1. Aerosol delivery during Mechanical Ventilation
11th Congress of APSR
Aerosol delivery during Mechanical Ventilation
Dr. Natalie Leung

2. In November 2006, there was a conference hold in Kyoto of Japan……

3. In this conference…
I ate a lot

4. I played a lot…

5. I learn some things and I want to share with you today
Aerosol delivery during Mechanical Ventilation
I learn some things and I want to share with you today

6. Introduction
Inhaled therapy has been employed for years in ambulatory patients with respiratory disorders
Inhaled drug therapy is also employed in ventilated patient in ICU

7. Drugs can be delivered by aerosol
Bronchodilators
Steroids
Mucokinetics
Anti-microbials
E.g. amikacin
Vasodilators
E.g. pulmonary HT
Surfactants

8. What are the advantages of inhaled therapy?
Direct delivery of drug to site of action
Rapid onset of action
Lower dose (than systemic administration) to produce desired effects
Minimizes systemic adverse effects

9. Delivery methods Nebulizer Metered dose inhaler (MDI)
Dry powder inhaler

10. Purpose of this presentation
Understand the factors that affect aerosol therapy in mechanical ventilated patients
Know more about the aerosol devices
MDIs and nebulizers
Common inhalation therapy in ICU

11. Factors influencing aerosol delivery in mechanical ventilation

12. Factors influencing aerosol delivery
Ventilator/ Circuit-related
Ventilator setting
Characteristics of the ventilator circuit and endotracheal tube
Humidity of the inspired air
Drug/ Device-related
Physical and chemical properties of the medications
Characteristics of aerosol-generating device
Position of the aerosol-generating device in the circuit
Patient-related

13. Ventilator-related Tidal volume Ventilation mode Respiratory rate
TV must be larger than the vol of the ventilator tubing and ETT
Average >500ml
Longer Tin allow a larger proportion of the nebulizer –generated aerosol to the inhaled with each breath

14. Circuit-related
Compare the delivery of aerosolized radiotracer to lower respiratory tracts
Non-intubated subjects
11.9%
Intubated subjects
2.9%
The radiotracer was deposited on
Endotracheal tube (ETT)
Ventilator circuit
Why there are such big discrepancy?
Aerosol delivery in intubated, mechanically ventilated patients
CCM 1985; 13(2):81-84

15. Circuit-related Endotracheal tube size
Smaller the size of ETT, greater the particle impaction (esp in pediatric ETT)
In adult ETT, not much difference between size 7-9

16. Circuit-related Heating and Humidity of inhaled gas
Greater aerosol deposition in the ventilator circuit and ETT with heated and humidified gas
Both diminishes pulmonary deposition of aerosols ~40%

17. Circuit-related Effect of humidity on aerosol delivery
The efficiency of aerosol delivery to the lower respiratory tract
Humidification reduced aerosol delivery by approximately 40%. *
p ** p *** p
Inhalaed bronchodilator therapy in mechanically ventilated patients Am J Respir Crit Care Med 1997; 156: 3-10

18. Circuit-related Under humidified condition
Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ.
Reconciling in vitro and in vivo measurements of aerosol delivery from a metered- dose inhaler during mechanical ventilation and defining efficiency enhancing factors. Am J Respir Crit Care Med 1999;159(1): 63–68.

19. Circuit-related Under dry condition
Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ.
Reconciling in vitro and in vivo measurements of aerosol delivery from a metered- dose inhaler during mechanical ventilation and defining efficiency enhancing factors. Am J Respir Crit Care Med 1999;159(1): 63–68.

20. Device-related: MDI
Pressurized canister
Metering valve

21. Device-related: MDI Device-related: MDI
After volatilization of the propellant, the final volume emitted from the MDI is 15 to 20 ml per dose
It can be actuated as frequent as every 15 seconds

22. Device-related: MDI
Commercially available MDIs are designed for ambulatory patients
In a ventilator circuit, the canister must be removed from the actuator

23. Device-related: MDI
MDI generate aerosol with mass median aero-dynamic diameter of 1-5µm
Larger aerosol particles
More likely to be trapped in the ventilator circuit and ETT
Aerosols with mass median aerodynamic diameter <2 µm are more efficient during MV

24. Device-related: MDI MDI Type of spacer or adapter
Position of spacer in circuit
Timing of MDI actuation
Synchronizing MDI actuation with insp increase 30% aerosol delivery

25. Device-related: Nebulizer
Jet and ultrasonic nebulizers
Connected in the inspiratory limb of the ventilator circuit or at the patient Y-piece

26. Device-related: Nebulizer
Type of nebulizer
Fill volume
Gas flow
Duration of nebulization
Position in the circuit
Proximal to humidifer: improve drug delivery
Placing it at a distance from the ETT offers better efficiency than placing it between the patientY-piece and ETT (as the ventilator circuit serves as a spacer for aerosol)

27. Drug-related
Dose
Formulation
Duration of action

28. Patient-related Severity of airway obstruction
Presence of dynamic hyperinflation
Patient-ventilator synchrony

29. Choice of aerosol-generating devices in mechanical ventilation

30. MDI vs Nebulizer
Both MDI and nebulizers are used to deliver inhaled therapies to mechanically ventilated patients
Traditionally, nebulizers were employed for inhalation therapy during MV
However, more centers have switched to MDIs for routine bronchodilator therapy

31. MDI vs Nebulizer
Many studies suggested that MDI with spacer is a reliable route in delivering bronchodilator
In vitro evaluation of aerosol bronchodilator delivery during mechanical ventilation: PC vs VC ventilation Intensive Care Med 2003; 29:1145

32. MDI vs Nebulizer
Compare the systemic bioavailabilty of albuterol administrated via MDI with right angle elbow adapter, MDI with chamber or jet nebulizer
Urine was collected
for 6 hours after drug administration and measured for amount of
albuterol and its sulfate conjugate. The efficiency of the delivery
device was determined by the percentage of drug excreted. The
drug-delivery efficiency of the 3 systems differed. The MDI with
elbow adapter had the lowest efficiency, the jet nebulizer was
intermediate, and the MDI with chamber spacer had the highest
efficiency.
Serum albuterol levels in mechanically ventilated patients and healthy subjects after metered-dose inhaler administration AJRCCM 1996; 154: 1658

33. MDI vs Nebulizer
Deposition of aerosol varied from 2.2 to 15.3% with nebulizers and from 3.2 to 10.8% with MDIs
Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients: a study comparing four different actuator devices. Chest 1995; 105:

34. Problems about nebulizers
Contamination and VAP
Use of aerosol was one of the independent factor associated with VAP
Need to be cleaned and disinfected to minimize the risk
Patient transport from intensive care increases the risk of developing ventilator-associated pneumonia Koller et al, Chest 1997: 112; 765

35. Problems about nebulizers
Difficulty triggering
In patient on PS mode, a –ve airway pressure must be generated before the ventilator deliver a breath
A continuous-flow nebulizer between the patient and the sensor in the ventilator makes it more difficult for the patient to generate the –ve pressure
May lead to under-ventilation of the patients
Continuous in-line nebulizers complicate pressure support ventilation Beaty et al, Chest 1989; 96: 1360

36. Problems about nebulizers
Damage to expiratory transducer
In some ventilator brand only
Variable rate and particle size (depends on the brand)
Operational efficiency of nebulizer changes with the pressure of the driving gas and with different fill volumes

37. Problems about nebulizers
FiO2 change
Increase tidal volume and/ or airway pressure
Cost
Time consuming (prepare the drug, disinfection…)
Purchasing the aerosol generating device

38. Advantages of MDIs Decreased cost Reliability of dosing
Ease of administration
Less personnel time
Freedom from contamination
The ventilator circuit need not be disconnected
Reduce VAP

39. More about MDIs in mechanical ventilated patients
Use of spacer
Timing of actuation

40. MDI-Spacer Allow MDI aerosol to have an opportunity to slow down
Propellant evaporation in the expanding flume decreases the size of the aerosol particles
The aerosol emerging from the distal end of the ETT has a mass median aerodynamic diameter of ~ 2µm
Decrease the drug loss

41. MDI-Spacer Use of spacer significant improved aerosol delivery
With the use of spacer
Increase 4-6 fold aerosol drug delivery
Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients: a study comparing four different actuator devices. Chest 1994; 105:

42. MDI-Spacer
Various types of spacer
Non-collapsible spacer chamber

43. MDI-Spacer
Collapsible spacer chamber

44. MDI-Spacer
In general
An MDI with chamber spacer connected to the circuit at ~ 15cm from the ETT
It provides efficient aerosol delivery to MV patients
Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients R Dhand et al, AJRCCM 1996; 154: 388

45. Synchronize with inspiratory airflow
The actuation of an MDI must be precisely synchronized with the onset of inspiratory airflow from the ventilator
Failure to syndronize actuations with inspiration resulted in significant reduction in inhaled mass (35% vs 72%)
Albuterol delivery in a model of mechanical ventilation. Comparison of metered-dose inhaler and nebulizer efficiency AJRCCM 1995; 152: 1391

46. Inhalation therapy with metered-dose inhalers and dry powder inhalers in mechanically ventilated patients. Respir Care 2005; 50:1331– 1334

47. Options of inhaled drug delivery during NIPPV

48. Remove patient from ventilator and administer drug by nebulizer or MDI
Administer nebulizer therapy inline with NIPPV
Administer MDI therapy inline with NIPPV

50. A 42-year-old intravenous drug user was transferred to the ward for noninvasive respiratory support after discharge from the intensive care unit, where she had been treated for fungal pneumonia and septicemia
A 42-year-old intravenous drug user was transferred to the ward for noninvasive respiratory support after discharge from the intensive care unit, where she had been treated for fungal pneumonia and septicemia. She had alcoholic cirrhosis, chronic active hepatitis B, and hepatitis C. She had a test negative for the human immunodeficiency virus. She received oxygen and nebulized albuterol (salbutamol) and ipratropium bromide through a face mask that was attached to a noninvasive bilevel positive-airway-pressure (BiPAP) ventilator. She was recovering well when her right pupil became fixed and dilated. Examination of the cranial nerves showed no other abnormalities. A computed tomographic scan of her head, performed to search for an intracranial cause of partial palsy of the right third cranial nerve, was normal. The BiPAP face mask was found to fit imperfectly and leak slightly to the right. The anisocoria resolved within 24 hours after the patient stopped receiving ipratropium. If the conjunctiva is exposed to ipratropium (an anticholinergic agent) by means of metered-dose inhalers or nebulizers, mydriasis as well as acute glaucoma may occur.
Iosson N. N Engl J Med 2006;354:e8

51. Inhalation therapy in ICU
Bronchodilator
Antibiotic

52. Bronchodilators Common indications Common bronchodilators Asthma COPD
Acute bronchospasm or wheezing
Difficulty in weaning
Elevated airway resistance
Common bronchodilators
B2 agonist
Anti-cholinergic bronchodilators
Combination of both
Most commonly used in MV patients

53. Efficiency In a study 0.3-97.5% for MDIs 0-42% for nebulizers
There are big differences because:
Different technique/ circuit
Different type of spacer device
The severity of lung disease of the study population
Inhaled bronchodilator therapy in mechanically ventilated patients
AJRCCM 1997; 156:3-10

54. Bronchodilator dosing
Based on the finding that aerosol deposition is lower in MV patients than in non-intubated patients
higher dose of BD were recommended
What is the precise dosing regimen?

55. Bronchodilator dosing
determined the response to increasing doses of albuterol administered by a MDI and cylindrical spacer to 12 mechanically ventilated patients with chronic obstructive pulmonary disease (COPD
). Four, eight, and 16 puffs of albuterol were given at 15-min intervals. Rapid airway occlusion were performed before and at 5-min intervals after albuterol for 80 min. Respiratory mechanics were also measured for 60 min in another group of seven patients with COPD who received four puffs of albuterol. Significant decrease in airways resistance occurred after administration of albuterol (p < 0.001). The decrease in airway resistance with four puffs of albuterol was comparable to that observed with cumulative doses of 12 puffs (p = 0.12) and 28 puffs (p = 0.25). Heart rate increased significantly (p < 0.01) after a cumulative dose of 28 puffs. The decrease in airway resistance was sustained for 60 min in the group that received only four puffs of albuterol (p < 0.003). In conclusion, four puffs of albuterol given by a MDI and spacer provided the best combination of bronchodilator effect and safety in stable mechanically ventilated patients with COPD.
Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients AJRCCM 1996; 154:

56. Bronchodilator dosing
In general, significant BD effects occur after administration of
4 puffs albuterol with a MDI+spacer
2.5mg of albuterol with a standard nebulizer
Potential side effects were increased if administrated higher doses

57. Bronchodilator dosing
In certain condition, higher dose of BD may be needed
Severe airway obstruction
Technique of administration is not optimal
E.g. not using spacer
Case dependent

58. Bronchodilator:Duration of effect
Duration of action (e.g. Ventolin)
Ambulatory patients: 4-6hrs
Mechanical ventilated: 2-4hrs vs 4-6hrs
Ventilated patients need more frequent administration of BD (short-acting)
E.g. every 3-4 hrs
The duration of BD response in stable MV patients with COPD appears to be shorter

59. Bronchodilators: Use of heliox
Heliox: Helium-oxygen mixtures
Lower density
Facilitate ventilation in MV patients with asthma due to a reduction in airway resistance
Improve drug delivery from a MDI
Drug delivery from a MDI was 50% higher with a helium-oxygen 80/20 mixture than the oxygen

60. Inhaled antibiotics Inhalation of aerosolized antibiotics However…
Allow direct delivery of antibiotics to the lung
Inhaled tobramycin is now routinely employed in patients in cystic fibrosis
However…
The efficacy of inhaled antibiotic therapy in MV patients is less well defined and controverial

61. Inhaled antibiotics In 1975, Feely and colleagues found that…
Increased mortality after administration of inhaled polymyxin to patients admitted to ICU
Increase incidence of polymyxin-resistant organisms
Aerosol polymyxin and pneumonia in seriously ill patients NEJM 1975; 293:

62. Inhaled antibiotics More recently, some studies found that…
In patients with pneumonia due to MDR G-ve bacteria, the combination of aerosolized colistin with IV antibiotics had beneficial effects without leading to emergence of resistant organisms
1. This report describes three patients with nosocomial pneumonia or tracheobronchitis due to multiresistant strains of P. aeruginosa for whom aerosolized colistin proved beneficial as supplemental therapy. Aerosolized colistin merits further consideration as a therapeutic intervention for patients with pulmonary infections due to MDR P. aeruginosa.
Although seven of eight patients who received nebulized colistin showed clinical improvement, some patients also received other active antibiotics. Microbiological eradication was demonstrated in only four of the eight patients. Serum levels of colistin were not measured
Treatment of Nosocomial Pneumonia and Tracheobronchitis Caused by Multidrug-Resistant Pseudomonas aeruginosa with Aerosolized Colistin AJRCCM 2000; 162: 328
Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis Critical Care 2005; 9: 53-59

63. Inhaled antibiotics
Reduce microbial biofilm formation on the inner wall of the endotracheal tube
Reduce bacterial seeding of the lung parenchyma
Eradication of endotracheal tube biofilm by nebulised gentamicin ICM 2002; 28: 426

64. Inhaled antibiotics However, the above studies were small studies
In the absence of convincing clinical data, the use of aerosolized antibiotics at the present time should be limited to
Adjunction therapy for patients with MDR organisms
Patients with severe pneumonia not responding to conventional therapy
Patients developed tracheo-bronchitis

65. Conclusion
Aerosol therapy is common in mechanical ventilated patients, however many factors can affect the efficiency of drug delivery
MDIs with spacer are more efficient and convenient to use than nebulizers in MV patients
Proper technique of administration is important
Numerous medications can be administrated via inhalation route

66. References
Aerosol delivery in intubated, mechanically ventilated patients CCM 1985; 13(2):81-84
Inhalaed bronchodilator therapy in mechanically ventilated patients Am J Respir Crit Care Med 1997; 156: 3-10
Reconciling in vitro and in vivo measurements of aerosol delivery from a metered- dose inhaler during mechanical ventilation and defining efficiency enhancing factors. Am J Respir Crit Care Med 1999;159(1): 63–68.
In vitro evaluation of aerosol bronchodilator delivery during mechanical ventilation: PC vs VC ventilation Intensive Care Med 2003; 29:1145
Serum albuterol levels in mechanically ventilated patients and healthy subjects after metered-dose inhaler administration AJRCCM 1996; 154: 1658
Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients: a study comparing four different actuator devices. Chest 1995; 105:
Patient transport from intensive care increases the risk of developing ventilator-associated pneumonia Koller et al, Chest 1997: 112; 765

67. Continuous in-line nebulizers complicate pressure support ventilation Beaty et al, Chest 1989; 96: 1360
Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients R Dhand et al, AJRCCM 1996; 154: 388
Albuterol delivery in a model of mechanical ventilation. Comparison of metered-dose inhaler and nebulizer efficiency AJRCCM 1995; 152: 1391
Aerosol polymyxin and pneumonia in seriously ill patients NEJM 1975; 293:
Treatment of Nosocomial Pneumonia and Tracheobronchitis Caused by Multidrug-Resistant Pseudomonas aeruginosa with Aerosolized Colistin AJRCCM 2000; 162: 328
Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis Critical Care 2005; 9: 53-59
Eradication of endotracheal tube biofilm by nebulised gentamicin ICM 2002; 28: 426

69. The End
Thank you

70. Efficacy In general Use of spacer with MDIs improves the efficacy
MDI actuation is synchronized with the onset of inspiration