Dry Powder Inhaler In Mechanical Ventilation And Influence .

W. Pornputtapitak et al.deposits instead of going to the lungs11. On theother hand, ventilated patients are delivered thedrug via the tube. Barriers that involved with thetube, the flow in the tube as well as biofilmformation are concerned12.3. DRUG DELIVERY IN MECHANICALVENTILATION3.1. Ventilator circuit-related factors influencingaerosol delivery during mechanical ventilationDuring patient initiated direct-to-mouthinhalation, the mouth and throat can be a majorsite of drug particle deposition, especially inpatients with poor coordination using pMDIs.The portion that deposits on the tongue or theback of the pharynx may be directly swallowedand absorbed in the gastrointestinal (GI) tract andpotentially enter systemic circulation via the oralroute. In contrast, patients on mechanicalventilation are delivered inhaled drugs throughan endotracheal tube, which is inserted into themouth until just above the first bifurcation;eliminating the potential for deposition in themouth and throat. While this can be advantageousat preventing un-intended oral exposure, drug losscan be observed in the endotracheal tube 13. Smallerdiameter endotracheal tubes offer more air flowresistance, which at higher flow rates can 5. Furthermore, utilizing shorterand/or smaller diameter tubing can improvedelivery yields by decreasing the surface areaavailable for particle impaction. It has also beensuggested that electrostatic charge of anendotracheal tube and circuit could be reduced by“priming” the ventilator line with several doseactuation 13; although a possibly more refinedapproach may be to utilize endotracheal tubeswith low electrostatic charge or to pre-coat theinside of the endotracheal tube prior to placementwith a relatively electrostatic inert and non-toxiccompound.3.1.1. Inspiration patternsThe mechanical ventilator controlsphases of breathing in either mandatory orspontaneous modes. Normally, inspiration patternson a ventilator can be categorized into three kindsof waveforms; sine, ramp (decelerating), andsquare waveform. A sine waveform provides acontinuous increase and decrease of flow rate inthe form of a sine wave. A ramp waveformPharm Sci Asia 2019; 46 (1), 1-11generates the highest inspiration flow rate at thebeginning of the cycle, and then the flow rategradually decreases along the cycle. A squarewaveform provides a constant flow ratethroughout an inspiration cycle14. In addition tothe inspiration cycles, ventilators areprogrammed with different inhalation modessuch as assisted support and full ventilationsupport, which can include pressure regulation tofit the respiratory needs of the patient.In terms of drug delivery, researchscientists showed that inspiration pattern causedstatistically significant differences in nebulizerperformance 15, 16. The square waveform at 30L/min showed better performance on deliveringaerosols through an endotracheal tube comparedto ramp waveform at 60 L/min17. While it isintuitive to hypothesize that waveform wouldaffect pMDI delivery, few studies havethoroughly evaluated these parameters andcurrent studies are inconclusive and may beaffected by other experimental variables 16, 18. Tofurther complicate ventilation, ventilators can betriggered by several events including flowtriggering, pressure triggering, and mandatorybreaths. The combination of these variablescreates additional challenges to consistentlyadminister inhaled drugs to ventilated patients.In addition, flow pattern also controlledby selected mode of operation. lation or pressure support ventilation shouldbe selected. A study of aerosol delivery vianebulizer indicated the importance of selectedmode to the deposition of aerosols. Volumecontrolled ventilation delivered the higheramount of aerosols to the lungs compared topressure support ventilation19.3.1.2. Inhalation volumePatients with respiratory diseases such asCOPD normally have lower inspiratory capacitycompared to healthy people20. Inhalation volumeis a critical parameter that can affect inhaled drugdelivery and is strictly controlled by a mechanicalventilator. During ventilation, tidal volume isdisplayed at the end of exhalation and plays avital role to ensure sufficient ventilation withoutcausing trauma to the lungs. A study reported thatsetting the tidal volume at greater than 500 mL inan adult model improved aerosol drug delivery21.Although a large tidal volume may increaseaerosol deposition efficiency, caution should beused since it also can cause volutrauma if the tidal4

Pharmaceutical Sciences Asiavolume achieves greater than 8-10 mL/kg 22.Moreover, some researchers showed an increasedincidence of acute respiratory distress syndrome(ARDS) with higher tidal volumes; however, thestudies were limited by their heterogeneity andhigh variability in baseline ARDS risk amongpatients23. No definitive recommendations cancurrently be made concerning the mostappropriate tidal volume strategy in patients onmechanical ventilation.3.1.3. Volumetric flow rateThis factor also alters drug deliveryefficiency for inhaled pharmacotherapies. Ingeneral, high flow rates can increase turbulentflow and the inertial impaction of aerosols. Somestudies suggested that a lower inspiration flowrate (e.g. 40 versus 80 L/min) improved aerosoldelivery in both non-ventilated patients andventilated patients24, 25. The volumetric flow rateis also important for aerosol delivery when usingDPIs. For passive DPIs, performance is typicallyflow-rate dependent5. The dispersion of drugpowders depends on the inspiration effort of thepatient and the resistance within the inhaler.Turbulence has an important effect on powderdispersion, resulting in an increased dispersion ofthe dry powder. The effect of the flow rate onDPI, is thus, an important parameter whendelivering the drug-aerosol to ventilated patients;however, to date, there are limited studiesevaluating the effect of flow rate on experimentalDPIs integrated into ventilator circuits26.For nebulizers, aerosol delivery has adirect correlation with the duty cycle (inspiratorytime (TI)/duration of total breathing cycle(TTOT)). Investigators have found that increasingthe duty cycle (TI/ TTOT) can improve lowerrespiratory-tract aerosol delivery and totalaerosol inhaled per each breath 16, 27.Additionally, greater albuterol delivery to thebronchi can be achieved with a TI/Ttot of 0.50 thanof 0.25 when delivered via MDIs. For routineclinical use, a slower inspiratory flow rate waspreferred to excessively long inspiratory times tomaximize aerosol delivery clinicians should ‘goslow with the flow’28.3.1.4. HumidityTraditional ventilator circuits arehumidified and heated although the use of heatand moisture exchangers as a source of humidityhas become more common in the hospital settingdue to their relatively low cost and ease ofreplacement. Humidity has long been a majorchallenge for delivering drugs to the lungs ofventilated patients. It has been estimated that 4050% of drugs can be lost when heated/humidifiedventilator circuits are used 29, 30. As nebulizers addmore humidity to the circuit, this can overwhelmthe heating elements and lead to ‘rain-out’ ofdrugs into a condensate on the circuit tubing wall.This may be due to increasing particle impactionor sedimentation in the ventilator tubing.Increasing humidity may also promotehygroscopic particle growth, which could reducethe delivered fine particle fraction. Studies onpMDIs have also noted increased drug loss inventilator circuits when humidity levels arehigh31. Although the new design spacer such asCombihaler and ACE was applied withpMDIs, the aerosol delivery still decreased inhumidified condition compared to nonhumidified one32.The loss of drug aerosol can be reducedby turning off or bypassing the ventilatorhumidifier during aerosol administration.Bypassing the humidifier for a long time;however, can harm the airway mucosa, whichcould be exacerbated in the case of somenebulizers that require up to 35 minutes tocomplete aerosolization29. De-humidifying theventilator air increases the risk for thick andsticky mucus secretions at the end of theendotracheal tube, but also runs the human riskof forgetting to re-introduce humidity after thedrug administration period.Relative humidity is also known to affectdry powder aerosols. Lower drug deliveryefficiency was achieved in both excessively dryand humid environments depending on thephysicochemical nature (e.g. hygroscopicity) ofthe drug33. For example, drug delivery efficiencycan be decreased because of capillary forcebetween the particles in a humid environment34,35or due to static charges between the particles ina dry environment36. These studies suggest thata balance of humidity in the ventilator circuitmay provide for a more ideal dry powder deliveryenvironment, whereby some humidity may maskrelative surface charge of particles, but excessivehumidity may accelerate particle-particleinteraction of highly hygroscopic drugformulations.5

W. Pornputtapitak et al.3.2. Device-related factors influencing aerosoldelivery during mechanical ventilationDevice placement plays a key role indrug delivery efficiency of inhaled aerosols. Astraditional nebulizers are in ‘on’ or ‘off’ mode forminutes at a time, studies have shown thatplacing the nebulizer farther away from thecircuit Y-connector integrated into the inhalationline leads to increased drug delivery efficiency asit reduces the amount of drug that diffuses intothe exhalation line19, 37. In one study, placing thenebulizer prior to the humidifier increased theamount of drug delivered, suggesting that thisplacement method may help control ‘rain-out’due to better regulation of the circuit humidity37.Another way to minimize drug diffusingto the ventilator line is to intermittently controlthe nebulizer, which is more efficient thancontinuous nebulization 38. Aeroneb Pro andAeroneb Solo, for example, are vibrating meshnebulizers with a specially designed CPAPadaptor which allows for aerosol delivery justbelow the “Y” connector for effectively treatingmechanically ventilated patients (Figure 1). It ismicroprocessor driven and exploits a pressuretransducer to identify changes in airway pressure,detect inspiratory time, and deliver aerosols onlyduring a specified portion of the inspiration.Currently, researchers are exploring the clinicaloutcomes (ventilator-associated events (VAEs),length of stay (LOS) in intensive care unit (ICU)and total days on mechanical ventilation) whenPharm Sci Asia 2019; 46 (1), 1-11using a traditional jet nebulizer versus a newergeneration of vibrating mesh nebulizers duringmechanical ventilation; automated innovationssuch as these look promising to the field ofinhaled therapeutics 39-42. A study showed highefficiency of vibrating mesh nebulizer comparedto jet nebulizer43. Vibrating mesh nebulizers alsoprovided smaller residual volume and relativelyconstant temperature of medication compared toultrasonic devices44. Although a study reportedindependence of drug delivery efficiency fromthe design of vibrating mesh nebulizers,delivered dose variation still found due to thedrug-device compatibility43. Nowadays, drugdevice combinations have been promising in thearea of development that should provide high andconsistent delivery performance45.Delivery of drugs through pMDIs alsosuffers from variability due to different circuitplacement46. In addition to placement, the marketis filled with a myriad of commercially availablein-line actuators and in-line actuator/spacerchambers to help improve drug delivery.Inhalation synchrony is also important for pMDIadministration as a reduction of inhaled mass by35% was reported when actuation was notsynchronized with inspiration29. Furthermore, astudy showed at least 40% higher dose wasadministered when the pMDI was actuated at theonset of inspiration compared to actuation duringexpiration47. Future ventilator actuators that includeautomation may dramatically improve dosingconsistency between different health care providers.Figure 1. Aeroneb Solo, a vibrating mesh nebulizer, in ventilator circuit.6

Pharmaceutical Sciences Asia3.3. Dry powders with DPIs in mechanicalventilationThe variability of drugs delivered to thelungs due to the low efficiency of pMDI andnebulizer liquid formulations beckons thedevelopment of dry aerosol powder technologyfor ventilated patients48. To date, dry powderinhalers have only been explored experimentallyin ventilator circuits, with limited success. Thismight be due to the fact that few devices havebeen specifically designed to be integrated and/orto perform optimally under various ventilatorconditions. In addition, DPIs pose newchallenges such as powder dispersion, humidityeffects (e.g. hygroscopic powders), and doseactuation. A DPI could be easily adapted toventilator circuits, either by using the ventilator’sinspiratory airflow to create an aerosol orutilizing a power source to first generate anaerosol from the DPI and then enter the drugparticles into the ventilator circuit26, 49.In an earlier trial using a commercial DPIin a ventilator circuit, Pulmicort Turbuhaler wasmodified by removing the outer covering of thedevice and putting it in a closed chamber thatconnected to the ventilator circuit48. Theresearchers suggested that dry powder drugdelivery was worthy of further improvement,especially in the intensive care setting, eventhough some drug was lost in the endotrachealtube. The percent of drug lost should be reducedwhen a dry endotracheal tube and nonhumidified system are applied12, 22. An in-linedelivery system was studied with adaptingMonodose inhaler that disconnection of patientsfrom mechanical ventilator did not require duringdry powder delivery50. A novel in-line DPI hasbeen developed to apply with the in-line deliverysystem51. Lately, a novel dry powder inhaler hasbeen designed to fit with ventilator connectionand to be suitable for delivering dry powderaerosols to ventilated patients (Figure 2). Thisinhaler has been proposed based on theunderstanding of the de-agglomeration process ofpowders in the inhaler and the ease of use of theinhaler26. The new inhaler device provided theconvenience of connecting with the ventilatorand endotracheal tubing while maintainingefficient aerosol delivery compared to the directto-mouth Monodose inhaler26, 49.Since breathing can be firmly controlledby ventilator settings, drug formulations andinhaler devices are the primary design metricsthat would affect DPI performance. Advances inparticle engineering compel efforts to exploredrug powder formulations owing to enhanceddrug delivery efficiency during mechanicalventilation. To increase powder deposition in thecentral airways and peripheral areas of the lungs,the size of drug particles should be within 1–5µm, while simultaneously reducing the cohesiveand adhesive forces that negatively affect powderdispersion 52.Figure 2. Direct connection of an inhaler device within the ventilator circuit. Here, the inhaler is placed between the ventilatortubing and the endotracheal tube. Aerosols may be generated using an external energy source (e.g. ultrasound) or by utilizingthe energy supplied by the ventilator.7

W. Pornputtapitak et al.Pulmonary formulations composed ofnanomaterials have been extensively examined.Emerging methods in particle fabrication such asspray drying, wet milling, and others haveallowed the formulation of dry powders withdecreased density, increased surface area, andincreased flowability. Formulation scientistshave also begun to experiment with several antistatic agents that may aid in the dispersionproperties of fine powder aerosols. Tobramycinpodhaler (TOBI ) is a currently approved inhaledtherapeutic that utilizes spray drying technique toform easily dispersed hollow spherical particles.Additionally, another approach is to wet millmicronized drug into NanoClusters 12, 26, 53.NanoClusters are the formulation that combinedthe properties of micronized particles andnanosized particles. The micronized particlesprovide the suitable size for drug deposition,while the agglomerated nanoparticles improvethe flowability of particles traveling along theairways, especially passing through the upperairway. Nanoparticle agglomerates yieldingmicron-sized ‘clusters’ that require very littleairflow to effectively deliver fine aerosolparticles. Despite the approach, identifying aprecision particle fabrication and/or formulationof dry inhaled powders with ideal dispersioncharacteristics would accelerate the process ofinhaler device design and ventilator integration.4. FUTURE DIRECTIONSTo date, pharmaceutical aerosoltechnologies have focused on direct-to-mouthaerosol delivery with far fewer initiatives todeliver aerosols to ventilated patients. Althoughnebulizer technology has advanced, many drugscannot be dissolved in water, which complicatesnebulizer formulations. Additionally, nebulizationtimes can be long. Introducing these wet aerosolsinto the ventilator circuit can lead to poor orinconsistent aerosol delivery to the lungs ofventilated patients. Dry powder aerosolsrepresent an attractive alternative to formulatepoorly water-soluble drugs, even drugs with lowpotency requiring a large delivered dose.Improvements must be made to existing drypowder formulations and devices in order to beused in ventilated patients.Sincedevicecomponentsandformulation are interlinked, new designs requirecareful evaluation when changes are made to anysingle element. For passive DPI design, thedevice has to be designated with reasonablePharm Sci Asia 2019; 46 (1), 1-11resistance since the resistance influences powderdispersion in the device and the resulting aerosolquality. The resistance across the device mustalso be balanced, as increased resistance limitsthe flow rate of air at a given pressure and modernventilators will shut off at high resistance (highcircuit pressure) to protect patients from injury.Most marketed DPIs loaded with micronizeddrug (e.g. Advair , Symbicort , Pulmicort ,Flexhaler ) require high device resistance todeagglomerate and aerosolize the dry powder.This suggests that particle engineering methods(e.g. NanoCluster, spray drying, others) thatcreate new formulations of dry powder drugs toeasily disperse into fine aerosols at low resistanceand/or flow rates will be essential for passiveDPIs integration into ventilator circuits.An alternative to the integration ofpassive DPIs is to create ventilator-specificactive DPIs (ActDPI). ActDPI would have all thebenefits of passive DPIs, but would have severaladvantages. First, the limitation of internaldevice resistance which is essential for drypowder dispersion, but it is limited by ventilatorsettings, could be eliminated entirely by utilizingan external high-pressure power source to shearthe powder through the device similar to pMDIs.Second, as high shear can be created using anexternal power source, a single high shear ActDPIcould be designed to deliver multipleformulations of drugs. This could lead to a (more)universal ActDPI that could easily be managed byinhalation therapy caregivers through eliminatingthe need for independent DPI devices andventilation integration adapters for each uniquedrug/drug formulation. Third, similar to newelectronically controlled vibrating meshtechnologies, ventilator-specific ActDPIs couldeasily be automated by triggering off of ventilatorair flow/pressure or could be assimilated into theventilator software itself, triggering at a specificseries of inhalation events and eliminating thehuman error associated with ‘timing’ inhalation.Automation has yet to be introduced intostandard pMDI delivery and could also increasedelivery of established inhaled pMDItherapeutics.Additionally, the internal geometry ofthe device including the shape and dimensions ofthe air channels should be investigated todeagglomerate drug powders while minimizingaerosol velocity to prevent impaction duringentrainment into the ventilator circuit. Effectivedesign of the device geometry can optimizefluidization and deagglomeration of powders8

Pharmaceutical Sciences Asiaafter they come out of the capsule, blister, orchamber and can help powder travel through theairstream with minimal powder loss in theconnection. Decreasing the contact surfacebetween the powder and surface of the devicemay reduce the static particle-particle andparticle-device interactions, leading to increaseddelivery efficiency. Moreover, the shape of theair channels (e.g. spirals, angles) can alter thedispersion of powder independent of deviceresistance. In sum, devices should be designedspecifically for ven

Individual pre-metered doses sealed in the device moisture in the Reproducibility of the formulation compared to that of multi-dose reservoir. More effective than -dose reservoir devices as they ensure dose consistency and avoid the effects of powder reservoir. dose reservoir Isolation of each