Safety of TCD “Bubble Study”
To the Editor:
We read with interest the recent article by Romero et al highlighting ischemic cerebrovascular complications that may occur in patients who undergo “Bubble Studies” (BS) either with transthoracic/transesophageal echocardiography or transcranial Doppler (TCD) for the detection of a right-to-left shunt.1 The authors identified 3 ischemic strokes and 2 transient ischemic attacks as cerebrovascular complications of 3314 BS performed in 4 different certified stroke centers. They underscored the absence of a validated protocol for performance of BS and indicated the need for standardization regarding creation and injection of bubbles and suggested that additional study is indicated to assess the true prevalence of cerebrovascular complications after BS.
However, before adopting the authors’ suggestions, we would like to express certain critical comments. First, there was only one case of ischemic stroke related to bubble injection during TCD (case 1), whereas the remaining 4 cases occurred during contrast-enhanced echocardiography. Even in the single TCD case, “TTE (transthoracic echocardiography) was negative for embolic source and was considered insufficient evidence of PFO (patent foramen ovale).” In view of the negative transthoracic echocardiography study, it would be presumptive to attribute the ischemic lesion documented on the follow-up MRI to paradoxical gas embolism because of bubble injection given the fact that the presence of a right-to-left shunt was never documented. Moreover, the authors did not report the results of the TCD study that may assist in elucidating the underlying mechanism of ischemic stroke in this patient, who was admitted 2 days before the BS with multiple infarctions both in the anterior and posterior cerebral circulation. For example, recurrent cardioembolism attributable to intermittent atrial fibrillation may be another plausible explanation for the new ischemic stroke that was documented after BS.
Second, a standardized protocol for TCD-BS is available, as the authors correctly pointed out in their discussion.2 This international consensus protocol advocates using 9 mL of isotonic saline solution and 1 mL of air as contrast agent. The dose of 1 mL of air is considered safe because studies in animals have suggested that either a large bolus of air (≥20 mL) or small continuous amounts (11 mL per minute) introduced into the venous system may generate intra-arterial bubbles able to cause embolism.3 In addition, Chang et al demonstrated in an animal experiment that 2 mL of air injected intra-arterially was the lowest dose needed to cause air embolism in a 7-kg macaque. By extrapolation, the critical volume for a 70-kg human should be well in excess of 2 mL even for intra-arterial injections of air.4 Thus, 1 mL of air may not be sufficient enough to cause cerebral embolism even if it is accidentally injected intra-arterially instead of intravenously during the TCD-BS.
Interestingly, the investigators who developed the International Consensus Protocol in 2000 state that “at the dose recommended, there are currently no reports on side effects after air/saline administration.”2 This statement is also supported by our own personal experience using different body positions and different software to increase the sensitivity of TCD-BS for right-to-left shunt detection.5–7 Indeed, despite the systematic documentation of changes in blood pressure and heart rhythm, we failed to document any adverse event in numerous TCD-BS, even in the presence of a large PFO with concomitant atrial septal aneurysm or intracardiac thrombi.5–7 Further, Romero et al cited in their introduction previous reports documenting cerebrovascular complications during transesophageal/transthoracic echocardiography BS without commenting on similar adverse events being reported during TCD examinations.1
In conclusion, we believe that the findings of Romero et al in combination with the existing literature indicate that the risk of cerebrovascular complications after BS may be much lower for TCD compared with transthoracic echocardiography. In addition, we share the authors’ view that proper standardization of microbubble infusions during echocardiographic BS should be developed by the appropriate organizations overseeing cardiac imaging, whereas the current recommendations2 for bubble injection during TCD for detection of right-to-left shunts should be followed to minimize the risk of cerebral embolism.
Romero JR, Frey JL, Schwamm LH, Demaerschalk BM, Chaliki HP, Parikh G, Burke RF, Babikian VL. Cerebral ischemic events associated with “bubble study” for identification of right to left shunts. Stroke. 2009; 40: 2343–2348.
Tsivgoulis G, Vadikolias K, Heliopoulos I, Manios E, Rallis K, Rigopoulos D, Bairaktaris C, Piperidou C. Development of unilateral power motion mode criteria for the detection of right-to-left shunts. Cerebrovasc Dis. 2009; 25: 165.