PARTIAL LIQUID VENTILATION

-DR. PRAPULLA CHANDRA

• INTRODUCTION• HISTORY• PERFLUOROCARBONS• PHYSICAL PROPERTIES• PHARMACOKINETICS• TYPES & TECHNIQUE• PHYSIOLOGY• INDICATIONS• ADVERSE EFFECTS• CLINICAL OUTCOME• SUMMARY &RECOMMENDATIONS

INTRODUCTION

• Liquid ventilation is a technique of mechanical ventilation in which the lungs are insufflated with an oxygenated perfluorochemical liquid rather than an oxygen containing gas mixture.

HISTORY• The use of fluids such as saline, silicone oils and perfluorocarbons

(PFC) for breathing has been under investigation for many decades.• In 1963, Clark & Gollan first demonstrated that spontaneously

breathing mice could survive when submerged in PFC liquid.• In 1970, Moskowitz, presented a demand regulated ventilator that used

PFC instead of gas.• 1989 marked the first trial of liquid ventilation in preterm neonates.

• In 1991, Fuhrman et al. & Lachman et al. presented a new method of using PFC at functional residual capacity (FRC) during conventional mechanical ventilation.

• In 1993, Richmond et al., also showed improvements in gas exchange and compliance with PFC liquids in an acute lung injury model using a simple PFC lavage technique.

PERFLUOROCARBONS

• The ideal fluid for liquid ventilation (LV) should be non-toxic, has a low surface tension, is capable of dissolving large amounts of O2 & CO2, has minimal systemic absorption and is chemically stable.

PHYSICAL PROPERTIES

• PFCs are derived from common organic compounds, such as benzene, by replacing all the carbon bound hydrogen atoms with fluorine atoms.

• PERFLUBRON (perfluorooctyl bromide) also called Liquivent – only PFC accepted by FDA for use in human LV trials.

• Perflubron contains one bromide atom, making it radiopaque.

• PFC fluids are clear, colourless, odourless and inert.• Stable, insoluble in water, can be stored indefinitely at room

temperature, can be autoclaved.• Oxygen, carbon dioxide and other gases are highly soluble in

PFCs.• They can dissolve 15 times the amount of oxygen per given

volume as plasma.• The O2 carrying capacity of PFCs can be more than 3 times

that of blood (35-70ml/dl at 250c) and that of CO2 is apprx 4times greater than that for O2(122-255 ml/dl)

• The PFC fluids have low surface tension (14-18dyne/cm) and high density (1.7-1.9 mg/ml) which allows PFC to serve as surfactant substitute.

• As PFC liquids are more dense and viscous than gas, assisted mechanical ventilation is needed to support pulmonary gas exchange when the lung is totally or partially filled with medium.

• The ideal PFC for liquid ventilation should have :-1. A high solubility for O2 & CO2 to maintain gas exchange.2. A greater density than body fluids so that it descends to the

dependent parts of the lungs and re-opens the areas of atelectasis,

3. A low surface tension to work like surfactant and improve lung compliance,

4. Property of being inert and not metabolized and eliminated intact by evaporation during exhalation or transportation through the skin.

5. Sufficient volatility to allow elimination in an acceptable time.

PHARMACOKINETICS• The main route of PFC elimination is through the lungs via

volatilization, and to a smaller extent through skin by transportation.

• Very small amounts of PFCs diffuse into pulmonary capillary blood.

• The rate of uptake in the blood depends upon the PFC vapour pressure, permeability coefficients of blood vessels, solubility of particular PFC used and the degree of ventilation/perfusion matching.

• Perflubron blood concentrations are low, and persists for atleast 8 days following administration of the last dose.

• It may persist in extrapulmonary tissues for years following LV.

TYPES

• Two types – -Total / Tidal liquid ventilation (TLV) -Partial liquid ventilation (PLV) -while TLV remains as an experimental technique, PLV is under clinical trials for its effectiveness.

TOTAL LIQUID VENTILATION• In this, the entire lung is filled with an oxygenated PFC liquid,

and a liquid tidal volume of PFC is actively pumped into and out of lungs.

• A specialized apparatus is required to deliver and remove the relatively dense, viscous PFC and to extracorporeally oxygenate and remove CO2 from the liquid.

• TLV is initiated by insufflating the desired volume of pre-oxygenated PFC liquid ( FRC+TV) into the lungs using a gravity assisted device.

• Optimum ventilation and oxygenation depend upon adequate minute ventilation coupled with sufficient time for diffusion of respiratory gases to and from the PFC liquid.

• During maintenance phase, a low respiratory rate (4-6 breaths/min) with an inspiratory-expiratory (I:E) ratio of 1:2 to 1:3.

• Tidal volumes and positive end expiratory pressures(PEEP) are adjusted same as in gas ventilation.

WEANING FROM TLV• The return to gas ventilation is done by a transition through a

period of partial liquid ventilation.• PFC liquid is removed at the end of expiratory phase upto

FRC of lung, gas ventilation is begun and PFC liquid is not replaced or augmented, as it is evaporated.

• Elimination from lung generally requires 1-7days.

PARTIAL LIQUID VENTILATION• In PLV, the lungs are slowly filled with a volume of PFC

equivalent to FRC (functional residual capacity)• The PFC within the lungs is oxygenated and CO2 is removed

by means of gas breaths by conventional ventilation.• PLV is initiated by insufflating PFC (apprx 20-30ml/kg) into

the lungs using an intravenous syringe pump or by slowly pushing the fluid over 15 min to 1hr period.

• The functional residual capacity is reached when a meniscus of PFC is present within the ET tube at end expiration.

Illustration of PLV in a preterm infant. 1.

Thomas H. Shaffer et al. Pediatrics in Review 1999;20:e134-e142

©1999 by American Academy of Pediatrics

• As the fluid evaporates out of lungs, it is intermittently and gradually replaced with additional PFC at 2-8 ml/kg to maintain a total liquid volume of FRC.

WEANING :• PLV is discontinued by ceasing to replace the PFC that is lost

through evaporation.• Most of the intrapulmonary liquid evaporates in 1-7days,

allowing a transition to gas ventilation.

Serial computerized tomography images of individual rabbits during partial liquid ventilation with perflubron (left) or perfluorodecalin (right) 15 min (top) and 4 h (bottom) after

perfluorochemical (PFC) instillation.

Thomas F. Miller et al. J Appl Physiol 2001;90:839-849

©2001 by American Physiological Society

PHYSIOLOGY• Liquid ventilation has many theoretical advantages over

conventional gas ventilation, including better gas exchange and functional lung recovery by different mechanisms.

-Alveolar recruitment -Better V/Q matching -Lavage -Anti inflammatory effects -Temperature regulation

ALVEOLAR RECRUITMENT

• Filling of alveoli with liquid eliminates air-liquid interfaces and greatly reduces surface tension forces.

• Collapsed alveoli may also be recruited and stabilized by hydraulic forces.

• Alveolar expansion and stability is facilitated at much lower airway pressures, reducing risk of barotrauma.

• As more alveoli are filled with PFC, effective diffusing surface of the lung increases improvement in arterial oxygenation and compliance.

V/Q MATCHING

• PFC fluids are denser than water, hence deposit in dependent regions of the lungs.

• They improve V/Q matching by facilitating gas exchange in lung units that were previously perfused but not ventilated.

• The weight of PFCs in dependent zones also redistribute pulmonary blood flow to nondependent zones that were previously ventilated but not perfused.

LAVAGE• LV facilitates the removal of exudative material from the

lung but doesnot interfere with production or function of surfactant.

• During TLV, the cyclical removal and replacement of fluid may lavage the exudate while maintaining gas exchange.

• During PLV, exudative material in peripheral airways and alveoli is lavaged into central airways and removed by suctioning.

ANTI-INFLAMMATORY EFFECTS• In the presence of PFCs, there is attenuation of neutrophil

adhesion, activation and migration.• There is removal of inflammatory cells and mediators from

alveolar spaces.• PFCs provide a mechanical barrier to intra alveolar exudation

and leukocyte translocation leading to reducing intensity of inflammation and second lung injury.

TEMPERATURE REGULATION

• PFCs have a higher heat capacity than conventional gas mixtures, and acts as a internal heat exchanger.

• They can be used to warm the lungs and increase core body temperature.

INDICATIONSNEONATAL : -Respiratory distress syndrome -Meconium aspiration -Persistant pulmonary hypertension of newborn -Congenital diaphragmatic hernia -Temperature control -Lung protection during cardiopulmonary bypass

RESPIRATORY DISTRESS SYNDROME• Exogenous surfactant therapy for hyaline membrane disease

is limited by unequal delivery and distribution within the injured or premature lung.

• LV may facilitate more uniform endogenous surfactant distribution and may be of use in surfactant unresponsive pts.

• It can reduce surface tension, thereby reducing inflation pressure and barotrauma and may stimulate surfactant synthesis.

• MECONIUM ASPIRATION: -Lavage with TLV and PLV may remove meconium from airways more effectively than conventional measures.

• PERSISTANT PULMONARY HYPERTENSION : -LV provides uniform delivery of oxygen to distal regions of the lungs, improving V/Q matching and facilitating pulmonary vasodilation.

• TEMPERATURE CONTROL : -The heat exchange may help to maintain normothermia in premature infants.

ADULT INDICATIONS :• -Acute respiratory distress syndrome• -Pneumonia• -Cancer therapy• -Drug delivery• -Donor lung preservation

• ARDS: -LV can improve gas exchange in ARDS by recruiting the atelectatic, consolidated, dependent regions of the lungs. -Pulmonary blood flow is also redistributed to less severely injured regions of the lungs, thus improving V/Q matching.

• PNEUMONIA : -Lavage with LV removes infectious and inflammatory debris from the airways.

• CANCER THERAPY : -LV may augment antineoplastic effects of RT &CT by inducing localized hyperthermia or hyperoxia. -Concentrated chemotherapeutic agents can also be delivered through PFC.

ADVERSE EFFECTS• The toxicity of PFCs is not fully known. Other complications are - -Mucous plug formation -Pneumothorax -Bleeding complications -Hypoxia -Hypotension -Bradycardia• But it is still unclear whether these adverse effects were due to PLV

or the underlying disease.

• LV can complicate the supportive and general care of the patients. -PFC is almost twice as dense as saline, hence patient weights should not be the sole index of fluid balance in ICU care. -PFCs are radio-opaque and will eliminate much of the diagnostic utility of chest radiography. -No audible breath sounds are heard during TLV. -The impact of LV upon the development of nosocomial pneumonia is uncertain. -Use of liquid ventilation is unpleasant for the patient, therefore, deep sedation and paralysis are necessary.

CLINICAL OUTCOMES

• The study included 13 premature infants with severe respiratory distress syndrome in whom conventional treatment had failed.

• The outcome of this study is, 8 out of the 13 infants survived to a corrected gestational age of 36 weeks.

Conclusions of the study:• Partial Liquid Ventilation leads to clinical

improvement and survival in some infants with severe respiratory distress syndrome who are not predicted to survive.

• This is a 2013 meta-analysis review of two randomized controlled trials that compared PLV with CMV in the treatment of acute lung injury with or without ARDS.

• The two RCTs are : -Kacmarck trial (2006) – 311 patients -Hirschl trial (2002) -90 patients

• Out of 401 participants, 170 – high dose PLV (mean dose of 20 ml/kg) 99 – low dose PLV (dose of 10 ml/kg) 132 – conventional mechanical ventilation

• The conclusion of this study is, -No evidence of benefit for the use of Partial Liquid Ventilation and some evidence suggests PLV may be associated with increased risk of adverse effects.

SUMMARY & RECOMMENDATIONS• LV is a technique of mechanical ventilation in which the lungs are

insufflated with oxygenated perfluorocarbon fluid rather than gas.• PFCs are stable and nontoxic with minimal systemic absorption. They

dissolve large amounts of O2 & CO2 ; thus ideal for gas exchange.• Two techniques of PFC based liquid ventilation : total & partial liquid

ventilation. • Theoretical advantages of LV over conventional MV include

recruitment and stabilization of alveoli, improvement in V/Q matching, removal of exudative material from the lung, anti-inflammatory effects and temperature regulation.

• In theory, LV may be of benefit for numerous neonatal and adult diseases. But, clinical trials have shown little improvement in important clinical outcomes.

• As a result, liquid ventilation cannot be recommended in routine clinical care.

• Adverse effects include mucous plug formation, pneumothorax, bleeding disorders, although it is unclear whether these are due to LV or the underlying disease.