The very high ICP seen in the three adult patients in the Gumerlock and Neuwelt
83 study and the time it took 
to administer DMSO may have determined the irreversibility of the injury and the inability by DMSO to affect the eventual outcome recorded. OPTIMAL DMSO DOSE FOR TRAUMATIC BRAIN INJURY
The findings published by Marshall et al.82 and by Gumerlock and Neuwelt using 
DMSO in human head injury and the experimental findings by de la Torre et al.75,76 
and Brown et al.77,78 using rhesus monkeys and by others using smaller mammals 
subjected to a variety of brain insults84–86 indicated that the optimal  dose of IV 
DMSO to be given after traumatic brain injury should be 28% solution at a staring concentration of 1–1.5 g/kg. The aforementioned volume and concentration of DMSO were theorized in order 
to avoid fluid overload, electrolyte disturbances, and significant hemolysis while ensuring a safer and more effective response to increased ICP. The DMSO fluid delivery time would also optimally range between a fast bolus and a fast drip as originally suggested by de la Torre et al. 76
The recommended dosing schedule for DMSO was adopted in a preliminary 
study by Turkish investigators. IV DMSO was administered as a first-line treatment to 10 patients with severe closed head injury by Karaça et al. 87 using a 28% solution 215 DMSO in Clinical Neuroprotection
at a concentration of 1.12 g/kg delivered as a fast drip. On admission, the mean ICP 
recorded was 73 mmHg and ranged from 40 to 127 mmHg. The DMSO dose was reduced by half if and when the ICP reached <20 mmHg. DMSO was continued for 10 days or until stabilization of the ICP or full recovery was observed. These investigators reported a dramatic lowering of ICP in all but three patients after a 6-day treatment. Neurological improvement and survival were observed in the remaining seven patients followed up for 3 months. 87 Two patients in 
this series died, and one patient had poor neurologic outcome. The modified DMSO dose and its application to severe head injury patients shortly 
after admission differed substantially from the previous trials that used DMSO as a second-line treatment. These findings using IV DMSO as a primary treatment for severe closed head injury could be described as dramatic  due to the reduction in 
permanent disability, 75% survival rate, and 25% mortality that historically has a 60%–70% mortality using standard therapy. Following the encouraging findings reported by Karaça et al. 87 using DMSO 
for severe head trauma, a second study was quickly undertaken by Kulah et al.88 
working from the same Turkish hospital and neurosurgical unit. This group gave IV DMSO as a bolus (50 mL of a 28% solution mixed in 5% dextrose) to 10 patients with ICPs exceeding 25 mmHg and GCS between 3 and 6. A marked decrease in the ICP and an increase in CPPs occurred within 10 min in most of the patients after the start of DMSO administration. No rebound effect was noted as it commonly occurs with mannitol treatment. 88
The increase in CPP was observed to parallel the decline in ICP in all cases.88 No 
serious adverse events were seen after DMSO treatments.88 Blood pressure, cardiac 
output and central venous pressure, and electrolytes were unaffected by DMSO infu-sions. When CBF was measured in the head injury patients, an average increase of 20% was observed following DMSO administration. 88 Brisk diuresis was noted in 
most patients shortly after the initiation of each DMSO administration.88 The mor -
tality rate using DMSO was 30%, and six patients survived with good-to-excellent neurological outcome after a 3-month follow-up. 88
Classically, a GCS score of 3–6 on presentation at the intensive care unit in 
patients with severe blunt trauma to the brain has been recognized as an ominous prognostic factor. The reported mortality rate in these patients ranges from 45% to 100%. 89 A poor neurological outcome is observed in 90% of patients with a GCS of 
3–6 when followed up for a year.90
Thus, a survival rate of 70% with good functional recovery in 60% of the 
patients with severe blunt trauma given IV DMSO as reported by teams led by Karaça et al. 87 and by Kulah et al.88 must be considered a highly significant 
improvement over standard therapy in the management of traumatic brain injury. It is clear from these findings that the mixed results reported by Waller et al.,
81 
Marshall et al.,82 and Gumerlock and Neuwelt83 using DMSO for severe head 
injury differed from those obtained by Karaça et al.87 and by Kulah et al.88 who 
also used DMSO for similar severe head injuries but who reported much better outcomes and responses to treatment. These important differences need to be more closely examined.216 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
COMPARING DMSO DOSES, DURATION OF 
TREATMENT, AND USE AS A FIRST- OR SECOND-LINE 
TREATMENT FOR TRAUMATIC BRAIN INJURY
Analyzing the findings of the studies on severe head injury reported by Waller 
et al.,81 Marshall et al.,82 Gumerlock and Neuwelt,83 Karaça et al.,87 and Kulah et al.88 
with regard to DMSO therapy as discussed earlier, several fundamental factors may partly explain the mixed results. First, it is an axiomatic in neurosurgery that the sooner a patient with moderate-
to-severe traumatic brain injury is successfully  treated to lower high ICP, the better 
the chances of a good response and a favorable outcome. This rule relies on the pathophysiological events that secondary damage may quickly introduce after brain trauma. Secondary damage appears in the form of the four H syndrome : hypotension, 
hypoperfusion, hypoxia, and hypercarbia. These systemic changes alter the local cerebral milieu at the cellular–molecular levels that involve the release of inflamma -
tory cytokines, excitotoxic amino acids’ induction of ionic fluxes, oxidative stress, and energy metabolic failure. Consequently, effective therapy that can target the local and systemic secondary 
sequelae that rise rapidly after brain trauma may be able to protect to some degree against devastating damage and brain cell death and thus help in the recovery of the brain trauma patient. In the Waller et al.,
81 Marshall et al.,82 and Gumerlock and Neuwelt83 preliminary 
studies, much precious time was spent administering standard therapy, which failed to control ICP before DMSO was administered. In the Karaça et al. 87 and Kulah et al.88 
studies, DMSO was given as a first-line treatment  to severe head injury patients upon 
arrival at the hospital. This was a critical difference from previous studies in the man -
agement of severe head injury using DMSO. This lapse of time difference, which ranged from 8 to 24 h, reasonably explains 
the mixed outcome results reported in the Waller et al.,81 Marshall et al.,82 and 
Gumerlock and Neuwelt83 trials and the more favorable outcomes reported by Karaça 
et al.87 and by Kulah et al.88 when DMSO is given as a primary agent within 6 h after 
trauma. The other important difference in comparing these trials is the DMSO con -
centration and the dosing time interval. The 10%–20% solution of DMSO administered in the Marshall et al.82 trial may 
not have been effective due to fluid overload and a suboptimal DMSO concentration, whereas in the Karaça and Kulah studies, the 28% DMSO solution given avoided fluid overload and prevented significant hemolysis and electrolyte disturbances. The IV administration of DMSO that was continued until absolute control of 
the ICP was attained may also have been a key factor in achieving the better survival rate and improved neurological outcome reported in the Karaç a–Kulah 
studies. 87,88
Both investigators reported that continuous or intermittent DMSO administra -
tion extended for 2–7 days of treatment if needed  generally prevented the return of 
increased ICP to the original levels seen at admission.87,88217 DMSO in Clinical Neuroprotection
Data from these two preliminary studies indicate that early, aggressive manage -
ment of CPP to increase CBF by DMSO can lead to improved neurological outcome 
despite extremely high ICPs91 (Figure 9.3). There are two key hemodynamic changes that may explain DMSO’s efficacy 
in controlling ICP following traumatic brain injury: (1) the ability to significantly increase CBF and (2) the ability to improve CPP. Both CBF and CPP values are lowered following brain insults. 36 Aggressive CPP therapy should be performed and 
maintained even though apparently lethal ICP levels may be present. It thus seems reasonable to correlate the increase in CPP and CBF by DMSO with the reduction of ICP. Aggressive CPP therapy should be performed and maintained even though appar -
ently lethal ICP levels may be present. It seems reasonable to correlate the increase in CPP and CBF by DMSO with the reduction of ICP. The reason is that traumatic brain injury is widely known to cause dynamic changes in CBF and secondary brain insults have been reported to decrease CPP. 36
In patients with moderate-or-severe head injury, CPP has also been shown to 
correlate with patients’ functional outcome. This action ostensibly may lead to 
 better tissue oxygenation, better control of brain autoregulation, reduced glutamate 
excitotoxicity, and stabilization of impaired neurometabolism and inflammatory responses. 17 These pathological processes are schematized in Figure 9.4, with respect 
to DMSO, and a general scheme of how DMSO may affect outcome  f ollowing head 
injury is  s ummarized in Figure 9.3. The most consequential detail to recognize about DMSO therapy in traumatic 
brain injury is that this apparently useful drug does not act as a miraculous lazaroid , 
that is, an imaginary agent that can wake up dead neurons. This is an unrealistic expectation which investigators often assume is the inability of a drug to reverse the symptoms and pathophysiological consequences of brain trauma.CPPC BFDMSO
ICP
Improv ed neurolo gical outcome
FIGURE 9.3  The main therapeutic effect by DMSO aims at lowering ICP ( ↓) follow -
ing severe traumatic brain injury (TBI). This action increases CPP ( ↑) and CBF ( ↑). Increasing CPP–CBF may prevent or diminish secondary damage involving inadequate cerebral oxygenation, cerebrovascular dysautoregulation, neurometabolic impairment, inflammatory responses, and excitotoxic cell death. (From Werner, C. and Engelhadt, K., Br. J. Anaesth ., 99, 4, 2007. )218 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
If function is regained after a severe traumatic brain injury with or without ther -
apy, it implies that surviving brain cells peripheral to the injury site have recuperated 
sufficiently either through an external intervention or through unknown internal fac -
tors. It also means that in the case of intervention, extension of brain cell damage beyond the penumbral region bordering the injury core has been prevented. Very little information is presently available to explain the recovery of penumbral 
neurons, that is, those nerve cells bordering the central core of injury that remain undamaged but nonfunctional. Needless to say, brain cells rarely recover by them -
selves after neural tissue damage and they are, by definition, at risk of sudden or protracted death by apoptosis or necrosis. Astr ocyte
NeuronSubcellular se condary damage af ter TBI
12 Synaptic failur e
InflammationCytokines
ChemokinesImpair ed axonal
transpo rt
Mitochondri a
4Reactive oxygen sp ecies
Low ATP
Ener gy failur e
Neuronal deat hGlutamate bind s
to NMDA re ceptors3
IINMDAGlutamate uptake
blockedIonic fluxes K+ Na+ Ca2+
FIGURE 9.4  (See color insert.) Diagram shows major subcellular events associated 
with secondary damage following primary traumatic brain injury (TBI). Astrocytes undergo reactive transformation in response to blunt head injury and release cyto -
toxic cytokines and chemokines. Reactive astrocytes are unable to uptake glutamate. Glutamate, in turn, accumulates in the extracellular space at the site of injury where it binds and opens NMDA channel receptors in neurons. This action by glutamate creates an influx of calcium (Ca
2+) and sodium (Na+) ions and an efflux of potassium (K+) ions, 
which result in the depolarization of neurons. This ionic dyshomeostasis damages intra -
cytoplasmic mitochondria that promote the formation of reactive oxygen species, reduced ATP synthesis, energy failure, and cell death. Studies have shown that DMSO is able to antagonize the formation of cytokines and chemokines in injured tissue (1), block Na
+ 
and Ca2+ influx into cells after neuronal depolarization (2), prevent glutamate induction 
of excitotoxic neuronal death by suppressing NMDA ion currents (3), and scavenge the formation of reactive oxygen species and the damage caused by these oxidizing radicals. See text for details.219 DMSO in Clinical Neuroprotection
Astrocytes undergo reactive transformation in response to physical brain injury by 
a process known as reactive gliosis, which may impede neural recovery. Astrocytes, 
like other brain cells, are vulnerable to reactive oxygen species generated by trau-matic brain injury and ischemia. 92
Intact brain studies93 suggest that the rise of extracellular glutamate in brain that 
occurs during energy failure secondary to brain trauma may be due to failure of astrocytes to uptake extracellular glutamate, which then accumulates excessively at the site of injury and binds to N -methyl- d-aspartate (NMDA) receptors in neurons 
where an influx of calcium and sodium ions and an efflux of potassium ions result in the depolarization of neurons. 94 This ionic imbalance damages neuronal mito -
chondria that leads to cytotoxic reactive oxygen species, reactive nitrogen species, mitochondrial ATP loss, energy failure, and neuronal death (Figure 9.4). Findings suggest that DMSO administration in traumatic brain injury appears to 
target several of these pathophysiological processes to either block or reverse their activity (Figure 9.4). For example, in normal brain metabolism, glutamate, the most abundant excit -
atory neurotransmitter, is taken up by astrocytes, which convert it to glutamine and deliver it to neurons where it is converted back to glutamate as a source of energy. All glutamate receptors are cation channels that allow the influx of sodium (Na
+) and 
calcium (Ca2+) ions and the efflux of potassium (K+) ions in response to glutamate 
binding to NMDA membrane receptors.95 In traumatic brain injury, astrocytes are 
unable to take up glutamate, which can accumulate outside brain cells. This excitotoxic process causes K+ ions to exit and Na+ and Ca2+ ions to enter 
nerve cells via NMDA receptor channels located on the neuronal membrane, a patho -
logic process leading to neuronal depolarization, damage, and eventual neuronal cell 
death (Figure 9.4). Ionic dyshomeostasis will uncouple mitochondrial ATP  s ynthesis, 
induce oxidative stress, reactive oxygen species, and neuronal cell death.96,97
The mechanism of neuronal cell death includes damage to mitochondria from 
excessively high intracellular Ca2+, while the production of reactive oxygen species 
will lead to lowered ATP energy fuel and eventual energy failure (Figure 9.4). Energy failure will disrupt axonal transport mechanisms and impede neurotransmission. The excitotoxic ischemic cascade will also create inflammatory cytokine and chemokine secretions from damaged astrocytes. 97 The delicate balance of glutamate metabolism 
in brain implies that too much or too little glutamate can be harmful. If glutamate lev -
els are too low, cognitive and behavioral problems can develop, but if glutamate levels are too high, the overstimulation of nerve cells can lead to cell death. Regulation of the subcellular events associated with traumatic brain injury is 
therefore vital for controlling the pathophysiological cascade and neurological dys -
function that will result following brain trauma. There are reports that DMSO is able to block Na
+ and Ca2+ ions entry into cells 
following tissue injury98,99 and block Na+ channel activation after neuronal depo -
larization.99,100 Drugs like DMSO that prevent abnormal sodium influx into injured 
cells provide effective protection against Na+ and Ca2+ overload. However, it remains 
unclear whether DMSO is capable of exerting this effect in normalizing ionic dys-homeostasis in traumatized brain tissue. The mechanisms exerted by DMSO on Na
+ 
and Ca2+ channels need to be further investigated in mammalian models of traumatic 220 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
brain injury since the results of such studies could produce extremely useful and 
relatively safe agents in treating neurotrauma. Another critically important action shown by DMSO is the prevention of glu -
tamate induction of excitotoxic neuronal death by the suppression of NMDA ion currents
101 (Figure 9.4). DMSO was observed to suppress NMDA-induced cation cur -
rents and excessive Ca2+ influx into plated hippocampal neurons within minutes after 
its introduction, sparing brain cells from excitotoxic death.101 This action by DMSO 
on cultured neurons did not appear to involve changes in gene expression or protein translation. It suggested instead a direct effect by DMSO on neuronal membrane receptors mediating glutamate receptor channels and excitatory transmission. 101
The decrease in NMDA ionic currents by DMSO could also be affected by the 
antioxidant action of DMSO, which is capable of modulating glutamate receptor activity. An important phase of traumatic brain injury is the inflammatory reaction seen 
with blunt head injuries. Although the peak inflammatory response to brain trauma can evolve after several days, cytokines and chemokines (Figure 9.4) are released from astrocytes, microglia, and polymorphonuclear cells within hours after injury, a 
process that leads to opening of the blood–brain barrier and to complement-  me diated 
activation of cell death.102,103
Prevention or control of cytokine release and accumulation in the extracellular 
space after brain injury, especially cytotoxic concentrations of several important pro-inflammatory interleukins, such as the IL-1 family, IL-6, and TNF- α, may be 
life saving in head injury if specific therapy can be applied to diminish their patho -
genic effect. 104
In this vein, the actions of DMSO on inflammatory cytokines have been reported 
in intestinal cells exposed to a variety of inflammatory cytokines in vitro .105
DMSO at 0.5% was shown to significantly decrease mRNA levels of inflam -
matory proteins, including IL-1 α, IL-1 β, and IL-6.105 The IL-1 family constitutes a 
complex network of cytokines involved in the initiation of inflammatory responses resulting from tissue injury, including brain ischemia and stroke. 106 These interleu -
kins have become a therapeutic target that when neutralized can result in a sustained reduction of ischemic trauma severity. 107
IL-6 plays a major role in many undesired effects of the immune system, and its 
expression has been found to increase quickly at the sites of axonal injury.108,109
In addition to suppressing cytokine production, DMSO was reported to decrease 
secretions of a macrophage chemoattractant protein-1 (MCP-1) in a dose-  d ependent 
manner in rodent intestinal cells.105 MCP-1 is a major chemokine involved in mac -
rophage migration and has been shown to play important roles in tumor growth and metastasis. Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation and activate the production and secretion of inflam -
matory cytokines such as the IL-1 family. 110 MCP-1 is involved in inflammation 
and has been isolated from monocyte and macrophages during an inflammatory 
reaction.110
It remains to be seen whether the actions of DMSO in suppressing inflammatory 
cytokines and chemokines in intestinal cells also apply to the formation and accu -
mulation of these small proteins in brain following neurotrauma.221 DMSO in Clinical Neuroprotection
Traumatic brain injury may result in a dynamic, pathological process that can 
evolve quickly if not aggressively treated. Thus, it seems clear from the collective findings relevant to traumatic brain injury 
that once secondary damage appears and remains uncontrolled, extensive neuronal 
cell populations will die, and the prognosis will be poor despite the best efforts of any successful therapy. For these reasons, it seems logical and proper to implement new procedures to 
treat moderate-to-severe head injuries as an emergency, much like a heart attack or stroke that requires immediate attention to improve the odds of diminishing returns. It has been suggested that prehospital treatment may be started by qualified ambu-lance paramedics trained to intubate head-injured patients whose airway may be compromised at the scene of an accident. 55
However, unless the patient is unconscious, intubation may require neuromuscu -
lar blocking agents or anesthetic drugs, which may pose a hurdle for even trained ambulance personnel. This dilemma is a problem that requires further studies to resolve because if rapid and appropriate prehospital treatment can be applied to the head-injured patient, as the Karaça et al. 87 and Kulah et al.88 studies imply, major 
success in preventing poor neurologic outlook and death following brain trauma could replace the grim statistics presently associated with this brain insult. Thus, prehospital neurotrauma care could address the 4H syndrome, hypoten -
sion, hypoxia, hypoperfusion, and hypercarbia seen in most head-injured patients and provide a preplanned therapeutic approach at the scene of accident to counteract the negative conditions that arise after blunt trauma to the brain. DMSO IN INTRACRANIAL ANEURYSM HEMORRHAGE
Intracranial aneurysms are bulging lesions where blood collects like an expanding balloon due to a weak area in the wall of an artery that supplies blood to the brain. Although aneurysms can occur in any weakened artery, brain aneurysms commonly occur at branch points of major cerebral arteries. When an aneurysm ruptures, a subarachnoid hemorrhage results as blood accu-
mulates into the subarachnoid space where it compresses the brain. Depending on the amount of the bleed, the resulting intracranial hemorrhage can cause sudden, severe headache, nausea, vomiting, stiff neck, LOC, and signs of a stroke, including hemiplegia. 111 Rupture of intracranial aneurysms is associated with high morbid -
ity and mortality if not immediately treated.112 Nonpharmacological treatment of 
a bleeding aneurysm includes clipping the neck of the aneurysm or inserting a coil inside the aneurysms to create a blood clot that stops the bleeding. Pharmacological treatments are given to manage the symptoms only and include 
vasopressors and calcium channel blockers that may alleviate the vascular resistance caused by the spastic, narrowed blood vessels and provide improved blood flow through these vessels. Once an intracranial aneurysm has bled, there is a very high 
chance that it will rebleed unless treatment is applied. Vasospasm, reduced blood flow to the brain, and hemiplegia remain the leading 
causes of morbidity in patients who survive the initial subarachnoid hemorrhage 
(Figure 9.5).222 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Mullan et al.113 reported on nine cases of patients who suffered partial or total 
hemiplegia following surgical repair of intracranial aneurysms. The rationale for 
using DMSO to manage postoperative hemiplegia secondary to aneurysmal bleeding was prompted by the ability of this drug to improve the neurological status of rhesus monkeys subjected to traumatic brain injury, high missile injury, and experimental stroke. 75–78
These reports indicated that DMSO treatment of rhesus monkeys subjected to 
various CNS insults was able to increase CPP, CBF, and metabolic rate of oxygen while reducing cerebral edema, elevated ICP, and significant mortality in all treated animals when compared to standard treatments. 75–78
A summary of how patients typically responded to DMSO treatment after sub -
arachnoid hemorrhage secondary to aneurysm rupture113 provides insight into how, 
and when, the proper use of DMSO can help achieve a successful outcome. Case 1 : A 61-year-old man suffered a subarachnoid hemorrhage and underwent 
clipping of two aneurysms located on the right middle cerebral artery (MCA) and 
right internal carotid artery without incident. After surgery, the blood pressure 
climbed spontaneously and mannitol was given every 4 h. Despite this regimen, left-sided paralysis developed and continued without improvement. A diagno -
sis of severe arterial spasm was made, and a decision to use DMSO was made 
Intracranial aneu rysm
Aneu rysm ruptureReduce d CB F
Vasospas m
FIGURE 9.5  (See color insert.) Rupture of intracranial aneurysm, depending on 
type, size, and location, can cause subarachnoid hemorrhage leading to serious and life-  
threatening complications including hemiplegia, aphasia, regional vasospasm, and brain swelling. Treatment with IV DMSO of ruptured aneurysms in people is reported to reverse progressive hemiplegia, vasospasm and resulting low CBF, and improve hemispheric motor deficits. (From Mullan, S. et al., Dimethyl sulfoxide in the management of postoperative hemiplegia, in: Wikins, R.H., ed., Arterial Spasm , William & Wilkins, Baltimore, MD, 
1980, pp. 646–653. )223 DMSO in Clinical Neuroprotection
in order to avoid permanent paralysis. DMSO at 1 g/kg bolus was given every 
8 h on day 1. The affected right hemispheric blood flow increased 20% and the contralateral left hemisphere by 11% some 30 min after the initial DMSO infu -
sion. After 24 h of DMSO, the clinical condition was satisfactory and DMSO was continued and stopped after 5 days when the patient’s condition was much improved. 113
On day 6, the patient developed low-grade fever, progressive weakness on the left 
side, and confusion. DMSO was restarted at 3 g/24 h and reduced to 1 g/24 h for the next 3 days when left side strength and alertness returned. On day 9, DMSO was reduced to 0.5 g/kg/8 h and stopped on day 12. The patient recovered progressively and was discharged on day 18. 113
Case 2 : A 67-year-old woman was diagnosed with a left MCA aneurysm and 
elected to have it clipped. After surgery, she was alert and had full strength in all four limbs. Shortly thereafter, she became aphasic and had right-sided hemiple -
gia. Mannitol was given for the next 8 h, but no improvement was seen. CBF was 49 mL/100 g/min on both hemispheres. DMSO was begun at a rate of 0.5 g/kg and increased to 1 g/kg/8 h. After 45 min, she was alert and strength returned to the right side. Two hours after the initial DMSO dose, her CBF was 60 on the right and 66 on the left, a 37% increased blood flow in the affected hemisphere. DMSO was continued for another 3  days at a dose of 1 g/kg daily. Her motor strength returned to normal levels within 12 h, and CBF remained at 60 mL/100 g/min until discharge. 113
In the same series of cases reported by Mullan et al.,113 two patients treated were 
relatively young adults. Case 3 : A 25-year-old woman was hospitalized with severe headache and 
high systolic pressure. Neuroimaging showed a left MCA aneurysm with spasm in the internal carotid artery. After clipping the aneurysm without incident and postsurgical recovery, the patient developed significant right-sided weakness, right-leg paralysis, and dysphasia 12 days postoperative. Mannitol was given, but after 8 h, all signs worsened. DMSO 1 g/kg was given over the first hour. Ninety minutes following DMSO, the patient could lift her right leg off the bed and by the following day her dysphasia had cleared. DMSO was continued and reduced to 2 g/kg/day until discharge 3 days later when she was symptom free. 113
Case 4 : A 28-year-old woman was admitted with excruciating headache and 
weakness on the right side. After 5  days, she developed hemiparesis and apha -
sia. A CT scan showed blood in her sylvian fissure and after craniotomy an MCA 
 aneurysm was discovered and clipped without incident. Steroids and mannitol were 
given for severe internal carotid artery spasm, but no improvement resulted. DMSO was given 1 g/kg/4 h and reduced to 1 g/kg/24 h for the next 3 days. A total recovery was seen at discharge. 113
The remaining five cases of aneurysmal hemorrhage were treated with DMSO 
using a similar regimen as the previous patients, and all except one patient had excel -
lent recoveries. The patient who died had a history of hypertension, cardiac defi -
cits, seizures, and heavy smoking and presented with giant aneurysm at the internal carotid artery bifurcation, which penetrated into the hypothalamus and right hemi -
sphere. Despite initial success with DMSO in raising CBF 27% on the affected 224 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
hemisphere, the patient developed high systolic blood pressure and seizures, which 
did not respond to treatment, and the patient expired after 25 days.113
The authors of this study concluded that little can be said for certain after this 
nine-patient minitrial, but the speed of action shown by DMSO administration to reverse specific motor deficits suggested that this drug was strikingly effective in preventing almost certain progressive hemiplegia and restoring hemispheric func -
tion at the early stages of treatment. 113 The authors also pointed out that DMSO 
appeared safe at the doses used and the most likely reason for its beneficial effect may be have been its ability to increase CBF. 113
The minitrial using DMSO to treat intracerebral hemorrhage and ensuing arterial 
spasm by Mullan et al.113 indicates that a DMSO bolus or very fast drip at doses of 
1 g/kg/8 h in a recommended 28% solution appears as a safe and effective regimen. As deficits resolve, the DMSO doses can be reduced as reflected by the patient’s status. Also, hematuria from red cell osmotic hemolysis was seen in all patients only after the initial loading dose of DMSO. Hematuria was seen to stabilize after subse -
quent doses of DMSO. 113 The loading DMSO dose has no other consequences other 
than lowering the hematocrit about 25%, a temporary reaction that paradoxically lowers blood viscosity and vascular resistance while increasing CBF. DMSO COMPARED TO PROGESTERONE 
FOR TRAUMATIC BRAIN INJURY
At the time of this writing, one of the most promising therapies proposed to com -
bat traumatic brain injury is the sex hormone progesterone. In 1996, Stein’s group114 
reported that subcutaneous injection of progesterone (4 mg/kg) given 1 h after bilateral 
frontal lobe contusion in male and pre-estrus female rats resulted in significantly less brain edema in the female rats when compared to male rats 24 h after brain contusion. The conclusion from this study suggested that higher progesterone levels in pre-estrus females were protective after induced brain trauma. 115 Other evidence in rodents indi -
cated that progesterone was beneficial in additional forms of neurotrauma, such as pen -
etrating brain injury,116 improved cognitive performance,117 and spinal cord injury.118
Reports of improved neurological outcomes and decreased cortical infarcts after 
induction of stroke in rats indicated a beneficial effect after progesterone whether it was administered preinjury or postinjury. 119,120 Curiously, one study reported using 
progesterone dissolved in 10% DMSO for middle cerebral artery occlusion (MCAO) in rats and showed significant improvement in reducing infarct volume when 
 progesterone–DMSO combination was compared to progesterone–saline solution.121
The same authors122 used 10% DMSO as a vehicle for 5 ′-deoxy-5-  i odotubercidin 
(5′d-5IT), an adenosine kinase inhibitor in a rat MCAO model, and found similar 
results, that is, a smaller infarct volume and reduced neurological deficits with DMSO-5 ′d-5IT when compared with no treatment. Improved neurologic scores were 
seen in both DMSO-5 ′d-5IT rat groups, with MCAO and in DMSO given alone. 122
In 2007, Wright et al.123 reported a phase II randomized controlled study com -
paring progesterone to placebo in 100 patients (77:23) with traumatic brain injury. The primary measure of benefit was 30-day mortality in patients whose GCS ranged from 4 (severe) to 12 (mild). Thirty days postinjury, patients with severe traumatic 225 DMSO in Clinical Neuroprotection
brain injury given progesterone had a lower mortality rate than the placebo group, 
but due to the small number of patients enrolled in the study, these differences did not reach significant levels. 123 Two smaller clinical studies on progesterone followed. Despite the many reports discussing the benefits of progesterone treatment in a 
variety of rodent CNS injuries,124 this hormone has been used in only three small 
human studies for traumatic brain injury.72
The three studies included 315 patients, of which 180 received progesterone 
(Table 9.1). Two studies involving 215 patients were done in China and one in the United States with 100 patients. 123,125,126 All three studies reported the results of pro -
gesterone on mortality as compared to placebo following traumatic brain injury.72 
The general protocol for progesterone administration was 0.71 mg/kg IV infusion for the first hour and 0.5 mg/kg for the next 11 h.
123 Progesterone 0.5 mg/kg was 
continued every 12 h for 3 days. The patients were divided according to their GCS, which ranged from 4–8, severe trauma, to 9–12, moderate trauma. 123
Results from these studies reported no differences between progesterone and pla -
cebo for ICP or CPP. An improved mortality rate for progesterone after a 30-day123 
or 6-month125,126 follow-up was observed. Paradoxically, disability in surviving U.S. 
patients was deemed to be better after placebo compared to progesterone, a detail that was attributed to slightly higher survival rate in the progesterone group. 123
However, disability was reported to be less for progesterone-treated patients 
compared to controls after 6 months follow-up in the China trials using a modified functional-independent measure score. 125,126 The reason for this disparity may be a 
slightly higher dose of progesterone used in the Chinese trials. None of the three studies reported the effects of progesterone on CBF, cerebro -
vascular resistance, or cerebral metabolic rate of oxygen (Table 9.1). A Cochrane data analysis72 of the three progesterone trials concluded that the 
evidence appeared insufficient to recommend the drug for isolated traumatic brain injury and that further multicenter RCTs were needed. It is not known how progesterone is able to lower elevated ICP and reduce brain edema 
although its neurosteroidal, anti-inflammatory actions may play an important role. 114,127
A comparison of the clinical effects for using progesterone versus DMSO treat -
ments in severe traumatic brain injury is summarized in Table 9.1. In this summary, TABLE 9.1
Clinical Comparison of Treatments Using DMSO or Progesterone after 
Severe Traumatic Brain Injury (TBI) in Humans
Lowers ICP Increases CPP Improves Clinical 
Outcome Reduces 
Mortality 
DMSO (N = 42) Yes Yes Yes Yes
Progesterone (N = 80) No No Yes Yes
Note:  Progesterone is reported to impro ve clinical outcome and reduce mortality but has no effect on 
ICP or CPP. DMSO is reported to lower both ICP and CPP, improve outcome, and reduce mortality. See text for details.226 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
it is seen that although progesterone is reported to reduce mortality and neurologic 
outcome, it does so without increasing CPP and, by inference, CBF. This is a curi -
ous twist because increasing CPP to optimize CBF delivery has become a stan -
dard method to lower the secondary injury pathologic cascade after traumatic brain injury. 128,129 The secondary damage cascade fundamentally involves the development 
of ischemia, hypoxia, and neuronal energy dysfunction, which have become primary determinants of secondary brain injury outcome. Consequently, considerable evidence now indicates that maintaining adequate 
CBF will improve the delivery of oxygen and energy substrates that are lowered during the period of ischemia and hypoxia that follows a moderate-to-severe trau -
matic brain injury. 130–133 This clinical goal has become a standard of practice for 
neurocritical care when using therapeutic interventions after brain trauma. It follows that managing CPP and CBF may have a beneficial effect in lowering ICP after brain injury and could also affect the molecular changes that promote Ca
2+ and Na+ 
cell influx, neuronal membrane instability, glutamate excitotoxicity, and mitochon-drial dysfunction that are known to progress after brain tissue damage
129,134,135 (see 
Figures 8.3 and 9.4). In contrast to progesterone therapy, DMSO improves CPP, CBF, and cerebro -
vascular resistance while increasing oxygen availability to ischemic tissue.75–78,101,113
These actions by DMSO may limit the damage caused by severe head injury, 
intracranial hemorrhage, and vasospasm secondary to aneurysm rupture in human patients. 76,87,88,113 Moreover, the cell and molecular pathology resulting from brain 
trauma is also targeted by DMSO and may help to explain the significant increase in survival and reduced morbidity following severe traumatic brain injury. 87,88
DMSO and progesterone are strong anti-inflammatory agents,136–139 but only 
DMSO is reported to block glutamate excitotoxicity following brain tissue trauma and stabilize Na
+ and Ca2+ influx into nerve cells that can destabilize neuronal mem -
branes and cause cell death.101
Since clinical evidence indicates that both DMSO and progesterone treatment are 
reported to successfully lower mortality and improve neurologic outcome following severe traumatic brain injury, it would seem reasonable to further compare these two drugs in multicenter RCTs to assess the value of each for a life-threatening condition that has no efficacious intervention at the present time. Such an RCT would establish the safety and efficacy of each compound and could provide the first effective treat -
ment available for brain and spinal cord insults. Moreover, we cannot overstate that an RCT of DMSO and progesterone could 
result in a major medical breakthrough in preventing mortality and the psychosocial burden suffered by traumatized patients and their caretakers. A drug that could limit the damage caused by brain trauma would also be cost-effective, in view of the bil -
lions of dollars expended globally on traumatic brain injury, especially for survivors with special needs and constant care. However, on December 25, 2014, as this book went to press, two phase III multi -
center, double-blind clinical trials using progesterone were carried out on moderate to severe TBI patients. 101a,101b These trials demonstrated no significant clinical benefit 
or functional improvement following progesterone administration when compared to placebo in the patients treated for TBI. 101a,101b227 DMSO in Clinical Neuroprotection
DMSO + FRUCTOSE-1,6-DISPHOSPHATE (FDP) 
FOR ISCHEMIC STROKE
Stroke is the third leading cause of death and severe disability in the United States. In the mid-1990s, great hope was created when tissue plasminogen activator (tPA) was approved by the United States Food and Drug Administration (FDA) for use as an IV agent in ischemic stroke. 140 This drug is a clot buster that works by catalyzing the 
conversion of plasminogen to the clot-breaking plasmin. tPA is the only drug currently authorized by the FDA for the treatment of acute ischemic stroke. Despite almost a decade of use after FDA approval, tPA is greatly underused and 
it is reported that in the United States about 1%–7% of potentially eligible patients actually receive this therapy. 141,142 The major reasons for underusing tPA is the tight 
3 h window of treatment required to ensure effectiveness in patients with ischemic stroke and, also, the fear of inducing cerebral hemorrhage. When one computes the delay time often involved in reaching a hospital following an acute ischemic stroke and the time required to rule out a hemorrhagic stroke with a CT scan, this 3 h win -
dow of treatment may be difficult to attain. It is estimated that ischemic stroke strikes about 75% of people over the age of 55. 143 
Elderly stroke patients are also more susceptible to neurologic disability and adverse events related to drug treatment following a cerebrovascular insult. Partly for these reasons, elderly patients are rarely included in large randomized clinical stroke trials involving investigational drug therapy. 144
The pathobiology associated with ischemic stroke is not unlike that seen in trau-
matic brain injury since it involves numerous processes, including increased intra -
cellular Ca2+ influx into cells, glutamate excitotoxicity, loss of cell ion homeostasis, 
free radical–mediated cell damage, cytokine-induced cytotoxicity, complement activation, reactive gliosis, energy failure, and infiltration of leukocytes through an impaired blood–brain barrier. 145
As with traumatic brain injury, early management of ischemic stroke stresses res -
toration of CBF to the ischemic core and surrounding region as a principal goal that can prevent further tissue damage and possibly reverse some or all lost hemispheric function. 146,147
The region bordering the stroke core is called the ischemic penumbra, an area 
encompassing as much as half of the total lesion volume during the initial stages of stroke. 147 The penumbral region therefore represents a neuronal population of dys -
functional but structurally undamaged brain cells, which may be salvaged via post -
stroke therapy.148 Unfortunately, no such therapy has yet been approved for rescuing 
penumbral neurons although studies in rhesus monkeys have shown the feasibility of neuronal rescue after experimental stroke using DMSO. 149–151
The rationale for using combined DMSO–FDP on ischemic stroke patients 
is based on clinical and experimental data indicating the beneficial properties of DMSO or FDP monotherapy following brain and cardiac ischemia. 152–154 Because 
neither DMSO nor FDP alone is able to target the multifactorial metabolic and physi -
ological abnormalities seen experimentally in animals or clinically in humans, it was considered that their combined use might provide improved neuroprotection follow -
ing ischemic stroke. Neither drug had been used for human ischemic stroke before.228 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
In previous studies, DMSO has shown a number of biological activities that 
could be useful in embolic stroke therapy. These include acting as a powerful 
free radical scavenger,155–158 blocking glutamate excitotoxicity,101 suppressing tis -
sue factor activity,98 preventing vascular smooth muscle migration during cardiac 
ischemia,98 inhibiting the formation of thrombin,98 blocking sodium channel acti -
vation,99,100 deaggregating platelets in brain microvessels,158–160 and stabilizing cell 
membranes.161–163
Additionally, DMSO has the ability to increase CBF when given for a variety of 
vascular insults.75–78,113,164 DMSO has also been reported to improve neurologic and 
functional outcome after stroke in animals, including nonhuman primates.155,157,159 
Unlike FDP, however, DMSO does not act as a substrate for aerobic glycolysis, nor does it reduce ischemic-induced cellular acidosis, or directly increases the synthesis of the energy-carrying molecule ATP, during tissue ischemia. These are biological activities that FDP is able to carry out as an energy substrate 
glycolytic intermediate. During anaerobic glycolysis, FDP is capable of boosting the yield of net ATP twice as much as glucose on a per mole basis. 165 FDP has been 
shown to reduce the harmful effects of cellular acidosis promoted by lactic acid production following cerebral ischemia
166 and to diminish the effects of brain isch -
emic hypoxia.167 These activities shown by FDP are highly desirable in combating 
ischemic stroke. Because previous experimental findings using a combination of DMSO and FDP 
showed marked beneficial results when this treatment was applied for blunt head injury and for induced cerebral hypoperfusion in rodents,
87,88,168,169 this dual drug 
combination was selected as a treatment for human stroke by Karaça et al.170
A total of 16 patients suffering from acute and subacute cerebral infarction was 
selected to receive DMSO–FDP or standard therapy.170 The patients ranged in age 
from 45 to 92 with a median age of 65.170 Eleven patients were given IV DMSO–FDP 
(DMSO 560 mg/kg in a 28% solution, FDP 200 mg/kg) mixed in 5% dextrose twice daily for an average of 12 days. Five patients were given standard treatment consist -
ing of fluids, oxygen, and osmotic agents when indicated. 170
Safety and tolerability to DMSO–FDP were evaluated by recording any clinical 
adverse effects to drug therapy, by MRI and by laboratory data. DMSO–FDP drug efficacy was assessed by a reduction in infarct size using MRI, as well as by any mass effect, midline shift or extent of edema, and by magnetic resonance angio -
graphic evidence of improved perfusion in affected vessels. 170
A neurologic and medical evaluation was performed on every patient immediately 
before, during, and after treatments and continued after 7, 30, and 90 days following DMSO–FDP and standard treatments. 170 All but 1 of the 11 DMSO–FDP-treated 
patients was followed up for 3 months after discharge from the hospital. Neurologic assessment included patients’ sensory-motor function and level of consciousness. A modified Rankin scale was used to predict outcome, and a five-point rating scale adapted from Tazaki et al. 171 was used to assess neurologic recovery. All patients were rated as to their daily living condition as follows: (1) markedly 
improved, (2) improved, (3) slightly improved, (4) no change, and (5) deteriorated or died. There were no deaths that could be attributed to any therapy in this series of patients.229 DMSO in Clinical Neuroprotection
Figure 9.6 shows the  MRI of a 63-year-old patient who had sustained a large infarct 
of the left posterior cerebral artery territory 8 h before treatment. After 11 days of 
twice daily DMSO–FDP infusions, MRI showed a dramatic reduction of edema and apparent reduction of thalamic involvement and lower signal intensity in gray matter. 170
A magnetic resonance angiogram is shown in Figure 9.7 of an 80-year-old patient 
who was diagnosed with a right MCA infarct that resulted in a mild mass effect and large hematoma affecting the basal ganglia territory. This patient was treated with DMSO–FDP twice daily after 48 h poststroke and showed improved perfusion in the MCA territory and reduced basal ganglia involvement. (a) (b)
FIGURE 9.6  (a) T2-weighted coronal view MRI of posterior cerebral artery (PCA) territory 
infarct before treatment. White matter changes are seen with lateral mass effect on lateral ventricle, left thalamus involvement, and widespread edema involving the brainstem (arrows). (b) After 11 days of daily DMSO–FDP IV administration, dramatic reduction of edema and lower signal intensity are seen with an apparent improvement  of gray matter and thalamic involvement (arrow). (From Karaça, M. et al., Neurol. Res ., 24(1), 73, 2002.) (a) (b)
FIGURE 9.7  Sagittal view of magnetic resonance angiograph of internal carotid artery ter -
ritory. A right MCA infarction with mild mass effect, large hematoma, and midline shift involving basal ganglia before treatment is seen (a) in an 80-year-old patient 48  h before DMSO–FDP treatment. (b) Eight days of twice daily DMSO–FDP infusions revealed no change in hematoma size, but there appeared an increased perfusion of the MCA ischemic territory, increased blood flow of MCA (arrow), and lessened basal ganglia involvement. (From Karaça, M. et al., Neurol. Res ., 24(1), 73, 2002. )230 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Neurologic evaluation of the 11 patients treated with DMSO–FDP showed that 
7 of 11 patients had moderate or negligible disability (neurologic score, 1–2) after a 
3-month follow-up. In the standard-treated patients at 3 months poststroke, one of five treated showed moderate disability (neurologic score, 3) and the others showed poor outcomes (neurologic score, 3–4). Neurologic reduction of deficits in the DMSO–FDP-treated patients included signif -
icant improvement of sensation, motor strength, higher cortical function (speech, alert -
ness, and comprehension), and ambulation in follow-ups conducted at 30 and 90 days after discharge from the hospital. 170 Significant motor improvement was recorded in 
54% of the patients 1 month after receiving DMSO–FDP. This was especially evident in the three subjects treated within 12 h after their stroke symptoms appeared. 170
In comparison, only 20% of patients showed minor motor improvement at 1 month 
poststroke when the standard treatment was given. The fact that 5 of 11 patients treated with DMSO–FDP improved their neurologic status even when treatment was admin -
istered 12 h after their stroke symptoms first appeared suggests that DMSO–FDP therapy may provide neuroprotective action to dysfunctional but surviving penumbral neurons by increasing CBF. This conclusion is supported by experimental findings that show CBF restoration after 2 weeks of chronic brain ischemia in rodents can rescue dysfunctional neurons from progressive damage and, at the same time, reverse reactive astrocytosis and preserve cognitive function from deteriorating, presumably by preventing glutamate excitotoxicity and the pathobiological changes that follow. 164
In addition, since the average age of the seven patients achieving a markedly 
improved or moderately improved status was 63 years, it is reasonable to assume that the dual drug treatment is safe and effective in elderly subjects. In summary, DMSO–FDP administration to mostly elderly subjects was well 
tolerated when given twice daily for an average of 12  days, following ischemic stroke. Moreover, DMSO–FDP might have provided neuroprotection to some of the patients in this small population group during a 3-month follow-up. Although this preliminary study of DMSO–FDP treatment for acute and subacute ischemic stroke examined a relatively small population, there was evidence that the dual treatment was more effective as a neuroprotector than standard treatment during the recovery period following an ischemic stroke. While no hard conclusions can be drawn from these observational findings, the 
preliminary impression on the use of DMSO–FDP for ischemic stroke is that the dual drug combination may have improved recovery of neurologic deficits in the majority of treated patients. This effect by DMSO in elderly subjects following stroke has not been reported for any other treatment. The remarkable finding of this study is that elderly patients who are known to 
be most vulnerable to ischemic stroke damage and more refractory to therapy than younger patients responded well to DMSO–FDP IV treatment with no major adverse effects and revealed an ostensible benefit to neurological outcome considerably past the 3 h window of opportunity offered by tPA therapy. The collective neuroimaging 
evidence gathered from the 11 patients treated for ischemic stroke with DMSO–FDP 
points to an apparent improvement of cerebral perfusion in the affected brain regions. The DMSO–FDP findings also signal the need for a larger population RCT to test 
the value of this drug combination under a more controlled setting.231 DMSO in Clinical Neuroprotection
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Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        The very high ICP seen in the three adult patients in the Gumerlock and Neuwelt
83 study and the time it took 
to administer DMSO may have determined the irreversibility of the injury and the inability by DMSO to affect the eventual outcome recorded. OPTIMAL DMSO DOSE FOR TRAUMATIC BRAIN INJURY
The findings published by Marshall et al. 82 and by Gumerlock and Neuwelt using 
DMSO in human head injury and the experimental findings by de la Torre et al. 75,76 
and Brown et al. 77,78 using rhesus monkeys and by others using smaller mammals 
subjected to a variety of brain insults84–86 indicated that the optimal  dose of IV 
DMSO to be given after traumatic brain injury should be 28% solution at a staring concentration of 1–1. 5 g/kg. The aforementioned volume and concentration of DMSO were theorized in order 
to avoid fluid overload, electrolyte disturbances, and significant hemolysis while ensuring a safer and more effective response to increased ICP. The DMSO fluid delivery time would also optimally range between a fast bolus and a fast drip as originally suggested by de la Torre et al. 76
The recommended dosing schedule for DMSO was adopted in a preliminary 
study by Turkish investigators. IV DMSO was administered as a first-line treatment to 10 patients with severe closed head injury by Karaça et al. 87 using a 28% solution 215 DMSO in Clinical Neuroprotection
at a concentration of 1. 12 g/kg delivered as a fast drip. On admission, the mean ICP 
recorded was 73 mmHg and ranged from 40 to 127 mmHg. The DMSO dose was reduced by half if and when the ICP reached <20 mmHg. DMSO was continued for 10 days or until stabilization of the ICP or full recovery was observed. These investigators reported a dramatic lowering of ICP in all but three patients after a 6-day treatment. Neurological improvement and survival were observed in the remaining seven patients followed up for 3 months. 87 Two patients in 
this series died, and one patient had poor neurologic outcome. The modified DMSO dose and its application to severe head injury patients shortly 
after admission differed substantially from the previous trials that used DMSO as a second-line treatment. These findings using IV DMSO as a primary treatment for severe closed head injury could be described as dramatic  due to the reduction in 
permanent disability, 75% survival rate, and 25% mortality that historically has a 60%–70% mortality using standard therapy. Following the encouraging findings reported by Karaça et al. 87 using DMSO 
for severe head trauma, a second study was quickly undertaken by Kulah et al. 88 
working from the same Turkish hospital and neurosurgical unit. This group gave IV DMSO as a bolus (50 mL of a 28% solution mixed in 5% dextrose) to 10 patients with ICPs exceeding 25 mmHg and GCS between 3 and 6. A marked decrease in the ICP and an increase in CPPs occurred within 10 min in most of the patients after the start of DMSO administration. No rebound effect was noted as it commonly occurs with mannitol treatment. 88
The increase in CPP was observed to parallel the decline in ICP in all cases. 88 No 
serious adverse events were seen after DMSO treatments. 88 Blood pressure, cardiac 
output and central venous pressure, and electrolytes were unaffected by DMSO infu-sions. When CBF was measured in the head injury patients, an average increase of 20% was observed following DMSO administration. 88 Brisk diuresis was noted in 
most patients shortly after the initiation of each DMSO administration. 88 The mor -
tality rate using DMSO was 30%, and six patients survived with good-to-excellent neurological outcome after a 3-month follow-up. 88
Classically, a GCS score of 3–6 on presentation at the intensive care unit in 
patients with severe blunt trauma to the brain has been recognized as an ominous prognostic factor. The reported mortality rate in these patients ranges from 45% to 100%. 89 A poor neurological outcome is observed in 90% of patients with a GCS of 
3–6 when followed up for a year. 90
Thus, a survival rate of 70% with good functional recovery in 60% of the 
patients with severe blunt trauma given IV DMSO as reported by teams led by Karaça et al. 87 and by Kulah et al. 88 must be considered a highly significant 
improvement over standard therapy in the management of traumatic brain injury. It is clear from these findings that the mixed results reported by Waller et al. ,
81 
Marshall et al. ,82 and Gumerlock and Neuwelt83 using DMSO for severe head 
injury differed from those obtained by Karaça et al.
The recommended dose of DMSO is 28% solution at a concentration of 1–1.5 g/kg, administered as a fast bolus or drip.
What is the recommended dose of DMSO for treating traumatic brain injury?
The difference lies in the timing of DMSO administration, as well as the concentration and dosing interval. The latter two studies administered DMSO as a first-line treatment, whereas the former studies did not.
What is the difference in the treatment approach between the studies by Waller et al. and Gumerlock and Neuwelt, and the studies by Karaça et al. and Kulah et al.?
The primary mechanism by which DMSO is thought to act is by increasing CBF and CPP, which may help prevent or reduce secondary damage and brain cell death.
What is the primary mechanism by which DMSO is thought to act in the treatment of traumatic brain injury?
The study concluded that DMSO may provide neuroprotection to dysfunctional but surviving penumbral neurons, potentially improving neurologic recovery.
What is the conclusion of the study by Mullan et al. regarding the use of DMSO in the treatment of aneurysmal hemorrhage?
The key difference is that DMSO increases CBF and CPP, whereas progesterone does not.
What is the key difference between the use of DMSO and progesterone in the treatment of traumatic brain injury?