ICUS Weekly News Monitor 1-15-2016

1.  Echocardiography,  Jan, 2016,  Letter to the Editor: Transient Ischemic Attack Caused by Contrast Echocardiography in a Patient with Platypnea- Orthodeoxia
Authors:  Michael L. Main, M.D., et al
2.  Journal of Controlled Release,  Jan 13, 2016,  Acoustic cluster therapy (ACT) – pre-clinical proof of principle for local drug delivery and enhanced uptake
Authors:  Annemieke van Wamela, et al
DOI: 10.1111/echo.13138
Jan, 2016
Letter to the Editor: Transient Ischemic Attack Caused by Contrast
Echocardiography in a Patient with Platypnea-Orthodeoxia
Authors:  Michael L. Main, M.D.,* Steven B. Feinstein,
M.D.,† Linda M. Feinstein, J.D.,‡ Paul A. Grayburn,
M.D.,§ and Stephanie R. Wilson, M.D.,¶
*Saint Luke’s Mid America Heart Institute, Kansas City, Missouri; †Rush University Medical Center,
Chicago, Illinois; ‡Dentons, Chicago, Illinois; §Baylor University Medical Center, Dallas, Texas; ¶University of Calgary, Calgary, Alberta, Canada
Dear Editor,
We read with interest the recent report by Loncaret al.1
The authors report a case of transient right hemiparesis temporally associated with the intravenous injection of agitated saline microbubbles. The study reportedly revealed “massive passage” of the agitated saline into the left heart in the setting of a large atrial septal aneurysm and two separate atrial septal defects. As the authors note, agitated saline studies have been associated with transient ischemic attacks (TIA),2 although this is the first report in a patient with platypnea-orthodeoxia.
Although the authors reach a broad conclusion regarding risk associated with “contrast echocardiography” in general, they fail to distinguish the known differences between ultrasound contrast agents (UCAs) comprised of agitated saline microbubbles, used in their study, and UCAs that are commercially prepared and FDAapproved.  Agitated saline studies utilize significant quantities (~10 mL) of large, unstable, air-filled microbubbles that have no shell and typically are injected with concomitant provocative maneuvers such as Valsalva or cough, aimed at actively potentiating atrial septal passage. In contrast, commercially prepared UCAs consist of very small microspheres (3–4 lm mean diameter) with a narrow size distribution and an encapsulating, biocompatible shell. Commercial UCAs have been approved by regulatory agencies worldwide and act as true intravascular flow tracers.3
The authors note that commercially available UCAs are contraindicated in patients with right to left shunts, based on theoretical concern for similar neurologic events following administration of these agents. However, the FDA has been asked to rescind the contraindication because it is not based on sound scientific data.3
In fact, there have been no published reports of ischemic neurologic events attributed to injection of commercial UCAs despite use in millions of patients worldwide, and empiric and experimental observations directly refute the contention that there is any neurologic risk with commercial UCAs. In a recent single-center study of 39 020 patients who were administered commercial UCAs, no TIAs or strokes were found in a subset of 418 patients with known PFOs.4  Additionally, large registries have reported no neurologic safety signals, despite the fact that based on population statistics, up to ~25% of these patients likely had PFOs.5
Further, as we have previously noted,3 FDA guidance regarding UCAs in patients with PFOs is contradicted by FDA’s own labeling for macroaggregated albumin (MAA), which is routinely used in ventilation–perfusion scans of the lungs. MAA has a particle size of 10–90 lm and is potentially capable of occluding arterioles, yet carries only a “warning” for use in patients with PFOs.
Recent data indicate that judicious use of commercial UCAs in critically ill patients with baseline technically difficult echocardiograms is associated with lower mortality,6 perhaps due to earlier and more accurate diagnosis. Withholding UCAs based on discredited theoretical risks is not evidence-based medicine or patient-centered care.
The authors should use more specificity when describing “contrast echocardiography” to avoid confusion between agitated saline studies and commercially prepared UCAs that have decidedly different physio-chemical attributes and safety profiles.
Michael L. Main, M.D., et al
1. Loncar G, Payot L, Dubois M: TIA caused by contrast
echocardiography in patient with platypnea-orthodeoxia.
Echocardiography 2015;32:1585–1587.
2. Romero JR, Frey JL, Schwamm LH, et al: Cerebral
ischemic events associated with ‘bubble study’ for identification
of right to left shunts. Stroke 2009;40:2343–
3. Parker JM, Weller MW, Feinstein LM, et al: Safety of ultrasound
contrast agents in patients with known or suspected
cardiac shunts. Am J Cardiol 2013;112:1039–1045.
4. Kalra A, Shroff GR, Erlien D: Perflutren-based echocardiographic
contrast in patients with right-to-left intracardiac
shunts. JACC Cardiovasc Imaging 2014;7:206–207.
5. Wei K, Mulvagh SL, Carson L, et al: The safety of definity
and optison for ultrasound image enhancement: A retrospective
analysis of 78,383 administered contrast doses.
J Am Soc Echocardiogr 2008;21:1202–1206.
6. Main ML, Hibberd MG, Ryan A, et al: Acute mortality in
critically ill patients undergoing echocardiography with or
without an ultrasound contrast agent. JACC Cardiovasc
Imaging 2014;7:40–48.
Journal of Controlled Release
Jan 13, 2016
Acoustic cluster therapy (ACT) – pre-clinical proof of principle for local drug delivery and enhanced uptake
Authors:  Annemieke van Wamela, Andrew Healeyb, Per Christian Sontumb, Svein Kvåleb, Nigel Bushc, Jeff Bamberc, Catharina de Lange Daviesa
a Dept. of Physics, NTNU, Trondheim, Norway
b Phoenix Solutions AS, Oslo, Norway
c Joint Dept. of Physics, ICR, London, UK
Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20–30 μm large bubbles in the microvasculature, occluding blood flow for ~ 5–10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.
Graphical abstract
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