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Norepinephrine, Dopamine, and Vasopressin in Patients with Sepsis and Preexisting or Acute Heart Failure: A Retrospective Cohort Study

Background The aim of this study was to assess the impact of norepinephrine (NE), norepinephrine plus vasopressin (NE+VAS) and dopamine in patients with sepsis and heart failure. Material/Methods Data were extracted from the Medical Information Mart for Intensive Care III database, v1.4. Adults aged >18 years in an Intensive Care Unit (ICU) who had heart failure and took vasopressors were included. The patients were divided into 3 groups: NE, NE+VAS, and dopamine. Differences in survival, treatment time, and organ function among the 3 groups were compared. Propensity score matching (PSM) was used to screen for possible prognostic differences, and regression analysis was used to further analyze and predict prognoses. Results A total of 1864 patients were included. There were significant differences among the 3 groups in 7-, 28-, and 90-day mortality after PSM. The 5-year survival rates among the 3 groups also were significantly different (P<0.001). After Cox regression analysis, NE+VAS was an independent risk factor affecting 5-year survival (P<0.001). After multiple linear regression, dopamine was the factor related to ICU and hospital lengths of stay. Conclusions Compared with NE or dopamine alone, NE+VAS can reduce survival in patients with sepsis and heart failure who need vasopressors. Compared with the other 2 treatment options, dopamine can shorten ICU and hospital stays for these patients.


Background
Sepsis is well-recognized as a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection. It is a life-threatening organ dysfunction that results from a dysregulated host response to infection. The clinical manifestations depend on the site of infection and the response of the host to the infection. Patients with sepsis often present with general malaise and nonspecific signs such as fever (although hypothermia can be present, too), tachycardia, or altered mental status [1]. As the disease progresses, arterial hypotension, gas exchange disorders (even when the focus of infection is outside the chest), oliguria, and increased capillary recanalization time can occur (Figure 1) [1].
In the United States, admissions for sepsis have overtaken those for myocardial infarction and stroke [2]. Although outcomes in patients with sepsis have improved, the mortality rate ranges from 25% to 30%, and when shock is present, it can approach 40% to 50% [3]. Sepsis-associated multiorgan dysfunction is the predominant cause of death. Clinical identification of organ dysfunction is based largely on surrogates such as serum creatinine, serum bilirubin, blood pressure, PaO 2 /FiO 2 ratio, Glasgow Coma Scale, platelet count, and respiratory rate [4]. However, little is known about the pathobiology of dysfunction in individual organ systems or prognosis.
Heart failure (HF) is a major cause of cardiovascular morbidity and mortality and affects 5.7 million US adults, and the prevalence is predicted to increase by 46% in the next 15 years [5]. In nearly 70% of patients with sepsis, the condition is severe, and it can manifest as hemodynamic instability, cardiac biomarker elevation, myocardial dysfunction on echocardiography, and end-organ hypoperfusion [6]. In about 1% of cases of severe sepsis, infective endocarditis, the most important cause of cardiac dysfunction, is associated with a mortality rate of 33% [7]. The onset of HF in sepsis greatly increases the risk of mortality and it is a major cause of therapy failure.
Currently, norepinephrine (NE), dopamine, and vasopressin (VAS) are commonly used as vasoactive drugs in the clinic. Most studies of these drugs have focused on their use in populations with sepsis or cardiogenic shock, and few have focussed on patients with sepsis and HF. Therefore, we conducted the present retrospective cohort study to evaluate these 3 drugs in patients with sepsis and HF.

Data sources
Data were obtained from the Medical Information Mart for Intensive Care (MIMIC)-III database, v1.4, which is an openaccess database containing information on patients admitted to Beth Israel Deaconess Medical Center (BIDMC) (Boston, Massachusetts, U.S.A.) between 2001 and 2012 [8]. Use of the MIMIC-III database was approved by the Institutional Review Boards of BIDMC and Massachusetts Institute of Technology (certification number: 36300529).

Study population and stratification
Patients older than age 18 years admitted to the Intensive Care Unit (ICU) for more than 24 h were included. For patients with multiple ICU admissions, only the first stay was analyzed. Because there was no criterion standard for sepsis, the diagnosis was identified in patients in the present study based on:
The following ICD-9 codes were used to identify a diagnosis of HF  (Figure 2).

Definitions and outcomes
Congestive HF (CHF) was defined as HF with limb edema or pulmonary congestion. Preexisting HF was defined as preexisting chronic HF or various cardiomyopathies, including acute exacerbations of chronic HF. The remainder of the population was patients who were originally heart-healthy and had a diagnosis of acute cardiac dysfunction during their current hospitalization. Information on heart rate (HR), temperature, laboratory tests, and scores were collected on admission to the ICU.
The primary endpoint of the study was all-cause mortality (7-, 28-, and 90-day mortality). Secondary endpoints included the following indicators: hospital length of stay (Hos LOS), ICU length of stay (LOS), incidence of mechanical ventilation (MV), MV duration, incidence and duration of new renal replacement therapy (RRT), incidence of acute kidney injury (AKI), increased HR, emerging arrhythmia, emerging malignant arrhythmia, and decreased hemoglobin level and platelet count. AKI was diagnosed using the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine-based criterion, which was defined as an absolute increase of ³1.5 times baseline [12]. New ventricular tachycardia, ventricular fibrillation, and asystole were described as emerging malignant arrhythmias. Increased HR was calculated as the difference between the maximum and baseline HR during ICU treatment, as measured by electrocardiogram. Hemoglobin and platelet declines were the baseline level minus the minimal value during a patient's ICU stay.

Statistical analysis
For continuous variables, mean ± standard error of mean, median, or interquartile range are given. Categorical variables are expressed as absolute and relative frequencies. Analysis of variance, the Wilcoxon rank sum test, or the Kruskal-Wallis test were used wherever applicable. Propensity score matching (PSM) was used for variables with baseline differences. Kaplan-Meier curves were plotted for survival analysis and log-rank tests were used as appropriate. A Cox proportional hazards model and a multiple linear regression model were used as follows. First, multivariate analyses were used to test all variables with P<0.1 in univariate analysis; then, a stepwise elimination procedure was used to remove variables with P>0.1; then, variables with latent multicollinearity were included in the 2 models for retrospective analysis. All statistical analyses were carried out with SPSS software (IBM SPSS Statistics v26). In all tests, the a level was set at 0.05 (2-sided).

Results
Initially, 61 532 records were identified in the MIMIC-III database, of which 53 898 were excluded (8200 were patients aged <18 years; 7481 spent <24 h in the ICU; 25 457 did not have sepsis; 12 760 were patients without HF). Of the remaining

DATABASE ANALYSIS
PSM was used to balance the differences among the 3 groups at baseline ( Table 3). After PSM, all outcome variables were significantly different among the 3 groups, especially the primary endpoint ( Table 4). A 5-year survival analysis suggested a significant difference in cumulative survival among the NE, dopamine, and NE+VAS groups (P<0.001, Figure 3). The combination of NE and VAS was negatively associated with 5-year cumulative survival in both unadjusted and adjusted Cox regression models ( Table 5). For the secondary endpoints, we focused on analysis of ICU and Hos LOS. A multivariate linear retrospective model was constructed to examine whether dopamine was an important negative factor associated with ICU and Hos LOS (Tables 6, 7; Simplified Acute Physiology Score II may have multiple collinearity problems with other variables, so it was not included in the multifactor analysis model). In addition, we performed a multiple linear regression analysis of mechanical ventilation duration in these patients and showed that dopamine was a negative factor (Supplementary Table 2).
Finally, it is well known that there is an ambivalent dose-effect role for dopamine. Therefore, we divided the dopamine group into low-, moderate-, and high-dose groups [13] and analyzed patient baselines and outcome variables. There were no significant differences in the baseline conditions, except for the criticality scores in the low-and high-dose groups ( Table 8). No significant differences in any outcome variables were observed between the high-and low-dose groups ( Table 9).  Table 5. Associations with 5-year mortality in patients with sepsis and heart failure in the NE, NE+VAS, and dopamine groups.

Discussion
In the present study, 3 main findings were elicited. First, the outcomes in the NE+VAS group were significantly worse than in the NE and dopamine groups in terms of all-cause mortality, treatment duration, and safety measures in patients with sepsis and HF who needed vasopressors (the incidence of emerging arrhythmias was lower, but the incidence of emerging malignant arrhythmias was higher.) Furthermore, after PSM, the dopamine group did not show a higher incidence of emerging arrhythmias, especially malignant arrhythmias, than the NE group. Last but not least, dopamine can shorten ICU and Hos LOS in these patients compared with the LOS in the NE and NE+VAS groups.
In the clinic, NE, VAS, and dopamine are the most commonly used vasoactive drugs. An intriguing and important question is regarding the best approach for patients with sepsis. NE was recommended as the first-choice vasopressor for sepsis in the Surviving Sepsis Campaign (SSC) guidelines [14]. An earlier systematic review and meta-analysis suggested that NE has more advantages than dopamine related to the occurrence of all-cause mortality and arrhythmia in septic shock [15]. Therefore, it is recommended that use of NE be prioritized in   Table 7. Multiple linear regression analysis of differences in hospital length of stay among the NE, NE+VAS, and dopamine groups.
patients with septic shock [14]. In addition, NE has replaced epinephrine as the first-line booster for patients in cardiogenic shock [16]. The guidelines are based on some randomized controlled trials (RCTs) that recommended NE instead of dopamine for cardiogenic shock, but the role of the 2 drugs in septic shock with HF remains controversial [17]. VAS is a noncatecholamine booster drug, and in some recent studies, use of it rather than epinephrine has been shown to significantly decrease mortality in patients with cardiovascular disease and sepsis [18]. VAS was recommended as the second-line vasopressor for sepsis in the SSC guidelines [14]. However, in animal studies, it has been demonstrated to have a negative impact on coronary perfusion [19]. VAS can also induce profound vasoconstriction in the fluid reservoir of the splanchnic vasculature. However, given the lack of human data on the drug's adverse effects and its efficacy when used in combination with NE, VAS should be the first choice when added to NE for sepsis in patients with preexisting HF [20]. Dopamine, which is recommended as a last-line vasopressor for septic shock, can increase arrhythmias [14]. However, some trials have not demonstrated that dopamine increases cardiac adverse effects in patients with acute HF [21,22]. Because of the lack of evidence for vasopressors in patients with sepsis who already have HF, the data on which the SSC guidelines were based are primarily from subgroups within studies on sepsis, septic shock, and other shock presentations [20].  Table 8. Demographic characteristics and clinical basis data for patients in the low-, moderate-, and high-dose dopamine groups.
In the present retrospective study based on real-world data, we have found that for patients with sepsis and HF who need vasopressors, NE+VAS may be harmful (7-, 28-, and 90-day mortality, and other endpoints). A 5-year cumulative survival analysis indicated that the rate of mortality was higher in patients treated with NE+VAS (P<0.001). Analyses using the adjusted Cox retrospective model showed that use of a combination of NE and VAS was an independent risk factor for longterm survival in these patients. This is consistent with a recent network meta-analysis suggesting that NE+VAS increases mortality rates in patients with sepsis [23]. We may need to avoid this combination in patients with sepsis and HF who require vasopressors.
In terms of arrhythmia, we compared our results those from published RCTs and found some similarities and differences [16,24]. One of the studies included patients with cardiogenic and septic shock. The double-blind and randomized Comparison of Dopamine and Norepinephrine in the Treatment of Shock [24] trial enrolled 1679 patients, of whom 858 were e927716-11 assigned to dopamine and 821 to NE, in 8 centers in Belgium, Austria, and Spain. No significant difference was shown in the mortality rates for patients with shock who were treated with dopamine and those who were treated with NE. This result was congruent with our study. However, dopamine was associated with more arrhythmias compared with NE. This is inconsistent with our results after PSM. Dopamine binds a1-and b1-adrenergic and dopaminergic DA1 and DA2 receptors, the latter causing splanchnic and renal vasodilation at low doses in preclinical studies and small clinical trials ("low-dose dopamine") [13]. Therefore, we also performed a subgroup analysis of the dopamine group. There  were no differences between the low-and high-dose dopamine groups in AKI or other secondary outcome indicators. Compared with high-dose dopamine, low doses may not be nephroprotective in critically ill patients [25].
The present study has several limitations. First, retrospective comparisons were performed with PSM to minimize selection bias, but unobserved confounders may remain. For example, different treatment periods could lead to changes in treatment concepts, which may bias the results. Treatment with inotropic drugs may be necessary in patients with severe sepsis. If the retrospective analysis is interpreted hastily without limiting for that, the protective effective of the drugs may not be taken into consideration. Therefore, the results of the present study should be considered in the context of the target population and the limited comparison of the drugs. Subsequent validation of the data in prospective RCTs is needed. In addition, given the limitations of the information in the database, we did not classify preadmission cardiac function and exercise tolerance per patient. These conditions may have affected the duration of treatment, especially for MV. In addition, both pathogens and antibiotics could cause alterations in blood composition. Last but not least, the present study was done in a single center. A prospective, multicenter study with a larger sample size would be more convincing.

Conclusions
In patients with sepsis and HF who need vasopressors, NE+VAS can reduce survival compared with NE or dopamine alone. Compared with the other 2 options, dopamine can shorten ICU and hospital stays in these patients.