Gail ter Haar
On October 10th 2007, the FDA requested that a "Boxed Warning and other warnings emphasizing
the risk for serious cardiopulmonary reactions be added to the labeling for ultrasound
micro-bubble contrast agents used in echocardiography and that use of these products
be contraindicated in patients with unstable cardiopulmonary status, including patients
with unstable angina, acute myocardial infarction, respiratory failure, or recent
worsening congestive heart failure" [FDA 2007]. The background for this warning was
that the FDA had "received reports of deaths and serious cardiopulmonary reactions
following the administration of ultrasound micro-bubble contrast agents used in echocardiography.
Four of the 11 reported deaths were caused by cardiac arrest occurring either during
infusion or within 30 minutes following the administration of the contrast agent;
most of the serious but non-fatal reactions also occurred in this time frame." One
patient died during a stress test, two patients were in severe heart failure, and
the fourth was a ventilated patient who had severe respiratory failure and pulmonary
emboli.
There has, understandably, been considerable discussion in the literature and at conferences,
about this action. It has been pointed out ([Grayburn 2008, Main et al 2007]) that the FDA has responsibility for product safety, but that this is not necessarily
the same as patient safety. Patient safety remains the responsibility of the clinician.
With more than 2 million ultrasound examinations using microbubble contrast agents
(UCAs) having been carried out since their approval by the FDA 6 years ago, even if
all these deaths can correctly be attributed to these bubbles, the associated risk
is 1:500,000. This compares favourably with the 1:1000 mortality risk associated
with diagnostic coronary angiography ([Johnson et al 1989]), and the 1:2500 risk of myocardial infarction or death with treadmill exercise
testing ([Stuart et al 1980]). In a recent paper in which over 18,500 cases were studied, Kuznetsky et al (2008)
were unable to show an increased mortality risk associated with contrast-enhanced
examination, with 0.4% of hospitalised patients dying within 24 hours of echocardiography,
but no statistical difference in mortality being seen between the group in which contrast
agents were administered and that which received none.
In the light of this, and other information, the FDA's Cardiovascular and Renal Drugs
advisory committee met in June 2008 to discuss the situation. The briefing document
(which is available at www.fda.gov/ohrms/dockets/AC/08/briefing/2008-4369b1-01.pdf) states that "FDA has finalized the risk management plan with the manufacturer of
Definity and has approved labeling changes that remove most of the contraindications
cited in the October, 2007 modification, as well as focused monitoring procedures
upon patients with underlying pulmonary hypertension or unstable cardiopulmonary conditions.
FDA is working with the manufacturer of Optison to effect similar changes to the
label and to finalize a risk assessment and management program." This document also
states that concern remains about the accumulating safety data for ultrasound contrast
agents, and that products should continue to show a boxed warning highlighting "the
risk for serious cardiopulmonary reactions". These contrast agents are now contra-indicated
only for patients with right-to-left, bi-directional, or transient right-to-left cardiac
shunts, and those with hypersensitivity to perflutren. The boxed warning has been
modified to include the instruction " In patients with pulmonary hypertension or unstable
cardiopulmonary conditions, monitor vital sign measurements, electrocardiography and
cutaneous oxygen saturation during and for at
least 30 minutes after DEFINITY®/ Optison administration" (www.definityimaging.com/pdf/prescribinginfo.pdf, md.gehealthcare.com/shared/pdfs/pi/optison_pi.pdf).
Echocardiology remains the examination of choice in patients who are sufficiently
ill to warrant invasive cardiovascular investigation. This therefore makes it difficult
to differentiate between "association" and "cause" of any adverse events. It is useful
in this context to examine the existing contrast agent safety literature. This has
recently been reviewed by both the World Federation of Societies for Ultrasound in
Medicine & Biology (WFUMB) ([Blomley et al 2007], [Dalecki 2007]) and the American Institute of Ultrasound in Medicine (2008, [Miller et al 2008]).
[Blomley et al] (2007), in a WFUMB report, concluded that while there is incomplete knowledge about
the potential risk from clinical use of UCAs, they are extremely safe, with a low
incidence of side effect. There is no evidence that they are nephrotoxic or cardiotoxic,
and result in a much lower incidence of hypersensitivity or allergic events than current
X-ray or MR contrast agents.
There appears to be a consensus that an MI value of 0.4 represents the threshold above
which bio-effects are seen in bio-effects studies in vivo [Miller et al 2008]. Above
this level, bio-effects appear to increase rapidly with both increasing acoustic pressure
amplitude and UCA concentration. Effects studied include premature ventricular contractions
and petechial haemorrhage. The cells that are most susceptible to damage from diagnostic
ultrasound exposure to UCAs are phagocytic cells that have engulfed the microbubbles.
In many cases, the damage may be reparable, and the clinical implications of such
findings are not known. Good practice would, however, suggest caution when using
UCAs.
The AIUM recommends that for ultrasound examinations involving MI values greater than
0.4, the minimum UCA dose and ultrasound exposure consistent with acquisition of good
diagnostic information should be used ([AIUM 2008], [2002]). This reinforces the need for the practitioner to be aware of the safety indices
(MI and TI) being used for any ultrasound examination. An initial (default start
up) setting of MI of less than 0.4 for contrast enhanced ultrasound examinations is
recommended.
EFSUMB's position is contained in its current safety statement (EFSUMB 2008):
Ultrasound contrast agents (UCA)
These usually take the form of stable gas filled microbubbles, which can potentially
produce cavitation or microstreaming, the risk of which increases with MI value. Data
from small animal models suggest that microvascular damage or rupture is possible.
Caution should be considered for the use of UCA in tissues where damage to microvasculature
could have serious clinical implications, such as in the brain, the eye, and the neonate.
As in all diagnostic ultrasound procedures, the MI and TI values should be continually
checked and kept as low as possible. It is possible to induce premature ventricular
contractions in contrast enhanced echocardiography when using high MI and end-systolic
triggering. Users should take appropriate precautions in these circumstances. The
use of contrast agents should be avoided 24 hours prior to extra-corporeal shock wave
therapy.
