IV Mannitol –
Expanding Perspectives for Use in
Neurogenic Inflammation &
Neuropathic Pain
Dr. Jason Hughes ND & Dr. Brenden
Cochran
Setting Expectations
• What this presentation will be;
– A brief overview of the history of use of IV
Mannitol
• Review of generally accepted mechanisms of action
• Review of generally accepted clinical uses
– An introduction of potential new uses of IV
Mannitol
• Particularly in view of mannitol’s mechanism of action
on TRVP1 receptors in Neuropathic Pain
– A description of several cases where IV Mannitol
has been used in from this new perspective.
Setting Expectations
• What this presentation won’t be;
– A conclusive review or “the final analysis”
– Neither of us have done exhaustive clinical trials
with Intravenous Mannitol
• Hopefully this presentation will pique interest
in experimentation with IV Mannitol within
you, so as to help us all better understand its
full clinical applications!
A Little Background...
• The 1st Masters Class...
– Both of us use Intravenous Therapies in our own
practice.
– The idea of exploring the use of IV Mannitol grew out
discussions around the dinner table between all of us
present at the Inaugural Master’s Class
– Some initial research into the potential revealed a fair
amount of history of use and several journal articles
– This lead to lots more exciting dinner conversations
and the commitment to try this clinically to see if it
was a viable treatment.
Mannitol: A Short History
• Mannitol is classified as a sugar alcohol; that
is, it is derived from a sugar (mannose) by
reduction
• A white, crystalline solid with the chemical
formula C6H8(OH)6
• Has been used in medicine as a
INTRACELLUALR DIURETIC for many decades
(Many studies go back to the 1940’s)
Mannitol:
Generally Accepted Pharmacokinetics
• “Because orally administered mannitol is not absorbed,
it must be administered parenterally. It distributes
almost entirely in the extracellular fluid, very little
penetrating cells. As a result, it is virtually inert, only 7
percent to 10 percent being metabolized, probably in
the liver, while the rest is freely filtered by the
glomeruli and excreted intact in the urine. About 7
percent is reabsorbed by the renal tubules. With
normal kidney function, after a single intravenous
dose, the half-life of mannitol in the circulating
plasma is 15 minutes. Of an injected dose, 90 percent
is recovered in the urine after 24 hours.” – Nissenson
et al.
Mannitol:
Generally Accepted Pharmacokinetics
• “With severe renal insufficiency the rate of
mannitol excretion is greatly reduced and
retained mannitol may increase extracellular
tonicity leading to a shift of water out of cells,
expanding the extracellular fluid as well as
inducing an apparent hyponatremia with
increased serum osmolality such as occurs in
hyperglycemia. Therefore, mannitol should be
used cautiously under these conditions.” –
Nissenson et al.
Mannitol:
Generally Accepted Physiological
Effects
• Renal
– Can basically be used as an Osmotic Diuretic
– An almost ideal prototype, mannitol was used
extensively in early physiological studies of
osmotic diuresis.
– Osmotic diuretics are freely filtered at the
glomerulus and poorly reabsorbed by the renal
tubules. The resulting high urinary concentration
profoundly affects renal water and sodium
reabsorption.
Mannitol:
Generally Accepted Physiological
Effects
• Cardiovascular
– Intravenously injected mannitol is confined to the
extracellular fluid space. The increased tonicity
obligates water to move from the intracellular to the
extracellular fluid to maintain osmotic equilibrium.
– With each 182 mg per dl increase in mannitol
concentration, a 10 milliosmole increase in
extracellular fluid osmolality occurs with the same
proportionate dilution of all serum electrolytes as
occurs in hyperglycemia.
Mannitol:
Generally Accepted Physiological
Effects
• Cardiovascular
– Various amounts of plasma volume expansion
have been reported with mannitol infusion
– Ranging from 1 ml per kg of body weight per 5
grams of mannitol infused to 3 ml per kg of body
weight per 5 grams of mannitol, depending upon
body osmolarity
– With each 100 mg per dl increase in mannitol
concentration in the extracellular fluid, serum
sodium falls 1.6 to 2.6 mEq per liter.
Mannitol:
Generally Accepted Physiological
Effects
• Cardiovascular
– After the expansion of the extracellular fluid and
blood volume by injection of mannitol mean
arterial pressure, cardiac output, heart rate,
coronary blood flow and left ventricular end
diastolic pressure all increase.
Mannitol:
Generally Accepted Physiological
Effects
• Cerebrovascular
– Mannitol has several physiologic effects on the
cerebrovascular system.
– Increased cerebral blood flow, increased cerebral
oxygen consumption and decreased cerebrospinal
fluid pressure have all been documented.
Mannitol:
Generally Accepted Physiological
Effects
• Cerebrovascular
– The decreased cerebrospinal fluid pressure, in
spite of increased cerebral blood flow, is of
interest. Since mannitol cannot cross the blood
brain barrier, it causes water to move out of the
brain into the extracellular fluid. This decrease in
brain water is the cause of the fall in cerebrospinal
fluid pressure. The movement of water out of the
brain in response to the osmotic effect of
mannitol decompresses the brain when cerebral
edema is present.
Mannitol:
Generally Accepted Physiological
Effects
• Ocular
– Mannitol profoundly lowers intraocular pressure
when given intravenously just as it lowers
cerebrospinal fluid pressure.
– Can also be used topically to create ocular
hypotensive effect!
Mannitol:
Generally Accepted Clinical Uses
• Raised Intracranial Pressure
– Osmotherapy has been the cornerstone of the
medical management of cerebral edema,
irrespective of its aetiology, for decades, and
mannitol is the most widely used agent.
– In a survey conducted in 1996, 100% of
neurosurgical units in the UK used mannitol
during the treatment of intracranial hypertension.
Mannitol:
Generally Accepted Clinical Uses
• Reduction in raised intracranial pressure
• Preservation of perioperative renal function in patients
undergoing major vascular and cardiac surgery and in
those with jaundice
• To promote diuresis and minimize the risk of acute
renal failure in patients after renal transplantation
• Preservation of renal function in rhabdomyolysis
secondary to crush injuries and compartment
syndrome
• Bowel preparation before colorectal surgery,
colonoscopy, and barium enemas
• Promotion of urinary excretion of toxic materials
Mannitol:
Generally Accepted Clinical Uses
• “Mannitol is a standard of care for the
management of intracranial hypertension and
is recommended by consensus guidelines.
There is little evidence to support its
continued use for other indications...” –
Shawkat et al, 2012
• Having said that, lets examine the history of
“off label” uses and potential future “off label”
uses.
Mannitol:
History of Use In Pain
• Hooshang Hooshmand, M.D.
– Has been researching and publishing about IV
Mannitol since at least 1969.
– It would seem that he is the person that innovated
the use of IV Mannitol for Neurogenic
Inflammation and Neuropathic Pain
– I have tried to contact him no less than 5 times,
but unfortunately he is retired and not taking any
calls!
Mannitol:
Hooshmand’s Concept of Neuropathic Pain
• Mechanism
– Principally views IV Mannitol as an intracellular
diuretic with action on the nerves as well
– “Intracellular water retention is quite important,
especially in the following conditions: In any
condition that causes traumatic or toxic
metabolic water retention in the nerve cells,
especially the brain, as well as in the peripheral
nervous system.”
Mannitol:
Hooshmand’s Concept of Neuropathic Pain
• Examples of Water Retention in Cells (Nerves)
1. Disturbance of Pituitary and Adrenal Hormones
•
This is seen in conditions such as Diabetes Insipidus,
hyper corticosteroid dysfunction such as Cushing's
Disease, hypothyroidism, and a condition
Pseudotumor cerebri. In such diseases, the water
concentration in the nerve cells is selectively
increased. This causes water toxicity, increased intracranial pressure, and even death.
2. Another example of intercellular edema is
glaucoma involving the eyes.
Mannitol:
Hooshmand’s Concept of Neuropathic Pain
• Examples of Water Retention in Cells (Nerves)
3. The third type of intercellular water retention is the
typical inflammatory changes seen in neuropathic
pain
•
•
Such as diabetic neuropathy or complex regional pain
syndrome (CRPS)
“The inflammation in neuropathic pain causes the
disturbance of permeability of the cell membrane
allowing the water, along with electrolytes such as
sodium and calcium, to enter the nerve cells. This cell
membrane disturbance causes the death of nerve cells,
especially in the grey matter of the spinal cord, in the
dorsal root ganglia(DRG), and in the peripheral nerves.”
Mannitol:
Hooshmand’s Concept of Neuropathic Pain
• Manifestations of Neurogenic Inflammation
• The inflammation becomes manifested in the form of
edema of the extremities, severe vascular headaches,
spontaneous cell membrane permeability of the
arterioles and venules resulting in cutaneous bleeding
and skin rash in absence of any kind of trauma.
• Such water retention and disturbance of cell
membrane function causes edema of the brachial
plexus, edema at the ankle or wrist, and these
conditions become mistaken for thoracic outlet
syndrome, carpal tunnel syndrome, tarsal tunnel
syndrome, etc.
Mannitol:
Hooshmand’s Clinical Observations
• “In the past decade we have applied the treatment with Mannitol
to patients with compression neuropathies, as mentioned above
(conditions mimicking carpal tunnel syndrome, tarsal tunnel
syndrome, thoracic outlet syndrome and rotator cuff tear), as well
as the patients who, due to CRPS, suffer from severe edema,
neurodermatitis, and trophic ulcers. There were surgical candidates
with the compression neuropathies who were divided into two
groups. Both groups were given the option of surgery or treatment
with IV Mannitol. The entire subject was discussed in detail with the
patient and with their referring physician. One group underwent
surgery, and the other underwent Mannitol treatment. After
comparing 32 patients in each group, it became obvious that
Mannitol treatment was quite successful and would eliminate the
necessity for surgery. “
Mannitol:
Hooshmand’s Clinical Observations
• The surgical group had a more rapid deterioration of
their CRPS post-operatively. The CRPS changed from
stage II to stage III in 2/3 of such patients, and the
edema continued to show a tendency for further
recurrence.
• The other equally comparable group of 32 patients,
who underwent Mannitol therapy, did not require
surgery, and their condition improved. The pain rating
post-operatively dropped from an average of 6-9 prior
to treatment with Mannitol, to an average of 2-5 after
treatment with Mannitol.
IV Mannitol
Hooshmand’s Guidelines
• Safety Guidelines
– “As long as the patient has normal renal clearance
(no protein in the urine), the IV Mannitol
treatment is quite safe” - Hooshmand
• Treatment Strategies
– 100 g Mannitol in 500cc D5W over 40-60 min.
Mannitol & TRVP1 Receptors:
Expanding Mechanism of Action?
• Expanding perspectives of use
• Can the only effect of Mannitol be as a
intracellular diuretic?
– Cleared from the body very quickly, but effects are
much longer lasting!
Mannitol & TRVP1 Receptors:
Expanding Mechanism of Action?
• Could the mechanism of Mannitol’s
effectiveness be also due to the response on
TRVP1 receptors?
• If so, would the same amount or
concentration need to be used?
• These are the questions that we are trying to
answer!
Why we are excited about this...
• The cardiovascular system is one hell of a delivery
system
– IV Mannitol could allow the treatment of system wide
neurogenic inflammation! (Neurogenic Storm, FM,
etc)
– IV Mannitol could allow the treatment of “hard to
get” areas without the risk of deep injections!
• One poke beats many pokes
– So says every patient I’ve known.
• There is a known safety signature and a long
history of use
Some Potential Drawbacks
• Its expensive and you potentially need to use
a lot more of it to get the effect.
• It can be difficult to obtain.
• You may need to compound yourself or have a
pharmacist do it.
• It takes longer to do a drip than subcutaneous
injections, longer visit times
Storage
• Don’t store in the refrigerator due to
crystallization
• Don’t store over 30 degrees Celsius
• MDV=Multiple dose vial
– Preservative and 28 day shelf life after opening
• SDV = Single dose vial
– Preservative free.
– Must be used no more then the day opened.
• Consider use of filter
Mannitol Concentrations
• 5% mannitol
(usually compounded or you have prepared by dilution)
– 225 mOsmol/L
– pH 4.5 – 7.0
• 10% mannitol (osmitrol)
– 550 mOsmol/L (Hypertonic)
– pH 4.5 – 7.0
• 20% mannitol (osmitrol)
– 1100 mOsmol/L (Very hypertonic) (OUCH!!!!)
– pH 4.5 – 7.0
Osmolarity
•
•
•
•
Hemolysis: <145 mOsmol
Hypotonic: <250 mOsmol
Isotonic: 250 – 375 mOsmol
Hypertonic: >375 mOsmol
Osmolarity
• Normal physiologic osmolarity range is 280 to 310
mOsmol/L
• Osmolarity:
– 150-450: Low risk of phlebitis
– 450-600: Moderate risk of phlebitis
– 600 + : 100% risk of some phlebitis (Gazitua, et al)
** Remember: changing osmolarity (dilution) does
not change pH. Both need to be assessed.
Contraindications
•
•
•
•
•
•
•
•
•
Hypersensitivity
Pre-existing plasma hyperosmolarity
Heart Failure (CHF)
Disturbances of the blood-brain barrier
Anuria
Pulmonary congestion/Pulmonary edema
Active intracranial bleed
Severe dehydration
Progressive renal or heart damage
Cautions
Electrolyte disturbances:
• Infusions of mannitol will cause depletion of
sodium and potassium.
• Dehydration: osmotic diuresis
• If using with dextrose (hyperinsulinism),
further potassium depletion.
Cautions
Use in Pregnancy: (Category B2)
• Teratogenic Effects: unknown
• Lactation: Not known if excreted in breast milk
Geriatrics:
• Dehydration and electrolyte disturbance
Cautions
Interactions with other medications:
• Diuretics due to potentiation
• Concomitant cyclosporin due to nephrotoxicity
• Concomitant aminoglycosides (potentiation of
ototoxicty)
• Anti-coagulants: reduce their effects by
increasing clotting factors secondary to
dehydration
• Digoxin: due to possible hypokalemia from
mannitol
Adverse Side Effects
•
•
•
•
•
•
•
•
Nausea and vomiting
Local pain, thrombophlebitis, phlebitis
Angioedema, allergy, anaphylactic shock
Chills, dizziness, urticaria, fever, headache,
blurred vision
Hypotension, hypertension, tachycardia,
arrhythmia, angina like pains, convulsions, CHF
Nephrosis, diuresis, renal failure
Acidosis, electrolyte imbalances
Dehydration, cramps, thirst, dry mouth
Lab and other Work Up
•
•
•
•
•
CBC
CMP
UA in office
Vitals pre and post
Patient is hydrating before and during
infusion.
• Drip will last generally 1 – 3 hours depending
on volume, strength and patient tolerance.
Dosing
• 250 – 500 ml 5% mannitol
• 250 – 500 ml 10 % mannitol
• 250/250 ml (10% mannitol: 10% Dextrose)
• Lower dosages are generally tolerated more
and safer.
IV Mannitol
• Most patient’s report that they like having less
injections.
• Better whole system treatment
• Best for fibromyalgia, CRPS, or other 4
quadrant pains.
• May benefit other neurological pathways.
Possible calming agent: see CASE
IV Mannitol
• Consider in future neurological cases.
• Parkinson’s
– http://phys.org/news/2013-06-artificialsweetener-potential-treatment-parkinson.html
– http://www.eurekalert.org/pub_releases/201304/gsoa-fma032913.php
Other IV agents
•
•
•
•
•
•
•
•
Alapha lipoic acid
EGCG
Vitamin C
Vitamin E
Magnesium
MSM
DMSO
MTHF
Other agents
• Topical magnesium, MSM, DMSO
• Injectable Vitamin D?
DIFFICULT
TO DO!
Anderson, PS (2012, August). Active comparator trial of addition of
MTHFR specific support versus standard integrative naturopathic
therapy for treating patients with diagnosed Fibromyalgia (FMS) and
Chronic Fatigue Syndrome (CFS). Poster Presentation, presented at the
American Association of Naturopathic Physicians annual convention,
Bellevue, WA.
Incidence
Data:
Hetero Hetero Compound Homo
A1298C C677T Hetero
A1298C
Homo
C677T
Study n = 88
23
12
19
9
22
% CFS/FMS
Participants
26
13
23
10
25
% Normal
population
43
43
15
11
11
% Incidence
Difference
- 40
- 70
+ 53
-1
+ 44
Outcomes:
Active
Hetero Hetero Compoun Homo
Homo
comparato A1298C C677T d Hetero A1298C C677T
r:
Interventi
on % (of
n)
22
25
47
50
27
%
outcome
improvem
ent
+ 55%
+ 75%
+ 56%
+ 56%
+ 71%
Approximately 45% of the population has 1 copy of the
MTHFR C677T
Wilcken B et al. J Med Genet 2003;40:619-625
Fibromyalgia
• 43 year old female fibromyalgia onset 2001
• Tried pain medications, muscle relaxers, trigger
point injections.
• Pelvic pain 8/10 (10- worst)
• B/L Jaw pain 5-6/10 (10- worst)
• B/L Hand pain 7/10 (10 worst)
• Burning aching pain
• Have done 3 – 4 sessions (PSI injections with 5%
mannitol) have benefited but not holding.
Pressure algometry
• Pre-treatment
– Left pelvis: 0.13 kg/m2
– Right thoracic lateral to T10- T11: 0.56 kg/m2
– Right upper thoracic T4-5: 0.28 kg/m2
– Other PE CV, Resp., reflexes WNL
– Vitals: BP 121/79, Pulse 94, RR 14
Infusion
• IV infusion:
– 250 ml 5% mannitol
– 250 ml 5% dextrose
• Infusion time 65 minutes.
• Patient reports feeling more relaxed during
the IV
Pressure algometry
• Post-treatment
– Left pelvis: 0.13 kg/m2  0.34 kg/m2
– Right thoracic lateral to T10- T11: 0.56 kg/m2 
2.84 kg/m2
– Right upper thoracic T4-5: 0.28 kg/m2  1.45
kg/m2
– Other PE CV, Resp., reflexes WNL
– Vitals: BP 125/44, Pulse 97, RR 14
Depression/Fibromyalgia
• 63 year old female, depression flare, irritable
and emotional
• Tried pain medications, muscle relaxers,
responding well to PSI treatments
• Left cervical pain C3-C4 8/10 (10- worst)
• Left T7 pain 8/10 (10- worst)
• Left T10 pain 8/10 (10 worst)
• Aching pain
Pressure algometry
• Pre-treatment
– Left C3-C4: 1.13 kg/m2
– Left thoracic T7: 1.10 kg/m2
– Left throacic T10: 1.10 kg/m2
– Other PE CV, Resp., reflexes WNL
– Vitals: BP 118/72, Pulse 76
Infusion
• IV infusion:
– 250 ml 5% mannitol
• Infusion time 60 minutes.
• Patient reports feeling more relaxed and very
calm. Pain not as prominent.
Pressure algometry
• Post-treatment
– Left C3-C4: 1.13 kg/m2  1.13 kg/m2
– Left thoracic T7: 1.10 kg/m2  1.55 kg/m2
– Left throacic T10: 1.10 kg/m2  1.30 kg/m2
– Other PE CV, Resp., reflexes WNL
– Vitals: BP 118/71, Pulse 70
Case History’s
• M.S. With Systemic Neuropathic Pain
– 65 y.o. Woman with M.S., Confined to wheelchair.
Pain – Entire spine, hips. Noticeable edema both
legs but worse right, Obese, Constipation
– Initial treatments
• Dietary changes, sensitivities, supportive GI protocol
• NPT – DRG relevant areas (thoracic / lumbar / cluneal)
– Significant benefit but recurring pain.
– Complained of “pain all over”
Case History’s
– 6 IV Treatments
•
•
•
•
No significant cardiovascular history
BP- WNL
No protein in urine
Started with 100cc 5% mannitol IV and worked up to
500cc 5% mannitol
– 100cc  200cc  300cc  400cc 500cc  500cc
• Infused over 45min
Case History’s
• Outcomes (to date)
– Initial treatment
• Headaches gone (didn’t report these)
• Lost significant weight (5 lbs)
– Observations over subsequent treatments
• Pain noticeably improved albeit still recurrent
• Weight loss (could be due to dietary factors as well as diuretic)
• Midway thru treatments she requested “just do the IV’s with me”
no longer wanted the injections she felt the IV was more effective
for systemic pain
• Noticeable improvement in peripheral edema and discoloration
• Noticeable relaxation during treatment as concentration increased
Case History’s
• 70 y o male – Fibromyalgia, systemic pain
• 36 y o female – Transverse Myelitis, HA’s
References
• 1.Hooshmand H, Suter C, Dove J: The effects of mannitol and
dexametheasone on CSF pressure. Excerpta Medical International
Congress 1969; Series No.193: 374-378.
• 2.Hooshmand H, Dove J, Houff S, et al: Effects of diuretics and
steroids in CSF pressure, a comparative study. Arch Neurol 1969;
21: 499-509.
• 3.Hooshmand, H., Houff, S., and Quin, J.: Cerebrospinal fluid
pressure changes with chemotherapy for intracerebral
hemorrhage. Neurology 22:56-61, 1972.
• 4.Hooshmand H and Hashmi M: Complex regional pain syndrome
(Reflex sympathetic dystrophy syndrome): Diagnosis and Therapy
- A Review of 824 Patients. Pain Digest 1999; 9 : 1-24.
• 5. Shawkat H, Westwood M, Mortimer A: “Mannitol: a review of
its clinical uses.” Continuing Education in Anaesthesia, Critical
Care & Pain. Published by Oxford University Press on behalf of the
British Journal of Anaesthesia. 2012.
• 6. Nissenson A, Weston R, Kleeman C: “Mannitol.” The Western
Journal of Medicine 131:277-282, Oct 1979