Re: Our Precious Little

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This was just posted by another member recently on what to avoid during

anesthesia. Hope it helps. Also, welcome to the group!

Anesthesia and Mitochondrial Cytopathies

Bruce H. Cohen, MD, Shoffner, MD, Glenn DeBoer, MD

ã United Mitochondrial Disease Foundation, 1998

Introduction

This article will outline some basic aspects of anesthesia and address the

issue of the special risks

of anesthesia in patients with mitochondrial cytopathies. The applicability

of these

recommendations to a particular patient is complex and should be

individualized by your

physician. Considerations include whether the patient is undiagnosed (i.e.

receiving their first

evaluation to determine whether a mitochondrial disease is present), whether

the patient carries

the diagnosis of a mitochondrial disease, and what criteria were used in

making the diagnosis. The

clinical condition of the patient is probably the most important aspect of

the pre-operative

evaluation. Some patients have minimal disease manifestations and are at low

risk for

complications, whereas, other patients have significant disease

manifestations such as respiratory

muscle weakness, swallowing difficulties, liver disease, and heart disease,

and are at high risk for

complications.

Anesthesia, often referred to as general anesthesia, is the medical

procedure that renders patients

unconscious, insensible to pain and provides muscle relaxation. With local

anesthesia, or regional

anesthesia, patients are awake or sedated, but do not feel pain because the

pain pathways are

" blocked " by the local anesthetics. Spinal anesthesia involves the use of

local anesthetics or

narcotics injected around the spinal cord, causing loss of sensation below

the level that the

medication is injected.

Intravenous Anesthetics

In ancient times orally administered extracts of poppy seeds (opium and

morphine), extracts of the

deadly night shade (hyoscene and belladonna), and extracts of fermentations

(alcohol) were used

for " anesthesia " . All of these drugs decrease consciousness and the

awareness of pain. At

present, most of these drugs or their modern counterparts are administered

intravenously.

Thiopental is a rapidly acting barbiturate used for induction (the first

part of anesthesia when the

awake patient is put to sleep) of anesthesia. Propofol and etomidate are new

rapidly acting

induction agents. epam (Valium) and midazolam (Versed) are drugs in the

benzodiazepine

category, which are potent hypnotics (induce a sleep-like state). Morphine,

meperidine (Demerol)

and fentanyl are examples of potent narcotic pain relievers (analgesics)

that are used as part of

some anesthetics.

Inhalation Anesthetics

The earliest modern inhalation anesthetics were the gas nitrous oxide (also

referred to as laughing

gas), and ether, a potent inhalational anesthetic. Potent inhalational

anesthetics are vapors

produced from a liquid that evaporates easily. Nitrous oxide is still a

basic in modern anesthesia;

however, the modern potent inhalational anesthetics include halothane,

enflurane, isoflurane,

sevoflurane, and desflurane. The potent inhalational anesthetic agents

provide all the modalities

of general anesthesia; which include unconsciousness, analgesia and mild

muscle relaxation.

Anesthesia and Mitochondrial Cytopathies

Cohen, Shoffner, DeBoer Page 2 ã UMDF

Muscle Relaxants

In addition to the drugs that induce the sleep-like state, a group of drugs

that provides muscle

relaxation are often part of a modern anesthetic. These drugs interfere with

the communication

between nerves and muscles, and induce a paralyzed state so that the patient

does not

unconsciously move during surgery. There are of two types of muscle

relaxants; the depolarizing

muscle relaxants (succinylcholine), which causes the patient's muscles to

move before paralysis

occurs and is relatively short acting, and the non-depolarizing muscle

relaxants which do not

cause such movements. When patients are paralyzed with these drugs, the

anesthesiologist or

anesthetist must breathe for the patient by either hooking the breathing

tube to a machine or

manually squeezing a " bag " often containing a mixture of oxygen, laughing

gas and a potent

inhalational anesthetic.

Issues of Anesthesia in Mitochondrial Cytopathies

Modern general anesthesia consists of induction with intravenous agent and

maintenance with

inhalational agents and/or with intravenous agents. Muscle relaxants may or

may not be used.

Concerns about the side effects and possible complications associated with

surgery and anesthesia

are shared by patients with mitochondrial cytopathies, their families and

their physicians.

The vast majority of patients with mitochondrial cytopathies have an

uneventful surgery and

anesthesia. Patients rarely experience a complication with a simple elective

surgical procedure

such as a muscle biopsy or gastrostomy tube placement. Patients with

preoperative respiratory

problems are at greater risk for worse problems after surgery. Similarly,

those with seizures may

experience post-operative seizures.

There are a limited number of reports describing adverse events and outcomes

in patients with

mitochondrial diseases following surgery and anesthesia. Our knowledge about

these potential

complications are based on these anecdotal reports. It is not possible to

draw conclusions about

the safety of a particular anesthetic agent based on the outcome of these

cases. Although it is

possible to test a particular anesthetic in a laboratory setting to see how

it affects mitochondrial

function, this work is based on animal experiments. How these animal studies

relate to humans in

a clinical (not laboratory) setting is impossible to determine. In reviewing

these reports, a number

of inferences can be made:

· Patients with mitochondrial cytopathies, on average, are " sicker " than the

unaffected patient

undergoing surgery and are having an operative procedure for potentially

more serious

reasons than the unaffected patient.

· As a general rule, patients with mitochondrial cytopathies are at greater

risk than unaffected

people for side effects of some medications. Although some medications may

interfere with

energy metabolism to some degree, complications are usually related to the

clinical condition

of the patient prior to surgery.

· The adverse events reported include new neurologic problems such a

strokes, worsening of

the overall neurologic status, respiratory difficulties, seizures, cardiac

arrhythmias, prolonged

coma and death.

Anesthesia and Mitochondrial Cytopathies

Cohen, Shoffner, DeBoer Page 3 ã UMDF

· Hypotonia (low muscle tone), bulbar dysfunction (weakness of the muscles

that protect the

airway) and relatively poor ventilatory function (decreased ability to

breathe deeply and

cough) are common in patients with mitochondrial diseases and pose an

increased risk for

perioperative pneumonia. In one study of patients with typical Leigh

syndrome (which

generally represents one of the more severe forms of mitochondrial

cytopathies), respiratory

difficulties prior to anesthesia and surgery were a predictor of

postoperative respiratory failure

and death. In the cases reported, the patients awakened from anesthesia but

deteriorated

within a day. There did not seem to be any specific anesthetic agent or

technique that

triggered these adverse events. It is not clear from this study whether the

deterioration was a

direct result of the surgical procedure, the anesthetic drugs, or as a

result of mitochondrial

failure due to inadequate oxygen, which resulted form an unrecognized

pneumonia or

respiratory failure. Understanding these factors may make anesthesia safer,

but will not avoid

all risks. (J Child Neurol 1990;5:137-41)

· Malignant Hyperthermia (MH) is a life threatening, inherited syndrome

triggered by potent

inhalational anesthetic agents and/or depolarizing muscle relaxants. It is

caused by abnormal

increases in muscle calcium concentrations leading to uncontrolled muscle

metabolism,

subsequent metabolic acidosis, muscle damage, and elevated potassium levels.

Without

treatment, MH will often result in death. Patients at risk for MH may

develop the disorder

with their first anesthetic, or may have a dozen or more anesthetics without

a problem, only to

develop MH with the next anesthetic. There are specific treatments available

for MH if it

should develop, but the best approach is to identify patients at risk and

use anesthetics that do

not trigger MH. Risk factors for MH include 1) prior MH episode in the

patient, 2) a family

history of MH and 3) muscle disease. Many patients with mitochondrial

cytopathies

sometimes have an associated myopathy (muscle disease), which places them at

a potential

risk for MH. There are anesthetics that are " safe " for those with or at risk

for MH, but these

anesthetics may adversely affect mitochondrial function in some patients.

· The risk of respiratory failure and worsening of neurologic function is

often noted in patients

with mitochondrial cytopathies after " stressful " illnesses, including

infections such as viral or

pneumonia. Infections may be associated with surgical procedures, either as

a complication of

surgery or as the need for surgery, as in the case of a ruptured appendix.

Infections, such as

the common cold, can also occur randomly around the time of surgery.

Certainly surgery

itself, even if for a non-emergency condition, is a major stress. The

following discussion is

quite complicated but necessary in order to understand that anesthetic drugs

alone should not

be considered the only element in leading to these adverse outcomes. During

infections, the

body responds by making chemicals known as cytokines. Cytokines help the

body fight

infection, and are also responsible for the fever, aches, chills and the

overall " rotten " feeling

we get when we are ill. Cytokines induce the formation of nitric oxide.

Nitric oxide (the

chemical formula is NO·) is a powerful oxidant with many useful purposes in

our bodies,

some of which seem quite unrelated, such as forming new memories and killing

bacteria.

However, nitric oxide inhibits cis-acotinase (a citric acid cycle enzyme)

and the ironcontaining

cytochromes of the respiratory chain. Therefore, NO· in high amounts may

decrease energy production, which is ill-afforded in patients who already

have an impaired

ability to generate energy. Nitric oxide can also interact with other

chemicals in the body that

result in damage to the mitochondrial DNA and mitochondrial structure

itself. One cytokine

Anesthesia and Mitochondrial Cytopathies

Cohen, Shoffner, DeBoer Page 4 ã UMDF

known as tumor necrosis factor (TNF), is known to be released by the body

during surgery,

and is also known to be a potent inhibitor of complex III. TNF has many

essential functions,

and serves as a natural defense against infections and cancer. In otherwise

healthy people, the

inhibitory effect on complex III is obviously not harmful, but may play some

role in people

with mitochondrial diseases, who are not able to tolerate any small

decrement in mitochondrial

function. Therefore, anesthetic agents may not be responsible, at least

without additional

factors, for causing neurologic deterioration. Both the stress of surgery as

well as any

associated infections may trigger the events leading to a deterioration in

susceptible patients.

(Anesthesiology 1997;87:420-5)

· Some patients have heart rhythm problems, such as those with Kearn-Sayres,

that are at risk

for severe heart electrical conduction blocks, which can lead to death.

Isoflurane may be a

preferred inhalational agent as opposed to Halothane, because Isoflurane

causes less

disturbances in heart rhythms. (Anesthesiology 1994;49:876-878)

· Although spinal anesthesia is safe, it should be used with extra caution

in patients with

neuropathies or myopathies, because of the possible deleterious effects on

blood pressure and

respiratory function.

Recommendations

There is no doubt that patients with mitochondrial disease can undergo

general anesthesia safely,

as demonstrated by untold thousands of uneventful surgeries and anesthetic

exposures. The

question that patients and their physicians wish to know is how to further

decrease the risk. The

following recommendations are made with the understanding that there are

little data suggesting

that any specific precautions can lower the risk of neurologic events.

However, these

recommendations seem to be prudent given what is known about the effects of

surgical stress,

infections and anesthetic agents in patients with mitochondrial cytopathies:

1. Strict attention should be made to respiratory function before, during

and after surgery,

especially in patients with abnormal preoperative respiratory signs and

symptoms. Vigorous

respiratory physiotherapy should be standard postoperative care in any

patient with pulmonary

difficulties. Early use of artificial ventilation, maintaining normal

oxygenation, CO2

elimination, and vigorous respiratory physiotherapy are recommended at the

first sign of

respiratory deterioration.

2. There should be a heightened level of suspicion for infections such as

pneumonia, which

should be promptly treated.

3. Lactated Ringer's solution (also known as Ringer's Lactate) should be

avoided as an

intravenous fluid, as it contains lactic acid.

4. Normal blood glucose, body temperature, and acid-base balance should be

maintained during

surgery. Low blood glucose should be avoided. However, a high blood glucose

may indicate

an acute disturbance in pyruvate metabolism or oxidative phosphorylation. In

this situation,

the lactic acid levels may also be elevated.

Anesthesia and Mitochondrial Cytopathies

Cohen, Shoffner, DeBoer Page 5 ã UMDF

5. Avoid depolarizing muscle relaxants, although these have been used safely

in many patients

with mitochondrial diseases. Anesthesiology 1979;51:343-345.

6. Delay elective surgery if there is any evidence of infection.

7. Potent inhalational anesthetic agents appear to be safe in the majority

of people with

mitochondrial diseases. In patients at risk for MH, such as those patients

with myopathies

that are often associated with their mitochondrial disease, the risks and

alternative methods of

anesthesia must be considered by the physician. Certainly if there has been

a previous adverse

reaction in the patient or family member, these agents should be avoided.

(Table 1)

8. Anesthesia with combinations of barbiturates, narcotics, benzodiazepines,

and nitrous oxide

also pose a theoretical risk for patients with disorders of oxidative

phosphorylation. (Table 2)

This risk should be considered only as a potential risk unless a patient has

experienced a bad

reaction to any of the medications. This apparent paradox between the two

methods of

general anesthesia must be addressed with each patient, and the

anesthesiologist must

determine what is the safest route.

9. Animal studies indicate that propofol, a new intravenous anesthetic,

impairs mitochondrial

function to a greater degree than other anesthetics. However, this drug has

been used safely

as an anesthetic in many patients with mitochondrial cytopathies. There have

been

observations that prolonged continuous use (days) at high dosages to treat

frequent seizures

causes a syndrome similar to mitochondrial failure, and therefore prolonged

use in a patient

with a mitochondrial cytopathy may not be safe.

Conclusion

An increased awareness is needed whenever a person with a mitochondrial

cytopathy is

contemplating or undergoing a surgical procedure. By virtue of the illness

itself, there are greater

risks involved with every medical intervention. The safest anesthetic is not

known and the choice

of anesthetic must be individualized to the patient's particular needs.

Although anesthetic agents

may play a contributing factor in causing an adverse event associated with

surgery, the illness, the

stress of that illness, the surgical procedure and concurrent infections may

play a larger role in

causing neurologic deterioration. With additional research, more will be

learned about these

problems.

See www.caringbridge.org/ia/mitomomof9 and www.heartbeatsformito.org to see

a photo look into what Mito looks like

Darla: mommy to

Asenath (5) Mito, CNS Vasculitis, strokes, migraines, seizures, G-tube,

hypotonicity, disautonomia, SID, global delays, asthma, cyclic vomiting,

bladder issues, wheelchair for distances, eye issues, autistic behaviors,

gastric emptying issues...

Zipporrah (17 months) Mito, strokes, neuro-motor planning dys., SID, GERD,

dysphasia, 100% G-tube fed, speech delays, extreme fatigue, excessive

phlegm, asthma, trach issues, aberrant subclavian artery, disautonomia,

hypertonicity, migraines, possible seizures, dumping syndrome, iron

deficiency...