Document Qk9gr78ZeNazQ803yVDGqzJQR

-: G(a e.S6 680 /W- IX tfO Tissue Reactions to Organotin-Stabilized Polyvinyl Chloride (PVC) Catheters Wallace L.^Guess, PhD, and John B. Stetson, AID There has been an increasing incidence of glottic in cerning the use of endotracheal tubes and devices flammatory reactions. A search of the literature for a in patients with diphtheria. The patients who un cause disclosed that leachable substances in polyvinyl derwent plastic surgery as a result of injuries re chloride (PVC) could cause tissue injury. A study re ceived during World War I afforded an opportunity vealed that PVC slivers cut from some catheters intended for the placement of endotracheal and nasotracheal for endotracheal use caused toxic reactions when implanted tubes for anesthesia and maintenance of the airway. in rabbit muscle. Cell culture studies were corroborative. The introduction of plastic tubes for prolonged The toxic substance was identified as an organotin com endotracheal use dates from about 1949 when Dwy pound. The investigators concluded that plastic devices er et al4 reported shaping tubes to avoid damaging for use in human patients should not contain organotin stabilizers or any other teachable toxic agent, and that the tracheal mucosa. They formed a mandrel of cop per tubing and shaped the tube over the mandrel standards for plastic devices used in medical practice with boiling water. After cooling, the tube assumed should be established. the shape of the mandrel. The mandrel had a pos terior curve at its lower end to form the tube so it lthough small tubes were used for resuscitation would not press against the anterior wall of the A,, during the 18th century, the first detailed ac trachea. count of the use of an endotracheal tube for main tenance of the ainvay was that of Macewen in For editorial comment see pupa 621. 1880.' In his article. Macewen noted priority in placing tubes in the trachea rather than in perform Following the lead of Dwyer, Briggs* published ing tracheostomy. He wrote: his report of the use of a plastic endotracheal tube The writer introduced cylindrical tubes by the mouth into the trachea, and retained them in situ for thirty-six hours, removing them when required for ablution (say every twelve hours); two such cases having been treated with perfect success. for a period of 42 days. He noted that the tube as sumed anatomical shape in the body. In 1951, Urry published a report dealing with this subject. During the 1960's, there has been renewed in terest in the prolonged use of endotracheal tubes.'13 At the end of the article. Macewen deduced, "the tubes, in these cases at least, were harmless." There have been various attempts to use endo tracheal tubes as airways at various times.1'3 Dur ing the late 1880's many articles appeared con- In many cases, intubation has been by the naso tracheal route. It has proved to be especially useful in infants and children. As popularity of the tech nique increased, various discussions arose as to when an endotracheal tube should be employed and when tracheostomy should be performed. At the From the Drug-Plastic Research end Toxicology Laboratories. College of Pharmacy. University of Texas, Austin (Dr. Guess', and the Division of Anesthesiology. Ohio Stale University Medi present time, consideration for prolonged therapy with tubes seems to follow these five general rules: (1) Prolonged use of tubes is employed rather than cal College. Columbus Dr Stetson). Reprint requests to 410 W Tenth Ave, Columbus, Ohio 43210 (Dr. Stetson). tracheostomy when "the end of the case is in view." By this rule, a patient with severe cerebral damage 118 BFG04312 t-2. -* -r JAMA. May 13. 1968 Vol 204, No 7 20640001 fc--------------------------------------------------------------------------------------------------- --............. TISSUE REACTIONS--GUESS & STETSON 581 would probably undergo tracheostomy at an early date for ease of prolonged ventilation or bronchial toilet or both. On the other hand, a patient who is expected to "be on his own" within five or six days would he treated with a tube maintained in place for a prolonged period of time. Because of the high incidence of complications with tracheostomy in infants and small children, they often are treated via nasotracheal intubation rather than by trache ostomy. (2) An endotracheal tube, when used, is not a "tight fit"; the tube need only to be big enough for the patient to breathe through or breathe through and around spontaneously, or for thera py with a ventilator. If such therapy is used, a volume ventilator is employed, often with a con trolled leak. (3) In infants and children, nasal in tubation is almost always used for prolonged thera py; in adults the oral route must be used at times. The size of the nares in the adult does not allow the passage of as large a tube (by relative size) as it does in an infant. (4) If a patient is awake, he can eat and drink while a nasal tube is in place. (5) Adequate humidification must be used to compen sate for bypassing the nose. Although one of us (J.B.S.) had been impressed by the lack of reactions to the use of polyvinyl chloride (PVC) endotracheal and nasotracheal tubes,'* during the past year or two he has seen an increased incidence of white plaque-like tissue re actions at the glottis. This he attributed to iatro. genic infection. During review of the literature on PVC products, the photographs seen in the article by Guess and Autian'3 were striking in that the tis sue reactions shown looked like those seen in the glottic area of patients treated by prolonged therapy with tubes. A joint study seemed to be indicated. This communication is the outgrowth of collabora tion of a clinician and a basic investigator. It is not meant to incriminate or endorse any particular manufacturer. All strive to have ideal products. As there can be a variation from lot to lot of PVC, it is imperative that there be tissue testing to assure that each lot is not injurious. It is readily apparent from rabbit tissue reac tions to the endotracheal tubes that some present testing programs for revealing potential toxicity may not be totally adequate. We'do not imply that all, or even most complications occurring after in tubation are due to tissue reactions. Rough instru mentation, tubes that are too large, infection due to unsterile equipment, rigid tubes, and even residual ethylene oxide from sterilization procedures may induce more morbidity than substances which are toxic to tissue. We do wish to focus attention on an overlooked and preventable cause of tissue dam age. The testing techniques used by one of us (W.L.G.) are able to detect the toxic nature of the tubes intended for endotracheal use. A critical com parison of why one technique of evaluation failed while another succeeded reveals one simple, yet sig nificant difference. One commercial technique dealt i a highly diluted extract from the plastic, while our technique used the plastic itself. The com mercial technique is a highly desirable method of evaluation for plastics that may bo used for pack aging food or pharmaceutical products, but it does not adequately test for the safety of medical ap plications of plastic devices. Although probably not adequate for testing food or pharmaceutical-pack aging plastics, out data are an indication of how our techniques revealed the toxicity (or lack of it) for products of three manufacturers or distributors of tubes intended for nasotracheal and endotra cheal use. What is surprising is that nearly five years have elapsed since the publication by Little anc! Parkhouse,1* of their paper entitled "Tissue Reactions to Polymers." Although the emphasis in their paper was directed toward particle size in polymers, they noted that inflammatory reactions of tissue to chemical additives do occur. As far as is known, no action has been taken on the last sentence in their paper: Reactions to chemical additives are less easy to charac terise [sic], and the introduction of a British Standard? specification, or the equivalent, to cover polymers and plas tics used medically is suggested. Methods and Results Experimental Procedure.--Three groups of plas tic devices used as nasotracheal, endotracheal, or tracheostomy tubes were received and labeled ac cording to source. Sections were cut from each de vice from a portion that would have intimate tis sue contact when the device was in location in a human patient. These sections were then evaluated for toxic potential. Control materials included a known toxic PVC formulation, a known nontoxic polyethylene formulation, and some widely used su ture material, including surgical gut, plastic, and silk. Cell Culture Evaluation.--The technique of cell culture evaluation of plastics has been reported in detail," but the essentials will be given here for ease of following the test procedure. Mouse fibroblasts (strain L-929) and ten-day chick embryo cells were allowed to grow into a mon olayer in Petri dishes. The growth medium was re moved and replaced with a thin layer of nutrient agar for support of the plastic test material. The cultures were stained with vital dye (neutral red) and the plastics were implanted on the surface of the agar. After 24 hours of incubation at 95 F (35 C), the plates were removed and examined for evi dence of toxicity as denoted by a clear, colorless zone of dead cells around the plastic sample. The area around the periphery unaffected by the toxic material remained a uniform pink color. Figure 1 depicts a typical plate from this experiment and il lustrates the toxicity of the PVC plastic tube in tended for endotracheal insertion to the cells by the clear zone surrounding the plastic ring. The results of this test on all three groups of plastics and controls are summarized in Table 1. Although reasonable doubt can be raised concerning 20640002 JAMA. May 13. 1968 Vol 204. No 7 BFG04313 119 562 TISSUC REACHONS-GUESS & STETSON the equaling of tissue cultures ; to laryngeal mucosa other than j muscle implantal ion, the authors know of no oilier reproducible "simple" technique for testing [ plastic medical products. 1 liohhit Muscle Implantation.-- The test plastics were cut into ! sli\ers approximately 1 mm wide \ and l cm long. These were in serted into a 15-gauge needle and i implanted into the paravertebral ; muscle of anesthetized, cleanly ; shaven New Zealand rabbits. The ' animals were killed and the im plantation site was examined p r grossly for evidence of a tissue , reaction to the plastics. Figure 2 i illustrates a typical negative re- ' sponsc to a nonplastic implant control. Figure 3 illustrates a typ ical toxic response characterized : by a zone of necrosis surrounding | the shaft of the implanted plastic. j It should be emphasized that mi- ' croscopic examination of all im- { plant sites is essential to a full , evaluation. Tissue reactions not j grossly visible may exhibit micro- j scopic toxic manifestations. In | 1. Typical toxic response of chick embryo cells to tube for endotracheal this study, the greatest reaction J jj use. Note dead ceils around circular tube sample. Positive control plastic (clear polyvinyl chloride square) has fewer surrounding dead noted was one of necrosis sur- . rounding the implant site of some j i cells. Negative control (darker square, polyethylene) shows normal of the evaluated plastics. l cell growth under and around sample. Analytical Examination.--In I 3. Necrotic reaction surrounding sliver of one of toxic 2. Negative control plastic (polyethylene) implant in samples of tubes for endotracheal use implanted for paravertebral muscle of rabbit. There is no visible dam one week into paravertebral muscle of rabbit. Note size ii;i age to surrounding tissue from plastic impfants. of necrotic area surrounding each implant. !i 'j t! I TISSUE REACTIONS--GUESS & STETSON 583 order to determine the exact na ture of the toxic material in the plastic tubes evaluated by coll Table 1.--Biological Evaluation of Plastic Tubes Reaction culture and muscle implantation, a section of one of the PVC tubes (X-427) was cut into small pieces, placed in an extractor, and extracted for 24 hours with 95% ethanol. The ethanol was removed by gentle heat under a Source Code No Oevicc and Application A X-423 Tube, endotracheal. Color Pale blue-green X-424 X-425 X-426 Tube with inflatable cuff, endotracheal Tube, Jackson-Rees. endotracheal Tube, tracheostomy Pale blue-green Pale blue-green Amber, clear Plastic Type pvet PVC PVC PVC Celt Culture f CEt P P PP PP PP Rabbit Intracular P P P P nitrogen flush, and the residue was saved for evaluation. Thin layer chromatographic (TLC) ex amination of the residue revealed the presence of several additives, X-427 X-432 A X-432 B X-432 C Tube with inflatable cuff, tracheostomy Tube. Jackson.Rees. endotracheal Tube with inflatable cuff, endotracheal Tube, endotracheal. nasal-oral Amber, clear Pate blue-green Pale blue-green Amber, clear PVC PVC PVC PVC PP PP PP N N P P P N and these were separated by col umn chromatography with silica gel and infusorial earth <50:50) in the column, and eluting with benzene and ether (varying ra tio). The primary plasticizer was examined by infrared analysis and was found to be identical with tributyl acetyl citrate. Tributyl acetyl citrate is not in general use in this country even though it is generally of a fairly low order of toxicity. In addition to the plasticizer, there was found an organotin compound. This sta X-432 D Tube with inflatable Amber, clear cuff, tracheostomy PVC X-432 E Tube, endotracheal, nasal Pale blue-green PVC X-432 F Tube, tracheostomy Palegreen.dear PVC 8 X-433 A Tube with inflatable Amber, clear cuff, tracheostomy PVC X 433 B X-433 C X-433 D Tube with inflatable cuff, tracheostomy Airway Tube, endotracheal Amber, clear White, opaaue Clear PVC PE* PVC X-433 e Tube, endotracheal Amber, opaque PVC X-433 F Tube, endotracheal White PVC X-433 G Cole lube Orange PVC C X-433 H Cole tube White, opaque PVC X-433 1 Tube, endotracheal White, opaque PVC X-433 J Tube with inflatable White, opaque cuff, endotracheal pvc X-438 Surgical gut chromic suture Controls X-439 Synthetic suture P PP P PP P PP N NN N NN N NN N NN P PP N NN P PP P PP P PP P PP N NN N NN bilizer has been identified as a mercapto' ester of an organotin. In the United States, it is be- 'ed that only one organotin npound (stannous stearate, a poor stabilizer and an organic-tin X-440 X-44I X-442 Surgical gut, plain 00 Polyester fiber. suture Braided silk suture 'Mouse fibroblasts (strain 1-929)tChick embryo. *PVC signifies polyvinyl chloride; PE, polyethylene. P signifies positive; N. negative. N NN N NN N NN compound not in general use) has been approved by the Food and Drug Administration for packaging material. For this rea son, it was surprising to find or ganotin in these plastics used for medical applications. A series of organotin esters have been evalu Table 2.--Analysis of Endotracheal Tubes Source A B C Code No. X-427 X-433 E X-433 J Oevice and Application Tube with inflatable cuff, tracheostomy Tube, endotracheal Tube, endotracheal - Stabilizer Mercapto ester Of organotin Organotin Organotin Primary Plasticizer Tributyl acetyl citrate Dialkyl phthalate Mixed phthalate and sebacate No. of Spots on TLC* 6 3 6 ated, and all in the series showed Thin layer chromatography. a corrosive action when in direct contact with tissue.1* dized soya bean oil and perhaps a sebacate secon Table 1 shows that tubes intended for endotra dary plasticizer, though the presence of these could cheal use from two other sources, X-433 E and not be confirmed. It is a credible supposition that X-433 I, were toxic to cells in monolayer culture the tissue reactions observed in human patients and to rabbit tissue. Attempts were made to assay were possibly due to the organotin stabilizer, which the nature of the toxicant in each of these tubes, leached from the plastic to the tissue, where it and it was found that these tubes contained an caused a corrosive, necrotic reaction. Analytic ex organotin stabilizer. Table 2 summarizes the ana amination revealed that organotin was not present lytical data from representative plastic tubes which in tubes that gave negative cell culture and nega -howed toxicity from each source. It was found that tive results of rabbit muscle implantation tests. he organotin stabilizers and not the primary plas ticizers were the primary cause of toxicity. From he number of spots observed in TLC, there were Comment ibviously other components, but the available quan- It was found that certain devices for intubation ity of these prevented absolute analysis. Prelimi- demonstrated toxicity to cells in culture and to iarv observations indicated these spots to be epoxy- rabbit muscle tissue. Analysis of a single toxic de- Ai,,, , May 13, 1968 Vol 204. No 7 121 20640004 BFG04315 584 TISSUE REACTIONS--GUESS & STETSON vice from each source showed (ho presence of an organotin compound mid specific plasticizers of a generally nontoxic nature. Devices that were not shown to be toxic by these; tests did not' contain organotin. It lias been demonstrated in prior re search that organotin compounds are highly toxic to rabbit tissue and generally cause necrosis when they come in direct contact with such tissue. Due to the boll-shaped curve of incidence of hu man reactions, it may lie impossible to pver fabri cate a medical device or drug that will not cause an unwanted reaction. As it is the aim of all com panies manufacturing plastic devices for use in hu man patients to make a nontoxic product, it is sug gested that controlled experiments he performed to compare the reactions of primate tracheal mucosa to those of rabbit paravertebral muscle and cell cul tures. If comparison of results show statistical va lidity, it is suggested that organotin stabilizers (or any other leaehablo toxic ngonL) not In; used in plastics that will be in prolonged contact with hu man body fluids. It is further suggested that stan dards for testing plastic devices used in medical practice should be established for the utmost safe ty in patients. As some plastics con migrate, ad sorb, or change structure, this testing should prob ably be of the sterile, packaged, printed unit as it will be used in the patient. References 1. Mai'cwcn, W.: Introduction of Tracheal Tubes by Ihe Month Instead of Performing Tincheolomv or l^aryngotomy. Brit Med / 2:122-124 (.July 24) 1880; 2:163-1(35 (July 31) 1880. 2. Gillespie. N.A.: Prolonged Use of an Endotracheal Tube: Report of Case. Anesthesiology 3:217-218 (March) 1942. 3. Foregger, R.: Use of Endotracheal Tuhc in Therapy of Post-Traumatic Pulmonary Secretions. Anesthesiology 7:285-290 (May) 1946. 4. Dwyer, C.S.: Krononherg. S.: ami Saklnd. M.: The Endo tracheal Tulie* A Consideration of Its Traumatic Effects With 8 Suggestion for the Modification Thereof. Anesthesiology 10: 714-72H (Nov) 1949. 3. Briggs. 13.D.; Prolonged Endotracheal Intubation, Anesthe siology 11:129-131 (.Jan) 19.50. 6. Urry. A.G.: The Prolonged Use of Endotracheal Tubes: Cl's; l(e[)ort.s. Anesthesiology 12:662-664 (Sept) 1901. 7. Davenport. H.: Management of Respiratory Obstruction Following Removal of a Tracheostomy Tube. Canail Med Assoc J 91:1074-1075 (Nov) 19G4. 8. McDonald, I.H.. and Stocks. J.G.: Prolonged Nasotracheal Irlubation, Brit J Anacslh 37:161-173 (March) 1965. 9. Held, D.H., and Tunslnll. M.-E.: Treatment of Respiratory- Distress Syndrome of Newljorn With Nasolracheal Intubation and Intermittent Positive-Pressure Respiration, Lancet 1:1196- 1197 (June 5) 19(Vi. 10. Thomas, D.V.. et nl: Prolonged Respirator Use in Pulmn. tmry Insuniciency of Now horn.-/A/l/A 193U83-190 ( July 19) littiS. 11. Steven. I.M.. and Allen. T.H.: Prolonged Endotracheal In tubation in Infants and Children, Brit J Anacslh 37:56(1-5/3 (Aug) 1965. 12. Stetson. J.B.: Tracheostomy or Prolonged Intubation, Anaesthesia 20:508 (Oi'l) 1965. 13. Rcca. G.J.. and Owcn-Thomas, .T.D.: A Technique of Pul monary Ventilation Wilh a Nasotracheal Tube. Brit J Anaesth 38:901 1906 (Nov) I960. 14. Stetson. J.R.: Discussion of ,,Hv|>ovenlilation in Patients"' by H. C. A. J-nssen. Ann JVV Acad Sci 121:897 (March 24) 1965. 15. Guess, W.L.. and Aulian. .1.: Biological Testing of Plasties: To be Used in Medical Practice. Amer J f-losp 1`Jiarm 21:260-267 (.June) 1964. 16. Little. K-. and I'arkliouse. J.: Tissue Reactions to Polymers, Lancet 2:857-861 (Oct *27) 1962. 17. Guess, W.L., el ol: Agar Diffusion Method for Toxicity Screening of Plastics on Cultured Cell Monolayers. J Pharm Sci 54:1545-1547 (Oct) 1965. 18. Guess. W.L.. et al: Parenteral Toxicity of a Series of Dioctyl and Dibutyl Tin Stabilizer^ Used in T'VO Formulations, Tech Papers Soc Plastic Engineers 12:XXV-4, 1950. SOVIET PHYSICIAN "PATHFINDER" IN SPACE MEDICINE.--Boris Yegorov (1937- ), Soviet JK^rwlK kOCMHSf.CKOfO KOPAkAfl kOMAPOR D M (DEOKTKCTOB KJl. Elt)POB b.S. wj, *-V*.*- .*..: w tWj BOCXOA* physician, became a "path finder" in space medicine in 1964 when he accompanied two cosmonauts in the first three-man flight in the space ship Voskhod The crew consisted of Col Vladimir Komarov, pilot; Konstantin Feoktistov, en MF.CTHbl* fcOCMKVtrXMp KOPABAb -foOCXOA" I2-X-ISBO r- gineer with a master's degree in the technical sciences; and Yegorov. While the pilot ancl engineer were busy with their duties, the physician collected data for an array of medical, biological, and psychological studies. The exploit was commemorated in postage stamps by the USSR and several satellite countries. In the two Large Soviet stamps illustrated, Yegorov is the third figure. He also is shown alone on a 4-kopeck issu$.-- Mirt, J.A., "Medical Pathfinders on Postage Stamps/' o ooO Komarov (at left on large stamps) was billed April 24, 1967, oo reentry after solo space flight. m JAMA. Moy 13. 2968 Vof 204. No 7 J/ BFG04316