Safety of dexmedetomidine in the cardiac intensive care unit

Abstract

Introduction

Sedation is an important component of care for mechanically ventilated patients. Dexmedetomidine and propofol are currently recommended by the Society of Critical Care Medicine as preferred sedative agents over benzodiazepines in critically ill, mechanically ventilated patients.¹ Little data exists describing sedation in the cardiac intensive care unit (CICU) population. Dexmedetomidine is an attractive option due to its ability to induce only light sedation without respiratory suppression. However, potential side effects of hypotension, bradycardia, and asystole associated with its use are particularly concerning for the CICU population.

Dexmedetomidine is the only sedative agent used that acts on the α-2 adrenergic receptor, providing unique benefits, but also a cardiovascular adverse event profile that differs from commonly used agents.² Dexmedetomidine has been shown in several double-blind randomized controlled trials to cause three times as much first-degree atrioventricular block compared to propofol, twice as much hypotension compared to midazolam, and three times as much bradycardia compared to midazolam.³

In a recent open-label, randomized trial, critically ill adults undergoing ventilation for less than 12 h in the intensive care unit (ICU) received dexmedetomidine as the sole or primary sedative or usual care (propofol, midazolam, or other sedatives).⁴ No difference in the primary outcome of rate of death at 90 days was evident between the two groups. However, more adverse events were reported in the dexmedetomidine group, most commonly bradycardia and hypotension as well as prolonged sinus arrest. Approximately 15% of patients were included in the study with a primary cardiovascular diagnosis necessitating ICU admission. Given the lack of data for use in the CICU population and concern for cardiovascular side effects, the purpose of this study was to determine the prevalence of adverse events in CICU patients treated with dexmedetomidine.

Methods

Study design and patient selection

This was a retrospective cohort analysis of patients greater than 18 years old admitted to the University of Michigan CICU from June 2014 to October 2019 who received dexmedetomidine therapy for any duration of time. Information was collected through chart review on patient demographics, comorbid conditions, vasoactive and inotropic medications, concomitant sedative medications, and haemodynamic variables. The laboratory values collected were those that were drawn closest to the start of dexmedetomidine. Dexmedetomidine was initiated and titrated at the discretion of the physician. The study was approved by the University of Michigan Institutional Review Board. Informed consent was waived given the retrospective nature of this work.

Primary and secondary outcomes

The primary outcome was the composite of adverse events including bradycardia, hypotension, increasing vasopressor/inotrope requirements, and asystole. Secondary outcomes included bradycardia, hypotension, increasing vasopressor/inotrope requirements, and asystole. A subgroup analysis of changes in pulmonary artery catheter variables prior to and following initiation of dexmedetomidine was also conducted for patients with a pulmonary artery catheter. Patients that experienced adverse events were compared to those that did not experience adverse events to identify risk factors for adverse events.

Adverse event definitions

Bradycardia was defined as any documentation of new-onset heart rate less than 50 b.p.m. within 24 h after initiation of dexmedetomidine. Hypotension was defined as systolic blood pressure (SBP) less than 90 mmHg and reduction of at least 10 mmHg from baseline SBP or new start of vasopressor medications within 24 h after dexmedetomidine initiation in patients that were not already on vasopressors at time of dexmedetomidine initiation. For patients that were receiving vasopressors at the time of dexmedetomidine initiation, increases in vasopressor doses were measured in norepinephrine equivalents. An increase in vasopressor requirements was defined as any increase in vasopressor dose within 24 h after dexmedetomidine initiation. Asystole was defined as any asystolic event attributed to dexmedetomidine lasting more than 3 s and requiring an intervention.

Statistical analysis

Comparisons between patients with and without adverse events were performed using χ² test for categorical variables, Student’s t-test to assess continuous variables distributed parametrically, and Mann–Whitney U test for continuous variables distributed non-parametrically. A P-value of <0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS 26.0 (Armonk, NY, USA).

Results

A total of 197 patients were included. Baseline demographics are summarized in Table 1. The mean age was 59.9 ± 15.4 years and the majority (63.4%) of patients were male. At the time of dexmedetomidine initiation, mean left ventricular ejection fraction (LVEF) was 45% and median B-type natriuretic peptide (BNP) was 664 pg/mL. Two patients were undergoing targeted temperature management at time of dexmedetomidine initiation. The majority (94.9%) of patients received dexmedetomidine while mechanically ventilated. Seventeen patients (8.6%) received a dexmedetomidine bolus prior to initiation of a continuous infusion. The median dexmedetomidine maximum rate was 0.84 µg/kg/h. Eighty-eight (44.7%) of patients received dexmedetomidine at a maximum rate ≥1 µg/kg/h. Median duration of dexmedetomidine was 17 h. Dexmedetomidine use characteristics are summarized in Table 2.

A total of 116 adverse events in 106 patients occurred as summarized in Table 3. Patients could have experienced one or more adverse events. Hypotension was the most common adverse event, occurring in 70 (35.5%) of patients. In patients that experienced hypotension, SBP decreased by a median (IQR) of 32 (23–55) mmHg and mean arterial pressure (MAP) decreased by a mean of 23 ± 14 mmHg from baseline at dexmedetomidine initiation. Increased vasopressor requirement occurred in 22 (11.1%) patients. Mean increase in norepinephrine equivalents was 0.09 ± 0.07 µg/kg/min. At the time of dexmedetomidine initiation, 9 (4.6%) patients were requiring an inotrope. Inotrope doses were not escalated in any of these patients following dexmedetomidine initiation. Bradycardia occurred in 22 (11.1%) of patients, with a median (standard deviation) decrease in heart rate of 26 (20) b.p.m. Asystole occurred in two patients for which both required initiation of cardiopulmonary resuscitation (CPR). Invasive haemodynamic data for patients with a pulmonary artery catheter can be found in Table 4.

Data are summarized in Table 5 demonstrates differences found between those patient with and without an adverse event. Receiving a bolus dose of dexmedetomidine was not associated with an increased risk of an adverse event (9.4% vs. 7.7%, P = 0.80). Similarly, a higher median maximum dose of dexmedetomidine was not associated with an increased risk of an adverse event (0.85 vs. 0.83 µg/kg/h, P = 0.97). LVEF was not significantly lower in patients that experienced adverse events (43% vs. 47%, P = 0.24); however, BNP was significantly higher in patients that experienced an adverse event (848 pg/mL vs. 431 pg/mL; P = 0.03).

Discussion

This study reports a higher incidence of adverse events associated with dexmedetomidine use in critically ill cardiovascular patients than previously reported for heterogeneous critically ill populations. Those experiencing adverse events had a higher BNP suggesting that patients admitted with acute decompensated heart failure (ADHF) or other cardiac diseases associated with increased myocardial wall stress may be at higher risk to suffer from adverse events.

Data are lacking regarding the safety of dexmedetomidine in patients with cardiac disease. While its use in patients undergoing cardiac surgery has been extensively reported, much of the existing data has not provided robust medication safety data.⁵ One meta-analysis reported that compared to control, dexmedetomidine use resulted in a reduction in SBP, MAP, and heart rate. However, the decrease in MAP was only 1.74 mmHg and decrease in heart rate was 3.44 b.p.m. The results of this meta-analysis are also difficult to interpret because studies included in the meta-analysis evaluated dexmedetomidine use intra-operatively and others evaluated dexmedetomidine in the post-operative setting where the degree of care and monitoring may differ significantly. Thus, it is challenging to draw conclusions about dexmedetomidine safety in cardiac patients from existing literature.^6,7 In contrast, patients in this cohort that developed hypotension and bradycardia experienced a mean decrease in MAP by over 20 mmHg and over 20 b.p.m., respectively.

Patients with acute cardiovascular disease may be susceptible to the effects of dexmedetomidine on biventricular systolic and diastolic function. The effects of dexmedetomidine on biventricular systolic and diastolic function in healthy patients have previously been reported.⁸ One study demonstrated an acute heart rate reduction and reduced cardiac output by echocardiography after initiation of a dexmedetomidine infusion. Other studies have replicated these findings.⁹ Such changes could significantly affect the ability of the right and left ventricle to compensate in the setting of haemodynamic stress from acute cardiovascular disease. The exact mechanism of myocardial depression from dexmedetomidine has yet to be fully elucidated with prior studies suggesting factors such as reduced inotropy due to a reduction in catecholamine release contributing to haemodynamic instability.^10–12 The effects of dexmedetomidine on myocardial function may be particularly detrimental for patients in ADHF. Indeed, in this study, patients with an elevated BNP, which represents higher filling pressures and wall stress, were at greater risk of adverse effects with dexmedetomidine use. While only a small subset of patients had haemodynamic data from pulmonary artery catheterization, all patients were observed to have a reduction in cardiac index on dexmedetomidine. Similar to the effect of beta-blocker therapy in ADHF, the negative inotropic and possibly sympathetic nervous system effects of dexmedetomidine may be poorly tolerated leading to further decompensation.

A potential strategy to reduce adverse events associated with dexmedetomidine use may be to limit the maximum infusion rate. However, in this study, no difference in median maximum infusion rate in patients who did and did not experience adverse events was observed. This is consistent with a study conducted by Jones et al.¹³ which noted that dexmedetomidine doses of excess of 0.7 µg/kg/h were not associated with more adverse events compared to lower doses. Other studies have even suggested that lower doses of dexmedetomidine may actually impair haemodynamics more than higher doses of the medication.^14–16 Bolus dosing of dexmedetomidine has also been associated with higher rates of adverse events. However, in this study, patients experiencing adverse events were not more likely to receive a dexmedetomidine bolus. These findings suggest that patients in this study experienced an adverse event not due to the administration method or amount of dexmedetomidine received. Rather, any use of dexmedetomidine in patients with decompensated cardiac function is associated with a high risk of haemodynamic adverse events due to the pharmacodynamic profile of the drug irrespective of the dose.

This study should be interpreted in the context of several limitations. The sample of patients for this study was limited by the availability of electronic medical record data to confirm medication initiation and adverse events. Adverse events were recorded within 24 h after initiation of dexmedetomidine therapy; however, adverse events may not have been captured if further drug titration was done after the initial 24-h period. Rapid escalation of dexmedetomidine doses have been associated with higher rates of dexmedetomidine-related hypotension in previous literature.^7,13,17 However, due to the retrospective nature of this study, time intervals between dexmedetomidine dose changes were unable to be accurately captured. The reported rate of adverse events in our study is quite high though this is somewhat dependent on the definitions used for these events. Definitions for these events have varied in prior trials; thus, we selected definitions that we thought represent clinically significant changes in each endpoint. Other factors such as vasoactive therapy, diuresis, concomitant sedative medications, or further patient decompensation could have contributed to rates of adverse events. It should be noted that many of the patients who received dexmedetomidine were stable on mechanical ventilation and received this agent in an effort to facilitate extubation; therefore, it was unlikely to have escalating doses of other sedatives during this time which may have put patients at risk for adverse events. In addition, given that the patient population in this study carried a higher acuity of cardiac disease than patients in previous trials, it is expected that haemodynamic adverse events associated with dexmedetomidine would be more common.

Conclusion

Patients admitted to the CICU experienced a high rate of adverse events with dexmedetomidine use. Those experiencing adverse events were more likely to have a higher BNP. Dose of dexmedetomidine and bolus administration did not appear to affect adverse event rates. Future studies should explore the safety of alternative sedative agents for patients admitted to the CICU.

Conflict of interest: The authors declare no conflicts of interest.

References