1 Klinik für Anästhesiologie und Intensivmedizin, Charité-Campus Virchow-Klinikum, Med. Fakultät der Humboldt Universität zu Berlin, Berlin, Germany. 2 Department of Anaesthesia, Critical Care and Pain Medicine, Western General Hospital,Crewe Road, Edinburgh EH4 2XU, Scotland |
Corresponding author. E-mail: Keith.Kelly@ed.ac.uk
Keywords: complications, acute respiratory distress syndrome; pharmacology, perfluorocarbons; ventilation, liquid
For 350 million years, fish have breathed liquid through gills. Mammals evolved lungs to breathe air. Rarely, circumstances can occur when a mammal needs to turn back the clock to breathe through a special liquid medium. This is particularly true if surface tension at the airliquid interface of the lung is increased, as in acute lung injury. In this condition, surface tension increases because the pulmonary surfactant system is damaged, causing alveolar collapse, atelectasis, increased right-to-left shunt and hypoxaemia.69 The aims of treatment are: (i) to offset increased forces causing lung collapse by applying mechanical ventilation with PEEP; (ii) to decrease alveolar surface tension with exogenous surfactant; (iii) to eliminate the airliquid interface by filling the lung with a fluid in which both oxygen and carbon dioxide are highly soluble to serve as a respiratory medium.
This third concept, liquid ventilation, recalls the early work of von Neergaard, who showed that the pressure necessary to expand a lung filled with air is almost three times that required to distend a lung filled with liquid.68
History of breathing a liquid medium
After the First World War, basic research in the treatment of poison gas inhalation was carried out using saline solutions applied to the lungs of dogs.70 It was Kylstra and colleagues in the 1960s who first showed that mammals could breathe a liquid medium, starting a resurgence of systematic research in this topic.40 At that time, breathing a liquid medium was studied to increase the escape depth from a submerged submarine. These investigators described the immersion of mice in physiological salt solutions. To allow sufficient oxygen to be dissolved in solution, the animals were subjected to increased pressures, in some cases up to 160 atm, which is the pressure 1 mile below the surface of the sea. However, the work of breathing was very great and the animals died within minutes of respiratory acidosis.
Thus, liquid breathing was described but to be practicable, a medium that could dissolve large amounts of the respiratory gases at atmospheric pressure was needed. Relatively few agents have these properties essentially only silicone oils and perfluorocarbons (PFCs). Clark and Gollan7 completely immersed small mammals in silicone oils and PFCs. Silicone oils proved to be toxic, and only PFCs remained for possible use.6 62
PFCs as a respiratory medium
PFCs were synthesized during the development of the atomic bomb (the Manhattan Project) where they were given the codename Joes stuff.6 They were synthesized during the search for substances that resisted attack by reactive uranium compounds, particularly uranium hexafluoride.47 The PFCs are organic compounds in which all hydrogen atoms have been replaced by halogens, usually fluoride. There are a number of methods for synthesis, such as electrochemical fluorination, heating of organic compounds with cobalt trifluoride, or careful direct fluorination with gaseous fluoride.61 Non-medical uses of PFC include in the cosmetic industry for their water retention properties, as cooling agents and as insulators. In medical applications, besides use as a respiratory medium, PFCs are being evaluated as contrast agents for computerized tomography and magnetic resonance imaging, as sensitizing agents during radiotherapy and as possible i.v. oxygen-carrying agents.62 48 PFCs are stable, inert compounds; they do not react with living tissues because of their carbonfluoride bonds and the electron-rich fluorine substituents protect the underlying carbon skeleton. PFCs also have low intermolecular forces, so the surface tension of these liquids is remarkably low.47 Most PFCs have a surface tension of 1218 dyne cm1.62 Although nearly twice as dense as water, most PFCs have a similar kinematic viscosity to water.
PFCs are immiscible with both hydrophobic and aqueous solutions. Of great interest is that at atmospheric pressure and body temperature, PFCs dissolve large amounts of gases, in particular oxygen and carbon dioxide. Generally, gas solubility in PFCs decreases in the order carbon dioxide >> oxygen > carbon monoxide > nitrogen. Linear PFCs such as Perflubron dissolve more oxygen than cyclic molecules such as Perfluorodecalin48 (see Fig. 2). However, oxygen solubility is inversely proportional to the molecular weight of the PFC and directly related to the number of fluorine atoms present.48 Of course, the solution of oxygen in PFCs is an entirely passive process, unlike the binding and release of oxygen to haemoglobin in the blood. Physicochemical properties of selected PFCs are given in Table 1.
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Clark and Gollan7 reported total immersion of small mammals in PFCs. Use of this novel concept clinically for liquid ventilation required a practical method, which was achieved by instilling PFCs into the respiratory tract.
The first liquid ventilation with PFCs in animals was done from a chamber above the animal (under the force of gravity), then draining the liquid into a chamber below the animal.18 29 39 62 71 In another method, liquid ventilation was performed with an extracorporeal circuit.25 55 These methods, when the subject is administered a liquid tidal volume, are termed total liquid ventilation. However, the technique is cumbersome and needs complex equipment (Fig. 1). In particular, the extracorporeal circuit had problems in development, in particular malfunction of the expiratory valve.
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Liquid ventilation in normal lungs
Studies in animals with normal lungs showed worse gas exchange with liquid ventilation compared with gas ventilation.15 23 65 In healthy lungs, oxygenation is impaired during liquid ventilation because the distribution of ventilation/perfusion ratios is changed and there is the imposition of an additional diffusion barrier to oxygen.49 In addition, lung mechanics are disturbed during liquid ventilation in healthy animals.65
Early liquid ventilation with PFCs in humans
In 1989, Greenspan and colleagues19 used a liquid-ventilation technique with the PFC, Rimar 101, in a 28-week-gestation baby. Conventional ventilation was failing, so ventilation was interrupted to allow two 3-min periods of total liquid ventilation, separated by 15 min. Pre-oxygenated Rimar 101 was given from a burette suspended above the patient, retained in the lungs for 15 s and then drained under gravity into a burette below the patient. A case series of three babies of 2328 weeks gestation, including this first one, was reported the following year.20 Lung compliance improved in all three and oxygenation in two. Thus, liquid ventilation appeared to have clinical potential. Although all three neonates died within 19 h, this was thought to reflect the severity of the clinical condition, rather than a failure of the technique per se.
In 1991, Fuhrman and colleagues15 described a hybrid technique which they named PFC-associated gas exchange. They filled the lungs of normal piglets to functional residual capacity (FRC) with FC-77, and superimposed tidal volumes with gas upon this. This technique has since become known as partial liquid ventilation (PLV).
Hirschl and co-workers27 first reported PLV in a mixed group of 19 adult, paediatric and neonatal patients, in an uncontrolled single-centre study to assess the safety and efficacy of PLV. The patients they recruited were already receiving extracorporeal lung assist (ELA), which could provide gas exchange if the PLV failed. They measured alveolararterial oxygen difference and static lung compliance when ELA was not taking place. PLV improved both measures. Fourteen of the patients were successfully weaned off ELA and 11 survived, which was the expected survival rate for patients with severe acute respiratory distress symptom (ARDS). The causes of death were irreversible lung injury (four patients), cerebrovascular accident (one patient), ischaemic encephalopathy after cardiac arrest (one patient) and multiple organ failure (two patients). It was concluded that PLV can be safely used in patients with severe respiratory failure and may improve lung function.
Possible benefits of liquid ventilation in acute lung injury (see Fig. 3)
Acute lung injury is characterized by pulmonary and endothelial inflammation, which causes permeability oedema; loss and dysfunction of surfactant with atelectasis and reduced pulmonary compliance; hypoxaemia from ventilation/perfusion mismatch, with increased intrapulmonary right-to-left shunt; and pulmonary hypertension.69 In these circumstances, liquid ventilation may be beneficial since it improves compliance of the injured lung and recruits alveoli by reopening collapsed lung regions, so reducing intrapulmonary right-to-left shunt. In addition, PFCs have anti-inflammatory properties in the alveolar space.10 The anti-inflammatory effects of liquid ventilation in acute lung injury are from inhibition of neutrophil and macrophage function, and the dilution of inflammatory debris in the airways.
Properties required for a PFC for liquid ventilation
The ideal PFC for liquid ventilation should have: (i) a high solubility for oxygen and carbon dioxide to maintain gas exchange; (ii) a greater density than body fluids so that it descends to the dependent regions of the lungs, where most atelectasis occurs, and re-opens them (an effect termed liquid PEEP); (iii) a low surface tension to compensate for deficient surfactant and improve lung compliance.
The vapour pressure of the ideal PFC has to represent a compromise for opposing requirements. If the substance is not volatile, there will be no requirement for it to be constantly replenished. However, because PFCs are inert, elimination from the body is almost entirely by exhalation in the unchanged form; hence, the substance should be sufficiently volatile to allow elimination in an acceptable time. A high vapour pressure will, however, reduce oxygen tension in the open alveoli. Table 1 gives the characteristics of some PFCs used.
Mechanisms of liquid ventilation with PFCs
In acute lung injury and ARDS, liquid ventilation with PFC may improve oxygenation and lung compliance. The mechanisms of these two effects are different.
Improvement in oxygenation
Several factors may allow improvement in oxygenation. In acute lung injury, collapse is mainly in the dependent regions of the lungs.16 57 Because PFCs are dense, they will gravitate to the dependent parts of the lungs.12 35 54 58 The bulk of the liquid will re-open collapsed regions of lung, acting as liquid PEEP. Ventilation/perfusion relationships may also improve for another reason.42 71 In PLV, some regions of lung, particularly the non-dependent regions, may be predominantly ventilated with gas.58 If pulmonary vessels in dependent lung regions are compressed by PFCs in the alveoli of these regions, blood flow could be diverted towards non-dependent, aerated lung.54 PLV thus improves matching of ventilation to perfusion.22 58
Improved lung compliance
By eliminating the airliquid interface, PLV is thought to reduce interfacial tension and improve lung compliance. Von Neergaard68 showed in 1929 that greater pressure was needed to expand a lung filled with gas than a lung filled with fluid. The additional force is needed to overcome the surface tension in the alveoli between gas and fluid. The exact pattern of distribution of PFCs in the alveoli during PLV is not yet known. Since elimination of the airliquid interface in the diseased lung will depend on the volume and distribution of the PFC, it may be that different quantities are needed for optimal effects on lung mechanics compared with optimal effects on oxygenation.64
Differences in dose requirement to improve oxygenation and improve lung mechanics
Tutunca and colleagues64 studied rabbits subjected to saline lavage, and found a maximum improvement in lung compliance after Perflubron 3 ml kg1, but oxygenation continued to improve with doses up to 15 ml kg1. When surfactant is deficient, this can be explained as follows:41 67 a small dose of PFC will allow a thin film of PFC to coat alveoli in contact with the compound. Evaporation of PFC allows the substance to reach the non-dependent, ventilated lung regions, above the fluid level of the PFC. Unlike surfactant, PFC has a constant surface tension. Giving more PFC will therefore not reduce the surface tension any more. In contrast, increasing doses of PFCs will progressively open up atelectatic alveoli by a PEEP-like effect and improve oxygenation.
Adjuncts to PLV
PLV could be added to other treatments intended to improve oxygenation, such as conventional gas PEEP,32 inhaled nitric oxide,30 37 66 exogenous surfactant56 and prone positioning.50 Although the combined treatments augmented the effects of PLV on gas exchange, no synergism was found.
Anti-inflammatory properties of PFCs
PLV may do more than improve gas exchange and respiratory mechanics it may also reduce pulmonary inflammation. Slutsky and colleagues34 studied rats with acid aspiration and found that PLV with Perflubron reduced serum tumour necrosis factor-alpha. In mice infected with the respiratory syncytial virus, intranasal application of Perflubron inhibited lung cellular inflammation and reduced activation of nuclear factor kappa B.21
In piglets subjected to surfactant wash-out, Merz and colleagues51 found the lowest concentrations of leukotriene-B4 and interleukin-6 in bronchoalveolar lavage fluid after PLV compared with either conventional or high-frequency ventilation, both plus exogenous surfactant. However, lung injury assessed histologically was not different between the groups.
Thus, PFCs may have anti-inflammatory actions in the alveolar space, but the molecular mechanisms remain to be clarified.
Pulmonary drug delivery by PFCs
Non-respiratory applications of PFCs are currently under evaluation. Delivery of drugs to the lungs by PFCs appears promising. The high solubility of oxygen and carbon dioxide, low surface tension, and their capacity to enter collapsed lung regions may allow better drug distribution in the diseased lung. PFCs have been studied for delivering antibiotics,73 anaesthetics,36 vasoactive substances72 and adenovirus-mediated gene transfer.45 In lambs with injury induced by acid lavage, Cox and colleagues8 found that giving a PFCgentamicin suspension (a 1:4 ratio of a nanocrystal suspension of gentamycin 5 mg kg1 and a stabilizer PFC) into the trachea during PLV resulted in homogenous lung tissue gentamicin levels at lower plasma levels than after i.v. administration. They concluded that when lung perfusion is impaired, as in pneumonia, tissue concentrations of systemic gentamicin can be reduced, and administration with a PFC suspension as carrier increases tissue delivery and distribution. Further research on the use of PLV to assist drug delivery to the lung is needed.
Further human studies of PLV
Following the first human studies,17 27 28 43 phase-II and -III studies were done in North America and Europe with Perflubron (marketed under the brand name LiquiVent® by the Alliance Pharmaceutical Corporation, San Diego, CA, USA). Perflubron has not been licensed by the US Food and Drug Administration.
Several factors complicated clinical studies of PLV with Perflubron. When these investigations were planned in the mid-1990s, the mortality for control groups treated with best conventional therapy for ARDS was assumed to be 4050%. Neonatal, paediatric and adult studies were started. In 1997, the paediatric phase-III trial was suspended after an interim review showed an unexpected low mortality in the control group. This was not a problem with the PLV, but rather that the results in the control group were too good. At about the same time, other work suggested that mortality could be reduced in ARDS patients with lung protective strategies for mechanical ventilation.1 4
In a prospective randomized controlled pilot study of 90 adults with lung injury, with PaO2/FIO2 ratios greater than 60 mm Hg but less than 300mm Hg, PLV with Perflubron did not affect ventilator-free days (the primary endpoint for this study), mortality or any clinical outcome.24 Randomization was weighted to give 65 PLV patients and 25 patients on conventional ventilation. This study was criticized for several reasons. Because of slow recruitment, entrance criteria were relaxed after 45 patients. There was no weaning protocol for patients given PLV, and there were disproportionately more patients over 55 yr of age in the PLV group. However, a post hoc analysis found a significantly more rapid discontinuation of mechanical ventilation and a trend towards more ventilator-free days in the PLV group in younger patients. The authors suggested further evaluation, particularly in certain well-defined (especially younger) patients. Most benefit might be gained from PLV in severe disease.
In 1999, Alliance started a large international multicentre phase-III trial to assess safety and efficacy of two different volumes of Perflubron, corresponding to full and 50% FRC. The hypothesis was that PLV with Perflubron would improve the number of ventilator-free days compared with conventional ventilation. A secondary aim was an improvement in 28-day all-cause mortality compared with mechanical ventilation. The study population consisted of adult patients with acute lung injury who had been on mechanical ventilation for less than 120 h, with a PaO2/FIO2 below 200 mmg Hg, FIO2 above 0.5 and PEEP above 5 cm H2O. Ventilator management was prescribed before and after randomization to one of the three arms. Prone positioning was only used in the control group if a defined severity of hypoxaemia occurred. The study was of 301 patients (99 subjects in the low-PFC group, 105 in the high-PFC group, and 97 to the control group).
There was no improvement in either the number of ventilator-free days (primary endpoint) or in 28-day all-cause mortality with either low- or high-dose PLV treatment. The mean number of ventilator-free days was 9.9 in the high-dose PLV group, compared with 13.0 days in the control group (P=0.012), and 7.4 days in the low-dose PLV group (P<0.001 vs control group). Mortality was greatest in the low-dose PLV group (26.3% compared with 19.1% in the high-dose group and 15% in the controls; not significant). Pneumothorax was more common with PLV.
Adverse effects of liquid ventilation (see Fig. 3)
Pneumothorax
Hirschl and colleagues27 reported pneumothorax in nine of their 19 patients who had PLV whilst on ELA, six of whom already had a pneumothorax. PLV may cause pneumothorax, and Verbrugge and Lachmann67 propose a number of reasons for this. If insufficient gas PEEP is applied (from gas or liquid) at end-expiration to support the non-PFC-filled alveoli, these alveoli will collapse and shear forces could cause pneumothorax. Another explanation is that the amount of gas PEEP applied depends on the disease state of the lungs. In those alveoli where surface tension is less than the surface tension of the PFC used, the values of gas PEEP needed during PLV will be less than values needed during conventional ventilation. However, in alveoli where alveolar surfactant is still functioning, adding a layer of PFC with a greater surface tension than normal surfactant will necessitate an increase in PEEP.
The distribution of gas during tidal ventilation when PLV is carried out is not clear. If the gas of the tidal volume goes to parts of the lungs not fully filled with liquid, this could cause severe overdistention, with possible pneumothorax. Verbrugge and Lachmann67 suggested that, to reduce the danger of overdistention, PLV should be combined with pressure-controlled ventilation so that the pressure in any alveolus does not exceed the pressure set on the ventilator. Even during PLV, using conventional PEEP increases oxygenation and may avoid shear stress in non-dependent lung regions.32 38
Circulatory impairment
A thorax filled to FRC with a dense non-compressible fluid is likely to have marked effects on cardiac pressure and cardiac output. However, Houmes and colleagues30 found no deleterious effects on the circulation even when the lungs of the sheep in their study (average thoracic antero-posterior diameter of 24 cm) were filled with Perflubron 25 ml kg1. Why are theoretical concerns less of a problem in practice?
The earlier studies suggesting haemodynamic compromise were of total liquid ventilation, where there was an uninterrupted column of PFC within the lungs and the tracheobronchial tree. This is not the case with PLV. Indeed some investigators argue that PLV has no known side-effects on the cardiovascular system.41 A dense fluid could increase pulmonary vascular resistance and impose strain on the right side of the heart. The effects on vascular resistance may be both positive and negative. Although PFC may compress blood vessels, increasing pulmonary arterial pressure and resistance, there may be reduction of hypoxic pulmonary vasoconstriction from improved oxygenation.
Lactic acidosis
Although the circulation is maintained during liquid ventilation, a metabolic acidosis has been reported,64 71 attributed to reduced regional blood flow during mechanical ventilation with PEEP, even though overall cardiovascular status was maintained. This suggestion is not universally accepted, however.64 There could be a redistribution of blood flow46 or an inadequate intravascular volume.11
Weaning from PLV and resuming conventional gas ventilation
Many studies report successful reversion to gas ventilation after a period of liquid ventilation.52 However, temporary impairment of oxygenation can occur, needing up to several days to return to breathing levels before liquid ventilation.52 63 This is attributed to residual PFC remaining in the lungs and impairing diffusion, reducing blood flow to some regions and reducing alveolar PaO2. Reversible changes in lung mechanics have also been noted after liquid ventilation.59 63
As PFC evaporates and is not replaced when changing back from liquid to gas ventilation, PEEP may have to be increased to prevent atelectasis,60 and compensate for the loss of the fluid PEEP. A worrying issue is that an occult pneumothorax may only become obvious when PFC evaporates.9 During liquid ventilation, there is also a worry that transient hypoxia could occur during dosing.2
Blocking of the tracheal tube
Hirschl and colleagues27 reported that mucous plugging occurred in one of 19 patients, impairing gas exchange and requiring suction and bronchoscopy.27 This conforms with the suggestion that the exudates in the peripheral airways and alveoli could be displaced into the central airways and then removed by suction.
Carbon dioxide clearance
Ineffective elimination of carbon dioxide was a particular problem with inadequate settings of total liquid ventilators, 52 59 attributed to the high viscosity of PFC compared with gas and a small carbon dioxide diffusion coefficient. This can be reduced by setting the ventilator appropriately.39
Elimination and toxicity
This problem may be largely theoretical. Studies of the metabolism of PFC report slow clearance from the body. Even after i.v. administration, elimination is largely via the lung and little if any metabolism takes place. PFC particles are taken up by the reticulo-endothelial system.13 PFCs used as i.v. oxygen carriers can have half-lives as long as 500 days.14 However, there seems to be no inflammatory reaction to these substances, which appear to be innocuous and chemically inert.13 Even after respiratory use, traces have been found 3 yr after a 1-h exposure to liquid ventilation.5 The authors concluded that the PFC (Caroxin-F) could be breathed without residual deleterious effects.5 Others have found no adverse effects on surfactant sampled from dogs 5 days after exposure.53 In the context of ARDS, with a high chance of death in the next few hours or days, the unproven theoretical risk of an indeterminate side-effect years in the future is perhaps small. However, agents that might be retained in the body for so long should be used with caution, even if they appear to do no harm.
Interference with radiographic imaging
PFCs, particularly those containing bromide or iodide ions, are radio-opaque.44 62 This can interfere with radiography and obscure structures such as tips of vascular catheters, and may persist for some weeks.
PFCs given by vapour or aerosol
Since human trials of PLV started, several animal studies have suggested that lung disease could be treated by PFCs given as an aerosol or vapour.3 31 33 Some authors suggest that adverse events could be less using these routes than other means of PFC administration.3 33 Aerosols or vapours are certainly already familiar methods of treatment.
In sheep with lung injury induced with oleic acid, vaporized Perfluorohexane caused an improvement in oxygenation and compliance for 2 h after treatment.3
In piglets depleted of surfactant, the effects of an aerosol of FC-77 were compared with PLV at FRC volume, low-volume PLV (10 ml kg1 h1) and control animals. Oxygenation was better after aerosol and FRC PLV, and the aerosol of PFC gave the greatest dynamic compliance.33 Future research may concentrate on these routes rather than true liquid ventilation.
Conclusion
PFCs have exceptional properties to provide gas exchange and alter respiratory mechanics, with beneficial effects in experimental acute lung injury. Clinical studies found that PLV was safe in patients with acute lung injury and early ARDS, but no improvement in survival or decrease in ventilator requirement was shown. At present it is uncertain if some types of patient with ARDS will respond to PLV treatment. Current research is under way on other possible uses for PLV, such as pulmonary drug delivery. Treatment with PFCs in other forms, such as aerosol or vapour, may have advantages.
Acknowledgement
Professor Kaisers work is supported in part by a grant from the DFG (DFG KA 1212/3-1).
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