EDITORIAL COMMENTS Nutrition Vol. 14, No. 2, 1998

Infusion Phlebitis and Peripheral Parenteral Nutrition A

The article by Kuwahara and colleagues1 in this issue of Nutrition is another interesting contribution to the vexed question of infusion phlebitis occurring during peripheral parenteral nutri- tion (PPN). This complication is probably the most important limiting factor to the more widespread application of PPN. The authors conclude that osmolality of the infusion solution is an important factor in the development of phlebitis regardless of infusion volume or infusion rate, and that dilution is effective in reducing the phlebitic potential of infusion solutions. The impor- tance of osmolality has been recognized as a cause of phlebitis in peripheral veins ever since Henriques commented upon it in conjunction with infusing protein hydrolysates into goats in 1913.2 Many studies since then have affirmed the role of osmolarity and, in particular, osmolarity rate as a predisposing factor to phlebitis; and modification of compounded solutions used in PPN is well- established as a means of reducing phlebitis.3,4 The experimental studies of Kuwahara and colleagues do, however, in addition point to the interesting, although not altogether surprising, observation that dilution is effective in reducing the phlebitic potential of infusion solutions. The important question from a clinical stand- point is, “How important is this in the context of PPN?” Or, to put it another way, how do clinicians decide on the relative importance of the large number and great diversity of methods to reduce phlebitis in clinical practice?

Review of the literature reveals conflicting recommendations for the reduction of phlebitis. For instance, there is no doubt that the size of the cannula, be it diameter, surface area, or length, all predispose to an increased incidence of phlebitis.js6 This would infer that we should all use the smallest cannula possible. And yet, currently, the most popular means of administering PPN is to use ultrafine long lines. Inevitably, these have a large surface area, but their use permits placement of the tip of me cannula in a large vein. Does this mean that the size of the vein and venous flow are relatively more important? Similarly, there is much evidence to show that duration of infusion is an important factor in the causation of phlebitis.’ Despite this, many centers administer PPN on a continuous basis for reasons of medical and nursing conve- nience, and numerous studies have reported successful PPN em- ploying these infusion techniques.8.9 Matters are further compli- cated by the many reports of successful reduction in phlebitis, or at least prolongation of cannula survival time, by means of phar- maceutical manipulation. The use of glyceryl trinitrate patches, the addition of heparin or hydrocortisone to the infusate, or the application of nonsteroidal creams or gels have all been shown to be effective.5 How high in importance do these rank when com- pared to other means of reducing phlebitis and, in this context, is their routine use, their inevitable cost, and the small risk of complication justified?

Attempts to determine the relative importance of the various factors involved are difficult, because most studies, for perfectly legitimate reasons of standardizing experimental design, have

assessed only one or possibly two independent variables. One notable exception to this was the report by HeckeriO in 1992 of a series of sophisticated me&analyses in which he attempted to determine the relative importance of the acidity of i&sates, additive heparin and corticosteroids, topical glyceryl trinitrate, and the use of in-line filters. He found that each technique significantly decreases infusion failure. Pooled odds ratios indicated that the proportions of lines failing decreased to about 50% for steroids, 40% for both heparin and filters, 35% for neutralization, 30% for glyceryl trinitrate, and about 20% for heparin combined with steroids. Neutralization had no additional effect to heparin plus steroids. More recent studies have confirmed the cumulative ben- efits from heparin and hydrocortisone, but the relative importance of glyceryl trinitrate patches, in-line filtration, and buffering as independent variables, remains unclear.li-i3 Another confounding variable is infection. Few would disagree that cannula-care pro- tocols, both on insertion and following, are an essential part of successful PPN; but the relative importance of these compared to other variables is difficult to judge. One prospective study did report that aseptic technique on line insertion was more important than additional steroids in terms of reducing phlebitisi As re- gards osmolarity, there is, as already stated, a wealth of data to show that osmolarity is important in the etiology of phlebitis. However, many studies have been reported that demonstrate that PPN with hyperosmolar solutions is easily achievable, suggesting that this should not be seen as a major limiting factor to successful PPN.sJ5

The next question, then, is to consider how important these pharmaceutical considerations are relative to other predisposing factors to the development of infusion phlebitis. The most impor- tant of these is mechanical trauma to the vein. Trauma may occur as a consequence of the venipuncture itself, as a result of the presence of the indwelling cannula in the vein, or as a conse- quence of the irritant effects of the infusion solutions on the vein wall. All of these may cause the release of inflammatory mediators and activation of the clotting cascade, with subsequent phlebitis and thrombosis. It is important to appreciate that these changes will, ultimately, always occur in any vein subjected to the pres- ence of an indwelling cannula. Strategies designed to reduce the incidence of phlebitis or minimize its severity must therefore address one or all of these factors. This has led to the evolution of two very different approaches to PPN administration.

Many now advocate the use of peripheral ultrafine cannulas (usually 23 steel wire gauge and 15-20 cm in length), which have the advantage of ensuring greater dilution of nutrient solution on delivery into a vein of larger caliber and higher flow rates than in a forearm vein.5,s,9 Further, it has been suggested that the cannula tip of these long lines floats within the wider lumen, thereby minimizing further mechanical abrasion to the venous endothe- lium. Additionally, as these lines are left in situ for as long as possible, this reduces direct venous trauma from repeated veni-

Nutrition 14:233-247, 1998 OElsevier Science Inc. 1998 Printed in the USA. All rights reserved. ELSEVIER 0899-9007/98/$19.00

234 EDITORIAL COMMENTS

puncture. It is recommended that these lines are inserted into the largest available forearm vein, usually the cephalic or basilic, and that they should be fixed to minimize movement of the cannula within the vein.5

The use of fine bore cannulas for the delivery of PPN was first described by Kohlhardt et al. in 1989.8 They used a cannula manufactured from silicone rubber with an external diameter of 0.6 mm (23 swg). Forty-six patients were fed for a mean duration of 9 d (range S-60), and the incidence of thrombophlebitis was 18%. The mean time to phlebitis was 7 d (range S-19), and the daily risk of phlebitis was 0.016 epi- sodes/patient day. The osmolarity of the solution was 1084 mosmll, and it contained heparin. Two subsequent studies in surgical patients were published by this group in which ultra- fine cannulas were compared to central peripheral nutrition.i6J7 Both confirmed long-term phlebitis-free delivery of PPN with minimal morbidity. In 1992 Madan and colleagues reported a randomized study in which a fine bore cannula (Epicutaneo Cava) was compared to the use of a standard short Teflon cannula, (Venflon) in surgical patients9 The median duration of feeding was 5 days in each group. Phlebitis developed in all the patients fed through the short teflon cannula, but in only 2 of 27 patients fed with the ultrafine long line. The median life span of the ultrafine cannula was significantly greater than the Teflon. Other randomized studies have also found a signif- icant increase in phlebitis using short Teflon cannulas com- pared to long lines, when continuous infusion without elective changes of line were standard practice.” From these studies one can conclude that ultrafine cannulas provide an effective means of administering PPN that is associated with minimal morbidity.

The alternative approach to PPN administration is to minimize the duration of time for which the vein is exposed to both nutrients and cannula. This method involves the daily rotation of venous access sites and cyclical infusion of solutions over 12-h periods. Because thrombophlebitis is, ultimately, an inevitable conse- quence in any vein in which there is an indwelling cannula, it is logical to interrupt the progression to phlebitis by early with- drawal of the cannula. It is interesting to note that infusion is not a prerequisite to the development of phlebitis. Studies in normal volunteers with cannulas placed in forearm veins with no infusion running demonstrated that after 108 h almost 44% of veins with cannulas in place will develop phlebitisi Nonetheless, the infu- sion itself potentiates the occurrence of phlebitis.5 This may occur as a consequence of trauma to the endothelium from the jet of fluid emanating from the cannula as well as a consequence of chemical irritation, which is determined by osmolarity, buffering pH, and infusion period. It is not surprising, therefore, that the incidence of phlebitis can be reduced by both elective change of peripheral venous cannulas and a reduction in infusion periods. Hessov,7 in 1985, reported a negligible incidence of phlebitis during the infu- sion of hypocaloric solutions with infusion periods shorter than 12 h, and he showed that the incidence approached 100% if infusions were continued for 4-5 d. Clinical as well as experimental studies show that the risk of phlebitis increases with the length of infusion time. Dinley, in a study comparing 4 different types of cannula, showed that when these were in place for less than 12 h that phlebitis did not occur, but that there was a 70% incidence when cannulas were in place for more than 72 h.19

Nordenstrom et al.*O were the first to describe this technique for PPN administration. They recommended using the largest possible forearm vein, to avoid the veins on the back of the hand, to use short thin (1 .O-mm diameter) plastic cannulas, to complete the daily nutritional program within 12 h, to remove the cannula immediately after completing the infusion, and to change the infusion site to the contralateral arm the following

day. Using this method, they reported an overall incidence of phlebitis of 18%, with a mean duration of PPN of about 5 d. A total of 75% of their patients were successfully fed by PPN until resumption of oral nutrition. Interestingly, severe phlebi- tis (Maddox grade 3) rarely occurred. Other groups have also reported successful PPN using this method of administration. For example, Hill,*l employing a solution of 640 mosm/L that provided 9 g of nitrogen and 1620 nonprotein calories, dem- onstrated that PPN administered in this way was as effective as CPN with respect to improvements in grip strength and peak expiratory flow. May et al.6 in 1996 reported the results of a prospective and randomized study in which the incidence of phlebitis was minimized in those patients who received their PPN on a cyclical basis with rotation of venous access sites when compared to groups receiving PPN as a continuous infu- sion with and without elective line changes.

To date, there has been only one prospective study reported that has compared the results of these two alternative means of PPN administration.22 In this study, surgical patients were randomly allocated to receive PPN using an ultrafine cannula (Nutriline) or by the method of rotation with cyclical infusion. Both techniques permitted successful PPN, with a mean dura- tion of feeding of 8.6 and 7.9 d in the two groups, respectively. However, failures of the designated technique necessitating alternative means of feeding occurred in 9 of 24 patients with ultrafine cannulas and only 2 of 26 patients with rotation. Severe phlebitis occurred in 4 patients with long lines, and in one there was a catheter-related fever. One explanation for the relatively poor results obtained in this study with ultrafine long lines and those reported elsewhere could be that no ancillary means of reducing phlebitis were employed. In most reports of successful PPN using ultrafine lines, management protocols have incorporated heparin, hydrocortisone, glyceryl trinitrate patches, and in-line filters either alone or in combination.

Whatever the cause of infusion phlebitis, the end result is always the same. Thrombosis, erythema, pain, and swelling at the site of cannula insertion are inevitably followed by occlu- sion or extravasation of infusate into local tissues. The initiat- ing factor in the development of infusion phlebitis is probably endothelial damage resulting in intraluminal thrombosis. Any- thing that causes endothelial damage can, then, set off a cycle of events which, if not interrupted, inevitably culminates in thrombophlebitis. Conversely, anything that minimizes endo- thelial damage will reduce the incidence of phlebitis. The decision as to which technique of PPN administration and what additional measures should be used to reduce phlebitis will to some extent be influenced by personal preference and available facilities within any institution. Cost, convenience, and com- plications must be considered. If the clinician opts to use ultrafine cannulas, there would seem little doubt that heparin and steroids should be added to the infusate.

A strong case can be made, in addition, for glyceryl trini- trate patches and in-line filters. There would appear to be little justification these days to use short Teflon cannulas in prefer- ence to ultrafine cannulas if the intention is to leave these in situ for as long as possible. Elective rotation of cannulas and cyclical infusion is demanding on staff, but they have such a negligible incidence of phlebitis, that ancillary means to reduce the incidence of this complication are probably unnecessary. Osmolarity is important, but it is not a limiting factor to successful PPN. Kuwahara and colleagues may well be cor- rect in their assertion that dilution of infusate may reduce infusion phlebitis, but the available evidence suggests that this

EDITORIAL COMMENTS 235

is unlikely to become a major priority in PPN management protocols.

12. Everitt NJ, Wong C, McMahon MJ. Peripheral infusion as the route of choice for intravenous nutrition: a prospective 2-year study. Clin Nutr 1996;15:69

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JOHN MACFIE, MD Consultant Surgeon

Scarborough General Hospital Scarborough, North Yorkshire, UK

REFERENCES

Kuwahara T, Asanami S, Tamura T, Kubo T. Dilution is effective in reducing infusion phlebitis in peripheral parenteral nutrition: Experi- mental study in rabbits. Nutrition 1998;14:186 Henriques V, Andersen AC. Uber parenterale Emahrung durch intra- venose Injektivnen. Physiol Chem 1913;88:2.57 Stare FJ. Parenteral administration of fructose. Nutr Rev 1951;9: 173 Timmer JG, Schipper HG. Peripheral venous nutrition: the equal relevance of volume load and osmolarity in relation to phlebitis. Clin Nutr 1991;10:71 Payne-James JP, Khawaga HT. First choice for total parenteral nutri- tion: the peripheral route. JPEN 1992;17:468 May J, Murchan P, MacFie J, et al. Prospective study of aetiology of infusion phlebitis and line failure during peripheral parenteral nutri- tion. Br J Surg 1996;83:1091 Hessov I, Bojsen-Muller M. Experimental infusion thrombophlebitis. Importance of the infusion rates. Eur J Intens Care Med 1976;2: 103 Kohlhardt SR, Smith RC. Fine-bore silicone catheters for peripheral intravenous nutrition in adults. Br Med J 1989;229:1380 Madan M, Alexander DJ, McMahon MJ. Influence of catheter type on the occurrence of thrombophlebitis during peripheral intravenous nu- trition. Lancet 1992;339:101 Hecker JF. Potential for extending survival of peripheral intravenous infusions. Br Med J 1992;304:619 Reynolds JV, Walsh K, Ruigrok J, Hyland JMP. Randomised com- parison of silicone versus teflon cannulas for peripheral intravenous nutrition. Ann R Co11 Surg Engl 1995;77:447

13. Dobbins BM, Deady P, Miller GV, Tighe MJ, Martin IG, McMahon MJ. Optimising catheter survival in peripheral parenteral nutrition: a randomised control trial. Gut 1997;4O(suppl l):W78

14. Lodge JPA, Chisholm EM, Brennan TG, MacFie J. Insertion tech- nique, the key to avoiding infusion phlebitis: a prospective clinical trial. Br J Clin Pratt 1987;2:315

15. Kane KF, Cologiovanni L, McKieman J, et al. High osmolality feedings do not increase the incidence of thrombophlebitis during peripheral IV nutrition. JPEN 1995;20:194

16. Kohlhardt SR, Smith RC, Wright CR, Sucick A. Fine-bore peripheral catheters versus central venous catheters for delivery of intravenous nutrition. Nutrition 1992;8:412

17. Kohlhardt SR, Smith RC, Wright CR. Peripheral versus central intra- venous nutrition. A comparison of two delivery systems. Br J Surg 1994;81:66

18. Payne-James JJ, Rogers J, Bray MJ, et al. Development of thrombo- phlebitis in peripheral veins with Vialon and PTFE-teflon cannulas. Prospective randomised double blind randomised controlled trial. Ann R Co11 Surg Engl 1991;73:322

19. Dinley RJ. Venous reactions related to indwelling plastic cannulae: a prospective clinical trial. Curr Med Res Opin 1976;3:607

20. Nordenstrom J, Jeppsson B, Loven L, Larsson J. Peripheral parenteral nutrition: effect of a standard&d compounded mixture on infusion phlebitis. Br J Surg 1991;78:1391

21. Hill GL. In: Hill GL, ed. Disorders of nufrition and metabolism in clinical surgery. Churchill Livingstone, 1992: 131

22. Palmer D, MacFie J, Bradford IM, Murchan PM, Harrison J, Mitchell CJ. Administration of peripheral parenteral nutrition: a prospective study comparing rotation of venous access sites with ultrafine cannu- las. Clin Nutr 1996;15:311

PI1 SO899-9007(97)00427-9

EDITORIAL COMMENTS Nutririon Vol. 14, No. 2, 1998

Fatty Acids and Cancer

INTRODUCTION

The role of fatty acids in the cause and cure of cancer has been topical for more than the past decade. The paper by Eynard again addresses the relationship between essential fatty acids levels and cancer.’ While the hypothesis that polyunsaturated fatty acid (PUFA) levels are in some way connected to a predisposition to tumorigenesis, the appearance of a single marker for essential fatty acid deficiency, eicosatrienoic acid, 20:3n-9, may require the consideration of a more complex picture. A number of consider- ations are described below that provide starting points for further discussion of the role of PUFA in cancer.

FATTY ACID COMPOSITION

Since the earliest demonstrations of differences in the fatty- acid patterns of normal and tumor tissues, mere has been much speculation about the role played by PUFA in the control of tumor

growth.* Tumor tissues have a lower PUFA content than normal tissue from the same organ.3 This has led to the hypothesis that tumor tissues have reduced levels of desaturase enzymes required for normal PUFA metabolism. In early studies, this was shown to be the case for a few cell lines4 although more recent results indicate that many tumor-derived cell lines have active desatura- tiomelongation systems capable of metabolizing 18:2n-6 and 18: 3n-3 to 20:4n-6 and 20:5n-3, respectively.5 The increased conver- sion of 18: ln-9 to 20:3n-9, which is known to be associated with essential fatty acid deficiency, is also a homeostatic mechanism for maintenance of tumor cell membrane fluidity.6 Although the controls that influence the activity of this pathway remain un- known, the appearance of measurable quantities of this fatty acid may be consistent with an inadequate supply of PUFA, either dietary or circulatory. However, because tumors are usually highly vascular, fatty acid supply may not be the cause of the unusual