Research and Opinion in Anesthesia & Intensive Care

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 4  |  Issue : 2  |  Page : 54--58

Prospective randomized study of the effect of nebivolol on the incidence of late invasive mechanical ventilation in ischemic heart disease patients with acute exacerbation of chronic obstructive pulmonary disease


Bishoy T.T Tadross1, Mahmoud I Mahmoud2, Akram M Fayed3,  
1 Critical care Specialist, Alexandria University, Egypt
2 Professor of Chest Diseases, Alexandria University, Egypt
3 Professor of Critical Care Medicine, Alexandria University, Egypt

Correspondence Address:
Bishoy T.T Tadross
128 Taowniat Smouha, Smouha, Alexandria
Egypt

Abstract

Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the USA and acute exacerbations result in more than 800 000 hospitalizations annually. The combination of COPD treatment often coexists with treatment for congestive heart failure or ischemic heart disease (IHD) and present complex therapeutic challenges. β2-Agonists, which are frequently used in the treatment of COPD, have the potential for adverse cardiovascular effects including ischemic events and arrhythmias. β-Blocker therapy improves symptoms and survival among patients with IHD and congestive heart failure, but is frequently withheld in patients with COPD. During an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), patients may be particularly vulnerable to develop acute cardiac events due to increased use in β2-agonists, tachycardia, and hypoxemia. The addition of a cardioselective β-blocker, especially nebivolol, may have a cardioprotective effect in this population, blunting the cardiac toxicity of the β2-agonists. We evaluated the association of the cardioselective β-blocker nebivolol treatment with the incidence of late invasive ventilation among patients with IHD who were hospitalized for an AECOPD. Hypothesizing that the nebivolol as a highly selective β-blocker is not deleterious and is safe in the setting of AECOPD, we also compared the outcomes with patients who are not treated with nebivolol in the setting of AECOPD. Objective The aim of the paper was to study the incidence of late invasive mechanical ventilation among a group of ischemic heart disease patients with AECOPD who received oral nebivolol and compare the results with another group of patients with the same diagnosis who did not receive it. Patients and methods This study was conducted on 90 adult patients of both sexes, who were admitted to the Critical Care Medicine Department of Alexandria Main University Hospital after fulfilling the inclusion and exclusion criteria and obtaining an informed consent from patients’ relatives, and from the local ethics committee. Patients were subjected to full routine examination and categorized into two groups; each group comprised 45 patients using the sealed-envelop technique as a method for randomization of participants in both groups. Group I, patients who received oral nebivolol tablets on the first and/or second day of admission. Group II, patients who did not receive oral nebivolol tablets on the first and/or second day of admission. Results In comparing the patients in both groups, there was no statistically significant difference between them with regard to age, sex, comorbidities, and Acute Physiology and Chronic Health Evaluation II score on admission. Incidence of late invasive ventilation was the same between the case and the control groups. There was no significant difference in causes of intubation between both groups. There was no statistically significant reduction in the duration of invasive ventilation, ICU and hospital stay between both studied groups. Acute ischemic events showed no statistically significant reduction between case and control groups. Regarding in-hospital and 28-day mortality, there was no statistically significant difference between both studied groups. Conclusion Our results suggest that among the studied population of patients with AECOPD with underlying coronary artery disease, using oral nebivolol tablet seems to be safe as it does not cause worsening of the clinical condition of the patients regarding the incidence of late invasive mechanical ventilation or incidence of acute ischemic events. In addition, it does not affect the duration of ICU or hospital stay and showed no effect on in hospital or 28-day mortality.



How to cite this article:
Tadross BT, Mahmoud MI, Fayed AM. Prospective randomized study of the effect of nebivolol on the incidence of late invasive mechanical ventilation in ischemic heart disease patients with acute exacerbation of chronic obstructive pulmonary disease.Res Opin Anesth Intensive Care 2017;4:54-58


How to cite this URL:
Tadross BT, Mahmoud MI, Fayed AM. Prospective randomized study of the effect of nebivolol on the incidence of late invasive mechanical ventilation in ischemic heart disease patients with acute exacerbation of chronic obstructive pulmonary disease. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2017 Oct 22 ];4:54-58
Available from: http://www.roaic.eg.net/text.asp?2017/4/2/54/206154


Full Text



 Introduction



β-Blocker therapy is frequently withheld in patients with chronic obstructive pulmonary disease (COPD) and particularly in acute exacerbations because of concerns that it may diminish the bronchodilator effect of β2-agonists and aggravate bronchospastic symptoms [1],[2], thus depriving the ischemic heart patients from the benefits of β-blocker therapy [3],[4].

There was no evidence that β-blockers reduce the beneficial effects of short-acting β-agonists when the two are used concomitantly during acute exacerbations. It has been suggested that β-blockers may in fact improve bronchodilator responsiveness by leading to upregulation of β-receptors within the lung [5].

The very high selectivity for β1 versus β2 adrenergic receptors of the d-isomer of nebivolol explains its limited effects on airway reactivity and insulin sensitivity as well as the lesser negative inotropic effect in patients with heart failure. Of note, this selectivity tends to be overcome at dosages more than 10 mg and in poor metabolizers, causing the loss of this positive characteristic of nebivolol [6],[7],[8].

Along with its cardiac effects, the most likely clinically relevant property of nebivolol is its ability to cause specific endothelial vasodilation; the main concepts in this regard include activation of nitric oxide synthase by the binding of a nebivolol metabolite to β2-receptor, direct binding of nebivolol to the β3-receptor, and/or stimulation of endothelial adenosine triphosphate efflux [6].

Hypothesis

We hypothesized that administration of oral nebivolol tablets during the setting of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not deleterious and does not affect the incidence of late invasive mechanical ventilation.

 Patients and Methods



This is a prospective randomized case–control study that was conducted on 90 adult patients of both genders, who were admitted to the Critical Care Medicine Department of Alexandria Main University Hospital after fulfilling the inclusion and exclusion criteria and obtaining informed consent from patients’ relatives and from the local ethics committee.

Patients were subjected to full routine examination and categorized into two groups: each group comprised 45 patients using the sealed-envelop technique as a method for randomization of participants in both groups:

Group I: patients who received oral nebivolol tablets in the first and/or second day of admission.Group II: patients who did not receive oral nebivolol tablets in the first and/or second day of admission.

The endpoints of the study were as follows:

Incidence of late invasive mechanical ventilation (defined as initiation of invasive mechanical ventilation on the third day of admission or later).Incidence of acute coronary events between the two groups.Duration of mechanical ventilation.Duration of ICU stay.Duration of hospital stay.28-days mortality.

 Results



Baseline characteristics, including age, sex, comorbidities, Acute Physiology and Chronic Health Evaluation II score, were similar between the two groups.

Late invasive ventilation

Late invasive mechanical ventilation (defined as intubation on day 3 or more after admission) has the same incidence in both studied groups; nine (20%) cases in each of them.

Timing of late invasive ventilation

No statistically significant difference was observed between both studied groups regarding the timing of late invasive ventilation (P=1.000) ([Table 1]).{Table 1}

Duration of invasive mechanical ventilation

There was no statistically significant difference between the two studied groups (P=0.963). The decrease in the duration of intermittent mandatory ventilation (IMV) was insignificantly greater in group I than in group II and ranged between 2.0–14.0 and 1.0–12.0 days, with a mean of 5.56±3.94 and 5.89±3.48 and a median of 4.0 and 5.0 days for groups I and II, respectively ([Table 2]).{Table 2}

Acute ischemic events

[Table 2] shows a comparison between both studied groups according to the incidence of acute coronary syndrome, regarding ST-segment elevation myocardial infarction: one case was reported in group II (2.2%). Regarding non-ST-segment elevation myocardial infarction, four (8.9%) cases were reported in group II and two (4.4%) cases in group I. No statistically significant difference was observed between the two studied groups regarding acute coronary syndrome.

Possible acute ischemic events were suspected in both studied groups including cases that showed dynamic changes only in ECG with negative results of serum troponin level or weak positive serum troponin levels without dynamic changes in ECG and/or presence of other noncardiac causes increasing serum troponin levels; five (11.1%) patients and 11 (24.4%) patients in groups I and II, respectively. No statistically significant difference was observed between the two studied groups regarding possible acute ischemic changes (P=0.098) ([Table 3]).{Table 3}

Days of ICU stay

There was no statistically significant difference between the two studied groups regarding the days of ICU stay (P=0.057). However, the reduce in the days of ICU stay was insignificantly greater in group I than in group II and ranged between 2.0–20.0 and 2.0–17.0 days, with a mean of 4.47±3.80 and 4.89±3.39 days and a median of 3 and 4 days for groups I and II, respectively ([Table 4]).{Table 4}

Days of hospital stay

There was no significant statistical difference between the two studied groups regarding the days of hospital stay (P=0.064). The reduce in the days of hospital stay was insignificantly greater in group I than in group II and ranged between 3.0–22.0 and 3.0–17.0 days, with a mean of 6.24±4.0 and 6.91±3.48 days and a median of 5 and 6 days for groups I and II, respectively.

Outcome

There was no statistically significant difference between the two studied groups regarding the outcome (P=0.748). In group I, 40 (88.9%) patients survived compared with 39 (86.7%) patients in group II, whereas five (11.1%) patients died in group I compared with six (13.3%) patients in group II.

Mortality at day 28

There was no statistically significant difference between the two studied groups regarding mortality at day 28 (P=0.903) ([Table 5]).{Table 5}

 Discussion



Incidence of late invasive ventilation was chosen as a primary end point in our study because it carries the highest in-hospital mortality in those who failed to respond to conventional medical therapy or failed noninvasive ventilation trial during AECOPD compared with those who were intubated from the first day and those who received noninvasive ventilation alone.

During the period of the study, the incidence of late invasive mechanical ventilation was the same in both groups: 20% (n=9) in each group (P=1.000). Also, there was no statistically significant difference in the timing of the late intubation between both studied groups (P=1.000). This was in agreement with results of Stefan et al. [3], who showed no association between β-blocker therapy and incidence of late invasive mechanical ventilation [odds ratio (OR)=0.98, 95% CI 0.77–1.24]. Of interest, in the Kargin et al. [6] trial, the need for IMV during the period of ICU stay was three times higher in the non-β-blockers group, although it was not statistically significant (P=0.85).

The decrease in the duration of IMV was greater in group I than in group II, but there was no statistical significant difference between the two studied groups regarding this parameter (P=0.963). This was in agreement with Kargin et al. [6] who showed a decrease in the duration of invasive ventilation in the β-blocker group without a statistically significant difference between both groups (P=0.10).

The use of nebivolol as a cardioselective β-blocker shortens the duration of IMV as it facilitates weaning from mechanical ventilation by reducing the ischemic burden of weaning on the myocardium by controlling heart rate, preventing malignant arrhythmias and increasing the diastolic time. The most likely clinically relevant property of nebivolol is its ability to cause specific endothelial vasodilation by the activation of nitric oxide synthase [6],[7],[8].

Along with its cardiac effects, the very high selectivity for β1 versus β2 adrenergic receptors of the nebivolol d-isomer explains the limited effects on airway reactivity enabling smooth weaning from IMV [6].

No statistically significant difference were shown between the two studied groups regarding possible acute ischemic changes (P=0.098). That was in agreement with Stefan et al. [3] who demonstrated in their multivariable and propensity-matched analysis that recipients of β-blockers were not subjected to increased incidence of acute coronary events during hospitalization with AECOPD (OR=1.08, 95% CI 0.97–1.20).

In the present study, there was no statistically significant difference between the two studied groups regarding the length of ICU stay, and this was in agreement with Kargin et al. [6], who showed that the length of ICU stay ranged between 4 and 10 days for both groups with median 6 and 7 days for case and control groups, respectively, without a statistically significant difference (P=0.69).

Days of hospital stay were not statistically significantly different between the two groups (P=0.064), and this was in agreement with Stefan et al. [3], who showed no statistically significant difference between β-blockers and non-β-blocker groups in the full cohort analysis regarding the length of hospital stay, but in the propensity-matched cohort, there was a statistically significant reduction regarding this point in the β-blocker group (P=0.05).

The present study showed no statistically significant difference between the two studied groups in terms of hospital mortality (P=0.748). These results were in agreement with Stefan et al. [3], who showed no association between β-blocker therapy and in-hospital mortality during AECOPD (OR=0.88, 95% CI 0.71–1.09), and Kargin et al. [6], who showed no statistically significant difference between the two studied groups regarding ICU (P=0.75) and in-hospital mortality (P=0.95).

Dransfield et al. [5] showed in their univariate analysis that there was no difference regarding the in-hospital mortality between the two groups. However, when evaluated in a multivariate regression model including a propensity score, β-blocker use was associated with reduced in-hospital mortality (OR=0.39; 95% CI 0.14–0.99) and β-blocker use was a powerful predictor of outcome.

In our study, mortality on day 28 was not significantly different between both studied groups (P=0.903). The incidence was 5 and 7.5% for groups I and II, respectively. This was not surprising as β-blockers have been proven to reduce mortality in COPD patients, especially those with underlying coronary artery disease or heart failure.

 Conclusion



Our results suggest that among the studied population of patients with AECOPD with underlying coronary artery disease, the use of oral nebivolol tablet seems to be safe as it does not cause worsening of the clinical condition of the patients regarding the incidence of late invasive mechanical ventilation or incidence of acute ischemic events. In addition, it does not affect the duration of ICU or hospital stay and showed no effect on the in-hospital or 28-day mortality.

Recommendations

Oral nebivolol tablet seems to be safe in the setting of AECOPD. Hence, we advise to use it for ischemic heart patients who are hospitalized with AECOPD and not to discontinue it on admission for patients on chronic therapy and even after discharge.Randomized placebo-controlled trials on a larger number of patients and in multiple centers must be performed.Strict application of ventilator-associated pneumonia bundles is necessary to reduce ventilator-associated pneumonia mortality.Improving medical recording in hospitals and outpatients regarding clinical status progress and medication history.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflict of interest.

References

1Lammers JW, Folgering HT, van Herwaarden CL. Ventilatory effects of long-term treatment with pindolol and metoprolol in hypertensive patients with chronic obstructive lung disease. Br J Clin Pharmacol 1985; 20:205–210.
2Van der Woude HJ, Zaagsma J, Postma DS, Winter TH, van Hulst M, Aalbers R. Detrimental effects of beta-blockers in COPD: a concern for nonselective beta-blockers. Chest 2005; 127:818–824.
3Stefan MS, Rothberg MB, Priya A, Pekow PS, Au DH, Lindenauer PK. Association between beta-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. Thorax 2012; 67:977–984.
4Zeng LH, Hu YX, Liu L, Zhang M. Impact of β2 agonists, beta blockers, and their combination on cardiac function in elderly male patients with chronic obstructive pulmonary disease. Clin Interv Aging 2013; 8:1157–1165.
5Dransfield MT, Rowe SM, Johnson JE, Bailey WC. Use of β blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax 2008; 63:3015.
6Kargin F, Takir HB, Salturk C, Goksenoglu NC, Karabay CY, Mocin OY et al. The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit. Multidiscip Respir Med 2014; 9:8.
7Van Bortel LM, van Baak MA. Exercise tolerance with nebivolol and atenolol. Cardiovasc Drugs Ther 1992; 6:239–247.
8Toblli JE, DiGennaro F, Giani JF, Dominici FP. Nebivolol: impact on cardiac and endothelial function and clinical utility. Vasc Health Risk Manag 2012; 8:151–160.