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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 134-142

Bronchoscopic instillation of amikacin in patients with ventilator-associated pneumonia


1 Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Chest Diseases Department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Date of Submission17-Nov-2016
Date of Acceptance16-Mar-2017
Date of Web Publication5-Jul-2017

Correspondence Address:
Mohamed E Fathy
Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Postal code: 21214
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_102_16

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  Abstract 

Introduction
In the era of the emergence of multidrug resistant organisms, it appears that bacteria are beating the battle against the poor development of new effective antibiotics. Aminoglycosides are effective against many Gram-negative bacteria especially when given in large doses, but unfortunately it may be potentially toxic; therefore, there was an inclination toward administration of these antibiotics directly to the airway to get a high concentration of the drug at the site of infection with minimal systemic adverse effects.
Patients and methods
A total of 130 patients with ventilator-associated pneumonia were randomized to amikacin instillation (amikacin-instillation group) (AIG) and intravenous control group (ICG). Bronchial amikacin and serum trough amikacin levels were measured. Enrolled patients were followed up, and clinical cure, microbiological cure, mortality, and length of stay in the ICU stay were monitored.
Results
In AIG, bronchial level of amikacin reached a concentration of 18 700 mcg/l (mean=13 156 mcg/l), associated with nonsignificant increase in the trough levels of amikacin. There was a significant expedition of the clearance of infection and decrease in the ventilator-free days in the AIG. However, there were no significant differences between the two groups regarding mortality and ICU stay.
Conclusion
Bronchoscopic instillation of amikacin is a feasible, effective, and safe mode of direct antibiotic delivery in patients with ventilator-associated pneumonia.

Keywords: amikacin, bronchoscope, instillation, ventilator-associated pneumonia


How to cite this article:
Fathy ME, Helmy TA, Elreweny EM, Mahmoud MI. Bronchoscopic instillation of amikacin in patients with ventilator-associated pneumonia. Res Opin Anesth Intensive Care 2017;4:134-42

How to cite this URL:
Fathy ME, Helmy TA, Elreweny EM, Mahmoud MI. Bronchoscopic instillation of amikacin in patients with ventilator-associated pneumonia. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2017 Nov 18];4:134-42. Available from: http://www.roaic.eg.net/text.asp?2017/4/3/134/209662


  Introduction Top


Ventilator-associated pneumonia (VAP) represents one of the most common hospital-acquired infections; its prevalence ranges from 9 to 48% in mechanically ventilated patients [1],[2],[3], and some networks reported pooled incidence ranging from 2 to 16 episodes per 1000 ventilator-days [4],[5].

The crude mortality in patients who developed VAP is 22–60% [6],[7], and direct attributable mortality is 6–13%. In addition, survivor patients with VAP have worse outcome than patients who did not acquire VAP with less ventilator-free days, longer ICU stay, and increased cost [3],[6].

On the contrary, there is widespread development of resistance to third-generation and fourth-generation cephalosporins [3],[8],[9] and carbapenems with increasing prevalence. This was associated with more use of colistin as a last-line treatment option [10],[11]. Even with colistin, there is a rise in the development of colistin resistance equivalent to the increase in its consumption [12],[13].

Aminoglycosides penetrate poorly into the epithelial lining fluid (ELF) because they are hydrophilic and carry polycationic charge and relatively large size [14]. In patients with pneumonia, high concentrations of the drug can be delivered topically to the lungs, and consequently, an adequate amount of aminoglycoside reaches the endobronchial site of infection but not the blood [15].

Despite limited lung diffusion, aminoglycosides are a preferred choice in VAP owing to the less prevalence of resistance frequencies [16]. The postantibiotic effect [16] and concentration-dependent killing [17] are two important pharmacodynamic properties of aminoglycosides.

Achieving optimal peak concentrations of aminoglycosides can lead to elevated trough concentrations which is a predisposing factor for nephrotoxicity.

In an online survey of 192 critical care units, 87 ICUs reported intratracheal administration of antibiotics in mechanically ventilated patients as a current practice, though 84 healthcare workers avoided intratracheal prescription of antibiotics. Lack of evidence-based guidelines, lack of experience with their use, and lack of appropriate resources were their main concern. Concerns regarding a potential increase in the resistance pattern or a potential risk of adverse effects were also reported [18].

Endotracheal instillation of aminoglycosides for lower respiratory tract infections has been tried in both prophylaxis and treatment regimens in small clinical trials with conflicting results [18],[19],[20].


  Aim Top


The aim of this study was to assess the clinical cure provided by selective instillation of amikacin (AMK) in the treatment of VAP and recognize any adverse events resulting from the instillation of AMK into the airways including the development of AMK resistance. Moreover, the effect of AMK instillation on ventilator-free days, length of ICU stay, and 28-day mortality was identified.


  Patients and methods Top


The study was approved by the ethical committee of the faculty. A written informed consent was obtained from the patients or the legal representative of the patients or their next of kin.

The sample size was calculated using NCSS 2004 and PASS 2000 Program. Group sample sizes of 33 instillation-treated and 33 placebo (total 66 patients with Gram-negative bacterial pneumonia) achieve 81% power to detect a difference of 0.37 between the null hypothesis that both group proportions of eliminated pathogens are 31% and the alternative hypothesis that the proportion of eliminated pathogens among group with instillation treatment is 0.68 using a two-sided χ2-test with continuity correction and with a significance level of .05.

VAP was diagnosed clinically through the Centre of Diseases Control criteria for clinical diagnosis of VAP [21]. Patients diagnosed as having VAP were assessed clinically based on APACHE II score [22], vital signs, and required FiO2.

All included patients were subjected to laboratory evaluation including complete blood picture with differential count, C-reactive protein (CRP) level, arterial blood gases analysis, and renal function testing.

The included 130 patients were randomized into two groups as follows:

The intravenous control group

This included 65 patients with VAP in which bronchoalveolar lavage (BAL) samples were taken using fiberoptic bronchoscope (FOB) and sent for routine culture, and then the included patients received combined intermittent intravenous dosages of ceftazidime and AMK. Subsequently, the antibiotics were changed guided by the results of culture and sensitivity.

The amikacin-instillation group

This included 65 patients with VAP. BAL samples were taken and sent for routine culture. The affected lung segments that were previously identified radiologically were wedged with the tip of the FOB, and then aliquots of AMK were instilled in a total dose of 25 mg/kg (maximum dose 1.5 g) as 35 mg/ml every 24 h for 3 consecutive days only combined with intravenous dosage of ceftazidime. Subsequently, the antibiotics were changed according to culture and sensitivity.

All patients included in the study were monitored radiologically, clinically, and through laboratory investigations including bronchial and trough serum levels of AMK.

Calculation of clinical pulmonary infection score (CPIS) [23] was carried out, and response to antibiotic treatment was classified into the following:
  1. Clinical cure of pneumonia, defined as the reduction of clinical and biological signs of infection, decrease in modified CPIS below 6, significant decrease in CRP, and significant lung reaeration on computed tomography chest/chest radiography.
  2. Microbiological cure, defined as lower respiratory tract specimens either sterile or with nonsignificant concentrations of the offending organism.
  3. Persistent pneumonia, defined as a lack of improvement of clinical and biological signs, CPIS greater than 6, nonsignificant decrease or increase of CRP, and absence of lung reaeration, with significant concentrations of the offending organism in lower respiratory tract specimens previously retrieved from the primary cultures.
  4. Superadded infection, defined as a lack of improvement of clinical and biological signs, CPIS greater than 6, nonsignificant decrease or increase of CRP, and absence of lung reaeration, with significant concentrations of another offending organism in the lower respiratory tract specimens other than the one previously retrieved in the primary cultures.


The two groups were compared based on the following final clinical outcomes
  1. Ventilator-free days.
  2. Length of ICU stay.
  3. Development of AMK-induced nephropathy, defined as 50% increase in serum creatinine and/or a 50% decline in the creatinine clearance by collection or calculation [24].
  4. Any adverse effects of AMK.
  5. Development of AMK resistance.
  6. Twenty-eight-day mortality.


Data were fed to the computer and analyzed using IBM SPSS; IBM SPSS STATISTIC program, version 19 statistical software packages (IBM Corporation, New York). Qualitative data were described using number and percentage. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level.

The used tests were as follows:
  1. χ2-test: for categorical variables, to compare between different groups.
  2. Fisher’s exact test: correction for χ2 when more than 20% of the cells have expected count less than 5.
  3. Student’s t-test: for normally quantitative variables, to compare between two studied groups.
  4. Mann–Whitney test: for abnormally quantitative variables, to compare between two studied groups.



  Results Top


This study was a randomized, controlled trial conducted at a single center (Alexandria Main University Hospital) on critically ill patients requiring mechanical ventilation who developed VAP. This study included 163 patients admitted to the ICUs in Alexandria Main University Hospital between December 2013 and July 2016, among which, 33 patients were excluded owing to resistant organisms to AMK (19 patients), methicillin-resistant Staphylococcus aureus (12 patients) in BAL, transfer to another facility (one patient), and death on first day (one patient). The remaining studied patients were randomized to the amikacin-instillation group (AIG) and the intravenous control group (ICG).

There were 40 (61.5%) males and 25 (38.5%) females in the AIG, whereas there were 43 (66.2%) males and 22 (33.8%) females in the control group. The age ranged from 29 to 83 years in the AIG, with a mean age of 57 years, whereas in the control group, it ranged from 24 to 82 years with mean age of 56.9 years, with no statistical significance between both the groups regarding age and sex.

[Figure 1] describes the progression in temperature of the studied patients in both the groups from days 1 to 9. The mean temperature in the AIG was 38.12°C at baseline, which decreased to reach a mean temperature of 37.4°C in the first 3 days, with a slight increase in the mean temperature of 37.6°C on days 4–6, and then it decreased in the last 3 days to reach a mean of 37.4°C, whereas in the control group, the mean temperature at baseline was 38.2°C, which reached ∼38°C in the first 6 days, and then to 37.8°C on days 7–9. There was no statistically significant difference regarding temperature at baseline, but there is a statistically significant decrease in body temperature in the AIG in comparison with the control group on days 1–3, 4–6, and 7–9 (P=0.008, 0.002, and 0.003, respectively).
Figure 1 Comparisons regarding temperature between the two studied groups. AIG, amikacin-instillation group.

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[Figure 2] shows the values of the white blood cells (WBCs) of the studied patients in both the groups from days 1 to 9. The mean value of the WBCs in the AIG was 18.90×103/ml at baseline, which decreased to a mean value of 16.50×103/ml on days 1–3, and then decreased again to reach 12.50×103/ml on days 4–6. The mean value of WBCs then normalized on days 7–9 to reach 10.90×103/ml. In the control group, the mean value of the WBCs was 19.12×103/ml, which decreased to 17.80×103/ml on days 1–3, and then to 14.00×103/ml on days 4–6 and 7–9. Comparing both the groups, there was no statistically significant decrease in WBCs on days 1–3, but later on, there was statistically significant decrease in the mean WBCs in the AIG in comparison with the control group on days 4–6 and 7–9 (P<0.001 and <0.001, respectively).
Figure 2 Comparison regarding total leukocytic count [white blood cells (WBCs)] between the two groups.

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[Figure 3] describes the CRP progression in the studied patients. The mean baseline CRP level in the AIG and the control group was 197.4 and 199.2 mg/dl, respectively (normal value<5 mg/dl), and it decreased on days 3 and 9 to reach a mean level of 130.8 and 107.6 mg/dl in the AIG and 156.5 and 139 mg/dl in the control group, respectively. It also shows that there was a statistically significant decrease in the CRP level on day 9 in the AIG.
Figure 3 Comparison regarding C-reactive protein (CRP) between the two studied groups.

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[Table 1] shows the bronchial levels of AMK in the studied patients, which ranged from 5900 to 18 700 mcg/l, with a mean level of 13 110.8 mcg/l, whereas in the control group, there were 12 cases with undetectable levels of AMK, and the mean level for the group was 3501 mcg/l. The difference between the bronchial levels of AMK in both the groups was statistically significant ([Figure 4]).
Table 1 Comparison between the two groups regarding bronchial levels of amikacin

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Figure 4 Comparing the bronchial level of amikacin in both the groups. AIG, amikacin-instillation group.

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[Table 2] describes the number of ventilator-free days in both the groups. It ranged from 7 to 22 days in the AIG (mean 14.8 days), whereas in the control group, it ranged from 5 to 20 days (mean 12.2 days). The difference was statistically significantly different.
Table 2 Comparison between the two groups regarding ventilator-free days

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[Table 3] represents the 28-day mortality in the studied groups. The mortality in the AIG was statistically insignificantly different from that in the control group, with 15 (23%) patients versus 18 (27.7%) patients, respectively. The length of ICU stay in the AIG ranged from 13 to 26 days, with a mean value of 19 days, and was also statistically insignificantly different from that seen in the control group [range: 13–27 days (mean 19.8 days)].
Table 3 Comparison between the two groups regarding the 28-day mortality and length of ICU stay (days)

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[Figure 5] represents the clinical cure based on calculation of CPIS among the studied patients. Clinical cure (CPIS<6) was achieved in 45 (69.2%) patients in the AIG and in 32 (49.2%) patients in the control group. This was statistically significant (P=0.020).
Figure 5 Comparison between the two groups regarding the clinical cure. AIG, amikacin-instillation group.

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Eradication of infection was seen in six patients in the AIG and in only one patient in the control group; persistent infection remained in 11 patients in the AIG and in nine patients in the control group. Superinfection occurred in nine patients in the AIG and 21 patients in the control group. Overall, 39 BAL results showed insignificant number of organisms in the AIG, whereas this was seen in 31 in the control group; three results were labeled contamination, and these were in the control group. All differences were statistically insignificant except that there was a significant superadded infection in the control group.

Baseline creatinine level ranged between 0.4 and 1.5 in the AIG, with a mean of 0.9 mg/dl, whereas in the control group, it ranged between 0.2 and 1.4, with a mean 0.85 mg/dl. There was no statistically significant difference between both the groups regarding the baseline creatinine level. On follow-up, the creatinine level ranged between 0.4 and 3 mg/dl, with a mean of 0.91 mg/dl in the AIG, and in the control group, it ranged between 0.3 and 2.9 mg/dl, with a mean of 1 mg/dl.

The prevalence of development of AMK resistance among the studied patients was not statistically significant between both the groups, with four (6.2%) patients in the AIG and 10 (15.4%) patients in the control group.


  Discussion Top


In the current study, FOB was used to assess the affected lung segment with VAP (also guided by chest radiography or computed tomography chest), where bronchial suction was done to remove any mucus or pus or blood clots, and then AMK was directly delivered to the site of infection resulting in high drug concentrations in the lung with minimal systemic toxicity. Furthermore, the high antibiotic concentrations achieved with the removal of the thick bronchial purulent secretions added to the effectiveness of resolution of infection.

Bronchoscopic instillation of AMK achieved high concentration of the drug in the bronchial lavage, which reached in some cases to 18 700 mcg/l with a mean level of 13 156 mcg/l, whereas in the control group, 12 cases exhibited nondetectable levels, with a mean level of 4300 mcg/l. This is attributed to the fact that systemic administration and transport of antibiotics across the bronchial epithelium are limited by the interepithelial tight junctions so that intraluminal antibiotic concentrations tend to be much lower than serum levels. Thus, there is limited antibiotic penetration into the ELF, airway lumen, and intraluminal secretions after systemic antibiotic administration. Furthermore, inhibitory factors in sputum could prevent eradication of organisms [25],[26].

Niederman et al. [27] recently used investigational drug–device combination of AMK, formulated for inhalation, and a proprietary pulmonary drug delivery system, based on vibrating mesh technology, for the treatment of Gram-negative pneumonia in 69 mechanically ventilated patients. In this study, they found that the tracheal aspirate AMK concentrations reached 6400 mcg/ml, with peak serum AMK concentrations several orders of magnitude below those in respiratory secretions and AMK accepted upper trough concentration limits for systemic AMK. Vibrating mesh nebulizers were also used by Luyte et al. [28]. who conducted a trial using nebulized AMK via the pulmonary drug delivery system to 28 mechanically ventilated patients. They found that the mean of ELF concentration was 2417 µg/ml always exceeding the AMK minimum inhibitory concentration for microorganisms usually responsible for VAP.

Delivering antibiotics via FOB solve many limitations of the inhalation method of antibiotic delivery as there are many complex factors that may affect delivery of inhaled particles to lung parenchyma. First, not all types of nebulizers deliver aerosol particles with the same efficiency. As during mechanical ventilation, large droplets (>5 µm) are more likely to be trapped in the circuit, whereas smaller particles (<0.5 µm) are more likely to be expulsed during expiration, so that the size of the particles generated should optimally be between 1 and 3 µm. Particle size depends on the aerosol generator and ventilator settings [29]. Vibrating mesh and ultrasonic nebulizers have appeared to be more efficient in drug delivery than jet nebulizers, because the latter generates aerosol by superimposing a highly turbulent flow to the inspiratory flow coming from the ventilator [30]. This mechanism is associated with lesser deposition of particles in lung parenchyma [31]. Using direct instillation of aminoglycosides via bronchoscope guarantees the delivery of a huge concentration of the drug with minimal or no loss of the drug in the ventilator circuit or the proximal airway.

Second, delivering antibiotics via bronchoscope allowed bypassing the ventilatory circuit, as delivering antibiotics via the inhalation method in spontaneously breathing patients is associated with high turbulent inspiratory flow and, consequently, delivery of aerosol particles mostly in proximal airways. Ventilator-patient asynchrony may also reduce drug delivery to the lung [32].

In addition, ventilator and circuit connections should have smooth inner surfaces and should not have obtuse angles that impair aerosol drug delivery. For the same reason, heat and moisture exchanges should be removed before inhaled therapy because the humidity within the ventilator circuits can result in delivery failure from hydroscopic growth and rainout effect within the tubing [33].

On the contrary, bronchoscope allows precise detection of affected segment that allows precise delivery of the drug to the affected segments, whereas in the inhalation method, airflow may be preferentially directed away from areas of consolidated lung, and this may favor distribution of the antibiotic into areas of less-involved lung parenchyma [34].

Additionally, antibiotic doses ignoring the inevitable extra-pulmonary deposition may also affect therapy efficacy [30], with the possibility of an increase in antimicrobial resistance, which was found by Ilowite et al. [35] who reported the complexity of this issue by considering the interaction of the type of nebulizer, droplet size, and the dose of aerosolized antibiotics to the lung. They showed that aerosolized gentamicin deposited on average 8% of the original amount placed in the nebulizer [35].

On calculating CPIS to estimate the clearance of VAP in the studied patients (CPIS<6), it was found that cure was achieved in 45 (69.2%) patients in the AIG and in 32 (49.2%) patients in the control group, and this was statistically significant (P=0.020). Lu et al. [36] studied 40 patients with VAP. They used nebulized AMK with a dose of 25 mg/kg/day. After 8 days of antibiotic administration, aerosol and intravenous groups were similar in terms of successful treatment (70 vs. 55%). In another small trial, Ghannam et al. [37] found a significant greater percentage of patients treated with inhaled antibiotics who developed complete clinical resolution than patients treated with intravenous antibiotic.

Ioannidou et al. [38] in a meta-analysis described 176 patients with pneumonia. Administration of antimicrobials via the respiratory tract was associated with better treatment success compared with control [38]. However, in a recently published systematic review, Zampieri et al. [20] found that the effects of nebulized antibiotics on the microbiological cure were uncertain [20].

Regarding the development of AMK resistance, the current study found four (6.2%) patients in the AIG and 10 (15.4%) patients in the control group who developed AMK resistance; however, the difference was statistically insignificant. This was also demonstrated by Mohr et al. [39] who reported that seven (40%) patients developed recurrent pneumonia with the same pathogen, but only one had a change in antibiotic susceptibility pattern. Palmer et al. [40] demonstrated that eight of 24 placebo participants acquired resistant organisms during treatment compared with zero of 19 aerosolized antibiotic patients.

In the current study, the number of ventilator-free days were statistically significantly longer in the AIG [range: 7–22 days (mean 14.8 days)] as compared with the control group [range: 5–20 days (mean 12.2 days)]. The length of ICU stay and the mortality in the AIG was statistically insignificantly different from that seen in the control group.

The mortality in the AIG was statistically insignificantly different from that in the control group, with 15 (23%) patients versus 18 (27.7%) patients, respectively. Mortality was assessed by Zampieri et al. [20] in 10 studies that enrolled 817 patients. Nebulized antibiotics were not associated with a lower mortality rate compared with the control groups,; moreover, the total duration of mechanical ventilation (six studies, 496 patients) and ICU length of stay (six studies, 498 patients) were not affected by nebulized antibiotic use [20].

This result matched with the outcomes reported by Lu et al. [36] in which the mean length of ICU stay was also insignificantly different from that seen in the control group (24 days in the aerosol group and 16 days in the control group). Mortality on day 28 was seen in two (5%) cases in the aerosol group and in only one (2%) case in the control group. The mean duration of mechanical ventilation was statistically insignificantly different in both the studied groups (29 days in the aerosol group and 18 days in the control group) [36].

In the current study, it was found that one patient developed AMK-induced nephropathy in the intravenous group, and no patient in the AIG. This was supported by the very low trough AMK level in the studied patients. This was in accordance with Crosby et al. [41] who included nine patients to receive endotracheally instilled tobramycin, and one patient to receive endotracheally instilled gentamicin directly into the endotracheal or tracheostomy tube via a syringe. They reported that the levels of the instilled aminoglycoside in serum were all less than 1.0 µg/ml (lower limit of detection of assay), so significant accumulation of endotracheally administered aminoglycoside did not occur in the serum.

In the trial by Ghannam et al. [37], five patients who received intravenous aminoglycosides developed drug-induced renal dysfunction versus none in the inhaled antibiotics group (31 vs. 0%; P≤0.04). In the same context, Montgomery et al. [42] studied nine adult patients to receive three escalating doses of a combination of 50 mg/ml AMK and 20 mg/ml fosfomycin using a nebulizer system in dose of 300/120 mg AMK/fosfomycin combination. Plasma concentrations were subtherapeutic; the highest observed AMK plasma concentration was 1.4 mcg/ml.

Limitations in the current study are as follows: the cost-effectiveness of this mode of drug delivery was not calculated, and it was a single center trial, so it may not reflect a wider cohort of patients and ethnic groups. Calculation of the ELF level of AMK is more accurate than the bronchial level of AMK, as it is only a rough estimate of the actual level of the drug in the alveoli. In addition, trough AMK level was measured once on the first day of instillation, which may lead to underestimation of the cumulative effect of AMK.


  Conclusion Top


Bronchoscopic AMK instillation provides an effective tool for achieving high clinical cure rate and radiological resolution from VAP associated with rapid recovery of signs of respiratory infection with earlier extubation and weaning from mechanical ventilation leading to more ventilator-free days without enhancing bacterial resistance and appears to eradicate offending pathogens more reliably. Instillation of AMK achieved a very high concentration of the drug in the bronchial lavage while maintaining safe serum concentrations and appears to have less deleterious effects on renal functions in comparison with conventional systemic antibiotic administration. It is a well-tolerated and safe procedure with no significant adverse events.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts on interest.

 
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    Figures

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    Tables

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