Use of low-dose β1-blocker for sinus tachycardia in patients with catecholamine support following cardiovascular surgery: a retrospective study

Background Sinus tachycardia coupled with high-dose catecholamine is common after cardiopulmonary bypass (CPB). The present study assessed the hemodynamic efficacy and safety of combination therapy using low-dose β1-selective adrenergic blocker (landiolol) and inotropes. Methods This was a retrospective, single center, self-comparison study at post-anesthesia care unit within a tertiary care center. The study included adults who underwent cardiac surgery with CPB and received landiolol between April 2007 and November 2011. We assessed hemodynamic data prior to and 1 h after initiation of landiolol therapy. Results We evaluated 11 patients who were administered 2.6 ± 1.3 μg/kg/min (mean ± SD) landiolol with sinus tachycardia and received catecholamine therapy after on-pump cardiovascular surgery. Landiolol administration led to a significant reduction in heart rate (HR; 112.4 ± 5.8 vs 126.0 ± 7.6 beats/min, p < 0.001), and a significant increase in stroke volume index (SVI) assessed by pulmonary artery catheterization (22.4 ± 5.4 vs. 18.9 ± 4.2 mL/m2, p = 0.04). Only one patient showed no HR reduction, whereas seven patients showed decreased HR and increased SVI (64, 95% confidence interval: 30–98%). Moreover, all five patients who received high-dose catecholamine support showed improved hemodynamics. In terms of safety, no patients required cessation of landiolol therapy. Conclusions Low-dose landiolol therapy may safely decrease HR and improve hemodynamics among patients with sinus tachycardia receiving catecholamine treatment after cardiovascular surgery. Trial registration This study is retrospective. Registration number: 11. Duration of registration: April 2007~November 2011.


Background
Sinus tachycardia coupled with high-dose catecholamine is a common problem after cardiopulmonary bypass (CPB). Since tachycardia is associated with mortality and cardiac morbidity in the general population [1,2] as well as in patients following surgery [3,4], heart failure [5], and/or coronary artery disease [6], anesthesiologists should carefully manage heart rate (HR) throughout the perioperative period.
Catecholamine therapy after CPB aids cardiac performance by stabilizing hemodynamic conditions. However, high-dose catecholamine therapy frequently induces sinus tachycardia, and its treatment remains highly controversial. Continuation of tachycardia may compromise the myocardial oxygen balance, ultimately followed by global cardiac performance deterioration. However, reducing inotropic stimulation can induce a decrease in cardiac output, followed by deterioration of hemodynamic conditions. Therefore, an effective approach that avoids this vicious circle is necessary.
Landiolol is an injectable, ultra-short-acting, highly selective β 1 -adrenoreceptor blocker with a potency ratio (β 1 /β 2 ) of 255 and an elimination half-life value of 4 min in healthy individuals, compared with esmolol, which has a potency ratio of 33 and elimination half-life of 9 min [7,8]. Since landiolol is more likely to have high β 1selectivity and a short half-life compared with esmolol or other β 1 -blockers, a bolus shot of landiolol may be used to safely attenuate tachycardia in response to endotracheal intubation under general anesthesia [9,10]. Recent studies have demonstrated the efficacy and safety of continuous intravenous landiolol infusion in different clinical settings to treat atrial fibrillation and/or atrial flutter after cardiac surgery [11][12][13] as well as acute heart failure [14]. However, these reports excluded unstable hemodynamic cases requiring high-dose catecholamine support. There have been some reports of clinical observations of combination therapy with β-blocker and lowdose inotrope in decompensated heart failure [15]. However, to date, the hemodynamic efficacy and safety of ultra-short-acting β 1 -blockers remains largely unclear in cases with concomitant administration of high-dose inotropes. We hypothesized that ultra-short-acting β 1 -blocker therapy could represent a valuable therapeutic option in cases of sinus tachycardia under high-dose catecholamine support. As a preliminary investigation, we conducted a retrospective, single center, self-comparison study.

Research design
The Research Ethics Review Board of National Cerebral and Cardiovascular Center approved the present study. Due to the use of de-identified data, informed consent was waived. Cardiac surgical intensive care unit charts for all adult patients who underwent on-pump cardiovascular surgery between April 2007 and November 2011 at the National Cerebral and Cardiovascular Center Hospital, Suita, Osaka were reviewed. The inclusion criteria were as follows: (1) patients who had persistent sinus tachycardia (HR > 100 beats/min) induced by catecholamine support after CPB; (2) patients who received continuous intravenous landiolol for sinus tachycardia based on the decision of the attending physician; (3) landiolol administration overlapped with constant dose of inotropic drugs (catecholamine, vasodilator, and/or phosphodiesterase 3 inhibitor) for at least for 1 h; (4) patients who had a pulmonary artery catheter; and (5) patients who were sedated and supported via mechanical ventilation. The exclusion criteria were as follows: (1) patients who had a temporary or permanent pacemaker; (2) patents who had any atrial arrhythmia except for sinus tachycardia; or (3) patients who had any mechanical circulatory support, including continuous renal replacement therapy.

Assessment of clinical features
In addition to general clinical features, we collected data on preoperative EuroSCORE, preoperative left ventricular ejection fraction, and fractional shortening via transthoracic echocardiography.
To evaluate adverse events, plasma creatine kinase-MB isozyme levels were measured every 6 h, as part of the routine daily clinical practice at our intensive care unit.

Statistical analysis
All data are presented as mean ± SD unless otherwise stated. Paired t test was used to compare hemodynamic variables. Pearson's correlation coefficient (r) was used to study the relationship between changes in rate of HR reduction and SVI elevation. All p-values < 0.05 (twotailed) were considered significant. Statistical analyses were performed using SPSS software version 11.0.1 J (IBM SPSS Inc., IL, USA). Table 1 summarizes the clinical characteristics of the patients.

Patient characteristics
We identified 11 out of 1762 adult patients who underwent on-pump cardiovascular surgery (0.6%). The average continuous infusion dose of β 1 -blocker landiolol was 2.6 ± 1.3 μg/kg/min (range, 1.1-5.0 μg/kg/min), indicating that our dose was lower than the manufacturer's recommended dose for tachycardia prevention (20-40 μg/kg/min). All landiolol infusions were started without an initial loading dose. No bolus shots or up-or down-titrations were used, even beyond the observation phase. The average CAI value was 14.6 ± 13.4. Five of the 11 patients (45%) received high-dose catecholamine therapy (> 10), but none of these used epinephrine.

Hemodynamic evaluation
Landiolol administration led to a reduction in HR by approximately 11%, and was significantly different (Table 2) within our study population (p < 0.001). Notably, administration of low-dose landiolol with concomitant used of inotropes led to an 18.5% increase in SVI (p = 0.04), with no deterioration in hemodynamic parameters.
A correlation between HR and SVI was observed (Fig. 1), and there was no evidence that SVI deterioration was caused by HR reduction. HR increased in response to landiolol in only one case (patient no. 1), followed by a decrease in SVI, suggesting that excess tachycardia harmed output. Three cases showed no changes in SVI despite reductions in HR (patient nos. 2, 5, and 8).

Subgroup analysis
Five patients received high-dose catecholamine support (CAI > 10), and are shown as a subgroup in Table 3. HR reduction led to an increase in SVI as well as improved CI, suggesting that low-dose landiolol may not only confer control rate ability, but may also exert a positive impact on cardiac function in conjunction with high doses of catecholamine.

Discussion
The findings of the present study highlight the usefulness of a low-dose infusion of the β 1 -blocker, landiolol, during the acute postoperative phase in patients with sinus tachycardia receiving high-dose catecholamine support. The successful use of landiolol for HR control was shown previously in clinical settings, including atrial fibrillation [17] and sepsis [18]. However, there is some uncertainty regarding administration of β-blockers in  Values represent mean ± SD. Change in HR is one of the coprimary end points HR heart rate (beats/min), SVI stroke volume index (mL/m 2 ), SV stroke volume (mL); CI cardiac index (L/min/m 2 ), CO cardiac output (L/min), SvO 2 mixed venous oxygen saturation (%), sBP systolic arterial blood pressure (mmHg), dBP diastolic arterial pressure (mmHg), mBP mean arterial blood pressure (mmHg), sPAP systolic pulmonary artery pressure (mmHg), dPAP diastolic pulmonary artery pressure (mmHg), mPAP mean pulmonary artery pressure (mmHg), CVP central venous pressure (mmHg), BT blood temperature (°C) patients who require a potent inotropic agent to guard against serious hemodynamic instability [19]. Some reports have shown beneficial effects of intravenous βblocker in a clinical setting of low-dose catecholamine support [20,21]. However, to the best our knowledge, no previous trials have examined this issue from the standpoint of high-dose inotropes. In the cases we studied, relatively low-dose landiolol reduced HR and increased SVI without adversely affecting patients treated with high-dose catecholamines.
Catecholamines are the first-line drug treatment to support cardiac performance after CPB. Since excess sinus tachycardia induced by high-dose catecholamine can reduce the duration of coronary perfusion [22] and coronary vasoconstriction [23], efforts must be made to prevent sinus tachycardia following cardiac surgery. Epinephrine is a choice catecholamine used to avoid tachycardia [24], but is not a first-line drug for low cardiac output syndrome treatment due to its detrimental effects on splanchnic blood flow and its ability to induce lactic acidosis [25]. The present study indicates the possibility of using the ultra-short-acting β1-blocker, landiolol, to optimize HR without inhibiting the favorable hemodynamic response brought about by the conventional use of inotropes.
Administration of landiolol should be initiated at a loading dose of 40 μg/kg/min, and then titrated to a maintenance dose. However, this method has been shown to cause hypotension [26]. Additionally, several reports have shown that landiolol administration without an initial loading dose was effective in preventing atrial fibrillation/atrial flutter/paroxysmal atrial tachycardia (maintenance dose range, 1-5 μg/kg/min) in surgical patients with left ventricular dysfunction [27,28]. Therefore, we did not administer a loading dose to patients receiving high-dose catecholamine support.
Surprisingly, our results suggest that landiolol has multiple beneficial effects, both in terms of controlling HR and positively affecting SVI under high-dose catecholamine support. This is similar to the manner by which a low-dose β-blocker infusion may decrease the undesirable response associated with catecholamine without significantly reversing the desired inotropic effects. Additionally, a slower HR facilitates a lengthier diastolic filling time and subsequently increases the static arterial elastance. Improved ventricular-arterial coupling is thought to increase the SVI [29]. Therefore, accurate evaluation of diastolic function may have a positive impact on HR reduction.
Human ventricular myocardium contains a mixed population of β 1 and β 2 adrenergic receptors, and patients with heart failure have lower a β 1 /β 2 ratio compared with healthy hearts [30]. Moreover, both β 1 and β 2 receptors in the ventricle were coupled to a positive inotropic response. Therefore, one can speculate that the β 2 receptor acts as an inotropic mediator to maintain systolic function in cases where there is concomitant use of landiolol and inotropes. The reaction stemming from combination of landiolol and inotropes Fig. 1 Relationship between change rates in heart rate reductions and stroke volume index increases for 11 patients. The following formula was used to calculate change rates: Change rate = (postlandiolol valuepre-landiolol value) / pre-landiolol value × 100 (%). Heart rate reduction showed a negative change rate. Closed circles indicate data from participants who received high-dose catecholamine support. The study treatment was considered clinically acceptable in terms of hemodynamic efficacy (one of the coprimary end points) (r = 0.7, p = 0.016). HR reduction, negative change rate of heart rate; SVI rise, change rate of stroke volume index Values represent mean ± SD HR heart rate (beats/min), SVI stroke volume index (mL/m 2 ), SV stroke volume (ml), CI cardiac index (L/min/m 2 ), CO cardiac output (l/min), SvO 2 mixed venous oxygen saturation (%), sBP systolic arterial blood pressure (mmHg), dBP diastolic arterial pressure (mmHg), mBP mean arterial blood pressure (mmHg), sPAP systolic pulmonary artery pressure (mmHg), dPAP diastolic pulmonary artery pressure (mmHg), mPAP mean pulmonary artery pressure (mmHg), CVP central venous pressure (mmHg), BT blood temperature (°C) may be altered depending upon the population of β-adrenergic receptors in the ventricle. However, landiolol cannot be administered based solely on the molecular evidence regarding the β 1 /β 2 ratio in the human ventricle. Therefore, careful titration and monitoring of the patient is required to assess the efficacy and safety of landiolol. Sinus tachycardia induced by high-dose catecholamine immediately after surgery requires a prompt strategy to control HR to avoid impaired impair cardiac systolic function. The present study provides important evidence supporting use of a safe and effective therapeutic regimen combining landiolol and inotropes.

Limitations
The present study has several limitations. First, our sample size was small and only included 11 patients because concomitant use of catecholamine with β 1 -blocker agent is still not specified as a clinical treatment regimen. Second, our analysis was retrospective in nature. Prospective multicenter trials are required. However, a prospective design is not easy since a therapeutic approach should be dependent upon the judgment of the attending physician. Third, our comparison was between pre-administration and post-administration and involved only a single time point. We limited the study duration to only 1 h to minimize the effects of other clinical factors, such as fluid resuscitation, temperature recovery, and reduced bleeding. Fourth, this study did not have a control group; therefore, our findings are not definitive. Future studies are required to overcome these limitations.

Conclusions
In the present study, low-dose β 1 -blocker landiolol therapy reduced HR and also increased SVI in patients who received sinus tachycardia-induced inotropic agents following on-pump cardiovascular surgery. While this study has some limitations in terms of low patient numbers and the study design, our findings suggest that landiolol is a promising therapy for the management of sinus tachycardia after CPB.
Reproducing these results using a large, appropriately powered and designed study could provide cardiovascular anesthesiologists and intensivists with a great addition to their pharmacological armamentarium.