Respiratory depression and somnolence in children receiving dimethylsulfoxide and morphine during hematopoietic stem cells transplantation

Dimethylsulfoxide (DMSO) has been commonly used for the past 20 years as a well-known cryo-protectant agent. It acts by penetrating the cell and binding water molecules; by doing so, it blocks the efflux of water and prevents cellular dehydration, maintains stable pH, intracellular salt concentration, and the formation of the ice crystals which endanger cell integrity. The most common clinical application of such a procedure is the cryo-protection of stem cells frozen in liquid nitrogen for their subsequent reinfusion in autologous stem cell transplantation.1

The infusion of DMSO may have several side effects, such as vasoconstriction, nausea, vomiting, abdominal cramps, cardiovascular and respiratory problems, and a variety of neurological events.2–4 Despite this, it is used by transplant specialists worldwide.

Morphine is widely used to control pain in patients with different clinical conditions. Its wider use has been repeatedly advocated by scientists, patients’ associations and the media in order to combat old prejudices restricting its use to terminal cancer patients. Patients undergoing hematopoietic stem cell transplantation (HSCT) may face pain for different causes, including severe mucositis.5 Thus the use of morphine and DMSO may concur in such patients. To our knowledge, reports of adverse events resulting from their interaction are not available.

Recently, we observed 3 patients who unexpectedly developed somnolence and clinically significant oxygen desaturation soon after reinfusion of autologous stem cells. Their main features are summarized in Table 1. Neurological alterations rarely occur as a primary complication during or soon after stem cell infusion. In a recent survey, only 3 out of 179 consecutive patients experienced neurological complications during stem cell infusion.6 In order to understand the pathogenesis of such unexpected events, we performed a thorough critical re-evaluation of the clinical course of the patients. We noted that all of them were already receiving i.v. morphine infusion at the time of stem cell infusion; this is quite unusual in our experience, since severe pain is more frequently observed later during the course of transplantation.5 Thus, we wondered if morphine interaction with any other transplant-related agent might have been responsible for the observed complication.

Table 1.Main features of the three patients.

DMSO is a solvent for water-insoluble drugs, and has a well known analgesic effect.7 In a recent report, Fossum et al.8 documented in a mouse model that DMSO enhances morphine potency when the two drugs are used by microinjection into the ventro-lateral peri-aqueductal gray, a part of the descending pain modulatory system that contributes to morphine anti-nociception and tolerance. In our 3 patients the unexpected neurological syndrome with clinically significant oxygen desaturation may thus be explained by concurrent DMSO and morphine infusion; the clinical picture being fully reversed following morphine withdrawal. We suggest that some patients receiving morphine may be at a higher risk for DMSO-associated neurological symptoms and respiratory depression. Studies are needed to verify if infusion of lower amounts of DMSO, as achieved by reducing its concentration,9,10 will contribute to limiting its neurotoxicity.