Advances in Peritoneal Dialysis, Vol. 30, 2014

Unexplained Hypotension and Exertional Dyspnea in a Night-Cycled Peritoneal Dialysis Patient—A Rare Form of Icodextrin Macaulay A.C. Onuigbo1,2 Hypersensitivity

In recent years, icodextrin 7.5% has been used in problems in susceptible patients (1–3). Icodextrin is PD as an alternative to glucose to achieve sustained generally well tolerated, with few side effects (1–3). reliable ultrafiltration (UF) and clearance without The most commonly reported adverse effects of adversely increasing glucose absorption. Icodextrin icodextrin are cutaneous hypersensitivity reactions is generally well tolerated. The most commonly re- (4–11). Even though icodextrin is known to produce ported adverse events are cutaneous reactions. We symptomatic hypotension in up to 40% of patients, ne- report a rare form of hypersensitivity to icodextrin cessitating a reduction in the use of antihypertensive 7.5% that was accompanied by dyspnea and symptom- medications, that hypotension is usually correlated atic hypotension, without increased UF to account with weight loss and concurrent higher achieved UF for the observed hypotension. in PD patients (12). Icodextrin produces symptomatic hypotension Recently, we used icodextrin to manage a 76-year- in up to 40% of patients by a known mechanism of old obese white woman with diabetic end-stage renal increased UF and corresponding weight loss. How- disease on night-cycled PD (IPD). She subsequently ever, it can also produce symptomatic hypotension presented with severe symptomatic hypotension accompanied by several other systemic symptoms (systolic blood pressure: 60 – 70 mmHg) absent in a hypersensitivity reaction. Discontinuation of significant UF or weight loss. The hypotension was the icodextrin results in prompt resolution of those also associated with other systemic symptoms such symptoms. Treating nephrologists must be aware of as early-morning upper-respiratory flu-like symp- this rare form of icodextrin hypersensitivity. toms, dysgeusia, fatigue, and dyspnea. An extensive workup (cardiopulmonary, endocrine, and other) was Key words negative. As a last resort, icodextrin hypersensitivity Hypersensitivity, icodextrin was suspected, and icodextrin was withdrawn from the patient’s IPD prescription. All her symptoms Background resolved promptly and dramatically within 36 hours In recent years, icodextrin 7.5% has increasingly of icodextrin discontinuation. been used in peritoneal dialysis (PD) patients as an Our patient demonstrates an unusual and rare form alternative to glucose for simultaneously achieving of icodextrin hypersensitivity reaction, producing a sustained, reliable ultrafiltration (UF) and enhanced syndrome of multiple symptoms (dyspnea; symptom- clearance, while not adversely increasing glucose atic hypotension with orthostatism, lightheadedness, absorption and therefore exacerbating diabetic control fatigue, and malaise; and dysgeusia) in the absence of any cutaneous reaction and without increased UF or From: 1Mayo Clinic College of Medicine, Rochester, weight loss. The symptoms promptly resolved after Minnesota, and 2Mayo Clinic Health System, Eau Claire, discontinuation of icodextrin and continuation of IPD Wisconsin, U.S.A. with dextrose-containing solution only. 88 A Rare Form of Icodextrin Hypersensitivity

Case description hypersensitivity was entertained (13–15). Icodextrin was Our patient had a prior history of a coronary artery discontinued from the IPD prescription. Within 24 hours, bypass graft procedure in 2005 and a subsequent aortic the patient was already feeling better. At 36 hours, she valve replacement for severe aortic stenosis in 2011. was asymptomatic. Blood pressure on day 2 of her hos- She had done well for more than a year (2012 – 2013) pitalization was 150/70 mmHg, and pulse was 88 bpm. on a 9-hour, night-cycled, 5-exchange IPD prescrip- On orthostatic testing, systolic BP was 146 mmHg sitting tion (2.3 L of dextrose solution per exchange), without and unchanged at 147 mmHg standing. any daytime dwell. She met monitored weekly Kt/V The patient has since remained asymptomatic targets. At the time, she had also maintained significant (through March 2014), while continuing on night- residual renal function. cycled IPD using only dextrose-based solutions (2.5% Peritonitis was treated in August 2013. With ob- and 4.25%) during an extended exchange period (6 servation of failing residual renal function after the exchanges over 11 hours). On her current modified peritonitis episode, delivered weekly Kt/V declined. icodextrin-free IPD prescription, she has continued As a result, an additional icodextrin day dwell (morn- to maintain adequate weekly Kt/V. As a consequence ing fill volume) was added to the IPD prescription in of the increased glucose exposure since icodextrin early September 2013. discontinuation, she has had to increase her insulin After the addition of icodextrin, the patient’s Kt/V dose to achieve the desired HbA1c goal (1–3,14). quickly improved to 1.9 from 1.57, but without any observed additional UF or weight loss. However, from Conclusions mid-September 2013, our patient started to experience Symptomatic hypotension has been reported in up to increasing lightheadedness; fatigue; dyspnea that was 40% of PD patients. Typically, observed changes in worse with exertion, including mere conversation; systolic BP are significantly correlated with weight early-morning flu-like symptoms of the upper respira- loss because of a higher achieved UF volume with tory tract; dysgeusia; and low at-home blood pressure icodextrin than with glucose—2.27% solution, for (BP) measurements. On admission to the critical care instance (12). Indeed, many patients require a reduc- unit during the first week of October 2013, she was tion in their antihypertensive medications to manage lightheaded and somnolent, and she complained of the resultant hypotension (12). increasing fatigue and exertional dyspnea. She was The hypersensitivity reactions most commonly otherwise alert, oriented in all three relevant dimen- reported with icodextrin use are cutaneous adverse ef- sions, nonfocal, and not depressed. Blood pressure was fects, and those cutaneous reactions to icodextrin are 64/44 mmHg, and pulse was 84 bpm with a regular estimated to occur in up to 15% of patients (4–11,16). heart rhythm. Orthostatism was not attempted. Other rare icodextrin hypersensitivity reactions that Chest and cardiac examinations were unremarkable. have been reported include cases of allergic sterile peri- The patient was not pale and had no evident peripheral tonitis (13,15,17–20). Even more rarely associated with edema. Her weight, at 98 kg, was unchanged from the use of icodextrin is a hypersensitivity-type reaction baseline. Hemoglobin was 11.4 g/dL, basic metabolic that includes dyspnea, symptomatic hypotension, flu- profile was otherwise unremarkable, and liver profile like symptoms, fatigue, generalized weakness, and an tests were normal. Thyroid function tests—including abnormal sense of taste (13–15). Most pertinently, and thyroid-stimulating hormone, free T3, free T4, and as was evident in our case report, the symptomatic hy- morning cortisone levels—all fell within normal lim- potension in that hypersensitivity setting is a component its. Chest radiography was stable, electrocardiography of a set of other apparently unrelated, albeit systemic, measures were unchanged, and acute myocardial symptoms (13–15). Most importantly, for the purposes infarction was ruled out by serial electrocardiography of differential diagnosis, the hypotension is dissociated and troponin I tests. Left ventricular ejection fraction from any weight loss or increased UF volume (14). was stable at 60% on echocardiography, without any We posit that physicians must be aware of this rare wall-motion abnormalities, and the stented tissue aortic form of icodextrin-induced hypersensitivity reaction, valve prosthesis appeared normal. because prompt discontinuation of icodextrin while After this extensive, albeit negative, workup of continuing PD with only dextrose-based solutions our patient’s symptoms, the possibility of icodextrin results in rapid resolution of the symptoms. Prompt Onuigbo 89 discontinuation of icodextrin can prevent further 10 Aanen MC, de Waart DR, Williams PF, Out TA, Zweers unnecessary and potentially hazardous and invasive MM, Krediet RT. Dextran antibodies in peritoneal diagnostic procedures during a workup for symptom- dialysis patients treated with icodextrin. Perit Dial Int atic hypotension in such patients. 2002;22:513–15. The exact mechanisms of this hypersensitiv- 11 Meier MJ, Adams BB. Acute generalized exanthema- tous pustulosis associated with icodextrin. J Am Acad ity reaction remain speculative at this point. Some Dermatol 2010;63:536–7. studies have suggested that dextran antibodies are 12 Woodrow G, Oldroyd B, Stables G, Gibson J, Turney potentially the culprits in some icodextrin reactions JH, Brownjohn AM. Effects of icodextrin in automated in PD patients (10). peritoneal dialysis on blood pressure and bioelectri- cal impedance analysis. Nephrol Dial Transplant Acknowledgments 2000;15:862–6. This case report is dedicated to all our patients, past, 13 Baxter Healthcare Corporation. Study RD-99-CA-060: present, and future, without whom there would be no a study to evaluate the pharmacokinetics of a single ex- change of 7.5% icodextrin peritoneal dialysis solution in case reports. patients treated with peritoneal dialysis. 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Perit Dial Int 2003;23:33–8. 6 Queffeulou G, Bernard M, Vrtovsnik F, et al. Severe 19 Lee SH, Park HC, Sim SR, et al. Severe cutaneous hy- cutaneous hypersensitivity requiring permanent ico- persensitivity to icodextrin in a continuous ambulatory dextrin withdrawal in a CAPD patient. Clin Nephrol peritoneal dialysis patient. J Nephrol 2006;19:673–6. 1999;51:184–6. 20 Li PK, Culleton BF, Ariza A, et al. on behalf of the 7 Goldsmith D, Jayawardene S, Sabharwal N, Cooney IMPENDIA and EDEN Study Groups. Randomized, K. Allergic reactions to the polymeric glucose-based controlled trial of glucose-sparing peritoneal dialysis in peritoneal dialysis fluid icodextrin in patients with renal diabetic patients. J Am Soc Nephrol 2013;24:1889–900. failure. Lancet 2000;355:897. 8 Queffeulou G, Lebrun–Vignes B, Wheatley P, Montag- Corresponding author: nac R, Mignon F. Allergy to icodextrin [comment on Goldsmith et al. (7)]. Lancet 2000;356:75. Macaulay A.C. Onuigbo, md msc fwacp fasn mba, 9 Wolfson M, Piraino B, Hamburger RJ, Morton AR on Department of Nephrology, Mayo Clinic Health behalf of the Icodextrin Study Group. A randomized System, 1221 Whipple Street, Eau Claire, Wiscon- controlled trial to evaluate the efficacy and safety of sin 54702 U.S.A. icodextrin in peritoneal dialysis. Am J Kidney Dis E-mail: 2002;40:1055–65. [email protected]