Orange Interventions for Symptoms Associated With Dimethyl Sulfoxide During Stem Cell Reinfusions

A Feasibility Study

Pamela Potter, DNSc, RN, CNS; Seth Eisenberg, RN, OCN; Kevin C. Cain, PhD; Donna L. Berry, PhD, RN, AOCN, FAAN


Cancer Nurs. 2011;34(5):361-368. 

In This Article

Abstract and Introduction


Background: For over 2 decades, oncology nurses at a regional comprehensive cancer center offered sliced oranges to patients during the reinfusion of autologous hematopoietic progenitor cells (HPCs) to relieve symptoms associated with the preservative dimethyl sulfoxide (DMSO). Objective: This randomized pilot study examined feasibility and efficacy of sliced orange intervention (OI), orange aromatherapy intervention (OAI), or deep breathing (control) to address unpleasant adverse effects during HPC infusion. Methods: Orange intervention sniffed or tasted a quartered orange, OAI sniffed orange aromatherapy, and control took deep breaths. Perceived "symptom intensity" for tickle/cough urge, nausea, retching, and perceived "relief" were measured on 0- to 10-point numerical scales. Results: Sixty of 72 eligible patients consented to participate and were randomized to OI (n = 19), OAI (n = 23), or control (n = 18). Study personnel successfully administered study procedures. Over the course of 2 bags of cells infused, the OI group reported significantly greater relief with the intervention (P = .032). Among participants less than 90 kg, OI group reported significantly lower symptom intensity (P = .012). Conclusions: Results suggest a feasible protocol and potential efficacy of sliced oranges for treating symptoms associated with DMSO-preserved stem cells. Study procedures provide a tested protocol for future studies. Follow-up study is warranted to confirm these findings and evaluate other treatment options. Implications for Practice: Oranges offer a simple, noninvasive intervention for relieving symptoms associated with DMSO preservative during autologous HPC infusion.

Autologous Hematopoietic Stem Cell Transplantation

Autologous hematopoietic stem cell (HPC) transplantation is a process in which stem cells are collected from a patient, cryopreserved in liquid nitrogen, and then reinfused after myeloablative chemotherapy. Although bone marrow has historically been the stem cell source, mobilized peripheral blood stem cells are now used in more than 95% of adult autologous transplants. Worldwide, 28 901 autologous transplants were performed at 1327 registered centers in 2006, more than onethird (10 348) in the Americas.[1] Autologous HPC transplantation is a viable treatment option for selected patients with lymphoma, multiple myeloma, leukemia, and autoimmune diseases.[2]

Dimethyl sulfoxide (DMSO) is commonly used as a cryoprotectant for hematopoietic progenitor cells (HPCs).[3,4] A byproduct of the paper manufacturing industry, the agent is soluble in both aqueous and organic media and allows viable cryopreservation of cells for a prolonged period.[5–7] Although concentrations vary depending on transplant center, a 10% volume-per-volume solution of DMSO is commonly used.[3]

The reinfusion of HPCs preserved in DMSO is associated with numerous adverse effects including cardiac, renal, and gastrointestinal adverse effects and anaphylaxis.[7,8] Gastrointestinal discomfort, such as nausea and vomiting, may already be present because the stem cell reinfusion occurs 1 to 2 days after high-dose chemotherapy.[9]

Dimethyl sulfoxide and its metabolites dimethyl sulfone and dimethyl sulfide are excreted in the urine, skin, and lungs. Patient, family, and staff may experience throat irritation, coughing, nausea, and headache.[6] Excreted DMSO metabolites produce an intense, noxious odor, commonly described as smelling like garlic or creamed corn.[8] The serum half-life is approximately 20 hours, although the odor may linger for 24 hours or longer, depending on the number bags of cells, total infused volume, and concentration of DMSO.[4,5]

Successful engraftment is dependent on infusing a minimum number of CD34+ cells per kilogram of patient weight, usually 2.5 ×106, although different centers may use a higher or lower threshold. At the Seattle Cancer Care Alliance (SCCA), collections are frozen in aliquots varying in size between 30 and 70 mL. Depending on the number of days required for collection, patients may receive multiple bags of cells, which increases the amount of DMSO infused. Likewise, heavier patients require more CD34+ cells than lighter ones, increasing the number of cells required and potentially the number of bags.

Historical Use of Oranges

For the past 2 decades, oncology nurses at the Fred Hutchinson Cancer Research Center/SCCA have offered cut oranges to patients to help obviate throat irritation, coughing, and nausea from DMSO. The nurses had observed that many patients benefited from smelling and/or tasting an orange during the reinfusion.[10] However, despite its clinical use and apparent benefits, no study had been conducted to validate or refute the efficacy of this nurse-initiated treatment.

In a related study, precedence for using oranges in odor management was documented in a qualitative descriptive study of oncology nurses' experience with DMSO.[6] The nurses described the use of cut-up oranges, orange peel, or orange aromatherapy burners as environmental interventions placed in the patient's room to mask the odor of dimethyl sulfide excreted through the breath, skin, urine, and feces of patients within the first 24 hours of receiving stem cells preserved in DMSO.

Aroma-associated Intervention Studies

Aromatherapy has been defined as the controlled use of plant essences—essential oils derived from plant constituents—for therapeutic purposes.[11] Essential oils are administered topically or aromatically. The primary mechanism of action is thought to be olfaction with subsequent activation of the limbic system, a center associated with the emotional response and learned memory formation and retrieval.

Clinical research evidence for the efficacy of aromatherapy is limited. Cooke and Ernst[12] reviewed research on aromatherapy clinical trials and concluded that aromatherapy massage has a mild and transitory anxiolytic effect. Tate[13] found significantly less (U = 3; P = .02) postoperative nausea in a group of 6 patients who were given a dropper bottle of peppermint oil to inhale as needed. A study of 313 patients who were given 3 drops of combined lavender, bergamot (similar scent to orange), and cedar wood essential oils on a paper bib worn while waiting to undergo radiation therapy demonstrated no significant effect for depression and anxiety.[14]

At the time of this study, 2 aromatherapy pilot trials associated with the Columbia University Integrative Therapies Program for Children were being conducted. The first tested aromatherapy (ginger, spearmint, peppermint essential oils) in conjunction with standard antiemetic therapy for relieving nausea and vomiting in children receiving chemotherapy.[15] Based on experience with aromatherapy in the bone marrow and stem cell transplant setting, the second study compared essential oil of bergamot with placebo to address the nausea and discomfort associated with DMSO preservative.[16] Results from these trials are not available at this time.

Ozdemir et al[17] reported on a preintervention-postintervention–design study (n = 158) of the effectiveness of sucking on a strawberry-flavored lollipop compared with usual care for decreasing the incidence of nausea and vomiting associated with DMSO preservative for autologous peripheral blood stem cell transplantation. Those receiving the intervention were instructed to suck on the lollipops just prior to and throughout the infusion until all bags were infused. The researchers found that significantly fewer of those receiving the lollipop during their infusion reported nausea (6.3%, n = 3) compared with the control (21.8%, n = 24, P = .02). Significantly fewer in the treatment group vomited (2%, n = 1) compared with the control (13.6%, n = 15, P = .04).

Conceptual Framework

The Human Response Framework provided the theoretical framework for this study.[18–21] The Human Response Framework is a conceptual framework describing individual vulnerability and environmental risk and the interplay of biological, psychological, and social human responses that influence illness outcomes. Interventions in this model aim to promote individual adaptation either through interventions to prevent the onset of pathological lesion, impairment, and functional disability or those to prevent the progression of disease, impairment, and functional disability. Human responses are measurable as physiological, pathophysiologic, experiential, or behavioral phenomena.

A pathophysiologic phenomenon, the vomiting reflex is initiated by the activation of the vomiting center, a nucleus of neurons located in the medulla oblongata.[22] Stimuli to this center sufficient to activate the vomiting reflex may come from physiological, pathophysiologic, experiential, or behavioral input. The vomiting center can be activated by various signal pathways that may initiate the vomiting reflex directly by (1) signals originating in the cerebral cortex relating fear, anticipation, or memory; (2) sensory organ signals responding to pain, disturbing smells and sights; and (3) vestibular signals associated with motion sickness and indirectly (4) by activation of the chemoreceptor trigger zone (CTZ). The CTZ responds indirectly to vagal afferent nerve signals from the stomach and small intestine and, lacking a true blood-brain barrier, responds directly to emetogenic compounds in the blood.

Most severe during infusion, the patient's reaction toDMSO dissipates upon infusion completion. Dimethyl sulfoxide may activate the vomiting center through the CTZ as soon as the agent is detected in the blood. This sensation may be compounded as it passes directly into the saliva and is then tasted and smelled upon entering the oral and nasal cavity.[23] Biomedical interventions (eg, antiemetics) act by blocking 1 or more of the vomiting center receptors to inhibit the vomiting reflex. Behavioral interventions such as encouraging deep breathing or offering comforting reassurance facilitate relaxation and may diminish fear and anticipation. The sight, smell, and taste of an orange, operating on sensory and memory pathways, may diminish the experience of nausea, retching, and vomiting (NRV) associated with DMSO. Furthermore, odor masking of DMSO by orange, wherein the orange odor map actually inhibits the odor map of the DMSO, could provide an explanatory model for the possible effectiveness of the interventions.[24]

Preliminary to a larger randomized control trial, the purpose of this randomized pilot study was to examine the feasibility and efficacy of using a sliced orange, orange aromatherapy, or deep breathing to address the symptoms of throat irritation, cough, and NRV in patients receiving autologous reinfusion of stem cells that have been cryopreserved in DMSO.


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