Carvedilol is a nonselective β-adrenoceptor and selective α1-adrenoceptor blocker and is widely used in the treatment of patients with hypertensive and/or chronic heart failure because, unlike classic β-blockers, this drug has additional endothelium-dependent vasodilatory effects.1–3 Several studies have indicated that carvedilol has beneficial effects in patients with cardiogenic failure and shock.4–6 The Carvedilol or Metoprolol European Trial showed that carvedilol was more effective than metoprolol5 in improving the outcomes of vascular events, such as myocardial infarction and stroke in patients with chronic heart failure. The Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction study indicated that early treatment with carvedilol was beneficial for clinically stabilized postmyocardial infarction patients with left ventricular dysfunction.6 Furthermore, β-blocker therapy during the perioperative period may improve morbidity and mortality in high-risk patients with ischemic heart disease.7,8
In a prehospital situation, cardiac arrest (CA) can lead to airway obstruction, or vice versa, airway obstruction can lead to CA. Furthermore, some CA patients may have difficult airways or may experience complications related to the airway during resuscitation. No study has examined the effects of carvedilol in an animal model of CA induced by airway obstruction.
We hypothesized that oral administration of carvedilol may have beneficial effects in animals with CA induced by airway obstruction. Therefore, we evaluated the effects of carvedilol administration on cardiopulmonary resuscitation (CPR) in a rat model of CA induced by airway obstruction.
The experimental protocol and ethical aspects were approved by the Animal Care Committee of Kanazawa University, and the care and handling of the animals were performed in accordance with the National Institutes of Health guidelines.
Experimental Design and Protocol
This study was performed in male Sprague-Dawley rats (weight 444 ± 41 g [mean ± SD]). The animals were randomly assigned to a control group (no medication) and treatment groups (oral administration of carvedilol [10 mg/kg/d] for 5 days) (n = 12 per group). Carvedilol was administered with food. In a preliminary study, carvedilol was administered at 1, 5, or 10 mg/kg/d to rats for 5 days. The dosage of 10 mg/kg/d was chosen because it was reported to cause a marked decrease in heart rate (HR), systolic arterial blood pressure (SBP), and diastolic blood pressure (DBP). Carvedilol was administered with food in both the preliminary and current study.9 In addition, the body weight and the amount of food consumed by the rats were measured daily to evaluate the intake of carvedilol.
All rats received an intraperitoneal injection of pentobarbital sodium (30 mg/kg) and were ventilated via a tracheotomy. The femoral artery was cannulated to monitor blood pressure and to draw blood samples. Lactated Ringer solution containing a muscle relaxant (pancuronium bromide, 0.02 mg/mL) and pentobarbital sodium (0.5 mg/mL) was continuously infused at a rate of 10 mL/kg/h through the femoral vein cannula. The rats were connected to a pressure-controlled ventilator (Servo 400C; Siemens-Elema, Solna, Sweden), which delivered 21% oxygen at a frequency of 32 breaths/min with an inspiratory/expiratory ratio of 1:1. After this procedure, the animals were rested for >15 minutes to allow the blood gases and hemodynamic variables to stabilize, and then the baseline readings of HR, SBP, and DBP were noted. This method of animal preparation was similar to that reported previously.9–11
CA was induced by tracheotomy obstruction. CA was defined as low blood pressure amplitude (<40 mm Hg in SBP). After 3 minutes of CA, animals received CPR. Chest compressions (CCs) were performed manually. The rate of CCs was 240 to 260 CCs/min and depth of CCs was titrated to maintain DBP between 25 to 30 mm Hg in both groups. The rate of ventilation was 32 breaths/min in fraction of inspired oxygen 7.21. After 5 minutes of CPR, epinephrine (0.02 mg/kg) was administered. There were no other therapies before, during, or after CA. Rectal body temperature was maintained between 36°C and 38°C with the aid of a heating pad before, during, and after CA.
The times to CA after airway obstruction and the rates of return of spontaneous circulation (ROSC) were measured in the 2 groups. Mortality rate was observed up to 5 hours after ROSC. Arterial blood samples (0.25 mL) were obtained 1, 3, and 5 hours after ROSC to measure pH, PaCO2, arterial oxygen tension (PaO2), lactate, and glucose values. In addition, arterial blood samples (1.5 mL) were obtained to measure plasma cytokine concentrations (tumor necrosis factor [TNF]-α and interleukin [IL]-6) 1 and 3 hours after ROSC. All cytokine (TNF-α and IL-6) concentrations were measured using enzyme-linked immunosorbent assay kits (BioSource, Camarillo, CA).
Data are presented as the mean ± SD. The times from airway obstruction to CA between the 2 groups were analyzed by an unpaired t test. Differences between the groups were analyzed by Mann-Whitney U test. Mortality rates were compared between the groups using the Kaplan-Meier and Mantel-Cox tests. Significance was defined as P < 0.05. Statistical analyses were performed using StatView software (version 5.0 for Macintosh; Abacus Concepts, Berkeley, CA).
The times from airway obstruction to CA were 203 ± 24 and 230 ± 27 seconds in the control and treatment groups, respectively (P < 0.05). The rates of ROSC were 50% (6 of 12 rats) and 92% (11 of 12 rats) in the control and treatment groups, respectively (P < 0.05). The survival rate 5 hours after ROSC was 100% in both the control (6 of 6 rats) and the treatment (11 of 11 rats) group.
The baseline HR and SBP in the treatment group were significantly lower than in the control group (P < 0.05) (Fig. 1). After ROSC, the HR and SBP values did not differ significantly between the 2 groups at any point.
There were no significant differences in the baseline or post-ROSC levels of PaCO2 or PaO2 between the 2 groups (Fig. 2).
There were no significant differences in baseline pH, base excess, lactate, or glucose values between the 2 groups (Figs. 3 and 4). The pH and base excess in the 2 groups were reduced immediately after ROSC, but recovered 60 minutes later. The pH in the treatment group was significantly higher than in the control group 3 and 5 hours after ROSC. The lactate and glucose values in the 2 groups increased immediately after ROSC, but recovered 60 minutes later. The glucose value in the treatment group was significantly lower than in the control group immediately after ROSC. The base excess and lactate values did not differ significantly between groups at any point during the experimental period.
Plasma Cytokine Concentrations
There were no significant differences in baseline TNF-α or IL-6 values between the 2 groups (Fig. 5). The TNF-α and IL-6 values in both groups were significantly increased 60 minutes after ROSC. The increase of TNF-α concentration was significantly less in the treatment group than in the control group (P < 0.05). However, the IL-6 values did not differ significantly between groups during the experiment.
Carvedilol was shown to prolong the time from airway obstruction to CA and increase the rate of ROSC in a rat model of CA induced by airway obstruction.
Many studies have demonstrated the efficacy of carvedilol in chronic heart failure.1,2,4,5 Moreover, several reports indicated that carvedilol was beneficial to patients soon after myocardial infarction and that β-blocker therapy during the perioperative period improves morbidity and mortality in high-risk patients with ischemic heart disease.6–8 These studies suggested that early and continuous administration of carvedilol may have beneficial effects in patients with ischemic heart disease. However, we could not find studies that examined the effects of β-blockers on CA induced by airway obstruction. Therefore, this study was performed to evaluate the effects of carvedilol on CA induced by airway obstruction in rats. These findings suggest that carvedilol therapy may prolong the safe ischemic time during ischemia induced by airway obstruction, and when CA does occur, improve outcome. Moreover, this study showed that carvedilol attenuated acidosis and hyperglycemia after ROSC in contrast to the control group.
There are several possible mechanisms that might explain the beneficial effects of carvedilol in airway obstruction–induced CA. First, carvedilol may increase the myocardial energy efficiency after CA. Several previous studies support this suggestion.12,13 Oliveira et al.12 showed that carvedilol protects cardiac mitochondria from oxidative stress events in vitro. Wallhaus et al.13 observed that carvedilol inhibited myocardial free fatty acid use without a significant change in glucose use in patients with heart failure.
Second, carvedilol may improve cardiac sympathetic nerve activity after CA. Kasama et al.14 showed that carvedilol can improve cardiac sympathetic nerve activity in patients with dilated cardiomyopathy. Azevedo et al.15 reported that carvedilol had the sympathoinhibitory effect of blocking peripheral, prejunctional β-adrenergic receptors in patients with congestive heart failure.
Several investigators have examined the relationship between β-blockers and cytokine responses.16–18 Mizuochi et al.16 showed that carvedilol inhibited the lipopolysaccharide-induced production of TNF-α and tissue factor in human monocytes in vitro. Suzuki et al.17 reported that the β-blocker esmolol attenuated the increase of TNF-α and lactate concentrations in septic rats. This study also showed that carvedilol attenuated the increase of TNF-α after ROSC. However, we did not find that carvedilol attenuated the increase of IL-6 after ROSC. Further research is required to clarify these points.
Two important questions are whether long-term use of carvedilol would have a similar effect and whether there is a dose-response relationship between carvedilol and outcome. Further research is needed to answer these questions.
In conclusion, this study showed that the oral administration of carvedilol prolonged the time to CA after airway obstruction and increased the rate of ROSC in a rat model of CA induced by airway obstruction. Furthermore, in these rats, carvedilol attenuated acidosis and hyperglycemia after ROSC.
1. Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8
2. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349–55
3. Noguchi N, Nishino K, Niki E. Antioxidant action of the antihypertensive drug, carvedilol, against lipid peroxidation. Biochem Pharmacol 2000;59:1069–76
4. Cleland JG, Charlesworth A, Lubsen J, Swedberg K, Remme WJ, Erhardt L, Di Lenarda A, Komajda M, Metra M, Torp-Pedersen C, Poole-Wilson PA; COMET Investigators. A comparison of the effects of carvedilol and metoprolol on well-being, morbidity, and mortality (the “patient journey”) in patients with heart failure: a report from the Carvedilol or Metoprolol European Trial (COMET). J Am Coll Cardiol 2006;47:1603–11
5. Remme WJ, Torp-Pedersen C, Cleland JG, Poole-Wilson PA, Metra M, Komajda M, Swedberg K, Di Lenarda A, Spark P, Scherhag A, Moullet C, Lukas MA. Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET. J Am Coll Cardiol 2007;49:963–71
6. Fonarow GC, Lukas MA, Robertson M, Colucci WS, Dargie HJ. Effects of carvedilol early after myocardial infarction: analysis of the first 30 days in Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN). Am Heart J 2007;154:637–44
7. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713–20
8. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;341:1789–94
9. Taniguchi T, Kurita A, Yamamoto K, Inaba H. Effects of carvedilol on mortality and inflammatory responses to severe hemorrhagic shock in rats. Shock 2009;32:272–5
10. Taniguchi T, Yamamoto K, Ohmoto N, Ohta K, Kobayashi T. Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats. Crit Care Med 2000;28:1101–6
11. Taniguchi T, Kanakura H, Yamamoto K. Effects of posttreatment with propofol on mortality and cytokine responses to endotoxin-induced shock in rats. Crit Care Med 2002;30:904–7
12. Oliveira PJ, Marques MP, Batista de Carvalho LA, Moreno AJ. Effects of carvedilol on isolated heart mitochondria: evidence for a protonophoretic mechanism. Biochem Biophys Res Commun 2000;276:82–7
13. Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001;103:2441–6
14. Kasama S, Toyama T, Hatori T, Sumino H, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M. Evaluation of cardiac sympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy on the treatment containing carvedilol. Eur Heart J 2007;28:989–95
15. Azevedo ER, Kubo T, Mak S, Al-Hesayan A, Schofield A, Allan R, Kelly S, Newton GE, Floras JS, Parker JD. Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity. Circulation 2001;104:2194–9
16. Mizuochi Y, Okajima K, Harada N, Molor-Erdene P, Uchiba M, Komura H, Tsuda T, Katsuya H. Carvedilol, a nonselective beta-blocker, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. Transl Res 2007;149:223–30
17. Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, Takeda J. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med 2005;33:2294–301
© 2010 International Anesthesia Research Society
18. Schmitz D, Wilsenack K, Lendemanns S, Schedlowski M, Oberbeck R. Beta-adrenergic blockade during systemic inflammation: impact on cellular immune functions and survival in a murine model of sepsis. Resuscitation 2007;72:286–94