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ORIGINAL ARTICLE  
Year : 2022  |  Volume : 25  |  Issue : 4  |  Page : 435-440
Randomized control study of nebulized colistin as an adjunctive therapy in ventilator-associated pneumonia in pediatric postoperative cardiac surgical population


1 Department of Cardiac Anaesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Mysore, Karnataka, India
2 Department of Cardiac Anaesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India

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Date of Submission12-Jun-2021
Date of Decision18-Jul-2021
Date of Acceptance20-Jul-2021
Date of Web Publication10-Oct-2022
 

   Abstract 


Background: Ventilator-associated pneumonia (VAP) with multidrug-resistant (MDR) gram negative organisms is a common problem in intensive care unit (ICU). Aerosolized antibiotics enhance the efficacy of systemic antibiotics when added as adjuvants.
Aim: The primary objective of the study was to compare the clinical and bacteriological outcome of patients with VAP who were administered intravenous (IV) antibiotics alone with those patients who were treated with adjunctive nebulized colistin (NC) along with IV antibiotics. The secondary objective was to study the occurrence of any adverse events during colistin nebulization.
Settings and Design: The study was a prospective, randomized, double-blinded controlled study conducted at a tertiary-care teaching institution.
Materials and Methods: Ninety-eight children from surgical ICU aged less than 12 years who were diagnosed with VAP due to gram negative bacteria following cardiac surgery were chosen and divided randomly into two groups. The experimental group (NC group) was treated with systemic antibiotics along with NC, whereas the control group (NS group) was administered systemic antibiotics with nebulized normal saline (NS). Clinical and bacteriological outcomes were noted. Statistical analysis was done using SPSS Version 20.0 software. The patient characteristics were compared using independent Student's t test and Chi-square test.
Results: There was a statistically significant reduction in the duration of mechanical ventilation, postoperative ICU and hospital stay (P < 0.05) in the NC group compared with the NS group.
Conclusion: Aerosolized colistin may be considered as an adjunct to systemic IV antibiotics in pediatric patients with VAP due to gram negative bacteria susceptible to colistin.

Keywords: Colistin, gram negative bacteria, nebulized antibiotics, ventilator-associated pneumonia

How to cite this article:
Bharathi K S, Bhat A, Pruthi G, Simha PP. Randomized control study of nebulized colistin as an adjunctive therapy in ventilator-associated pneumonia in pediatric postoperative cardiac surgical population. Ann Card Anaesth 2022;25:435-40

How to cite this URL:
Bharathi K S, Bhat A, Pruthi G, Simha PP. Randomized control study of nebulized colistin as an adjunctive therapy in ventilator-associated pneumonia in pediatric postoperative cardiac surgical population. Ann Card Anaesth [serial online] 2022 [cited 2022 Dec 4];25:435-40. Available from: https://www.annals.in/text.asp?2022/25/4/435/358140





   Introduction Top


Ventilator-associated pneumonia (VAP) is one of the frequent nosocomial infection in the surgical intensive care unit (SICU), with an incidence ranging from 5% to 40%.[1] It is often associated with prolonged hospitalization, increased health care costs, and has an average of 10% attributable mortality.[1] There is an increasing occurrence of multidrug-resistant (MDR) gram negative bacterial infections with pathogens such as Pseudomonas aeruginosa, extended-spectrum β-lactamase producing Klebsiella pneumoniae, and Acinetobacter baumannii in intensive care unit (ICU) patients who develop VAP.[2] It is often caused due to prolonged duration of endotracheal intubation. Studies have demonstrated that endotracheal intubation in pediatric patients beyond 30 days was associated with a 40% risk of VAP.[3],[4]

From early 2000, antimicrobial resistance (MDR) in gram negative bacteria has been a worrisome problem in ICU patients. As the possible antimicrobial options are limited, there is increasing use of intravenous (IV)[5] and nebulized colistin (NC).[6] Patients who develop VAP with MDR gram negative bacterial organisms may have better survival with adjunctive aerosolized antibiotics despite greater severity of illness.[4],[5],[6] Aerosolized antibiotics appear to be useful in the treatment of VAP when added as adjuvants to systemic antibiotics.[7],[8] This is especially effective in managing drug-resistant pathogens.[8] Studies have demonstrated that aerosolized antibiotics reach higher concentrations in the lung, thereby increasing their potency.[9],[10] From 2005, there are about 12 studies reporting the effectiveness of NC as monotherapy for VAP due to MDR.[11] Although the evidence regarding aerosolized antibiotics is of low quality, that too in very selected conditions,[12] the guidelines also recommend the necessity for large randomized trials to define the role of aerosolized antibiotics.

There is limited data regarding inhaled colistin for the management of VAP in postoperative pediatric cardiac patients.

The purpose of the study is to compare clinical outcomes in children treated with intravenous antibiotics with aerosolized colistin as an adjunct with those who were administered only IV antibiotics for VAP attributed to gram negative bacteria. The study also aims to evaluate the safety of inhaled colistin in this age group.


   Materials and Methods Top


Study design and participants

The study was carried out as a prospective, double-blinded, randomized controlled trial. The study was conducted over a period of 2 years from January 2016 to December 2017. A total of 524 pediatric patients underwent cardiac surgery during the study period.

Ninety-eight children from SICU aged less than 12 years who are mechanically ventilated and diagnosed with VAP due to gram negative bacteria in the postoperative period following cardiac surgery for congenital heart disease were included in the study. VAP was defined as per American Thoracic Society Consensus Conference criteria: by the presence of fever greater than 38°C with no other recognized cause; leucopenia (<4,000 white blood cells/mm3) or leukocytosis (>12,000 white blood cells/mm3); purulent tracheal secretions; and new and persistent infiltrate on chest X-ray, in patients being on mechanical ventilator support for at least 48 hours.[6]

Patients who underwent emergency surgery were excluded from the study.

Randomization and blinding

The participants were randomized by a computer-generated algorithm to the control group (NS group) who were treated with systemic antibiotics plus nebulized sterile normal saline (NS) or the experimental group (NC group) who were administered systemic antibiotics plus NC. Both the patient and the primary physician were blinded to the nebulized drug administered.

Ethical approval and informed consent

After approval from the Institutional Ethics Committee, informed consent was obtained from the patient's parents prior to the commencement of the study.

Administration of the drugs

In the NC group, every 12th hourly, NC equivalent to 4 mg/kg of colistin base[6] (1 mg = 12,500 units) reconstituted in 4 mL of sterile NS was administered immediately on reconstitution in mechanically ventilated patient via a breath-actuated jet nebulizer connected as near to the patient as possible with the patient in volume control mode and heated humidifier switched off[9] until the nebulized solution container was empty. Similarly, in the NS group every 12th hourly, 4 mL of sterile NS was given as nebulization. The patient's primary physician was responsible for the regimen and duration of the systemic antibiotics. NC or NS was administered until the end of systemic antibiotic therapy for VAP.

Data regarding the participant demographics and other clinical parameters including vital parameters and arterial blood gas analysis were obtained from the hospital records. The Pediatric Logistic Organ Dysfunction–2 (PELOD-2) score using the European Society of Paediatric and Neonatal Intensive Care score calculator was done for every patient at the time of inclusion to the study. Each patient was clinically assessed daily until the systemic antibiotic therapy of VAP was discontinued. Microbiological culture of the respiratory specimen was aspirated from the endotracheal tube on the third day following the initiation of treatment and once in every 7 days thereafter. Biochemical parameters including renal function tests and liver function tests were done every third day. The dosage of NC, the duration of antibiotic treatment, and any side effects related to the drug administration were noted.

Data regarding the bacteriological and clinical response of VAP were as follows:

Participant's outcome was defined in terms of clinical and bacteriological outcomes as follows.

Clinical outcome was described as favorable when at the termination of colistin treatment presenting symptoms and signs of infection were completely or partially resolved; favorable outcome was also considered when there is normalization of white blood cell counts, improvement of arterial blood gases, and reduction or disappearance of radiological findings on chest X- ray.

Recurrence of infection was considered as any new episode of infection at least 72 hours following the clinical resolution of a preceding episode.[6]

Bacteriological outcome of the infection was defined as follows:

Eradication – final culture of specimens demonstrating no growth of the pathogen during the entire hospitalization;

Persistence – persistent growth of the responsible pathogen regardless of the clinical outcome of the infection;

Recurrence (regrowth) – reappearance of the same pathogen regardless of the clinical outcome of the infection;

Colonization – persistence or reappearance of the same pathogen with no symptoms and signs of infection.[6]

The duration of mechanical ventilation, the ICU length of stay, and duration of postoperative hospital stay were also recorded.

Safety parameters

Adverse effects (if any) such as bronchospasm, cough, apnea, chest tightness, and arterial hypoxemia were recorded in each participant. Also, safety was assessed on the basis of the results of renal and hepatic functions tests. Any consequent nosocomial-acquired infection, the occurrence of colistin resistance, or the development of fungal infection following administration of colistin were recorded.[7]

The primary end point of the study was the clinical and bacteriological outcome of the VAP.

The secondary end point was the occurrence of adverse events during colistin treatment.

Statistical analysis

Data were recorded and analyzed using SPSS Version 20.0 software (SPSS Inc., California, USA). The bacteriological outcomes and the clinical outcomes were expressed as percentages. The biochemical parameters were expressed as mean ± standard deviation. Association between the clinical outcomes and the type of therapy administered was performed using Chi-square test and independent Student's t test. The association was found to be statistically significant at P < 0.05.


   Results Top


The prospective, randomized, double-blinded, controlled trial was carried out among 98 participants, of which 51 belonged to the NC group and 47 belonged to the NS group. The majority of the participants in the study were males, of which 56.8% belonged to the NC group and 59.6% belonged to the NS group [Figure 1].
Figure 1: Gender distribution among the study participants

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There is no statistically significant difference in the mean age of the participants in the NC group (10.2 months) and the NS group (13.02 months; P = 0.591). The PELOD-2 score was 16.9 and 16.2 for NC and NS groups, respectively, which was comparable and statistically insignificant (P = 0.625) [Table 1].
Table 1: Mean value of patient parameters

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The bacteriological study revealed that 25.5% of the VAP in the NC group was caused by K. pneumonia, 17.6% by Pseudomonas, and another 17.6% by Escherichia coli, whereas in the NS group K. pneumonia attributed to 10.6%, E. coli 19.1%, and Pseudomonas 12.9% of VAP infections. The type of organism grown in both groups is statistically comparable [Table 2].
Table 2: Infection characteristics and type of bacterial growth among the study participants

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The resistance pattern of the gram negative organisms in both the groups was plotted as a bar diagram [Figure 2]. The majority of the gram negative organisms showed resistance to augmentin (NC31 + NS32), cefoperazone–sulbactam (NC22 + NS23), piperacillin–tazobactam (NC18 + NS22), and to ciprofloxacin (NC20 + NS21).
Figure 2: Antibiotic resistance pattern of Gram negative organisms among NC and NS groups

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The bacteriological outcome was studied at the end of colistin therapy. There has been eradication of the gram negative bacteria causing VAP in 80.4% of the patients in NC group and 68.1% in NS group (P = 0.16). Persistence of growth of the organism was 13.7% in the NC group and 25.5% in the NS group (P = 0.13), recurrence of the growth of the same organism was 5.9% in the NC group and 6.4% in the NS group (P = 0.9) [Table 3]. There is no statistically significant benefit of adjuvant NC on the bacteriological outcome.
Table 3: Comparison of bacteriological outcomes between the groups

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The systemic antibiotics used in both NC and NS groups are colistin, antipseudomonal antibiotics such as meropenem, piperacillin–tazobactam, amikacin, tigecycline, linezolid, and cefoperazone–sulbactam. About 47.1% in the NC group and 44.6% in the NS group received both colistin along with one of the antipseudomonal antibiotic (P = 0.81), whereas 17.65 in the NC group and 38.2% in the NS group received only colistin. Rest of them received only antipseudomonal (P = 0.13). However, there is statistically no significant difference (P > 0.05) in the usage of antibiotics between the groups [Table 4].
Table 4: Systemic antibiotic therapy among the study participants

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The duration of mechanical ventilation was prolonged in the NS group (18.1 days) when compared with the NC group (11.2 days; P < 0.002). Similarly, the duration of postoperative ICU stay in the NC group was 14.04 days, whereas it was 22.3 days in the NS group, which is statistically significant (P = 0.004). The duration of hospital stay was comparatively lower in the NC group (17.6 days) compared with the NS group (26.2 days; P < 0.005) [Table 5].
Table 5: Comparison of clinical outcome between the two groups

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There was no statistically significant difference in the occurrence of adverse effects with the use of adjunctive NC.


   Discussion Top


The present study is among the few randomized trials that evaluate the efficacy and safety of NC among pediatric patients in the postoperative period. VAP occurs frequently in critically ill patients resulting in significant morbidity. It is commonly associated with prolonged ventilation as a postsurgical sequela following cardiovascular surgeries. They are often considered as nosocomial infections resulting from the hospital setting. In our study, majority of the gram negative bacteria were K. pneumonia followed by Pseudomonas and E. coli. Almost all of them were multidrug resistant. In a study done by Michalopoulos and Falagas,[13] majority of the infections were attributed to Acinetobacter followed by Pseudomonas and Klebsiella. In another study done by Foglia et al.,[3] the most common gram negative bacteria associated with VAP was Pseudomonas followed by Enterobacter and Klebsiella. Abdellatif et al.,[14] in their study, demonstrated the beneficial effects of inhaled colistin in VAP due to MDR bacilli. They also concluded that the therapeutic effectiveness of inhaled colistin was as effective as parenteral colistin with additional benefits of renal safety, improvement in PaO2/FiO2 ratio, shortened bacterial eradication time, and earlier weaning from the ventilator.[14]

Colistin has rapid concentration-dependent bactericidal[11] activity against gram negative pathogens, including P. aeruginosa, A. baumannii, and K. pneumoniae. Increased antibiotic resistance rates among gram negative bacteria have paved the way for reintroduction of polymyxins in clinical practice. Several studies have shown that IV administration of colistin is effective and safe for treating drug-resistant gram negative bacteria.[5] However, the effectiveness of IV colistin is shadowed by its systemic adverse effects.[10] In addition, the lack of targeted therapeutic delivery of the drug results in lower efficacy rates. Lu et al.[15] studied that colistin was found undetected in the lung tissue following IV infusion but after nebulization peak lung tissue concentrations were significantly higher in the lung tissue.[11] Zhu et al.[10] in their extensive review of pharmacokinetics and pharmacodynamics (PKPD) of NC suggested that the complex PKPD of IV colistin advocates for nebulization rather than IV administration. Aerosolized colistin administration as an adjunctive management technique along with systemic antibiotic therapy has the potential to improve outcomes as targeted therapy.[13] Lu et al.[15] in their study concluded that high-dose colistin was effective in treating VAP caused by MDR P. aeruginosa or A. baumannii. Its therapeutic effect was noninferior to IV antipseudomonals for treating VAP. Many studies have proved the efficacy of aerosolized colistin in the prevention of relapse of lung infection,[16] the eradication of P. aeruginosa from the respiratory tract, and the treatment of respiratory tract infections due to P. aeruginosa in patients with cystic fibrosis.[17],[18]

Also, aerosolized colistin has been used successfully for prophylaxis and treatment of pneumonia caused by P. aeruginosa in patients with human immunodeficiency virus infection.[19]

Very few studies have been done to evaluate the effectiveness of aerosolized colistin in the management of VAP in pediatric patients.[20],[21] The present study aimed to examine the differences in the clinical and bacteriological outcome among patients treated with NC as an adjunctive and standard treatment of care. It was observed that the duration of mechanical ventilation, the duration of postoperative ICU stay and the duration of postoperative hospital stay were significantly lower in the group that received NC compared with the control group. The association was statistically significant (P < 0.05). However, there was no significant difference in the mortality between the groups. In the study done by Michalopoulos et al.,[6] the addition of colistin significantly altered the attributable mortality rates. Moreover, there was a significant improvement in the clinical presentation of VAP, which is similar to the current study. Similar findings were also observed in a study published by Korbila et al.,[16] where they demonstrated improved outcomes with the use of inhaled colistin in combination with IV antibiotics compared with IV colistin alone in adult patients with VAP as a result of MDR gram negative pathogens.[17]

The possible adverse effects of aerosolized colistin are bronchospasm, chest tightness, and apnea.[13] However, in the current study no such adverse effects were seen. The occurrence of nephrotoxicity associated with the administration of NC was explored, and there was no statistically significant difference in the change in serum creatinine levels between the two groups (P = 0.081).

Aerosolized colistin may be used as a therapeutic adjunct for ventilator-associated pneumonia as it has shown minimal adverse effects.

Although aerosolized colistin in the current study has demonstrated clinically favorable outcomes, it failed to demonstrate improved bacteriological outcome. This could be due to the variations in the type of organisms grown. Another limitation of the study is the lack of availability of long-term clinical data regarding mortality and morbidity.


   Conclusion Top


The present study has demonstrated that NC administered as an adjunct in the treatment of VAP has significant clinically favorable outcomes in terms of reduction in the duration of mechanical ventilation and reduced postoperative ICU and hospital stay in postoperative pediatric cardiac patients. Although the present study has not demonstrated significant nephrotoxicity, there is a need to exercise caution with the use of the drug, considering the age group of the patients. There is a growing need to carry out long-term exploratory research to look at the mortality and survival trends and also assess the reinfection patterns of gram negative VAP among children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: A narrative review. Intensive Care Med 2020;46:888-906.  Back to cited text no. 1
    
2.
Dey A, Bairy I. Incidence of multidrug resistant organisms causing ventilator-associated pneumonia in a tertiary care hospital: A nine months' prospective study. Ann Thorac Med 2007;2:52-7.  Back to cited text no. 2
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Foglia E, Meier MD, Elward A. Ventilator-Associated Pneumonia in neonatal and paediatric intensive care unit patients. Clin Microbiol Rev 2007;20:409-25.  Back to cited text no. 3
    
4.
Kwa AL, Loh C, Low JG, Kurup A, Tam VH. Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Clin. Infect Dis 2005;41:754-7.  Back to cited text no. 4
    
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Falagas ME, Kasiakou SK, Tsiodras S, Michalopoulos A. The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: A review of the recent literature. Clin Med Res 2006;4:138-46.  Back to cited text no. 5
    
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Michalopoulos A, Fotakisa D, Virtzilia S, Vletsas C, Raftopoulou S, Mastora Z, et al. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: Prospective study. Respir Med 2008;102:407-12.  Back to cited text no. 6
    
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Xu F, He LL, Che LQ, Li W, Ying SM, Chen ZH, et al. Aerosolised antibiotics for ventilator associated pneumonia: A pairwise and Bayesian network meta-analysis. Crit Care 2018;22:301.  Back to cited text no. 7
    
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Wenzler E, Fraidenburg DR, Scardina T, Danziger LH. Inhaled antibiotics for gram- negative resp infections. Clin Microbiol Rev 2016;29:581-632.  Back to cited text no. 9
    
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Zhu Y, Monsel A, Roberts JA, Pontikis K, Mimoz O, Rello J, et al. Nebulized colistin in ventilator-associated pneumonia and tracheobronchitis: Historical background, pharmacokinetics and perspectives. Microorganisms 2021;9:1154.  Back to cited text no. 10
    
11.
Vardakas KZ, Voulgaris GL, Samonis G, Falagas ME. Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: A systematic review and meta-analysis. Int J Antimicrob. Agents 2018;51:1-9.  Back to cited text no. 11
    
12.
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61-111.  Back to cited text no. 12
    
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Michalopoulos AS, Falagas ME. Colistin: Recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care 2011;1:30.  Back to cited text no. 13
    
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Abdellatif S, Trifi A, Daly F, Mahjoub K, Nasri R, Ben Lakhal S. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: A prospective, randomised trial. Ann Intensive Care 2016;6:26.  Back to cited text no. 14
    
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Lu Q, Luo R, Bodin L, Yang J, Zahr N, Aubry A, et al. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology 2012;117:1335-47.  Back to cited text no. 15
    
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Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled Colistin as adjunctive therapy to intravenous Colistin for the treatment of microbiologically documented ventilator-associated pneumonia: A comparative cohort study. Clin Microbiol Infect 2010;16:1230-6.  Back to cited text no. 16
    
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Zylberberg H, Vargaftig J, Barbieux C, Pertuiset N, Rothschild C, Viard JP. Prolonged efficiency of secondary prophylaxis with Colistin aerosols for respiratory infection due to Pseudomonas aeruginosa in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23:641-3.  Back to cited text no. 19
    
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Nakwan N, Wannaro J, Thongmak T, Pornladnum P, Saksawad R, Nakwan N, et al. Safety in treatment of ventilator-associated pneumonia due to extensive drug-resistant Acinetobacter baumannii with aerosolized colistin in neonates: A preliminary report. Pediatr Pulmonol 2011;46:60-6.  Back to cited text no. 20
    
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Iosifidis E, Antachopoulos C, Ioannidou M, Mitroudi M, Sdougka M, Drossou-Agkidou V et al. Colistin administration to paediatric and neonatal patients. Eur J Pediatrcs 2010;169:867-74.  Back to cited text no. 21
    

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Correspondence Address:
K S Bharathi
Department of Cardiac Anaesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, K. R. S. Road, Mysore - 570 016, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aca.aca_81_21

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