Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of tidal volume Aerosol delivery with two ventilation modes during mechanical ventilation: a randomized study Rapid pulmonary delivery of inhaled tobramycin for Pseudomonas infection in cystic fibrosis: a pilot project. Pharmacokinetics and tolerability of amikacin administered as BAY41-6551 aerosol in mechanically ventilated patients with gram-negative pneumonia and acute renal failure. A comparison of bronchodilator therapy delivered by nebulization and metered-dose inhaler in mechanically ventilated patients. Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients. A study comparing four different actuator devices. Placement of the nebulizer before the humidifier during mechanical ventilation: Effect on aerosol delivery. Comparison of jet and ultrasonic nebulizer pulmonary aerosol deposition during mechanical ventilation. Amikacin levels in bronchial secretions of 10 pneumonia patients with respiratory support treated once daily versus twice daily. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Pharmacokinetics of Salbutamol Delivered from the Unit Dose Dry Powder Inhaler: Comparison with the Metered Dose Inhaler and Diskus Dry Powder Inhaler. Variability in the measurement of nebulized aerosol deposition in man. Aerosolized ceftazidime for prevention of ventilator-associated pneumonia and drug effects on the proinflammatory response in critically ill trauma patients. Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Disposition of instilled versus nebulized tobramycin and imipenem in ventilated intensive care unit (ICU) patients. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Comparison of dose to the lungs. Metered dose inhalers for bronchodilator delivery in intubated, mechanically ventilated patients. Aerosolized antibiotics in mechanically ventilated patients: delivery and response. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia Controlled, parametric, individualized, 2D and 3D imaging measurements of aerosol deposition in the respiratory tract of healthy human volunteers: in vivo data analysis. Efficiency of a New Mesh‐Type Nebulizer (NE‐SM1 NEPLUS) for Intrapulmonary Delivery of Ipratropium Bromide in Surgical Patients
Objective : The delivery of bronchodilator drugs with metered-dose inhaler ( MDI ) and a spacer in mechanically ventilated patients has become a widespread practice . However , the various ventilator setting s that influence the efficacy of MDI are not well established . The tidal volume ( VT ) during drug delivery has been suggested as one of the factors that might increase the effectiveness of this therapy . To test this , the effect of two different VT on the bronchodilation induced by β2-agonists administered with MDI and a spacer in a group of mechanically ventilated patients with chronic obstructive pulmonary disease ( COPD ) was examined.¶ Methods : Nine patients with COPD , mechanically ventilated on volume-controlled mode , were prospect ively r and omised to receive six puffs of salbutamol ( S , 100 μg/puff ) either with a VT of 8 ml/kg ( normal VT , 582 ± 85 ) or with a VT of 12 ml/kg ( high VT , 912 ± 137 ) . With both modes inspiratory flow was identical . S was administered with an MDI adapted to the inspiratory limb of the ventilator circuit using an aerosol cloud enhancer spacer . After a ¶6-h washout , patients were crossed-over to receive S by the alternative mode of administration . Static and dynamic airway pressures , minimum ( Rint ) and maximum ( Rrs ) inspiratory resistance , the difference between Rrs and Rint ( ΔR ) , static end-inspiratory respiratory system compliance ( Cst , rs ) , intrinsic positive end-expiratory pressure ( PEEPi ) and heart rate ( HR ) were measured before and at 15 , 30 and 60 min after S.¶ Results : S caused a significant decrease in dynamic and static airway pressures , PEEPi , Rint and Rrs . These changes were not influenced by VT and were evident at 15 , 30 and 60 min after S. With normal and high VT , Cst , rs , ΔR and HR did not change after S.¶ Conclusions : We conclude that S delivered with an MDI and a spacer device induces significant bronchodilation in mechanically ventilated patients with COPD , the magnitude of which is not affected by at least a 50 % increase in VT . These results do not support the VT manipulations when bronchodilators are administered in adequate doses during controlled mechanical ventilation Abstract Background Volume-controlled ventilation has been suggested to optimize lung deposition during nebulization although promoting spontaneous ventilation is targeted to avoid ventilator-induced diaphragmatic dysfunction . Comparing topographic aerosol lung deposition during volume-controlled ventilation and spontaneous ventilation in pressure support has never been performed . The aim of this study was to compare lung deposition of a radiolabeled aerosol generated with a vibrating-mesh nebulizer during invasive mechanical ventilation , with two modes : pressure support ventilation and volume-controlled ventilation . Methods Seventeen postoperative neurosurgery patients without pulmonary disease were r and omly ventilated in pressure support or volume-controlled ventilation . Diethylenetriaminepentaacetic acid labeled with technetium-99 m ( 2 mCi/3 mL ) was administrated using a vibrating-mesh nebulizer ( Aerogen Solo ® , provided by Aerogen Ltd , Galway , Irel and ) connected to the endotracheal tube . Pulmonary and extrapulmonary particles deposition was analyzed using planar scintigraphy . Results Lung deposition was 10.5 ± 3.0 and 15.1 ± 5.0 % of the nominal dose during pressure support and volume-controlled ventilation , respectively ( p < 0.05 ) . Higher endotracheal tube and tracheal deposition was observed during pressure support ventilation ( 27.4 ± 6.6 vs. 20.7 ± 6.0 % , p < 0.05 ) . A similar penetration index was observed for the right ( p = 0.210 ) and the left lung ( p = 0.211 ) with both ventilation modes . A high intersubject variability of lung deposition was observed with both modes regarding lung doses , aerosol penetration and distribution between the right and the left lung . Conclusions In the specific conditions of the study , volume-controlled ventilation was associated with higher lung deposition of nebulized particles as compared to pressure support ventilation . The clinical benefit of this effect warrants further studies . Clinical trial registration BACKGROUND Patients with cystic fibrosis spend as much 30 min a day inhaling tobramycin . Could a new rapid system deposit the equivalent amount of tobramycin faster ? METHODS Six healthy adult males inhaled 5 ml ( 300 mg ) of tobramycin from a breath enhanced nebulizer and either 125 mg ( n = 3 ) or 150 mg ( n = 3 ) from a vibrating membrane system with a large or small aerosol mixing chamber respectively . A radiolabel was added to the solution and shown to " track " with the tobramycin . Imaging was done with a dual headed gamma camera . Because the radiolabel will be cleared by mucociliary action during administration , algorithms were developed to allow the comparison of a slower system to a faster one . RESULTS Both formulations were well tolerated . The lung deposition was 16.6 + /- 3.2 % ( mean + /- SD ) of the charge dose delivered in 10.9 + /- 1.0 min for the breath enhanced nebulizer versus 32.0 + /- 5.1 % delivered in 2.5 + /- 0.4 min from the vibrating membrane system . The absolute pulmonary delivery of tobramycin was 49.9 + /- 9.6 versus 43.9 + /- 4.8 mg for the two systems respectively , differences that were statistically significant ( pair t-test ) but unlikely to be clinical ly significant . There was a similar deposition of tobramycin for the 125 and 150 mg dose . CONCLUSIONS It is possible to deliver an equivalent amount of tobramycin in a shorter period of time with the new vibrating membrane system and a more concentrated formulation . These data will allow the design of a comparison in patients with CF BACKGROUND BAY41 - 6551 , a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in intubated and mechanically ventilated patients , consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System ( PDDS ) Clinical aerosol delivery platform . Given the predominantly renal clearance of aminoglycosides , underst and ing systemic amikacin exposure and safety during administration of BAY41 - 6551 to patients with acute renal failure ( ARF ) is clinical ly important . METHODS Seven mechanically ventilated patients with Gram-negative pneumonia and ARF receiving continuous veno-venous hemodiafiltration ( CVVHDF ) were treated with multiple administrations of BAY41 - 6551 400 mg amikacin twice daily using the PDDS Clinical on-ventilator device [ in addition to st and ard intravenous ( i.v . ) antimicrobial therapy ] . CVVHDF parameters were recorded and a PK analysis was performed using serum , urine , and bronchoalveolar lavage fluid sample s. RESULTS Maximum serum amikacin concentration [ median 1.93 ( range : 0.63 - 3.99 ) mg/L ] and area under the concentration-time curve from zero to 12 h on day 3 [ median 19.32 ( range 6.32 - 36.87 ) mg · h/L ] were elevated compared with mechanically ventilated patients with normal renal function ; however , serum amikacin trough concentrations were within accepted safety limits . The median amikacin concentration in epithelial lining fluid [ 887 ( range : 406 - 12,819 ) mg/L ] was similar to that reported previously in mechanically ventilated patients with normal renal function . BAY41 - 6551 demonstrated acceptable safety and tolerability with most adverse events ( AEs ) as expected for the patient population . One serious AE of bronchospasm was attributed to the study medication ; no reported AEs were related to the PDDS Clinical device . CONCLUSIONS CVVHDF appears to provide adequate clearance of systemically absorbed amikacin in mechanically ventilated patients with ARF , suggesting that dose adjustments for BAY41 - 6551 are probably not necessary for this patient population . Nonetheless , the st and ard pre caution ary measures for critically ill patients receiving i.v . amikacin should be followed for patients with ARF who are treated with BAY41 - 6551 BACKGROUND The optimal method of delivering bronchodilators in mechanically ventilated patients is unclear . The purpose of this study was to compare the pulmonary bioavailability of albuterol delivered by the nebulizer , the metered-dose inhaler ( MDI ) and spacer , and the right-angle MDI adaptor in ventilated patients using urinary analysis of drug levels . METHODS Mechanically ventilated patients who had not received a bronchodilator in the previous 48 h and who had normal renal function were r and omized to receive the following : ( 1 ) five puffs ( 450 microg ) of albuterol delivered by the MDI with a small volume spacer ; ( 2 ) five puffs of albuterol delivered by the MDI port on a right-angle adaptor ; or ( 3 ) 2.5 mg albuterol delivered by a nebulizer . Urine was collected 6 h after the administration of the drug , and the amounts of albuterol and its sulfate conjugate were determined in the urine by a chromatographic assay . RESULTS Thirty patients were studied , 10 in each group : their mean age and serum creatinine level were 62 years and 1.3 mg/dL , respectively . With the MDI and spacer , ( mean + /- SD ) 169+/-129 microg albuterol ( 38 % ) was recovered in the urine ; with the nebulizer , 409+/-515 microg albuterol ( 16 % ) was recovered in the urine ; and with the MDI port on the right-angle adaptor , 41+/-61 microg albuterol ( 9 % ) was recovered in the urine ( p = 0.02 between groups ) . The level of albuterol in the urine was below the level of detection in four patients in whom the drug was delivered using the right-angle MDI adaptor . CONCLUSION The three delivery systems varied markedly in their efficiency of drug delivery to the lung . As previous studies have confirmed , this study has demonstrated that using an MDI and spacer is an efficient method for delivering inhaled bronchodilators to the lung . The pulmonary bioavailability was poor with the right-angle MDI port . This port should not be used to deliver bronchodilators in mechanically ventilated patients STUDY OBJECTIVE To compare aerosol delivery to the lungs in ventilated patients from two devices with holding chamber and two devices without holding chamber . DESIGN A controlled clinical trial with r and omization to one of four delivery devices . SETTING An academic university-affiliated Canadian ICU . PATIENTS Forty-eight patients undergoing mechanically assisted ventilation for a variety of clinical reasons and each judged to require inhaled bronchodilator therapy by the attending physician . INTERVENTIONS Patients received 4 puffs of fenoterol labeled with technetium 99 m pertechnetate delivered by metered-dose inhaler via 1 of the following : A , a 167-ml chamber device ; B , a 700-ml chamber device ; C , a nonchamber device ( A , B , and C , all in the ventilator inspiratory line ) ; and D , a nonchamber device on the end of the endotracheal tube . MEASUREMENTS AND RESULTS One-minute images of the thorax were made by a portable gamma camera at the bedside . Deposition of radioactivity in the lungs ( uncorrected for tissue absorption and calculated as a percentage of the radioactivity delivered from 4 puffs ) was 5.53 + /- 0.72 ( mean + /- 1 SEM ) , 6.33 + /- 1.16 , 1.67 + /- 0.43 , and 3.89 + /- 0.52 percent for devices A , B , C , and D , respectively ( p = 0.004 ) . Subgroup analysis showed a statistically significant difference in delivery between devices A and C and between devices B and C only . CONCLUSION There were statistically significant differences between delivery from both chamber devices and the inline nonchamber device , but not between delivery from other devices . Further work will be necessary to determine the effect of device position in the ventilator circuit on aerosol delivery BACKGROUND Therapeutic aerosols are commonly used in mechanically ventilated patients . The position of the nebulizer in the ventilator circuit and the humidification of inhaled gases can influence the efficiency of aerosol delivery . We evaluated the effect of nebulizer position on the pulmonary bioavailability of nebulized ipratropium  in ventilated patients without known preexisting respiratory disease . METHODS The study included 38 mechanically ventilated and se date d patients after open heart surgery .  Ipratropium ( 500 microg ) was delivered by an ultrasonic nebulizer . Patients were r and omized into 2 groups : the nebulizer positioned before the heat humidification system ( group 1 , n = 19 ) or at the end of the inspiratory limb before the Y-piece ( group 2 , n = 19 ) . The amount of ipratropium in the urine collected during the 4 hours after drug administration was measured by mass spectrometry . RESULTS There were no statistically significant differences in tidal volume or respiratory rate between groups . There were no significant differences between the 2 groups in the amount of drug excreted ( group 1 vs 2 : 13,237 + /- 2313 pg/mL vs 15,529 + /- 3204 pg/mL ) or in pulmonary bioavailability ( .9 % + /- .1 % vs 1.1 % + /- .2 % ) . CONCLUSION The position of the nebulizer in the ventilatory circuit had no effect on the pulmonary bioavailability of ipratropium Increased delivery of aerosol to a model lung ( attached to a mechanical ventilator ) has been demonstrated with an ultrasonic nebulizer as compared to a jet nebulizer . This study examined whether the increased aerosol deposition with an ultrasonic nebulizer could also be demonstrated in vivo . Seven patients ( 6 male and 1 female ) were studied during mechanical ventilalion ( Siemens Servo 900C , Middlesex , UK ) after open heart surgery . Two studies were performed in each patient . In the first study , aerosol was delivered via a Siemens Servo 945 nebulizer system ( high setting ) driving a System 22 Acorn jet nebulizer ( Medic-Aid , Sussex , UK ) containing 3 mL (99m)technetium-labelled human serum albumin ( 99mTc-HSA ) ( 50 microg ; activity 74 MBq ) . In the second study , a DP100 ultrasonic nebulizer ( DP Medical , Meylan , France ) containing 12 mL 99mTc-HSA ( 50 microg ; activity 185 MBq ) was used . Pulmonary deposition was quantified using a gamma camera . The humidification of the circuit and the ventilator setting s were kept constant according to the patient 's clinical requirements . The total lung aerosol deposition ( mean+/-SD ) , as a percentage of initial nebulizer activity , was greater using the ultrasonic nebulizer than using the jet nebulizer ( 53+/-1.4 vs 2.3+/-0.9 % ; p<0.002 ) . The ultrasonic nebulizer was also associated with a reduction in the time required to complete nebulization ( 9 vs 21 min , respectively ) ( p<0.0001 ) . Use of the DP100 ultrasonic nebulizer more than doubled lung deposition compared with the System 22 jet nebulizers in mechanically-ventilated patients . Their efficiency , speed of drug delivery , and compatibility with mechanical ventilator circuits make ultrasonic nebulizers potentially attractive for use during mechanical ventilation In this study , concentrations of  amikacin  in blood and bronchial secretions of 10 patients with mechanical ventilation for acute respiratory failure due to pneumonia were measured . One-half of the patients received amikacin twice daily , and the others received once-daily administration .  Concentrations in bronchial secretions of the patients treated twice daily ranged from 3 to 4 mg/liter , i.e. , they were similar to those in previously published reports . Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion , and they reached 4.8 + /- 2.6 mg/liter on day 1 and 4.0 + /- 2.7 mg/liter on day 3 . For the patients treated with amikacin once daily , concentrations in bronchial secretions were more than twofold higher , above 8 mg/liter for 12 h. Peak concentrations in bronchial secretions occurred between 3 and 4 h after the onset of infusion and reached 13.6 + /- 9.3 mg/liter on day 1 and 10.4 + /- 3.5 mg/liter on day 3 . These concentrations are higher than the MICs for less sensitive bacterial strains , such as Acinetobacter spp . and Pseudomonas aeruginosa OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity AIM To compare the systemic exposure of  salbutamol  following delivery from the unit dose dry powder inhaler ( UD-DPI ) system with that from the Diskus ® and metered dose inhaler ( MDI ) . MATERIAL S AND METHODS This open-label , two-part , six-way crossover , r and omized single-dose study in healthy subjects evaluated salbutamol systemic exposure of three dose strengths ( using three inhalations : 3 × 150 μg [ 450 μg ] , 3 × 200 μg [ 600 μg ] , and 3 × 250 μg [ 750 μg ] ) and 2 % of drug in lactose blends ( 1.6 % and 1.0 % [ 600 μg dose only ] by weight ) following delivery through the UD-DPI compared with systemic exposure from the Diskus and MDI ( 600 μg dose ) . Systemic exposure in the presence of charcoal block was also evaluated . Primary treatment comparisons were area under the concentration-time curve from time zero to 12 hours [ AUC0 - 12 ] and maximum plasma concentration [ Cmax ] . RESULTS Delivery of salbutamol 600 μg from the UD-DPI result ed in total systemic exposure similar to that from the Diskus and approximately half of that from the MDI ( AUC0 - 12 geometric least squares mean ratio [ GMR ] [ 90 % confidence interval ( CI ) ] for UD-DPI [ 1.6 % blend]/Diskus : 0.91 [ 0.83 - 1.00 ] ; UD-DPI [ 1.6 % blend]/MDI : 0.46 [ 0.42 - 0.50 ] . Cmax GMR [ 90 % CI ] for UD-DPI [ 1.6 % blend]/Diskus : 1.20 [ 1.07 - 1.33 ] ; UD-DPI [ 1.6 % blend]/MDI : 0.58 [ 0.52 - 0.64 ] ) . Results were consistent between the 1.6 % and the 1.0 % blends and systemic exposure for the 3 dose strengths of salbutamol ( 1.6 % blend ) showed increases that were 12 - 16 % greater than dose proportional . Systemic exposure due to pulmonary absorption ( as calculated from AUC0 - 12 in the presence and absence of charcoal block ) was 48 % for the UD-DPI , 24 % for Diskus , and 37 % for MDI of the total salbutamol systemic exposure , and the corresponding estimated lung dose was 65 % for the UD-DPI and 34 % for the Diskus relative to the MDI . CONCLUSIONS Salbutamol total systemic exposure following UD-DPI was similar to that from the Diskus and was lower than that following the MDI . The different blend formulations tested result ed in consistent salbutamol systemic exposure . The contribution of the lung and gut to systemic exposure revealed a different profile for the three inhaler platforms . These data suggest that the UD-DPI warrants further evaluation 1 . This study was performed to determine the variability of two different scintigraphic methods of measuring pulmonary aerosol deposition , and to examine nebulizer particle size and drug output as potential sources of this variability . 2 . A radioaerosol was produced from a 3 ml solution of 99mTc-labelled colloidal human serum albumin ( 0.05 mg , 37 MBq ) using a st and ard jet nebulizer and air compressor . This was inhaled on three separate occasions by nine healthy male subjects . One one of these occasions , a further inhalation was performed to assess immediate repeatability using increased 99mTc activity ( 92 MBq ) . 3 . Intrapulmonary aerosol deposition was measured with a gamma-camera and was corrected for tissue attenuation and geometric distribution by using two different methods . 4 . Estimated mean pulmonary deposition was 4.3 % of the nebulizer dose using a lung phantom correction method , and 6.1 % using a tissue attenuation method . For these two methods respectively variability between subjects ( coefficient of variation ) was 54 and 47 % . For both methods , within-subject variability ( coefficient of variation ) was 37 % between occasions and 23 % within occasions . 5 . The particle-size output of several nebulizers was highly reproducible ( coefficient of variation less than 4 % ) , but the nebulizer mass and radionuclide output of two nebulizers was more variable ( coefficient of variation 5 - 19 % ) , and appeared to be an important contributor to the variability in pulmonary aerosol deposition . 6 . The data presented here for pulmonary deposition , used with appropriate power statistics formulae , can be used to estimate the sample sizes required for comparative studies of lung aerosol deposition STUDY OBJECTIVES To evaluate the safety and efficacy of aerosolized ceftazidime for prevention of  ventilator-associated pneumonia ( VAP )  and to evaluate the effects of the drug on the proinflammatory response . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled clinical trial . SETTING University teaching hospital . PATIENTS Forty critically ill trauma patients at high risk for VAP Intervention . Within 48 hours of admission to the intensive care unit ( ICU ) , patients were r and omly assigned to receive aerosolized ceftazidime 250 mg every 12 hours or placebo ( normal saline ) for up to 7 days . Bronchoalveolar concentrations of tumor necrosis factor-alpha ( TNF-alpha ) , interleukin (IL)-1beta , IL-6 , and IL-8 were determined at baseline and the end of therapy ( days 4 - 7 ) . MEASUREMENTS AND MAIN RESULTS The frequency of VAP in patients receiving aerosolized ceftazidime was 73 % lower than that in patients receiving placebo at ICU day 14 ( 15 % vs 55 % , p = 0.021 ) , and 54 % lower for the entire ICU stay ( 30 % vs 65 % , p = 0.022 ) . No clinical ly significant changes in bacterial culture and sensitivity patterns were observed . No adverse events from aerosolized ceftazidime were reported . Pulmonary TNF-alpha , IL-beta , and IL-8 concentrations were attenuated in the ceftazidime group compared with those in the placebo group ( p < 0.001 , p = 0.02 , and p = 0.003 ) . The frequency of VAP was related directly to changes in TNF-alpha and IL-beta ( p < 0.001 , p = 0.02 ) . CONCLUSIONS Aerosolized ceftazidime decreased the frequency of VAP in critically ill trauma patients , without adversely affecting ICU flora . Aerosolized ceftazidime also may attenuate the proinflammatory response in the lung RATIONALE In experimental pneumonia , nebulization of antibiotics provides high lung tissue concentrations and rapid bacterial killing . OBJECTIVES To assess the efficacy and safety of nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa . METHODS Forty patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa were included in a r and omized comparative phase II trial . Twenty patients infected with susceptible or intermediate strains received nebulized ceftazidime ( 15 mg·kg(-1)·3 h(-1 ) ) and amikacin ( 25 mg·kg(-1)·d(-1 ) ) . Seventeen patients infected with susceptible strains received intravenous ceftazidime ( 90 mg·kg(-1)·d(-1 ) , continuous administration ) and amikacin ( 15 mg·kg(-1)·d(-1 ) ) . In three patients infected with intermediate strains , amikacin was replaced by ciprofloxacin ( 400 mg·12 h(-1 ) ) . MEASUREMENTS AND MAIN RESULTS After 8 days of antibiotic administration , aerosol and intravenous groups were similar in terms of successful treatment ( 70 vs. 55 % ) , treatment failure ( 15 vs. 30 % ) , and superinfection with other microorganisms ( 15 vs. 15 % ) . Antibiotic-induced changes in lung aeration , determined by computed tomography , were not different between groups ( increase in gas volume , 159 ± 460 vs. 251 ± 583 ml ; decrease in tissue volume , -58 [ -77 , 25 ] vs. -89 [ -139 , 5 ] ml ) . Acquisition of per-treatment antibiotic resistance was observed exclusively in the intravenous group . In the aerosol group , four patients infected with intermediate strains were successfully treated . Nebulization induced an obstruction of the expiratory filter in three patients . The obstruction caused cardiac arrest in one patient , who fully recovered after brief cardiopulmonary resuscitation . CONCLUSIONS Nebulization and intravenous infusion of ceftazidime and amikacin provide similar efficiency for treating ventilator-associated pneumonia caused by Pseudomonas aeruginosa . Nebulization is efficient against intermediate strains and may prevent per-treatment acquisition of antibiotic resistance BACKGROUND Delivery of antibiotics to the lower respiratory tract could potentially achieve antimicrobial bronchial drug concentrations without toxicity . AIM To assess bronchial and serum concentrations of imipenem or tobramycin obtained by nebulization or instillation in critically ill mechanically ventilated patients . METHODS Prospect i ve r and omized open trial . Eighteen patients ventilated for more than 48 h were included . Two doses of imipenem/cilastatin ( 1000/500 mg ) separated by 8 h , or two doses of tobramycin 200 mg separated by 12 h were r and omly nebulized or instilled into the tracheal tube . Five bronchoaspirates ( two bronchoscopic , three blind ) and five blood sample s were collected on a timed schedule after the second dose . Respiratory and serum sample s were analysed by HPLC , and a subset of blood sample s was also evaluated by enzyme-immunoassay . RESULTS When instilled , imipenem/cilastatin obtained higher concentrations in respiratory secretions than when nebulized ( P=0.022 , 1 h after the last dose ; P=0.029 , 2 h after the last dose ) . Tobramycin showed equally high concentrations when nebulized or instilled . Instillation of tobramycin may result in significant accumulation in patients with renal failure .  CONCLUSIONS High bronchial concentrations of imipenem  could only be achieved by instillation , whereas tobramycin seems suitable for both modes of administration . Instillation of these antibiotics is a safe procedure that achieves high drug concentrations in respiratory secretions The purpose of this study was to compare deposition of aerosol to the lung from a metered-dose inhaler ( MDI ) and aerosol holding chamber and from a jet nebulizer in ventilator-dependent patients . Twenty-one patients were entered into the study , all receiving assisted ventilation and inhaled bronchodilators because of airflow limitation . The average age was 68 yr ; there were 10 men and 11 women . The patients were r and omized to receive either 4 puffs ( 800 micrograms ) of radiolabeled fenoterol by MDI of 1.75 ml ( 1,750 micrograms ) of radiolabeled fenoterol solution by nebulizer . Imaging of lung fields was made by a portable scintillation camera at 5-min intervals during the study . Results showed that 20 patients completed the study , 9 receiving fenoterol by MDI , and 11 by jet nebulizer . Four were excluded from analysis because of previous pneumonectomy , two from each group . Lung deposition measured as a percent of given dose from either system was 5.65 + /- 1.09 ( mean + /- SEM ) for MDI plus extension chamber and 1.22 + /- 0.35 for jet nebulizer ( p less than 0.001 ) . Therefore , this trial shows significantly greater efficiency of aerosol deposition to the lung in ventilator-dependent patients when using an MDI plus aerosol holding chamber than when using a jet nebulizer We determined the relative efficacy of two bronchodilator aerosol delivery methods in 18 intubated mechanically ventilated patients with airways obstruction . Two treatment arms , consisting of albuterol 270 micrograms ( three puffs ) from a metered dose inhaler and albuterol 2.5 mg from a saline solution nebulized with an updraft inhaler , were compared in a single blind , r and omized crossover design . Pulmonary function was evaluated using an interrupter technique . Changes in passive expiratory flow at respiratory system recoil pressures between 6 and 10 cm H2O provided the therapeutic endpoints . Paired measurements were made before and 30 minutes after drug delivery . The MDI and NEB result ed in similar improvements in iso-recoil flow ( mean increase for both groups = 0.1 L/s ) . Treatment sequence , severity of obstruction , and bronchodilator responsiveness had no effect on relative efficacy . Albuterol caused a small but significant increase in heart rate that was similar following both delivery methods . We conclude that bronchodilator aerosol delivery with metered dose inhalers provides a viable alternative to nebulizer therapy in intubated mechanically ventilated patients and may result in a cost savings to hospitals and patients OBJECTIVES To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents . DESIGN Prospect i ve serial study with cases as their own control . SETTING A 10-bed respiratory care unit for patients with chronic respiratory failure in a tertiary university hospital . PATIENTS Ventilator dependent patients who are otherwise medically stable . All subjects had a tracheostomy in place , were colonized with gram-negative organisms , and produced purulent secretions which could be sample d daily . INTERVENTIONS Six patients received nine courses of nebulized therapy  , which consisted of treatments every 8 hrs of gentamicin ( 80 mg ) or amikacin ( 400 mg ) for 14 to 21 days . MEASUREMENTS AND MAIN RESULTS Doses to the lung were measured using radiolabeled aerosols and antibiotic concentrations in sputum . The response was assessed by a ) changes in the volume of respiratory secretions ; b ) effect on bacterial cultures ; and c ) changes in the inflammatory cells and mediators of inflammation of the respiratory secretions ( interleukin-1beta [ IL-1beta ] , tumor necrosis factor-alpha [ TNF-alpha ] , soluble intercellular adhesion molecule-1 [ sICAM-1 ] , and human leukocyte elastase ) . On average , patients inhaled 35.4 + /- 5.08 % ( SD ) of the initial drug placed in the nebulizer ( neb-charge ) . Of this neb-charge , 9.50 + /- 2.78 % was found on the respirator tubing and tracheostomy tube and 21.9 + /- 7.15 % was actually deposited in the lungs . The remainder of the neb-charge was sequestered in the nebulizer or exhaled . Trough sputum concentrations averaged 4.3 + /- 3.2 microg/mL/mg neb-charge ( range 234 to 520 microg/mL ) and increased to 16.6 + /- 8.1 microg/mL/mg neb-charge ( range 1005 to 5839 microg/mL ) immediately after therapy ( p = .011 ) . Serum concentrations were undetectable in most determinations except for a single patient who was in renal failure ( 8.7 microg/mL amikacin ) . Treatment caused a significant reduction in the volume of secretions ( p = .002 ) . Weekly cultures revealed eradication of Pseudomonas species , Serratia marcescens , and Enterobacter aerogenes in most of the trials . Before antibiotic treatment , concentrations of IL-1beta were higher than those reported in acute respiratory distress syndrome . Throughout the duration of the study , IL-1beta correlated significantly with the absolute number of macrophages , neutrophils , and lymphocytes , respectively ( r2 = .55 , p = .002 ; r2 = .50 , p < .0004 , r2 = .36 , p = .005 ) . TNF-alpha concentrations correlated with lymphocytes and neutrophils , respectively ( r2 = .27 , p = .013 , r2 = .21 , p = .033 ) . sICAM-1 concentrations increased two-fold ( p < .001 ) during treatment and then returned to baseline . The volume of secretions was related to neutrophil and IL-1beta concentrations , respectively ( r2 = .25 , p = .008 , r2= .35 , p = .006 ) . CONCLUSIONS Nebulizer delivery of aerosolized aminoglycosides is efficient and predictable . In our clinical model , aerosolized antibiotics can make a significant impact on respiratory secretions . Their efficacy in treatment of critically ill patients remains to be determined Purpose To conduct a multicenter , r and omized , placebo-controlled , double-blind , phase II study of BAY41 - 6551 ( NCT01004445 ) , an investigational drug – device combination of amikacin , formulated for inhalation , and a proprietary Pulmonary Drug Delivery System , for the treatment of Gram-negative pneumonia in mechanically ventilated patients . Methods Sixty-nine mechanically ventilated patients with Gram-negative pneumonia , a clinical pulmonary infection score ≥6 , at risk for multidrug-resistant organisms , were r and omized to BAY41 - 6551 400 mg every 12 h ( q12h ) , 400 mg every 24 h ( q24h ) with aerosol placebo , or placebo q12h for 7–14 days , plus st and ard intravenous antibiotics . The combined primary endpoint was a tracheal aspirate amikacin maximum concentration ≥6,400 μg/mL ( 25 × 256 μg/mL reference minimum inhibitory concentration ) and a ratio of area under the aspirate concentration – time curve ( 0–24 h ) to minimum inhibitory concentration ≥100 on day 1 . Results The primary endpoint was achieved in 50 % ( 6/12 ) and 16.7 % ( 3/18 ) of patients in the q12h and q24h groups , respectively . Clinical cure rates , in the 48 patients getting ≥7 days of therapy , were 93.8 % ( 15/16 ) , 75.0 % ( 12/16 ) , and 87.5 % ( 14/16 ) in the q12h , q24h , and placebo groups , respectively ( p = 0.467 ) . By the end of aerosol therapy , the mean number of antibiotics per patient per day was 0.9 in the q12h , 1.3 in the q24h , and 1.9 in the placebo groups , respectively ( p = 0.02 for difference between groups ) . BAY41 - 6551 was well tolerated and attributed to two adverse events in one patient ( mild bronchospasm ) . Conclusions BAY41 - 6551 400 mg q12h warrants further clinical evaluation BACKGROUND To provide a validation data set for aerosol deposition modeling , a clinical trial was performed in which the inhalation parameters and the inhaled aerosol were controlled or characterized . METHODS Eleven , healthy , never-smokers , male participants completed the study . Each participant performed two inhalations of (99m)Tc-labeled aerosol from a vibrating mesh nebulizer , which differed by a single controlled parameter ( aerosol particle size : " small " or " large " ; inhalation : " deep " or " shallow " ; carrier gas : air or a helium-oxygen mix ) . The deposition measurements were made by planar imaging , and single photon emission computed tomography-computed tomography ( SPECT-CT ) . RESULTS The difference between the mean activity measured by two-dimensional imaging and that delivered from the nebulizer was 2.7 % , which was not statistically significant . The total activity deposited was significantly lower in the left lung than in the right lung ( p<0.0001 ) with a mean ratio ( left/right ) of 0.87±0.1 st and ard deviation ( SD ) . However , when normalized to lung air volume , the left lung deposition was significantly higher ( p=0.0085 ) with a mean ratio of 1.08±0.12 SD . A comparison of the three-dimensional central -to-peripheral ( nC/P3D ) ratio showed that it was significantly higher for the left lung ( p<0.0001 ) with a mean ratio ( left/right ) of 1.36±0.20 SD . The effect of particle size was statistically significant on the nC/P3D ratio ( p=0.0014 ) , extrathoracic deposition ( p=0.0037 ) , and 24-hr clearance ( p<0.0001 ) , contrary to the inhalation parameters , which showed no effect . CONCLUSIONS This article presents the results of an analysis of the in vivo deposition data , obtained in a clinical study design ed to provide data for model validation . This study has demonstrated the value of SPECT imaging over planar , the influence of particle size on regional distribution within the lung , and differences in deposition between the left and right lungs This study was aim ed to evaluate the efficiency of a new mesh‐type nebulizer for the intrapulmonary delivery of ipratropium bromide  in surgical patients under mechanical ventilation . A total of 20 patients were r and omly allocated to receive 0.5 mg ipratropium bromide using either a control ( Pariboy SX , Pari , Co. , Starnberg , Germany , n = 10 ) or test ( NE‐SM1 NEPLUS , KTMED INC . , Seoul , Korea , n = 10 ) nebulizer during general anaesthesia . Ipratropium bromide was nebulized continuously for 20 min . in each group . Plasma concentrations of ipratropium bromide  were obtained from blood sample s at preset intervals . Non‐compartmental analysis of ipratropium bromide was performed to compare the efficiency of pulmonary drug delivery in both nebulizers . Population pharmacokinetic analysis of ipratropium bromide was performed . Additionally , the noise level during the nebulizer operation and the aerosol particle size for each device were measured . The dose‐normalized AUClast was 0.10 min/L for both nebulizers . The pharmacokinetics of nebulized ipratropium bromide can be described best by a one‐compartment model with first‐order absorption . The apparent volume of distribution and metabolic clearance were 1340 L and 6.78 L/min , respectively . Type of nebulizer was a significant covariate for absorption rate constant . The equivalent sound level and median aerosol particle diameter were 35.0 dB and 4.52 μm for the test nebulizer , and 60.2 dB and 3.85 μm for the control nebulizer , respectively . From the st and point of the dose‐normalized AUClast , a new vibrating mesh‐type nebulizer shows similar performance in the intrapulmonary delivery of ipratropium bromide  to that of a jet‐type nebulizer in surgical patients
Background This systematic review aim ed to assess inhaled drug delivery in mechanically ventilated patients or in animal models .
Whole lung and regional deposition and the impact of the ventilator circuit , the artificial airways and the administration technique for aerosol delivery were analyzed .