International Scholarly Research Notices

International Scholarly Research Notices / 2013 / Article

Clinical Study | Open Access

Volume 2013 |Article ID 650532 | https://doi.org/10.1155/2013/650532

Tetsunori Inagaki, Shintaro Makino, Takashi Yorifuji, Motoi Sugimura, Satoru Takeda, "Effectiveness of Heparin during Long-Term Tocolysis", International Scholarly Research Notices, vol. 2013, Article ID 650532, 4 pages, 2013. https://doi.org/10.1155/2013/650532

Effectiveness of Heparin during Long-Term Tocolysis

Academic Editor: E. Cosmi
Received16 Jan 2013
Accepted05 Mar 2013
Published27 Mar 2013

Abstract

Objective. Drip infusion during long-term tocolysis causes mechanical and infectious vasculitis and increases the frequency of peripheral venous catheter exchange (PVC), thereby placing a burden on patients. Our study aim is to confirm whether heparin ameliorates pain due to vasculitis during long-term tocolysis and reduces the frequency of peripheral venous catheter exchange. Design. Prospective study. Setting and Sample. All the patients requiring admission because of the presence of uterine contraction or progressive cervical dilatation from August 2009 to June 2011 at Juntendo University in Japan. Methods. Heparin was used for patients at the time the total number of peripheral venous catheter exchanges exceeded 5 in two weeks, and we evaluated whether heparin reduced the frequency of peripheral venous catheter exchange and improved the visual analog scale (VAS) for patients. The main outcome measures frequency of PVC exchange and VAS. Results. This study demonstrated that heparin reduced the frequency of peripheral venous catheter exchange ( ) and VAS ( ). No side effects were noted. Conclusion. Heparin could satisfy patients during long-term tocolysis in terms of ameliorating pain due to vasculitis and reducing the PVC exchange frequency.

1. Introduction

Preterm labor is considered differently in Japan and USA. Continuous tocolysis for more than 48 hours is not recommended in the USA. But in Japan Ritodrine hydrochloride is usually used for long-term tocolysis under the presence of uterine contraction or progressive cervical dilatation. This therapy leads to the lower premature delivery rate in Japan (actually 5.7% in 2007) than the other country (10.6% in north America). But drip infusion therapy during long term tocolysis causes pain due to vasculitis, and the PVC must be exchanged often.

Three kinds of vasculitis mechanism have recently been proposed [1]. One is chemical, another is mechanical, and the third is bacterial vasculitis. Chemical vasculitis is caused by hypertonic infusion. The pH discrepancy between the infusion and inside blood vessels is also a cause of vasculitis. The peripheral venous catheter itself also causes vasculitis by injuring endothelial cells, a form of mechanical vasculitis. Infection with bacteria also causes vasculitis. These three elements can combine to exacerbate vasculitis during long term tocolysis. These elements are thought to be prevented by heparin’s anti-inflammatory [2], anticoagulant [3, 4], and cell migration effects. Heparin’s anti-coagulant effect can improve blood flow. Furthermore, cell migration is induced to repair endothelial cells. Heparin also prevents both vessel fibrosis and neutrophil gathering at inflammatory sites [5]. Many retrospective and prospective studies [610] confirmed the effect of heparin against vasculitis but few research is done against pregnant women. As we paid attention to these effects, heparin was injected with Ritodrine into the 5% glucose bottle during drip infusion. By reducing pain and the frequency of peripheral venous catheter exchanges, patients’ satisfaction during hospitalization can be improved. Heparin’s effect during long term tocolysis was assessed prospectively in this study.

2. Methods

The observation period was from August 2009 to June 2011. We obtained a written informed consent from patients. All patients required admission for long term tocolysis were eligible for enrollment in this prospective study, if consent was obtained.

Vasculitis increases the pain, where peripheral venous catheter (PVC) placed, and the frequency of PVC exchange. So we used PVC exchange frequency and VAS of the patients to assess the objective scale in this study.

The frequency of PVC exchange was counted for two weeks after drip infusion tocolysis being started in admission. When PVC exchange exceeded 5 times in two weeks, heparin was administered with patient consent. We used the PVC, (the Sure Seald SHURflo , made by Terumo Corporation, Tokyo, Japan). The amount of heparin in the bottle was set at almost 6000 IU per day. The precise amount regulated by the velocity of drip infusion is described in Table 1. After induction, we evaluated the PVC exchange frequency, VAS, and blood examination results (platelets, liver enzymes, and coagulation system). The precise protocol of this study is described in Figure 1. For the statistical analysis, Welch’s -test was selected and a predictive value <0.05 was regarded as indicating a statistically significant difference.


VelocityHeparin per bottleTotal dose per day

20 mL/h6000 IU5760 IU/day
25 mL/h5000 IU6000 IU/day
30 mL/h4000 IU5760 IU/day
35 mL/h3500 IU5880 IU/day
40 mL/h3000 IU5760 IU/day

3. Results

The total number of patients enrolled in this study was 45. Adaptations for tocolysis are described in Table 2. For the first 2 weeks, the frequency of PVC exchange exceeded 5 times in 30 patients, and the rest 15 patients also needed the heparin rescue in more two weeks. Patient backgrounds are presented in Table 3. 27 patients were primipara and 18 were multipara. Three twin pregnancies were included. The average gestation when drip infusion started was about weeks and heparin was induced at weeks. For the first two weeks, the frequency of peripheral venous catheter exchange was times per week. After heparin inducement, the number of peripheral venous catheter exchanges was reduced to ( ). There was a significant difference in the frequency of PVC exchange between before and after inducement of heparin (Figure 2).


Adaptation for tocolysis

Progressive cervical dilatation39
Previa1
Polyamnios4
Fetal AV block1


Background


Age
Pri/para
Single/twin
Gestation of Ritodrine inducement
Gestation of heparin inducement
Gestation tocolysis finished

The VAS before induction was and improved to after induction ( ). There was a significant difference before versus after heparin rescue (Figure 3).

No drug-induced liver enzyme elevation or anti-coagulant abnormalities occurred (Table 4). The total average blood loss at delivery was  mL, indicating no adverse effect of heparin usage. The birth outcomes are shown in Table 5.


Before heparin inducementAfter heparin inducement value

Plate (×103) 0.787
AST (IU) 0.706
ALT (IU) 0.787
APTT % 0.273


Outcome

Gestation at birth weeks
Birth weight  g
pH of umbilical artery
Apgar score (1/5)

4. Discussion

Our study confirmed heparin’s beneficial effect on vasculitis. Patients during long term tocolysis are highly stressed due to the pain caused by the vasculitis. If heparin has an anti-inflammatory effect and ameliorates vasculitis, the patient’s stress during admission can be improved.

Civelek et al. reported that low-molecular-weight heparin may adversely affect incisional wound healing by suppressing the early inflammatory process [11]. Lever et al. used size-fractioned heparin experimentally [5]. They assessed the effect on elastase release induced of formyl Met Leu Phe (fMLP) from neutrophils. Elastase release was inhibited by the very-low-molecular-weight fraction of heparin, while neutrophil endothelial adhesion was unaffected. Heparin’s anti-inflammatory effect was examined in these reports.

In the surgical field, peripheral parenteral nutrition (PPN) is used instead of total parenteral nutrition. With PPN, however, peripheral vein thrombophlebitis and vascular pain are problems. Inoue et al. reported that a 1 IU/mL heparin injection into the bottle reduced both vascular pain and the rate of peripheral venous catheter exchange [12].

A prospective study on prolonging the usability of peripherally placed percutaneous central venous catheters in neonates demonstrated the beneficial effects of heparin on these catheters [1316].

Our study confirmed heparin’s beneficial effect on the pain during long term tocolysis. By ameliorating inflammation and coagulation, patients can maintain the peripheral venous catheter less painful. During this study, most of our patients felt less painful after heparin induction. Heparin inducement can mitigate pain, and thereby improve VAS.

In this study, neither drug induced hepatitis nor anti-coagulant abnormalities occurred. However, heparin induced thrombocytopenia (HIT) develops in approximately 0.5% of patients during heparin-induction therapy [17, 18]. In some cases of pregnancy, HIT were induced by heparinization [1921]. Thus, we must conduct precise blood examinations during heparinization.

The risk of heparin’s side effects is unacceptable. However, the benefits of heparin should also be considered. The stress on patients during therapy is considerable. Even if complications such as HIT occur, simply discontinuing heparin is enough to achieve recovery.

Some groups have suggested that a lower dose of heparin than that of our study would be effective. Our study is the effective dose for curing coagulant abnormalities. Thus, a lower dose of heparin might be enough to improve the pain. The next survey must consider the lower effective dose of heparin. Furthermore, a larger subject number and in vitro experiments would be needed for the next survey to prove that heparin ameliorates vasculitis itself in patients.

Key Message. Heparin can ameliorate the pain due to vasculitis during long term tocolysis and reduce the frequency of peripheral venous catheter exchange. This method lifts the burden from patients during admission.

Abbreviation

VAS:visual analog scale
PVC: peripheral venous catheter.

Conflict of Interests 

I. Inagaki state that there is no conflict of interests in connection with this paper.

References

  1. B. D. Vidosava, C. Vladan, Z. C. Lilika et al., “Endothelial cells and vasculitis advances in the etiology,” Pathogenesis and Pathology of Vasculitis, pp. 153–178, 2011. View at: Google Scholar
  2. P. V. Wooley, J. D. Ahlgren, P. J. Byrne, V. M. Priego, and P. S. Schein, “The usefulness of heparin in the prevention of phlebitis in patients undergoing anticancer chemotherapy. A Phase I trial of spirogermanium administered on a continuous infusion schedule,” Invest New Drugs, vol. 2, pp. 305–309, 1984. View at: Google Scholar
  3. Y. Ebina, H. Yamada, E. H. Kato, R. Yamamoto, N. Sakuragi, and S. Fujimoto, “Thromboprophylaxis with low molecular weight heparin in thromboprophilia—complicated pregnancy,” Journal of Obstetrics and Gynaecology Research, vol. 28, pp. 251–257, 2002. View at: Google Scholar
  4. B. Schmidt and M. Andrew, “Neonatal thrombotic disease: prevention, diagnosis, and treatment,” Journal of Pediatrics, vol. 113, no. 2, pp. 407–410, 1988. View at: Google Scholar
  5. R. Lever, W. T. Lo, M. Faraidoun et al., “Size-fractionated heparins have differential effects on human neutrophil function in vitro,” British Journal of Pharmacology, vol. 151, no. 6, pp. 837–843, 2007. View at: Publisher Site | Google Scholar
  6. J. J. Castellot, D. L. Cochran, and M. J. Karnovsky, “Effect of heparin on vascular smooth muscle cells. I. Cell metabolism,” Journal of Cellular Physiology, vol. 124, no. 1, pp. 21–28, 1985. View at: Google Scholar
  7. B. Brismar, C. Hardstedt, S. Jacobson, L. Kager, and A. S. Malmborg, “Reduction of catheter-associated thrombosis in parenteral nutrition by intravenous heparin therapy,” Archives of Surgery, vol. 117, no. 9, pp. 1196–1199, 1982. View at: Google Scholar
  8. B. Krafte-Jacobs, C. J. Sivit, R. Mejia, and M. M. Pollack, “Catheter-related thrombosis in critically ill children: Comparison of catheters with and without heparin bonding,” Journal of Pediatrics, vol. 126, no. 1, pp. 50–54, 1995. View at: Publisher Site | Google Scholar
  9. A. G. Randolph, D. J. Cook, C. A. Gonzales, and M. Andrew, “Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomised controlled trials,” British Medical Journal, vol. 316, no. 7136, pp. 969–975, 1998. View at: Google Scholar
  10. P. Appelgren, U. Ransjö, L. Bindslev, F. Espersen, and O. Larm, “Surface heparinization of central venous catheters reduces microbial colonization in vitro and in vivo: results from a prospective, randomized trial,” Critical Care Medicine, vol. 24, no. 9, pp. 1482–1489, 1996. View at: Google Scholar
  11. A. Civelek, K. Ak, O. Kurtkaya et al., “Effect of a low molecular weight heparin molecule, dalteparin, on cellular apoptosis and inflammatory process in an incisional wound-healing model,” Surgery Today, vol. 37, no. 5, pp. 406–411, 2007. View at: Publisher Site | Google Scholar
  12. Inoue et al., “Risk factors for infusion-related thrombophlebitis with peripheral venous catheters,” Surgical Therapy, vol. 82, pp. 627–634, 2000. View at: Google Scholar
  13. A. Daneman, S. Salem, P. Glanc et al., “A randomized, controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates: The HIP (heparin infusion for PCVC) study,” Pediatrics, vol. 119, no. 1, pp. e284–e291, 2007. View at: Publisher Site | Google Scholar
  14. P. S. Shah, E. Ng, and A. K. Sinha, “Heparin for prolonging peripheral intravenous catheter use in neonates,” Cochrane Database of Systematic Reviews, no. 4, Article ID CD002774, 2005. View at: Google Scholar
  15. P. Shah and V. Shah, “Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD002772, 2005. View at: Google Scholar
  16. A. Moclair and I. Bates, “The efficacy of heparin in maintaining peripheral infusions in neonates,” European Journal of Pediatrics, vol. 154, no. 7, pp. 567–570, 1995. View at: Publisher Site | Google Scholar
  17. T. E. Warkentin, “Heparin-induced thrombocytopenia: diagnosis and management.,” Circulation, vol. 110, no. 18, pp. e454–e458, 2004. View at: Google Scholar
  18. S. A. Baroletti and S. Z. Goldhaber, “Heparin-induced thrombocytopenia,” Circulation, vol. 114, no. 8, pp. e355–e356, 2006. View at: Publisher Site | Google Scholar
  19. R. Mehta and A. Golichowski, “Treatment of heparin inducedthrombocytopenia and thrombosis during the first trimester of pregnancy,” Journal of Thrombosis and Haemostasis, vol. 2, pp. 1665–1666, 2004. View at: Google Scholar
  20. K. Hassell, “The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy,” Chest, vol. 127, no. 2, pp. 1S–8S, 2005. View at: Publisher Site | Google Scholar
  21. A. Aijaz, J. Nelson, and N. Naseer, “Management of heparin allergy in pregnancy,” American Journal of Hematology, vol. 67, no. 4, pp. 268–269, 2001. View at: Publisher Site | Google Scholar

Copyright © 2013 Tetsunori Inagaki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

942 Views | 641 Downloads | 0 Citations
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.