Anesthesia in Patients With Mitochondrial Disease
Phase: NA
Conditions: Mitochondrial Diseases
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anesthesia in Patients with Mitochondrial Disease 
 
NCT02053766 
 
Version Date: 06/08/2018 
 
 

IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
 
The University of Texas McGovern Medical School 
Neurometabolic & Mitochondrial Center 
 
Clinical Research Protocol 
 
 
Title: 
Anesthesia in Patients with Mitochondrial Disease 
Investigational Drug(s): 
Sevoflurane, Propofol, Dexmedetomidine 
IND/EudraCT Number: 
Not Applicable 
Principle Investigator: 
Maria Matuszczak, MD 
Professor, Department of Anesthesiology 
Director, Pediatric Anesthesia 
 
Institution: 
The University of Texas McGovern Medical School 
Neurometabolic & Mitochondrial Center 
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IRB Number: 
HCS-MS-13-0600 
 
Date of Protocol: 
Version 1.0: 20-November-2013, IRB Approval 
 
Version 2.0: 19-April-2018, Pending IRB Approval 
Date of Amendment: 
19-April-2018 
 
Co- Principle Investigators: Mary Kay Koenig, MD 
Associate Professor, Department of Pediatrics 
Endowed Chair of Mitochondrial Medicine 
Division of Child & Adolescent Neurology 
Director, Neurometabolic and Mitochondrial 
Clinic 
Co-Director, Tuberous Sclerosis Center 

IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
Jael Carbajal, MD 
Assistant Professor, Department of Anesthesiology 
 
 
Rahmat Adejumo, MBBS, MPH 
Instructor in Pediatrics, Department of Pediatrics 
Division of Child & Adolescent Neurology 
 
 
Marc Rhoads, MD 
Professor, Department of Pediatrics 
Division of Gastroenterology 

IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
 
TABLE OF CONTENTS 
TITLE PAGE 
i 
TABLE OF CONTENTS 
ii 
LIST OF ABBREVIATIONS 
iii 
I. 
SUMMARY .......................................................................................................................................... 1 
II. 
BACKGROUND INFORMATION ..................................................................................................... 1 
A. MITOCHONDRIA ........................................................................................................................... 1 
B. 
MITOCHONDRIAL DISORDERS .................................................................................................. 2 
C. 
ANESTHETIC AGENTS ................................................................................................................. 3 
D. ANESTHESIA AND MITOCHONDRIAL DYSFUNCTION ......................................................... 6 
III. 
PRELIMINARY DATA ................................................................................................................... 8 
IV. 
STUDY OBJECTIVES ..................................................................................................................... 9 
V. 
STUDY DESIGN ................................................................................................................................. 9 
A. SELECTION AND WITHDRAWAL OF SUBJECTS .................................................................... 9 
B. 
STUDY GROUPS........................................................................................................................... 11 
C. 
EVALUATIONS AND ASSESSMENTS ...................................................................................... 13 
D. ADVERSE EVENTS ...................................................................................................................... 15 
E. 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS ......................... 15 
F. 
POWER AND SAMPLE SIZE CALCULATION .......................................................................... 16 
G. DATA ANALYSIS ......................................................................................................................... 16 
VI. 
RISKS ............................................................................................................................................. 16 
VII. 
BENEFITS ...................................................................................................................................... 17 
VIII. 
ETHICS........................................................................................................................................... 18 
IX. 
APPENDIX ..................................................................................................................................... 20 
FIGURES AND TABLES .............................................................................................................. 20 
REFERENCES ............................................................................................................................... 25 

IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
LIST OF ABBREVIATIONS 
 
 
ATP 
Adenosine Triphosphate 
DNA 
Deoxyribonucleic Acid 
FADH2 
Flavine Adenine Dinucleotide 
mtDNA 
Mitochondrial DNA 
NADH 
Nicotinomide Adenine Dinucleotide 
nDNA 
Nuclear DNA 
RNA 
Ribonucleic Acid 
rRNA 
Ribosomal RNA 
tRNA 
Transfer RNA 
VA 
Volatile agents 
EC50 
Half Maximal Effective Concentration 
PRIS 
Propofol infusion syndrome 
MAC 
Monitored Anesthesia Care 
CNS 
Central Nervous System 

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I. 
SUMMARY 
 
This pilot study is a prospective, randomized clinical trial to evaluate the effect of 
anesthesia in the mitochondrial dysfunction patient. Subjects undergoing a routine 
medical care non-emergent procedure will be randomized into three different groups to 
receive one of the following anesthetic agents; Sevoflurane, Propofol or 
Dexmedetomidine. 
 
The primary outcome of this pilot study is to evaluate and compare the incidence of 
adverse events in mitochondrial patients undergoing a diagnostic or therapeutic procedure 
up to 48 hours post anesthesia. The secondary outcome is to compare the metabolic 
derangements between three study groups by comparing changes in blood sugar, serum 
pH, serum bicarbonate, serum lactate and serum pyruvate levels before, during and after 
anesthesia in the groups. 
 
 
II. 
BACKGROUND INFORMATION 
INTRODUCTION 
A. 
MITOCHONDRIA 
 
Mitochondria are membrane bound organelles found inside most eukaryotic cells. 
Mitochondria provide cells with an advanced system for energy production, i.e., 
oxidative phosphorylation. Oxidative phosphorylation is the process in which 
ATP is formed as a result of the transfer of electrons from NADH or FADH2 to 
oxygen by a series of electron carriers, i.e., the electron transport chain. The 
process of oxidative phosphorylation is the major source of ATP in aerobic 
organisms. Other intra-mitochondrial processes include the Krebs cycle, beta- 
oxidation and urea cycle. In addition to producing cellular energy, mitochondria 
are involved in cell signaling, cell differentiation, cell death, and control of the 
cell cycle and growth. In the absence of oxygen, pyruvate formed from glycolysis 
is converted to lactate or alanine producing only a small source of ATP 

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Mitochondria contain their own DNA with 16,569 base pairs. The mtDNA codes 
for 37 proteins, including specific subunits for several complexes of the electron 
transport chain (ETC), ribosomal RNA (rRNA), and transfer RNA (tRNA) 
(Figure 1). A defect in any of these genes can produce clinical disease. About 
1100 other gene products within the organelle are encoded by genes within the 
nuclear genome [1, 2] and they follow the classical Mendelian inheritance 
patterns [3]. Nuclear DNA (nDNA) contains genes involved in mitochondrial 
function that code for the remainder of the specific complex subunits. Mutations 
in either mtDNA or nDNA can result in a deficit of a specific electron transport 
chain complex or can give rise to global mitochondrial dysfunction via signaling, 
transcription, or translation. 
Cells and tissues can have both normal and mutant mtDNA. The state of having 
more than one type of mtDNA within a given cell is termed “heteroplasmy” [3] 
(Figure 2). If only some of the inherited mitochondria contain mutant mtDNA, 
there could be an uneven distribution into tissues, with varied thresholds for 
displaying a physiologic defect. This could result in different offspring from a 
single mother demonstrating strong variation in phenotype despite being 
genetically similar [3]. 
 
B. 
MITOCHONDRIAL DISORDERS 
 
Mitochondrial disorders are a heterogeneous group of clinical diseases resulting 
from dysfunction of the mitochondria. They occur as a result of pathogenic 
defects in the mtDNA and nuclear DNA that code for specific complex subunits 
involved in mitochondrial function. Initially described as a rare disease, Elliot et 
al. reported the prevalence of pathogenic mitochondrial DNA mutations to be at 
least 1 in 200 people(4), and the incidence of respiratory chain disorders have 
been estimated to be within range of other well-known neurologic diseases [5, 6]. 
The study of mitochondrial disease however remains in infancy [5, 6]. 
The first disorder of mitochondrial function was described in 1959 by Luft [7]. It 
was in a young woman with generalized weakness, inability to gain weight, and 

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extensive perspiration. Her muscle pathology demonstrated large accumulations 
of variable sized mitochondria containing paracrystalline inclusions [7]. Over 
time, many cases of mitochondrial dysfunction were described and the term 
“mitochondrial disorder” arose to describe defects in the mitochondrial electron 
transport chain [8]. The sequence and organization of the human mitochondrial 
genome was first defined by Anderson in 1981[9]. By 1989 Holt had described 
the first deletion in the mitochondrial genome associated with clinical pathology 
[10]. 
Patients with mitochondrial dysfunction, most of which are children, typically 
have multi-systemic, multi-organ involvement, with the organs requiring more 
energy being mostly affected. Mitochondrial disease is now well recognized as an 
important cause of neurologic, muscular, cardiac, endocrine, hepatic, and renal 
disorders [11]. Diagnosis of mitochondrial disorders has remained difficult due to 
the wide range of clinical presentation these patients may have. Traditionally 
patients have been diagnosed using the modified Walker criteria that classify 
patients into either a “Definite” or a “Probable” category based on major and 
minor clinical and histopathological findings. More recently, advanced 
technologies in molecular studies have enabled definite genetic diagnosis of 
pathogenic mtDNA and nDNA mutations. 
 
C. 
ANESTHETIC AGENTS 
 
1. 
SEVOFLURANE 
 
Sevoflurane is a volatile halogenated general inhalation anesthetic drug 
used for induction and maintenance of general anesthesia. It is a 
nonflammable liquid administered by vaporization. 
Volatile agents (VA) promote extensive neuro-apoptosis by promoting the 
release of intracellular calcium from the endoplasmic reticulum. This 
increase in calcium load results in loss of mitochondrial integrity, release 
of pro-apoptotic factors, impairment of ATP synthesis, and enhanced 
accumulation of reactive oxygen species [11]. Sevoflurane like other VAs 

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in use currently is capable of interacting negatively with a mitochondrial 
myopathy [3]. 
 
Studies have consistently shown Complex I to be most sensitive to 
inhibition by VAs [12-15]. Complex I inhibition have been demonstrated 
with VA concentrations that range from 1 to 2 times the EC50 of an 
organism. Other components of the ETC are affected with increasing 
concentrations of VAs [3]. 
 
Niezgoda et al noted that “as VAs exert much of their effects in high- 
energy tissues; it is possible that patients with mitochondrial disease may 
have an abnormal sensitivity to VAs” [3]. All of the volatile anesthetics 
depress respiration to varying degrees [16]. More direct muscle relaxation, 
although with small differences, is seen in Sevoflurane than other VAs 
[17, 18]. Currently used volatile anesthetics are exhaled and do not require 
metabolism for excretion, an advantage over intravenous anesthetics, 
which are dependent on energy-requiring metabolism [3]. This to an 
extent lowers the risk from exposure to Sevoflurane in comparison to 
intravenous agents for mitochondrial disease patients [19, 20]. 
 
2. 
PROPOFOL 
 
Propofol is a short-acting, intravenous sedative-hypnotic agent used for 
induction and maintenance of anesthesia or sedation. It has its primary 
effects on ligand-gated ion channels or G-protein-coupled receptors 
similar to other parenteral sedatives [3]. Its excretion is metabolism 
dependent. Propofol has many of the same side effects as volatile 
anesthetics, with the exception of muscle relaxation [3]. It is however 
capable of decreasing ventilatory drive, cardiac output and contractility 
[3]. 

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Propofol inhibits complex I and IV functions, as well as carnitine transport 
of fatty acids into the mitochondria blocking beta-oxidation. It also 
uncouples the electron transport chain, preventing ATP synthesis and 
generating free radicals [21-25]. 
Propofol infusion syndrome (PRIS) is a serious reaction in patients 
receiving long-term infusions. The syndrome comprises of severe lactic 
acidosis, liver and renal failure, rhabdomyolysis, hyperlipidemia and 
refractory bradycardia which can lead to, cardiovascular collapse and 
death [3, 26]. PRIS is assumed to occur from long-chain acylcarnitine 
esters transport inhibition coupled with an indirect effect on complexes I 
and II [26, 27]. Risk factors for developing PRIS include; young age, high 
dose of propofol, prolonged duration of propofol administration, 
underlying, neurologic disorder and concomitant steroid infusion [3]. 
As of 2007, 61 cases had been reported in the literature, with 62% 
mortality (20 children & 18 adults. Although generally thought to only 
occur during prolonged propofol administration, 7 (11%) of these patients 
developed PRIS during routine anesthesia [19]. Two independent clinical 
reports have documented mitochondrial dysfunction during PRIS [28, 29]. 
Several authors have proposed that patients who develop PRIS actually 
have undiagnosed mitochondrial disease and recommend that all patients 
who develop PRIS should be screened for mitochondrial dysfunction [28]. 
 
3. 
DEXMEDETOMIDINE (PRECEDEX®) 
 
Dexmedetomidine is a centrally acting α-2 receptor agonist with an 
unusual ability to provide sedation without causing respiratory depression 
[30-32]. It has an analgesic-sparing effect, thereby reducing opioid 
requirements during and after surgery [33-38] and a sympatholytic effect 
that can reduce the stress response to surgery such as tachycardia and 
hypertension [34, 37]. It is increasingly being used as a sedative for 
Monitored Anesthesia Care (MAC) because of the advantage it has over 

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other drugs such as midazolam, propofol, and fentanyl, all of which cause 
respiratory depression [39, 40]. There have been several reports on its 
successful use as the primary sedative drug for diagnostic and therapeutic 
procedures [37, 38, 41-44]. Reported adverse effects with 
Dexmedetomidine infusion include bradycardia, sinus arrest and 
hypotension [45]. 
A randomized, multicenter, double-blind, Phase III study evaluating the 
safety and efficacy of Dexmedetomidine in patients requiring MAC 
showed it had an effective baseline sedation with less opioid requirements, 
and less respiratory depression than placebo rescued with midazolam and 
fentanyl [45]. However, there is no data in the literature currently on its 
safety in myopathic and mitochondrial patients. 
 
D. 
ANESTHESIA AND MITOCHONDRIAL DYSFUNCTION 
 
Patients with mitochondrial disorders often present to the radiology suite and 
operating room for diagnostic and therapeutic - elective and emergent - 
procedures that require general anesthesia. The vast majority of them have an 
uneventful surgery and anesthesia course [46]. There are reports however of 
profound and unexpected complications occurring during and following 
anesthetic exposure, some of which have been fatal [47-49]. 
As with many disorders of metabolism, children with mitochondrial disease are at 
risk of metabolic decompensation. This risk increases during times of stress, such 
as with an inter-current illnesses, reduced oral intake or fasting, and surgery. A 
mitochondrial crisis occurs when multiple organs and physiologic systems begin 
failing. It can be precipitated by a minor illness, metabolic stressor or exposure 
that tips the patient over their baseline threshold, and develops hours or weeks 
following the insult. 
Prolonged respiratory depression and Central Nervous System (CNS) white 
matter degeneration have been reported in patients seemingly only mildly affected 
preoperatively with relatively uneventful anesthetic courses during surgery [47- 

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49]. Respiratory depression can occur as a result of muscle weakness seen in any 
myopathic state, as well as from the combination of anesthetics [3]. It is well 
documented that mitochondrial patients may face an increased risk in the 
operating room from a combination of both surgical stress and anesthetic 
exposure [50-52]. General anesthetic agents could tip a patient past their threshold 
resulting in decompensation hours or days post-operatively. 
Volatile anesthetics and propofol have been shown to depress mitochondrial 
function in vitro. Several reports have shown that exposure to general anesthetics 
at critical stages of brain development can cause neurotoxicity to immature 
neurons [53]. Other authors have reported the safe use of different anesthetic 
drugs and approach in mitochondrial patients [19, 54]. Based on these reports, an 
author has suggested that “patients with myopathies and mitochondrial disease 
usually do well regardless of the specific anesthetic approach that is chosen” [46]. 
As Niezgoda et al. stated; it would be unwise to infer that an anesthetic agent or 
approach used safely with one mitochondrial dysfunction patient would be 
equally safe in all other patients with mitochondrial disease, or even in siblings 
with similar genetic mutations because of heteroplasmic variations that typically 
occur in cells and tissues [3]. 
With the limited data available on the effects of anesthesia in mitochondrial 
disease, current recommendations are based on the biochemical understanding of 
mitochondrial function and in vitro knowledge regarding anesthetic agents [3, 55- 
57]. 
Mitochondrial patients may be more susceptible to Propofol Infusion Syndrome 
and avoidance of propofol use has been recommended when possible. 
Mitochondrial patients may also have underlying myopathy, sub-clinical or 
undiagnosed cardiac disease (cardiomyopathy or arrhythmia) making them more 
sensitive to neuromuscular blockage. These patients may also not be able to 
tolerate the lactate load from lactated fluids. Fasting periods should be minimized, 
with dextrose-containing fluids administered pre-operatively except in cases 
where ketogenic diet is indicated. 

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III. 
PRELIMINARY DATA 
 
There are no prospective studies assessing the use and effects of anesthetic agents in 
mitochondrial patients. There are several case reports, case series, and review articles 
describing the use of various anesthetic agents (presented in Table 1). These reports have 
shown contradictory and inconclusive findings on the effect of general anesthesia in 
patients with mitochondrial dysfunction. While some have reported profound clinical 
complications including death, others have reported their safe use. It is important to note 
that the absence of published reports of adverse effects with a given agent does not 
confirm that the agent is safe; it may instead simply reflect a publication or sampling bias 
Other limitations of these reports include their small sample size and study design. Most 
of the reports do not extend beyond the immediate operative period and therefore would 
miss a mitochondrial crisis that occurs hours to days following anesthesia administration. 
They have also not been able to adequately measure the incidence, nor characterize the 
peri-operative complications in patients with mitochondrial dysfunction. All of which has 
created an information gap in the peri-operative management of mitochondrial disease 
patient with regards to anesthesia. 
There is a general consensus among anesthesiologists that this patient population is at an 
increased risk of peri-operative complications from both anesthetic and surgical stress [3, 
47-50, 55, 56, 58]; including but not limited to respiratory failure, cardiac depression, 
conduction defects and dysphagia. Results from a national survey of pediatric 
anesthesiologists in the United States done by Rafique MB et al. to investigate their 
current practice in regards to anesthesia in mitochondrial patients is presented in Table 2 
[59]. Table 3 shows the results of a survey of the clinical directors of the recognized 
mitochondrial centers in the United States and Canada done by the mitochondrial 
medicine society of mitochondrial disease specialists to determine practices for clinical 
care of patients with mitochondrial disease pertaining to anesthesia [60]. 

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IV. 
STUDY OBJECTIVES 
 
1. The primary outcome of this pilot study is to evaluate and compare the incidence of 
adverse events in mitochondrial patients undergoing a diagnostic or therapeutic 
procedure up to 48 hours post anesthesia. 
2. The secondary outcome is to compare the metabolic derangements between three 
study groups by comparing changes in blood sugar, serum pH, serum bicarbonate, 
serum lactate and serum pyruvate levels before, during and after anesthesia in the 
groups. 
 
V. 
STUDY DESIGN 
 
A. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
1. 
STUDY SUBJECT RECRUITMENT 
 
Institutional approval and written informed consent from parents/ legal 
guardians of children 0- 17 years of age with definitive, probable or 
suspected diagnosis of mitochondrial disease (Walker’s criteria) will be 
obtained. Subjects 0-17 years, both genders, scheduled for diagnostic or 
therapeutic procedure requiring general anesthesia that is estimated to last 
for at least one hour will be included in the study. Minor assent will be 
obtained from children 7 – 17 years. Pregnant females, nursing females 
and subjects who have participated in the same study within 48 hours will 
be excluded. This pilot study is a prospective, randomized clinical trial 
and we need permission from CPHS to enroll 60 patients. We need 
permission to approach 100 families considering screen failures, study 
withdrawals and drop outs. Copies of a flyer with explanation of the study 
will be provided at the office of pediatric neurologist at UT Mitochondrial 
clinic, surgeons at UT professional building, pediatric floors at MHH and 
anesthesia clinic. We will communicate with the nurses’ of the above 
mentioned offices and ask them to give the flyer to the parents, and 
adolescents. The flyer will be sent to the IRB for review and approval. 

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The PI, Co PI and the research coordinator will invite parents of children, 
and adolescents with mitochondrial disease in the pediatric neurology 
clinic, in the DSU, anesthesia clinic and floor to participate in the study. 
Ample time will be given to read the consent forms and ask questions 
about the study. HIPPA consent will also be obtained. 
 
2. 
INCLUSION OF WOMEN & MINORITIES 
 
Female subjects and minorities will be enrolled in the study based on the 
inclusion/exclusion criteria described below. 
 
3. 
INCLUSION OF CHILDREN 
 
Children up to 17 years of age will be included in the study based on the 
inclusion/exclusion criteria described below. 
. 
4. 
INCLUSION CRITERIA 
 
Subjects must fulfill the following inclusion criteria: 
a. Subject is informed and given ample opportunity to consider his/her 
participation and has given his/her written consent. 
b. Subject is willing and able to comply with all study requirements. 
c. Subject is between 0 - 17 years of age. 
d. Subject has been diagnosed with mitochondrial dysfunction based on 
modified Walker criteria. 
e. Subject is scheduled to have a non-emergent diagnostic or therapeutic 
procedure for routine medical care requiring general anesthesia. 
estimated to last at least one hour. 
f. Subject is classified ASA I - IV 

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5. 
EXCLUSION CRITERIA 
 
Subjects are not permitted to enroll in the study if any of the following 
criteria are met: 
a. Subject is older than 17 years 
b. Subject is pregnant 
c. Subject is a nursing female and 
d. Subject has participated in the same study within 48 hours 
e. Subject is allergic or has had any adverse effect to any of the study 
agents in the past 
f. Anesthesia time is less than one hour 
g.f. Subject is classified ASA V 
 
 
6. 
CRITERIA FOR WITHDRAWAL 
 
Participation in this study may be discontinued for any of the reasons 
listed below. 
• The subject is unwilling or unable to continue and withdraws his/her 
consent. 
 
B. 
STUDY GROUPS 
 
Consented subjects will be randomized in to three study groups using a computer 
generated randomization list. 
 
1. 
STUDY GROUP I -SEVOFLURANE 
 
These subjects will receive Sevoflurane gas. 
In the Operating Room (OR) after applying routine monitors, anesthesia 
will be induced with a mask using Sevoflurane up to 8%. Sevoflurane will 
be used for maintenance for the rest of the procedure with dosage between 
1.5% and 4%. Vitals will be monitored. Fentanyl will be used as needed. 

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Rocuranium will be used as needed for muscle relaxation. At the end of 
the procedure twitches will be evaluated and muscle relaxation will be 
reversed. Sevoflurane will be turned off at the end of procedure. 
 
2. 
STUDY GROUP 2 – DEXMEDETOMIDINE (PRECEDEX®) 
 
These subjects will receive Dexmedetomidine intravenously. 
In the OR routine monitors will be placed. Vitals will be monitored. A 
loading dose of Precedex 1mcg/ kg will be given over 10 minutes. 
Infusion will be started using Precedex 1mcg/ kg/ hr and can be increased 
or decreased as needed. Fentanyl will be used as needed. Rocuranium will 
be used as needed for muscle relaxation. At the end of the procedure 
twitches will be evaluated and muscle relaxation will be reversed. 
Precedex infusion will be stopped at the end of the procedure. 
 
 
3. 
STUDY GROUP 3 – PROPOFOL 
 
These subjects will receive propofol for anesthesia maintenance. 
In the OR routine monitors will be placed. Vitals will be monitored. A 
loading dose of Propofol 2mg/ kg will be given over 2 minutes. Infusion 
will be started using Propofol 50 mcg/ kg/min and can be increased or 
decreased as needed (range 50-300mcg/kg/min). Fentanyl will be used as 
needed. Rocuranium will be used as needed for muscle relaxation. At the 
end of the procedure twitches will be evaluated and muscle relaxation will 
be reversed. Propofol infusion will be stopped at the end of the procedure. 
 
4. 
ALL STUDY GROUPS 
 
As a standard for all patients with mitochondrial disease every study 
subject will have IV access placed prior to induction. All subjects without 
IV line will have 1-2 lignocaine patches before premedication. All 
subjects will receive po midazolam 15 minutes before IV placement. If 

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midazolam is contraindicated, then premedication will be administered at 
the discretion of the anesthesiologist. All subjects will receive regional 
anesthesia as indicated per standard of care. All groups will receive 
normal saline (NS) infusion at the rate of 10 ml/kg/hr to maintain 
normovolemia. If needed 5% dextrose with NS not to exceed 10ml/kg/hr 
will be given to maintain normoglycemia. In open abdominal procedures 
fluid may be increased or decreased as required. 
 
C. 
EVALUATIONS AND ASSESSMENTS 
 
1. 
PREOPERATIVE: 
 
Before the induction of anesthesia, after midazolam is given, and IV 
access has been established, baseline blood glucose, serum lactate and 
serum pyruvate, serum bicarbonate and pH will be obtained 
 
2. 
INTRAOPERATIVE: 
 
Blood glucose, serum lactate and serum pyruvate, serum bicarbonate and 
pH will be obtained 1 hour15 minutes after start of anesthesia. These 
parameters will be repeated every hour till the end of anesthesia. 
Blood glucose, serum lactate and serum pyruvate, serum bicarbonate and 
pH will be obtained 30 minutes after the end of anesthesia. 
 
3. 
POST OPERATIVE: 
 
a) 
12 hours follow up post anesthesia 
 
• Blood glucose, serum lactate and serum pyruvate, serum 
bicarbonate and pH will be obtained 6 hours after end of 
anesthesia if patient is in house or next morning at the UT 
Mitochondrial Clinic if discharged. 

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• Admitted patient: The patient will be monitored up to 12h 
after end of anesthesia by an independent blinded observer for 
feeding difficulties, temperature >100 F, tachycardia, vomiting, 
nausea, lethargy, change in admission plan and any other 
change in baseline as per parent. The parents will be blinded to 
the anesthetic procedure. If any adverse events occur the 
treating physicians will follow the standard of care and the 
investigators will be notified. 
 
• Discharged patient: The patient will be monitored by the 
parent every 4 h for feeding difficulties, temperature >100 F, 
tachycardia, vomiting, nausea, lethargy, any other change in 
baseline. The patient will be seen the next morning at the UT 
Mitochondrial clinic by the blinded pediatric neurologist and 
reevaluated for feeding difficulties, temperature >100 F, 
tachycardia, vomiting, nausea, lethargy, hospital readmission/ 
ER visit and any other change in baseline as per parent. The 
parents will be blinded to the anesthetic procedure. 
 
b) 
48 hours follow up post anesthesia 
 
• For in-patients the child will be followed from 48 hours post 
anesthesia by the independent blinded observer and the 
blinded pediatric neurologist for feeding difficulties, 
temperature >100 F, vomiting, nausea, lethargy, change in 
admission plan and any other change in baseline as per parent. 
Blood glucose, serum lactate and serum pyruvate, serum 
bicarbonate and pH will be also obtained 
• If patient is discharged then the independent observer will 
follow up for the above mentioned parameters. Blood glucose, 
serum lactate and serum pyruvate, serum bicarbonate and pH 

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will be obtained 48 hours after end of anesthesia if patient is in 
house or 2nd post-operative day at the UT Mitochondrial Clinic 
if discharged. 
 
D. 
ADVERSE EVENTS 
 
An adverse event (AE) is any untoward medical occurrence in a subject, 
compared with pre-existing condition that occurs during any phase of the research 
study. An AE is defined as being independent of assumption of any causality. 
The following laboratory values and physical findings are to be considered AEs: 
 
 
a. Laboratory value(s) that change from a subject’s baseline by greater than 10% 
and is outside the normal range. 
b. Any of the following parameters; feeding difficulties, temperature >100 F, 
vomiting, nausea, lethargy, change in admission plan and any other change in 
baseline that are clinically relevant. 
 
E. 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE 
EVENTS 
 
All problems having to do with subject safety must be documented and reported 
to the investigators (Dr. Maria Matuszczak, |||||||||||||||||||||||||| 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||; Dr. Mary Kay Koenig, |||||||||||||||||||||||||||||||||| 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||; Dr. Jael Carbajal, 713-500-6200, 
Jael.G.Carbajal@uth.tmc.edu). Specifically the following must be reported: 
 
a. All serious adverse events associated with the study procedures. 
b. All deaths, whether or not they are directly related to study procedures. 
c. Any incidents or problems involving the conduct of the study or subject. 
 
 
If a subject is develops an adverse event, the subject will be followed as 
frequently as necessary until resolution of the event or for as long as the 
investigators deem necessary. 

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IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
 
F. 
POWER AND SAMPLE SIZE CALCULATION 
 
Since the current study is a pilot study, 60 patients will be enrolled and 
randomized to Sevoflurane, Propofol and Dexmedetomidine in a 1:1:1 ratio using 
a block randomization with block size of 6 (20 patients per group). 
 
G. 
DATA ANALYSIS 
 
All statistical analyses will be performed in SAS 9.3 (Cary, NC). Descriptive 
statistics; mean (± standard deviation) for continuous variables and frequency 
(percent) for discrete variables, will be summarized for all study variables. Before 
performing any analysis, the distribution of all variables will be examined for 
appropriateness of distribution assumptions. Extreme values and influential data 
points will be carefully examined for accuracy. The primary endpoint is to 
evaluate and compare the incidence of adverse events up to 48 hours post 
anesthesia. Intention to treat principle will be applied for the primary analysis. A 
binomial confidence interval approach will be used to estimate the incidence rate 
of adverse events as well as 95% confidence interval for each group. To compare 
the incidence rate with a pre-specified safety cutoff, 0.10, a binomial test will be 
applied. Secondary analysis of the primary outcome will include an unadjusted 
analysis using an extension of Fisher’s exact test and covariate adjusted analysis 
through logistic regression, evaluating potential confounding variables. The 
exploratory analysis for the secondary outcome include comparison the metabolic 
derangements between three groups. Analysis of variance method will be 
performed to compare the changes in blood sugar, serum PH, serum bicarbonate, 
serum lactate and serum pyruvate levels before and after anesthesia. Data will be 
sub-analyzed in three categories based on the duration of exposure to anesthesia. 
The categories will consist of: (a) Total anesthesia time is 30 minutes or less; (b) 
total anesthesia time is more than 30 minutes but less than one hour; and (c) total 
anesthesia time is up to an hour or more.  

17 
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VI. 
RISKS 
 
Study participants are not subjected to any additional risks other than those that are 
associated with receiving general anesthesia for routine medical care, including but not 

18 
IRB NUMBER: HSC-MS-13-0600 
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limited to an increased risk of metabolic decompensation in children with mitochondrial 
disease. 
 
VII. 
BENEFITS 
 
A. 
STUDY SUBJECTS 
 
Study subjects are not able to directly benefit from participating in the study. 
 
 
B. 
MITOCHONDRIAL DISORDER COMMUNITY 
 
Study findings may provide knowledge on the comparative safety amongst 
different anesthetic agents and approach for patients with mitochondrial 
dysfunction. 
It will also add to the body of knowledge on the effects of anesthetic agents in 
mitochondrial disease. 

19 
IRB NUMBER: HSC-MS-13-0600 
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VIII. ETHICS 
 
A. 
INFORMED CONSENT 
 
Institutional approval and written informed consent from parents/legal guardians 
of children 0 - 17 years of age with definitive, probable or suspected diagnosis of 
mitochondrial disease (Walker’s criteria) will be obtained. Subjects 0-17 years, 
both genders, scheduled for diagnostic or therapeutic procedure requiring general 
anesthesia will be included in the study. Minor assent will be obtained from 
children 7-17 years. 
Subject’s informed consent will be obtained and documented in accordance with 
local regulations and the ethical principles that have their origin in the Declaration 
of Helsinki. Prior to obtaining informed consent, information will be given in a 
language and at a level of complexity understandable to the subject in both oral 
and written form by the investigator. Each subject will have the opportunity to 
discuss the study and its alternatives with the investigator. 
 
Prior to participation in the study, the written informed consent form will be 
signed and dated by the subject, and/or his/her legal guardian, and by the person 
who conducted the informed consent discussion (investigator or designee). The 
subject and/or his/her legal guardian will receive a copy of the signed and dated 
informed consent form. 
 
For minors and cognitively disabled subjects, assent will be obtained from the 
subject in addition to consent from the legal guardian. 

20 
IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
B. 
INTERNAL REVIEW BOARD 
 
The study will be conducted under the auspices of the University of Texas Health 
Science Center Houston CPHS and in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki. Before initiating the study, the 
investigator will have written and dated full approval from the CPHS for the 
protocol. 
 
The investigator will promptly report to the CPHS all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any 
protocol deviations to eliminate immediate hazards to subjects. 
 
C. 
SUBJECT PRIVACY 
 
Study investigators will affirm and uphold each subject’s confidentiality. Every 
effort to maintain confidentiality will be taken. Upon enrollment subjects will be 
assigned a subject identification (ID) number. Files matching subject name with 
the subject ID number will be kept in the office of the PI (limited access) in a 
locked file, as well as in a spread sheet on the computer of the PI. Subjects will 
not be personally identified in any reports or publications that may result from 
this study. Information identifying subjects will not appear on records viewed by 
anyone other than study personnel. Names will not appear on any of the 
summaries or statistical analyses. 

21 
IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
APPENDIX 
 
FIGURES AND TABLES 
 
 
 
Figure 1. Human Mitochondrial DNA. 

22 
IRB NUMBER: HSC-MS-13-0600 
IRB APPROVAL DATE: 0161/0280/20183 
 
 
 

 
 
Table 1: Classification of case reports and series on inhaled and intravenous anesthetic agents for patients with mitochondrial dysfunction into safe and unsafe 
categories 
 
Volatile agents - Sevoflurane 
Intravenous agents - propofol 
Iv - ketamine 
Muscle relaxants - rocuronium 
Case series (multiple agents) 
Safe 
Unsafe 
Safe 
Unsafe 
Safe 
Unsafe 
Safe 
Unsafe 
Burns AM and MP . 
Casta A, EJ Quackenbush, CS 
Thompson VA and JA . 
Anesthetic considerations in 
patients presenting with 
MELAS syndrome. 
Anesthesia and Analgesia 
1997;85:1404-1406. Single 
case report; Propofol 
induction and maintenance; 
No complications 
Cheam EWS and LAH 
. Anesthesia for a 
child with complex I 
respiratory chain enzyme 
deficiency. Journal of clinical 
anesthesia 1998;10:524- 
527. Single case. Propofol for 
induction and maintenance; 
No complications 
Sasano N, Y Fujita, MH So, K 
Sobue, H Sasano, and H 
. Anesthestic 
management of a patient 
with MELAS during 
laparotomy. Journal of 
Anesthesia 2007;21:72-75. 
Single report; Propofol 
induction and maintenance; 
Lactated Ringers; No 
complications 
Vanlander AV, PG Jorens, J 
Smet, B De Paepe, W 
Verbrugghe, GG Van Den 
Eynden, F Meire, P Pauwels, N 
Van der Aa, S Seneca, W 
Lissens, JG Okun, and R Van 
. Inborn ox phos defect 
as risk factor for propofol 
infusion syndrome. Acta 
Anaesthesiologica 
Scandinavica 2012;56:520- 
525. Single case of patient 
with LHON developing PRIS; 
Long-term propofol use 
following TBI (>88 hours) 
Mehta N, DeMunter C, Habibi 
P, Nadel S, and J 
. 
Short-term propofol infusion in 
children. The Lancet 
1999;354:866-867. Single 
case; Propofol induction and 
maintenance 
Developed severe metabolic 
decompensation; Found to 
have Complex IV deficient 
mitochondrial disease 
Z Shenkman, I Krichevski, 
Finsterer J, U Stratil, R Bittner, 
Driessen J, S Willems, S 
Dercksen, J Giele, F Van 
der Staak, and J 
. Anesthesia- 
related morbidity and 
mortability after surgery 
for muscle biopsy in 
children with 
mitochondrial defects. 
Pediatric Anesthesia 
2007;17:16-21. 
Retrospective review of 
122 muscle biopsies in 
patients with 
mitochondrial disease 
Induction: propofol, 
thiopental, sevoflurane, 
halothane 
Maintenance – propofol, 
sevoflurane, isoflurane, 
halothane; No 
complications; Mean 
duration of procedure 
was 36 minutes 
Footitt EJ, MD Sinha, JAJ 
Raiman, A Dhawan, S 
Moganasundram, and MP 
. Mitochondrial 
disorders and general 
anesthesia: a case series and 
review. British journal of 
anesthesia 2008;100:436-441. 
Retrospective review of 58 cases 
of anesthesia in 38 patients with 
mitochondrial disease 
Did not specify agents used; 
There were no adverse events 
during the anesthesia but post- 
operatively there was one 
metabolic decompensation and 
one patient who developed acute 
renal failure (3%); Both cases 
used propofol for induction; one 
used sevoflurane and one used 
isoflurane for maintenance 
Gurrieri C, JE Kivela, K Bojanic, 
RH Gavrilova, RP Flick, J Sprung, 
and TN 
(70). 
Anesthetic considerations in 
MELAS: a case series. Canadian 
Journal of Anesthesia 
2011;58:751-763. 
Retrospective review of 20 cases 
of anesthesia in 9 patients with 
MELAS; Did not specify agents 
used; There were no adverse 
events during the anesthesia but 
post-operatively there were two 
cases of acute renal failure 
(10%) 
Anaesthesia for patients with 
Houch, and MS 
. 
ON Elpeleg, A Joseph, and A 
and P 
. Increased 
mitochondrial myopathy. 
Perioperative white matter 
. Anaesthetic 
sensitivity to rocuronium and 
Anaesthesia 1989;44:975- 
degeneration and death in a 
management of a patient 
atracurium in mitochondrial 
977. 
patient with a defect in 
with Leigh’s syndrome. 
myopathy. Canadian Journal of 
Single case; Thiopentone 
mitochondrial oxidative 
Canadian Journal of 
Anesthesiology 1998;45:781-784. 
induction; Nitrous oxide & 
phosphorylation. Anesthesiology 
Anesthesiology 
Single case report; Propofol 
Isoflurane maintenance; No 
1997;87:420-425. Single case; 
1997;44:1091-1095. Single 
induction and maintanence 
complications 
Thiopental induction; Isoflurane 
report; Ketamine induction 
Increased sensitivity to 
Pvalizza EG, KJ Ando, and 
MS . Kearns-Sayre 
syndrome and cardiac 
maintenance; Neurologic 
deterioration post-op with death 
at 5 weeks 
and propofol/nitrous oxide 
maintenance; No 
complications 
rocuronium and atracurium 
anesthesia. Journal of 
cardiothoracic and vascular 
Farag E, Argalious M, 
anesthesia 1995;9:189-191. 
Narouze S, DeBoer GE, and J 
Single case report; Induction 
. The anesthetic 
and maintenance with 
management of ventricular 
sevoflurane; No 
septal defect repair in a child 
complications 
with mitochondrial 
cytopathy.Obstetrical and 
Vilela H, Garcia-Fernandez J, 
Pediatric Anesthesia 
Parodi E, Reinoso-Barbero F, 
2002;49:958-962. Single 
P Duran, and F 
. 
report; Ketamine induction 
Anesthetic management of a 
and maintenance; No 
patient with MERRF 
complications 
syndrome. Pediatric 
Anesthesia 2005;15:77-79. 
Single case report; 
Sevoflurane induction and 
maintenance; No 
complications. 
 
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IRB NUMBER: HSC-MS-13-0600 
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Table 2: Results from a national survey of pediatric anesthesiologists in the United States to investigate their 
current practice in regards to anesthesia in mitochondrial 
 
Total number of respondents 
503 
Reports having institutional guidelines for anesthesia management in mitochondrial 
patients 
11% 
Reports the use of standard NPO guidelines with liberal oral fluids until 2 hours pre- 
operatively 
80% 
Reports taking precautions for malignant hyperthermia 
18% 
Considers Sevoflurane as the safest inhaled agent for induction 
90% 
Considers Sevoflurane as the safest inhaled agent for maintenance 
79% 
Considers Ringers Lactate fluid safe 
49% 
Use dextrose containing fluids 
48% 

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IRB NUMBER: HSC-MS-13-0600 
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Table 3: Results from a survey of the clinical directors of the recognized mitochondrial centers in the 
United States and Canada pertaining to anesthesia in mitochondrial 
 
Total number of respondents 
32 
Recommends anesthesia “precautions” in patients with possible or diagnosed 
mitochondrial disease 
Specific recommendations varied but generally involved 
- 
Restriction of select anesthetic agents 
- 
Limiting pre and post-operative fasting 
- 
Maintaining IV hydration with dextrose containing fluids 
100% 
Avoidance of Propofol for long term sedation 
100% 
Restricts Propofol use for short term sedation (less than 2 hours) 
27% 
Avoids Succinylcholine 
16% 
Avoids Sevoflurane 
9% 
Provide patients with written anesthesia protocol including information about 
preferred anesthetic agents and risks of fasting 
72% 
Routinely admit patients prior to surgery for IV hydration 
- 
Remaining 49% only admits patients pre-operatively if the patient reports a 
problem with fasting in the past 
59% 

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