Abstract
Rationale
Despite increasing recognition of mixed cardiogenic shock—particularly in patients with concomitant sepsis, there remains limited guidance on optimal inotropic selection, and the comparative effectiveness of different inotropes in this population is unclear.
Objective
To examine the association between inotrope selection and in-hospital outcomes, including all-cause mortality, among patients with cardiogenic shock and sepsis.
Methods
Using the PINC AI enhanced-claims Database (2016-2022), we identified patients with cardiogenic shock and sepsis using International Classification of Diseases, 10th revision codes (ICD-10) that were present on hospital admission and a pharmacy charge code for dobutamine or milrinone within 2 days of hospitalization. The primary outcome was all-cause hospital mortality. Secondary outcomes included inotrope duration, in-hospital length of stay, atrial arrhythmia, initiation of renal replacement therapy (RRT), use of mechanical circulatory support devices (MCS), and heart transplantation. We used greedy nearest neighbor matching on the propensity score (dobutamine vs. milrinone) followed by g-computation to estimate effects of inotrope selection on outcomes. We examined heterogeneity of treatment effect in patients with renal disease, congestive heart failure, pulmonary circulatory diseases, and on epinephrine prior to inotrope initiation.
Results
Out of 10,447 included patients, 74.4% received dobutamine and 25.6% received milrinone. Post-matching characteristics between the milrinone and dobutamine groups were similar (all Standard Mean Differences< 0.1). The primary outcome all-cause mortality was similar between post-matched milrinone and dobutamine groups (41.6% vs. 42.7%, risk difference −1.4 (95% confidence interval [CI}: −3.7, 1.5] %, p= 0.40). Patients initiated on milrinone (vs. dobutamine) had longer inotrope durations (5.1 days vs. 3.5 days, mean difference 1.7 [95% CI: 1.4, 1.9] days, p< 0.001), longer in-hospital length of stay (10.0 days vs. 9.1 days, mean difference 0.9 [95% CI: 0.4, 1.3] days, p<0.001), and more usage of antiarrhythmic agents (56.0% vs. 44.5%, mean difference 11.5 [95% CI: 8.9, 14.1] %, p<0.001). We did not observe any heterogeneity of treatment effect for all-cause mortality based on the pre-existing conditions of interest.
Conclusions
Using a large multicenter cohort, we identified no differences in all-cause mortality between dobutamine and milrinone among patients with concurrent cardiogenic shock and sepsis overall. However, secondary outcomes favored dobutamine.
Additional MeSH Keywords: mixed shock, cardiogenic shock, sepsis, ionotropic support
Introduction
Shock is a complex condition characterized by inadequate tissue perfusion and hypoxia from various underlying mechanism. Traditionally, shock is categorized into four main types: vasodilatory (distributive), cardiogenic, obstructive, and hypovolemic. More recently, the “mixed cardiogenic shock”—defined as cardiogenic shock with at least one additional contributory shock mechanism—has gained recognition, with combined vasodilatory shock being most common (1, 2). The prevalence of mixed cardiogenic shock is increasing (3, 4) and mixed cardiogenic shock is associated with higher mortality relative to isolated cardiogenic shock (10, 19). Unlike classic cardiogenic shock, which is characterized by increased systemic vascular resistance (SVR) in response to low cardiac output, mixed cardiogenic shock is distinguished by an inappropriate compensatory hemodynamic response, often presenting with a borderline or low SVR (2, 5, 6). A recent review proposed a further classification of mixed shock into three subtypes based on the dominant pathophysiological mechanism: vasodilatory (primary)-cardiogenic shock, cardiogenic (primary)-vasodilatory shock, and primary mixed shock (1). Sepsis, defined as a dysregulated host response to infection, plays a central role in both vasodilatory-cardiogenic shock and cardiogenic-vasodilatory (7, 8). In vasodilatory-cardiogenic shock, sepsis can exacerbate pre-existing cardiovascular dysfunction, cause direct myocardial injury from certain infections, and precipitates cardiomyopathy (including Takotsubo) (11-13). Conversely, in cardiogenic-vasodilatory shock patients, while systemic inflammatory response is the primary driver of vasodilatory shock, critically ill patients with underlying cardiac disease are particularly susceptible to sepsis (11, 14, 15).
Inotropic agents, such as dobutamine and milrinone, are frequently used in cardiogenic shock to augment cardiac output. While milrinone is recognized for its greater vasodilatory effect relative to dobutamine, both agents have traditionally considered interchangeable in terms of clinical outcomes (20, 21). To date, the only randomized trial comparing dobutamine to milrinone – the DoReMi trial in 2021 – found no significant differences in outcomes between milrinone- and dobutamine-treated patients with cardiogenic shock (20, 21). However, this trial did not characterize or examine the presence of concurrent sepsis. Moreover, the current Surviving Sepsis Campaign guidelines from 2021 give a weak recommendation on adding dobutamine to norepinephrine in patients with septic shock and concomitant cardiac dysfunction based on low quality of evidence (22). Despite the clinical relevance of inotropic selection in mixed cardiogenic shock with sepsis, no guidelines exist, and limited data are available to guide clinical decision-making. In this study, we aim to investigate associations between inotrope selection (milrinone versus dobutamine) and clinical outcomes in patients with cardiogenic shock and concurrent sepsis. Some of the result of this study have been previously reported in the form of the abstract (23).
Methods
This study was deemed not human subjects research by the Boston University Institutional Review Board. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Data source
In this retrospective cohort study, we utilized the Premier PINC AI Healthcare Database—formerly recognized as the Premier Healthcare Database (PHD). The PHD is a comprehensive, United State hospital-based, service-level, all-payer inpatient discharge database, representing approximately 25% of all inpatient admissions in the United States. The standard hospital discharge files within the PHD database include demographic characteristics, discharge diagnoses, and a log of billed items such as medications, diagnostic services, and procedures granular to the level of the calendar day with minimal missing data. PHD also provides the geographic location, teaching status and bed capacity of the hospitals for each patient visit. All data are deidentified and compliant with the Health Insurance Portability and Accountability Act (HIPAA) regulation (24).
Study Cohort
We evaluated patients discharged between January 1, 2016 and September 30, 2022 for study inclusion. The inclusion criteria were: 1) adult (aged 18 years and above); 2) admission to an intensive care unit (ICU) or intermediate care unit on the first day of hospitalization (excluding those admitted via transfer from another hospital); 3) diagnoses of both cardiogenic shock (International Classification of Diseases [ICD-10] code R57.0) and severe sepsis and septic shock (as per Angus criteria (25)) that were labeled as present at the time of admission; 4) on any vasoactive agents (either vasopressors or inotropes) at the time of admission; and 5) initiation of either dobutamine or milrinone but not both on the first or second day of hospitalization. If patients had multiple admissions to the hospital, a random admission was selected. We excluded patients who 1) had an out-of-hospital cardiac arrest (ICD-10 codes: I46.2 and I46.9) prior to admission; 2) were pregnant ; 3) were on inotropic agents prior to hospital admission; 4) were on mechanical circulatory support devices (MCS) on or before inotrope initiation; or 5) were admitted to an ICU post cardiac surgery. We used the Angus criteria to select the septic cohort instead of diagnosis code for sepsis or septic shock to catch a broader septic population based on previous study (26). We did not exclude patients who were started on other vasoactive agents (including those with inotrope activity such as epinephrine) before or on the same day as dobutamine or milrinone initiation but did account for concurrent use of these vasoactive medications in matching steps of the analysis (see statistical analysis section). Study day 0 was defined as the calendar day on which dobutamine or milrinone was first initiated. Patient cohort selection criteria definitions are shown in Table E1.
Outcomes of Interest
Outcomes were identified from study day 0 until hospital discharge or day 30, whichever came first. The primary outcome was all-cause hospital death; patients who died after 30 days were coded as not meeting the primary outcome. Secondary outcomes included length of hospital stay, duration of inotrope infusion (defined as the total days that patient received milrinone or dobutamine during hospitalization) infusion, use of renal replacement therapy (RRT), use of advanced heart failure therapy (MCS and heart transplantation), atrial fibrillation diagnosis (not present on admission), administration of common nodal blockers or antiarrhythmics (digoxin or amiodarone), vasopressor free days, and mechanical ventilation free days. Free day outcomes were calculated as 30 minus the number of days of vasopressor use (or invasive mechanical ventilation) within 30 days of study day 0. Patients who died within 30 days were coded as 0 free days. Thus, higher free day scores correspond to lower mortality or fewer days of organ support. Details of ICD-10-CM codes used to define covariates and outcomes can be found in Table E1.
Covariate Identification
We identified covariates likely to confound the association of inotropic choice and outcome from on or before study day 0. Included covariates were age, sex, validated measures of comorbidity severity and acute organ dysfunctions present on admission (27-29), administration of commonly used cardiovascular medications, vasoactive agents and antibiotics, days from hospital admission to inotrope initiation, use of renal replacement therapy (including both continuous and intermittent), use of invasive mechanical ventilation, discharge year, admission to a cardiac intensive care unit, and hospital characteristics (teaching status, safety-net status, presence of cardiac surgery, bed size and United States census region). We used the value closest to day 0 if covariates were entered more than once. Detailed variable definitions are summarized in Table E1.
Statistical Analysis
We performed all statistical analyses using R software, version 4.0.5 (R Foundation for Statistical Computing). We used the R package Matchit for propensity score matching (30) and the marginaleffects package for g-computation (31). Covariates were summarized overall and by treatment group before and after matching using means (standard deviations) or medians (interquartile range) for continuous variables and counts (percentages) as appropriate. Covariate balance between treatment groups was assessed using absolute standardized mean differences (SMD) with SMDs <0.1 defining well-balanced matching (32). We calculated propensity scores (for receipt of dobutamine [versus milrinone]) using logistic regression including all covariates. The distribution of propensity scores was visualized using density plots before and after matching. We used 1:1 greedy nearest neighbor matching without replacement on the propensity score to generate exposure groups with similar observed covariates. We then used g-computation(33) on the matched cohort to generate effect estimates comparing milrinone to dobutamine (average treatment effect among the treated – ATT). We did not include covariates in the g-computation model. For dichotomous outcomes, such as the primary outcome of hospital mortality, we calculated absolute risk differences, relative risks and associated 95% confidence intervals (CIs); for continuous outcomes, we calculated the mean risk differences and 95% CIs; 95% CIs were calculated using cluster robust standard errors (34).
Sensitivity Analyses
We repeated primary outcome analyses using the following sensitivity cohorts: (1) among patients who remained alive and hospitalized past study day 0 (the inotrope initiation day); (2) among patients who received antibiotics and norepinephrine on study day 0; and (3) among patients without a primary admitting explicit diagnosis of sepsis (ICD-10 codes: R65.2x or A41.x; to identify a cohort more likely to have cardiogenic shock driving their care).
Subgroup Analyses
We examined heterogeneity of treatment effect in subgroups based on renal disease (comorbid diagnosis, acute organ dysfunction or renal replacement therapy), congestive heart failure present on admission, pulmonary circulation disorders or use of pulmonary vasodilators, use of epinephrine at the time of inotrope initiation, and number of vasopressors at the time of inotrope initiation (dichotomized using the median number of vasopressors in the cohort). A p-value for a test of interaction was generated by including an interaction term for each subgroup variable with the exposure term in g-computation models.
Results
During the study period, 109,350 patients had an admission diagnosis of cardiogenic shock and received vasoactives on hospital day 1 or 2; 725,582 patients met the Angus sepsis criteria and received vasoactives on hospital day 1 or 2. Out of 46,176 who met both criteria, a total of 12,392 received milrinone or dobutamine on hospital day 1 or 2, but not both. After exclusion criteria selection, 10,447 were included in analyses (Figure 1). A total of 7,774 (74.4%) patients received dobutamine and 2,673 (25.6%) received milrinone. Prior to matching, patients who received dobutamine were likely to receive norepinephrine than those who received milrinone (59.4% vs. 45.2%, SMD 0.288). Patients who received milrinone were more likely to be admitted to a hospital with capacity to perform cardiac surgery (65.1% vs. 52.8%, SMD 0.253), a teaching hospital (64.5% vs. 52.7%, SMD 0.240), and a hospital with bed size of 500 and above (49.1% vs. 38.1%, SMD 0.223) (Table E2). The most common heart failure diagnoses present on admission were related to hypertensive heart disease in both exposure groups (Table E3). The most common infection diagnoses present on admission were related to unspecified sepsis, pneumonia, and urinary tract infections in both exposure groups (Table E4). Among the examined included patients, there was no missing data. After matching, there were 2,673 patients in each arm; all variables were balanced well between matched treatment assignment groups (all SMDs <0.1) and the distribution of propensity scores between treatment assignments were similar (Table 1 and Figure E1). Post-matching, the overall median age of matched patients was 66 (IQR 56-75); 1945 (36.4%) were female sex; 45.9% received norepinephrine on the day of inotrope initiation; and 33.8% received invasive mechanical ventilation (Table 1).
Figure 1:
Study flow diagram. ICD-10: International Classification of Diseases 10th Edition; POA: prior to admission.
*: Listed diagnosis/criteria were presented on admission to an ICU or stepdown units on hospital day 1 or 2. Patients transferred from another hospital were excluded. Discharge occurred between Q1 2016 – Q3 2022.
Table 1:
Baseline characteristics after matching
| Dobutamine (n=5,346) |
Milrinone (n=2,673) |
SMD | |
|---|---|---|---|
| Age, median (IQR) - years | 66 (56-75) | 66 (56-75) | 0.001 |
| Female, No. (%) | 983 (36.8) | 962 (36.0) | 0.016 |
| Diagnoses present on admission, No. (%) | |||
| Hypertension | 2177 (81.4) | 2180 (81.6) | 0.003 |
| Complicated Diabetes | 942 (35.2) | 965 (36.1) | 0.018 |
| Acute coronary disease | 915 (34.2) | 898 (33.6) | 0.013 |
| Congestive heart failure | 2528 (94.6) | 2548 (95.3) | 0.034 |
| Right heart failure | 427 (16.0) | 412 (15.4) | 0.015 |
| Cardiac arrhythmia | 1844 (69.0) | 1856 (69.4) | 0.01 |
| Atrial fibrillation | 1240 (46.4) | 1217 (45.5) | 0.017 |
| Mitral valve disease | 295 (11.0) | 286 (10.7) | 0.011 |
| Aortic valve disease | 135 (5.1) | 119 (4.5) | 0.028 |
| Tricuspid valve disease | 54 (2.0) | 55 (2.1) | 0.003 |
| Peripheral vascular diseases | 466 (17.4) | 466 (17.4) | <0.001 |
| Liver diseases | 351 (13.1) | 358 (13.4) | 0.008 |
| Renal failure | 1479 (55.3) | 1474 (55.1) | 0.004 |
| Chronic pulmonary disease | 1442 (53.9) | 1443 (54.0) | 0.001 |
| Pulmonary circulatory disorders | 913 (34.2) | 906 (33.9) | 0.006 |
| Pulmonary embolism | 117 (4.4) | 110 (4.1) | 0.013 |
| COVID-19 | 75 (2.8) | 68 (2.5) | 0.016 |
| ARDS present on admission | 49 (1.8) | 39 (1.5) | 0.029 |
| Acute organ dysfunctions present on admission (Angus), No. (%) | |||
| Neurologic | 627 (23.5) | 602 (22.5) | 0.022 |
| Hematologic | 441 (16.5) | 445 (16.6) | 0.004 |
| Hepatic | 531 (19.9) | 530 (19.8) | 0.001 |
| Respiratory | 1580 (59.1) | 1533 (57.4) | 0.036 |
| Renal | 1948 (72.9) | 1923 (71.9) | 0.021 |
| Treatments initiated prior or on the same day of inotropes, No. (%) | |||
| Renal replacement therapy (procedure codes) | 101 (3.8) | 102 (3.8) | 0.002 |
| Dialysis (charge codes) | 92 (3.4) | 91 (3.4) | 0.002 |
| Invasive mechanical ventilation | 919 (34.4) | 889 (33.3) | 0.024 |
| Antibiotics | 2009 (75.2) | 1987 (74.3) | 0.019 |
| Pulmonary vasodilators | 50 (1.9) | 46 (1.7) | 0.011 |
| Parenteral heparin | 982 (36.7) | 999 (37.4) | 0.013 |
| Glycoprotein inhibitors | 34 (1.3) | 33 (1.2) | 0.003 |
| ADP receptor inhibitors | 73 (2.7) | 82 (3.1) | 0.02 |
| Aspirin | 736 (27.5) | 706 (26.4) | 0.025 |
| Nitroglycerin | 143 (5.3) | 143 (5.3) | <0.001 |
| Amiodarone | 635 (23.8) | 642 (24.0) | 0.006 |
| Digoxin | 185 (6.9) | 194 (7.3) | 0.013 |
| Diuretics | 1438 (53.8) | 1448 (54.2) | 0.008 |
| ACE inhibitor or ARB | 87 (3.3) | 87 (3.3) | <0.001 |
| Calcium channel blocker | 260 (9.7) | 265 (9.9) | 0.006 |
| Beta-blocker | 492 (18.4) | 506 (18.9) | 0.013 |
| Norepinephrine | 1245 (46.6) | 1208 (45.2) | 0.028 |
| Epinephrine | 337 (12.6) | 325 (12.2) | 0.014 |
| Dopamine | 178 (6.7) | 163 (6.1) | 0.023 |
| Phenylephrine | 266 (10.0) | 280 (10.5) | 0.017 |
| Vasopressin | 1245 (46.6) | 1208 (45.2) | 0.028 |
| Nitroprusside | 20 (0.7) | 21 (0.8) | 0.004 |
| Number of vasopressors on the day of inotrope initiation, median (IQR) | 1 (0-1) | 1 (0-1) | 0.019 |
| Hospital-level variables, No. (%) | |||
| Safety-net hospital | 728 (27.2) | 715 (26.7) | 0.011 |
| Teaching hospital | 1710 (64.0) | 1723 (64.5) | 0.01 |
| Urban hospital | 2514 (94.1) | 2505 (93.7) | 0.014 |
| Cardiac surgery hospital | 1722 (64.4) | 1741 (65.1) | 0.015 |
| Bed size | 0.036 | ||
| 0-99 | 69 (2.6) | 78 (2.9) | |
| 100-199 | 239 (8.9) | 252 (9.4) | |
| 200-299 | 364 (13.6) | 358 (13.4) | |
| 300-399 | 408 (15.3) | 391 (14.6) | |
| 400-499 | 296 (11.1) | 282 (10.5) | |
| 500 and above | 1297 (48.5) | 1312 (49.1) | |
| United States Census region | 0.043 | ||
| Midwest | 403 (15.1) | 388 (14.5) | |
| Northeast | 472 (17.7) | 503 (18.8) | |
| South | 1239 (46.4) | 1257 (47.0) | |
| West | 559 (20.9) | 525 (19.6) | |
| CICU admission (compared to other units), No. (%) | 420 (15.7) | 421 (15.8) | 0.001 |
| Discharge year, No. (%) | 0.028 | ||
| 2016 | 198 (7.4) | 204 (7.6) | |
| 2017 | 257 (9.6) | 263 (9.8) | |
| 2018 | 435 (16.3) | 423 (15.8) | |
| 2019 | 430 (16.1) | 416 (15.6) | |
| 2020 | 474 (17.7) | 488 (18.3) | |
| 2021 | 455 (17.0) | 466 (17.4) | |
| 2022 | 424 (15.9) | 413 (15.5) | |
| First inotrope on hospital day 2 (versus on hospital day 1), No. (%) | 1183 (44.3) | 1150 (43.0) | 0.025 |
ACE: angiotensin converting enzyme; ADP: Adenosine diphosphate; ARB: Angiotensin II receptor blocker; ARDS: acute respiratory distress syndrome; CICU: cardiovascular intensive care unit; COVID-19: coronavirus disease 2019; ICD-10: International classification of diseases, tenth revision; ICU: intensive care unit; IQR: interquartile range; SMD: absolute standardized mean difference.
After matching, the primary outcome of all-cause hospital mortality was similar between the milrinone and dobutamine groups (41.6% vs. 42.7%, risk difference −1.4 [95% confidence interval {CI}: −3.7, 1.5] %, relative risk for milrinone vs dobutamine 0.97 [95% CI 0.92, 1.04], p=0.40) (Table 2). There was also no association between inotrope selection and hospital mortality in any of the three sensitivity analyses (Table 3). In the subgroup analyses, there was no evidence of heterogeneity of treatment effect based on pre-existing renal failure, congestive heart failure, pulmonary circulation disorders, use of epinephrine on the day of inotrope initiation or median number of vasopressors on the day of inotrope initiation (Figure 2).
Table 2:
Post-matching primary and secondary outcomes in patients with concurrent cardiogenic shock and sepsis using milrinone or dobutamine as initial inotropic treatment.
| Dobutamine (Reference) (n=2,673) |
Milrinone (n=2,673) |
Risk or Mean Difference (95% CI) |
Relative risk (95% CI) | P-value | |
|---|---|---|---|---|---|
| In-patient mortality (%) | 42.7 | 41.6 | −1.1 (−3.7, 1.5) | 0.97 (0.92, 1.04) | 0.40 |
| Inotrope duration (mean, 95% CI, days) | 3.5 | 5.1 | 1.7 (1.4, 1.9) | NA | <0.001 |
| Hospital LOS (mean, 95% CI, days) | 9.1 | 10.0 | 0.9 (0.4, 1.3) | NA | <0.001 |
| New onset atrial fibrillation* (%) | 6.4 | 8.9 | 2.4 (0.5, 4.4) | 1.38 (1.07, 1.78) | 0.01 |
| Anti-Arrhythmic agent (%) | 44.5 | 56 | 11.5 (8.9, 14.1) | 1.26 (1.19, 1.33) | <0.001 |
| Renal replacement therapy (%) | 16.4 | 16.5 | 0.1 (−1.9, 2.1) | 1.00 (0.89, 1.13) | 0.94 |
| MCS (%) | 2.1 | 3.5 | 1.3 (0.5, 2.2) | 1.63 (1.18, 2.25) | 0.003 |
| Cardiac transplant (%) | 0.1 | 0.6 | 0.4 (0.1, 0.7) | 3.75 (1.24, 11.30) | 0.02 |
| Vasopressor free days (mean, 95% CI, days) | 18.4 | 18.7 | 0.2 (−0.5, 0.9) | NA | 0.51 |
| Mechanical ventilation free days (mean, 95% CI, days) | 18.2 | 18.6 | 0.4 (−0.3, 1.1) | NA | 0.37 |
Among post-matched patients without atrial fibrillation present on admission (n=2,889)
CI: confidence interval; LOS: length of stay; MCS: mechanical circulatory support
Table 3:
Post-matching sensitivity analyses for all-cause in-hospital mortality in patients with concurrent cardiogenic shock and sepsis using milrinone or dobutamine as initial inotropic treatment.
| Sensitivity Analyses | Dobutamine (%, reference) |
Milrinone (%) |
Risk Difference (95% CI) |
Relative risk (95% CI) |
P-value |
|---|---|---|---|---|---|
| Patient remaining alive and hospitalized past the day of inotrope initiation (n=5,076) | 30.9 | 30.4 | −0.5 (−3.0, 2.0) | 0.98 (0.91, 1.07) | 0.69 |
| Patients receiving antibiotics and norepinephrine on the day of inotrope initiation (septic shock cohort; n=2,078) | 46.0 | 43.5 | −2.5 (−6.8, 1.8) | 0.95 (0.86, 1.04) | 0.25 |
| Patients without a primary explicit admission diagnosis of sepsis (ICD-10 codes: R65.2x or A41.x) (n=3,258) | 24.8 | 25.0 | 0.2 (−2.7, 3.2) | 1.01 (0.9, 1.13) | 0.87 |
ICD-10: International Classification of Diseases, Tenth Revision
Figure 2:
In-hospital mortality in subgroups. Shown are relative risks (relative risks below 1 favor milrinone and above 1 favor dobutamine) and 95% confidence intervals within post-matching subgroups. P-values testing for interaction between subgroups are shown on the right-hand side of the plot. CHF: congestive heart failure; CI: confidence interval.
For secondary outcomes, patients initiated on milrinone (compared with dobutamine) had longer inotrope durations (5.1 days vs. 3.5 days, mean difference 1.7 [95% CI: 1.4, 1.9] days, p<0.001) and hospital lengths of stay (10.0 days vs. 9.1 days, mean difference 0.9 [95% CI: 0.4, 1.3] days, p<0.001) as well as higher rates of advanced heart therapy-related outcomes: cardiac transplant (0.6% vs. 0.1%, risk difference 0.4 [95% CI: 0.1, 0.7] %, p= 0.02) and MCS (3.5% vs. 2.1%, risk difference 1.3 [95% CI: 0.5, 2.2] %, p= 0.003). Patients initiated on milrinone were also more likely to be administered antiarrhythmic agents compared to patients initiated on dobutamine (56.0% vs. 44.5%, mean difference 11.5 [95% CI: 8.9, 14.1] %, p< 0.001), and more likely to develop new onset of atrial fibrillation (among those without atrial fibrillation present on admission; n=2,889) compared to those who received dobutamine (8.9% vs. 6.4%, risk difference 2.4 [95% CI: 0.5, 4.4] %, p= 0.01). There were no differences in renal replacement therapy, vasopressor free days, or mechanical ventilation free days between exposure groups (Table 2).
Discussion
In this large, retrospective, multicenter study of patients admitted to United States hospitals with cardiogenic shock and sepsis who were initiated on dobutamine or milrinone, we found no significant association between initial inotrope selection and all-cause mortality. However, patients who received milrinone had longer inotrope durations, extended in-patient lengths of stay, increased risks of atrial fibrillation and anti-arrhythmic use, and greater utilization of MCS and cardiac transplant. These findings suggest that inotrope selection in mixed cardiogenic shock patients, as opposed to isolated cardiogenic shock, may require a more nuanced and individualized approach.
Our results should be considered in the context of prior work that also found no difference in mortality between dobutamine in patients with cardiogenic shock and, separately, in patients with septic shock. The DoReMi clinical trial comparing milrinone to dobutamine in cardiogenic shock found no difference in all-cause mortality based on initial inotrope assignment, although it did not specifically analyze patients with concurrent sepsis and may have been underpowered to detect outcome differences related to inotrope selection (20). Unlike our study, DoReMi found no differences in length of stay, arrhythmia risk, or use of advanced cardiac therapies, including either MCS or cardiac transplantation in their study period (21). Small studies in patients with sepsis and septic shock have either found no difference or identified worse mortality with dobutamine compared to milrinone (35, 36). Compared to these prior investigations, our study specifically addresses patients with both cardiogenic shock and sepsis and leveraged a larger sample size, enabling more precise effect estimates. Our findings align with the Surviving Sepsis Campaign 2021 guideline, which recommend dobutamine for inotropic support for septic patients with concomitant cardiac dysfunction (22). However, it is important to note that only one study cited in this guideline included milrinone as an inotrope option, and was underpowered to draw meaningful conclusions regarding milrinone’s efficacy in septic shock patients (37).
The secondary outcome results from our study demonstrate both alignment and discordance with previous studies. Consistent with two meta-analyses in cardiogenic shock and heart failure population (38, 39), as well as observational study in septic patients (36), we observed longer hospital stays in patients treated with milrinone. However, the higher rates of arrhythmia and anti-arrhythmic medication use in patients receiving milrinone identified in our study our discordant from a prior single center retrospective study which patients with cardiogenic shock who received dobutamine had nearly twice the risk of arrhythmia compared to those who received milrinone (62.9% vs 32.8%) (40).
The molecular mechanisms of dobutamine and milrinone might provide insight into the observed results. While both dobutamine and milrinone increase myocardial contractility via cyclic AMP-mediated pathway, they act on different target receptors at different regulatory steps, leading to distinct hemodynamic profiles. In pure cardiogenic shock, compensatory vasoconstriction mitigates the impact of differential vasodilatory effects between two agents. However, in mixed cardiogenic shock with concurrent vasodilatory components, vasodilatory properties may become clinically significant, potentially amplifying the hemodynamic consequences of inotrope selection. The degree to which this differential impact manifests in clinical outcomes likely depends on both the primary shock phenotypes (vasodilatory vs. cardiogenic) and the severity of illness. Future research should explore impact of inotrope choice on hemodynamic profiles in mixed cardiogenic shock to elucidate potential mechanisms underlying the differences in secondary outcomes observed in our study. Additionally, future studies should seek to identify patient subgroups that benefit from one inotrope over another (i.e., heterogeneity of treatment effect).
Limitations
The observational nature of our study increases the risk of unmeasured confounders including the specific rationale for inotrope choice (e.g., candidacy for future advanced therapy, individual risk of arrhythmia), vasoactive dosing, and cardiogenic shock etiology (ischemia- vs. non-ischemic related), type (left ventricular, right ventricular, or bi-ventricular), severity (left ventricular ejection fraction and invasive hemodynamics), and acuity (de novo vs. acute on chronic). Lack of data concerning cardiogenic shock etiology also precluded us from exploring heterogeneity of treatment effect based on etiology. In addition, the ‘calendar day’ granularity may introduce immortal time bias, although the active comparator design may minimize this risk (41). We did not exclude patients from the primary analysis that received epinephrine (a vasoactive with inotropic properties). However, post-matching, exposure groups had similar use of epinephrine at baseline. Moreover, the subgroup analysis stratifying patients based on baseline epinephrine use did not identify evidence of heterogeneity of treatment effect. Conceptually, the validated algorithm we used to identify sepsis is similar to the Sepsis-3 definition (infection and organ dysfunction). However, we did not have access to laboratory data or infusion dose data that is necessary to calculate Sepsis-3 criteria directly. We did not compare use of inotropes to no use of inotropes. Thus, our results should not be used to inform clinical decisions about whether inotropes should be started in mixed shock. We were not able to determine the cause of death and thus were unable to examine differences in cause-specific mortality. Although we accounted for admission to hospitals with cardiac surgery capability in analyses, it is possible that the observed findings of higher cardiac transplantation and MCS use in patients received milrinone reflect preference for milrinone among patients with planned future cardiac transplantation rather than a true difference in inotrope effectiveness.
Conclusions
In this large multicenter retrospective cohort study from an administrative database, we found no differences in all-cause hospital mortality between patients with cardiogenic shock and sepsis who were initiated on dobutamine versus milrinone. However, several secondary outcomes including length of stay and arrhythmia risk favored dobutamine.
Supplementary Material
This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org.
Acknowledgements
The authors used OpenAI to assist with language editing and proofreading during manuscript preparation.
Funding Sources:
This study was supported by National Institute of Health (NIH) National Center for Advancing Translational Sciences (NCATS) grant number 1KL2TR001411, 1UL1TR001430, the Boston University Chobanian & Avedisian School of Medicine Department of Medicine Career Investment Award, and University of Miami Hospital and Clinics Data Analytics Research Team (UHealth-DART). This study's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, Boston University, or University of Miami. The NIH, Boston University, and University of Miami had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, approval of the manuscript, or decision to submit the manuscript for publication.
Footnotes
Descriptor Number: 4.12 Sepsis/Multiple Organ Failure
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