Use of Contrast in the Intensive Care Unit and Emergency Department

Contrast Use in the Intensive Care Unit

Patients in the intensive care unit (ICU) setting have a variety of illnesses, and echocardiography can offer real-time information on cardiac function, hemodynamics, and, in certain patients, potential causes of their illnesses. Furthermore, because echocardiography is noninvasive, portable, and free of ionizing radiation, it is an ideal tool for ICU patient care. However, the ICU is an often hostile environment for acquisition of transthoracic echocardiography (TTE) images. ICU patient rooms are often crowded with less than ideal lighting, and patient- and disease-state related factors, including endotracheal intubation and mechanical ventilation; obscuration of optimal imaging windows because of surgical dressings, chest tubes, and other support devices; and inability to properly position the patient because of a lack of a drop section, presence of restraints, and inability of the patient to cooperate (among many others), all increase the degree of imaging difficulty and worsen the odds for completion of a technically adequate examination, which completely answers the attending physician’s clinical questions.

Following approval of the first transpulmonary ultrasound-enhancing agent (UEA) (Optison, GE Healthcare, 1995), several early studies described the efficacy of UEAs in improving image quality and diagnostic accuracy in the ICU. UEAs improve image quality, wall motion scoring, and left ventricular ejection fraction (LVEF) calculation in both unselected ICU patients and in patients who are mechanically ventilated. Additionally, in ICU patients with baseline very technically difficult echocardiograms (>50% of the myocardial segments not visualized from any view), UEA use improved the ability to estimate ejection fraction from 31% of studies to 97% and improved agreement with transesophageal echocardiography (TEE) for regional wall motion assessment from 48% at baseline to 70% with UEAs. Furthermore, contrast echocardiography was cost-effective in comparison with TEE.

In 2007, the United States Food and Drug Administration (FDA) issued a Black Box warning, contraindicating the use of UEA in most ICU patients, including patients with the following diagnoses: “acute myocardial infarction or acute coronary syndromes, worsening or decompensated heart failure, serious ventricular arrhythmias or patients at high risk for arrhythmias based on QT interval prolongation, as well as respiratory failure, severe emphysema, pulmonary emboli or other conditions which may cause pulmonary hypertension.”

These warnings followed spontaneous healthcare provider reports of four patient deaths, which occurred in close temporal relationship to UEA administration. Critics of the FDA action noted the lack of a documented causal relationship between UEA administration and these outcomes, the previously described excellent safety and efficacy profile of UEAs, the potential risks of alternative procedures such as TEE and nuclear scintigraphy, and the likely contribution of “pseudo complications” to these serious adverse events (complications caused by progression of the underlying disease state rather than a contemporaneous procedure or diagnostic examination). ^,

In early 2008, Kusnetzky and colleagues described acute mortality rates in a large cohort of 18,671 hospitalized patients who underwent echocardiography. A total of 12,475 patients underwent unenhanced echocardiography, and 6196 patients underwent echocardiography with the UEA Definity (Lantheus Medical Imaging). At 24 hours after the transthoracic echocardiogram, 0.37% of patients in the unenhanced echocardiography arm and 0.42% of patients in the UEA arm had died (not significant). The authors concluded that there was no demonstrable increased mortality risk with UEA administration, even in sick patients (and in fact in this study, there were no deaths in the contrast arm within 1 hour of UEA administration).

Over the next several years, multiple studies were conducted in the inpatient and ICU settings (several of which were mandated by the FDA) that have better informed us regarding both the safety and efficacy of UEAs. These studies are summarized in Table 21.1 . Based on this evidence and other considerations, the FDA modified the Black Box warning, and there is now widespread agreement that these agents are not only safe but also indicated in the ICU setting, including patients with clinical diagnoses previously on the FDA contraindication list.

One risk of UEA has been identified in several series, serious allergic (anaphylactoid) reactions, occurred in ∼1:10,000 patients. ^, These reactions are categorized as CARPA reactions (complement activation–related pseudoallergy), a recently described variant of the classic type 1 hypersensitivity reaction. Unlike common food and drug type 1 hypersensitivity reactions, CAPRA reactions are not immunoglobulin E mediated, do not require prior exposure, tend to me milder or absent on repeat exposure, and usually resolve spontaneously. Additionally, there is a higher reaction rate among the general population, particularly in women and individuals with preexisting food and drug allergies, so-called “atopic” individuals. CARPA reactions may occasionally be life threatening and manifest similar to any other anaphylactic reaction. Although there is no evidence that these reactions occur more frequently in the critically ill patient population, patients with serious illness may be more likely to succumb given lack of clinical reserve. Rapid point-of-care administration of intramuscular epinephrine may be lifesaving in very serious CARPA reactions, and this medication (and other drugs used in the treatment of serious allergic reactions such as inhaled beta-agonists) should be readily available at the point of care (and particularly in ICUs) outside of the usual “crash cart” provision.

Several studies have also confirmed the association between UEA use in ICUs and improved patient outcomes. Main and colleagues used the Premier database (Premier Inc., the largest US hospital–based service-level comparative database) to compare 48-hour mortality and hospital stay mortality in a cohort of critically ill, propensity-matched patients undergoing echocardiography either with (16,217 patients) or without (16,217 patients) a UEA. At 48 hours, mortality in the UEA group was lower than the unenhanced echocardiography group (1.7% vs 2.5%; 95% confidence interval [CI], 0.54–0.80) ( Fig. 21.1 ). This difference between the two groups persisted until hospital discharge. Although the underlying etiologic explanation for lower mortality rate in the UEA group was beyond the scope of this study, potential mechanisms include earlier and more accurate diagnosis leading to better patient management and the avoidance of inherent risks associated with downstream testing. In fact, limited data have documented clinical utility and safety even in patients with left ventricular assist devices and patients undergoing extracorporeal membrane oxygenation (although a perfusionist or critical care physician should be present during the UEA examination given propensity of these systems to automatically shut down if bubbles are detected by the sensing mechanism).

In a pivotal outcomes study by Kurt and colleagues, 632 consecutive patients with baseline technically difficult or uninterpretable studies underwent both an unenhanced and a UEA study. After UEA, the percent of uninterpretable studies decreased from 11.7% to 0.3%, and the technically difficult rate decreased from 86.7% to 9.8%. This dramatic improvement in study quality was associated with important management changes: overall, 35.6% of patients had a downstream procedure avoided, a change in medication, or both a medication and procedure change because of the UEA examination. This effect was even more dramatic in the surgical ICU, where approximately two-thirds of patients had an important management change attributable to the UEA study ( Fig. 21.2 ).

Confirmation of these findings was recently presented in a follow-up study using the Premier database. A total of 1,538,864 ICU patients from 773 hospitals underwent transthoracic echocardiography either with ( n = 51,141) or without ( n = 1,487,723) a UEA. After adjusting for patient, clinical, and hospital characteristics, patients in the UEA cohort were less likely to undergo a subsequent TTE or TEE (odds ratio [OR], 0.704 for TTE; OR, 0.841 for TEE; P < .001 for both). Additionally, the mean ICU length of stay was shorter in the UEA cohort (4.15 days vs 4.59 days, P <0.001), and UEA patients were more likely to experience either an initiation or discontinuation of a parenteral inotrope, anticoagulant, or vasopressor on the day of or the day after the echocardiographic study, consistent with results of the study by Kurt and colleagues.

Pulmonary hypertension is frequently encountered in ICUs and was identified in 2007 as a disease state contraindication by the FDA. In conjunction with the FDA, two invasive cardiac catheterization studies were conducted to evaluate the effect of UEAs on pulmonary hemodynamics in patients with normal and elevated baseline pulmonary artery systolic pressure. No significant changes in pulmonary artery systolic pressure or pulmonary vascular resistance were noted after intravenous injection of clinically relevant does of Optison or Definity. More recently, Wever-Pinzon and colleagues evaluated the potential effects of the UEA Definity in 1513 hospitalized patients with pulmonary hypertension (60% mild pulmonary hypertension, 34% moderate pulmonary hypertension, and 6% severe pulmonary hypertension). The incidence of adverse events was extremely low (0.002%), and no events were attributable to the UEA. Based on these three studies, UEA use in patients with pulmonary hypertension is considered safe and is no longer contraindicated by the FDA.

UEA use may be particularly helpful in cardiac ICUs in the treatment of patients with acute myocardial infarction. With drug and device therapy increasingly dependent on LVEF partition values, accurate and reproducible LVEF data are critical. UEA use improves LVEF agreement with cardiac magnetic resonance imaging (the standard reference technique) in unselected patients and improves interobserver agreement in assessment of left ventricular (LV) systolic function even in patients with good baseline endocardial border resolution. Additionally, contrast markedly improves our ability to diagnose or exclude LV thrombus. In the Kurt study of 632 patients with technically difficult echocardiograms, an LV thrombus was suspected in 35 patients and thought to be definitely present in 3 patients at baseline; with addition of an UEA, only 1 patient had a suspected thrombus, and 5 additional patients with thrombus were identified ( P < 0.0001). Finally, myocardial contrast echocardiography can differentiate myocardial stunning from necrosis immediately after percutaneous intervention in acute myocardial infarction, and aids in risk stratification.

In light of this data, the 2018 American Society of Echocardiography (ASE) Guidelines Update for Clinical Applications of Ultrasonic Enhancing Agents lists the following recommendations for UEA use in the ICU setting :

• 1.

  “Given a demonstrated impact on patient management and an association with mortality reduction, UEAs are recommended in all technically difficult ICU and ED patients to more quickly and accurately diagnose potentially life-threatening conditions and to reduce the need for downstream diagnostic testing. Contrast echocardiography should not be withheld on the basis of any particular diagnosis or co-morbidity.” (Class I recommendation, Level of Evidence B-NR [moderate-quality evidence from one or more well-designed nonrandomized trials, observational studies, or registry studies of meta-analysis of such studies.])

• 2.

  “Myocardial contrast echocardiography with very low mechanical index imaging may be used in post-STEMI patients to evaluate for LV-systolic function, intracavitary thrombi, and microvascular flow within the infarct territory at institutions with sonographer and physician expertise in performance and interpretation of myocardial perfusion echocardiography.” (Class IIa recommendation, Level of Evidence B-NR [moderate-quality evidence from one or more well-designed nonrandomized trials, observational studies, or registry studies of meta-analysis of such studies.])