Author + information
- Received January 16, 2008
- Revision received February 26, 2008
- Accepted March 5, 2008
- Published online April 29, 2008.
- Lisa L. Kusnetzky, BA,
- Adnan Khalid, MD,
- Taiyeb M. Khumri, MD,
- Tabitha G. Moe, MD,
- Philip G. Jones, MS and
- Michael L. Main, MD, FACC⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Michael L. Main, Saint Luke's Mid America Heart Institute, 4330 Wornall Road, Suite 2000, Kansas City, Missouri 64111.
Objectives We sought to define acute mortality in hospitalized patients undergoing clinically indicated echocardiography with and without use of an ultrasound contrast agent.
Background The U.S. Food and Drug Administration recently issued a boxed warning and new contraindications for the perflutren-containing ultrasound contrast agents following post-marketing reports of 4 patient deaths that were temporally related to Definity (Bristol-Myers Squibb Medical Imaging, Billerica, Massachusetts) administration. To appreciate the incremental risk of any medical procedure, the ambient risk of untoward outcome in the population in question must first be defined. There are no published data on short-term major adverse cardiac events in hospitalized patients undergoing echocardiography, either with or without administration of an ultrasound contrast agent.
Methods A retrospective analysis of hospitalized patients undergoing clinically indicated echocardiography between January 2005 and October 2007, within Saint Luke's Health System, Kansas City, Missouri, was performed. Studies were separated into 2 groups, those performed without contrast enhancement (n = 12,475) and those performed with Definity (n = 6,196). Vital status within 24 h of the echocardiographic study was available for all patients using a combination of the Social Security Death Master File and Saint Luke's Health System medical records. Incidence of death within 24 h was compared by chi-square test between Definity and unenhanced procedures.
Results Of the 18,671 patient events, 72 patients died within 24 h. Of those that underwent unenhanced echocardiography, 46 died within 24 h (0.37%). Of patients receiving Definity during the echocardiogram, 26 died within 24 h (0.42%). There was no statistical difference between these 2 groups (p = 0.60). No patient died within 1 h of the echocardiographic study. In a random sampling from the unenhanced (n = 201) and Definity groups (n = 202), patients who underwent Definity-enhanced echocardiography exhibited higher clinical acuity, and more significant comorbidities.
Conclusions Approximately 0.4% of hospitalized patients die within 24 h of echocardiography. There is no increased mortality risk associated with Definity-enhanced examinations, despite evidence for higher clinical acuity and more comorbid conditions in patients undergoing contrast studies.
Ultrasound contrast agents are indicated to enhance endocardial border delineation in patients with technically difficult echocardiographic examinations (1) and have proven utility in the diagnosis and management of critically ill patients (2–4). On October 10, 2007, the U.S. Food and Drug Administration issued new boxed warnings and contraindications for the ultrasound contrast agents Optison (GE Healthcare, Buckinghamshire, United Kingdom) and Definity (Bristol-Myers Squibb Medical Imaging, Billerica, Massachusetts), effectively restricting their use in patients with acute coronary syndromes (ACS), worsening or decompensated heart failure (HF), and respiratory failure (5). These warnings were largely based on reports of 4 deaths occurring during or immediately after Definity injection (5). Although these deaths were temporally related to contrast use, there is little evidence for causation; a recent publication suggested these deaths may have been caused by “pseudocomplication” (progression of underlying disease) (6).
To appreciate the incremental risk of any medical procedure, the ambient risk of untoward outcome in the population in question must first be defined. To our knowledge, there are no published data on short-term major adverse cardiac events in hospitalized patients undergoing echocardiography. The purpose of this study was to define short-term (1-h and 24-h) mortality in a large cohort of hospitalized patients undergoing clinically indicated echocardiography, both with and without an ultrasound contrast agent.
We performed a retrospective analysis of 18,942 consecutive echocardiographic studies performed on hospitalized patients between January 2005 and October 2007 within the Saint Luke's Health System, Kansas City, Missouri. During this period, Optison was not commercially available. Patients received intravenous Definity (administered as a slow bolus of 1.5 ml Definity/8.5 ml saline) when the baseline study was “technically difficult” (2 or more contiguous myocardial segments with inadequate visualization) (1). Patients also were administered contrast agent when qualitative left ventricular (LV) systolic function appeared reduced to allow accurate and reproducible calculation of LV ejection fraction (7). For both causes, cardiac sonographers made the decision to administer contrast based on standing orders. Two hundred fifty-eight patients with invalid social security numbers and 13 patients who were declared brain dead before the echocardiogram or in whom echocardiography was performed during a cardiac arrest were excluded from further analysis. The remaining 18,671 examinations comprised the study group. These studies were separated into 2 groups: procedures performed without contrast enhancement (n = 12,475) and those performed with Definity (n = 6,196). Vital status within 24 h of the echocardiographic study was available for all patients using a combination of the Social Security Death Master File (8) and Saint Luke's Health System medical records. Incidence of death within 24 h was compared by the chi-square test between Definity and non-Definity procedures. Because some patients (n = 2,589 of 14,063, 18.4%) received multiple procedures, a further analysis was conducted to account for within-patient correlation, using repeated-measures logistic regression with generalized estimating equations.
Patient characteristics were obtained for a random sample of 403 patients (202 Definity and 201 unenhanced) to determine the baseline demographics and clinical acuity. Continuous variables are reported as mean ± standard deviation and/or median and interquartile range as appropriate, and were compared using t tests. Categorical variables are reported as frequency and percent and were compared using chi-square tests. Values of p < 0.05 denoted statistical significance. All analyses were conducted using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina).
Baseline characteristics from a random sample of patients in the unenhanced (n = 201) and Definity (n = 202) groups are shown in Table 1. Patients who underwent Definity-enhanced echocardiography showed higher clinical acuity and more significant comorbidities.
Of the 18,671 patient events, 72 patients died within 24 h. Of those who underwent unenhanced echocardiography, 46 died within 24 h (0.37%). Of patients receiving Definity during the echocardiogram, 26 died within 24 h (0.42%). There was no statistical difference between these 2 groups (p = 0.60) (when corrected for repeated measures, p = 0.62). No patient died within 1 h of the echocardiographic study. Given the observed mortality rate of 0.37% among patients not receiving Definity, with our sample size of 18,671 studies we would have 80% power to detect a Definity mortality rate of 0.68%, corresponding to a relative risk of 1.84.
The primary cause of death was determined by review of medical records and included sepsis (n = 14), acute myocardial infarction/ACS (n = 10), HF (n = 8), pneumonia or chronic lung disease (n = 8), cancer (n = 5), stroke (n = 5), post-operative complications (n = 4), intracranial hemorrhage (n = 3), ruptured intra-abdominal aortic aneurysm (n = 2), pulmonary embolism (n = 2), pulmonary hypertension (n = 1), and miscellaneous causes (n = 10). In the patients who died within 24 h of Definity administration, there was no evidence for acute allergy or anaphylaxis. Review of hospital medical records in the 202 randomly selected Definity patients showed that 56% (n = 114) had 1 or more of the new contraindications to contrast administration (ACS, worsening or decompensated HF, or respiratory failure).
To determine the clinical utility of contrast in this population, an experienced echocardiographer reviewed the 403 echocardiograms in the random sample. Endocardial resolution was graded as adequate or suboptimal for each of 16 myocardial segments (9). The mean number of adequately visualized segments was 13.5 for the unenhanced group, 10.1 for the pre-contrast images in the Definity group, and 14.4 for the contrast-enhanced Definity images (p < 0.0001 for the Definity group comparisons). Pathological findings, including LV apical mural thrombus (n = 4), LV apical aneurysm (n = 1), and LV apical ballooning (n = 1), were identified in the Definity group.
The recently issued boxed warning and new contraindications for ultrasound contrast agents were largely based on post-marketing reports of 4 deaths that were temporally related to, but not clearly causally attributable to, Definity administration. As outlined in a recent publication (6), untoward outcomes after a medical procedure may be attributable to the procedure itself (complication) or progression of the underlying disease state (pseudocomplication).
In this study, unenhanced echocardiography was associated with a 0.37% acute (24-h) mortality rate in hospitalized patients. This should not be surprising because echocardiography is frequently performed in those who are most critically ill. Contrast-enhanced echocardiography was not associated with any increased mortality risk. Given the higher clinical acuity and more comorbid conditions in the contrast-enhanced group, we believe these data represent a very conservative estimate of contrast echocardiography safety.
Approximately 0.4% of hospitalized patients die within 24 h of echocardiography. There is no increased mortality risk associated with Definity-enhanced echocardiographic examinations in hospitalized patients, despite evidence for higher clinical acuity and more comorbid conditions in patients undergoing contrast-enhanced studies.
Dr. Main has received research support from and has a consultant relationship with POINT Biomedical, Acusphere, Inc., and Bristol-Myers Squibb Medical Imaging.
- Abbreviations and Acronyms
- acute coronary syndromes
- heart failure
- left ventricular
- Received January 16, 2008.
- Revision received February 26, 2008.
- Accepted March 5, 2008.
- American College of Cardiology Foundation
- Reilly J.P.,
- Tunick P.A.,
- Timmermans R.J.,
- Stein B.,
- Rosenzweig B.P.,
- Kronzon I.
- ↵New U.S. Food and Drug Administration prescribing information for Definity, approved October 10, 2007. http://www.fda.gov/cder/foi/label/2007/021064s007lbl.pdf. Accessed October 15, 2007.
- Main M.L.,
- Goldman J.H.,
- Grayburn P.A.
- Hundley W.G.,
- Kizilbash A.M.,
- Afridi I.,
- Franco F.,
- Peshock R.M.,
- Grayburn P.A.
- ↵Social Security Death Master File. http://www.ssdmf.com. Accessed November 28, 2007.
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