Patients who present to an emergency department (ED) with hypotension may have hypoperfusion indicative of shock, indicating an elevated risk of mortality across etiologies (1–4). A cardiogenic etiology is found in ∼15% of patients with shock in the ED setting (3, 4), and cardiogenic shock is associated with nearly 33% short-term mortality when present in the ED (3). Yet early identification can facilitate early interventions, including percutaneous coronary intervention or potentially mechanical circulatory support (MCS) (5, 6), which may reduce mortality in this population.
Identifying cardiogenic etiologies of hypotension can be challenging in the ED due to clinical overlap with other etiologies (7). For instance, cardiogenic shock can cause an inflammatory state similar to that observed in septic shock, while myocardial dysfunction often complicates septic shock (8–10). This overlap can complicate the early recognition of cardiogenic shock, especially given the current clinical emphasis placed on recognition of sepsis, the more prevalent disease (4, 11).
The early implementation of any intervention in cardiogenic shock, including MCS, is likely important to prevent irreversible end-organ damage (12). Patients and future studies could benefit from a clinical prediction rule to identify cardiogenic etiologies of hypotension in the ED. This investigation seeks to identify independent predictors of cardiogenic etiology among ED patients with persistent hypotension, and to assess the clinical utility of these predictors in identifying cardiogenic hypotension, shock, and mortality among hypotensive ED patients.
This was retrospective analysis of a previous prospective, observational cohort study of consecutive patients with shock in the ED from November 11, 2012 to September 23, 2013 (13). The study was conducted at an urban, academic ED that has 55,000 annual visits. This study was granted a waiver of documented written consent under minimal risk criteria by the human subjects committee of the institutional review board. STROBE guidelines were used to report the results of this study (14).
We included all admitted adult (age 18 or older) patients with persistent hypotension in the ED: systolic blood pressure < 90 mm Hg after resuscitation with at least 1 L intravenous fluid, hypotension with intravenous fluids restricted due to documented concern of fluid overload (i.e., patients with known heart failure or hemodialysis dependent), or a vasopressor requirement. We excluded patients with hypotension due to atrial fibrillation with rapid ventricular response or supraventricular tachycardia who were discharged once rate control was achieved, intoxication, and hypotension due to transient medication effect. We also excluded patients who had a documented baseline systolic blood pressure < 90 mm Hg, unless a 10 mm Hg decrease in systolic blood pressure occurred.
ED screening and enrollment occurred using an alert preprogrammed into clinical information technology systems. All patients with hypotension noted at triage, in nursing notes, or on the bedside monitors (two readings more than 5 min apart), or who required vasopressor medications at any point during their ED stay, were prospectively identified for possible inclusion in the study. Eligible patients then underwent a confirmatory chart review to affirm the presence of shock and absence of exclusion criteria. This confirmatory review and subsequent data abstraction typically occurred 1 month after ED arrival and was performed without subsequent knowledge of the hospital course.
Elements of the history of present illness, initial vital signs, physical examination, past medical history, and medications were abstracted from the hospital record into an a priori standardized database for each enrolled patient. The history and physical examination came exclusively from the ED attending and resident charts. Basic demographics, length of stay, disposition data, and all laboratory values were obtained from the electronic health record. Electrocardiogram ischemia was defined as any electrocardiographic findings that suggested ischemia according to the final cardiologist interpretation.
A study investigator adjudicated each patient's underlying cause of instability using all available information (e.g., diagnostic testing results, physician notes, etc.) at the end of the hospital stay. Underlying causes were initially classified as septic, cardiogenic, hemorrhagic, hypovolemic, anaphylactic, neurogenic, or other based on previously published methods and definitions (10, 11, 15), and then reclassified as a binary outcome: cardiogenic or non-cardiogenic. Patients were systematically screened for evidence to determine a cause of shock, and each patient was assigned a single diagnosis that represented the most likely cause of shock in the ED. To determine inter-rater reliability, a second physician reviewer adjudicated a 25% sample, and the agreement between the two reviewers was found to be sufficient to proceed with a single adjudication for each patient (kappa = 0.92, 95% CI: 0.83–1.0).
The primary outcome was the adjudicated diagnosis: cardiogenic or non-cardiogenic etiology of hypotension. Secondary outcomes included cardiogenic shock in the ED (patients meeting any one criteria for end-organ damage: altered mental status, lactate ≥ 2 mmol/L, or vasopressor requirement) (10, 16, 17) and in-hospital mortality.
Data analysis was performed using SAS v9.3 statistical software (SAS Institute Inc, Cary, NC). A binary outcome variable was created for the primary outcome of cardiogenic etiology (i.e., cardiogenic or non-cardiogenic). A univariate assessment of the association between diagnosis and binary clinical covariates was performed using chi-square. For continuous covariates, Student t test or Wilcoxon rank sum was used as appropriate. A multivariate logistic regression model was to predict cardiogenic etiology of hypotension. All covariates from the initial univariate analysis with P < 0.1 were included in the logistic regression model selection process. A stepwise model selection process was used, with P < 0.05 required for entry and P < 0.1 required to stay in the model. Model discrimination was assessed using area under the curve (AUC). The Hosmer–Lemeshow test was used to assess model calibration. The model was internally validated using bootstrapping techniques. The logistic regression analysis was repeated on 1,000 different samples of the same size drawn with replacement from the original dataset. Median β-estimates and odds ratios with 95% confidence intervals were recalculated for each model covariate using these repeated samples.
β-coefficients from the initial logistic regression analysis were used to assign weight to each independent predictor. The test characteristics for different score thresholds were calculated to optimize sensitivity and specificity when predicting cardiogenic etiology for hypotension. As sensitivity analyses, the prediction score test characteristics were calculated in two subpopulations of cardiogenic hypotension to assess the efficacy in identifying the highest risk cardiogenic population most likely to benefit from early interventions: cardiogenic shock in the ED and cardiogenic patients who died in hospital.
Sample size justification
This study sought to identify predictors of cardiogenic hypotension using multivariable logistic regression. We estimated a priori that 15% of patients had cardiogenic etiology, allowing up to 10 predictors to be included in the logistic regression model using the n/10 rule to prevent over fitting.
Of 700 patients enrolled in the parent study, 107 of 700 (15.3%) had a cardiogenic cause as the most likely etiology of hypotension in the ED. Seventy-six of 700 (10.9%) met criteria for cardiogenic shock, and 68 of 700 (9.7%) were cardiogenic patients who died in-hospital. Cardiogenic patients had a higher prevalence of comorbidities generally associated with cardiac disease, including coronary artery disease, heart failure, myocardial infarction, and chronic obstructive pulmonary disease, while non-cardiogenic hypotension was more frequently associated with alcoholism and end-stage liver disease (Table 1). Cardiogenic patients had higher mean troponin concentrations, whereas non-cardiogenic patients demonstrated higher initial temperatures and percentage of immature granulocytes (Table 2).
The cohort had an overall mortality of 19.6% (95% CI: 16.8%–22.7%) before discharge. Patients with cardiogenic hypotension had mortality of 26.2% (95% CI: 18.7%–35.3%) which increased to 34.2% (95% CI: 24.5%–45.4%) if evidence of cardiogenic shock (altered mental status, lactate ≥ 2 mmol/L, or vasopressor requirement) was observed in the ED. Patients determined to have cardiogenic hypotension, but not meeting criteria for shock, had 6.5% (95% CI: 0.8%–21.8%) mortality (Supplemental Table 1, https://links.lww.com/SHK/A618).
The covariates reported shortness of breath (4.1, 95% CI: 2.5–6.7), history of heart failure (2.0, 95% CI: 1.1–3.3), absence of measured or reported fever (4.5, 95% CI: 2.3–8.7), troponin ≥ 0.1 ng/mL (OR 37.5, 95% CI: 7.1–198.2), and ischemia on electrocardiogram (8.9, 95% CI: 4.0–19.8) (AUC 0.827) were independently predicted cardiogenic hypotension (Table 3). The bootstrapping internal validation provided similar estimates (Supplemental Table 2, https://links.lww.com/SHK/A619).
The prediction score assigned points based on the covariate β-coefficients from the logistic regression model (Table 4). A composite score of 2 or more had 78% sensitivity and 77% specificity for cardiogenic hypotension in this population (Table 5). In the sensitivity analyses for higher-risk cardiogenic patients, a score ≥ 2 had 82% sensitivity and 75% specificity identifying cardiogenic shock in the ED and 79% sensitivity and 71% specificity for patients who died in-hospital. In the overall study population, 28.6% of patients with a score ≥ 2 had cardiogenic shock in the ED, and 10.4% of patients with a score ≥ 2 had cardiogenic hypotension and died before discharge (Fig. 1).
Among patients with persistent hypotension in the ED, the likelihood of a cardiogenic etiology can be assessed using simple history, physical, and laboratory information. A clinical prediction score of ≥ 2 has reasonable sensitivity and specificity for cardiogenic cause of hypotension, increasing the likelihood of cardiogenic hypotension from 15.3% in the overall hypotensive population to 38.3%. Only 5% of patients with < 2 points had cardiogenic hypotension.
The clinical prediction score identified patients within the two higher-risk sub-populations of cardiogenic hypotension with similar efficacy. While prospective validation and rule refinement to include echocardiography are necessary, this novel prediction score demonstrated adequate sensitivity for high-risk cardiogenic patients to justify clinical implementation as an ED screening tool. The specificity of 75% significantly narrows the hypotensive population to one where the assessment for early MCS would not overwhelm cardiology or system resources. Based on the low incidence of cardiogenic shock across an already infrequent group of patients with persistent hypotension, only one in four patients screened in by the score would have cardiogenic shock. Yet, using the study institution as a model, a patient would meet score threshold less than once daily. In exchange for the opportunity to initiate early cardiac interventions, the resources required to implement this screening may be inexpensive to the health system.
The logistic regression model and prediction score give weights to the various findings typically integrated into an ED diagnosis. Notably, a history of coronary artery disease or myocardial infarction were not significant independent predictors of cardiogenic hypotension after controlling for the other model covariates. Similarly, a history of heart failure only met score threshold if accompanied by another independent predictor. Conversely, 2 of 15 (13.3%) patients with a troponin ≥ 0.1 ng/mL and 14 of 39 (35.9%) with ischemia on electrocardiogram had non-cardiogenic hypotension, reminding clinicians to avoid basing clinical diagnoses on the presence or absence of a single data point. Along these lines, our recent study demonstrated that patients with suspected septic shock often did not have measured or reported fever (18). That study informs the application of the proposed criteria here, reminding clinicians that while hypotensive patients without signs of fever have a higher likelihood of cardiogenic cause, sepsis may still be present and an assessment for infectious causes is still necessary. Until novel diagnostic approaches improve the identification of cardiogenic hypotension, this process provides a reasonable approach.
Prior studies describe cardiogenic shock most frequently occurring as the sequela of myocardial infarction (19, 20), and typically occurring after a patient is admitted (21). Likely reflecting the lower incidence of cardiogenic shock in the emergency setting, expert recommendations give the vague guidance that a “cardiogenic cause of shock should be considered for shock in the ED without an obvious cause” (19), without acknowledging the diagnostic difficulty in identifying those patients with a cardiogenic cause of shock in the absence of an obvious ischemic event. We found that cardiogenic hypotension accounted for nearly one of seven ED patients with persistent hypotension. These cardiogenic patients frequently met criteria for cardiogenic shock in the ED, which was associated with a 34.2% mortality rate (20). Furthermore, the majority of our patients with cardiogenic hypotension did not have a troponin > 0.1 ng/mL or electrocardiogram ischemia, suggesting that myocardial infarction is less frequently the cause of shock in ED patients. Still, early MCS may benefit patients with cardiogenic shock, even without myocardial infarction, by offloading the heart to promote recovery and maintaining cardiac output to prevent end-organ damage as a bridge to more definitive treatment such as durable ventricular assist devices or cardiac transplant (22, 23). An emphasis in the current literature on managing shock in the context of acute myocardial infarction likely reflects the inherent difficulty when identifying nonischemic presentations of cardiogenic shock.
As the emphasis shifts to the earlier treatment of cardiogenic shock, developing reliable methods for early identification will allow interventions to be moved into the ED. If the strong predictors of cardiogenic hypotension described here are prioritized in the diagnostic work-up of persistent hypotension, the ambiguity surrounding this diagnosis could decrease.
Future studies should validate our findings in an independent, prospective ED patient population, ideally incorporating point-of-care ultrasound, which may decrease time to diagnosis (24, 25). Likewise, the ability of our proposed prediction score to identify patients who may benefit from MCS should be investigated, so that studies that attempt to move mechanical support into the earliest stages of care can identify candidate patients reliably.
This is a secondary analysis of a single-center study that prospectively identified consecutive patients with hypotension after resuscitation. Yet, data were abstracted retrospectively, so misclassification bias may exist as the clinical data collected were limited to what we were able to obtain from the medical records. Likewise, diagnoses were adjudicated by retrospective chart review, although the strong agreement between reviewers makes diagnostic misclassification less likely to influence results. While a broad spectrum of clinical data was included in our analysis, the vast majority of patients did not have formal echocardiography performed in the ED. While myocardial depression on echocardiography may suggest a cardiogenic cause of hypotension, in our institution these studies are rarely performed in the ED. Given that nearly one in three patients with septic shock will have systolic myocardial dysfunction as well (9), echocardiography alone cannot provide a definitive diagnosis. Patients with atrial fibrillation who were discharged explicitly after rate control was achieved were excluded from the original study. While hypotension due to primary atrial fibrillation was rare, this exclusion does remove a group of patients with cardiogenic hypotension from the population, although treatment of this patient group is targeted toward resolving the arrhythmia rather than inotropic or MCS. Last, this study was performed at a tertiary care center, to which patients with a larger burden of disease and those with hemodynamic instability are often referred. This limits the generalization of our findings to smaller community hospitals and may also affect the rates of adverse outcomes.
Cardiogenic etiologies often underlie persistent hypotension in the ED, are frequently associated with clinical criteria for shock, and carry a high mortality rate. Simple data that are readily available at the bedside offer robust leverage to predict cardiogenic etiologies of hypotension with sufficient sensitivity and specificity to screen ED patients. Such screening would allow the treatment of cardiogenic shock, including MCS initiation, to be moved earlier in the course of care, potentially improving the outcomes for this high-risk patient population.
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