were: (1) transient, lasting less that 300 ms; (2) intense, having an amplitude at least 3 dB higher than that of the background blood flow signal; (3) unidirectional; and (4) audible, emitting a "snap, chirp or moan" [4]. These HITS were recorded and judged not to be artifact by a blinded investigator. A venous infusion of perfluorocarbon emulsion (particle size, 0.16 to 0.18 micron) for 10 minutes as dictated by the study protocol would be unlikely to produce brief, intense Doppler signals in the cerebral arteries that could be mistaken for microemboli. Furthermore, HITS did not occur continuously but tended to occur in bursts of activity that were recorded over predetermined time periods during the surgical procedure similar to the pattern expected from a shower of atheroemboli resulting from aortic manipulation. Although perfluorocarbon emulsion was administered during the period emcompassed by "aortic cannulation to aortic cross clamp," HITS were also significantly elevated in the high-dose treatment group during the period from aortic cross-clamp placement to aortic cross-clamp removal when no study drug was administered. Therefore we submit that the HITS observed in the phase II trial likely represent true microemboli and not artifact.

Although we acknowledge that data from the smaller phase II trial have significant limitations, and we agree that definitive conclusions can not be drawn from this information, a higher stroke rate was observed for treated patients in the larger trial. When combined with evidence of higher CBF and an increased number of emboli during cardiopulmonary bypass (CPB), we suggest that further study is warranted to better understand the risk to benefit ratio of PFC administration in patients undergoing CPB, and we maintain our assertion (with our current level of understanding) that PFC emulsion as an adjunct to hemodilution may not be suited for use in cardiac surgery.

	References

Top References

 

1. Mattrey RF. Are cerebral emboli real when perfluorocarbon emulsion (AF0144) is used in cardiac surgery?(letter) Ann Thorac Surg 2007;83:1922-1923.[Free Full Text]
2. Hill SE, Grocott HP, Leone BJ, White WD, Newman MF. Cerebral physiology of cardiac surgical patients treated with the perfluorocarbon emulsion, AF0144 Ann Thorac Surg 2005;80:1401-1407.[Abstract/Free Full Text]
3. Hill SE, Leone BJ, Faithfull NS, et al. Perflubron emulsion (AF0144) augments harvesting of autologous blood: a phase II study in cardiac surgery J Cardiothorac Vasc Anesth 2002;16:555-560.[Medline]
4. Consensus Committee of the Ninth International Cerebral Hemodynamic Symposium Basic identification criteria of Doppler microembolic signals Stroke 1995;26:1123.[Free Full Text]

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