1. Dr. Jason Hughes ND & Dr. Brenden Cochran
IV Mannitol – Expanding Perspectives for Use in Neurogenic Inflammation & Neuropathic Pain
Dr. Jason Hughes ND & Dr. Brenden Cochran

2. 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.

3. 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!

4. 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.

5. 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)

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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!

15. 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.

16. 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

17. 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.

18. 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!

19. 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.”

20. Mannitol: Hooshmand’s Concept of Neuropathic Pain
Examples of Water Retention in Cells (Nerves)
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 intra-cranial pressure, and even death.
Another example of intercellular edema is glaucoma involving the eyes.

21. 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.”

22. 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.

23. 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. “

24. 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.

25. 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 min.

26. 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!

27. 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!

28. 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

29. 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

30. 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

31. Mannitol Concentrations
(usually compounded or you have prepared by dilution)
225 mOsmol/L
pH 4.5 – 7.0
10% mannitol (osmitrol)
550 mOsmol/L (Hypertonic)
20% mannitol (osmitrol)
1100 mOsmol/L (Very hypertonic) (OUCH!!!!)

32. Osmolarity Hemolysis: <145 mOsmol Hypotonic: <250 mOsmol
Isotonic: 250 – 375 mOsmol
Hypertonic: >375 mOsmol

33. Osmolarity Normal physiologic osmolarity range is 280 to 310 mOsmol/L
: Low risk of phlebitis
: 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.

34. 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

35. Cautions Electrolyte disturbances:
Infusions of mannitol will cause depletion of sodium and potassium.
Dehydration: osmotic diuresis
If using with dextrose (hyperinsulinism), further potassium depletion.

36. Cautions Use in Pregnancy: (Category B2) Teratogenic Effects: unknown
Lactation: Not known if excreted in breast milk
Geriatrics:
Dehydration and electrolyte disturbance

37. 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

38. 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

39. 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.

40. 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.

41. 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

42. IV Mannitol Consider in future neurological cases. Parkinson’s

43. Other IV agents Alapha lipoic acid EGCG Vitamin C Vitamin E Magnesium
MSM
DMSO
MTHF

44. Other agents
Topical magnesium, MSM, DMSO
Injectable Vitamin D?

46. DIFFICULT TO DO!

47. % CFS/FMS Participants 26 13 10 25
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 A1298C
Hetero C677T
Compound Hetero
Homo A1298C
Homo C677T
Study n = 88 23 12 19 9 22
% CFS/FMS Participants 26 13 10 25
% Normal population 43 15 11
% Incidence Difference
- 40
- 70
+ 53
- 1
+ 44

48. Outcomes: Active comparator : Hetero A1298C Hetero C677T
Compound Hetero
Homo A1298C
Homo C677T
Intervention % (of n) 22 25 47 50 27
% outcome improvement
+ 55%
+ 75%
+ 56%
+ 71%

49. Approximately 45% of the population has 1 copy of the MTHFR C677T
Wilcken B et al. J Med Genet 2003;40:

52. 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.

53. 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

54. Infusion IV infusion: Infusion time 65 minutes.
250 ml 5% mannitol
250 ml 5% dextrose
Infusion time 65 minutes.
Patient reports feeling more relaxed during the IV

55. 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

56. 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

57. 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

58. Infusion IV infusion: Infusion time 60 minutes.
250 ml 5% mannitol
Infusion time 60 minutes.
Patient reports feeling more relaxed and very calm. Pain not as prominent.

59. 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

60. 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”

61. 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

62. 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

63. Case History’s 70 y o male – Fibromyalgia, systemic pain
36 y o female – Transverse Myelitis, HA’s

64. 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:
2.Hooshmand H, Dove J, Houff S, et al: Effects of diuretics and steroids in CSF pressure, a comparative study. Arch Neurol 1969; 21:
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
6. Nissenson A, Weston R, Kleeman C: “Mannitol.” The Western Journal of Medicine 131: , Oct 1979