Interactive CardioVascular and Thoracic Surgery 18 (2014) 830 834 doi:10.1093/icvts/ivu061 Advance Access publication 12 March 2014 BEST EVIDENCE TOPIC THORACIC Does ambroxol confer a protective effect on the lungs in patients undergoing cardiac surgery or having lung resection? Shaohua Wang, Dayu Huang, Qinyun Ma and Xiaofeng Chen* Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China * Corresponding author. Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China. Tel: +86-21-52889999; fax: +86-21-52889999; e-mail: dr_chenxiaofeng@126.com (X. Chen). Received 1 December 2013; received in revised form 10 February 2014; accepted 18 February 2014 Abstract A best evidence topic in perioperative care was written according to a structured protocol. The question addressed was Does ambroxol confer a protective effect on the lung in patients undergoing cardiac surgery or having lung resection? A total of 247 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. Several studies indicate that for patients with chronic obstructive pulmonary disease (COPD) who undergo cardiac surgery or upper abdominal surgery, perioperative ambroxol administration is associated with improved pulmonary function and reduced postoperative pulmonary complications (PPCs). In patients with pulmonary lobectomy, large-dose ambroxol treatment (1000 mg/day for 3 days) is correlated with reduced PPCs (6 vs 19%, P = 0.02), decreased postoperative hospital stay (5.6 vs 8.1 days, P = 0.02) and lower postoperative cost (2499 vs 5254, P = 0.04) compared with low-dose ambroxol treatment. Ambroxol also has a protective effect on the lungs during extracorporeal bypass, ameliorating inflammatory reaction and oxygen stress and preserving pulmonary surfactant. However, there is no evidence for any advantage of reducing PPCs after extracorporeal circulation. We conclude that perioperative application of ambroxol, a versatile mucoactive drug, particularly in high doses, is associated with lower PPCs, especially in high-risk patients with fundamental lung disease such as COPD. Large doses of ambroxol are correlated with even lower PPCs after lung resection. We recommend that routine intravenous ambroxol should be used in large doses in high-risk patients in the perioperative period to reduce the risk of PPCs. Keywords: Ambroxol Lung Perioperative INTRODUCTION A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1]. THREE-PART QUESTION In [ patients undergoing cardiac or thoracic surgery] does treatment with [Ambroxol] reduce [ pulmonary complications]? SEARCH STRATEGY Medline from 1950 to November 2013 using the Pubmed interface: ( ambroxol [MeSH Terms] OR ambroxol [All Fields]) AND (( surgery [Subheading] OR surgery [All Fields] OR surgical procedures, operative [MeSH Terms] OR ( surgical [All Fields] AND procedures [All Fields] AND operative [All Fields]) OR operative surgical procedures [All Fields] OR surgery [All Fields] OR general surgery [MeSH Terms] OR ( general [All Fields] AND surgery [All Fields]) OR general surgery [All Fields]) OR ( lung [MeSH Terms] OR lung [All Fields])). CLINICAL SCENARIO You are seeing a 75-year old patient with moderately impaired left ventricular function and severe triple vessel coronary artery disease and a recent myocardial infarction, who has ongoing angina. He clearly needs surgery but his lung function is very poor due to a long smoking history and you are concerned that he is at significant risk of respiratory failure postoperatively. You discuss this with your anaesthetist and he suggests a course of high-dose Ambroxol pre- and postoperatively. You have never tried this strategy, so resolve to look it up in the literature. SEARCH OUTCOME A total of 247 papers were found using the reported search. From these, seven papers were identified that provided the best evidence to answer the question. These are presented in Table 1. RESULTS Dreger et al. [2] observed the effect of pulmonary conditioning from 1 mg budenoside twice a day, 1.25 mg salbutamol four times The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
S. Wang et al. / Interactive CardioVascular and Thoracic Surgery 831 Best evidence papers Dreger et al. (2011), J Cardiovasc Surg (Torino), Germany [2] Case series (level 4) Study included 18 COPD patients who underwent urgent cardiac surgery Patients were administered pulmonary conditioning composed of 1 mg budenoside twice a day, 1.25 mg salbutamol four times a day and 15 mg ambroxol three times a day for 5.1 ± 2.1 days on average FEV1 in PFT Predicted FEV1 in PFT Total resistance in PFT Percentage of patients in GOLD stages III IV Improved by 16% from baseline P < 0.001 Increased from 48.3 ± 13.6% at baseline to 55.4 ± 16.1% after treatment P < 0.001 Reduced from 0.933 ± 0.418 to 0.631 ± 0.344 kpa s/l after treatment P = 0.004 Reduced from 55.6% at baseline to 27.8% after treatment short-term treatment with budenoside, salbutamol and ambroxol significantly improved lung function parameters If surgery can be delayed for several days, pulmonary conditioning should be considered for patients with insufficiently treated COPD The study lacks a control group, and the improvement in lung function was attributed to a combination of three drugs, instead of ambroxol alone Refai et al. (2009), Eur J Cardiothorac Surg, Italy [3] 140 cases of lobectomy for lung cancer (April 2006 to November 2007) were randomized in two groups (70 patients): ambroxol was administered by intravenous infusion in the context of the usual therapy on the day of operation and on the first 3 postoperative days (1000 mg/ day) (70 patients): fluid therapy only without ambroxol Pulmonary complications: Cardiac complications: Total complications: Unplanned ICU admissions: Postoperative hospital stay (days): 6% 19% P = 0.02 13% 10% P = 0.8 13% 27% P = 0.03 1.4% 8.6% P = 0.1 5.6 8.1 P = 0.02 short-term perioperative treatment with ambroxol improved early outcomes after lobectomy and might be used to implement fast-tracking policies and cut postoperative costs The results were obtained in a dedicated thoracic surgery unit with standardized perioperative pathways of care Other independent trials are needed to verify the effect of this treatment in different settings BEST EVIDENCE TOPIC Postoperative cost ( ): 2499 5254 P = 0.04 Ulas et al. (2008), J Cardiovasc Pharmacol, Turkey [4] 50 patients without known pulmonary disease were randomly assigned to two groups (n = 25): patients were given ambroxol for a week before and after elective CABG coronary artery bypass grafting (n = 25): a placebo was given Postoperative L/S in BALF: PaO 2 on POD2 (mmhg): Postoperative FVC (l): Data not shown P = 0.51 62.4 ± 7.1 55.2 ± 6.4 2.1 ± 0.6 1.5 ± 0.5 Ambroxol improved postoperative PFTs and PaO 2 levels without any significant clinical implications in low-risk on-pump CABG. These effects may have been due to factors other than surfactant modulation The sample size was small, and cardiac function and compliance might have an impact on pulmonary function Continued
832 S. Wang et al. / Interactive CardioVascular and Thoracic Surgery (Continued) Postoperative FEV1 (l): 1.8 ± 0.5 1.4 ± 0.8 Zhou et al. (2004), J Cent South Univ, China [5] Study included 24 patients with American Society of Anesthesiologists Grade II III receiving on-pump valve replacement : 75 mg intravenous ambroxol at the beginning of the surgery and another 75 mg ambroxol added in the primed fluid in the extracorporeal circuit Serum TNF-α at CPB 30 min (ng/ml): Serum IL-1β at CPB 30 min (ng/ml): 7.10 ± 0.81 13.8 ± 3.05 0.218 ± 0.010 0.271 ± 0.009 Ambroxol reduced inflammatory response and scavenged the free radical that was likely responsible for the protective effect on the lungs The sample size was small, and the best dosage, timing and approach were somewhat arbitrary : treated without ambroxol and served as a control group Serum IL-10 at CPB 3 min (pg/ml): 78.81 ± 8.09 64.95 ± 13.45 Serum MDA at CPB 30 min (nmol/ml): 8.68 ± 2.19 13.8 ± 4.04 Serum TNF-α at 4 h after surgery (ng/ml): 5.18 ± 0.79 8.32 ± 1.53 Serum IL-1β at 4 h after surgery (ng/ml): 0.169 ± 0.007 0.214 ± 0.014 Serum IL-10 at 4 h after surgery (pg/ml): 65.59 ± 17.35 56.26 ± 24.52 Serum MDA at 4 h after surgery (nmol/ml): 7.04 ± 1.45 10.84 ± 2.75 Fegiz et al. (1991), Lung, Italy [6] Double-blind multicentre randomized, (level 1a) 252 patients with COPD undergoing upper abdominal surgery were randomly assigned to receive either 1 g/day of ambroxol intravenously for 6 consecutive days () in the perioperative period or a placebo () Decrease in PaO 2 on POD2 compared with preoperative PaO 2 (mmhg): Rate of atelectasis: 80.4 ± 9.9 vs 76.6 ± 12.3 81.4 ± 11.5 vs 72.5 ± 12.3 10.6% 23.9% The authors thought that ambroxol should be considered as an alternative and new pharmacological approach for the prevention of postoperative pulmonary complications for high-risk patients receiving upper abdominal surgery This is a double-blind multicentre randomized,, with only 16 cases that dropped out Continued
S. Wang et al. / Interactive CardioVascular and Thoracic Surgery 833 (Continued) Rate of pulmonary infection: Nausea: 8.8% 12.4% 9/119 1/117 P = 0.05 Marcartili et al. (1990), Respiration, Italy [7] : 5 patients were given 1 g/day of ambroxol on the 4 days prior and 4 days after surgery with extracorporeal circuit : 5 control patients Total phosphorus in BALF 24 h after surgery (µg/ml): Total phosphorus in BALF 8 days after surgery (µg/ml): 9.04 ± 0.40 4.07 ± 0.34 12.35 ± 0.47 6.24 ± 0.48 The authors thought that ambroxol could cause a progressive increase in the total phosphorus content, thereby keeping the individual phospholipid species within the normal range, which was responsible for the lower incidence of atelectasis The sample size was too small Lamella atelectasis seen in X-ray: 4 cases (80%) 1 case (20%) Romanini et al. (1986), Int J Clin Pharmacol Res, Italy [8] 40 patients receiving chest surgery were randomly assigned into two groups (n = 20): patients were given 1 g/day of ambroxol 3 days before the operation, on the day of the operation and 5 days after the operation (n = 20): a placebo was given Surface tension of the BALF Postoperative PaO 2 Re-expansion of the residual lung shown by X-ray Patients in returned to preoperative level significantly more rapidly than did (detailed Significantly higher in Group A than in (detailed Significantly earlier in Group A than in (detailed ambroxol might be able to prevent acute respiratory distress syndrome development and limit the development of infection The first randomized, controlled trial on this question All the results are shown in figures, and detailed values are not given BEST EVIDENCE TOPIC Mucociliary clearance of the respiratory tract Less quantity and better quality of sputum with easier expectoration, and greater reduction of cough intensity in than in (data not shown) ICU: intensive care unit; CABG: coronary artery bypass grafting; L/S: lecithin/sphingomyelin, BALF: bronchoalveolar fluid; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; PFT: pulmonary function tests; COPD: chronic obstructive pulmonary disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; PaO 2 : arterial oxygen pressure; POD2: Postoperative Day 2; TNF-α: tumor necrosis factor-alpha; IL-1β: interleukin 1 beta; IL-10: interleukin 10; MDA: malondialchehyche. a day and 15 mg ambroxol three times a day on pulmonary function in patients with COPD who required urgent cardiac surgery. Pulmonary conditioning improved the forced expiratory volume in 1 s (FEV1) by 16% (P < 0.001). Predicted FEV1 increased from 48.3 ± 13.6% at baseline to 55.4 ± 16.1% after treatment (P < 0.001). Total resistance was reduced from 0.933 ± 0.418 to 0.631 ± 0.344 kpa s/l after PC (P = 0.004). The percentage of patients in GOLD stages III IV was reduced from 55.6% at baseline to 27.8% after treatment. short-term treatment with budenoside, salbutamol and ambroxol should be considered for patients with insufficiently controlled COPD. Refai et al. [3] studied the effect of high-dose ambroxol on the reduction of postoperative pulmonary complications (PPCs) after lobectomy in a randomized, (RCT). They found
834 S. Wang et al. / Interactive CardioVascular and Thoracic Surgery that short-term perioperative treatment with high doses of intravenous ambroxol significantly reduced the overall incidence of PPCs (6 vs 19%, P = 0.02), decreasing the postoperative in-hospital stay (5.6 vs 8.1 days, P = 0.02) and the postoperative cost (2499 vs 5254, P = 0.04). Ulas et al. [4] studied the effect of ambroxol on lecithin/ sphingomyelin in BALF, arterial oxygen level and pulmonary function in patients without fundamental lung disease who underwent on-pump CABG. The authors reported similar lecithin/sphingomyelin in BALF and no significant increase in pulmonary function in patients given ambroxol. Only arterial oxygen pressure (PaO 2 ) on Postoperative Day 2 was significantly increased, compared with control cases (62.4 ± 7.1 vs 55.2 ± 6.4 mmhg, ). Zhou et al. [5] studied the effect of ambroxol on modulating systemic inflammation in patients with American Society of Anesthesiologists Grade II III who received on-pump valve replacement. The authors found that ambroxol has a protective effect on lungs by ameliorating the systemic inflammation and increase of respiratory index, which was commonly seen after extracorporeal bypass surgery. In a multicentre RCT, Fegiz et al. [6] focused on high-risk patients undergoing upper abdominal operations, which might be performed by cardiothoracic surgeons. The authors reported a significantly lower incidence of atelectasis (10.6 vs 23.9%, ), a smaller decrease in PaO 2 and a trend towards less pneumonia (8.8 vs 12.4%, ) in patients administrated intravenous high-dose ambroxol (1 g/day) for 6 consecutive days in the perioperative period compared with patients administered a placebo. Marcatili et al. [7] studied the role of ambroxol on the endoalveolar surfactant level after extracorporeal circulation. They found that postoperative phospholipids in bronchoalveolar lavage in the ambroxol group were significantly higher than in the control group at 24 h (9.04 ± 0.40 vs 4.07 ± 0.34 µg/ml, ) and at 8 days (12.35 ± 0.47 vs 6.24 ± 0.48 µg/ml, ). They concluded that ambroxol increases the endoalveolar surfactant level after extracorporeal circulation and might play a role in reducing PPCs after extracorporeal circulation. Romanini et al. [8] studied the effectiveness of ambroxol in reducing the surface tension after chest surgery. They found that a high dose of ambroxol (1 g/day) was associated with lower in-alveolar surface tension and better mucociliary clearance of the respiratory tract, thus leading to better re-expansion of the pulmonary parenchyma after surgery, which was indispensable for limiting PPCs. CLINICAL BOTTOM LINE Perioperative use of ambroxol, a versatile mucoactive drug, is associated with lower PPCs, especially in high-risk patients with chronic lung disease. Large-dose ambroxol treatment (1 g/day for 3 days) reduces PPCs in patients undergoing lung resection, compared with low-dose ambroxol treatment. Ambroxol also has a protective role on lungs during extracorporeal bypass. However, there is no evidence for any advantage of reducing PPCs after extracorporeal circulation. We recommend intravenous ambroxol use in high doses in high-risk patients in the perioperative period in order to reduce the risk of PPCs. Conflict of interest: none declared. REFERENCES [1] Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405 9. [2] Dreger H, Schaumann B, Gromann T, Hetzer R, Melzer C. Fast-track pulmonary conditioning before urgent cardiac surgery in patients with insufficiently treated chronic obstructive pulmonary disease. J Cardiovasc Surg (Torino) 2011;52:587 91. [3] Refai M, Brunelli A, Xiumé F, Salati M, Sciarra V, Socci L et al. Short-term perioperative treatment with ambroxol reduces pulmonary complications. Eur J Cardiothorac Surg 2009;35:469 73. [4] Ulas MM, Hizarci M, Kunt A, Ergun K, Kocabeyoglu SS, Korkmaz K et al. Protective effect of ambroxol on pulmonary function after cardiopulmonary bypass. J Cardiovasc Pharmacol 2008;52:518 23. [5] Zhou HY, Chang YT, Lü ZP. Protective effects of ambroxol on lung injury during cardiacpulmonary bypass in patients undergoing valve replacement. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004;29:723 4. [6] Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery: double-blind Italian multicenter clinical study versus placebo. Lung 1991;169:69 76. [7] Marcatili S, Guarino C, Giannattasio A, Marcatili A, Festa M, Cautiero V et al. Alterations of the endoalveolar surfactant after surgery with extracorporeal circulation. Respiration 1990;57:233 8. [8] Romanini BM, Sandri MG, Tosi M, Mezzetti M, Mazzetti A. Ambroxol for prophylaxis and treatment of bronchopulmonary complications after chest surgery. Int J Clin Pharmacol Res 1986;6:123 7.