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article-title
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Adverse reactions of dimethyl sulfoxide in humans: a systematic review
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[version 2; peer review: 2 approved]
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[version 2; peer review: 2 approved]
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abstract
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Background: Dimethyl sulfoxide (DMSO) has been used for medical treatment and as a pharmacological agent in humans since the 1960s. Today, DMSO is used mostly for cryopreservation of stem cells, treatment of interstitial cystitis, and as a penetrating vehicle for various drugs. Many adverse reactions have been described in relation to the use of DMSO, but to our knowledge, no overview of the existing literature has been made. Our aim was to conduct a systematic review describing the adverse reactions observed in humans in relation to the use of DMSO.
Methods: This systematic review was reported according to the PRISMA-harms (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines. The primary outcome was any adverse reactions occurring in humans in relation to the use of DMSO. We included all original studies that reported adverse events due to the administration of DMSO, and that had a population of five or more.
Results: We included a total of 109 studies. Gastrointestinal and skin reactions were the commonest reported adverse reactions to DMSO. Most reactions were transient without need for intervention. A relationship between the dose of DMSO given and the occurrence of adverse reactions was seen.
Conclusions: DMSO may cause a variety of adverse reactions that are mostly transient and mild. The dose of DMSO plays an important role in the occurrence of adverse reactions. DMSO seems to be safe to use in small doses.
Registration: PROSPERO CRD42018096117.
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p
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Background: Dimethyl sulfoxide (DMSO) has been used for medical treatment and as a pharmacological agent in humans since the 1960s. Today, DMSO is used mostly for cryopreservation of stem cells, treatment of interstitial cystitis, and as a penetrating vehicle for various drugs. Many adverse reactions have been described in relation to the use of DMSO, but to our knowledge, no overview of the existing literature has been made. Our aim was to conduct a systematic review describing the adverse reactions observed in humans in relation to the use of DMSO.
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p
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Methods: This systematic review was reported according to the PRISMA-harms (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines. The primary outcome was any adverse reactions occurring in humans in relation to the use of DMSO. We included all original studies that reported adverse events due to the administration of DMSO, and that had a population of five or more.
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p
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Results: We included a total of 109 studies. Gastrointestinal and skin reactions were the commonest reported adverse reactions to DMSO. Most reactions were transient without need for intervention. A relationship between the dose of DMSO given and the occurrence of adverse reactions was seen.
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p
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Conclusions: DMSO may cause a variety of adverse reactions that are mostly transient and mild. The dose of DMSO plays an important role in the occurrence of adverse reactions. DMSO seems to be safe to use in small doses.
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Registration: PROSPERO CRD42018096117.
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body
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Introduction
The first medical report on the use of dimethyl sulfoxide (DMSO) as a pharmacological agent was published in 1964 1. A year later, the use of DMSO in humans was terminated because experimental studies had shown refractive index changes to the lens of the eye 1, 2. Years later, DMSO was again approved for use in humans since this side effect was only proven in animal studies 2. DMSO has since been used for a variety of purposes, such as treatment of musculoskeletal and dermatological diseases, cryopreservation of stem cells, treatment of interstitial cystitis, treatment of increased intracranial pressure, and many more 3– 9.
DMSO is a colourless liquid, which is rapidly absorbed when administered dermally or orally 10, 11. DMSO is used as a cryoprotectant because it decreases osmotic stress and cellular dehydration, and thereby enables stem cells to be stored for several years 12. DMSO is mostly excreted through the kidneys, but a small part is excreted through the lungs and liver 10. Part of the DMSO is transformed to the volatile metabolite dimethyl sulfide, which gives a characteristic garlic- or oyster-like smell when excreted through the lungs 10. DMSO may induce histamine release, which can be the reason for adverse reactions such as flushing, dyspnoea, abdominal cramps, and cardiovascular reactions 11.
To our knowledge, no systematic reviews have been performed on the adverse reactions of DMSO. Our aim was therefore to provide an extensive overview of the suspected adverse reactions to DMSO in humans.
Methods
Protocol and eligibility criteria
Our study-protocol is registered at PROSPERO (Registration number: CRD42018096117). The systematic review was performed according to PRISMA-harms (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 13.
No limitations were set on the date of publication. The language was restricted to English, Danish, Swedish, Norwegian, and Russian. We included all original studies that administered DMSO to humans and included five or more participants. There was no gender or age restriction. For a study to be included, the authors had to suspect that an observed adverse reaction could be caused by DMSO.
Primary outcome
The primary outcome was any adverse reaction seen in relation to the use of DMSO in humans.
Literature search
The search was performed in PubMed (1966-present), EMBASE (1980-present), and the Cochrane Library. The databases were last searched on February 23, 2018. Our search strategy was formulated with the help of a medical research librarian.
The search string used in PubMed was: ((dimethyl sulfoxide) OR DMSO) AND ((((((administration and dosage) OR adverse reactions) OR alternate effects) OR secondary response) OR toxicology) OR side effects)). The search was restricted to humans. The search string was adapted to EMBASE and Cochrane Library using the same search-words as abovementioned.
The search string used in EMBASE was: ((dmso or dimethyl sulfoxide) and ((side effect or toxicology or secondary response or alternate effects or alternate reactions or (administration and dosage)) and (dmso or dimethyl sulfoxide))).mp. The search was restricted to humans, articles and Medline journals were excluded.
The search string used in Cochrane was: (adverse drug events and dimethyl sulfoxide). The search was restricted to trials.
Study selection and data extraction
Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria using www.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H. was in doubt regarding inclusion of a study the results were presented to B.K.M. and then discussed until a mutual decision was made.
After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest). Data extracted were: author, publication year, country, study characteristics (study design, sample size, size of comparison group if present, time to follow-up), use of DMSO (reason for use, treatment duration, administration route, dose of DMSO), and adverse reactions observed (number of persons experiencing an adverse reaction, method of assessing, and duration of adverse reaction).
Analysis
The Newcastle-Ottawa-Scale was used to assess the risk of bias in non-randomized observational studies 14. Risk of bias in randomized controlled trials was assessed using the Cochrane Handbook “Risk of Bias” assessment tool 15. Risk of bias was assessed at the outcome level.
The primary summary measure was percentage of persons experiencing an adverse reaction, as well as the range in which a reaction occurred in the studies included. No meta-analysis and further summery measures were planned due to the expected large heterogeneity of the studies.
Results
Study selection
Our primary search identified 2599 studies ( Figure 1). After the evaluation process, 109 studies were included in the final review 2, 4, 6– 9, 16– 118.
Figure 1. PRISMA flow diagram.
Gastrointestinal reactions
Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials 16, 30, 33, 55, 57, 59, 67, 79, 93, 95, 49 were cohort studies 2, 4, 7, 9, 18, 19, 23, 25– 27, 29, 35, 38– 43, 45, 46, 48, 50– 54, 58, 60, 66, 68, 69, 71, 73, 83, 85– 88, 90, 94, 97, 98, 101, 104, 105, 112, 113, 115, 118, and 2 were case series 84, 109. Most studies reported the number of patients experiencing an adverse reaction ( Table 1). Other studies reported adverse reactions observed in relation to the number of treatments given ( Table 2).
Table 1. Gastrointestinal adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
Oral administration [ 9] 15 4 (27)
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
Table 2. Gastrointestinal adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
Intravesical administration [ 105] 151 24 (16)
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
Halitosis ‡ [ 68] 262 4 (2)
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration. The most commonly reported gastrointestinal adverse reactions were nausea and vomiting. The incidence of nausea seems to be less common with the transdermal administration of DMSO compared with intravenous administration. The majority of studies reported an incidence of nausea between 2–14%, with the exception of one study, reporting an incidence of 32% 2. In one study that failed to specify the dose, 8 of 42 patients reported nausea and anorexia, but the symptoms disappeared in five of the eight patients when the dose of DMSO was reduced 45.
Often the studies had short follow-up periods (less than 24 hours), especially when DMSO was used as a cryoprotectant. The study reporting the highest incidence of nausea had a follow-up period of 5 days 48, and the authors concluded that the high incidence of nausea observed might be due to the long follow-up period 48. In another article using the same data 119, it was suggested that the delayed nausea was due to gastrointestinal mucosal damage, and only the initial nausea could be related to DMSO, and therefore we decided only to include the data from the first 2 days after infusion 48.
Halitosis was reported in 29 studies 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113. In five studies, patients discontinued treatment due to halitosis 9, 45, 83, 94. In five studies, all patients experienced halitosis 9, 45, 83, 94. Unlike halitosis, other gastrointestinal side effects were reported more often when DMSO was administered intravenously, than transdermally or intravesically.
One study reported a severe case of nausea, vomiting, and abdominal cramps in one patient with an acute allergic reaction 59. However, in most studies the reported gastrointestinal reactions were transient and mild, often lasting only minutes to a couple of hours 16, 38, 41, 68, 85, 87, 90. Several studies reported a relationship between the dose of DMSO and the occurrence of gastrointestinal adverse reactions 26, 33, 53, 73, 83, 85.
Cardiovascular and respiratory reactions
Cardiovascular and respiratory adverse reactions were reported in 33 studies. Of these, two were randomized controlled trials 33, 59, 30 were cohort studies 7, 18, 23, 25– 27, 36, 39– 41, 51, 54, 61, 65, 66, 68, 73, 74, 80, 85– 87, 90, 100– 102, 104, 115, 117, and one was a preliminary report 91. Except for one study 66, all studies reporting cardiovascular and respiratory reactions administered DMSO intravenously ( Table 3 and Table 4).
Table 3. Cardiovascular and respiratory adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
Left cardiac insufficiency [ 85] 194 1 (1)
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
Respiratory
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
Table 4. Cardiovascular and respiratory adverse reactions observed per number of treatments.
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
Decrease in heartrate ‡ [ 39] 32 30 (94)
Tachycardia ‡ [ 51] 54 4 (7)
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
Respiratory
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
Shortness of breath ‡ [ 74] 1269 40 (3)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously. Bradycardia was defined as a heart rate less than 60 beats per minute 41, 61 and was often transient 23, 61, 90, 115, but cases where atropine was needed are described 49, 96. A lowered heart rate not enough to be considered bradycardia was observed in four studies 39, 41, 54, 61.
In some studies, hypertension did not require intervention 61, 102, but cases where medication was needed to control the hypertension, or where treatment was stopped due to hypertension, are described 41, 54, 85. Hypotension was also described as transient most of the time 18, 23, 68, 87, 104, with some cases needing intervention 40, 51, 54.
One study reported 11 cases of transient extrasystoles in 22 patients receiving cryopreserved autologous blood stem cells, monitored with Holter during infusion 73. There were two studies reporting cases of asystole during embolization of dural arteriovenous fistulas with a substance called Onyx, a non-adhesive liquid embolic agent dissolved in DMSO 91, 100.
Dyspnea was reported in seven studies 18, 25, 27, 54, 66, 68, 85. A single study reported eight patients with transient shock after stem cell transfusion 51. Some of these patients developed loss of consciousness and cyanosis but recovered promptly and had no need for additional therapy, whereas the rest of the patients developed severe hypotension or transient dyspnea, which was described as the reason for the transient shock. Further description of the condition was not provided.
Several of the studies found a correlation between the dose of DMSO used and the incidence of cardiovascular adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115.
Dermatological reactions
Dermatological side effects are common when DMSO is administered transdermally. Skin reactions or allergic reactions were reported in 58 studies. DMSO was applied transdermally in 43 studies 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 44, 45, 52, 55, 57, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82, 83, 88, 89, 93, 95, 96, 106, 108, 109, 111– 113, intravenously in 14 studies 25, 40, 41, 51, 59, 73, 74, 77, 85, 86, 92, 98, 101, 110 and intraarticular in one 103 ( Table 5).
Table 5. Dermatological and allergic adverse reactions observed per number of patients.
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
Skin reactions
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies. The most common skin reaction was a local burning sensation reported in 13 studies 17, 21, 24, 28, 30, 45, 55, 57, 67, 69, 79, 93, 106. In one study, all participants experienced this burning sensation 45. In the same study, four participants experienced a transient peripheral edema associated with itching and erythema 45. A single study described a burning sensation in four of 669 patients when DMSO was given as a local injection 92; another study described burning in two out of 17 patients when DMSO was injected intraarticularly 103.
Most skin reactions were transient, only lasting minutes 17, 24, 32, 67, 72, but some studies reported cases described as serious, causing discontinuation of treatment 2, 6, 52, 63, 78, 96. There were two studies describing that skin reactions to DMSO would disappear after days of continuous treatment 45, 83. Another study reported that 1 of 18 patients treated for psoriasis with DMSO was hospitalized due to exfoliative erythroderma 63. In another study, two patients, diagnosed with dermographia developed prominent areas of weals after DMSO application 95.
Acute allergic reactions due to use of DMSO were reported in six studies 37, 44, 59, 86, 98, 110. One study reported that 63 of 144 patients experienced allergic reactions, which was not described as serious adverse events (bronchospasms, facial flushing, rash) 86. In two other studies, acute allergic reactions were characterized as serious adverse events 59, 110.
Flushing was regarded as an allergic reaction in this review and was only reported when DMSO was administered intravenously 25, 40, 41, 51, 54, 73, 74. A total of four studies, not depicted in Table 5, reported 204 cases of flushing during 1439 stem cell infusions 25, 40, 51, 74. Several studies observed a relationship between the dose of DMSO and the occurrence of adverse reactions 67, 75, 78, 83, 88, 93.
Neurological reactions
Headache is the most common neurological adverse reaction reported. In one study, headache was the reason for withdrawal of 2 out of 21 patients being treated with DMSO 116.
Three studies using DMSO as a cryoprotectant in stem cell transfusions described seizures after administration 18, 36, 47. Severe encephalopathy was observed in one patient 99, and transient cranial nerve III and IV palsy was observed in one patient after Onyx embolization 34. One study described neurological symptoms occurring during and after transfusion, but they did not define neurological symptoms in detail 86.
Urogenital reactions
Few urogenital reactions were described ( Table 6 and Table 7). Hemoglobinuria was described as an adverse reaction seen after transfusion of stem cell products 39, 51, 56, 73. However, hemoglobinuria is often attributed to erythrocyte debris in the transplant material and has thus not been interpreted as being caused by DMSO 39, 73. The other urogenital reactions ( Table 6 and Table 7) all occurred after DMSO instillation in the bladder 38, 49, 97.
Table 6. Neurological and urogenital adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Neurological
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
Intravesical administration [ 38] 20 1 (5)
Rectal administration [ 116] 21 3 (14)
>1 administration route [ 84] 7 2 (29)
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
Neurological symptoms, unspecified [ 86] 144 5 (3)
Transient CN III and IV palsy [ 34] 12 1 (8)
Severe encephalopathy [ 99] 124 1 (1)
Urogenital
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
Dysuria/strangury [ 49] 36 6 (17)
Renal and urinary disorder [ 49] 36 8 (22)
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
Table 7. Neurological and urogenital adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Neurological
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
Urogenital
Urethral irritation [ 73] 151 110 (73)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
Other reactions
Only one study in this review administered DMSO as eye-drops 114. In this study, two patients experienced severe conjunctival hyperemia due to allergic reactions, and 25% of patients experienced a stinging sensation when eye-drops were applied 114. Other studies performed eye examinations to determine whether DMSO caused changes in the lens; however, no such cases were observed 2, 45.
Hyponatremia occurred in six patients after they received large doses of DMSO as treatment for cranial hypertension 62. This adverse reaction was not reported in other studies ( Table 8).
Table 8. Other adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
Sedation [ 2] 78 34 (44)
Hyponatremia [ 62] 6 6 (100)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included. Very few cases of serious adverse reactions associated with DMSO have been described 18, 36, 51, 59.
Overall, most studies administered DMSO intravenously or transdermally ( Table 9)
Table 9. Way of administration of DMSO in included studies.
Administration Number of studies References
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
Oral 2 [ 9, 60]
Eye-drops 1 [ 114]
Local injection 1 [ 92]
Intra-articular 1 [ 103]
Rectal 1 [ 116]
Risk of bias within studies
In this review, we included 76 cohort studies, of which 64 were prospective 2, 4, 6, 7, 20, 22, 24– 27, 29, 31, 32, 34– 38, 40– 45, 48, 50– 54, 56, 58, 60, 63, 65, 66, 68– 70, 72, 73, 77, 80, 81, 83, 85, 88, 90, 92, 94, 97, 98, 101– 104, 107, 108, 110, 112, 115, 117, 118 and 13 were retrospective 9, 18, 23, 39, 46, 47, 61, 71, 74, 86, 87, 100, 105. Bias was assessed using The Newcastle-Ottawa-Scale 14. Using this scale, studies were given zero to nine stars. A high number of stars equals low risk of bias and vice versa. The studies in this review had a median value of 5 stars, with a range of 2–8. No studies received the highest possible value of nine stars. Very few studies had a comparison group that did not receive DMSO, and often the occurrence of adverse reactions was poorly described. There were 24 randomized controlled trials ( Figure 2). Many studies received an unclear risk of bias because often it was vaguely described how adverse reactions were reported.
Figure 2. Risk of bias in randomized controlled trials. Overall, there was a high risk of bias when assessing the description of adverse reactions. Some studies were not assessed for bias due to being case-reports, preliminary trials, or because they included more than one study design 17, 19, 28, 62, 84, 91, 99, 109, 111, 113.
Discussion
Gastrointestinal and dermatological adverse reactions were the most commonly reported in the included studies. Cardiac adverse reactions only occurred when DMSO was administered intravenously, whereas dermatological reactions mostly occurred when DMSO was administered on the skin. Serious neurological and cardiac reactions were rare and only described in few studies. There seems to be a dose-response relationship between DMSO and adverse reactions with no or mild reactions in low doses.
Many studies on the use of DMSO have been performed in Russia. These studies have not been readily accessible to the global community due to the language barrier. In this review, we have included not only studies dating back almost 50 years, but also articles written in Russian, which is an important strength of the review. This study has several limitations: 1) Some studies used the NCI-CTC (National Cancer Institute’s Common Terminology Criteria for adverse events), but often no scale was used, and the occurrence of adverse reactions were poorly reported. 2) It was difficult to make conclusions on the frequency of a specific adverse reaction, because the exact number of patients experiencing a reaction was often not stated. 3) Several studies using DMSO as a cryoprotectant concluded that other factors affected the occurrence of adverse reactions 7, 85, 86. One study prospectively looked at the adverse reactions observed in relation to autologous transplantation in 64 European Blood and Marrow Transplant Group centers 7. They had difficulties isolating the effects of DMSO from confounding factors such as cell breakdown products and conditioning chemotherapy. Factors such as age, gender, volume transfused, granulocyte concentration, clumping of transplant material, and amount of red blood cells played a role in the occurrence of adverse reactions 61, 86, 120– 122. Another study believed that acute volume expansion, electrolyte imbalance and vagal responses to the coldness of the freshly thawed infusate were more likely reasons for cardiac arrhythmias during stem cell transfusions than the DMSO infused 123. This differs from other studies, which found a clear connection between dose of DMSO and occurrence of cardiac adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115. Therefore, it is possible that some adverse reactions are more or less common than found in this review. The rarer side effects are often reported in case reports, which often did not meet the eligibility criteria in this review. However, we have included several larger studies in this review, and they found a very small occurrence of serious adverse events 7, 55, 66, 74.
In conclusion, adverse reactions due to DMSO are often mild and transient and do not qualify as serious adverse events. Cardiovascular and respiratory adverse reactions occur mostly when DMSO is administered intravenously, whereas dermatological reactions have a higher incidence when DMSO is administered transdermally. An important finding is that the occurrence of adverse reactions seems to be related to the dose of DMSO, and it therefore seems safe to continue the use of DMSO in small doses.
Data availability
All data underlying the results are available as part of the article and no additional source data are required.
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Introduction
The first medical report on the use of dimethyl sulfoxide (DMSO) as a pharmacological agent was published in 1964 1. A year later, the use of DMSO in humans was terminated because experimental studies had shown refractive index changes to the lens of the eye 1, 2. Years later, DMSO was again approved for use in humans since this side effect was only proven in animal studies 2. DMSO has since been used for a variety of purposes, such as treatment of musculoskeletal and dermatological diseases, cryopreservation of stem cells, treatment of interstitial cystitis, treatment of increased intracranial pressure, and many more 3– 9.
DMSO is a colourless liquid, which is rapidly absorbed when administered dermally or orally 10, 11. DMSO is used as a cryoprotectant because it decreases osmotic stress and cellular dehydration, and thereby enables stem cells to be stored for several years 12. DMSO is mostly excreted through the kidneys, but a small part is excreted through the lungs and liver 10. Part of the DMSO is transformed to the volatile metabolite dimethyl sulfide, which gives a characteristic garlic- or oyster-like smell when excreted through the lungs 10. DMSO may induce histamine release, which can be the reason for adverse reactions such as flushing, dyspnoea, abdominal cramps, and cardiovascular reactions 11.
To our knowledge, no systematic reviews have been performed on the adverse reactions of DMSO. Our aim was therefore to provide an extensive overview of the suspected adverse reactions to DMSO in humans.
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title
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Introduction
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The first medical report on the use of dimethyl sulfoxide (DMSO) as a pharmacological agent was published in 1964 1. A year later, the use of DMSO in humans was terminated because experimental studies had shown refractive index changes to the lens of the eye 1, 2. Years later, DMSO was again approved for use in humans since this side effect was only proven in animal studies 2. DMSO has since been used for a variety of purposes, such as treatment of musculoskeletal and dermatological diseases, cryopreservation of stem cells, treatment of interstitial cystitis, treatment of increased intracranial pressure, and many more 3– 9.
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DMSO is a colourless liquid, which is rapidly absorbed when administered dermally or orally 10, 11. DMSO is used as a cryoprotectant because it decreases osmotic stress and cellular dehydration, and thereby enables stem cells to be stored for several years 12. DMSO is mostly excreted through the kidneys, but a small part is excreted through the lungs and liver 10. Part of the DMSO is transformed to the volatile metabolite dimethyl sulfide, which gives a characteristic garlic- or oyster-like smell when excreted through the lungs 10. DMSO may induce histamine release, which can be the reason for adverse reactions such as flushing, dyspnoea, abdominal cramps, and cardiovascular reactions 11.
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To our knowledge, no systematic reviews have been performed on the adverse reactions of DMSO. Our aim was therefore to provide an extensive overview of the suspected adverse reactions to DMSO in humans.
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Methods
Protocol and eligibility criteria
Our study-protocol is registered at PROSPERO (Registration number: CRD42018096117). The systematic review was performed according to PRISMA-harms (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 13.
No limitations were set on the date of publication. The language was restricted to English, Danish, Swedish, Norwegian, and Russian. We included all original studies that administered DMSO to humans and included five or more participants. There was no gender or age restriction. For a study to be included, the authors had to suspect that an observed adverse reaction could be caused by DMSO.
Primary outcome
The primary outcome was any adverse reaction seen in relation to the use of DMSO in humans.
Literature search
The search was performed in PubMed (1966-present), EMBASE (1980-present), and the Cochrane Library. The databases were last searched on February 23, 2018. Our search strategy was formulated with the help of a medical research librarian.
The search string used in PubMed was: ((dimethyl sulfoxide) OR DMSO) AND ((((((administration and dosage) OR adverse reactions) OR alternate effects) OR secondary response) OR toxicology) OR side effects)). The search was restricted to humans. The search string was adapted to EMBASE and Cochrane Library using the same search-words as abovementioned.
The search string used in EMBASE was: ((dmso or dimethyl sulfoxide) and ((side effect or toxicology or secondary response or alternate effects or alternate reactions or (administration and dosage)) and (dmso or dimethyl sulfoxide))).mp. The search was restricted to humans, articles and Medline journals were excluded.
The search string used in Cochrane was: (adverse drug events and dimethyl sulfoxide). The search was restricted to trials.
Study selection and data extraction
Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria using www.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H. was in doubt regarding inclusion of a study the results were presented to B.K.M. and then discussed until a mutual decision was made.
After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest). Data extracted were: author, publication year, country, study characteristics (study design, sample size, size of comparison group if present, time to follow-up), use of DMSO (reason for use, treatment duration, administration route, dose of DMSO), and adverse reactions observed (number of persons experiencing an adverse reaction, method of assessing, and duration of adverse reaction).
Analysis
The Newcastle-Ottawa-Scale was used to assess the risk of bias in non-randomized observational studies 14. Risk of bias in randomized controlled trials was assessed using the Cochrane Handbook “Risk of Bias” assessment tool 15. Risk of bias was assessed at the outcome level.
The primary summary measure was percentage of persons experiencing an adverse reaction, as well as the range in which a reaction occurred in the studies included. No meta-analysis and further summery measures were planned due to the expected large heterogeneity of the studies.
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title
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Methods
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sec
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Protocol and eligibility criteria
Our study-protocol is registered at PROSPERO (Registration number: CRD42018096117). The systematic review was performed according to PRISMA-harms (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 13.
No limitations were set on the date of publication. The language was restricted to English, Danish, Swedish, Norwegian, and Russian. We included all original studies that administered DMSO to humans and included five or more participants. There was no gender or age restriction. For a study to be included, the authors had to suspect that an observed adverse reaction could be caused by DMSO.
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title
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Protocol and eligibility criteria
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p
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Our study-protocol is registered at PROSPERO (Registration number: CRD42018096117). The systematic review was performed according to PRISMA-harms (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 13.
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p
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No limitations were set on the date of publication. The language was restricted to English, Danish, Swedish, Norwegian, and Russian. We included all original studies that administered DMSO to humans and included five or more participants. There was no gender or age restriction. For a study to be included, the authors had to suspect that an observed adverse reaction could be caused by DMSO.
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Primary outcome
The primary outcome was any adverse reaction seen in relation to the use of DMSO in humans.
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title
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Primary outcome
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p
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The primary outcome was any adverse reaction seen in relation to the use of DMSO in humans.
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sec
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Literature search
The search was performed in PubMed (1966-present), EMBASE (1980-present), and the Cochrane Library. The databases were last searched on February 23, 2018. Our search strategy was formulated with the help of a medical research librarian.
The search string used in PubMed was: ((dimethyl sulfoxide) OR DMSO) AND ((((((administration and dosage) OR adverse reactions) OR alternate effects) OR secondary response) OR toxicology) OR side effects)). The search was restricted to humans. The search string was adapted to EMBASE and Cochrane Library using the same search-words as abovementioned.
The search string used in EMBASE was: ((dmso or dimethyl sulfoxide) and ((side effect or toxicology or secondary response or alternate effects or alternate reactions or (administration and dosage)) and (dmso or dimethyl sulfoxide))).mp. The search was restricted to humans, articles and Medline journals were excluded.
The search string used in Cochrane was: (adverse drug events and dimethyl sulfoxide). The search was restricted to trials.
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title
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Literature search
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p
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The search was performed in PubMed (1966-present), EMBASE (1980-present), and the Cochrane Library. The databases were last searched on February 23, 2018. Our search strategy was formulated with the help of a medical research librarian.
|
|
p
|
The search string used in PubMed was: ((dimethyl sulfoxide) OR DMSO) AND ((((((administration and dosage) OR adverse reactions) OR alternate effects) OR secondary response) OR toxicology) OR side effects)). The search was restricted to humans. The search string was adapted to EMBASE and Cochrane Library using the same search-words as abovementioned.
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p
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The search string used in EMBASE was: ((dmso or dimethyl sulfoxide) and ((side effect or toxicology or secondary response or alternate effects or alternate reactions or (administration and dosage)) and (dmso or dimethyl sulfoxide))).mp. The search was restricted to humans, articles and Medline journals were excluded.
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p
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The search string used in Cochrane was: (adverse drug events and dimethyl sulfoxide). The search was restricted to trials.
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sec
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Study selection and data extraction
Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria using www.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H. was in doubt regarding inclusion of a study the results were presented to B.K.M. and then discussed until a mutual decision was made.
After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest). Data extracted were: author, publication year, country, study characteristics (study design, sample size, size of comparison group if present, time to follow-up), use of DMSO (reason for use, treatment duration, administration route, dose of DMSO), and adverse reactions observed (number of persons experiencing an adverse reaction, method of assessing, and duration of adverse reaction).
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title
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Study selection and data extraction
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p
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Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria using www.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H. was in doubt regarding inclusion of a study the results were presented to B.K.M. and then discussed until a mutual decision was made.
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p
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After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest). Data extracted were: author, publication year, country, study characteristics (study design, sample size, size of comparison group if present, time to follow-up), use of DMSO (reason for use, treatment duration, administration route, dose of DMSO), and adverse reactions observed (number of persons experiencing an adverse reaction, method of assessing, and duration of adverse reaction).
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Analysis
The Newcastle-Ottawa-Scale was used to assess the risk of bias in non-randomized observational studies 14. Risk of bias in randomized controlled trials was assessed using the Cochrane Handbook “Risk of Bias” assessment tool 15. Risk of bias was assessed at the outcome level.
The primary summary measure was percentage of persons experiencing an adverse reaction, as well as the range in which a reaction occurred in the studies included. No meta-analysis and further summery measures were planned due to the expected large heterogeneity of the studies.
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title
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Analysis
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p
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The Newcastle-Ottawa-Scale was used to assess the risk of bias in non-randomized observational studies 14. Risk of bias in randomized controlled trials was assessed using the Cochrane Handbook “Risk of Bias” assessment tool 15. Risk of bias was assessed at the outcome level.
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The primary summary measure was percentage of persons experiencing an adverse reaction, as well as the range in which a reaction occurred in the studies included. No meta-analysis and further summery measures were planned due to the expected large heterogeneity of the studies.
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Results
Study selection
Our primary search identified 2599 studies ( Figure 1). After the evaluation process, 109 studies were included in the final review 2, 4, 6– 9, 16– 118.
Figure 1. PRISMA flow diagram.
Gastrointestinal reactions
Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials 16, 30, 33, 55, 57, 59, 67, 79, 93, 95, 49 were cohort studies 2, 4, 7, 9, 18, 19, 23, 25– 27, 29, 35, 38– 43, 45, 46, 48, 50– 54, 58, 60, 66, 68, 69, 71, 73, 83, 85– 88, 90, 94, 97, 98, 101, 104, 105, 112, 113, 115, 118, and 2 were case series 84, 109. Most studies reported the number of patients experiencing an adverse reaction ( Table 1). Other studies reported adverse reactions observed in relation to the number of treatments given ( Table 2).
Table 1. Gastrointestinal adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
Oral administration [ 9] 15 4 (27)
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
Table 2. Gastrointestinal adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
Intravesical administration [ 105] 151 24 (16)
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
Halitosis ‡ [ 68] 262 4 (2)
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration. The most commonly reported gastrointestinal adverse reactions were nausea and vomiting. The incidence of nausea seems to be less common with the transdermal administration of DMSO compared with intravenous administration. The majority of studies reported an incidence of nausea between 2–14%, with the exception of one study, reporting an incidence of 32% 2. In one study that failed to specify the dose, 8 of 42 patients reported nausea and anorexia, but the symptoms disappeared in five of the eight patients when the dose of DMSO was reduced 45.
Often the studies had short follow-up periods (less than 24 hours), especially when DMSO was used as a cryoprotectant. The study reporting the highest incidence of nausea had a follow-up period of 5 days 48, and the authors concluded that the high incidence of nausea observed might be due to the long follow-up period 48. In another article using the same data 119, it was suggested that the delayed nausea was due to gastrointestinal mucosal damage, and only the initial nausea could be related to DMSO, and therefore we decided only to include the data from the first 2 days after infusion 48.
Halitosis was reported in 29 studies 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113. In five studies, patients discontinued treatment due to halitosis 9, 45, 83, 94. In five studies, all patients experienced halitosis 9, 45, 83, 94. Unlike halitosis, other gastrointestinal side effects were reported more often when DMSO was administered intravenously, than transdermally or intravesically.
One study reported a severe case of nausea, vomiting, and abdominal cramps in one patient with an acute allergic reaction 59. However, in most studies the reported gastrointestinal reactions were transient and mild, often lasting only minutes to a couple of hours 16, 38, 41, 68, 85, 87, 90. Several studies reported a relationship between the dose of DMSO and the occurrence of gastrointestinal adverse reactions 26, 33, 53, 73, 83, 85.
Cardiovascular and respiratory reactions
Cardiovascular and respiratory adverse reactions were reported in 33 studies. Of these, two were randomized controlled trials 33, 59, 30 were cohort studies 7, 18, 23, 25– 27, 36, 39– 41, 51, 54, 61, 65, 66, 68, 73, 74, 80, 85– 87, 90, 100– 102, 104, 115, 117, and one was a preliminary report 91. Except for one study 66, all studies reporting cardiovascular and respiratory reactions administered DMSO intravenously ( Table 3 and Table 4).
Table 3. Cardiovascular and respiratory adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
Left cardiac insufficiency [ 85] 194 1 (1)
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
Respiratory
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
Table 4. Cardiovascular and respiratory adverse reactions observed per number of treatments.
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
Decrease in heartrate ‡ [ 39] 32 30 (94)
Tachycardia ‡ [ 51] 54 4 (7)
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
Respiratory
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
Shortness of breath ‡ [ 74] 1269 40 (3)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously. Bradycardia was defined as a heart rate less than 60 beats per minute 41, 61 and was often transient 23, 61, 90, 115, but cases where atropine was needed are described 49, 96. A lowered heart rate not enough to be considered bradycardia was observed in four studies 39, 41, 54, 61.
In some studies, hypertension did not require intervention 61, 102, but cases where medication was needed to control the hypertension, or where treatment was stopped due to hypertension, are described 41, 54, 85. Hypotension was also described as transient most of the time 18, 23, 68, 87, 104, with some cases needing intervention 40, 51, 54.
One study reported 11 cases of transient extrasystoles in 22 patients receiving cryopreserved autologous blood stem cells, monitored with Holter during infusion 73. There were two studies reporting cases of asystole during embolization of dural arteriovenous fistulas with a substance called Onyx, a non-adhesive liquid embolic agent dissolved in DMSO 91, 100.
Dyspnea was reported in seven studies 18, 25, 27, 54, 66, 68, 85. A single study reported eight patients with transient shock after stem cell transfusion 51. Some of these patients developed loss of consciousness and cyanosis but recovered promptly and had no need for additional therapy, whereas the rest of the patients developed severe hypotension or transient dyspnea, which was described as the reason for the transient shock. Further description of the condition was not provided.
Several of the studies found a correlation between the dose of DMSO used and the incidence of cardiovascular adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115.
Dermatological reactions
Dermatological side effects are common when DMSO is administered transdermally. Skin reactions or allergic reactions were reported in 58 studies. DMSO was applied transdermally in 43 studies 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 44, 45, 52, 55, 57, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82, 83, 88, 89, 93, 95, 96, 106, 108, 109, 111– 113, intravenously in 14 studies 25, 40, 41, 51, 59, 73, 74, 77, 85, 86, 92, 98, 101, 110 and intraarticular in one 103 ( Table 5).
Table 5. Dermatological and allergic adverse reactions observed per number of patients.
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
Skin reactions
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies. The most common skin reaction was a local burning sensation reported in 13 studies 17, 21, 24, 28, 30, 45, 55, 57, 67, 69, 79, 93, 106. In one study, all participants experienced this burning sensation 45. In the same study, four participants experienced a transient peripheral edema associated with itching and erythema 45. A single study described a burning sensation in four of 669 patients when DMSO was given as a local injection 92; another study described burning in two out of 17 patients when DMSO was injected intraarticularly 103.
Most skin reactions were transient, only lasting minutes 17, 24, 32, 67, 72, but some studies reported cases described as serious, causing discontinuation of treatment 2, 6, 52, 63, 78, 96. There were two studies describing that skin reactions to DMSO would disappear after days of continuous treatment 45, 83. Another study reported that 1 of 18 patients treated for psoriasis with DMSO was hospitalized due to exfoliative erythroderma 63. In another study, two patients, diagnosed with dermographia developed prominent areas of weals after DMSO application 95.
Acute allergic reactions due to use of DMSO were reported in six studies 37, 44, 59, 86, 98, 110. One study reported that 63 of 144 patients experienced allergic reactions, which was not described as serious adverse events (bronchospasms, facial flushing, rash) 86. In two other studies, acute allergic reactions were characterized as serious adverse events 59, 110.
Flushing was regarded as an allergic reaction in this review and was only reported when DMSO was administered intravenously 25, 40, 41, 51, 54, 73, 74. A total of four studies, not depicted in Table 5, reported 204 cases of flushing during 1439 stem cell infusions 25, 40, 51, 74. Several studies observed a relationship between the dose of DMSO and the occurrence of adverse reactions 67, 75, 78, 83, 88, 93.
Neurological reactions
Headache is the most common neurological adverse reaction reported. In one study, headache was the reason for withdrawal of 2 out of 21 patients being treated with DMSO 116.
Three studies using DMSO as a cryoprotectant in stem cell transfusions described seizures after administration 18, 36, 47. Severe encephalopathy was observed in one patient 99, and transient cranial nerve III and IV palsy was observed in one patient after Onyx embolization 34. One study described neurological symptoms occurring during and after transfusion, but they did not define neurological symptoms in detail 86.
Urogenital reactions
Few urogenital reactions were described ( Table 6 and Table 7). Hemoglobinuria was described as an adverse reaction seen after transfusion of stem cell products 39, 51, 56, 73. However, hemoglobinuria is often attributed to erythrocyte debris in the transplant material and has thus not been interpreted as being caused by DMSO 39, 73. The other urogenital reactions ( Table 6 and Table 7) all occurred after DMSO instillation in the bladder 38, 49, 97.
Table 6. Neurological and urogenital adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Neurological
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
Intravesical administration [ 38] 20 1 (5)
Rectal administration [ 116] 21 3 (14)
>1 administration route [ 84] 7 2 (29)
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
Neurological symptoms, unspecified [ 86] 144 5 (3)
Transient CN III and IV palsy [ 34] 12 1 (8)
Severe encephalopathy [ 99] 124 1 (1)
Urogenital
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
Dysuria/strangury [ 49] 36 6 (17)
Renal and urinary disorder [ 49] 36 8 (22)
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
Table 7. Neurological and urogenital adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Neurological
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
Urogenital
Urethral irritation [ 73] 151 110 (73)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
Other reactions
Only one study in this review administered DMSO as eye-drops 114. In this study, two patients experienced severe conjunctival hyperemia due to allergic reactions, and 25% of patients experienced a stinging sensation when eye-drops were applied 114. Other studies performed eye examinations to determine whether DMSO caused changes in the lens; however, no such cases were observed 2, 45.
Hyponatremia occurred in six patients after they received large doses of DMSO as treatment for cranial hypertension 62. This adverse reaction was not reported in other studies ( Table 8).
Table 8. Other adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
Sedation [ 2] 78 34 (44)
Hyponatremia [ 62] 6 6 (100)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included. Very few cases of serious adverse reactions associated with DMSO have been described 18, 36, 51, 59.
Overall, most studies administered DMSO intravenously or transdermally ( Table 9)
Table 9. Way of administration of DMSO in included studies.
Administration Number of studies References
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
Oral 2 [ 9, 60]
Eye-drops 1 [ 114]
Local injection 1 [ 92]
Intra-articular 1 [ 103]
Rectal 1 [ 116]
Risk of bias within studies
In this review, we included 76 cohort studies, of which 64 were prospective 2, 4, 6, 7, 20, 22, 24– 27, 29, 31, 32, 34– 38, 40– 45, 48, 50– 54, 56, 58, 60, 63, 65, 66, 68– 70, 72, 73, 77, 80, 81, 83, 85, 88, 90, 92, 94, 97, 98, 101– 104, 107, 108, 110, 112, 115, 117, 118 and 13 were retrospective 9, 18, 23, 39, 46, 47, 61, 71, 74, 86, 87, 100, 105. Bias was assessed using The Newcastle-Ottawa-Scale 14. Using this scale, studies were given zero to nine stars. A high number of stars equals low risk of bias and vice versa. The studies in this review had a median value of 5 stars, with a range of 2–8. No studies received the highest possible value of nine stars. Very few studies had a comparison group that did not receive DMSO, and often the occurrence of adverse reactions was poorly described. There were 24 randomized controlled trials ( Figure 2). Many studies received an unclear risk of bias because often it was vaguely described how adverse reactions were reported.
Figure 2. Risk of bias in randomized controlled trials. Overall, there was a high risk of bias when assessing the description of adverse reactions. Some studies were not assessed for bias due to being case-reports, preliminary trials, or because they included more than one study design 17, 19, 28, 62, 84, 91, 99, 109, 111, 113.
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Results
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Study selection
Our primary search identified 2599 studies ( Figure 1). After the evaluation process, 109 studies were included in the final review 2, 4, 6– 9, 16– 118.
Figure 1. PRISMA flow diagram.
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Study selection
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Our primary search identified 2599 studies ( Figure 1). After the evaluation process, 109 studies were included in the final review 2, 4, 6– 9, 16– 118.
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Figure 1. PRISMA flow diagram.
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Figure 1.
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PRISMA flow diagram.
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PRISMA flow diagram.
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Gastrointestinal reactions
Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials 16, 30, 33, 55, 57, 59, 67, 79, 93, 95, 49 were cohort studies 2, 4, 7, 9, 18, 19, 23, 25– 27, 29, 35, 38– 43, 45, 46, 48, 50– 54, 58, 60, 66, 68, 69, 71, 73, 83, 85– 88, 90, 94, 97, 98, 101, 104, 105, 112, 113, 115, 118, and 2 were case series 84, 109. Most studies reported the number of patients experiencing an adverse reaction ( Table 1). Other studies reported adverse reactions observed in relation to the number of treatments given ( Table 2).
Table 1. Gastrointestinal adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
Oral administration [ 9] 15 4 (27)
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
Table 2. Gastrointestinal adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
Intravesical administration [ 105] 151 24 (16)
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
Halitosis ‡ [ 68] 262 4 (2)
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration. The most commonly reported gastrointestinal adverse reactions were nausea and vomiting. The incidence of nausea seems to be less common with the transdermal administration of DMSO compared with intravenous administration. The majority of studies reported an incidence of nausea between 2–14%, with the exception of one study, reporting an incidence of 32% 2. In one study that failed to specify the dose, 8 of 42 patients reported nausea and anorexia, but the symptoms disappeared in five of the eight patients when the dose of DMSO was reduced 45.
Often the studies had short follow-up periods (less than 24 hours), especially when DMSO was used as a cryoprotectant. The study reporting the highest incidence of nausea had a follow-up period of 5 days 48, and the authors concluded that the high incidence of nausea observed might be due to the long follow-up period 48. In another article using the same data 119, it was suggested that the delayed nausea was due to gastrointestinal mucosal damage, and only the initial nausea could be related to DMSO, and therefore we decided only to include the data from the first 2 days after infusion 48.
Halitosis was reported in 29 studies 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113. In five studies, patients discontinued treatment due to halitosis 9, 45, 83, 94. In five studies, all patients experienced halitosis 9, 45, 83, 94. Unlike halitosis, other gastrointestinal side effects were reported more often when DMSO was administered intravenously, than transdermally or intravesically.
One study reported a severe case of nausea, vomiting, and abdominal cramps in one patient with an acute allergic reaction 59. However, in most studies the reported gastrointestinal reactions were transient and mild, often lasting only minutes to a couple of hours 16, 38, 41, 68, 85, 87, 90. Several studies reported a relationship between the dose of DMSO and the occurrence of gastrointestinal adverse reactions 26, 33, 53, 73, 83, 85.
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Gastrointestinal reactions
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p
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Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials 16, 30, 33, 55, 57, 59, 67, 79, 93, 95, 49 were cohort studies 2, 4, 7, 9, 18, 19, 23, 25– 27, 29, 35, 38– 43, 45, 46, 48, 50– 54, 58, 60, 66, 68, 69, 71, 73, 83, 85– 88, 90, 94, 97, 98, 101, 104, 105, 112, 113, 115, 118, and 2 were case series 84, 109. Most studies reported the number of patients experiencing an adverse reaction ( Table 1). Other studies reported adverse reactions observed in relation to the number of treatments given ( Table 2).
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Table 1. Gastrointestinal adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
Oral administration [ 9] 15 4 (27)
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
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Table 1.
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Gastrointestinal adverse reactions observed per number of patients.
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Gastrointestinal adverse reactions observed per number of patients.
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table
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Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
Oral administration [ 9] 15 4 (27)
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
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tr
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Adverse reaction Studies Total patients, n Patients with adverse reaction, n (%) (%, min-max) †
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th
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Adverse reaction
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th
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Studies
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th
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Total patients, n
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th
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Patients with adverse reaction, n (%)
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th
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(%, min-max) †
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tr
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Nausea (overall incidence) [ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118] 2214 257 (12) (2–41) [ 55] - [ 48]
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td
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Nausea (overall incidence)
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td
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[ 2, 18, 27, 33, 45, 46, 48, 53, 55, 57, 59, 60, 67, 84, 90, 93, 109, 118]
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td
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2214
|
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td
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257 (12)
|
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td
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(2–41) [ 55] - [ 48]
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tr
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Intravenous administration [ 18, 27, 33, 46, 48, 53, 59, 90, 118] 1154 199 (17) (2–41) [ 59] - [ 48]
|
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td
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Intravenous administration
|
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td
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[ 18, 27, 33, 46, 48, 53, 59, 90, 118]
|
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td
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1154
|
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td
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199 (17)
|
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td
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(2–41) [ 59] - [ 48]
|
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tr
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Transdermal application [ 2, 45, 55, 57, 67, 93, 109] 1039 51 (5) (2–32) [ 55] - [ 2]
|
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td
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Transdermal application
|
|
td
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[ 2, 45, 55, 57, 67, 93, 109]
|
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td
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1039
|
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td
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51 (5)
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td
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(2–32) [ 55] - [ 2]
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tr
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>1 administration route [ 60, 84] 21 7 (33) (29–36) [ 84] - [ 60]
|
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td
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>1 administration route
|
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td
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[ 60, 84]
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td
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21
|
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td
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7 (33)
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td
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(29–36) [ 84] - [ 60]
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tr
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Vomiting (overall incidence) [ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118] 1611 115 (7) (0–64) [ 55] - [ 48]
|
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td
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Vomiting (overall incidence)
|
|
td
|
[ 2, 18, 27, 33, 46, 48, 55, 57, 59, 118]
|
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td
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1611
|
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td
|
115 (7)
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td
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(0–64) [ 55] - [ 48]
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tr
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Intravenous administration [ 18, 27, 33, 46, 48, 59, 118] 972 108 (11) (2–64) [ 59] - [ 48]
|
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td
|
Intravenous administration
|
|
td
|
[ 18, 27, 33, 46, 48, 59, 118]
|
|
td
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972
|
|
td
|
108 (11)
|
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td
|
(2–64) [ 59] - [ 48]
|
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tr
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Transdermal application [ 2, 55, 57] 639 7 (1) (0–6) [ 55] - [ 2]
|
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td
|
Transdermal application
|
|
td
|
[ 2, 55, 57]
|
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td
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639
|
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td
|
7 (1)
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td
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(0–6) [ 55] - [ 2]
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tr
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Nausea and vomiting ‡ [ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115] 4529 591 (13) (0–46) [ 66] - [ 73]
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|
td
|
Nausea and vomiting ‡
|
|
td
|
[ 7, 38, 41, 54, 66, 69, 73, 85, 87, 115]
|
|
td
|
4529
|
|
td
|
591 (13)
|
|
td
|
(0–46) [ 66] - [ 73]
|
|
tr
|
Abdominal cramps/stomach ache (overall incidence) [ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115] 1629 88 (5) (1–52) [ 117] - [ 116]
|
|
td
|
Abdominal cramps/stomach ache (overall incidence)
|
|
td
|
[ 18, 26, 27, 39, 41, 54, 55, 59, 73, 85, 87, 93, 115]
|
|
td
|
1629
|
|
td
|
88 (5)
|
|
td
|
(1–52) [ 117] - [ 116]
|
|
tr
|
Intravenous administration [ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115] 1253 72 (6) (1–52) [ 18] - [ 26]
|
|
td
|
Intravenous administration
|
|
td
|
[ 18, 26, 27, 39, 41, 54, 59, 73, 85, 87, 115]
|
|
td
|
1253
|
|
td
|
72 (6)
|
|
td
|
(1–52) [ 18] - [ 26]
|
|
tr
|
Transdermal application [ 55, 93] 376 16 (4) (2–16) [ 55] - [ 93]
|
|
td
|
Transdermal application
|
|
td
|
[ 55, 93]
|
|
td
|
376
|
|
td
|
16 (4)
|
|
td
|
(2–16) [ 55] - [ 93]
|
|
tr
|
Halitosis/garlic-like breath (overall incidence) [ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113] 5782 607 (11) (0–100) [ 30] - [ 19, 43, 45, 83, 98]
|
|
td
|
Halitosis/garlic-like breath (overall incidence)
|
|
td
|
[ 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113]
|
|
td
|
5782
|
|
td
|
607 (11)
|
|
td
|
(0–100) [ 30] - [ 19, 43, 45, 83, 98]
|
|
tr
|
Intravenous administration [ 16, 85, 94, 98] 239 14 (6) (1–100) [ 85] - [ 98]
|
|
td
|
Intravenous administration
|
|
td
|
[ 16, 85, 94, 98]
|
|
td
|
239
|
|
td
|
14 (6)
|
|
td
|
(1–100) [ 85] - [ 98]
|
|
tr
|
Transdermal application [ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113] 5333 556 (10) (0–100) [ 30] - [ 19, 45, 83]
|
|
td
|
Transdermal application
|
|
td
|
[ 4, 19, 29, 30, 42, 45, 50, 52, 55, 57, 58, 66, 67, 79, 83, 88, 95, 109, 112, 113]
|
|
td
|
5333
|
|
td
|
556 (10)
|
|
td
|
(0–100) [ 30] - [ 19, 45, 83]
|
|
tr
|
Intravesical administration [ 35, 43, 97] 165 33 (20) (1–100) [ 35] - [ 43]
|
|
td
|
Intravesical administration
|
|
td
|
[ 35, 43, 97]
|
|
td
|
165
|
|
td
|
33 (20)
|
|
td
|
(1–100) [ 35] - [ 43]
|
|
tr
|
Oral administration [ 9] 15 4 (27)
|
|
td
|
Oral administration
|
|
td
|
[ 9]
|
|
td
|
15
|
|
td
|
4 (27)
|
|
tr
|
Diarrhea (overall incidence) [ 2, 18, 41, 54, 57, 85, 93] 1107 27 (2) (1–6) [ 85] - [ 93]
|
|
td
|
Diarrhea (overall incidence)
|
|
td
|
[ 2, 18, 41, 54, 57, 85, 93]
|
|
td
|
1107
|
|
td
|
27 (2)
|
|
td
|
(1–6) [ 85] - [ 93]
|
|
tr
|
Intravenous administration [ 18, 41, 54, 85] 744 15 (2) (1–6) [ 85] - [ 41]
|
|
td
|
Intravenous administration
|
|
td
|
[ 18, 41, 54, 85]
|
|
td
|
744
|
|
td
|
15 (2)
|
|
td
|
(1–6) [ 85] - [ 41]
|
|
tr
|
Transdermal application [ 2, 57, 93] 363 12 (3) (2–6) [ 57] - [ 93]
|
|
td
|
Transdermal application
|
|
td
|
[ 2, 57, 93]
|
|
td
|
363
|
|
td
|
12 (3)
|
|
td
|
(2–6) [ 57] - [ 93]
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
‡ Nausea and vomiting are reported as one combined adverse reaction in some studies.
|
|
table-wrap
|
Table 2. Gastrointestinal adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
Intravesical administration [ 105] 151 24 (16)
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
Halitosis ‡ [ 68] 262 4 (2)
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration.
|
|
label
|
Table 2.
|
|
caption
|
Gastrointestinal adverse reactions observed per number of treatments.
|
|
title
|
Gastrointestinal adverse reactions observed per number of treatments.
|
|
table
|
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
Intravesical administration [ 105] 151 24 (16)
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
Halitosis ‡ [ 68] 262 4 (2)
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
|
|
tr
|
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
|
|
th
|
Adverse reaction
|
|
th
|
Studies
|
|
th
|
Total treatments, n
|
|
th
|
Adverse reactions observed, n (%)
|
|
th
|
(min%–max%) †
|
|
tr
|
Nausea (overall incidence) [ 40, 51, 68, 84, 105] 474 161 (34) (16–57) [ 105] - [ 40]
|
|
td
|
Nausea (overall incidence)
|
|
td
|
[ 40, 51, 68, 84, 105]
|
|
td
|
474
|
|
td
|
161 (34)
|
|
td
|
(16–57) [ 105] - [ 40]
|
|
tr
|
Intravenous administration [ 40, 51, 68] 323 137 (42) (41–57) [ 68] - [ 40]
|
|
td
|
Intravenous administration
|
|
td
|
[ 40, 51, 68]
|
|
td
|
323
|
|
td
|
137 (42)
|
|
td
|
(41–57) [ 68] - [ 40]
|
|
tr
|
Intravesical administration [ 105] 151 24 (16)
|
|
td
|
Intravesical administration
|
|
td
|
[ 105]
|
|
td
|
151
|
|
td
|
24 (16)
|
|
tr
|
Vomiting ‡ [ 51, 68] 316 112 (35) (29 - 71) [ 68] - [ 51]
|
|
td
|
Vomiting ‡
|
|
td
|
[ 51, 68]
|
|
td
|
316
|
|
td
|
112 (35)
|
|
td
|
(29 - 71) [ 68] - [ 51]
|
|
tr
|
Nausea and/or vomiting ‡ [ 25, 74, 101] 1557 220 (14) (8–17) [ 25] - [ 101]
|
|
td
|
Nausea and/or vomiting ‡
|
|
td
|
[ 25, 74, 101]
|
|
td
|
1557
|
|
td
|
220 (14)
|
|
td
|
(8–17) [ 25] - [ 101]
|
|
tr
|
Abdominal cramps/stomach ache ‡ [ 51, 68, 101] 495 16 (5) (1–19) [ 68] - [ 51]
|
|
td
|
Abdominal cramps/stomach ache ‡
|
|
td
|
[ 51, 68, 101]
|
|
td
|
495
|
|
td
|
16 (5)
|
|
td
|
(1–19) [ 68] - [ 51]
|
|
tr
|
Halitosis ‡ [ 68] 262 4 (2)
|
|
td
|
Halitosis ‡
|
|
td
|
[ 68]
|
|
td
|
262
|
|
td
|
4 (2)
|
|
tr
|
Diarrhea ‡ [ 51, 101] 233 2 (1) (1–2) [ 101] - [ 51]
|
|
td
|
Diarrhea ‡
|
|
td
|
[ 51, 101]
|
|
td
|
233
|
|
td
|
2 (1)
|
|
td
|
(1–2) [ 101] - [ 51]
|
|
table-wrap-foot
|
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration.
|
|
footnote
|
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ Intravenous administration.
|
|
p
|
† Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
|
|
p
|
‡ Intravenous administration.
|
|
p
|
The most commonly reported gastrointestinal adverse reactions were nausea and vomiting. The incidence of nausea seems to be less common with the transdermal administration of DMSO compared with intravenous administration. The majority of studies reported an incidence of nausea between 2–14%, with the exception of one study, reporting an incidence of 32% 2. In one study that failed to specify the dose, 8 of 42 patients reported nausea and anorexia, but the symptoms disappeared in five of the eight patients when the dose of DMSO was reduced 45.
|
|
p
|
Often the studies had short follow-up periods (less than 24 hours), especially when DMSO was used as a cryoprotectant. The study reporting the highest incidence of nausea had a follow-up period of 5 days 48, and the authors concluded that the high incidence of nausea observed might be due to the long follow-up period 48. In another article using the same data 119, it was suggested that the delayed nausea was due to gastrointestinal mucosal damage, and only the initial nausea could be related to DMSO, and therefore we decided only to include the data from the first 2 days after infusion 48.
|
|
p
|
Halitosis was reported in 29 studies 4, 9, 16, 19, 29, 30, 35, 42, 43, 45, 50, 52, 55, 57, 58, 66– 68, 79, 83, 85, 88, 94, 95, 97, 98, 109, 112, 113. In five studies, patients discontinued treatment due to halitosis 9, 45, 83, 94. In five studies, all patients experienced halitosis 9, 45, 83, 94. Unlike halitosis, other gastrointestinal side effects were reported more often when DMSO was administered intravenously, than transdermally or intravesically.
|
|
p
|
One study reported a severe case of nausea, vomiting, and abdominal cramps in one patient with an acute allergic reaction 59. However, in most studies the reported gastrointestinal reactions were transient and mild, often lasting only minutes to a couple of hours 16, 38, 41, 68, 85, 87, 90. Several studies reported a relationship between the dose of DMSO and the occurrence of gastrointestinal adverse reactions 26, 33, 53, 73, 83, 85.
|
|
sec
|
Cardiovascular and respiratory reactions
Cardiovascular and respiratory adverse reactions were reported in 33 studies. Of these, two were randomized controlled trials 33, 59, 30 were cohort studies 7, 18, 23, 25– 27, 36, 39– 41, 51, 54, 61, 65, 66, 68, 73, 74, 80, 85– 87, 90, 100– 102, 104, 115, 117, and one was a preliminary report 91. Except for one study 66, all studies reporting cardiovascular and respiratory reactions administered DMSO intravenously ( Table 3 and Table 4).
Table 3. Cardiovascular and respiratory adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
Left cardiac insufficiency [ 85] 194 1 (1)
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
Respiratory
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
Table 4. Cardiovascular and respiratory adverse reactions observed per number of treatments.
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
Decrease in heartrate ‡ [ 39] 32 30 (94)
Tachycardia ‡ [ 51] 54 4 (7)
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
Respiratory
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
Shortness of breath ‡ [ 74] 1269 40 (3)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously. Bradycardia was defined as a heart rate less than 60 beats per minute 41, 61 and was often transient 23, 61, 90, 115, but cases where atropine was needed are described 49, 96. A lowered heart rate not enough to be considered bradycardia was observed in four studies 39, 41, 54, 61.
In some studies, hypertension did not require intervention 61, 102, but cases where medication was needed to control the hypertension, or where treatment was stopped due to hypertension, are described 41, 54, 85. Hypotension was also described as transient most of the time 18, 23, 68, 87, 104, with some cases needing intervention 40, 51, 54.
One study reported 11 cases of transient extrasystoles in 22 patients receiving cryopreserved autologous blood stem cells, monitored with Holter during infusion 73. There were two studies reporting cases of asystole during embolization of dural arteriovenous fistulas with a substance called Onyx, a non-adhesive liquid embolic agent dissolved in DMSO 91, 100.
Dyspnea was reported in seven studies 18, 25, 27, 54, 66, 68, 85. A single study reported eight patients with transient shock after stem cell transfusion 51. Some of these patients developed loss of consciousness and cyanosis but recovered promptly and had no need for additional therapy, whereas the rest of the patients developed severe hypotension or transient dyspnea, which was described as the reason for the transient shock. Further description of the condition was not provided.
Several of the studies found a correlation between the dose of DMSO used and the incidence of cardiovascular adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115.
|
|
title
|
Cardiovascular and respiratory reactions
|
|
p
|
Cardiovascular and respiratory adverse reactions were reported in 33 studies. Of these, two were randomized controlled trials 33, 59, 30 were cohort studies 7, 18, 23, 25– 27, 36, 39– 41, 51, 54, 61, 65, 66, 68, 73, 74, 80, 85– 87, 90, 100– 102, 104, 115, 117, and one was a preliminary report 91. Except for one study 66, all studies reporting cardiovascular and respiratory reactions administered DMSO intravenously ( Table 3 and Table 4).
|
|
table-wrap
|
Table 3. Cardiovascular and respiratory adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
Left cardiac insufficiency [ 85] 194 1 (1)
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
Respiratory
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
|
|
label
|
Table 3.
|
|
caption
|
Cardiovascular and respiratory adverse reactions observed per number of patients.
|
|
title
|
Cardiovascular and respiratory adverse reactions observed per number of patients.
|
|
table
|
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
Left cardiac insufficiency [ 85] 194 1 (1)
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
Respiratory
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
|
|
tr
|
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
|
|
th
|
Adverse reaction
|
|
th
|
Studies
|
|
th
|
Total patients, n
|
|
th
|
Patients with adverse reactions, n (%)
|
|
th
|
(min%–max%) †
|
|
td
|
Cardiac
|
|
tr
|
Cardiac
|
|
tr
|
Hypotension ‡ [ 7, 18, 23, 33, 71, 73, 87, 104, 115] 2752 115 (4) (1–14) [ 18, 71] - [ 87]
|
|
td
|
Hypotension ‡
|
|
td
|
[ 7, 18, 23, 33, 71, 73, 87, 104, 115]
|
|
td
|
2752
|
|
td
|
115 (4)
|
|
td
|
(1–14) [ 18, 71] - [ 87]
|
|
tr
|
Hypertension § [ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102] 2998 385 (13) (2–95) [ 85] - [ 61]
|
|
td
|
Hypertension §
|
|
td
|
[ 7, 18, 23, 33, 41, 54, 61, 73, 85, 87, 102]
|
|
td
|
2998
|
|
td
|
385 (13)
|
|
td
|
(2–95) [ 85] - [ 61]
|
|
tr
|
Bradycardia (mild and severe) ‡ [ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117] 882 94 (11) (0–49) [ 36] - [ 61]
|
|
td
|
Bradycardia (mild and severe) ‡
|
|
td
|
[ 23, 36, 54, 61, 65, 85, 90, 91, 115, 117]
|
|
td
|
882
|
|
td
|
94 (11)
|
|
td
|
(0–49) [ 36] - [ 61]
|
|
tr
|
Decrease in heart rate ‡ [ 41, 54, 61, 80] 193 152 (79) (11–94) [ 80] - [ 41]
|
|
td
|
Decrease in heart rate ‡
|
|
td
|
[ 41, 54, 61, 80]
|
|
td
|
193
|
|
td
|
152 (79)
|
|
td
|
(11–94) [ 80] - [ 41]
|
|
tr
|
Tachycardia ‡ [ 23, 27, 36] 565 13 (2) (0–6) [ 36] - [ 23]
|
|
td
|
Tachycardia ‡
|
|
td
|
[ 23, 27, 36]
|
|
td
|
565
|
|
td
|
13 (2)
|
|
td
|
(0–6) [ 36] - [ 23]
|
|
tr
|
Ventricular extrasystoles ‡ [ 73] 22 11 (50)
|
|
td
|
Ventricular extrasystoles ‡
|
|
td
|
[ 73]
|
|
td
|
22
|
|
td
|
11 (50)
|
|
tr
|
Cardiac event, unspecified ‡ [ 26, 86] 165 18 (11) (5–12) [ 26] - [ 86]
|
|
td
|
Cardiac event, unspecified ‡
|
|
td
|
[ 26, 86]
|
|
td
|
165
|
|
td
|
18 (11)
|
|
td
|
(5–12) [ 26] - [ 86]
|
|
tr
|
Asystole ¶ [ 91, 100] 45 3 (7) (3–20) [ 100] - [ 91]
|
|
td
|
Asystole ¶
|
|
td
|
[ 91, 100]
|
|
td
|
45
|
|
td
|
3 (7)
|
|
td
|
(3–20) [ 100] - [ 91]
|
|
tr
|
Left cardiac insufficiency [ 85] 194 1 (1)
|
|
td
|
Left cardiac insufficiency
|
|
td
|
[ 85]
|
|
td
|
194
|
|
td
|
1 (1)
|
|
tr
|
Chest discomfort/tightness ‡ [ 18, 27, 54, 73, 87, 91, 115] 901 22 (2) (1–10) [ 27] - [ 54]
|
|
td
|
Chest discomfort/tightness ‡
|
|
td
|
[ 18, 27, 54, 73, 87, 91, 115]
|
|
td
|
901
|
|
td
|
22 (2)
|
|
td
|
(1–10) [ 27] - [ 54]
|
|
td
|
Respiratory
|
|
tr
|
Respiratory
|
|
tr
|
Unspecified respiratory symptoms ‡ [ 26, 86] 165 43 (26) (21–62) [ 86] - [ 26]
|
|
td
|
Unspecified respiratory symptoms ‡
|
|
td
|
[ 26, 86]
|
|
td
|
165
|
|
td
|
43 (26)
|
|
td
|
(21–62) [ 86] - [ 26]
|
|
tr
|
Dyspnea d [ 18, 27, 54, 66, 85] 2748 26 (1) (0–10) [ 66] - [ 54]
|
|
td
|
Dyspnea d
|
|
td
|
[ 18, 27, 54, 66, 85]
|
|
td
|
2748
|
|
td
|
26 (1)
|
|
td
|
(0–10) [ 66] - [ 54]
|
|
tr
|
Cough [ 85, 101] 373 52 (14) (5–22) [ 101] [ 85]
|
|
td
|
Cough
|
|
td
|
[ 85, 101]
|
|
td
|
373
|
|
td
|
52 (14)
|
|
td
|
(5–22) [ 101] [ 85]
|
|
tr
|
Lung edema ‡ [ 59, 85] 241 3 (1) (1–2) [ 85] - [ 59]
|
|
td
|
Lung edema ‡
|
|
td
|
[ 59, 85]
|
|
td
|
241
|
|
td
|
3 (1)
|
|
td
|
(1–2) [ 85] - [ 59]
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
‡ DMSO was administered intravenously in all studies.
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction.
|
|
p
|
‡ DMSO was administered intravenously in all studies.
|
|
p
|
§ DMSO was administered intravenously in all studies. Horacek et al. [ 102] measured 42 patients with an increase in systolic blood pressure, and 31 patients with an increase in diastolic blood pressure. This was counted as 73 cases of hypertension.
|
|
p
|
¶ In both studies, asystole occurred because of DMSO effect on the trigeminal nerve and activation of the trigeminal cardiac reflex. d) in one study DMSO was administered transdermally
|
|
table-wrap
|
Table 4. Cardiovascular and respiratory adverse reactions observed per number of treatments.
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
Decrease in heartrate ‡ [ 39] 32 30 (94)
Tachycardia ‡ [ 51] 54 4 (7)
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
Respiratory
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
Shortness of breath ‡ [ 74] 1269 40 (3)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously.
|
|
label
|
Table 4.
|
|
caption
|
Cardiovascular and respiratory adverse reactions observed per number of treatments.
|
|
title
|
Cardiovascular and respiratory adverse reactions observed per number of treatments.
|
|
table
|
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
Cardiac
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
Decrease in heartrate ‡ [ 39] 32 30 (94)
Tachycardia ‡ [ 51] 54 4 (7)
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
Respiratory
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
Shortness of breath ‡ [ 74] 1269 40 (3)
|
|
tr
|
Adverse reaction Studies Total number of treatments Adverse reactions observed, n (%) (min%–max%) †
|
|
th
|
Adverse reaction
|
|
th
|
Studies
|
|
th
|
Total number of treatments
|
|
th
|
Adverse reactions observed, n (%)
|
|
th
|
(min%–max%) †
|
|
td
|
Cardiac
|
|
tr
|
Cardiac
|
|
tr
|
Hypotension ‡ [ 40, 51, 68] 323 10 (3) (2–14) [ 68] - [ 40]
|
|
td
|
Hypotension ‡
|
|
td
|
[ 40, 51, 68]
|
|
td
|
323
|
|
td
|
10 (3)
|
|
td
|
(2–14) [ 68] - [ 40]
|
|
tr
|
Hypertension ‡ [ 25, 51, 68] 425 60 (14) (3–21) [ 25] - [ 68]
|
|
td
|
Hypertension ‡
|
|
td
|
[ 25, 51, 68]
|
|
td
|
425
|
|
td
|
60 (14)
|
|
td
|
(3–21) [ 25] - [ 68]
|
|
tr
|
Bradycardia (mild and severe) ‡ [ 51] 54 4 (7)
|
|
td
|
Bradycardia (mild and severe) ‡
|
|
td
|
[ 51]
|
|
td
|
54
|
|
td
|
4 (7)
|
|
tr
|
Decrease in heartrate ‡ [ 39] 32 30 (94)
|
|
td
|
Decrease in heartrate ‡
|
|
td
|
[ 39]
|
|
td
|
32
|
|
td
|
30 (94)
|
|
tr
|
Tachycardia ‡ [ 51] 54 4 (7)
|
|
td
|
Tachycardia ‡
|
|
td
|
[ 51]
|
|
td
|
54
|
|
td
|
4 (7)
|
|
tr
|
Cardiac event, unspecified ‡ [ 74] 1269 35 (3)
|
|
td
|
Cardiac event, unspecified ‡
|
|
td
|
[ 74]
|
|
td
|
1269
|
|
td
|
35 (3)
|
|
tr
|
Chest discomfort/tightness ‡ [ 25, 68, 74] 1640 83 (5) (0–6) [ 68] - [ 74]
|
|
td
|
Chest discomfort/tightness ‡
|
|
td
|
[ 25, 68, 74]
|
|
td
|
1640
|
|
td
|
83 (5)
|
|
td
|
(0–6) [ 68] - [ 74]
|
|
td
|
Respiratory
|
|
tr
|
Respiratory
|
|
tr
|
Dyspnea [ 25, 68] 371 3 (1) (0–2) [ 68] - [ 25]
|
|
td
|
Dyspnea
|
|
td
|
[ 25, 68]
|
|
td
|
371
|
|
td
|
3 (1)
|
|
td
|
(0–2) [ 68] - [ 25]
|
|
tr
|
Shortness of breath ‡ [ 74] 1269 40 (3)
|
|
td
|
Shortness of breath ‡
|
|
td
|
[ 74]
|
|
td
|
1269
|
|
td
|
40 (3)
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously.
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ DMSO was administered intravenously.
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
‡ DMSO was administered intravenously.
|
|
p
|
Bradycardia was defined as a heart rate less than 60 beats per minute 41, 61 and was often transient 23, 61, 90, 115, but cases where atropine was needed are described 49, 96. A lowered heart rate not enough to be considered bradycardia was observed in four studies 39, 41, 54, 61.
|
|
p
|
In some studies, hypertension did not require intervention 61, 102, but cases where medication was needed to control the hypertension, or where treatment was stopped due to hypertension, are described 41, 54, 85. Hypotension was also described as transient most of the time 18, 23, 68, 87, 104, with some cases needing intervention 40, 51, 54.
|
|
p
|
One study reported 11 cases of transient extrasystoles in 22 patients receiving cryopreserved autologous blood stem cells, monitored with Holter during infusion 73. There were two studies reporting cases of asystole during embolization of dural arteriovenous fistulas with a substance called Onyx, a non-adhesive liquid embolic agent dissolved in DMSO 91, 100.
|
|
p
|
Dyspnea was reported in seven studies 18, 25, 27, 54, 66, 68, 85. A single study reported eight patients with transient shock after stem cell transfusion 51. Some of these patients developed loss of consciousness and cyanosis but recovered promptly and had no need for additional therapy, whereas the rest of the patients developed severe hypotension or transient dyspnea, which was described as the reason for the transient shock. Further description of the condition was not provided.
|
|
p
|
Several of the studies found a correlation between the dose of DMSO used and the incidence of cardiovascular adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115.
|
|
sec
|
Dermatological reactions
Dermatological side effects are common when DMSO is administered transdermally. Skin reactions or allergic reactions were reported in 58 studies. DMSO was applied transdermally in 43 studies 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 44, 45, 52, 55, 57, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82, 83, 88, 89, 93, 95, 96, 106, 108, 109, 111– 113, intravenously in 14 studies 25, 40, 41, 51, 59, 73, 74, 77, 85, 86, 92, 98, 101, 110 and intraarticular in one 103 ( Table 5).
Table 5. Dermatological and allergic adverse reactions observed per number of patients.
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
Skin reactions
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies. The most common skin reaction was a local burning sensation reported in 13 studies 17, 21, 24, 28, 30, 45, 55, 57, 67, 69, 79, 93, 106. In one study, all participants experienced this burning sensation 45. In the same study, four participants experienced a transient peripheral edema associated with itching and erythema 45. A single study described a burning sensation in four of 669 patients when DMSO was given as a local injection 92; another study described burning in two out of 17 patients when DMSO was injected intraarticularly 103.
Most skin reactions were transient, only lasting minutes 17, 24, 32, 67, 72, but some studies reported cases described as serious, causing discontinuation of treatment 2, 6, 52, 63, 78, 96. There were two studies describing that skin reactions to DMSO would disappear after days of continuous treatment 45, 83. Another study reported that 1 of 18 patients treated for psoriasis with DMSO was hospitalized due to exfoliative erythroderma 63. In another study, two patients, diagnosed with dermographia developed prominent areas of weals after DMSO application 95.
Acute allergic reactions due to use of DMSO were reported in six studies 37, 44, 59, 86, 98, 110. One study reported that 63 of 144 patients experienced allergic reactions, which was not described as serious adverse events (bronchospasms, facial flushing, rash) 86. In two other studies, acute allergic reactions were characterized as serious adverse events 59, 110.
Flushing was regarded as an allergic reaction in this review and was only reported when DMSO was administered intravenously 25, 40, 41, 51, 54, 73, 74. A total of four studies, not depicted in Table 5, reported 204 cases of flushing during 1439 stem cell infusions 25, 40, 51, 74. Several studies observed a relationship between the dose of DMSO and the occurrence of adverse reactions 67, 75, 78, 83, 88, 93.
|
|
title
|
Dermatological reactions
|
|
p
|
Dermatological side effects are common when DMSO is administered transdermally. Skin reactions or allergic reactions were reported in 58 studies. DMSO was applied transdermally in 43 studies 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 44, 45, 52, 55, 57, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82, 83, 88, 89, 93, 95, 96, 106, 108, 109, 111– 113, intravenously in 14 studies 25, 40, 41, 51, 59, 73, 74, 77, 85, 86, 92, 98, 101, 110 and intraarticular in one 103 ( Table 5).
|
|
table-wrap
|
Table 5. Dermatological and allergic adverse reactions observed per number of patients.
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
Skin reactions
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies.
|
|
label
|
Table 5.
|
|
caption
|
Dermatological and allergic adverse reactions observed per number of patients.
|
|
title
|
Dermatological and allergic adverse reactions observed per number of patients.
|
|
table
|
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
Skin reactions
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
|
|
tr
|
Adverse reactions Studies Total patients, n Patients with adverse reactions, n (%) (%, min-max) †
|
|
th
|
Adverse reactions
|
|
th
|
Studies
|
|
th
|
Total patients, n
|
|
th
|
Patients with adverse reactions, n (%)
|
|
th
|
(%, min-max) †
|
|
td
|
Skin reactions
|
|
tr
|
Skin reactions
|
|
tr
|
Erythema ‡ [ 19, 32, 64, 66, 82, 95] 2352 201 (9) (3–95) [ 95] - [ 82]
|
|
td
|
Erythema ‡
|
|
td
|
[ 19, 32, 64, 66, 82, 95]
|
|
td
|
2352
|
|
td
|
201 (9)
|
|
td
|
(3–95) [ 95] - [ 82]
|
|
tr
|
Itching/Pruritus ‡ [ 6, 55, 57, 64, 66, 72, 82, 93] 3421 215 (6) (0–70) [ 55] - [ 82]
|
|
td
|
Itching/Pruritus ‡
|
|
td
|
[ 6, 55, 57, 64, 66, 72, 82, 93]
|
|
td
|
3421
|
|
td
|
215 (6)
|
|
td
|
(0–70) [ 55] - [ 82]
|
|
tr
|
Urticaria ‡ [ 24, 31, 83] 58 9 (16) (4–59) [ 24] - [ 83]
|
|
td
|
Urticaria ‡
|
|
td
|
[ 24, 31, 83]
|
|
td
|
58
|
|
td
|
9 (16)
|
|
td
|
(4–59) [ 24] - [ 83]
|
|
tr
|
Rash [ 29, 30, 55, 57, 64, 93, 101, 111] 2682 121 (5) (1–40) [ 30] - [ 93]
|
|
td
|
Rash
|
|
td
|
[ 29, 30, 55, 57, 64, 93, 101, 111]
|
|
td
|
2682
|
|
td
|
121 (5)
|
|
td
|
(1–40) [ 30] - [ 93]
|
|
tr
|
Paresthesia/burning or stinging sensation § ‡ [ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106] 2141 335 (16) (0–100) [ 30] - [ 45]
|
|
td
|
Paresthesia/burning or stinging sensation § ‡
|
|
td
|
[ 17, 21, 24, 28, 30, 44, 45, 55, 57, 67, 69, 79, 91, 93, 106]
|
|
td
|
2141
|
|
td
|
335 (16)
|
|
td
|
(0–100) [ 30] - [ 45]
|
|
tr
|
Scaling of skin/desquamation/ dry skin/local irritant ‡ [ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106] 4739 731 (15) (1–96) [ 66] - [ 52]
|
|
td
|
Scaling of skin/desquamation/ dry skin/local irritant ‡
|
|
td
|
[ 22, 29, 30, 37, 52, 55, 57, 64, 66, 69, 75, 82, 88, 89, 106]
|
|
td
|
4739
|
|
td
|
731 (15)
|
|
td
|
(1–96) [ 66] - [ 52]
|
|
tr
|
Blistering ‡ [ 31, 32, 66, 69, 93, 112] 2038 79 (4) (3–20) [ 66] - [ 112]
|
|
td
|
Blistering ‡
|
|
td
|
[ 31, 32, 66, 69, 93, 112]
|
|
td
|
2038
|
|
td
|
79 (4)
|
|
td
|
(3–20) [ 66] - [ 112]
|
|
tr
|
Roughness and/or thickening of skin ‡ [ 66, 82, 93] 1986 191 (10) (6–10) [ 93] - [ 82]
|
|
td
|
Roughness and/or thickening of skin ‡
|
|
td
|
[ 66, 82, 93]
|
|
td
|
1986
|
|
td
|
191 (10)
|
|
td
|
(6–10) [ 93] - [ 82]
|
|
tr
|
Bullous dermatitis/dermatitis with vesicles ‡ [ 20, 29, 64] 1116 79 (7) (1–9) [ 64] - [ 29]
|
|
td
|
Bullous dermatitis/dermatitis with vesicles ‡
|
|
td
|
[ 20, 29, 64]
|
|
td
|
1116
|
|
td
|
79 (7)
|
|
td
|
(1–9) [ 64] - [ 29]
|
|
tr
|
Contact dermatitis ‡ [ 6, 20, 28– 30, 64, 111] 2587 161 (6) (1–13) [ 28] - [ 29]
|
|
td
|
Contact dermatitis ‡
|
|
td
|
[ 6, 20, 28– 30, 64, 111]
|
|
td
|
2587
|
|
td
|
161 (6)
|
|
td
|
(1–13) [ 28] - [ 29]
|
|
tr
|
Skin reaction, unspecified ‡ [ 2, 78, 96, 113] 457 159 (35) (4–48) [ 96] - [ 113]
|
|
td
|
Skin reaction, unspecified ‡
|
|
td
|
[ 2, 78, 96, 113]
|
|
td
|
457
|
|
td
|
159 (35)
|
|
td
|
(4–48) [ 96] - [ 113]
|
|
tr
|
Increase in skin pigmentation ‡ [ 6] 548 28 (5)
|
|
td
|
Increase in skin pigmentation ‡
|
|
td
|
[ 6]
|
|
td
|
548
|
|
td
|
28 (5)
|
|
tr
|
Peripheral edema ‡ [ 45, 55, 66, 109] 2291 22 (0) (1–14) [ 66] - [ 109]
|
|
td
|
Peripheral edema ‡
|
|
td
|
[ 45, 55, 66, 109]
|
|
td
|
2291
|
|
td
|
22 (0)
|
|
td
|
(1–14) [ 66] - [ 109]
|
|
tr
|
Allergic reactions [ 37, 44, 59, 86, 98, 110] 309 75 (24) (3–55) [ 44, 110] - [ 86]
|
|
td
|
Allergic reactions
|
|
td
|
[ 37, 44, 59, 86, 98, 110]
|
|
td
|
309
|
|
td
|
75 (24)
|
|
td
|
(3–55) [ 44, 110] - [ 86]
|
|
tr
|
Intravenous administration [ 59, 86, 98, 110] 229 66 (29) (2–55) [ 59] - [ 86]
|
|
td
|
Intravenous administration
|
|
td
|
[ 59, 86, 98, 110]
|
|
td
|
229
|
|
td
|
66 (29)
|
|
td
|
(2–55) [ 59] - [ 86]
|
|
tr
|
Transdermal application [ 37, 44] 86 9 (10) (3–19) [ 44] - [ 37]
|
|
td
|
Transdermal application
|
|
td
|
[ 37, 44]
|
|
td
|
86
|
|
td
|
9 (10)
|
|
td
|
(3–19) [ 44] - [ 37]
|
|
tr
|
Flushing ¶ [ 41, 54, 73] 292 34 (12) (2–9) [ 54] - [ 73]
|
|
td
|
Flushing ¶
|
|
td
|
[ 41, 54, 73]
|
|
td
|
292
|
|
td
|
34 (12)
|
|
td
|
(2–9) [ 54] - [ 73]
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies.
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
‡ Transdermal application only.
§ One study administered DMSO through intraarticular injection [ 38].
¶ DMSO was administered intravenously in all studies.
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
‡ Transdermal application only.
|
|
p
|
§ One study administered DMSO through intraarticular injection [ 38].
|
|
p
|
¶ DMSO was administered intravenously in all studies.
|
|
p
|
The most common skin reaction was a local burning sensation reported in 13 studies 17, 21, 24, 28, 30, 45, 55, 57, 67, 69, 79, 93, 106. In one study, all participants experienced this burning sensation 45. In the same study, four participants experienced a transient peripheral edema associated with itching and erythema 45. A single study described a burning sensation in four of 669 patients when DMSO was given as a local injection 92; another study described burning in two out of 17 patients when DMSO was injected intraarticularly 103.
|
|
p
|
Most skin reactions were transient, only lasting minutes 17, 24, 32, 67, 72, but some studies reported cases described as serious, causing discontinuation of treatment 2, 6, 52, 63, 78, 96. There were two studies describing that skin reactions to DMSO would disappear after days of continuous treatment 45, 83. Another study reported that 1 of 18 patients treated for psoriasis with DMSO was hospitalized due to exfoliative erythroderma 63. In another study, two patients, diagnosed with dermographia developed prominent areas of weals after DMSO application 95.
|
|
p
|
Acute allergic reactions due to use of DMSO were reported in six studies 37, 44, 59, 86, 98, 110. One study reported that 63 of 144 patients experienced allergic reactions, which was not described as serious adverse events (bronchospasms, facial flushing, rash) 86. In two other studies, acute allergic reactions were characterized as serious adverse events 59, 110.
|
|
p
|
Flushing was regarded as an allergic reaction in this review and was only reported when DMSO was administered intravenously 25, 40, 41, 51, 54, 73, 74. A total of four studies, not depicted in Table 5, reported 204 cases of flushing during 1439 stem cell infusions 25, 40, 51, 74. Several studies observed a relationship between the dose of DMSO and the occurrence of adverse reactions 67, 75, 78, 83, 88, 93.
|
|
sec
|
Neurological reactions
Headache is the most common neurological adverse reaction reported. In one study, headache was the reason for withdrawal of 2 out of 21 patients being treated with DMSO 116.
Three studies using DMSO as a cryoprotectant in stem cell transfusions described seizures after administration 18, 36, 47. Severe encephalopathy was observed in one patient 99, and transient cranial nerve III and IV palsy was observed in one patient after Onyx embolization 34. One study described neurological symptoms occurring during and after transfusion, but they did not define neurological symptoms in detail 86.
|
|
title
|
Neurological reactions
|
|
p
|
Headache is the most common neurological adverse reaction reported. In one study, headache was the reason for withdrawal of 2 out of 21 patients being treated with DMSO 116.
|
|
p
|
Three studies using DMSO as a cryoprotectant in stem cell transfusions described seizures after administration 18, 36, 47. Severe encephalopathy was observed in one patient 99, and transient cranial nerve III and IV palsy was observed in one patient after Onyx embolization 34. One study described neurological symptoms occurring during and after transfusion, but they did not define neurological symptoms in detail 86.
|
|
sec
|
Urogenital reactions
Few urogenital reactions were described ( Table 6 and Table 7). Hemoglobinuria was described as an adverse reaction seen after transfusion of stem cell products 39, 51, 56, 73. However, hemoglobinuria is often attributed to erythrocyte debris in the transplant material and has thus not been interpreted as being caused by DMSO 39, 73. The other urogenital reactions ( Table 6 and Table 7) all occurred after DMSO instillation in the bladder 38, 49, 97.
Table 6. Neurological and urogenital adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Neurological
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
Intravesical administration [ 38] 20 1 (5)
Rectal administration [ 116] 21 3 (14)
>1 administration route [ 84] 7 2 (29)
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
Neurological symptoms, unspecified [ 86] 144 5 (3)
Transient CN III and IV palsy [ 34] 12 1 (8)
Severe encephalopathy [ 99] 124 1 (1)
Urogenital
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
Dysuria/strangury [ 49] 36 6 (17)
Renal and urinary disorder [ 49] 36 8 (22)
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
Table 7. Neurological and urogenital adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Neurological
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
Urogenital
Urethral irritation [ 73] 151 110 (73)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
title
|
Urogenital reactions
|
|
p
|
Few urogenital reactions were described ( Table 6 and Table 7). Hemoglobinuria was described as an adverse reaction seen after transfusion of stem cell products 39, 51, 56, 73. However, hemoglobinuria is often attributed to erythrocyte debris in the transplant material and has thus not been interpreted as being caused by DMSO 39, 73. The other urogenital reactions ( Table 6 and Table 7) all occurred after DMSO instillation in the bladder 38, 49, 97.
|
|
table-wrap
|
Table 6. Neurological and urogenital adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Neurological
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
Intravesical administration [ 38] 20 1 (5)
Rectal administration [ 116] 21 3 (14)
>1 administration route [ 84] 7 2 (29)
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
Neurological symptoms, unspecified [ 86] 144 5 (3)
Transient CN III and IV palsy [ 34] 12 1 (8)
Severe encephalopathy [ 99] 124 1 (1)
Urogenital
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
Dysuria/strangury [ 49] 36 6 (17)
Renal and urinary disorder [ 49] 36 8 (22)
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
label
|
Table 6.
|
|
caption
|
Neurological and urogenital adverse reactions observed per number of patients.
|
|
title
|
Neurological and urogenital adverse reactions observed per number of patients.
|
|
table
|
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
Neurological
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
Intravesical administration [ 38] 20 1 (5)
Rectal administration [ 116] 21 3 (14)
>1 administration route [ 84] 7 2 (29)
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
Neurological symptoms, unspecified [ 86] 144 5 (3)
Transient CN III and IV palsy [ 34] 12 1 (8)
Severe encephalopathy [ 99] 124 1 (1)
Urogenital
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
Dysuria/strangury [ 49] 36 6 (17)
Renal and urinary disorder [ 49] 36 8 (22)
|
|
tr
|
Adverse reaction Studies Total patients, n Patients with adverse reactions, n (%) (min%–max%) †
|
|
th
|
Adverse reaction
|
|
th
|
Studies
|
|
th
|
Total patients, n
|
|
th
|
Patients with adverse reactions, n (%)
|
|
th
|
(min%–max%) †
|
|
td
|
Neurological
|
|
tr
|
Neurological
|
|
tr
|
Headache [ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116] 2516 150 (6) (1–50) [ 101] - [ 70]
|
|
td
|
Headache
|
|
td
|
[ 2, 18, 29, 33, 38, 41, 55, 59, 70, 71, 81, 84, 85, 98, 101, 104, 116]
|
|
td
|
2516
|
|
td
|
150 (6)
|
|
td
|
(1–50) [ 101] - [ 70]
|
|
tr
|
Intravenous administration [ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104] 1271 42 (3) (1–50) [ 101] - [ 70]
|
|
td
|
Intravenous administration
|
|
td
|
[ 18, 33, 41, 59, 70, 71, 81, 85, 98, 101, 104]
|
|
td
|
1271
|
|
td
|
42 (3)
|
|
td
|
(1–50) [ 101] - [ 70]
|
|
tr
|
Transdermal application [ 2, 29, 55] 1197 102 (8) (5–35) [ 55] - [ 2]
|
|
td
|
Transdermal application
|
|
td
|
[ 2, 29, 55]
|
|
td
|
1197
|
|
td
|
102 (8)
|
|
td
|
(5–35) [ 55] - [ 2]
|
|
tr
|
Intravesical administration [ 38] 20 1 (5)
|
|
td
|
Intravesical administration
|
|
td
|
[ 38]
|
|
td
|
20
|
|
td
|
1 (5)
|
|
tr
|
Rectal administration [ 116] 21 3 (14)
|
|
td
|
Rectal administration
|
|
td
|
[ 116]
|
|
td
|
21
|
|
td
|
3 (14)
|
|
tr
|
>1 administration route [ 84] 7 2 (29)
|
|
td
|
>1 administration route
|
|
td
|
[ 84]
|
|
td
|
7
|
|
td
|
2 (29)
|
|
tr
|
Seizures [ 18, 36, 47] 301 2 (1) (0–2) [ 18] - [ 47]
|
|
td
|
Seizures
|
|
td
|
[ 18, 36, 47]
|
|
td
|
301
|
|
td
|
2 (1)
|
|
td
|
(0–2) [ 18] - [ 47]
|
|
tr
|
Neurological symptoms, unspecified [ 86] 144 5 (3)
|
|
td
|
Neurological symptoms, unspecified
|
|
td
|
[ 86]
|
|
td
|
144
|
|
td
|
5 (3)
|
|
tr
|
Transient CN III and IV palsy [ 34] 12 1 (8)
|
|
td
|
Transient CN III and IV palsy
|
|
td
|
[ 34]
|
|
td
|
12
|
|
td
|
1 (8)
|
|
tr
|
Severe encephalopathy [ 99] 124 1 (1)
|
|
td
|
Severe encephalopathy
|
|
td
|
[ 99]
|
|
td
|
124
|
|
td
|
1 (1)
|
|
td
|
Urogenital
|
|
tr
|
Urogenital
|
|
tr
|
Pelvic discomfort/pain/ irritation [ 38, 49, 97] 107 10 (9) (6–30) [ 49] - [ 38]
|
|
td
|
Pelvic discomfort/pain/ irritation
|
|
td
|
[ 38, 49, 97]
|
|
td
|
107
|
|
td
|
10 (9)
|
|
td
|
(6–30) [ 49] - [ 38]
|
|
tr
|
Dysuria/strangury [ 49] 36 6 (17)
|
|
td
|
Dysuria/strangury
|
|
td
|
[ 49]
|
|
td
|
36
|
|
td
|
6 (17)
|
|
tr
|
Renal and urinary disorder [ 49] 36 8 (22)
|
|
td
|
Renal and urinary disorder
|
|
td
|
[ 49]
|
|
td
|
36
|
|
td
|
8 (22)
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (min%–max%) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
table-wrap
|
Table 7. Neurological and urogenital adverse reactions observed per number of treatments.
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Neurological
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
Urogenital
Urethral irritation [ 73] 151 110 (73)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
label
|
Table 7.
|
|
caption
|
Neurological and urogenital adverse reactions observed per number of treatments.
|
|
title
|
Neurological and urogenital adverse reactions observed per number of treatments.
|
|
table
|
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
Neurological
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
Urogenital
Urethral irritation [ 73] 151 110 (73)
|
|
tr
|
Adverse reaction Studies Total treatments, n Adverse reactions observed, n (%) (min%–max%) †
|
|
th
|
Adverse reaction
|
|
th
|
Studies
|
|
th
|
Total treatments, n
|
|
th
|
Adverse reactions observed, n (%)
|
|
th
|
(min%–max%) †
|
|
td
|
Neurological
|
|
tr
|
Neurological
|
|
tr
|
Headache [ 39, 51] 86 40 (47) (6 - 73) [ 39] - [ 51]
|
|
td
|
Headache
|
|
td
|
[ 39, 51]
|
|
td
|
86
|
|
td
|
40 (47)
|
|
td
|
(6 - 73) [ 39] - [ 51]
|
|
td
|
Urogenital
|
|
tr
|
Urogenital
|
|
tr
|
Urethral irritation [ 73] 151 110 (73)
|
|
td
|
Urethral irritation
|
|
td
|
[ 73]
|
|
td
|
151
|
|
td
|
110 (73)
|
|
table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
sec
|
Other reactions
Only one study in this review administered DMSO as eye-drops 114. In this study, two patients experienced severe conjunctival hyperemia due to allergic reactions, and 25% of patients experienced a stinging sensation when eye-drops were applied 114. Other studies performed eye examinations to determine whether DMSO caused changes in the lens; however, no such cases were observed 2, 45.
Hyponatremia occurred in six patients after they received large doses of DMSO as treatment for cranial hypertension 62. This adverse reaction was not reported in other studies ( Table 8).
Table 8. Other adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
Sedation [ 2] 78 34 (44)
Hyponatremia [ 62] 6 6 (100)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included. Very few cases of serious adverse reactions associated with DMSO have been described 18, 36, 51, 59.
Overall, most studies administered DMSO intravenously or transdermally ( Table 9)
Table 9. Way of administration of DMSO in included studies.
Administration Number of studies References
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
Oral 2 [ 9, 60]
Eye-drops 1 [ 114]
Local injection 1 [ 92]
Intra-articular 1 [ 103]
Rectal 1 [ 116]
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title
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Other reactions
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p
|
Only one study in this review administered DMSO as eye-drops 114. In this study, two patients experienced severe conjunctival hyperemia due to allergic reactions, and 25% of patients experienced a stinging sensation when eye-drops were applied 114. Other studies performed eye examinations to determine whether DMSO caused changes in the lens; however, no such cases were observed 2, 45.
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p
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Hyponatremia occurred in six patients after they received large doses of DMSO as treatment for cranial hypertension 62. This adverse reaction was not reported in other studies ( Table 8).
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table-wrap
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Table 8. Other adverse reactions observed per number of patients.
Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
Sedation [ 2] 78 34 (44)
Hyponatremia [ 62] 6 6 (100)
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
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label
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Table 8.
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caption
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Other adverse reactions observed per number of patients.
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title
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Other adverse reactions observed per number of patients.
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table
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Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
Sedation [ 2] 78 34 (44)
Hyponatremia [ 62] 6 6 (100)
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tr
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Adverse reaction Studies Total patients, n Patients with reaction, n (%) (min%–max%) †
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th
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Adverse reaction
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th
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Studies
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th
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Total patients, n
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th
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Patients with reaction, n (%)
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th
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(min%–max%) †
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tr
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Fever [ 27, 71, 73, 77, 101] 547 44 (8) (2–19) [ 27] - [ 77]
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td
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Fever
|
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td
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[ 27, 71, 73, 77, 101]
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td
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547
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td
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44 (8)
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td
|
(2–19) [ 27] - [ 77]
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tr
|
Chills [ 27, 33, 70, 71, 81, 85, 101] 852 60 (7) (1–31) [ 101] - [ 71]
|
|
td
|
Chills
|
|
td
|
[ 27, 33, 70, 71, 81, 85, 101]
|
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td
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852
|
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td
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60 (7)
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td
|
(1–31) [ 101] - [ 71]
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tr
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Dizziness [ 2, 46, 55, 85, 101] 885 18 (2) (1–15) [ 55] - [ 2]
|
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td
|
Dizziness
|
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td
|
[ 2, 46, 55, 85, 101]
|
|
td
|
885
|
|
td
|
18 (2)
|
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td
|
(1–15) [ 55] - [ 2]
|
|
tr
|
Weakness [ 33, 45, 46] 293 19 (6) (1–29) [ 46] - [ 45]
|
|
td
|
Weakness
|
|
td
|
[ 33, 45, 46]
|
|
td
|
293
|
|
td
|
19 (6)
|
|
td
|
(1–29) [ 46] - [ 45]
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tr
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Sedation [ 2] 78 34 (44)
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td
|
Sedation
|
|
td
|
[ 2]
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td
|
78
|
|
td
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34 (44)
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tr
|
Hyponatremia [ 62] 6 6 (100)
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|
td
|
Hyponatremia
|
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td
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[ 62]
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td
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6
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td
|
6 (100)
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table-wrap-foot
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
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footnote
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
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p
|
†Incidences of the adverse reactions have been calculated for all the individual studies. (%, min-max) are the lowest and highest observed incidence of an adverse reaction observed in the group of studies included.
|
|
p
|
Very few cases of serious adverse reactions associated with DMSO have been described 18, 36, 51, 59.
|
|
p
|
Overall, most studies administered DMSO intravenously or transdermally ( Table 9)
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table-wrap
|
Table 9. Way of administration of DMSO in included studies.
Administration Number of studies References
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
Oral 2 [ 9, 60]
Eye-drops 1 [ 114]
Local injection 1 [ 92]
Intra-articular 1 [ 103]
Rectal 1 [ 116]
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label
|
Table 9.
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caption
|
Way of administration of DMSO in included studies.
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title
|
Way of administration of DMSO in included studies.
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table
|
Administration Number of studies References
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
Oral 2 [ 9, 60]
Eye-drops 1 [ 114]
Local injection 1 [ 92]
Intra-articular 1 [ 103]
Rectal 1 [ 116]
|
|
tr
|
Administration Number of studies References
|
|
th
|
Administration
|
|
th
|
Number of studies
|
|
th
|
References
|
|
tr
|
Intravenous 49 [ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
|
|
td
|
Intravenous
|
|
td
|
49
|
|
td
|
[ 7, 16, 18, 23, 25, 26, 33, 34, 36, 39– 41, 46– 48, 51, 53, 54, 56, 59, 61, 62, 65, 68, 70– 74, 77, 80, 81, 84– 87, 90, 91, 94, 98– 102, 104, 110, 115, 117, 118]
|
|
tr
|
Transdermal 48 [ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
|
|
td
|
Transdermal
|
|
td
|
48
|
|
td
|
[ 2, 4, 6, 17, 19– 22, 24, 28– 32, 37, 42, 44, 45, 50, 52, 55, 57, 58, 63, 64, 66, 67, 69, 72, 75, 76, 78, 79, 82– 84, 88, 89, 93, 95, 96, 106– 109, 111– 113]
|
|
tr
|
Intravesical 7 [ 8, 35, 38, 43, 49, 97, 105]
|
|
td
|
Intravesical
|
|
td
|
7
|
|
td
|
[ 8, 35, 38, 43, 49, 97, 105]
|
|
tr
|
Oral 2 [ 9, 60]
|
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td
|
Oral
|
|
td
|
2
|
|
td
|
[ 9, 60]
|
|
tr
|
Eye-drops 1 [ 114]
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|
td
|
Eye-drops
|
|
td
|
1
|
|
td
|
[ 114]
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tr
|
Local injection 1 [ 92]
|
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td
|
Local injection
|
|
td
|
1
|
|
td
|
[ 92]
|
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tr
|
Intra-articular 1 [ 103]
|
|
td
|
Intra-articular
|
|
td
|
1
|
|
td
|
[ 103]
|
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tr
|
Rectal 1 [ 116]
|
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td
|
Rectal
|
|
td
|
1
|
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td
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[ 116]
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sec
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Risk of bias within studies
In this review, we included 76 cohort studies, of which 64 were prospective 2, 4, 6, 7, 20, 22, 24– 27, 29, 31, 32, 34– 38, 40– 45, 48, 50– 54, 56, 58, 60, 63, 65, 66, 68– 70, 72, 73, 77, 80, 81, 83, 85, 88, 90, 92, 94, 97, 98, 101– 104, 107, 108, 110, 112, 115, 117, 118 and 13 were retrospective 9, 18, 23, 39, 46, 47, 61, 71, 74, 86, 87, 100, 105. Bias was assessed using The Newcastle-Ottawa-Scale 14. Using this scale, studies were given zero to nine stars. A high number of stars equals low risk of bias and vice versa. The studies in this review had a median value of 5 stars, with a range of 2–8. No studies received the highest possible value of nine stars. Very few studies had a comparison group that did not receive DMSO, and often the occurrence of adverse reactions was poorly described. There were 24 randomized controlled trials ( Figure 2). Many studies received an unclear risk of bias because often it was vaguely described how adverse reactions were reported.
Figure 2. Risk of bias in randomized controlled trials. Overall, there was a high risk of bias when assessing the description of adverse reactions. Some studies were not assessed for bias due to being case-reports, preliminary trials, or because they included more than one study design 17, 19, 28, 62, 84, 91, 99, 109, 111, 113.
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title
|
Risk of bias within studies
|
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p
|
In this review, we included 76 cohort studies, of which 64 were prospective 2, 4, 6, 7, 20, 22, 24– 27, 29, 31, 32, 34– 38, 40– 45, 48, 50– 54, 56, 58, 60, 63, 65, 66, 68– 70, 72, 73, 77, 80, 81, 83, 85, 88, 90, 92, 94, 97, 98, 101– 104, 107, 108, 110, 112, 115, 117, 118 and 13 were retrospective 9, 18, 23, 39, 46, 47, 61, 71, 74, 86, 87, 100, 105. Bias was assessed using The Newcastle-Ottawa-Scale 14. Using this scale, studies were given zero to nine stars. A high number of stars equals low risk of bias and vice versa. The studies in this review had a median value of 5 stars, with a range of 2–8. No studies received the highest possible value of nine stars. Very few studies had a comparison group that did not receive DMSO, and often the occurrence of adverse reactions was poorly described. There were 24 randomized controlled trials ( Figure 2). Many studies received an unclear risk of bias because often it was vaguely described how adverse reactions were reported.
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figure
|
Figure 2. Risk of bias in randomized controlled trials.
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label
|
Figure 2.
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caption
|
Risk of bias in randomized controlled trials.
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title
|
Risk of bias in randomized controlled trials.
|
|
p
|
Overall, there was a high risk of bias when assessing the description of adverse reactions. Some studies were not assessed for bias due to being case-reports, preliminary trials, or because they included more than one study design 17, 19, 28, 62, 84, 91, 99, 109, 111, 113.
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sec
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Discussion
Gastrointestinal and dermatological adverse reactions were the most commonly reported in the included studies. Cardiac adverse reactions only occurred when DMSO was administered intravenously, whereas dermatological reactions mostly occurred when DMSO was administered on the skin. Serious neurological and cardiac reactions were rare and only described in few studies. There seems to be a dose-response relationship between DMSO and adverse reactions with no or mild reactions in low doses.
Many studies on the use of DMSO have been performed in Russia. These studies have not been readily accessible to the global community due to the language barrier. In this review, we have included not only studies dating back almost 50 years, but also articles written in Russian, which is an important strength of the review. This study has several limitations: 1) Some studies used the NCI-CTC (National Cancer Institute’s Common Terminology Criteria for adverse events), but often no scale was used, and the occurrence of adverse reactions were poorly reported. 2) It was difficult to make conclusions on the frequency of a specific adverse reaction, because the exact number of patients experiencing a reaction was often not stated. 3) Several studies using DMSO as a cryoprotectant concluded that other factors affected the occurrence of adverse reactions 7, 85, 86. One study prospectively looked at the adverse reactions observed in relation to autologous transplantation in 64 European Blood and Marrow Transplant Group centers 7. They had difficulties isolating the effects of DMSO from confounding factors such as cell breakdown products and conditioning chemotherapy. Factors such as age, gender, volume transfused, granulocyte concentration, clumping of transplant material, and amount of red blood cells played a role in the occurrence of adverse reactions 61, 86, 120– 122. Another study believed that acute volume expansion, electrolyte imbalance and vagal responses to the coldness of the freshly thawed infusate were more likely reasons for cardiac arrhythmias during stem cell transfusions than the DMSO infused 123. This differs from other studies, which found a clear connection between dose of DMSO and occurrence of cardiac adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115. Therefore, it is possible that some adverse reactions are more or less common than found in this review. The rarer side effects are often reported in case reports, which often did not meet the eligibility criteria in this review. However, we have included several larger studies in this review, and they found a very small occurrence of serious adverse events 7, 55, 66, 74.
In conclusion, adverse reactions due to DMSO are often mild and transient and do not qualify as serious adverse events. Cardiovascular and respiratory adverse reactions occur mostly when DMSO is administered intravenously, whereas dermatological reactions have a higher incidence when DMSO is administered transdermally. An important finding is that the occurrence of adverse reactions seems to be related to the dose of DMSO, and it therefore seems safe to continue the use of DMSO in small doses.
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title
|
Discussion
|
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p
|
Gastrointestinal and dermatological adverse reactions were the most commonly reported in the included studies. Cardiac adverse reactions only occurred when DMSO was administered intravenously, whereas dermatological reactions mostly occurred when DMSO was administered on the skin. Serious neurological and cardiac reactions were rare and only described in few studies. There seems to be a dose-response relationship between DMSO and adverse reactions with no or mild reactions in low doses.
|
|
p
|
Many studies on the use of DMSO have been performed in Russia. These studies have not been readily accessible to the global community due to the language barrier. In this review, we have included not only studies dating back almost 50 years, but also articles written in Russian, which is an important strength of the review. This study has several limitations: 1) Some studies used the NCI-CTC (National Cancer Institute’s Common Terminology Criteria for adverse events), but often no scale was used, and the occurrence of adverse reactions were poorly reported. 2) It was difficult to make conclusions on the frequency of a specific adverse reaction, because the exact number of patients experiencing a reaction was often not stated. 3) Several studies using DMSO as a cryoprotectant concluded that other factors affected the occurrence of adverse reactions 7, 85, 86. One study prospectively looked at the adverse reactions observed in relation to autologous transplantation in 64 European Blood and Marrow Transplant Group centers 7. They had difficulties isolating the effects of DMSO from confounding factors such as cell breakdown products and conditioning chemotherapy. Factors such as age, gender, volume transfused, granulocyte concentration, clumping of transplant material, and amount of red blood cells played a role in the occurrence of adverse reactions 61, 86, 120– 122. Another study believed that acute volume expansion, electrolyte imbalance and vagal responses to the coldness of the freshly thawed infusate were more likely reasons for cardiac arrhythmias during stem cell transfusions than the DMSO infused 123. This differs from other studies, which found a clear connection between dose of DMSO and occurrence of cardiac adverse reactions 41, 67, 71, 75, 78, 85, 86, 93, 101, 115. Therefore, it is possible that some adverse reactions are more or less common than found in this review. The rarer side effects are often reported in case reports, which often did not meet the eligibility criteria in this review. However, we have included several larger studies in this review, and they found a very small occurrence of serious adverse events 7, 55, 66, 74.
|
|
p
|
In conclusion, adverse reactions due to DMSO are often mild and transient and do not qualify as serious adverse events. Cardiovascular and respiratory adverse reactions occur mostly when DMSO is administered intravenously, whereas dermatological reactions have a higher incidence when DMSO is administered transdermally. An important finding is that the occurrence of adverse reactions seems to be related to the dose of DMSO, and it therefore seems safe to continue the use of DMSO in small doses.
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sec
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Data availability
All data underlying the results are available as part of the article and no additional source data are required.
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title
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Data availability
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p
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All data underlying the results are available as part of the article and no additional source data are required.
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back
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Supplementary material
Supplementary File 1. Completed PRISMA harms checklist.
Click here for additional data file.
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sec
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Supplementary material
Supplementary File 1. Completed PRISMA harms checklist.
Click here for additional data file.
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title
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Supplementary material
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p
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Supplementary File 1. Completed PRISMA harms checklist.
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p
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Click here for additional data file.
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caption
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Click here for additional data file.
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Click here for additional data file.
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