Re: Need help again Laurie

[Guest guest]

Laurie,

Thanks so much! That was very helpful. I'm on the fence whether I should bug my doc. about doing these labs he isn't familiar with or try and wait until next Tues. when Dr. Cohen is back. I feel like I have held on for an eternity already..what would a few more days be? Thanks again!

[Guest guest]

Thank you so much! I printed it out to give my doctor asap.

[Guest guest]

Dr. Cohen will likely tell you to have a local doctor order things, so why not get it done. The article I mentioned should be on the UMDF site or the Mitoldies site. If you can't find it in either place, let me know and I will scan it and send it to you privately.

laurie

From: LILQT4U1984@...

Reply-To:

Date: Thu, 9 Jan 2003 08:29:28 EST

To:

Subject: Re: Need help again Laurie

Laurie,

Thanks so much! That was very helpful. I'm on the fence whether I should bug my doc. about doing these labs he isn't familiar with or try and wait until next Tues. when Dr. Cohen is back. I feel like I have held on for an eternity already..what would a few more days be? Thanks again!

Medical advice, information, opinions, data and statements contained herein are not necessarily those of the list moderators. The author of this e mail is entirely responsible for its content. List members are reminded of their responsibility to evaluate the content of the postings and consult with their physicians regarding changes in their own treatment.

[Guest guest]

Here is the article again.

Management Strategy for Acute Illness in Patients with Mitochondrial Cytopathy

by P. Saneto, DO, PhD, Pediatric Epilepsy

and Bruce H. Cohen, MD, Pediatric Neurology

The Cleveland Clinic Foundation, Cleveland, OH.

Introduction

The precarious health of a patient with a mitochondrial cytopathy represents the

fine line between little energy reserve and potential energy deficiency. When

demands of added energy requirements

occur, as they do in an acute illness, the decreased reservoir of stored energy

in a patient with a mitochondrial

cytopathy often cannot compensate for the new energy demand. When combined with

the decreased inherit capacity to manufacture energy, the patient’s bioenergetic

health is altered and a bioenergetic

crisis can occur. This is especially true in young children, who have little

energy reserves to begin with, and in those with a severe mitochondrial

cytopathy. Although the number of things that can

cause excessive bioenergetic stress is large, we mostly see compromised

bioenergetic health in the context of another illness. Viral illnesses and

fevers for example, can have mitochondrial consequences.

A quick and simple review of mitochondrial function is important to understand

this article. We consume

food to make the energy our body needs to function. The energy in food is

contained in the cleavable bonds

between the atoms in molecules of sugars (carbohydrate), fats, and proteins.

Healthy mitochondria will generate 36 molecules of ATP (adenine triphosphate,

each ATP represents a unit of energy) for

each molecule of glucose that the mitochondria can burn or oxidize. If the

mitochondria do not function (which is not compatible with even a brief life of

any person), glucose is not fully burned and

only 2 ATP molecules will be produced. In this situation, there is also the

production of two molecules of lactic acid. Studies of mitochondrial function in

some of our sicker patients show that under

ideal laboratory conditions, only about 40 - 60% of the maximal energy can be

produced (14 - 21 ATP molecules for each glucose burned). This is an estimate of

theoretical ATP production, which would

decrease if laboratory conditions mimicked what occurs in the body during severe

viral illnesses, dehydration, and high fever.

A useful analogy is to think of an eight-cylinder car that is running on only 6

or 7 cylinders. As long as the car is on horizontal ground the car’s performance

can appear acceptable. However, when

the demands are increased, such as when the car is loaded with passengers,

attempts to climb a hill, or accelerates to enter the freeway, there is not

sufficient energy performance to accomplish the

task. The car knocks, sputters, and lags in acceleration. Under these

circumstances, the car can stop working completely. In everyday life, the

patient with a mitochondrial cytopathy may function well

enough to get by. But when the demands of an illness or other stressful

situation require a higher performance state, the ability of the body to

manufacture the needed energy to meet that demand is

not optimal. It takes longer for a mitochondrial patient to recover from an

illness, and sometimes the illness is far more severe than if the same illness

happened to someone with normal mitochondrial

function. So when illness occurs, the mitochondrial cytopathy patient is faced

with a situation of having both less energy reserves to fight off the illness

and the inability to maximize energy

production, to help overcome and recover from the illness’ effects on the body.

Little is known how to prevent an energy imbalance and possible subsequent

physiological damage. There is not much in the medical literature that is

instructive in medically managing the crises of

illness or other

stressful event in a mitochondrial patient. What follows is based on our

experience and understanding of some of the practical and theoretical

implications of how the body’s biochemistry affects the

bioenergetic health of a mitochondrial patient.

Preparation is the Key to Energetic Health

There is a wide spectrum of mitochondrial cytopathies. Each one is expressed in

a unique way that is particular to a specific person. Therefore, there is no

“one” best treatment for those with a

mitochondrial cytopathy. Each patient has to be cared for on an individual

basis. Furthermore, our current understanding of mitochondrial diseases is

limited and hence, a best treatment protocol does

not exist. At present, there are many more unknowns than proven treatments in

the medical care of a patient with a mitochondrial cytopathy.

The fragility of someone with a mitochondrial cytopathy requires a working

knowledge of what signs to look for during an acute illness. For the purposes of

this discussion, we will be discussing the

management of fevers, inability to consume enough liquid and food, and

dehydration. Some patients vomit excessively, others have increased

tremulousness, while still others stop drinking and eating,

and some have cognitive changes. It is important for the parent or caregiver to

know these signs (Table 1) for their loved one and call their doctor if these

signs develop. In addition, there should

be a good working relationship with the primary care physician, so when the

parent or caregiver begins to see the signs of rapid bioenergetic decline, the

physician can make arrangements for

hospitalization. A plan for such events should be well developed by the

physician prior to a crisis. Past experiences will dictate the need for

hospitalization and the immediate treatment once the

patient has arrived at the hospital. Unnecessary hospitalization may occur on

occasion, when the patient is not as sick as originally believed to be, but both

physician and caregivers quickly learn

when and when not hospitalization is needed.

Table 1. Some Worrisome Signs

Unexplained or excessive fever

Alteration of usual level cognitive function

Confusion, excessive sleepiness, excessive crying

Vomiting

Loss of appetite

Rapid breathing

Abdominal pain

At the first signs of an illness, the parent or caregiver should be quick to

implement treatment. This generally includes fluid and sugar, and we find that

some common sports drinks such as Gatorade

help. High carbohydrate meals, given by frequent feedings, also may help

replenish and sustain the needed levels of glucose for metabolism. For example,

we have used added uncooked cornstarch in a

meal to increase the level of glucose in the meal.

The use of medication to reduce fever, such as ibuprofen or acetaminophen should

be used. The doctor should calculate the proper dose of these medications (10 –

15 mg/kg/dose given every 4 – 6 hours),

so that there are no fevers.

Treatment for Worsening Clinical Status

It is difficult to pinpoint the time when the patient needs hospitalization.

Experience and communication with the physician/heath care team are needed.

Decisions can be made when the parent/caregiver

notices that, despite the added measures of increased fluids and extra

carbohydrate-containing meals/drinks, the patient has not responded

appropriately. This would be more urgent if the patient

continues to worsen. For each patient, the dictating symptoms are different,

however, through consultation with the health care team the appropriate decision

can be made.

Once the decision is made, the patient and parent/caregiver should go to the

nearest hospital. We tend to have our patients admitted directly to the

hospital, but this will vary according to the

patient’s doctor. Our decisions on what to do next are based on our knowledge of

what deficit our patient may have. Once the patient has been checked into the

hospital, we have a general plan for

proceeding ahead. Most patients will

need blood and urine tests, placement of an IV, and fluids initiated.

Laboratory Tests: The underlying reason for the change in bioenergetic status

needs to be addressed. For example, if there is an infection, this may need to

be treated. If it is asthma, then the

proper respiratory medications need to be given.

Laboratory tests may need to be obtained, including lactate, pyruvate, ammonia,

electrolytes and urine analysis. These values may assist in understanding the

depth of bioenergetic compromise. For

instance, if the lactate level is high, then the amount of dextrose added to the

balanced salt solution used for hydration can be determined. The level of BUN

will help determine the level of

dehydration and the rate of fluid administration. If the urine analysis

indicates that ketone bodies are being excreted in the urine, this is an

indication that fats are being mobilized and maybe

carnitine needs to be added to the fluids.

Dehydration: The degree of dehydration is very important. This is because

dehydration may adversely affect the brain, muscle, heart, and kidney. Even mild

degrees of dehydration, caused by vomiting,

diarrhea, or fever may greatly limit the kidney’s ability to get rid of a toxic

metabolite, set the conditions for rising metabolite levels and induce further

injury. This is the likely mechanism for

the evolution of basal ganglia injury in cases of methyl-malonic aciduria and

type I glutaric aciduria.

We usually begin dextrose containing a balanced salt solution, usually D5 or D10

with 1/4 or 1/2 nor-mal saline (a salt mixture containing 5% or 10% dextrose)

and added carnitine. Given a particular

situation, the amount of salt or sugar could be higher or lower in the IV

solution. The percentage of dextrose containing fluid depends on the abnormality

of the patient. The rate at which fluid is

given is individualized depending on the degree of dehydration, and is the same

regardless of whether or not someone has a mitochondrial disease. The normal

criteria used to decide whether to

administer IV fluids should be abandoned in those with acute illness and

dehydration, as oral rehydration therapy does not offer the same degree of

control and there is not as much room for error in

someone with a mitochondrial disease.

Glucose: Why use added dextrose (glucose) in a mitochondrial cytopathy patient

that is dehydrated and/or has lactic acidosis? Let’s use the automobile engine

analogy again. In a mitochondrial

cytopathy patient, the need for fuel is more pronounced, than in a normal

patient. Since the engine does not function optimally, we need to either

increase the octane of the fuel so the engine gets

more output from the fuel or give the engine more fuel to burn. By giving the

patient more glucose in intravenous fluids we are accomplishing both, more

glucose or fuel to burn and a higher octane by

enhancing the purity of the fuel to burn, and there-fore produce more immediate

energy (instead of the fatty acids from the breakdown of fats). By treating

dehydration, we are also producing an

environment for the engine, which is better for energy efficiency.

In more scientific terms, what we are trying to do is decrease the lactic

acidosis while expanding the volume of fluid in the body. Lactate, but also

other toxins, can be poisons to the brain and as

previously mentioned dehydration can concentrate toxic metabolites and decrease

the kidney’s ability to get rid of these metabolites. Lactate is the by-product

of inefficient glucose metabolism due to

mitochondrial dysfunction. When lactate builds up, it causes the blood to become

acidotic. The liver, in a non-mitochondrial patient, can utilize much of the

lactate produced to remake glucose for

storage and also burn it for fuel. However, when the pH falls below a certain

point, below 7.1, the liver ceases using lactate and instead produces lactate.

By giving fluid, we are expanding the

volume of the blood and allowing the kidneys to help remove some of the toxins.

In addition, the added fluid is helping the kidneys reverse the acidosis. Under

conditions of severe illness, it is

easier for the body to burn glucose, rather than fat, for energy. The hopeful

result of IV flu-ids with added glucose and carnitine is the resolution of

lactic acidosis, correction of electrolyte

balance, and the resolution of symptoms. It is critical to note that excess of

glucose can be highly toxic to a person with pyruvate dehydrogenase (PDH)

deficiency. In some situations of severe

mitochondrial failure, excess glucose can result in worsening lactic acidosis as

well.

In certain emergent cases, we have had to add an insulin drip (0.03 units/kg/hr

- 0.1 units/kg/hr) to help improve mitochondrial function by making glucose more

available to the mitochondria and

lowering free

fatty acid levels, which can improve the function of sick mitochondria. These

are very select cases, and consultation with a mitochondria expert is needed to

assess and implement insulin in these

special cases.

Levo-Carnitine: In some patients, we will give a bolus of levo-carnitine

(usually 50 mg/kg, followed by 100 mg/kg/day in 3 divided doses) as these

patients usually present with a lactate acidosis and

have begun to break down fats into fatty acids. In the analogy of the car

engine, when the fuel is improper for the engine there are by-products produced

that can decrease the performance of the

engine. One can think of carnitine as a fuel additive to help prevent the build

up of toxic by-products created by inefficient fuel utilization.

Carnitine binds toxic-free fatty acids and organic acids. In addition, it acts

as a mitochondrial membrane stabilizer (seals the “leaky” gasket). Often

patients with mitochondrial cytopathies have a

secondary carnitine deficiency as a result of overproduction of free fatty

acids. The carnitine deficiency would be worsened by an acute insult to the

mitochondria and the metabolic machinery. Added

carnitine during the acute stage of an illness would help in removing toxins and

improving the carnitine deficiency. However, there are situations when added

carnitine may not be needed or may

potentially worsen the situation

Other Supplements: There are occasions when other supplements, in addition to

those above, may be needed. We have patients who have severe muscle and

peripheral nerve impairment when illness also

induces changes in bioenergetic homeostasis, very similar to chronic

inflammatory demyelinating

polyneuropathy. Other patients have severe movement disorders, such as dystonia.

We have found that intravenous gamma globulin (1 - 2 gm/kg in 1 or 2 doses)

temporarily improves these conditions.

Although not FDA approved for these diseases, we have seen this treatment help

reverse neuropathic weakness and dystonic movements. There is some experience

with the use of creatine in patients having

mitochondrial myopathies. We have used creatine as only a short-term treatment

when trying to prevent a patient from being placed on a breathing machine. The

body adapts to long term use of creatine

and presumably its effectiveness lessens. We would only recommend these types of

treatment in consultation

with a mitochondria expert.

Conclusion

There are a few important points to remember when dealing with an intervening

illness in a person with a

mitochondrial cytopathy.

1. The patient or caregiver, along with the primary care physician, should

develop a plan of how these illnesses will be approached ahead of time.

2. In many patients, there is little ability to compensate during an acute

illness, so early intervention and the use of IV fluids are often warranted.

3. Once IV hydration has started, it may be necessary to stop all attempts at

feeding, allowing the bowel to rest, until the patient begins to request fluids

or food.

4. Improvement can be slower than would be expected in otherwise healthy

persons, but most patients restart oral hydration and feeding within 12 - 24

hours of the IV fluids having begun.

5. The source of infection should be sought, and if there is a bacterial

infection, it should be treated with appropriate antibiotics. Viral infections

should not be treated with antibiotics, as

these do not work against viruses and many antibiotics can further limit

mitochondrial function.

Glossary of Terms

Sugars: a general term used to define a simple carbohydrate.

Glucose: a common sugar contained in sucrose (table sugar) or lactose (milk

sugar).

Dextrose is the pharmaceutical term for glucose.

Bioenergetic Health: a descriptive term used to define the ability to produce an

adequate supply of energy that will meet the body’s energy demands.

Laureta Fitzgerald wrote:

>

>

> Dr. Cohen will likely tell you to have a local doctor order things, so

> why not get it done. The article I mentioned should be on the UMDF site

> or the Mitoldies site. If you can't find it in either place, let me know

> and I will scan it and send it to you privately.

>

> laurie

>

>

> From: LILQT4U1984@...

> Reply-To:

> Date: Thu, 9 Jan 2003 08:29:28 EST

> To:

> Subject: Re: Need help again Laurie

>

>

> Laurie,

>

> Thanks so much! That was very helpful. I'm on the fence

> whether I should bug my doc. about doing these labs he isn't

> familiar with or try and wait until next Tues. when Dr. Cohen is

> back. I feel like I have held on for an eternity already..what

> would a few more days be? Thanks again!

> Medical advice, information, opinions, data and statements contained

> herein are not necessarily those of the list moderators. The author

> of this e mail is entirely responsible for its content. List members

> are reminded of their responsibility to evaluate the content of the

> postings and consult with their physicians regarding changes in

> their own treatment.

>

>