HDLVEF was present in 8.6 % of ICU patients who had a TTE during their ICU admission. The median time to TTE after arrival to the ICU was similar between groups (Table 1), which suggests that the presence of HDLVEF and its association with the outcome were not confounded by the timing of TTE.

The finding of HDLVEF was associated with female sex, increased age, and diagnoses of hypertension and cancer. There was a trend toward association with CHF and sepsis. In multivariate logistic regression analysis, patients with HDLVEF had increased 28-day mortality compared with those with NLVEF.

The exact cause of HDLVEF in the ICU is not well understood. Cardiac function is extremely variable in the setting of critical illness and depends on multiple physiologic determinants [3]. Cardiac systolic function is related to heart rate, preload, afterload, and contractility. A patient’s EF may be hyperdynamic in the setting of critical illness owing to changes in these basic physiologic parameters.

Prior research suggested that hypovolemia could lead to HDLVEF [14]. In contrast, a small study showed that three of four patients with HDLVEF on transesophageal echocardiography had pulmonary capillary wedge pressures >20 mmHg, which argues against hypovolemia as an etiology [15]. In our study, patients with NLVEF and HDLVEF received a similar amount of intravenous fluid in the first 24 h (Table 1), although this cannot exclude hypovolemia and decreased systemic vascular resistance as contributors to HDLVEF.

HDLVEF was also found to be associated with cancer. Many studies have shown increased cytokine levels in patients with various types of cancer [16–19], which may explain the presence of HDLVEF among critically ill patients with cancer.

It is unclear if diastolic dysfunction contributes to the development of HDLVEF. It is plausible that patients with diastolic dysfunction are more likely to develop HDLVEF, either chronically or in the setting of acute illness, to compensate for the reduced preload from impaired relaxation during ventricular filling. Another mechanism could be increased circulating cytokines within the tumor necrosis factor α axis, which has been suggested to be a contributor to the development of CHF with preserved EF [20]. Several other biomarkers of myocyte stress, inflammation, and extracellular matrix remodeling have been shown to be associated with CHF with preserved EF [21]. It is unknown if this may be seen in HDLVEF as well. Alternatively, mismatch of myocardial contractility and arterial compliance may be present in patients with HDLVEF, which might explain the trend toward development of CHF. The presence of ventriculoarterial decoupling, defined as the ratio of the arterial elastance to the ventricular elastance, can be found in many disease states and may lead to worse outcomes [22]. These inferences cannot be deduced from our analysis and should be investigated further.

As anticipated based on a literature review, we found that HDLVEF is more frequently seen with a diagnosis of sepsis. Adequately resuscitated patients with severe sepsis can have warm peripheries, high cardiac output, and HDLVEF [23]. Despite a prior study suggesting that HDLVEF was highly specific for sepsis, our study showed that HDLVEF was seen frequently outside the diagnosis of sepsis. It is also important to note that EF may be depressed in sepsis, as has been demonstrated in prior studies [19, 24–28]. The information in the literature is mixed with regard to EF and prognosis in patients with sepsis [29, 30]. In addition to systolic dysfunction, diastolic dysfunction has been described in sepsis [26, 27]. It might contribute to the development of HDLVEF, though this present study was not designed for such an investigation.

Limitations

Our study is limited by its retrospective nature and its inclusion of a relatively heterogeneous group of patients whose data were extracted from electronic medical records in a large clinical database. Other variables not captured in the database may account for residual confounding. Disease associations such as hypertension and cancer are based on ICD-9 codes, which can lead to inconsistent levels of reporting, but this may be somewhat mitigated by the single-center scope of the study. The indications for TTE could be variable and could not be accounted for in this study. Common reasons for TTE in our institution include workup for hypotension and heart failure and evaluation for bacterial endocarditis or right heart strain owing to acute pulmonary embolism. In this study, the need for TTE was at the discretion of the ordering physicians. The indication was not documented.

Bias might have been introduced by excluding patients without TTE during their ICU admission. We compared patients who had TTE to those without TTE with respect to the parameters listed in Table 1, in addition to mortality data. On the basis of this additional analysis, we found that the patients who did not undergo TTE were younger, had fewer comorbidities, were less sick (based on SOFA scores, vital signs, laboratory results, use of vasopressors, and mechanical ventilation), and had better outcomes (data not shown) than other patients. This makes sense from a clinical standpoint—the physicians did not feel that additional information provided by TTE was necessary to manage these patients. These patients who were excluded because they did not undergo TTE look more similar to those patients with NLVEF than to those with HDLVEF. If most of the excluded patients indeed had NLVEF, their inclusion into the analysis, assuming that they had NLVEF, would likely have increased the effect size, given their better outcomes.

Implications

To our knowledge, this study is the first large-scale evaluation of HDLVEF in the ICU setting. It is difficult to determine exactly why HDLVEF has a worse prognosis when seen during critical illness. The etiology of increased mortality in the HDLVEF group may be related to the myocardial mechanics of HDLVEF, or it could be a marker or proxy of a pathophysiologic process. The presence of HDLVEF, in addition to traditional mortality risk predictors, may provide additional prognostic implications for ICU patients.

Further research

HDLVEF patients may respond differently to common interventions such as fluid administration, vasopressor use, and mechanical ventilation. If cardiovascular mechanics are the etiology of worse prognosis, then further studies might be considered to investigate whether modulating HDLVEF with pharmacotherapy improves outcomes. Interestingly, β-blockade has been shown to decrease mortality in patients with severe septic shock [31]. If catecholamine surge is the etiology of HDLVEF, closely monitored β-blockade might be examined to attenuate the HDLVEF. Similarly, the trend toward association between CHF and HDLVEF is interesting and warrants further investigation.