In the modern medical practice, up to 80% of the hospitalized patients receive intravenous (IV) therapy at some time during their admission [1]. The peripheral venous catheterization is a commonly done invasive procedure to administer medications, fluids and bio products. The most common complication associated with it is thrombophlebitis with incidence varying according to different settings [2].

ST physiopathology, similarly to deep venous thrombosis (DVT), is also related to Virchow's triad (1856). ST more frequently occurs in varicose veins, since they can have morphological changes in their wall that predispose to stasis and consequently to the development of the thrombotic process [3]. Many factors have been implicated in the genesis of phlebitis. These can be divided into chemical factors, such as irritant drugs and fluids and physical factors, such as catheter material and the site and duration of cannulation [4]. A large number of ST cases is secondary to chemical intimal lesion, by injections of infusions of different solutions, with diagnostic or therapeutic purposes, and/or mechanical lesions, such as, for example, venous catheterization [5].

Keeping this in perspective, the objective of our study was to determine the contribution of various drugs towards thrombophlebitis and the significance of contribution of drugs under study as a risk factor, thereof.

All adult patients admitted in Medicine wards and requiring intravenous cannulation during the period from July 2018 to June 2019 were included in this observational study conducted in Department of Medicine, Indira Gandhi Medical College (IGMC), Shimla, Himachal Pradesh. The patients were excluded if already suffering from thrombophlebitis at the time of admission, unconscious patients, patients with pre-existing septicaemia, patients who were hemodynamically unstable, patients who were cannulated in casualty, and/or patients who had already been cannulated at periphery. The study was initiated following approval from institute ethics committee at IGMC Shimla. All the study participants were included after they agreed to participate in the study.

Data was entered in Microsoft Excel spreadsheet and analysed using Epi Info software version 7.2.2. Categorical data were presented as number of patients, their percentage and 95% Confidence Intervals. For quantitative variables, means and standard deviations was calculated. Chi square test was applied to determine the association between the use of different drugs and the occurrence of thrombophlebitis. A p-value of less than 0.05 was considered to be statistically significant.

Different drugs were included in this study and followed for their association as the risk factors for the development of thrombophlebitis (Table 1).

Different drugs which are commonly used in medicine ward were studied as a risk factor for thrombophlebitis. Piperacillin tazobactam was associated with thrombophlebitis in 28 (87.50%) patients  with P value of 0.000, ceftriaxone in 48 (57.14%) patients with P value of 0.473, levofloxacin in 5 (83.33%) patients with p value of 0.222, doxycycline in 10 (55.56%)  patients with P value of 0.884, vancomycin in 4 (66.67%) patients with P value of 0.690, pantoprazole in 41 (66.13%) patients with P value of 0.028, metronidazole in 6 (66.67%) patients with P value of 0.513, ranitidine in 19 (51.35%) patients with P value of 0.737, metoclopramide in 15  (46.88%) patients with P value of 0.395,hydrocortisone in 5 (50%) patients with P value of 1.000. Thrombophlebitis occurred in 34 (42.50%) patients who were given frusemide compared to 111 (58.25%) patients who were not given frusemide with P value of 0.015. So, frusemide was rather found to be protective against thrombophlebitis.

Table 1: Description of drugs causing thrombophlebitis (N=269)

Mannitol was associated with thrombophlebitis in 14 (93.33%) patients with P value of 0.002, D25 in 25 (100%) patients with p value of 0.000 and others in 24 (52.17%) patients with P value of 0.796. So, injection piperacillin tazobactam, pantoprazole, mannitol and D25 were found to be associated with increased risk of thrombophlebitis (Table 2).

Increased incidence of thrombophlebitis was observed with piperacillin tazobactam, pantoprazole, furosemide, mannitol and D25. This is in consistence with   other studies   which have shown that medications and fluids of low pH and high osmolality are associated with chemical thrombophlebitis [6].Our study confirms the findings of the study conducted by Karadag et al. [7] that the administration of IV antibiotics substantially increases the risk of phlebitis. One of the reasons may be related to the fact that the intravenous antibiotics cause a chemical reaction of the endothelium with resultant phlebitis.

A great deal of evidence indicates that the nature of the infusate administered through a peripheral intravenous catheter powerfully influences the occurrence of infusion phlebitis. Glucose-containing admixtures, which are quite acidic and hypertonic glucose, amino acids and lipid emulsion, which are used in parenteral nutrition, are all far more phlebitogenic than is normal saline. Moreover, additives, such as potassium chloride [8,9] and various intravenously administered drugs, such as vancomycin,

Table 2: Determining the association of drugs as the causative agents of thrombophlebitis (N=269)

amphotericin B, most betalactam antibiotics, benzodiazepines, barbiturates, phenytoin, vasoactive pressor amines and many cancers chemotherapeutic agents, can produce severe venous inflammation [10]. Some of the drugs, such as norepinephrine, phenytoin or adriamycin, can produce frank necrosis if the drug extravasates outside the vein [11]. Stable peripheral venous access can prevent the considerable pain and the risk for tissue necrosis that are associated with extravasation of infusate. Stable access is achieved far more reliably with plastic catheters than with steel needles, as shown in several randomized trials [12]. Fortunately, the risk for device-related infection that is associated with the small Teflon and PEU-Vialon catheters now available is so low that, recommending the routine use of steel needles rather than of plastic catheters for peripheral intravenous therapy, especially if phlebitogenic or cytotoxic infusate is to be administered, no longer seems to be justifiable.

Randomized controlled trials have shown that adding hydrocortisone, heparin or both to infusate or topically applying a corticosteroid or transdermal glyceryl trinitrate at the insertion site can reduce the risk for infusate-related phlebitis [13]. The routine use of these drugs to prevent infusion-related phlebitis cannot be recommended, however, without the conduction of large-scale randomized trials that show clear benefit without serious adverse effects, such as spurious results of coagulation tests or an increased risk for bleeding, heparin-related thrombocytopenia, hemolysis, osteoporosis, adrenocortical suppression or catheter-related infection. 

Thrombophlebitis may occur secondary to the administration of infusate through cannula. In our study, we found that use of antibiotics, diuretics and proton pump inhibitors were found to be significantly associated with the occurrence of thrombophlebitis. Further studies are needed to determine whether the administration of injectable drugs are independently associated with thrombophlebitis or that the procedure and duration of insertion of cannula also attributes as a risk factor in addition to the infusate.

1. Sharifi, J. et al. "Oral versus intravenous rehydration therapy in severe gastroenteritis." Archives of Disease in Childhood, vol. 60, 1985, pp. 856–60.

2. Oliveira, A.S. and Parreira P.M. "Nursing interventions and peripheral venous catheter related phlebitis: Systemic literature review." Referencia: Scientific Journal of the Health Science Research Unit: Nursing, vol. 3, no. 2, 2010, pp. 137–47.

3. Samlaska, C.P. and James W.D. "Superficial thrombophlebitis I: Primary hypercoagulable states." Journal of the American Academy of Dermatology, vol. 22, no. 6 Pt 1, 1990, pp. 975–89.

4. Wahrenbrock, M. et al. "Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas." Journal of Clinical Investigation, vol. 112, 2003, pp. 853–62.

5. Jackson, A. "Infection control: A battle in infusion phlebitis." Nursing Times, vol. 94, no. 4, 1998, pp. 68–71.

6. Tully, J.L. et al. "Complications of intravenous therapy with steel needles and Teflon catheters: A comparative study." American Journal of Medicine, vol. 70, 1981, pp. 702–06.

7. Karadag, A. and Görgülü S. "Effect of two different short peripheral catheter materials on phlebitis development." Journal of Intravenous Nursing, vol. 23, 2000, pp. 158–66.

8. Larson, E. and Hargiss C. "A decentralized approach to maintenance of intravenous therapy." American Journal of Infection Control, vol. 12, 1984, pp. 177–86.

9. Adams, S.D. et al. "In-line filtration and infusion phlebitis." Heart & Lung, vol. 15, 1986, pp. 134–40.

10. Nelson, D.B. and Garland J.S. "The natural history of Teflon catheter-associated phlebitis in children." American Journal of Diseases of Children, vol. 141, 1987, pp. 1090–92.

11. Gaukroger, P.B. et al. "Infusion thrombophlebitis: A prospective comparison of 645 Vialon and Teflon cannulae in anaesthetic and postoperative use." Anaesthesia and Intensive Care, vol. 16, 1988, pp. 265–71.

12. Bassan, M.M. and Sheikh-Hamad D. "Prevention of lidocaine-infusion phlebitis by heparin and hydrocortisone." Chest, vol. 84, 1983, pp. 439–41.

13. Sketch, M.H. et al. "Use of percutaneously inserted venous catheters in coronary care units." Chest, vol. 62, 1972, pp. 684–89.