April 2014 FAQs

Is there a benefit to using colloid solutions versus crystalloid solutions as fluid resuscitation for patients with hypovolemic shock?

Introduction

In hypovolemic shock, intravenous fluid administration is the cornerstone of therapy; however, a long-standing controversy exists surrounding the selection of fluid products, specifically between crystalloid solutions and colloid solutions. 1-7 While the debate often focuses on the high cost of colloid solutions versus the larger required volume for crystalloid solutions, a clinical controversy also exists regarding which type of fluid resuscitation most benefits patients in hypovolemic shock. This crystalloid-colloid debate has existed for decades, leading to a general consensus that the composition of fluids utilized for resuscitation does not influence the morbidity or mortality of patients in hypovolemic shock; rather, the chief differences involve cost and total volume required for resuscitation.1-6 However, emerging data and updated clinical practice guidelines have shed new light on potential differences in morbidity and mortality among solution types.7-12 After one of the longest-running debates in clinical medicine, fluid composition may indeed be important after all, at least in certain patient subpopulations.

Background

True volume depletion, or hypovolemia, generally refers to a state of combined salt and water loss that leads to contraction of the extracellular fluid volume (ECFV).13 As such, hypovolemic shock, defined as decreased peripheral perfusion with shock, requires rapid volume repletion to help prevent detrimental ischemic injury and potentially irreversible multi-organ system failure. In providing volume repletion, clinicians need to consider the rate of fluid replacement, the type of fluid to infuse, as well as the potential need for buffers.

Three major classes of fluid replacement are currently available for intravascular resuscitation: crystalloids, colloids, and blood products or substitutes.13 Crystalloids include saline, buffered solutions, and chloride-restrictive fluids (also known as Hartmann’s). Colloids include albumin, hypertonic starch, dextran, and gelatin. Blood products or substitutes include packed red cells or blood substitutes. Choice of replacement fluid largely depends upon the presumed type of fluid lost; for example, a trauma patient who experienced significant blood loss would largely require blood products. Both crystalloid and colloid solutions are used to replace extracellular deficits not due to bleeding. Generally, crystalloid solutions and colloid solutions are equally effective in expanding the plasma volume; however, 2 to 4 times as much crystalloid volume must be given for effective resuscitation due to the extravascular distribution of such solutions. However, the exorbitant cost of colloid solutions limits their practicality.

The origin of the crystalloid-colloid debate dates back to World War II, when albumin was first used to treat burned soldiers at Pearl Harbor.14 In the 1970s and 1980s, colloids became more widely used and, as such, consumed a larger proportion of pharmacy budgets, often without clear indication for use. The controversy came to a head in 1998 when the British Medical Journal published a meta-analysis reporting an absolute risk of mortality of 4% (95% confidence interval (CI) 0% to 8%) in critically ill patients who were treated with colloid solutions as compared to those treated with crystalloids.2 Also in 1998, a Cochrane analysis was published in the British Medical Journal that focused specifically on albumin, but also mentioned concern for mortality in patients receiving colloids versus crystalloids.3 The net effect of these publications was a decline in use of colloids for fluid resuscitation. In response, a third, more rigorous meta-analysis of colloid use in critically ill patients was published in Critical Care Medicine in 1999.4 The authors also investigated possible co-morbidities that could have potentiated the higher risk of mortality. They found no overall difference in mortality between patients treated with crystalloids versus colloids. This analysis provided the first rebuttal to the rising concerns with colloid use at this time.

The Saline vs Albumin Fluid Evaluation (SAFE) trial conducted by the Australia and New Zealand Intensive Care Society in 2004 was another landmark trial for this heated debate. The trial randomized 7,000 critically ill patients to receive normal saline (crystalloid) or 4% albumin (colloid) for fluid resuscitation.5 The relative risk (RR) of mortality among patients randomized to receive albumin versus those assigned to receive saline was 0.99 (95% CI 0.91 to 1.09, p=0.87). There was no significant difference in survival between the two groups (p=0.96). In contrast, the patient subset with severe sepsis given albumin was reported to have a RR of mortality of 0.87 (95% CI 0.74 to 1.02, p=0.09) as compared to those given normal saline. The subset of patients with traumatic injuries were reported to have a RR of mortality of 1.36 when given albumin versus saline (95% CI 0.99 to 1.86, p=0.06). Thus, the SAFE trial provided insight into the safety and effectiveness of both crystalloids and colloids in critically ill patients by shedding light on potentially deleterious effects with colloids in certain patient sub-populations; however, none of the differences between populations were significant. Thus the controversy continued.

Also in 2004, the American Thoracic Society issued a consensus statement on the use of colloids in the critically ill; however, several pertinent articles have been published in the literature since this document was published.1 In 2008, the Society of Critical Care Medicine took their first stance on volume resuscitation in the management of sepsis, albeit indeterminate.6 An updated and more detailed stance was recently published in the 2012 “Surviving Sepsis Campaign Guidelines for the Management of Severe Sepsis and Septic Shock,” published in February of 2013.7

Current Practice Guidelines and Recent Literature

The most recent Surviving Sepsis Campaign guidelines state that crystalloids are recommended as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B).7 This recommendation is supported by the absence of any clear benefit of colloid solutions versus crystalloid solutions for this indication, together with the significantly higher expense seen with colloids. However, in the event that a patient is requiring substantial amounts of crystalloids for fluid resuscitation, albumin (a colloid) is recommended (grade 2C). Finally, the use of hydroxyethyl starches (colloids) are not recommended for use in fluid resuscitation at all, due to evidence of increased risk of acute kidney injury, need for renal replacement therapy, and mortality. The recommendations for fluid resuscitation provided in the Surviving Sepsis Guidelines were largely based on the data obtained from 4 multicenter, randomized, controlled trials (Table 1). 8-11

Table 1. Findings from the VISEP, CRYSTMAS, 6S, and CHEST trials.8-11

The CRISTAL Trial

The Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was an international, multicenter, 9-year, open-label, randomized trial that was designed to test whether the use of colloids compared with crystalloids for fluid resuscitation altered mortality in patients with hypovolemic shock admitted to the intensive care unit (ICU).12 The trial enrolled a total of 2857 patients with hypovolemic shock due to any cause who were then randomized to 2 parallel groups of resuscitation with intravenous crystalloid solutions (1443 patients) or intravenous colloid solutions (1414 patients). Allowed solutions in the crystalloid group included isotonic or hypertonic saline and buffered solutions. Allowed treatments in the colloid group included gelatins, 4% or 5% albumin, dextrans, hydroxyethyl starches, and 20% or 25% albumin. Investigators were permitted to use the fluid formulations that were available at their institution, and the amount and duration of treatment was left to their discretion. Restriction was placed on the total daily dose of hydroxyethyl starch, which could not exceed 30 mL/kg of body weight if used. Study members blinded to treatment assignment were responsible for collecting and evaluating the mortality end points.

Mortality at 28-days was the primary outcome of this study. Death at 90 days and ICU/hospital discharge; number of days alive without renal replacement therapy, mechanical ventilation or vasopressor therapy; days without organ failure; and days not in the ICU or hospital were secondary outcomes of this study. The intention-to-treat principle was used to perform the final analysis. No difference was found in 28-day mortality or need for renal replacement therapy between groups. For the primary outcome, there were 359 deaths (25.4%) in the colloids group versus 390 deaths (27.0%) in the crystalloids group (relative risk [RR], 0.96 [95% confidence interval (CI), 0.88 to1.04; p=0.26]). However, patients who were resuscitated with colloids had more days free of mechanical ventilation (mean 14.6 days versus 13.5 days, p=0.01) and vasopressor therapy (mean 16.2 days versus 15.2 days, p=0.03), as well as a lower 90-day mortality (30.7% versus 34.2% [RR 0.92, 95% CI 0.86 to 0.99, p=0.03]). Previous trials investigating fluid resuscitation also demonstrated an increase in the magnitude of treatment effect between the 28-day and 90-day time points.8,10 Additionally, the results of this study demonstrate a lack of harm with the use of colloids overall, which is consistent with previous trials.8,10 However, the authors note that the finding of decreased mortality at 90 days should be considered exploratory until validated in a study focusing on this outcome.

These results are internationally generalizable due to the large sample size, participation of ICUs from 3 continents, and from both university and community hospitals. However, none of the participants were from the United States. It can be argued that the current guidelines followed at most institutions are the international Surviving Sepsis Campaign guidelines, but this fact cannot be ignored in generalizing this study’s results to patients in the United States. Of note, the study population also differed from those of other recent trials of fluid administration in ICU patients in that this trial specifically looked at patients presenting with hypotension and lactic acidosis. This may account in part for the inconsistency in observed effects of colloids on mortality between this trial and those previously performed. Limitations of the study include its open-label design and prolonged enrollment period of 9 years. Such an extended enrollment period could allow for confounding in terms of varying trends in hypovolemic management based on publications of conflicting literature during that time period. Also, the heterogeneity of the fluids used in these patients could also be deemed a limitation. Overall, this study was well-designed and provides important insight into the usefulness of crystalloid solutions versus colloid solutions in the treatment of hypovolemic shock.

Conclusion/Recommendations

Most of the currently available data suggests that crystalloid solutions are preferred over colloid solutions, due to their ease of use and cost-effectiveness. Colloid solutions have inconsistently shown a clear benefit in patients who have been resuscitated with them and, as such, their role in clinical practice is limited. Per the current Surviving Sepsis Campaign guidelines, albumin is recommended only in the event that a patient is requiring large volumes of crystalloids; but this is the only distinction that is made for colloids in current practice guidelines. However, in light of the more recent CRISTAL trial, colloids could potentially be beneficial in preventing 90-day mortality and minimizing the need for life-support measures. The open-label design, lengthy study period, and heterogeneity of fluids that were compared between the groups remain limitations to this study’s interpretation. As such, these findings should be considered exploratory and require further validation before these solutions can be routinely administered as a first-line option for the resuscitation of patients with hypovolemic shock.

Clinicians should also always remain mindful of the advantages and disadvantages of individual solution types within these 2 broad categories when selecting a resuscitation fluid. For example, normal saline is known to cause hyperchloremia and metabolic acidosis and Lactated Ringer’s is able to give rise to respiratory acidosis from accumulated carbon dioxide. As a result, fluid therapy should be individualized to each patient’s individual needs. Not all crystalloids or colloids are created equal, thus promulgating this controversy and further limiting the ability of clinical trials to distinguish the superiority of one class of fluids over the other.

References

1. American Thoracic Society. Evidence-based Colloid Use in the Critically Ill: American Thoracic Society Consensus Statement. Am J Respir Crit Care Med. 2004;170(11):1247-1259.

2. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systemic review of randomised trials. BMJ. 1998;316(7136):961-964.

3. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317(7153):235-240.

4. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med. 1999;27(1):200-210.

5. Finfer S, Bellomo R, Boyce, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit (SAFE). N Engl J Med. 2004;350(22):2247-2256.

6. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008:36(1):296-327.

7. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013:39(2):165-228.

8. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis (VISEP). N Engl J Med. 2008;358(2):125-139

9. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16(3):R94.

10. Perner A, Haase N, Guttormsen A, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis (6S). N Engl J Med. 2012;367(2):124-134.

11. Myburgh JA, Finfer A, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care (CHEST). N Engl J Med. 2012;367(20):1901-1911.

12. Annane D, Siami S, Jaber A, Martin C, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310(17):1809-1817.

13. Kang-Birken SL, Killgore-Smith K. Chapter 128. Severe Sepsis and Septic Shock. In: Wells BG, ed. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=8005066. Accessed November 22, 2013.

14. Caironi P, Gattinoni L. The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7(4):259-267.

Prepared by:

Laura M. Lourenço, PharmD

PGY-1 Pharmacy Practice Resident

April 2014

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What drug products may be used in patients with anemia or hemorrhage who are Jehovah’s Witnesses?

Introduction

The treatment of hematological problems in patients who are Jehovah’s Witnesses can present difficulties because of these patients’ faith-based refusal of blood and some blood-related drug products.1 This refusal is rooted in interpretations of biblical passages, specifically Genesis 9:3-4 and Leviticus 17:10-16, which prohibit accepting any blood that has been “lost” from the body or the consumption of food that contains blood.2 Some passages in Deuteronomy also are interpreted as instructing that after blood leaves the body it should be poured “out upon the ground as water.” These interpretations have become tenets in the Jehovah’s Witnesses faith, and their violation may compromise a patient’s belief in his or her ability to obtain eternal life.1,2

Jehovah’s Witnesses are instructed to refuse transfusions of whole blood and any of its major components, including red blood cells, white blood cells, platelets, and plasma.1,2 Additionally, preoperative autologous blood donation is prohibited, as religious belief does not allow for the storing of blood.3,4 Acceptable treatments are limited to blood conservation strategies, non-blood volume expanders, and some pharmacologic agents not derived from or containing certain blood components. The use of these pharmacologic agents in Jehovah’s Witnesses with anemia or hemorrhage is the focus of this review.

Stimulation of erythropoiesis to avoid transfusion

Because of the clear contraindication to blood transfusion, many Jehovah’s Witnesses alternatively accept erythropoiesis-stimulating agents (ESAs) to reduce the risk of anemia and avoid transfusion. 3,5-8 The use of ESAs in Jehovah’s Witnesses is one of the most described and well-known issues in these patients’ medical care. Recombinant human erythropoietin (rHuEPO) has been used in numerous cases of critically ill Jehovah’s Witnesses requiring the drug as an alternative to transfusion.6 While dosing has varied, typical rHuEPO regimens in these patients have been higher than those for labeled indications, ranging from 300 to 500 units/kg/day intravenously or subcutaneously in settings of trauma, burn, general surgery, and gastrointestinal hemorrhage.1,6-8 Nearly all reports described concomitant use of iron and folic acid. Although evidence is limited to case studies, literature reviews have found improvements in measures of erythropoiesis and support the use of rHuEPO as an alternative to blood products in this setting.6 However, the transfusion-sparing effect of rHuEPO should be weighed against the potential for serious adverse events such as thromboembolism and hypertension.

Similarly, rHuEPO has been used prior to surgical procedures in Jehovah’s Witnesses for blood augmentation.9-26 Pretreatment with rHuEPO, normally in combination with iron and folic acid, has been described in patients undergoing cardiac, gastrointestinal, obstetric, orthopedic, and transplantation procedures. Most literature describes the use of rHuEPO for approximately 2 weeks preprocedurally and those describing weight-based dosing have utilized 100 IU/kg 3 times weekly in adults and 180 IU/kg/day in children.10,11 Target hematologic indices that warranted discontinuation of pretreatment have included hemoglobin of 14 g/dL and hematocrit of 45%.10,12 A standardized dosing regimen for preoperative rHuEPO use, including treatment duration and dose modification, was described by Sparling and colleagues for use in Jehovah’s Witnesses undergoing hip arthroplasty. 10

Patient discretion in accepting blood subfractions

Because human albumin is present in vials of rHuEPO, its acceptance varies among Jehovah’s Witnesses, illustrating the importance of patients’ individual decisions regarding blood subfractions.6-8 The Watchtower Society, the governing body of Jehovah’s Witnesses, encourages followers to exercise individual discretion in the determination of their willingness to accept products containing blood components.2 The 2001 statement directed followers to refuse receipt of blood and its 4 main fractions, but declared that acceptance of subfractions such as albumin, immunoglobulins, blood factor concentrates, cryoprecipitate, and recombinant products should be based in “conscientious decision.” Thus, acceptance of products containing these fractions may vary among Jehovah’s Witnesses. Those concerned with receipt of albumin-containing rHuEPO products should be advised that Procrit and Epogen contain human albumin, while some formulations of darbepoetin (Aranesp) contain polysorbate 80 rather than albumin.4,7,8,27 However, no reports exist describing the use of darbepoetin in Jehovah’s Witnesses.

Procoagulants used in acute bleeding

In addition to ESAs, the use of procoagulant drug products may be considered in Jehovah’s Witnesses who experience acute bleeding, as many who refuse receipt of fresh frozen plasma require alternatives.1,3 Procoagulants that are derived from pooled human plasma may be options if deemed acceptable by the patient. Case reports in Jehovah’s Witnesses have detailed the use of such products, including cryoprecipitate, human antithrombin, and 4-factor prothrombin complex concentrates (Octaplex and Beriplex P/N).28-31 Reports are lacking on the use in Jehovah’s Witnesses of other human plasma-derived procoagulants commonly used in life-threatening bleeding, such as Kcentra and Profilnine.32,33 Although they are not derived from human blood and do not contain albumin, the use of vitamin K, desmopressin, tranexamic acid, and recombinant activated factor VII in Jehovah’s Witnesses requiring hemostasis has also been described and recommended.1,29,30,34-42

Summary

The refusal of blood and some blood-related products by Jehovah’s Witnesses may lead to dilemmas in these patients’ medical care. While blood and its 4 main fractions are generally always refused, personal decision directs the acceptance of products containing blood subfractions such as albumin, immunoglobulins, or clotting factors. These wishes should be discussed with patients and caregivers and be respected in treatment plans. A growing body of literature describes the use of rHuEPO in Jehovah’s Witnesses who require transfusion alternatives and who undergo surgical procedures; the use of blood-derived procoagulants has also been reported in Jehovah’s Witnesses requiring hemostasis.

References

1. Berend K, Levi M. Management of adult Jehovah's Witness patients with acute bleeding. Am J Med. 2009;122(12):1071-1076.

2. Watchtower Bible and Tract Society. Questions from readers: do Jehovah's Witnesses accept any medical products derived from blood? Watchtower. 2000;15:29-31.

3. Rogers DM, Crookston KP. The approach to the patient who refuses blood transfusion. Transfusion. 2006;46(9):1471-1477.

4. Hughes DB, Ullery BW, Barie PS. The contemporary approach to the care of Jehovah's witnesses. J Trauma. 2008;65(1):237-247.

5. Nash MJ, Cohen H. Management of Jehovah's Witness patients with haematological problems. Blood Rev. 2004;18(3):211-217.

6. Ball AM, Winstead PS. Recombinant human erythropoietin therapy in critically ill Jehovah's Witnesses. Pharmacotherapy. 2008;28(11):1383-1390.

7. Epogen [package insert]. Thousand Oaks, CA: Amgen Inc.; 2012.

8. Procrit [package insert]. Horsham, PA: Janssen Products, LP; 2012.

9. Nagy CJ, Wheeler AS, Archer TL. Acute normovolemic hemodilution, intraoperative cell salvage and PulseCO hemodynamic monitoring in a Jehovah's Witness with placenta percreta. Int J Obstet Anesth. 2008;17(2):159-163.

10. Sparling EA, Nelson CL, Lavender R, Smith J. The use of erythropoietin in the management of Jehovah's Witnesses who have revision total hip arthroplasty. J Bone Joint Surg Am. 1996;78(10):1548-1552.

11. Perez-Ferrer A, De Vicente J, Gredilla E, Garcia-Vega MI, Bourgeois P, Goldman LJ. Use of erythropoietin for bloodless surgery in a Jehovah's witness infant. Paediatr Anaesth. 2003;13(7):633-636.

12. Baldry C, Backman SB, Metrakos P, Tchervenkov J, Barkun J, Moore A. Liver transplantation in a Jehovah's Witness with ankylosing spondylitis. Can J Anaesth. 2000;47(7):642-646.

13. Cheung EH, Sutton SW, Marcel R. Aortic valve replacement in a dialysis-dependent Jehovah's Witness: successful use of a minicircuit, microplegia, and multimodality blood conservation technique. Proc (Bayl Univ Med Cent). 2007;20(1):32-35.

14. Baciewicz FA, Williams M. Off-pump myocardial revascularizaton in a Jehovah's Witness patient with pheochromocytoma. Interact Cardiovasc Thorac Surg. 2006;5(4):505-506.

15. Jamdar S, Siriwardena AK. Strategic management of severe acute pancreatitis in the Jehovah's witness. Int J Clin Pract. 2005;59(11):1368-1370.

16. Jabbour N, Gagandeep S, Mateo R, Sher L, Genyk Y, Selby R. Transfusion free surgery: single institution experience of 27 consecutive liver transplants in Jehovah's Witnesses. J Am Coll Surg. 2005;201(3):412-417.

17. Detry O, Roover AD, Delwaide J, et al. Liver transplantation in Jehovah's witnesses. Transpl Int. 2005;18(8):929-936.

18. Jabbour N, Gagandeep S, Mateo R, et al. Live donor liver transplantation without blood products: strategies developed for Jehovah's Witnesses offer broad application. Ann Surg. 2004;240(2):350-357.

19. Alexi-Meskishvili V, Stiller B, Koster A, et al. Correction of congenital heart defects in Jehovah's Witness children. Thorac Cardiovasc Surg. 2004;52(3):141-146.

20. Jabbour N, Gagandeep S, Mateo R, et al. Live donor liver transplantation: staging hepatectomy in a Jehovah's Witness recipient. J Hepatobiliary Pancreat Surg. 2004;11(3):211-214.

21. Williams M, Blocksom JM, Baciewicz FA, Jr. Coronary artery bypass grafting in a dialysis-dependent Jehovah's Witness. Tex Heart Inst J. 2004;31(2):181-183; discussion 183.

22. Panousis K, Rana B, Hunter J, Grigoris P. Rapid sequence quadruple joint replacement in a rheumatoid Jehovah's Witness. Arch Orthop Trauma Surg. 2003;123(2-3):128-131.

23. Shiozawa S, Haga S, Kumazawa K, et al. Pylorus-preserving pancreaticoduodenectomy without homologous blood transfusion in a Jehovah's witness with pancreatic cancer: report of a case. Hepatogastroenterology. 2003;50(49):272-274.

24. Dohmen PM, Liu J, Lembcke A, Konertz W. Reoperation in a Jehovah's Witness 22 years after aortic allograft reconstruction of the right ventricular outflow tract. Tex Heart Inst J. 2003;30(2):146-148.

25. Singla AK, Lapinski RH, Berkowitz RL, Saphier CJ. Are women who are Jehovah's Witnesses at risk of maternal death? Am J Obstet Gynecol. 2001;185(4):893-895.

26. Chikada M, Furuse A, Kotsuka Y, Yagyu K. Open-heart surgery in Jehovah's Witness patients. Cardiovasc Surg. 1996;4(3):311-314.

27. Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc.; 2013.

28. Greenberg A, Macphee I, Popoola J, et al. HLA antibody-incompatible kidney transplantation between jehovah's witnesses–a case report. Transplant Proc. 2013;45(5):2069-2071.

29. Sniecinski RM, Chen EP, Levy JH, Szlam F, Tanaka KA. Coagulopathy after cardiopulmonary bypass in Jehovah's Witness patients: management of two cases using fractionated components and factor VIIa. Anesth Analg. 2007;104(4):763-765.

30. Robblee JA, Wilkes PR, Dickie SJ, Rubens FD, Bormanis J. Bleeding in a Jehovah's Witness patient undergoing a redo aortic valve replacement controlled with cryoprecipitate and a prothrombin complex concentrate. Can J Anaesth. 2012;59(3):299-303.

31. Bhardwaj M, Bunsell R. Beriplex P/N: an alternative to fresh frozen plasma in severe haemorrhage. Anaesthesia. 2007;62(8):832-834.

32. Kcentra [package insert]. Kankakee, IL: CSL Behring GmbH; 2013.

33. Profilnine [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; 2013.

34. Phytonadione [package insert]. Lake Forest, IL: Hospira Inc., 2004.

35. Desmopressin acetate [package insert]. Lake Forest, IL: Hospira Inc.; 2011.

36. Cyclokapron [package insert]. New York, NY: Pfizer Inc.; 2013.

37. NovoSeven RT [package insert]. Plainsborough, NJ: Novo Nordisk; 2013.

38. French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. Neurocrit Care. 2012;17(1):107-111.

39. Arab TS, Al-Wazzan AB, Maslow K. Postpartum hemorrhage in a Jehovah's Witness patient controlled with Tisseel, tranexamic acid, and recombinant factor VIIa. J Obstet Gynaecol Can. 2010;32(10):984-987.

40. Kandane-Rathnayake RK, Isbister JP, Zatta AJ, Aoki NJ, Cameron P, Phillips LE. Use of recombinant activated factor VII in Jehovah's Witness patients with critical bleeding. ANZ J Surg. 2013;83(3):155-160.

41. Haan J, Scalea T. A Jehovah's Witness with complex abdominal trauma and coagulopathy: use of factor VII and a review of the literature. Am Surg. 2005;71(5):414-415.

42. Majumdar G, Savidge GF. Recombinant factor VIIa for intracranial haemorrhage in a Jehovah's Witness with severe haemophilia A and factor VIII inhibitors. Blood Coagul Fibrinolysis. 1993;4(6):1031-1033.

April 2014

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What data are available to direct the dosing weight used for daptomycin in obesity?

Introduction

Daptomycin is the first antibiotic in the lipopeptide class with bactericidal activity against gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, or MRSA) and enterococci (including vancomycin-resistant Enterococci, or VRE).1 The US Food and Drug Administration (FDA)-labeled treatment indications and dosing include complicated skin and soft tissue infections (4 mg/kg/day) and bacteremia/right-sided endocarditis (6 mg/kg/day). The manufacturer recommends the dosing to be based on the actual or total body weight (TBW) of the patient. The medication is renally cleared and dosing must be adjusted for a creatinine clearance (CrCl) <30 mL/min. The main concerns related to toxicity are the development of rhabdomyolysis and/or myalgias, so optimal dosing is important from both an efficacy and a safety standpoint.

There are several different types of body weights that can be considered for dosing of antibiotics.2,3 Examples of commonly used weights and the formulas used to calculate them are listed in Table 1. Depending on the pharmacokinetic parameters of the drug, certain body weights may be recommended for antibiotic dose calculations when patients are obese. Obesity is often defined based on the body mass index (BMI) of individuals.A BMI of ≥30 kg/m2 is commonly considered obese; 35 to <40 kg/m2 is severely obese, and >40 kg/m2 is morbidly obese.

ABW=adjusted body weight; BMI=body mass index; FFM=fat-free mass; Ht (m2)=height (in meters); IBW=ideal body weight; LBW=lean body weight; TBW=total body weight.

*All weights are represented in kilograms

With the exception of aminoglycosides and vancomycin, there are limited data on the pharmacodynamics and dosing of antibiotics in obesity.2,3 A safe and efficacious dosing weight of daptomycin in obese patients has not been clearly defined. The optimal dosing weight in obese patients is of particular relevance to pharmacy departments, as unwarranted supratherapetic dosing may cause concerns for safety, efficacy, adverse drug events (ADEs), and increased cost in the obese patient population.

Daptomycin pharmacokinetics in obesity

Changes in physiology occur in obesity that can alter the pharmacokinetics of antibiotics.2 Some pharmacokinetic parameters that are altered are the volume of distribution (Vd) and drug clearance. The Vd of lipophilic drugs is generally higher and requires dosing based on TBW. 3 In contrast, hydrophilic drugs have a lower Vd and can be dosed based on ideal body weight (IBW) or adjusted body weight (ABW). Daptomycin has both hydrophilic and hydrophobic components. Obesity has been shown to affect the glomerular filtration rate and therefore can also affect the clearance of antibiotics when they are renally eliminated.2 There is also a lack of consensus on the type of body weight to use for dosing of daptomycin. Using IBW or TBW to calculate CrCl can either underestimate or overestimate the true clearance. The area under the curve/minimum inhibitory concentration (AUC24h/MIC) and maximum concentration (Cmax)/MIC ratios are the most significant clinical parameters to consider for daptomycin in regards to efficacy.3

Dvorchik and Damphousse researched the pharmacokinetics of daptomycin in both moderate and morbidly obese healthy patients and controls matched for sex, age, and renal function.4 They looked at the effects of daptomycin dosed at 4 mg/kg based on TBW. The investigators found that drug clearance and the Vd were lower in the morbidly obese group as compared to the non-obese group, and the Cmax and AUC were 25% and 30% to 35% higher, respectively, in obese patients compared to controls. There were no differences in safety noted between the 2 groups. The authors concluded that dosing daptomycin based on TBW in morbidly obese (56 to 147 kg) patients is appropriate and safely tolerated even though drug exposure is increased by 25% to 30%.

Pai and colleagues compared the pharmacokinetics of a 4 mg/kg dose in morbidly obese patients matched with non-obese patients based on age, sex, and serum creatinine.5 The study was only conducted in female patients and also assessed fat-free weight (FFW). The study found that the Cmax and AUC24h were about 60% higher in the obese patients, but they were not statistically significant. Also, the Vd and clearance differences were not statistically significant when weight-normalized. The correlation between IBW and Vd was weak (r2 =0.0004), whereas it was strong (r2=0.66) for TBW and Vd. This led the authors to conclude that TBW-based dosing was appropriate in obese patients.

Literature review of clinical studies: efficacy and safety

Some studies have evaluated the use of daptomycin in obese patients.6-9 A recent retrospective study published by Ng and colleagues evaluated the clinical outcomes of dosing daptomycin based on IBW versus TBW in obese patients with various infection types.6 The mean BMI and weight were 31 kg/m2 and 91 kg, respectively, and similar between groups. The dosing of either 4 mg/kg or 6 mg/kg was used to compare the IBW versus the TBW dosing weights. A total of 117 patients were evaluated; 69 received doses based on TBW and 48 received doses based on IBW. The primary outcome of clinical success was defined as the number of patients with clinical cure (clinical signs and symptoms resolved and/or no additional antibiotics with gram-positive coverage were needed) or clinical improvement (additional antibiotic therapy used after daptomycin was stopped, but de-escalation of therapy was able to be done) divided by the overall number of patients evaluated. There was no statistically significant difference in clinical success between the 2 groups (p=0.97), although the odds ratio favored dosing based on TBW. Given the small sample size, a possibility of a type II error could not be excluded. The secondary outcomes of microbiological outcomes, length of stay, mortality, and adverse effects were also similar between the 2 groups.

Bookstaver and colleagues evaluated the safety and efficacy of daptomycin dosed on TBW and administered for at least 7 days in hospitalized obese patients (n=126) in a retrospective, multicenter study that evaluated data from a 4-year time period.7 Patients were stratified based on 3 classifications of obesity according to BMI. The primary outcome was safety, which was evaluated by the incidence of creatine phosphokinase (CPK) elevation more than 500 units/L and 1000 units/L, incidence of myalgias, and discontinuation of therapy due to an ADE. The secondary endpoint was clinical success, which was considered to be achieved in the absence of the following situations (when applicable): positive blood culture 7 days post-therapy with daptomycin due to the same causative pathogen, recurrent bacteremia within 60 days of discontinuation of therapy due to the same causative pathogen, recurrent osteomyelitis at the same site, or change of therapy to an alternative agent for any reason other than de-escalation of therapy. About 28% of the patients received concomitant statins, which is significant because statins are known to have the potential to cause rhabdomyolysis and/or myalgias. There was no statistically significant difference in CPK elevation among the 3 BMI classes and the incidence was about 14% for more than 500 units/L and 8% for more than 1000 units/L. Discontinuation of treatment secondary to an ADE occurred in 8 patients (1 developed rhabdomyolysis) and there was no statistically significant difference in the 3 BMI classes for other ADEs or clinical success rates. The authors concluded that although an elevation in CPK was seen, discontinuation rates due to ADEs remained low when dosing based on TBW in their study.

Bhavnani and colleagues evaluated the relationship between daptomycin exposure (6 mg/kg daily) and the probability of CPK elevation in patients with Staphylococcus aureus bacteremia with or without endocarditis.8 Daptomycin therapy was stopped for 3 out of the 6 patients that had CPK elevations (n=108) that had musculoskeletal effects. The relationship between TBW ≥ 111 kg and CPK elevation was not significant; however, 4 of the 6 patients were ≥111 kg. Dosing based on lean body weight (LBW) for those weighing ≥111 kg and those <111 kg produced similar AUC distributions and showed no significant difference in AUC/MIC ratios, which would indicate that therapeutic concentrations were achieved. The authors recommended that TBW would be appropriate for those <111 kg, but LBW should be considered as an option for those ≥111 kg.

Farkas and Sussman reviewed pharmacokinetic data from obese patients matched with patients of normal body weight to assess various body weights when dosing daptomycin.9 Both 4 mg/kg and 6 mg/kg doses were evaluated using Monte Carlo Simulation to assess the extent of drug exposure based on the dosing strategies using TBW, IBW, ABW, LBW and FFW. They found that use of ABW for both doses best correlated to the exposure in the controls. Use of IBW, LBW, and FFW was estimated to result in suboptimal daptomycin exposure. The authors concluded that ABW should be considered when dosing in the morbidly obese.

Case reports

The case reports listed below are evidence to support the use of the TBW for dosing daptomycin.10,11 Both are reports of TBW used for dosing daptomycin in morbidly obese individuals. There were no ADEs reported in these individuals that required discontinuation of daptomycin therapy.

BMI=body mass index; TBW=total body weight.

Conclusion

There is not a consensus on the optimal body weight to use for the dosing of daptomycin in obese patients. Dosing based on TBW has been most commonly studied in the published literature, and there does not seem to be increased safety issues when daptomycin is dosed this way. Further studies should assess dosing weights for both daptomycin 4 mg/kg and 6 mg/kg, as well as for various infection types.

References

1. Cubicin [package insert]. Lexington, MA: Cubist Pharmaceuticals, Inc; 2013.

2. Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27(8):1081-1091.

3. Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis. 2012;25(6):634-649.

4. Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol. 2005;45(1):48-56.

5. Pai MP, Norenberg JP, Anderson T, et al. Influence of morbid obesity on single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother. 2007;51(8):2741-2747.

6. Ng JK, Schultz LT, Rose WE, et al. Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes. Antimicrob Agents Chemother. 2014;58(1):88-93.

7. Bookstaver PB, Bland CM, Qureshi ZP, et al. Safety and effectiveness of daptomycin across a hospitalized obese populations: results of a multicenter investigation in the southeastern united states. Pharmacotherapy. 2013;33(12):1322-1330.

8. Bhavnani SM, Rubino CM, Ambrose PG, et al. Daptomycin exposure and the probability of elevations in the creatinine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis. 2010;50(12):1568-1574.

9. Farkas A, Sussman R. Dosing of daptomycin in the morbidly obese: which body weight is it? J Pharm Pract. 2013;26:294: 50th Annual Infectious Disease Society of America (IDSA) Meeting (abstract 1634); San Diego, CA; October 17-21, 2012.

10. Pai MP, Mercier RC, Allen SE. Using vancomycin concentration for dosing daptomycin in a morbidly obese patient with renal insufficiency. Ann Pharmacother. 2006;40(3):553-558.

11. Pea F, Cojutti P, Sbrojavacca R, et al. TDM-guided therapy with daptomycin and meropenem in a morbidly obese, critically ill patient. Ann Pharmacother. 2011;45(7-8):e37.

Written by:

Tamkeen Quraishi Abreu, PharmD

PGY-1 Pharmacy Practice Resident

Loyola University Medical Center

Edited by:

Lara K. Ellinger, PharmD, BCPS

Clinical Assistant Professor

April 2014

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