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(Chest. 2000;118:1436-1440.)
© 2000 American College of Chest Physicians

A Morphologic Study of Long-term Retention of Fluorocarbon After Liquid Ventilation*

C. Ian Hood, MB, ChB and Jerome H. Modell, MD, FCCP

* From the University of Florida College of Medicine, Gainesville, FL.

Correspondence to: Jerome H. Modell, MD, FCCP, Department of Anesthesiology, PO Box 100254, Gainesville, FL 32610-0254; e-mail: modell{at}dean.med.ufl.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To determine how long perfluorinated hydrocarbons remain in the lung after they are used for lung ventilation in dogs, and to determine if residual perfluorinated hydrocarbons cause structural alteration or an inflammatory reaction of the lung.

Design: Adult dogs were anesthetized and received ventilation with oxygenated perfluorinated hydrocarbon liquid. Morphologic studies of tissue from the lungs of these dogs were performed at intervals of a few minutes to 10 years after reconversion to breathing gas.

Setting: University College of Medicine.

Participants: Adult mongrel and beagle dogs.

Interventions: Anesthetized adult dogs breathed oxygenated liquid fluorocarbons for 1 h and then were reconverted to breathing air. Three fluorocarbons, FX-80 (C8F16O; 3M Company; St. Paul, MN), Caroxin-D (C10F22O2; P-1D; Allied Chemical Company; Morristown, NJ), and Caroxin-F (C9F20O; P-12F; Allied Chemical Company), were used. Morphologic studies of the lungs of these animals were performed immediately after restoration of air breathing and at intervals for up to 10 years. Not all animals were studied at each time interval.

Measurements and results: A transient, acute inflammatory reaction was followed by a massive influx of macrophages, which were at first intra-alveolar and later interstitial, especially around vessels and bronchioles. Fluorocarbons remained in the lung in diminishing amounts for at least 5 years, as evidenced by persistent vacuolated macrophages in the alveoli, interstitium, and hilar lymph nodes; fluorocarbon was also detected in these tissues by chemical assays. In no case was there fibrosis or any other structural alteration associated with the residual fluorocarbon, which suggests that it was inert. At 10 years, no evidence of residual fluorocarbon was seen morphologically.

Key Words: alveolar macrophages • dogs • fluorocarbons • hypoxemia • liquid breathing • perfluorinated organic liquid • pulmonary function • pulmonary lavage • respiratory distress


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Supporting life by breathing an oxygenated liquid or by circulating an oxygenated blood substitute has great potential. Such a liquid could be used as follows: (1) therapeutically for pulmonary lavage and to expand atelectatic alveoli while providing necessary oxygenation; (2) as a noncompressible life-support system for underwater workers, one that would obviate the necessity for slow decompression and the hazards of hyperbarism1 ; and (3) as a blood substitute for patients with chronic anemias or in cases of severe blood loss, which would avoid the problems of compatibility testing and induced autoantibodies.2

In 1962, Kylstra et al3 demonstrated that mice submerged in aqueous fluids hyperbarically oxygenated at 8 atmospheres (atm) survived up to 18 h, and in 1966 that dogs could be sustained by ventilation with a lactated Ringer’s solution hyperbarically oxygenated at 5 atm.4 In 1966, Clark and Gollan5 reported not only the survival of mice submerged in fluorocarbon FC-75 (3M Company; St. Paul, MN) equilibrated with oxygen at atmospheric pressure, but also the temporary survival of cats that underwent ventilation with this liquid.

Subsequent studies by Gollan and Clark6 showed that a series of fluorocarbons with widely different vapor pressures were capable of sustaining life; however, cessation of liquid ventilation was followed by a variety of complications, including alveoli dilated and ruptured from trapped gas with the most volatile fluorocarbons, and dense and diffuse intra-alveolar macrophage infiltrates with the least volatile fluorocarbons.

In the 1970s, we showed that long-term survival was possible when dogs underwent ventilation for 30 min,7 1 h,8 and 8 h7 with the oxygenated fluorocarbon liquid FX-80. However, two of the four dogs that underwent liquid ventilation for 8 h were killed because they could not maintain acceptable PaO2 when reconverted to breathing gas. The peak intratracheal pressure during liquid ventilation reached 60 mm Hg in one animal and 90 mm Hg in the other. The two dogs that underwent ventilation at peak intratracheal pressures of < 30 mm Hg survived.

Subsequently, we investigated the effects of liquid ventilation with three different fluorocarbons: (1) FX-80 (C8F16O; 3M Company), an azeotropic mixture of perfluorobutyltetrahydrofuran that contained eight isomeric compounds; (2) Caroxin-D (P-1D; C10F22O2; Allied Chemical Company; Morristown, NJ), perfluorobis (1, 4-isopropoxy) butane; and (3) Caroxin-F (P-12F; C9F20O; Allied Chemical Company), perfluoro-1-isopropoxyhexane.8 9 10 11 12 13 This report describes the morphologic aspects of these studies, and compares and contrasts the short- and long-term retention of the three liquids. Although commonly referred to as fluorocarbons, these fluids contain elements other than fluorine and carbon, and are more accurately described as perfluorinated organic liquids (POLs).


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The research described in this report involved animals maintained in animal care facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care.

POL Agents Studied
The first POL available for study was FX-80, which has a vapor pressure of 58 mm Hg at 37°C. The second, Caroxin-D, is a much less volatile, purer compound, with a single chromatographic peak and a vapor pressure of 12.8 mm Hg. As a result of experiments with FX-80 and Caroxin-D, the third POL, Caroxin-F, was developed because its vapor pressure of 29.1 mm Hg is between that of the other two fluids.13

The most volatile of the three fluorocarbons, FX-80, caused respiratory distress and hypoxemia for 7 to 10 days after restoration of air breathing, which cleared within 1 month of liquid ventilation.8 In contrast, the less volatile Caroxin-D was associated with a very brief and milder period of respiratory distress and hypoxemia.14

Groups 1 (FX-80) and 2 (Caroxin-D)
Thirty-six anesthetized adult mongrel dogs underwent ventilation with FX-80, and 43 (32 mongrels and 11 beagles) with Caroxin-D for 1 h through a cuffed endotracheal tube. The weight of the dogs was 11 to 18 kg. The POLs were oxygenated by bubbling oxygen at a rate of 3 to 5 L/min through an aerator in a 1,200-mL reservoir connected by a flexible hose to the endotracheal tube. Ventilation was performed by raising and lowering this reservoir to give a tidal volume of 300 to 400 mL three to four times per minute; the frequency was determined by the duration of exhalation, ie, drainage of lungs after each breath.

After 1 h of continuous liquid ventilation, the POL was drained from the lungs by gravity and the animal then breathed 100% gaseous oxygen for 3 h. This was followed by 30 to 45% supplemental oxygen in a tent until the PaO2 was > 65 mm Hg while the animal breathed room air. The arterial blood gas results have been reported previously.8 14

The dogs underwent biopsy under barbiturate anesthesia or were killed with sodium pentobarbital and IV potassium chloride at various time periods according to Table 1 . The lungs and tracheas were removed en bloc and photographed. The majority were fixed for >=2 days by tracheal infusion with 10% buffered formalin at 20 to 30 cm (formalin) pressure before sectioning. The lungs from the remaining dogs were sectioned fresh without inflation. Samples for histologic examination generally were taken from each lobe of each lung, usually one section from the smaller lobes and two or more from the larger lobes. All lobes were inspected, and if any gross abnormality was seen or suspected, that area was included in the tissue samples. Up to 15 pulmonarysections from each animal were stained with hematoxylin-eosin and were examined under light microscopy. Selected sections were stained with Masson’s trichrome, Verhoeff’s elastic, periodic acid-Schiff, or Oil-red-O stains.


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  		Table 1. Time of Autopsy After Liquid Ventilation

 
Group 3 (Caroxin F)
Twenty adult beagle dogs (mean ± SD weight, 9 ± 1 kg) were treated in a similar manner but underwent ventilation with Caroxin F for 1 h. These dogs then were classified into four groups: (1) 3 dogs had serial pulmonary function studies and were killed after 12 months; (2) 5 dogs had sequential lung biopsies at 3, 6, 9, and 12 months and were killed after 15 months; (3) 2 dogs had serial pulmonary function studies and were killed at 24 months; and (4) 10 dogs had serial pulmonary function studies and then had three to five biopsies at intervals up to 10 years after liquid ventilation (Table 2 ). Between 5 and 10 years, three dogs died and did not have biopsy due to excessive autolysis.


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  		Table 2. Time of Tests After Ventilation With Caroxin-F

 
The detailed physiologic studies performed on these animals have been reported previously.10 13 This article reports the morphologic studies.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Groups 1 (FX-80) and 2 (Caroxin-D)
After drainage of POL, 300 to 400 mL less than the original volume instilled was usually recovered. An unknown quantity of this may have evaporated through our open system of liquid ventilation. The remainder likely remained in the lung or was absorbed and distributed to other organs, with the greatest concentrations being found in lung, fat, and the white matter of the brain.10 15 16

Approximately 1 week after liquid breathing with FX-80, the dogs were hypoxemic and respiration was labored when room air was breathed.8 In contrast, the dogs that underwent ventilation with Caroxin-D did not display such obvious severe respiratory distress,9 14 which suggests that less residual effect occurred after ventilation with Caroxin-D than after ventilation with FX-80. Detailed studies of pulmonary morphology and function after liquid ventilation with FX-80 and Caroxin-D have been reported previously.8 9 14

Group 3 (Caroxin-F)
Air breathing was restored most smoothly in dogs that underwent ventilation with Caroxin-F, and respiratory distress was not apparent in any of the animals. Detailed studies of pulmonary function after liquid ventilation with Caroxin-F have been reported previously,13 as well as short-term studies on morphology, persistence of POL in selected tissues, and biochemical studies.10

At each biopsy or autopsy, the lungs of this group were pink, expanded, and free from any gross lesion, except for local scars and adhesions at previous biopsy sites. Up to 15 months after Caroxin-F was breathed, all lungs examined contained large vacuolated macrophages, generally in discrete perivascular and peribronchiolar foci, sparse in some areas, numerous in others. However, no evidence of fibrosis or alveolar distortion attributable to the accumulated macrophages was seen. The findings of macrophages on histologic examination of subsequent lung samples obtained by biopsy or autopsy are summarized in Table 3 . Of the nine biopsy specimens obtained at 24 months, five contained numerous clusters of vacuolated macrophages, chiefly interstitial in peribronchiolar and perivascular sites; two contained only a few small clusters; and in two there were no identifiable macrophage clusters.


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  		Table 3. Macrophage Content of Lung Tissue Sampled After Liquid Ventilation With Caroxin-F

 
All these dogs underwent biopsy again at 36 months, except for one that died and underwent autopsy. All survivor dogs underwent biopsy again at 48 months, and then biopsy or autopsy at 60 months, leaving four survivors. Two of these subsequently died, and were unsuitable for histologic examination; two survived 10 years.

At 36 months, macrophages had decreased significantly except in two dogs. Those positive at 24 months were still positive, and those negative at 24 months were still negative. However, two dogs that remained positive had negative results at 33 months, and one dog who had negative results at 24 months and 36 months had positive results at 33 months.

At 48 months, all biopsy specimens were positive, except for one dog that had been negative at 33 months. Biopsy specimens from two dogs that had had two and three previous negative biopsy results, respectively, were now positive. At 60 months, one of these was still positive, while the other was again negative. All other biopsy specimens were positive at 60 months.

The two dogs that survived for 10 years were killed. One appeared in good health, and the other was feeble at that time. The latter at autopsy had widespread hematogenous metastases from a carcinoma of undetermined primary site. In neither animal were macrophages detected in the lungs or hilar lymph nodes, nor was there any fibrosis or inflammation attributable to exposure to POL.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is clear that oxygenated POLs can support life, and that dogs13 14 and primates17 not only consistently survive when gas breathing is restored, but also can recover apparent good health for long periods. A modification of this technique has recently led to the widespread investigation of partial liquid ventilation in humans with yet another fluorocarbon compound, perflubron.18 19 20 21 Although the long-term follow-up studies reported in this article were completed 16 years ago, they were not published because of a waning interest in liquid ventilation at that time. With the resurgence of interest in partial liquid ventilation in the 1990s,18 19 20 21 we believed this material should be made available to current and future investigators. If liquid ventilation, either partial or total, is to be clinically useful, it is important to know that fluorocarbon is not retained for excessive periods of time, or that it is totally inert and causes no harm.

The POLs are generally considered biologically inert,6 do not interfere with pulmonary surfactant,11 and at 1 atm of 100% oxygen can carry > 42 mL/dL of oxygen,14 compared with the 22 mL/dL that normal whole blood can carry, assuming 15 g hemoglobin per 100 mL. However, POLs do have certain physical characteristics that limit their usefulness, the most critical of these being density, viscosity, and vapor pressure. If the density and viscosity are too high relative to air, the effort required to move the liquid through the airways is prohibitive. If the vapor pressure is too high, the rate of evaporation is so high that vapors are trapped in the periphery of the lung, which distends and can destroy the parenchyma.6 Conversely, if the vapor pressure is too low, significant elimination of residual fluorocarbon via the lungs may not be possible.

FX-80 is usable; however, it has the disadvantage of resulting in an initial 3- to 10-day period of hypoxemia and respiratory distress after reconversion to gas breathing.8 Caroxin-D, although causing less immediate distress, has a potential long-term disadvantage, ie, a persistent macrophagic response in the pulmonary tissues for at least 20 months,4 the significance of which has not been determined in dogs.14 In a similar experiment with adult monkeys, numerous clusters of macrophages still were present in the peribronchial, perivascular, and subpleural interstitium, as well as in the alveolar spaces after 3 years.17 In addition, there was cuboidal metaplasia of alveolar epithelium among the interstitial aggregates, but no evidence of reactive fibrosis.17

The finding of persistent macrophages 20 months after ventilation with Caroxin-D was unexpected because of the relatively smooth restoration of breathing, the apparent long-term well-being of these animals, and the normal results of their pulmonary function tests.13 Because of the persistence of Caroxin-D after 20 months in dogs and 36 months in primates, another POL was developed, Caroxin-F, which has a vapor pressure intermediate to those of Caroxin-D and FX-80. It was expected that the more volatile fluid would clear more rapidly from the lungs than did Caroxin-D.

Of the three POLs, ventilation with Caroxin-F was followed by the smoothest recovery, in that pulmonary function and blood gas values were normal within 24 to 72 h of liquid ventilation.13 Comparing lung samples taken every 3 months after liquid ventilation with Caroxin-F with those taken at the same intervals after ventilation with Caroxin-D revealed no quantifiable difference. The findings of two negative samples in the first group of the sequential biopsy specimens obtained at 24 months (Table 3) seemed to indicate that Caroxin-F might be eliminated from the lungs more rapidly than Caroxin-D. Subsequent positive biopsy specimens from animals in which previous biopsy results had been negative raise doubts about the anticipated rate of clearance of Caroxin-F and the representativeness of the biopsy specimens.

Review of whole lungs, available at 2 years and 3 years after liquid ventilation with Caroxin-F, revealed numerous aggregates of macrophages. However, although these were present in all lobes, they varied greatly in number and distribution, so that the sampling error of small biopsy specimens was high. This was exemplified by the biopsy specimens taken at 4 years and 5 years, in which biopsy specimens previously negative were positive and vice versa. However, in the whole lungs of four dogs killed at 5 years, vacuolated macrophages were still present in all lobes, but in greatly reduced numbers compared with earlier years. Concurrent analysis of the lung samples for Caroxin-F by gas chromatography revealed an exponential decrease in residual values over the years from 0.31 mg/100 g of tissue at 6 months, to 0.16 mg/100 g at 1 year, and approximately 0.11 mg/100 g at 5 years. Importantly, in no case was there any evidence of fibrosis or other permanent damage associated even with the heaviest macrophage burden. By chance, the two dogs that survived 10 years, although equally exposed to Caroxin-F and having the same postventilatory effects on pulmonary function and blood gas values as the others in their group, appeared to have the lightest fluorocarbon load as judged by the numbers of macrophages in their earlier biopsy specimens.

The response to ventilation with POL closely resembles that to liquid hydrocarbon (mineral oil), in that the hydrocarbon is ingested by macrophages that fill the alveoli, enter the interstitium, and accumulate in the regional lymph nodes. However, the reaction to POL differs in that, while the hydrocarbon eventually provokes a fibroblastic response, there was no evidence of such a reaction to FX-80, Caroxin-D, or Caroxin-F at any time during the study.

In summary, the most volatile POL studied, FX-80, appeared to be cleared almost completely from the lungs by 1 month after ventilation. In contrast, the less volatile Caroxin-D and Caroxin-F lingered on in macrophages, in diminishing quantities. The volatile FX-80 was associated with considerable respiratory distress and hypoxemia for up to 10 days after liquid ventilation. However, after Caroxin-F, recovery was very smooth, and pulmonary function studies and blood gas values were within normal limits by 24 to 72 h.

We conclude from these experiments that in dogs that underwent ventilation with oxygenated POL for 1 h, ventilation with gas can be restored with only a brief period of hypoxia, and dogs can survive in apparent good health with normal pulmonary function for at least 10 years. We also conclude that, although POL persists in the lung for at least 5 years, as evidenced by vacuolated macrophages and confirmed by chemical assays, the substance appears to be completely inert. The vapor pressure of the fluorocarbon used for liquid ventilation is important in determining the relative ease of reconversion to gaseous ventilation and may influence the retention time.


   Acknowledgements
 
Fluorocarbon FX-80 was provided courtesy of 3M Company, St. Paul, MN; P-1D (Caroxin-D) and P-12F (Caroxin-F) were provided courtesy of Allied Chemical Company, Morristown, NJ.


   Footnotes
 
Abbreviations: atm = atmosphere; POL = perfluorinated organic liquid

Supported in part by National Institutes of Health Research Training Grant 5 T01 GM00427 and Research Grant GM 17246.

Received for publication February 25, 2000. Accepted for publication February 28, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gollan, F, Clark, LC (1967) Prevention of bends by breathing an organic liquid. Trans Assoc Am Physicians 80,102-110[Medline]
  2. Geyer, RP (1982) Oxygen transport in vivo by means of perfluorochemical preparations. N Engl J Med 307,304-305[ISI][Medline]
  3. Kylstra, JA, Tissing, MO, Van der Maen, A (1962) Of mice as fish. Trans Am Soc Artif Intern Organs 8,378-383
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  9. Calderwood, HW, Modell, JH, Rogow, L, et al (1973) Morphologic and biochemical changes in dogs after ventilation with Caroxin-D fluorocarbon. Anesthesiology 39,488-495[ISI][Medline]
  10. Calderwood, HW, Ruiz, BC, Tham, MK, et al (1975) Residual levels and biochemical changes after ventilation with perfluorinated liquid. J Appl Physiol 39,603-607[Abstract/Free Full Text]
  11. Modell, JH, Gollan, F, Giammona, ST, et al (1970) Effect of fluorocarbon liquid on surface tension properties of pulmonary surfactant. Dis Chest 57,263-265
  12. Pinkerton, H (1928) The reaction to oils and fats in the lung. Arch Pathol 5,380-401
  13. Saga, S, Modell, JH, Calderwood, HW, et al (1973) Pulmonary function after ventilation with fluorocarbon liquid P-12F (Caroxin-F). J Appl Physiol 34,160-164[Free Full Text]
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  21. Hirschl, RB, Pranikoff, T, Wise, C, et al (1996) Initial experience with partial liquid ventilation in adult patients with the acute respiratory distress syndrome. JAMA 275,383-389[Abstract]




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