October 2017 FAQs

What is the appropriate management of hemorrhagic cystitis?

Introduction

Hemorrhagic cystitis (HC) may be a complication of infection (particularly in immunocompromised patients), chemotherapy, or radiation to the pelvic area.¹  To date, there are no published guidelines available in the United States to guide clinical decision making for optimal management of patients presenting with this syndrome.²  Hence, treatment can be challenging.¹  This document reviews the currently available evidence for prevention and management of HC.

Cystitis is generally defined as inflammation of the urinary bladder.^3,4 It may result from an ascending infection from an external source by way of the urethra or from a descending infection that has originated in the kidney.  A simple cystitis that does not involve the rest of the urinary tract, for example confined to the urethra, is not as serious as the descending type in which various parts of the urinary system (eg, ureters, kidneys and bladder) may be involved. Hemorrhagic cystitis, however, is cystitis with hemorrhage depicted by sustained hematuria.⁵  It is a complex inflammatory response that is characterized by the sudden appearance of blood in the urine due to structural injury to the bladder’s epithelial cell wall and blood vessels.^5,6  The severity of bleeding may range from microscopic to gross with the presence of blood clots.²  Diagnosis is based on a detailed history and thorough physical examination, along with laboratory workup, which may include a urinalysis, urine culture, cystoscopy (under general anesthesia) and cytology, if necessary.⁷  Presenting signs and symptoms, such as dysuria, urinary frequency and urgency, are characteristic of other disorders.  Therefore, a key goal of the evaluation is to rule out other possible causes of hematuria. 

Droller and colleagues developed a grading system, which has been commonly used to determine the severity of HC (Table 1).⁸  This grading system allows for clarity and consistency in reporting HC in the literature.⁵  In severe HC (Grades III and IV), bleeding may become life-threatening and/or clot formation may result in urinary obstruction and acute renal failure.  Severe HC is associated with prolonged hospitalization and increased morbidity and mortality.^2,5,9-11

Table 1.  Hematuria grading system.⁸ 

Etiology of HC and Management Approach

As noted prior, HC may be the result of infectious or noninfectious causes.^12,13  Infectious sources, which are less common causes of HC, include bacteria, fungi or viruses.¹²  Bacteria that are most commonly associated with HC in this setting include:  Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis, and Klebsiella species.¹  This form of HC is generally resolved with appropriate antibiotic therapy with no long term sequela observed.^1,12  Cases of fungal-associated HC are rare and may occur as a consequence of exposure to broad spectrum antibiotics.¹²  Fungi implicated in HC include: Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Torulopsis glabrata.¹  Cases of fungal-associated HC, once identified, are also usually resolved with treatment of the underlying fungal etiology.

More published information is available with regard to viral-induced HC.  A variety of viruses, including the BK virus, JC virus, adenovirus, and cytomegalovirus can cause HC.  The BK virus can lie dormant for years in various body sites, including the kidneys.  When the immune system is compromised, the virus may reactivate, taking on a virulent, pathologic course.¹⁴  Primary and renally-activated BK virus infection may manifest as hemorrhagic and nonhemorrhagic cystitis.  BK virus reactivation has been described as significant and often severe complications occur, especially in patients with hematopoietic stem cell transplantation (HSCT).¹⁵  BK virus-related HC is difficult to treat in these patients and, to date, the approach to treatment remains to be optimized.¹⁶  According to the 2009 American Society for Blood and Marrow Transplantation (ASBMT) guidelines for preventing infectious complications among hematopoietic cell transplant recipients, evidence is lacking for support of universal prophylactic treatment of BK virus with quinolones or cidofovir, as well as routine testing of HSCT recipients or donors for BK virus antibodies.¹⁷  However, the guidelines do mention that treatment with either a low-dose or high-dose regimen of cidofovir has been used in HSCT patients with HC but emphasize that randomized controlled trials are necessary to clearly establish benefits and associated harms of this treatment approach (Table 2).  Additionally, both Park et al. and Chen et al. present case series in which leflunomide was successfully used as salvage therapy to treat refractory BK-induced HC; however, the complete response rate was approximately only 50%.^18,19

The JC virus is a member of the Polyomaviridae family with a structure and genome similar to that of the BK virus.²⁰  Infection is typically acquired during childhood via the respiratory tract.  The virus invades various body tissues, including the kidneys, where it resides latently and asymptomatically in immunocompetent patients.  When its host becomes immunosuppressed, the virus reactivates to cause disease.  Although the JC virus may be implicated in the development of HC, its role is unclear and appropriate treatment remains to be clearly delineated.^11,21,22

Adenoviruses are non-enveloped DNA viruses that are part of the Adenoviridae family, which includes more than 57 serotypes and 7 species.  Associated clinical features of adenovirus infection are based on the type of virus invading the host.²²  Subgroups B1 and B2, serotypes 7, 11, 34 and 35 are the prominent pathogens associated with adenovirus-induced HC.^22,23  Adenovirus-related HC is more persistent in susceptible populations, including HSCT patients and renal transplant patients, as well as immunocompromised children and adults.  However, when pathogenic, the virus can also impart life-threatening diseases even to those who are immunocompetent.^22,23  Currently, approach to treatment is based on published case reports, primarily involving cidofovir (Table 2).²⁴  When initiating intravenous cidofovir therapy, a major side effect is renal toxicity.²⁵  To ameliorate this event, Lindemans et al. developed an algorithm for the treatment of adenovirus in HSCT patients consisting of a low dose regimen of cidofovir, along with hyperhydration and probenecid, which is also mentioned in the 2009 ASBMT guidelines.^17,24  Of note, Sakurada, et al. describe a case series in which no nephrotoxicity occurred with administration of intravesical cidofovir, and this route of administration was effective in HC refractory to intravenous cidofovir.²⁵  Additionally, case reports of both adult and pediatric use of ribavirin (PO/IV) have been published but clinical efficacy is highly conflicting.^26,27

Cytomegalovirus (CMV) is a member of the Herpes viridae family.  Similar to BK and JC viruses, primary infection usually occurs during childhood and the virus recedes to a latent state.²⁸  Risk of reactivation is highest when immunosuppression occurs.  Cytomegalovirus-associated HC is rare and, to date, the literature regarding its occurrence is sparse.  A case report by Tutuncuoglu, et al. mentions a bone marrow transplantation patient who received foscarnet for treatment of CMV-induced HC.²⁹  Other authors report success with ganciclovir and valganciclovir.^30,31

Table 2.  Management options for BK- and adenovirus-induced HC in HSCT

patients.^{17,18,24,25,32,33}

In addition to infectious causes, there are noninfectious factors, which may contribute to the development of HC.  In general, these factors may be classified into 2 broad categories: chemotherapy-induced and radiation-induced HC.¹² 

Chemotherapy-induced HC is a serious complication of chemotherapeutic agents used to treat a wide variety of malignancies, most notably ifosfamide and cyclophosphamide.³⁴  Both of these oxazaphosphorine compounds are hepatically metabolized, producing a cytotoxic metabolite known as acrolein.^12,34 Filtration of acrolein by the kidneys causes its excretion in the urine.  It is subsequently stored in the bladder where it concentrates.³⁵  Prolonged exposure of this noxious agent to the bladder urothelium allows acrolein to release its inflammatory mediators, causing bladder mucosal edema which ultimately results in HC.¹  The incidence of HC with both ifosfamide and cyclophosphamide is increased with higher individual doses and larger cumulative doses.³⁶

Prevention

One of the best strategies for the management of chemotherapy-induced HC is prevention.⁷  Although not all chemoprotective agents are approved by the Food and Drug Administration (FDA) for this indication, their use can be beneficial.  In 2014, the British Association of Urological Surgeons (BAUS) published guidelines to aid healthcare practitioners in clinical decision making when caring for patients who are at risk for chemical- and radiation- induced cystitis.  Guideline recommendations are based on expert opinion due to the limited amount of high quality clinical evidence available in the literature to support therapy.⁷  For bone marrow transplant patients who require preventive treatment, guideline authors recommend hyperhydration to maintain high urine flow (unless contraindicated), along with intravesical sodium hyaluronate (Table 3).  Cranberry juice and tablets are also proposed as additional preventive therapy.⁷ In 2008, the American Society of Clinical Oncology (ASCO) released updated clinical practice guidelines regarding use of chemotherapy and radiation therapy protectants.  The guideline committee recommends mesna for the prevention of urothelial toxicity associated with the chemotherapeutic agents ifosfamide and cyclophosphamide.³⁷ 

Table 3.  Prevention of ifosfamide- and cyclophosphamide-induced HC.^37,38,39

In addition to the administration of certain chemotherapeutic drugs, exposure to radiation can result in HC.³⁶  Radiation-induced HC is a serious complication of pelvic radiation and is very difficult to treat.¹  The pathogenesis is not clearly understood, but multiple mechanisms involved in the damage process have been reported.⁴⁰  In general, damage occurs to vascular endothelial cells in the bladder as a result of exposure to radiation.  Progressive obliterative endarteritis ensues, eventually causing ischemia to bladder mucosa along with tissue hypoxia.  Due to this damage, the uroepithelium no longer maintains its optimal functioning, subsequently leading to HC.  Fibrosis also occurs when damaged detrusor muscle is replaced with fibrotic tissue resulting in decreased bladder capacity.¹  Hence, patients often present with urinary urgency, frequency and dysuria, in addition to HC. 

Radiation-induced HC can be characterized as acute onset (development of symptoms within 90 days of treatment) or delayed/late-onset (symptom occurrence up to 10 years or more after radiation exposure).⁴¹  Fibrosis and obliterative endarteritis are associated with late-onset HC with injuries that are progressive and irreversible.¹

Unlike chemotherapy-induced HC, prophylaxis in the radiation-induced HC setting is not well established.¹  The 2014 BAUS guidelines recommend intravesical therapy with sodium hyaluronate and 40 ml chondroitin sulphate 0.2% solution; however, the authors state data for chondroitin sulphate is limited to a small pilot study consisting of 20 patients undergoing radiotherapy for gynecological malignancies.⁷

Treatment

According to the 2014 BAUS guidelines, once a diagnosis of HC has been confirmed, the principle therapeutic approach to treatment is the same, regardless of the cause.⁷  Due to variations in the spectrum of severity in patients presenting with HC, guideline authors recommend a multimodal, stepwise approach to care.  Initially, patients may be managed with conservative care consisting of intravenous hydration and careful observation if the presentation of HC is of mild to moderate (Grades I-II/III), without obstructing clots, and the patient is voiding well.  Other considerations for conservative treatment include analgesics for pain, spasmolytic medications, cranberry juice daily and oral tranexamic acid to induce clot formation if hemorrhage or risk of hemorrhage is present.  If HC persists despite these methods, a more aggressive approach is encouraged.  For severe HC (Grades III and IV), therapy involves normal saline continuous bladder irrigation along with appropriate clot removal.  It is important that clot evacuation precedes any further irrigation treatment measures, otherwise subsequent intravesical therapy may not prove successful.  For patients nonresponsive to conservative therapy and for patients with severe HC who have had successful evacuation of clots, the next step in management includes intravesical therapy, hyperbaric oxygen (if available), as well as treatment with systemic agents such as pentosan polysulfate, estrogen, recombinant factor VIIa/factor VIII, and aminocaproic acid.  Treatment options are shown in Table 4. 

Table 4.  Treatment options for HC.^{2,34,36,41-45}

Conclusion

Hemorrhagic cystitis is a potentially life-threatening, severe complication of infections, radiation, or chemotherapy.  Signs and symptoms of HC include hematuria, dysuria, and urinary urgency and frequency.  Published information on the appropriate management is limited, particularly in patients with infection-related HC.  For prevention and treatment of chemotherapy- and radiation-induced HC, multiple management approaches have been discussed in the literature; however, published data is generally of low quality (eg, case reports/series and small studies).  Clinicians must consider this when choosing management options for specific patients.

References

1.         Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis: a challenge to the urologist. Indian J Urol. 2010;26(2):159-166.

2.         Zwaans BMM, Nicolai HG, Chancellor MB, Lamb LE. Challenges and opportunities in radiation-induced hemorrhagic cystitis. Rev Urol. 2016;18(2):57-65.

3.         O'Toole M, ed. Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health.  7th ed. London, UK: Elsevier, Inc.; 2003. http://medical-dictionary.thefreedictionary.com/hemorrhagic+cystitis. Accessed August 14, 2017.

4.         Yeung S-CJ, Manzullo EF. Oncologic emergencies.  In: Kantarjian HM, Wolff RA, eds. The MD Anderson Manual of Medical Oncology. 3rd ed.  New York, NY: McGraw-Hill; 2016. https://accessmedicine.mhmedical.com/content.aspx?bookid=1772&sectionid=121826976. Accessed September 22, 2017.

5.         Decker DB, Karam JA, Wilcox DT. Pediatric hemorrhagic cystitis. J Pediatr Urol. 2009;5(4):254-264.

6.         Dobrek L, Thor PJ. Bladder urotoxicity pathophysiology induced by the oxazaphosphorine alkylating agents and its chemoprevention. Postepy Hig Med Dosw (Online). 2012;66:592-602.

7.         Thompson A, Adamson A, Bahl A, et al. Guidelines for the diagnosis, prevention and management of chemical- and radiation-induced cystitis. J Clin Urol. 2016;7(1):25-35.

8.         Droller MJ, Saral R, Santos G. Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology. 1982;20(3):256-258.

9.         Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008;41(1):11-18.

10.       Hassan Z. Management of refractory hemorrhagic cystitis following hematopoietic stem cell transplantation in children. Pediatr Transplant. 2011;15(4):348-361.

11.       Mischitelli M, Fioriti D, Anzivino E, et al. Viral infection in bone marrow transplants: is JC virus involved? J Med Virol. 2010;82(1):138-145.

12.       Haldar S, Dru C, Bhowmick NA. Mechanisms of hemorrrhagic cystitis. Am J Clin Exp Urol. 2014;2(3):199-208.

13.       Lee G, Romih R, Zupancic D. Cystitis: from urothelial cell biology to clinical applications. Biomed Res Int. 2014;2014:473536.

14.       Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. Clin Infect Dis. 2001;33(2):191-202.

15.       Pinto M, Dobson S. BK and JC virus: A review. J Infect. 2014;68(Suppl 1):S2-S8.

16.       Philippe M, Ranchon F, Gilis L, et al. Cidofovir in the treatment of BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(4):723-730.

17.       Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238.

18.       Park YH, Lim JH, Yi HG, Lee MH, Kim CS. BK virus-hemorrhagic cystitis following allogeneic stem cell transplantation: Clinical characteristics and utility of leflunomide treatment. Turk J Haematol. 2016 Apr 18. doi: 10.4274/Tjh.2015.0131. [Epub ahead of print]

19.       Chen XC, Liu T, Li JJ, He C, Meng WT, Huang R. Efficacy and safety of leflunomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Acta Haematol. 2013;130(1):52-56.

20.       Hayden RT, Carroll K, Tang Y, Wolk DM, eds. Diagnostic Microbiology of the Immunocompromised Host. 3rd ed. Washington, DC: ASM Press; 2016.

21.       Akiyama H, Kurosu T, Sakashita C, et al. Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow transplantation. Clin Infect Dis. 2001;32(9):1325-1330.

22.       Ison MG. Adenovirus diseases. In. Goldman-Cecil Medicine. Vol 2. 25th ed. Philadelphia, PA: Elsevier; 2016: 2197-2199.

23.       Florescu MC, Miles CD, Florescu DF. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant. 2013;28(8):2003-2010.

24.       Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010;116(25):5476-5485.

25.       Sakurada M, Kondo T, Umeda M, Kawabata H, Yamashita K, Takaori-Kondo A. Successful treatment with intravesical cidofovir for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: A case report and a review of the literature. J Infect Chemother. 2016;22(7):495-500.

26.       Sahu KK, Prakash G, Khadwal A, Varma SC, Malhotra P. A rare case of hemorrhagic cystitis in allogeneic hematopoietic stem cell transplant patient. Indian J Hematol Blood Transfus. 2016;32(Suppl 1):196-200.

27.       Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics. 2002;110(1 Pt 1):e9.

28.       Ersan S, Yorukoglu K, Sert M, et al. Unusual case of severe late-onset cytomegalovirus-induced hemorrhagic cystitis and ureteritis in a renal transplant patient. Ren Fail. 2012;34(2):247-250.

29.       Tutuncuoglu SO, Yanovich S, Ozdemirli M. CMV-induced hemorrhagic cystitis as a complication of peripheral blood stem cell transplantation: case report. Bone Marrow Transplant. 2005;36(3):265-266.

30.       Studemeister A. Cytomegalovirus-induced hemorrhagic cystitis in AIDS patient treated successfully with valganciclovir. AIDS. 2002;16(10):1437-1438.

31.       Spach DH, Bauwens JE, Myerson D, Mustafa MM, Bowden RA. Cytomegalovirus-induced hemorrhagic cystitis following bone marrow transplantation. Clin Infect Dis. 1993;16(1):142-144.

32.       VISTIDE [package insert]. Foster City, CA: Gilead Sciences; 2010.

33.       Clinical Pharmacology [database online]. Elsevier, The Netherlands: 2017. https://www.clinicalkey.com/pharmacology/monograph/542?sec=monindi. Accessed September 19, 2017.

34.       Payne H, Adamson A, Bahl A, et al. Chemical- and radiation-induced haemorrhagic cystitis: current treatments and challenges. BJU Int. 2013;112(7):885-897.

35.       Matz EL, Hsieh MH. Review of advances in uroprotective agents for cyclophosphamide- and ifosfamide-induced hemorrhagic cystitis. Urology. 2017;100:16-19.

36.       Boorjian S, Raman JD, Barocas DA. Evaluation and management of hematuria. In: Campbell MF WA, Kavoussi LR, ed. Urology. 11th ed. Philadelphia: W.B. Saunders; 2016. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455775675000091?scrollTo=%23hl0000743. Accessed August 1, 2017.

37.       Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009;27(1):127-145.

38.       Micromedex Solutions [database online]. Ann Arbor, MI: 2017. http://www.micromedexsolutions.com.  Accessed August 19, 2017.

39.       Lexicomp online [database online]. St. Louis, MO: Wolters Kluwer; 2017. http://online.lexi.com.  Accessed August 20, 2017.

40.       Browne C, Davis NF, Mac Craith E, et al. A narrative review on the pathophysiology and management for radiation cystitis. Adv Urol. 2015;2015:346812.

41.       Giannitsas K, Athanasopoulos A. Intravesical therapies for radiation cystitis. Curr Urol. 2014;8(4):169-174.

42.       West NJ. Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy. 1997;17(4):696-706.

43.       Athanassiou H, Antonadou D, Coliarakis N, et al. Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: results of a randomized trial. Int J Radiat Oncol Biol Phys. 2003;56(4):1154-1160.

44.       Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol. 2010;7(4):206-214.

45.       Mendenhall WM, Henderson RH, Costa JA, et al. Hemorrhagic radiation cystitis. Am J Clin Oncol. 2015;38(3):331-336.

Prepared by:

Elana Nelson, PharmD

PGY2 Drug Information Resident

College of Pharmacy

University of Illinois at Chicago

October 2017

The information presented is current as of September 20, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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How can sodium acetate be used as a substitute for sodium bicarbonate, and what other strategies are recommended for sodium bicarbonate shortage management?

Introduction

Intravenous sodium bicarbonate is a systemic alkalinizing agent used for a variety of indications, including acidosis, hyperkalemia, and select toxicological emergencies.^1,2  However, in March 2017, the Federal Food and Drug Administration announced a shortage of sodium bicarbonate injection, citing reasons of manufacturing delays and increased demand.^1,3  This shortage has impacted patient care and daily operations for many hospitals nationwide.⁴  In a survey conducted by the American Society of Health-System Pharmacists (ASHP), 71% of respondents reported that their hospital has used alternatives to sodium bicarbonate due to the shortage.

Unfortunately, few alternatives to sodium bicarbonate are available.¹  Traditionally, tromethamine (THAM) has been used as an alternative, but this product has been discontinued since May of 2016.⁵  Sodium acetate is another product that has been proposed as an alternative to sodium bicarbonate, because the acetate component is metabolized to bicarbonate.²  However, recommendations for sodium bicarbonate shortage management vary based on indication, and in some cases, sodium acetate administration may not be appropriate.^1,5  The goal of this article is to discuss the potential role of sodium acetate in sodium bicarbonate shortage management, and provide other possible strategies for health care providers to manage specific indications in the context of sodium bicarbonate shortage.

Role of Sodium Acetate as an Alternative to Sodium Bicarbonate

The acetate component of sodium acetate is metabolized and converted to bicarbonate.⁶  This conversion occurs on a 1:1 basis, so 1 mEq of acetate is equivalent to 1 mEq of bicarbonate.²  Unlike bicarbonate, which is metabolized quickly by carbonic anhydrase, acetate may go through many different complex metabolic pathways.⁶  It was initially thought that acetate metabolism occurred primarily in the liver, but it has since been found to occur in other areas of the body as well, including skeletal muscle.  Liver disease does not appear to impact sodium acetate handling during a standard infusion; however, acetate metabolism may be adversely impacted by other factors, such as critical illness and circulatory failure.^6,7

Adverse reactions with sodium acetate may include flushing (particularly when given as a bolus), hypernatremia, hypocalcemia, injection site reaction, lactic acidosis, peripheral edema, pulmonary edema, seizures, tetany, thrombosis, and tremor.^2,6  High doses of sodium acetate may cause myocardial depression, hypotension, and hypopnea.⁶  These adverse effects have primarily been observed in patients receiving sodium acetate dialysate buffer, which usually delivers a sodium acetate load much larger than that delivered by a standard infusion.  It is thought that these adverse effects occur when the amount of acetate administered exceeds the metabolic threshold: thus, administering a large amount of sodium acetate over a short period of time is more likely to result in adverse effects.  While sodium bicarbonate is often administered as a rapid bolus, administration of sodium acetate as a rapid bolus is not recommended.  Some sources recommend administering sodium acetate over 15 to 20 minutes, while others recommend a maximum infusion rate of 1 mEq/kg/hr.^1,2,6  Sodium acetate must be diluted prior to administration, and hypertonic solutions (>154 mEq/L or >2.8% sodium acetate in sterile water) should be infused through a central line.^2,8 The most appropriate fluid and final sodium acetate concentration remains unclear, but one source recommends dilution with dextrose 5% water, which requires infusion through a central line due to increased osmolarity.^6,8  Although there are no stability data for sodium acetate diluted in any fluid, diluents described in the literature for specific indications include dextrose 5% water and sterile water for injection.

Literature support for the use of sodium acetate as an alternative to sodium bicarbonate is limited to a few key indications.  In most cases, no systematic studies have been done.  Sodium acetate use for each of these indications will be specifically addressed below, along with other possible management strategies in the setting of sodium bicarbonate shortage.

Toxicology Indications

Intravenous sodium bicarbonate is used in a variety of different poisonings for the purpose of serum alkalinization, urine alkalinization, and sodium ion loading.⁶  Most commonly, it may be used to treat tricyclic antidepressant overdose and salicylate poisoning, but it may also be used in the treatment of cocaine-induced ventricular dysrhythmias, type 1A and 1C antiarrhythmic poisonings, and poisonings with methanol or ethylene glycol.  Because sodium acetate has similar effects on serum pH, urine pH, and sodium ion concentration, it may be potentially useful as a replacement for sodium bicarbonate.

While there is a lack of evidence regarding use of sodium acetate in the toxicology setting, Neavyn and collegues suggest that it may be useful for certain poisonings based on its pharmacology and the data for its use in acidemia.⁶ According to Neavyn and colleagues, sodium acetate may be used to treat cardiotoxicity associated with sodium channel antagonists (tricyclic antidepressants and type 1A and 1C antiarrhythmics).  In this situation, the purpose of sodium acetate or sodium bicarbonate is to alkalinize the serum and increase sodium ion concentration.  The goal of treatment is narrowing of the QRS complex.  Sodium acetate may also be useful as a urine alkalinizing agent in the setting of salicylate toxicity.  In this setting, urine alkalinization enhances salicylate excretion.  Urine alkalinization is recommended for patients with symptoms of salicylate overdose, elevated salicylate levels, and adequate renal function/urine output.

When administering sodium acetate in place of sodium bicarbonate for toxicology indications, it is important to be aware of differences between the two drugs in terms of preparation and administration.⁶  Sodium acetate must be diluted in dextrose 5% water, and it cannot be given as a rapid bolus like sodium bicarbonate.  Infusion should take place via a central line.  Dosing recommendations vary according to the indication and goals of treatment (table 1).

Table 1. Suggested sodium acetate dosing for toxicology indications.⁶

Urine Alkalinization with High-Dose Methotrexate

Intravenous sodium bicarbonate is commonly used to raise urine pH during high-dose methotrexate therapy.⁹  This increased urine pH is necessary to increase methotrexate solubility in the urine and prevent crystalluria, which may in turn lead to acute renal failure and increased risk of other methotrexate toxicities.^9,10  While the intravenous form of sodium bicarbonate is widely used for this indication, other parenteral and enteral methods of urinary alkalinization have been explored.

Sodium acetate was examined as an alternative to sodium bicarbonate in a single-center retrospective chart review.⁹  In this analysis of 43 patients over 94 patient encounters, there was no significant difference between sodium acetate and sodium bicarbonate in terms of time from admission to achievement of goal urine pH ≥8 (mean 16.7 hours with sodium acetate versus 15.5 hours with sodium bicarbonate, p=0.53).  There were also no significant differences between sodium acetate and sodium bicarbonate in terms of mean length of stay (5.0 days versus 4.6 days respectively, p=0.24), mean time to serum methotrexate concentration ≤ 0.1 mmol/L (71.1 hours versus 70.6 hours respectively, p=0.93), or percent increase in serum creatinine from baseline (17.3% versus 17.1% respectively, p=0.96).  While this study is limited by the small number of patients, retrospective design, and lack of dosing information, it offers some preliminary evidence to suggest that sodium acetate can be used in place of sodium bicarbonate for this indication.

Another retrospective study examined the use of enteral alkalinizing agents in place of parenteral alkalinizing agents for urine alkalinization with high-dose methotrexate.¹⁰  This analysis included 41 adult methotrexate cycles and 18 pediatric methotrexate cycles.  Enteral alkalinizing agents could have been either sodium bicarbonate tablets (one 650mg tablet = 8 mEq sodium bicarbonate) or sodium citrate/citric acid suspension (1mL of 500mg/334mg per 5mL suspension = 1 mEq sodium bicarbonate).  There was no significant difference in mean time to goal urine pH (6.5 hours with parenteral alkalinization versus 7.9 hours with enteral alkalinization, p=0.051), and there was no significant difference in mean time to methotrexate level deemed safe for discharge (63.5 hours versus 62.5 hours, p=0.835).  More milliequivalents of sodium bicarbonate were required in the enteral group (mean 240 mEq) than the parenteral group (mean 150 mEq), but the difference was not statistically significant (p=0.21).  Among the 59 patients with serum creatinine values available for analysis, there was no significant difference in degree of serum creatinine change during therapy.  However, patients in the enteral group experienced diarrhea more frequently than patients in the parenteral group (5% versus 25%, p=0.002).  The study concluded that enteral forms of urinary alkalinization were effective and safe for use during times of parenteral agent shortages.  The ASHP drug shortages website states that oral sodium bicarbonate tablets may be an appropriate alternative to parenteral sodium bicarbonate for urine alkalinization in this patient population.¹

Metabolic Acidosis

Sodium bicarbonate is often used to manage metabolic acidosis; however, depending on the underlying cause and severity of acidosis, sodium bicarbonate may not be indicated, and the use of sodium acetate as an alternative may not be supported. 

Evidence for the use of sodium acetate in metabolic acidosis is scarce.  One retrospective single center study in critically ill trauma patients with hyperchloremic metabolic acidosis found that patients who received sodium acetate infusions had faster improvements in serum pH than patients who received normal saline infusions.¹¹  In this study, sodium acetate was diluted with sterile water for injection, but the exact dilution and dosing were unclear.  The rate of infusion varied based on patient weight and anticipated fluid volume deficit.  This was the only study to examine sodium acetate use in the setting of metabolic acidosis.  Tertiary sources indicate that when sodium acetate is used as an alternative to sodium bicarbonate in metabolic acidosis, it should be dosed the same as sodium bicarbonate, because 1 mEq of acetate is converted to 1 mEq of bicarbonate.²  For metabolic acidosis not associated with cardiac arrest, Clinical Pharmacology recommends a sodium bicarbonate dose of 2 to 5 mEq/kg over 4 to 8 hours, or the use of the following equation to determine bicarbonate requirement: [0.5 L/kg x body weight in kg x desired change in serum bicarbonate] = bicarbonate dose in mEq.  Dosing is also dependent on the clinical condition, fluid and electrolyte balance, and acid-base status of the individual patient.  Administration of sodium acetate should occur no faster than 1 mEq/kg/hr, and hypertonic solutions (>154 mEq/L) should be infused through a central line.  Sodium acetate may not be a reliable source of alkali in critically ill patients, because its alkalinizing effect relies on metabolic conversion to bicarbonate.¹²

The Society for Critical Care Medicine recommends against the use of sodium bicarbonate for certain kinds of acidosis in times of shortage.⁵  For diabetic ketoacidosis, sodium bicarbonate should not be used: instead, the underlying cause of ketogenesis should be treated.  This recommendation is supported by retrospective and prospective studies, which have found no benefit with sodium bicarbonate therapy in this setting.¹³  In general, guidelines for diabetic ketoacidosis recommend against sodium bicarbonate administration unless serum pH is less than 6.90, although the true benefit of sodium bicarbonate administration in patients with pH < 6.90 is unknown.¹⁴  Sodium acetate has not been studied as an alternative in the setting of diabetic ketoacidosis.

Sodium bicarbonate should also be avoided in the setting of lactic acidosis: two prospective trials have found no benefit with sodium bicarbonate therapy, and a single-center retrospective trial found an increased mortality rate associated with sodium bicarbonate administration.¹³  According to the Surviving Sepsis Guidelines, sodium bicarbonate is not recommended for septic patients with pH ≥ 7.15 due to lack of demonstrated benefit.^5,15  While sodium bicarbonate does produce a transient increase in plasma pH, this effect has not been linked to hemodynamic improvements or better outcomes.¹⁶  Efficacy in septic patients with pH < 7.15 is unknown.¹⁵  The Society for Critical Care Medicine recommends treatment of the underlying shock and/or other cause of acidemia rather than administration of sodium bicarbonate in the setting of a sodium bicarbonate shortage.⁵  Sodium acetate has not been studied in patients with lactic acidosis or sepsis-induced acidosis, but lactic acidosis has been documented after sodium acetate infusion, which indicates that it may not an appropriate substitute for sodium bicarbonate.^2,17

Other Strategies for Sodium Bicarbonate Conservation

Direct alternatives to sodium bicarbonate are not readily available, so the conservation of sodium bicarbonate becomes an important shortage management strategy for many indications.^1,5  Sodium bicarbonate should be reserved for uses where it is critically needed and no other options for treatment exist.  Some common uses of sodium bicarbonate may not be well-supported when the strength of current evidence is weighed against the need for sodium bicarbonate conservation.  The following section will address indications for which sodium bicarbonate conservation measures may be appropriate or recommended.

Acute Hyperkalemia

Sodium bicarbonate is commonly used in the treatment of acute hyperkalemia to promote the uptake of potassium into cells.¹⁸  However, there are other agents that may be used to achieve the same effect.  The Society of Critical Care Medicine recommends the use of insulin 10 units IV push with 50 mL of 50% dextrose to treat acute hyperkalemia in the setting of bicarbonate shortage.⁵  Inhaled β₂-agonists such as albuterol may also be useful as adjunct therapy.  Sodium bicarbonate should be reserved for the treatment of hyperkalemia in patients with severe concomitant metabolic acidosis.

Advanced Cardiac Life Support (ACLS)

Sodium bicarbonate was traditionally recommended as an ACLS intervention to counteract the severe metabolic acidosis that occurs during cardiac arrest; however, current guidelines do not support its use except in specific situations.^19-21  Most studies examining sodium bicarbonate in cardiac arrest found either no benefit with sodium bicarbonate administration or a relationship between sodium bicarbonate administration and poor outcome.  While sodium bicarbonate may be useful for cardiac arrest secondary to hyperkalemia or tricyclic antidepressant overdose, its routine use in cardiac arrest is not recommended.  Alternatives to sodium bicarbonate for hyperkalemia and tricyclic antidepressant overdose are discussed separately in their respective sections above.

Prevention of Contrast-Induced Nephropathy

Sodium bicarbonate infusions have been used as a preventative strategy for contrast-induced nephropathy, which is a common cause of acute kidney injury in hospitalized patients.²²  However, sodium bicarbonate therapy has been associated with mixed results in this setting, and in times of shortage, the Society of Critical Care Medicine recommends using 0.9% saline in place of sodium bicarbonate.⁵  One meta-analysis of 22 studies found that sodium bicarbonate was not superior to 0.9% saline for the prevention of contrast-induced nephropathy (risk difference among studies with low risk of bias, 0.00; 95% confidence interval [CI], -0.02 to 0.03; p=0.83).  Studies with a high risk of bias had results that favored bicarbonate, but heterogeneity among these studies was high.  Another meta-analysis of 20 studies found that sodium bicarbonate decreased the risk of contrast-induced nephropathy in patients with pre-existing renal insufficiency (odds ratio, 0.67; 95% CI, 0.47 to 0.96; p=0.027).²³  However, this did not result in a significant decrease in dialysis requirement (odds ratio, 1.08; 95% CI, 0.52 to 2.25; p=0.841) or mortality (odds ratio, 0.69; 95% CI, 0.36 to 1.32; p=0.263), and moderate heterogeneity was present.  Several meta-analyses of studies specific to the cardiac surgery population have been conducted, with similarly mixed results.  Some meta-analyses have found harm or no benefit with sodium bicarbonate therapy, while others have found benefit, including one meta-analysis of individual patient data that found a lower 1-year mortality risk in patients who received sodium bicarbonate.^24-27  Due to the conflicting nature of available evidence, the Society of Critical Care Medicine recommends using 0.9% saline for prevention of contrast-induced nephropathy during the sodium bicarbonate shortage.⁵  It is recommended to administer 0.9% saline at a rate of 1 mL/kg/hr for 6 to 12 hours before the contrast procedure and 6 to 12 hours after the procedure: if the procedure is emergent, a 3 mL/kg bolus should be given, followed by a 1 mg/kg/hr infusion for 6 to 12 hours after the procedure.  Additionally, the Society of Critical Care Medicine recommends minimizing modifiable risks, such as concomitant nephrotoxins, and using iso-osmolar, non-ionic contrast when possible.

Rhabdomyolysis

Sodium bicarbonate has traditionally been used in addition to aggressive fluid resuscitation to minimize acute renal injury in patients with rhabdomyolysis.²⁸  It is thought that the urinary alkalinization achieved with sodium bicarbonate may help decrease myoglobin toxicity and prevent renal injury.^28,29  However, there is little evidence to indicate that sodium bicarbonate plus aggressive fluid resuscitation is more effective than aggressive fluid resuscitation alone.  There are no well-controlled studies comparing aggressive fluid therapy plus sodium bicarbonate to aggressive fluid therapy alone, and the limited retrospective studies that have been done did not find a difference in acute renal failure rates between those who received sodium bicarbonate and those who did not.²⁸  One systematic review suggested that sodium bicarbonate therapy should only be used in rhabdomyolysis if it is necessary to correct a systemic acidosis.  Similarly, a systematic review of therapies for exertional rhabdomyolysis concluded that there was insufficient evidence to determine if the addition of sodium bicarbonate to intravenous fluid resuscitation resulted in better outcomes.²⁹  According to the Society of Critical Care Medicine, it is appropriate to forego the administration of sodium bicarbonate in the setting of a drug shortage and manage rhabdomyolysis patients with aggressive 0.9% saline resuscitation alone.⁵

Buffered Lidocaine Syringes

Low pH lidocaine solutions cause pain on injection: 8.4% sodium bicarbonate is often used to buffer these solutions and raise the pH, theoretically decreasing the pain associated with injection.³⁰  The ASHP shortage website considers this a non-essential use, and recommends to avoid using sodium bicarbonate for this purpose during the shortage.¹  No alternative agents have been studied for this purpose, but if institutions choose to continue buffering lidocaine syringes with sodium bicarbonate, it may be possible to modify processes to maximize the available sodium bicarbonate supply and minimize waste.  If buffered lidocaine syringes are aseptically compounded in the pharmacy using multiple-dose vials of bicarbonate, they may be stored for up to 4 weeks at refrigerated or room temperature.^31,32  Compounding in advance may help decrease the amount of sodium bicarbonate wasted during the preparation of these syringes.  Another possible alternative would be to use a different strength of sodium bicarbonate to prepare the buffered syringes: however, the data for this strategy are limited.  One study makes reference to a buffered lidocaine syringe that was prepared using 4% sodium bicarbonate, but long-term stability data and compounding recipes for this preparation are not available.³³

Extemporaneous Oral Solutions of Proton Pump Inhibitors

In some institutions, sodium bicarbonate for injection may be used in the preparation of extemporaneous oral proton pump inhibitor solutions.¹  However, there are alternative methods of preparing oral liquid proton pump inhibitor formulations.  Oral solutions of omeprazole or lansoprazole may be prepared with a baking soda solution rather than sodium bicarbonate for injection: the baking soda solution can be prepared by dissolving 1 teaspoon of baking soda in 240 mL of water.  There are compounding recipes for pantoprazole oral suspension and omeprazole oral solution that utilize sodium bicarbonate powder rather than sodium bicarbonate for injection.²  Additionally, an oral suspension of lansoprazole may be prepared from orally disintegrating tablets without the use of sodium bicarbonate.

Minimizing Sodium Bicarbonate Waste

In addition to the indication-specific strategies discussed above, waste minimization strategies may be useful to help conserve a limited supply of sodium bicarbonate.  The ASHP shortages website recommends reviewing storage locations such as crash carts and reducing inventory where possible.¹  Additionally, hospitals should consult the FDA Drug Shortages page for sodium bicarbonate: in some cases, manufacturers have extended the expiration dates for particular lots of specific sodium bicarbonate injection products.³

Conclusion

The sodium bicarbonate injection shortage has impacted hospitals nationwide and prompted a strong interest in alternative agents.  Appropriate sodium bicarbonate shortage management strategies vary based on indication, and may include use of alternatives or conservation strategies (see Table 2).  While sodium acetate may be a useful alternative to sodium bicarbonate in some situations, the data for its use are extremely limited, and it is not appropriate to use in every situation. For some indications, conservation may be a more appropriate strategy for shortage management than use of an alternative agent.  Finally, it is important to note that the use of uncommon alternatives during a drug shortage may present new safety concerns and potential for error at all levels of the medication use process.⁵  Increased vigilance is warranted to ensure that all providers are able to prescribe, prepare, and administer these medications safely.

Table 2. Summary of potential sodium bicarbonate shortage management strategies.^1,5,9,11,20

References

1.         Sodium bicarbonate injection. American Society of Health-System Pharmacists website. https://www.ashp.org/drug-shortages/current-shortages/Drug-Shortage-Detail.aspx?id=788. Updated September 20, 2017. Accessed September 22, 2017.

2.         Clinical Pharmacology [database online]. Tampa, FL: Elsevier, Inc.; 2017. http://clinicalpharmacology.com/. Accessed September 7, 2017.

3.         FDA Drug Shortages. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/scripts/drugshortages. Updated September 22, 2017. Accessed September 22, 2017.

4.         Thompson C. Survey finds sodium bicarbonate shortage affecting hospitals' daily operations. American Society of Health-System Pharmacists website. https://www.ashp.org/news/2017/07/10/17/35/survey-finds-sodium-bicarbonate-shortage-affecting-hospitals-daily-operations. Updated July 10, 2017. Accessed September 7, 2017.

5.         Drug shortages alert. Society of Critical Care Medicine website. http://www.learnicu.org/Lists/Web%20Contents/Attachments/14258/Drug-Shortages-Alert-9-16.pdf. Updated September 2016. Accessed September 7, 2017.

6.         Neavyn MJ, Boyer EW, Bird SB, Babu KM. Sodium acetate as a replacement for sodium bicarbonate in medical toxicology: a review. J Med Toxicol. 2013;9(3):250-254.

7.         Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders. First of two parts. N Engl J Med. 1998;338(1):26-34.

8.         Lexicomp [database online]. Hudson, OH: Wolters Kluwer; 2017. http://online.lexi.com/lco/action/home. Accessed September 18, 2017.

9.         Alrabiah Z, Luter D, Proctor A, Bates JS. Substitution of sodium acetate for sodium bicarbonate for urine alkalinization in high-dose methotrexate therapy. Am J Health Syst Pharm. 2015;72(22):1932-1934.

10.       Rouch JA, Burton B, Dabb A, et al. Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate. J Oncol Pharm Pract. 2017;23(1):3-9.

11.       McCague A, Dermendjieva M, Hutchinson R, Wong DT, Dao N. Sodium acetate infusion in critically ill trauma patients for hyperchloremic acidosis. Scand J Trauma Resusc Emerg Med. 2011;19:24.

12.       Devlin JW, Matzke GR. Acid-base disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017.  http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146062232. Accessed September 7, 2017.

13.       Adeva-Andany MM, Fernandez-Fernandez C, Mourino-Bayolo D, Castro-Quintela E, Dominguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. ScientificWorldJournal. 2014;2014:627673.

14.       Kamel KS, Schreiber M, Carlotti AP, Halperin ML. Approach to the treatment of diabetic ketoacidosis. Am J Kidney Dis. 2016;68(6):967-972.

15.       Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.

16.       Velissaris D, Karamouzos V, Ktenopoulos N, Pierrakos C, Karanikolas M. The use of sodium bicarbonate in the treatment of acidosis in sepsis: a literature update on a long term debate. Crit Care Res Pract. 2015;2015:605830.

17.       McCague A, Bowman N, Wong DT. Lactic acidosis after resuscitation with sodium acetate. J Surg Res. 2012;173(2):362-364.

18.       Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int. 2016;89(3):546-554.

19.       Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S444-464.

20.       Velissaris D, Karamouzos V, Pierrakos C, Koniari I, Apostolopoulou C, Karanikolas M. Use of sodium bicarbonate in cardiac arrest: current guidelines and literature review. J Clin Med Res. 2016;8(4):277-283.

21.       Part 7: Adult Advanced Cardiovascular Life Support. American Heart Association website. https://eccguidelines.heart.org/wp-content/themes/eccstaging/dompdf-master/pdffiles/part-7-adult-advanced-cardiovascular-life-support.pdf. Accessed September 11, 2017.

22.       Zapata-Chica CA, Bello Marquez D, Serna-Higuita LM, Nieto-Rios JF, Casas-Arroyave FD, Donado-Gomez JH. Sodium bicarbonate versus isotonic saline solution to prevent contrast-induced nephropathy : a systematic review and meta-analysis. Colomb Med (Cali). 2015;46(3):90-103.

23.       Zhang B, Liang L, Chen W, Liang C, Zhang S. The efficacy of sodium bicarbonate in preventing contrast-induced nephropathy in patients with pre-existing renal insufficiency: a meta-analysis. BMJ Open. 2015;5(3):e006989.

24.       Brown JR, Pearlman DM, Marshall EJ, et al. Meta-analysis of individual patient data of sodium bicarbonate and sodium chloride for all-cause mortality after coronary angiography. Am J Cardiol. 2016;118(10):1473-1479.

25.       Dong Y, Zhang B, Liang L, et al. How strong is the evidence for sodium bicarbonate to prevent contrast-induced acute kidney injury after coronary angiography and percutaneous coronary intervention? Medicine (Baltimore). 2016;95(7):e2715.

26.       Kim JH, Kim HJ, Kim JY, et al. Meta-analysis of sodium bicarbonate therapy for prevention of cardiac surgery-associated acute kidney injury. J Cardiothorac Vasc Anesth. 2015;29(5):1248-1256.

27.       Tie HT, Luo MZ, Luo MJ, Zhang M, Wu QC, Wan JY. Sodium bicarbonate in the prevention of cardiac surgery-associated acute kidney injury: a systematic review and meta-analysis. Crit Care. 2014;18(5):517.

28.       Scharman EJ, Troutman WG. Prevention of kidney injury following rhabdomyolysis: a systematic review. Ann Pharmacother. 2013;47(1):90-105.

29.       Manspeaker S, Henderson K, Riddle D. Treatment of exertional rhabdomyolysis in athletes: a systematic review. JBI Database System Rev Implement Rep. 2016;14(6):117-147.

30.       Lugo-Janer G, Padial M, Sanchez JL. Less painful alternatives for local anesthesia. J Dermatol Surg Oncol. 1993;19(3):237-240.

31.       Pate DA, Shimizu I, Akin R, Snodgrass K, Emrick A. Safety of prefilled buffered lidocaine syringes with and without epinephrine. Dermatol Surg. 2016;42(3):361-365.

32.       Pascuet E, Donnelly RF, Garceau D, Vaillancourt R. Buffered lidocaine hydrochloride solution with and without epinephrine: stability in polypropylene syringes. Can J Hosp Pharm. 2009;62(5):375-380.

33.       Peterfreund RA, Datta S, Ostheimer GW. pH adjustment of local anesthetic solutions with sodium bicarbonate: laboratory evaluation of alkalinization and precipitation. Reg Anesth. 1989;14(6):265-270.

October 2017

The information presented is current as of September 6, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are cardioplegia solutions?

The cardioplegia solutions are mainly used in open-heart surgeries to intentionally and temporarily cease cardiac activity.^1,2 Due to the difficulty of operating on the beating heart, cardioplegia can protect cardiac muscle and increase the safety during cardiac surgeries. Myocardium injury can be caused by ischemia during arrest phase or reperfusion when coronary blood flow is restored. The use of cardioplegia solution provides a rapid and sustained electromechanical cardiac arrest.  A non-contracting heart decreases the risk of air embolism and eliminates blood flow to the myocardium to enhance operative visibility. Rapid electromechanical cardiac arrest also allows storing the adenosine triphosphate (ATP) and creatine phosphate for future use in the post-ischemic period. To sustain electromechanical quiescent after achieving cardiac arrest, the cold cardioplegia solution is administered at regular intervals to reduce energy needs during ischemia period. The cardioplegia solution can also minimize reperfusion damage by providing energy substrates and reducing Ca²⁺ overload.

Different methods are used to administrate cardioplegia solutions.^1,2 The most frequently used method is to deliver the cardioplegia solution into coronary circuit by the cardiopulmonary-bypass pump. Administering hypothermic cardioplegia solution provides additional benefits in lowering the cardiac activity and maintaining cardiac arrest. Hyperosmolar (>320 mOsm/L) cardioplegia solutions can minimize the possible cardiac edema, and slightly alkaline (pH at 7.4 to 7.6) solutions can buffer the acid produced from cardiac arrest.  The goal of cardioplegia solution is to enhance the changes occurring during arrest phase and during reperfusion stage at the end of surgery. Inappropriate management of the ischemia or reperfusion stage can lead to irreversible myocardial cell death or injury. It is important to understand the use of cardioplegia solutions in order to achieve the optimal patient outcomes.

Components of cardioplegia solutions

Cardioplegia solutions contain different components to prevent the myocardial damage during the surgery.^1,2 In order to fully understand the mechanism of the solution, it is important to know each component of cardioplegia solutions. Table 1 includes the most commonly used components, their concentrations, and the mechanism of each component.  

Table 1. Common components in cardioplegia solution.^1,2

Classification of cardioplegia solutions

The cardioplegia solutions are classified into 2 categories based on their formulations: extracellular or intracellular solutions.^1,3 Extracellular solutions contain calcium and sodium at normal extracellular ionic concentrations. Cardiac arrest is achieved by moderate elevations of potassium and magnesium. Ease of equilibrating with myocardial tissue is the major advantage of these solutions. However, these solutions are easily removed by non-coronary blood flow. Blood-based cardioplegia solutions are classified as extracellular solutions. Intracellular solutions usually do not contain any calcium or sodium, and their composition is similar to the composition of cell’s intracellular fluid. Cardiac arrest is produced by calcium and sodium depletion. The low osmolality of intracellular solutions allows the addition of other high concentration components without excessive hyperosmolarity. 

Blood versus crystalloid cardioplegia solutions

There are two vehicles for cardioplegia solutions: blood or crystalloid fluids.^1,2 The advantage of blood cardioplegia includes the oxygen carried by hemoglobin, the physiologic buffers, the physiologic osmotic pressure, and the metabolic substrates contained in the blood. However, it may cause clumping of red blood cells. The shape of red blood cells might obstruct capillary flow and release vasoactive substances at low temperatures. Compared to blood solution, the crystalloid solution is easier to prepare and inexpensive. However, the low oxygen-carrying capacity may reduce efficacy in preserving cardiac function due to insufficient oxygen supply.

A meta-analysis of 12 randomized controlled trials with 2,866 patients evaluated the use of cold blood versus crystalloid cardioplegia solutions for cardiac surgery.⁴ No differences were found in the overall incidence of spontaneous sinus rhythm, mortality, atrial fibrillation, or stroke between the 2 vehicles. The incidence of perioperative myocardial infarction was lower in patients receiving cold blood cardioplegia (1.19%) versus crystalloid cardioplegia solutions (2.44%) [relative risk, 2.30; p=0.003]. Another meta-analysis compared the use of blood versus crystalloid cardioplegia solutions for coronary artery bypass grafting and heart valve replacement.⁵ Thirty-four randomized controlled trials were identified, with a total of 5,044 patients. The incidence of low output syndrome was lower with blood cardioplegia (odds ratio, 0.54; 95% confidence interval [CI], 0.34 to 0.84; p=0.006). The incidence of death and myocardial infarction were similar in both groups.

A similar meta-analysis compared the efficacy between 2 vehicles in pediatric cardiac surgery.⁶ This study included 5 studies with a total of 323 patients. The lactate levels were reduced in the blood cardioplegia group (standard mean difference, 1.09; 95% CI, 0.12 to 2.06; p=0.03). No differences were found in postoperative cardiac troponin, mechanical ventilation time, and length of intensive unit stay. However, a recent meta-analysis did not show any differences in clinical outcomes between blood and crystalloid cardioplegia solutions for cardiac surgery.⁷ Thirty-six studies were included, with a total of 5,576 patients.  No significant differences were observed in the risk of death, myocardial infarction, or low cardiac output syndrome between the 2 solutions. 

Overall, cardiac outcomes were comparable between blood cardioplegia and crystalloid cardioplegia solutions. A big limitation of these meta-analyses is the heterogeneity across the identified randomized trials. Other limitations included the lack of detailed randomization techniques, the blinding of patients, the small patient population, and the short duration of follow up. The different components of cardioplegia solutions might also affect the outcomes.

Formulations of cardioplegia solutions

Different types of cardioplegia solutions are available on the market. A systematic review of 40 journal articles discussed the current practice for utilization of cardioplegia solutions (mainly microplegia, del Nido, Custodial, and 4:1 blood cardioplegia) and the lack of comparative effectiveness studies.⁸ The del Nido solution, the most popular and commonly used cardioplegia solution, contains 20% of fully oxygenated whole blood and 80% of Plasma-Lyte A.⁹  The unique 1:4 ratio provides several benefits such as the physiological pH, the relatively calcium depleted nature, the buffer properties, and the sufficient oxygen supply. However, well-designed human clinical trials and comparative studies to other cardioplegia solutions are lacking for del Nido solution.⁸ Overall, del Nido solution was not significantly different for clinical outcomes when compared to blood cardioplegia solutions but the data had very small sample size.

Custodiol histidine-tryptophan-ketoglutarate (HTK) and 4:1 blood cardioplegia solutions comprised around 80% of trials included in the review.⁸ Compared to HTK, blood cardioplegia had less postoperative atrial fibrillation, less need for intervention, while HTK had a lower number of administrations.

Pharmacy role in cardioplegia solutions

The pharmacist can play an important role in the preparation, distribution, and quality control of cardioplegia solutions.^1,2 Three basic methods to supply cardioplegia solution exist: in-house preparation, kit system, or commercial solution. The pharmacy department needs to consider several factors, such as surgeon’s preference, the number of surgeries, the capability of the pharmacy department, and cost to decide the best method to supply and prepare cardioplegia solutions. Pharmacists have to work closely with perfusionists, who are in charge of cardiopulmonary pass machine during cardiac surgery, to determine the dose and route of the cardioplegia solution. For example, the dose of del Nido solution is a single 20 mL/kg dose (maximum: 1000 mL). The pharmacist needs to calculate the dose and mix the crystalloid cardioplegia correctly with the patient's blood to achieve the 1:4 ratio. The pharmacist can also provide the stability and compatibility information for agents that are added to the solution. If the solution has been modified, it must be used within 24 hours. The solution should be stored under refrigeration and be cooled to 4°C prior to administration. The distribution of cardioplegia solution will be based on the agreement between the pharmacy department and the perfusion department. It can either be delivered from central pharmacy daily or be a floor stock item in the operating room. The ingredients and preparation procedure for each cardioplegia solution should be documented and verified by pharmacists to ensure the quality.

Conclusion

The use of cardioplegia solutions has increased the safety and success of open-heart surgeries. No significant differences were detected between blood and crystalloid cardioplegia solutions. Further comparative studies are needed to evaluate the efficacy and safety of different cardioplegia solutions in the future. The pharmacist plays an important role in the preparation, dosage, distribution, and quality control of cardioplegia solutions.

References:

1. Donnelly AJ, Djuric M. Cardioplegia solutions. Am J Hosp Pharm. 1991;48(11):2444-2460.

2. Golembiewski J, Bourtsos N. Cardioplegia solution. J Pharm Pract. 1993;6(4):182-189.

3.  Molina JE/Laizzo PA. Cardiopulmonary bypass and cardioplegia. In: Handbook of Cardiac Anatomy, Physiology, and Devices. 2^nd ed. Minneapolis, MN: Springer; 2009: 371-382.

4. Zeng J, He W, Qu Z, Tang Y, Zhou Q, Zhang B. Cold blood versus crystalloid cardioplegia for myocardial protection in adult cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2014;28(3):674-681.

5. Guru V, Omura J, Alghamdi AA, Weisel R, Fremes SE. Is blood superior to crystalloid cardioplegia? A meta-analysis of randomized clinical trials. Circulation. 2006;114(suppl 1):I331-338.

6. Sá MP, Rueda FG, Ferraz PE, Chalegre ST, Vasconcelos FP, Lima RC. Is there any difference between blood and crystalloid cardioplegia for myocardial protection during cardiac surgery? A meta-analysis of 5576 patients from 36 randomized trials. Perfusion. 2012;27(6):535-546.

7. Fang Y, Long C, Lou S, Guan Y, Fu Z. Blood versus crystalloid cardioplegia for pediatric cardiac surgery: a meta-analysis. Perfusion. 2015;30(7):529-536.

8. Ferguson ZG, Yarborough DE, Jarvis BL, Sistino JJ. Evidence-based medicine and myocardial protection–where is the evidence? Perfusion.2015;30(5):415-422.

9. Matte GS, Del Nido PJ. History and use of del Nido cardioplegia solution at Boston children's hospital. J Extra Corpor Technol. 2012;44(3):98-103.

Prepared by:
Po-hung Lin, PharmD
PGY1 Pharmacy Practice Resident
University of Illinois at Chicago College of Pharmacy
 

October 2017

The information presented is current as of August 31, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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