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Clinical pharmacology considerations for children supported with ventricular assist devices

Published online by Cambridge University Press:  11 July 2018

Jennifer Sherwin
Affiliation:
From the Department of Pediatrics, Duke University Hospital, Durham, NC, USA
Elizabeth Thompson
Affiliation:
From the Department of Pediatrics, Duke University Hospital, Durham, NC, USA
Kevin D. Hill
Affiliation:
From the Department of Pediatrics, Duke University Hospital, Durham, NC, USA Duke Clinical Research Institute, Duke University, Durham, NC, USA
Kevin Watt
Affiliation:
From the Department of Pediatrics, Duke University Hospital, Durham, NC, USA Duke Clinical Research Institute, Duke University, Durham, NC, USA
Andrew J. Lodge
Affiliation:
Department of Surgery, Duke University Hospital, Durham, NC, USA
Daniel Gonzalez
Affiliation:
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Christoph P. Hornik
Affiliation:
From the Department of Pediatrics, Duke University Hospital, Durham, NC, USA Duke Clinical Research Institute, Duke University, Durham, NC, USA
Corresponding
E-mail address:

Abstract

The ventricular assist device is being increasingly used as a “bridge-to-transplant” option in children with heart failure who have failed medical management. Care for this medically complex population must be optimised, including through concomitant pharmacotherapy. Pharmacokinetic/pharmacodynamic alterations affecting pharmacotherapy are increasingly discovered in children supported with extracorporeal membrane oxygenation, another form of mechanical circulatory support. Similarities between extracorporeal membrane oxygenation and ventricular assist devices support the hypothesis that similar alterations may exist in ventricular assist device-supported patients. We conducted a literature review to assess the current data available on pharmacokinetics/pharmacodynamics in children with ventricular assist devices. We found two adult and no paediatric pharmacokinetic/pharmacodynamic studies in ventricular assist device-supported patients. While mechanisms may be partially extrapolated from children supported with extracorporeal membrane oxygenation, dedicated investigation of the paediatric ventricular assist device population is crucial given the inherent differences between the two forms of mechanical circulatory support, and pathophysiology that is unique to these patients. Commonly used drugs such as anticoagulants and antibiotics have narrow therapeutic windows with devastating consequences if under-dosed or over-dosed. Clinical studies are urgently needed to improve outcomes and maximise the potential of ventricular assist devices in this vulnerable population.

Type
Review Article
Copyright
© Cambridge University Press 2018 

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Footnotes

Cite this article: Sherwin J, Thompson E, Hill KD, Watt K, Lodge AJ, Gonzalez D, Hornik CP. (2018) Clinical Pharmacology Considerations for Children Supported with Ventricular Assist Devices. Cardiology in the Young 28: 1082–1090. doi: 10.1017/S1047951118001075

References

1. Hsu, DT, Pearson, GD. Heart failure in children: part I: history, etiology, and pathophysiology. Circ Heart Fail 2009; 2: 6370.CrossRefGoogle ScholarPubMed
2. Rossano, JW, Dipchand, AI, Edwards, LB, et al. The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant 2016; 35: 11851195.CrossRefGoogle ScholarPubMed
3. Almond, CS, Thiagarajan, RR, Piercey, GE, et al. Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009; 119: 717727.CrossRefGoogle ScholarPubMed
4. Zafar, F, Castleberry, C, Khan, MS, et al. Pediatric heart transplant waiting list mortality in the era of ventricular assist devices. J Heart Lung Transplant 2015; 34: 8288.CrossRefGoogle ScholarPubMed
5. Section on Cardiology and Cardiac Surgery; Section on Orthopaedics. Off-label use of medical devices in children. Pediatrics 2017; 139: pii: e20163439.CrossRefGoogle Scholar
6. Fraser, CD Jr, Jaquiss, RD, Rosenthal, DN, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med 2012; 367: 532541.CrossRefGoogle ScholarPubMed
7. Almond, CS, Morales, DL, Blackstone, EH, et al. Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation 2013; 127: 17021711.CrossRefGoogle ScholarPubMed
8. Blume, ED, Rosenthal, DN, Rossano, JW, et al. Outcomes of children implanted with ventricular assist devices in the United States: first analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pediatric Interagency Registry for Mechanical Circulatory Support). J Heart Lung Transplant 2016; 35: 578584.CrossRefGoogle Scholar
9. Sutcliffe, DL, Pruitt, E, Cantor, RS, et al. Post-transplant outcomes in pediatric ventricular assist device patients: A PediMACS-Pediatric Heart Transplant Study linkage analysis. J Heart Lung Transplant 2018; 37: 715722.CrossRefGoogle ScholarPubMed
10. Upperman, JS, Lacroix, J, Curley, MA, et al. Specific etiologies associated with multiple organ dysfunction syndrome in children: part 1. Pediatr Crit Care Med 2017; 18: S50S57.CrossRefGoogle ScholarPubMed
11. Jarral, OA, Saso, S, Harling, L, et al. Organ dysfunction in patients with left ventricular impairment: what is the effect of cardiopulmonary bypass? Heart Lung Circ 2014; 23: 852862.CrossRefGoogle ScholarPubMed
12. Sasse, M, Dziuba, F, Jack, T, et al. In-line filtration decreases systematic inflammatory response syndrome, renal and hematologic dysfunction in pediatric cardiac intensive care patients. Pediatr Cardiol 2015; 36: 12701278.CrossRefGoogle Scholar
13. Apostolakis, E, Filos, KS, Koletsis, E, Dougenis, D. Lung dysfunction following cardiopulmonary bypass. J Card Surg 2010; 25: 4755.CrossRefGoogle ScholarPubMed
14. Dang, NC, Naka, Y. Perioperative pharmacotherapy in patients with left ventricular assist devices. Drugs Aging 2004; 21: 9931012.CrossRefGoogle ScholarPubMed
15. Ensor, CR, Paciullo, CA, Cahoon, WD Jr, Nolan, PE Jr. Pharmacotherapy for mechanical circulatory support: a comprehensive review. Ann Pharmacother 2011; 45: 6077.CrossRefGoogle ScholarPubMed
16. Fragasso, T, Ricci, Z, Grutter, G, et al. Incidence of healthcare-associated infections in a pediatric population with an extracorporeal ventricular assist device. Artif Organs 2011; 35: 11101114.CrossRefGoogle Scholar
17. Cabrera, AG, Khan, MS, Morales, DL, et al. Infectious complications and outcomes in children supported with left ventricular assist devices. J Heart Lung Transplant 2013; 32: 518524.CrossRefGoogle ScholarPubMed
18. Monkowski, DH, Axelrod, P, Fekete, T, Hollander, T, Furukawa, S, Samuel, R. Infections associated with ventricular assist devices: epidemiology and effect on prognosis after transplantation. Transpl Infect Dis 2007; 9: 114120.CrossRefGoogle ScholarPubMed
19. Acharya, MN, Som, R, Tsui, S. What is the optimum antibiotic prophylaxis in patients undergoing implantation of a left ventricular assist device? Interact Cardiovasc Thorac Surg 2012; 14: 209214.CrossRefGoogle ScholarPubMed
20. Walker, PC, DePestel, DD, Miles, NA, Malani, PN. Surgical infection prophylaxis for left ventricular assist device implantation. J Card Surg 2011; 26: 440443.CrossRefGoogle ScholarPubMed
21. Kusne, S, Mooney, M, Danziger-Isakov, L, et al. An ISHLT consensus document for prevention and management strategies for mechanical circulation support infection. J Heart Lung Transplant 2017; 36: 11371153.CrossRefGoogle Scholar
22. Massicotte, MP, Bauman, ME, Murray, J, Almond, CS. Antithrombotic therapy for ventricular assist devices in children: do we really know what to do? J Thromb Haemost 2015; 13 (Suppl 1): S343S350.CrossRefGoogle ScholarPubMed
23. Feldman, D, Pamboukian, SV, Teuteberg, JJ, et al. The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013; 32: 157187.CrossRefGoogle ScholarPubMed
24. Baumann Kreuziger, LM. Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices. J Thromb Thrombolysis 2015; 39: 337344.CrossRefGoogle ScholarPubMed
25. Steiner, ME, Bomgaars, LR, Massicotte, MP. Berlin Heart EXCOR Pediatric VAD IDE study investigators. Antithrombotic therapy in a prospective trial of a pediatric ventricular assist device. ASAIO J 2016; 62: 719727.CrossRefGoogle Scholar
26. Moffett, BS, Cabrera, AG, Teruya, J, Bomgaars, L. Anticoagulation therapy trends in children supported by ventricular assist devices: a multi-institutional study. ASAIO J 2014; 60: 211215.CrossRefGoogle ScholarPubMed
27. Adachi, I, Kostousov, V, Hensch, L, Chacon-Portillo, MA, Teruya, J. Management of hemostasis for pediatric patients on ventricular-assist devices. Semin Thromb Hemost 2018; 44: 3037.CrossRefGoogle ScholarPubMed
28. Rutledge, JM, Chakravarti, S, Massicotte, MP, Buchholz, H, Ross, DB, Joashi, U. Antithrombotic strategies in children receiving long-term Berlin Heart EXCOR ventricular assist device therapy. J Heart Lung Transplant 2013; 32: 569573.CrossRefGoogle ScholarPubMed
29. Monagle, P, Chan, AKC, Goldenberg, NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e737Se77801.CrossRefGoogle ScholarPubMed
30. Stein, ML, Robbins, R, Sabati, AA, et al. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-defined morbidity and mortality associated with pediatric ventricular assist device support at a single US center: the Stanford experience. Circ Heart Fail 2010; 3: 682688.CrossRefGoogle Scholar
31. Butler, AC, Tait, RC. Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up. Br J Haematol 1998; 103: 10641066.CrossRefGoogle ScholarPubMed
32. Romualdi, E, Micieli, E, Ageno, W, Squizzato, A. Oral anticoagulant therapy in patients with mechanical heart valve and intracranial haemorrhage. A systematic review. Thromb Haemost 2009; 101: 290297.Google ScholarPubMed
33. Kormos, RL, Teuteberg, JJ, Pagani, FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010; 139: 13161324.CrossRefGoogle ScholarPubMed
34. Lampert, BC, Teuteberg, JJ. Right ventricular failure after left ventricular assist devices. J Heart Lung Transplant 2015; 34: 11231130.CrossRefGoogle ScholarPubMed
35. Klodell, CT Jr, Morey, TE, Lobato, EB, et al. Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices. Ann Thorac Surg 2007; 83: 6871; discussion 71.CrossRefGoogle ScholarPubMed
36. Houston, BA, Kalathiya, RJ, Hsu, S, et al. Right ventricular afterload sensitivity dramatically increases after left ventricular assist device implantation: a multi-center hemodynamic analysis. J Heart Lung Transplant 2016; 35: 868876.CrossRefGoogle ScholarPubMed
37. Modica, M, Ferratini, M, Torri, A, et al. Quality of life and emotional distress early after left ventricular assist device implant: a mixed-method study. Artif Organs 2015; 39: 220227.CrossRefGoogle ScholarPubMed
38. Brouwers, C, Denollet, J, Caliskan, K, et al. Psychological distress in patients with a left ventricular assist device and their partners: an exploratory study. Eur J Cardiovasc Nurs 2015; 14: 5362.CrossRefGoogle ScholarPubMed
39. Wildschut, ED, Ahsman, MJ, Houmes, RJ, et al. Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO). Curr Drug Metab 2012; 13: 767777.CrossRefGoogle Scholar
40. Wildschut, ED, van Saet, A, Pokorna, P, Ahsman, MJ, Van den Anker, JN, Tibboel, D. The impact of extracorporeal life support and hypothermia on drug disposition in critically ill infants and children. Pediatr Clin North Am 2012; 59: 11831204.CrossRefGoogle ScholarPubMed
41. Harthan, AA, Buckley, KW, Heger, ML, Fortuna, RS, Mays, K. Medication adsorption in to contemporary extracorporeal membrane oxygenator circuits. J Pediatr Pharmacol Ther 2014; 19: 288295.Google ScholarPubMed
42. Shekar, K, Roberts, JA, McDonald, CI, et al. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care 2012; 16: R194.CrossRefGoogle ScholarPubMed
43. Watt, KM, Gonzalez, D, Benjamin, DK Jr, et al. Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation. Antimicrob Agents Chemother 2015; 59: 39353943.CrossRefGoogle ScholarPubMed
44. Jennings, DL, Makowski, CT, Chambers, RM, Lanfear, DE. Dosing of vancomycin in patients with continuous-flow left ventricular assist devices: a clinical pharmacokinetic analysis. Int J Artif Organs 2014; 37: 270274.CrossRefGoogle ScholarPubMed
45. Shimamoto, Y, Fukuda, T, Tominari, S, et al. Decreased vancomycin clearance in patients with congestive heart failure. Eur J Clin Pharmacol 2013; 69: 449457.CrossRefGoogle ScholarPubMed
46. Heil, EL, Lowery, AV, Thom, KA, Nicolau, DP. Treatment of multidrug-resistant pseudomonas aeruginosa using extended-infusion antimicrobial regimens. Pharmacotherapy 2015; 35: 5458.CrossRefGoogle ScholarPubMed
47. Lexicomp. Cefepime drug information, 2013. Retrieved 13 September 2017, from http://online.lexi.com/action/home.Google Scholar
48. Nicasio, AM, Ariano, RE, Zelenitsky, SA, et al. Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 2009; 53: 14761481.CrossRefGoogle ScholarPubMed
49. Jennings, DL, Brewer, R, Williams, C. Impact of continuous flow left ventricular assist device on the pharmacodynamic response to warfarin early after implantation. Ann Pharmacother 2012; 46: 12661267.CrossRefGoogle ScholarPubMed
50. Shekar, K, Roberts, JA, McDonald, CI, et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care 2015; 19: 164.CrossRefGoogle ScholarPubMed
51. Preston, TJ, Hodge, AB, Riley, JB, Leib-Sargel, C, Nicol, KK. In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit. J Extra Corpor Technol 2007; 39: 234237.Google ScholarPubMed
52. Preston, TJ, Ratliff, TM, Gomez, D, et al. Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit. J Extra Corpor Technol 2010; 42: 199202.Google ScholarPubMed
53. Duke University Hospital ECMO Steering Committee. ECMO Set Up and Management Policy, 2015. Retrieved 13 September 2017, from https://sites.duke.edu/micu/files/2016/02/ECMO-Set-Up-Management.pdf.Google Scholar
54. Food and Drug Administration (FDA) Pediatric Advisory Committee. Berlin Heart Inc. EXCOR Pediatric the Ventricular Assist Device for Children. 2015, Retrieved 13 September 2017, from https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM461241.pdf.Google Scholar
55. Thoratec Corporation. CentriMag: Magnetically Levitated Circulatory Support System. Columbia University Department of Surgery. Retrieved 13 September 2017, from http://columbiasurgery.org/sites/default/files/lvad_centrimag.pdf.Google Scholar
56. Anderson, HL 3rd, Coran, AG, Drongowski, RA, Ha, HJ, Bartlett, RH. Extracellular fluid and total body water changes in neonates undergoing extracorporeal membrane oxygenation. J Pediatr Surg 1992; 27: 10031007; discussion 1007–1008.CrossRefGoogle ScholarPubMed
57. Butler, J, Pathi, VL, Paton, RD, et al. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg 1996; 62: 538542.CrossRefGoogle ScholarPubMed
58. Seghaye, MC, Grabitz, RG, Duchateau, J, et al. Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations. J Thorac Cardiovasc Surg 1996; 112: 687697.CrossRefGoogle ScholarPubMed
59. Corry, DC, DeLucia, A 3rd, Zhu, H, et al. Time course of cytokine release and complement activation after implantation of the HeartMate left ventricular assist device. ASAIO J 1998; 44: M347M351.CrossRefGoogle ScholarPubMed
60. Petretta, M, Condorelli, GL, Spinelli, L, et al. Circulating levels of cytokines and their site of production in patients with mild to severe chronic heart failure. Am Heart J 2000; 140: E28.CrossRefGoogle ScholarPubMed
61. Clark, AL, Loebe, M, Potapov, EV, et al. Ventricular assist device in severe heart failure: effects on cytokines, complement and body weight. Eur Heart J 2001; 22: 22752283.CrossRefGoogle ScholarPubMed
62. Caruso, R, Verde, A, Campolo, J, et al. Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance. Cytokine 2012; 59: 138144.CrossRefGoogle ScholarPubMed
63. Slaviero, KA, Clarke, SJ, Rivory, LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003; 4: 224232.CrossRefGoogle ScholarPubMed
64. Reddy, RC, Goldstein, AH, Pacella, JJ, Cattivera, GR, Clark, RE, Magovern, GJ Sr. End organ function with prolonged nonpulsatile circulatory support. ASAIO J 1995; 41: M547M551.CrossRefGoogle ScholarPubMed
65. Russell, SD, Rogers, JG, Milano, CA, et al. Renal and hepatic function improve in advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation 2009; 120: 23522357.CrossRefGoogle ScholarPubMed
66. Demirozu, ZT, Etheridge, WB, Radovancevic, R, Frazier, OH. Results of HeartMate II left ventricular assist device implantation on renal function in patients requiring post-implant renal replacement therapy. J Heart Lung Transplant 2011; 30: 182187.CrossRefGoogle ScholarPubMed
67. Imamura, T, Kinugawa, K, Shiga, T, et al. Preoperative levels of bilirubin or creatinine adjusted by age can predict their reversibility after implantation of left ventricular assist device. Circ J 2013; 77: 96104.CrossRefGoogle ScholarPubMed
68. Imamura, T, Kinugawa, K, Shiga, T, et al. Novel risk scoring system with preoperative objective parameters gives a good prediction of 1-year mortality in patients with a left ventricular assist device. Circ J 2012; 76: 18951903.CrossRefGoogle ScholarPubMed
69. Gonzalez, D, Melloni, C, Yogev, R, et al. Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. Clin Pharmacol Ther 2014; 96: 429437.CrossRefGoogle Scholar
70. Hornik, CP, Wu, H, Edginton, AN, Watt, K, Cohen-Wolkowiez, M, Gonzalez, D. Development of a pediatric physiologically-based pharmacokinetic model of clindamycin using opportunistic pharmacokinetic data. Clin Pharmacokinet 2017; 56: 13431353.CrossRefGoogle ScholarPubMed

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