IRB/FDA Approved Clinical Study on the Efficacy of Ketamine to Treat Children with Treatment Resistant Bipolar Disorder

The Juvenile Bipolar Research Foundation (JBRF) has launched a study to document the efficacy of intranasal ketamine to improve the behavioral and physical symptoms of a subgroup of children who are likely to be classified as either Bipolar I, II or NOS and for whom the traditional pharmacopeia has not provided adequate relief.

It is a placebo controlled, double-blind study with both IRB and FDA approval. Registration of the study can be found at: http://www.clinicaltrials.gov/ct2/show/NCT01504659?term=ketamine+bipolar+disorder&rank=1

This document provides an overview of the rationale and context for the study as well as information about the safety of ketamine generally and in relation to this study. We hope that it addresses questions and concerns that you may have as you evaluate whether participation in the study is in the best interest of your child or your patient.

_____________________________________________

 

RATIONALE

The current clinical study follows a 4 year pilot study (published article) in which Dr. Demitri Papolos, our Director of Research and author of the book The Bipolar Child, has administered intranasal ketamine to over 50 children and adolescents characterized by the recently defined Fear of Harm phenotype. The study was conducted in a private practice setting. Treatment resulted in a rapid and enduring resolution of a large majority of their most severe behavioral and physiological symptoms. Many have been treated for 6 months to a year, several children for up to 2 years and the first-treated patient has been stable for almost 4 years.

A unique and important characteristic of the pilot study is that treatment selection followed a 10 year research effort which delineated the syndrome and prompted a hypothesis of its underlying pathophysiology.

The syndrome, called the Fear of Harm phenotype (published articles) describes a population of children who are severely impaired, often refractory to treatment, suffer repeated hospitalizations and currently fall under a bipolar classification. Our research indicates that two thirds of the children who currently have a community diagnosis of bipolar disorder fall within an FOH spectrum: 1/3 high and 1/3 low.

Symptoms experienced by these children include not only those typical of bipolar disorder, but also a broad range of symptoms currently included in classifications considered co-morbid to bipolar disorder as well as some symptoms never previously associated with any psychiatric classification.

This new constellation of symptoms allowed investigators to suspect that the condition may originate from the most ancient sensory pathway in the brain, one which is instrumental in homeostasis; the orexigenic neuropeptide pathway. The neuroanatomical model of the condition that developed, in which thermal dysregulation and fear sensitization are primary characteristics, ultimately led to a determination that ketamine, a drug known to lower core body temperature and reduce fear sensitization, would  be an appropriate agent to target the dysregulation in the pathway.

In this study, we hope to collect the evidence that will bolster the observations of the pilot study. Further, a specific biological marker has been attributed to this severe condition. This marker will be further studied with the use of a novel monitor designed to collect a wide range of physiological signals related to temperature, sleep, oxygen saturation, activity and galvanic skin response.

 

INFORMATION RELEVANT TO THE IMPLEMENTATION AND SAFETY OF THIS STUDY

THE USE OF KETAMINE FOR MOOD DISORDER:

Concurrent to the pilot study described above, several small, controlled studies have illustrated the considerable potential of ketamine to provide fast-acting and sustained relief in refractory depression, refractory bipolar disorder and in patients with severe suicidal ideation. Due to their impressive findings, these studies have recently come into the popular media. The landmark clinical study, by Berman et al. (2000) found that in a randomized, double-blind study, 7 subjects with major depressive disorder experienced significant improvement in depressive symptoms within 72 hrs. post-treatment with  0.5 mg/kg IV ketamine.[i]  In 2 randomized, placebo-controlled, double-blind crossover studies by Zarate el al., one in 2006 in which 18 patients with refractory major depressive disorder were studied and the other in 2010, in which 18 patients with refractory bipolar depression were studied, investigators found that 71% of the patients in each study achieved significant, rapid and enduring clinical improvement after 40 minute intravenous infusion of 0.5 mg/kg ketamine.[ii],[iii] Similar findings have now been replicated by several groups.[iv],[v],[vi],[vii]

There are many characteristics that associate children with the FOH phenotype to the treatment refractory adults of the above studies –but they will not be addressed here. What is relevant is that, like the adults in the above studies, children with the FOH phenotype have responded to ketamine in an equally positive manner. Administration of the intranasal formulation is easy to manage and its effects typically endure for 3-5 days.

 

EXCLUSION CRITERIA:

Prior to enrollment, potential subjects will need to obtain medical clearance from their doctor. Clearance is predicated on:

  • Satisfactory results from: EKG with rhythm strip, CBC, Chem Screen Panel and Urinalysis.  These tests must be ordered specifically for the study.
  • A satisfactory physical exam of all body systems which has be conducted within the past 4 months
  • Evaluation by the Primary Investigator of responses regarding drug sensitivity, general health care and congestion in particular.
  • Evaluation by the Primary Investigator of responses regarding physical and sexual abuse.
  • Absence of any exclusionary criteria as delineated in the Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update[viii] by Green et al. These Guidelines, developed to guide the safe and appropriate use of ketamine to achieve a dissociative state, is a well recognized protocol. Since we will administer doses that result in a sub-dissociative state, adoption of its exclusionary criteria insures a margin of safety.

Guideline criteria are itemized on our Medical Clearance Form. We have deviated from the Guidelines in the following manner:

  • We have omitted exclusionary criteria that are directly relevant to surgical procedures.
  • We have inserted several exclusionary conditions mandated by FDA approval of this study.

The criteria section of our Medical Clearance Form is reprinted at the end of this overview –following the links to Other Sources of Information.

 

DATA COLLECTION:

Ketamine will be administered to the child in his/her home by an RN, PA, NP or APRN specifically trained for this study. He or she will arrive an hour before the administration to confirm that the child is healthy enough to receive the dose and to irrigate the child’s nasal passages. The latter is to maximize an accurate delivery of drug/placebo. After administration, the RA, PA, NP or APRN will remain in the child’s home for another 2 hours to monitor for adverse events. Two hours is the well established window in which all the side effects of ketamine resolve.

 

DOSING PROTOCOL:

In addition to the significant amount of information that the pilot study has shed in regards to the effectiveness of ketamine to provide relieve for these otherwise treatment resistant children, its duration has also accrued significant titration experience to Dr. Papolos. For this study, children have been divided into two groups depending upon weight. Group A, with minimum-maximum weight of 20 kg-40 kg will receive a fixed initial dose of 10 mg (0.25-0.5mg/kg). Group B with minimum – maximum weight of 40.01kg-100kg will get a fixed initial dose of 20 mg (0.20-0.5mg/kg). Over the following 3 administrations, the dose will increase to a maximum of 40 mg for the smaller children and 120 mg for the larger children.  This dosing protocol reflects the dose-response range demonstrated in the pilot study.  These doses are significantly lower than a dissociative dose and are more similar to doses used for analgesia. While psychotomimetic effects may occur at these lower doses, there is a wide berth to dissociative sedation levels.

The dose at which a response is achieved seems to be fairly idiosyncratic; hence the wide window for titration upwards. Increases will be based on an algorithm of the side effects combined with the subjective input of the child.  A therapeutic dose is considered achieved if, 48 hours post-dose, there is a behavioral improvement of 80% from baseline on the Young Mania Rating Scale and/or the Overt Aggression Scale. There will be no increase in dose as long as this improvement is maintained.

 

SAFETY MEASURES:

Prior to titration the nurse will administer the Systematic Assessment for Treatment Emergent Effects During. Vital signs will be measured prior to, and at increasing intervals for the 60 minutes after the dose.  Approximately one hour post-dose the RN/PA/NP/APRN will administer the Clinician-Administered Dissociative States Scale (CADSS) to measure the psychotomimetic emergence reactions which can follow the use of ketamine.

As for the rare respiratory distress caused by ketamine, our review of the literature finds that the overwhelming recommendation is for the presence of a person dedicated to the observation of the patient who is skilled in advanced airway management and has access to appropriate equipment such as a bag valve mask. The current study wholly adopts this recommendation.

In regards to the possibility of LUTS, the medical screening and urinalysis required prior to participation will insure that the child has no preexisting bladder condition. Further, we will inquire about changes in urination pattern during the study, at three month follow up, and advise parents to seek treatment at any time that they notice such a change. Over the entire course of the pilot study, no child has experienced any urination anomalies.

Other less serious adverse effects such as nausea or vomiting, while unpleasant, are not of clinical concern. Side effects specific to the intranasal method of administration also include a bitter taste and a sensation of burning in the pharynx.75 However, techniques which significantly mitigate these unpleasant aspects have been honed from pilot study experience.

In the pilot study, we have also reported on a chilling sensation prior to therapeutic response.

 

 

USE, EFFICACY AND SAFETY INFORMATION OF KETAMINE

CHARACTERISTICS and HISTORICAL USE:

Since its creation in 1961 and introduction to clinical practice in 1970, ketamine has garnered a long record of efficacy and safety as a sedation and analgesic agent. It has been used both in combination with other sedation agents and by itself in both clinical and veterinary arenas. Ketamine is a core medicine in the World Health Organization’s “Essential Drugs List” and its ability to provide sedation without the need for intubation has made it a standard technique for the American Red Cross.[ix]

When ketamine is administered in doses between 1-3mg/kg IV or 3-4mg/kg IM, it induces a unique dissociative state which disconnects the central nervous system (CNS) from external stimuli (i.e. pain, sight, sound) and accomplishes potent analgesia, amnesia and sedation.[x] However, this state is pharmacologically and clinically distinct from general anesthetics in three important ways: 1) it does not impair respiration, airway reflexes or cardiovascular stability, 2) it does not exert its effect along a dose-response continuum; that is, once a dissociative state is reached, that state does not deepen nor will it deepen with additional drug administration, and 3) it does not exert its effects through global CNS depression, instead it dissociates the CNS through its effects on the thalamoneocortical and limbic systems.[xi] Due to the first two points, unlike anesthetic agents, once a dissociative-sedation state is produced by ketamine, increased administration is not accompanied by an increased probability of ventilatory depression[xii] and therefore intubation is rarely needed. Within the range of standard, clinically administered dissociative sedation doses and using standard administration methods, there are neither clinically important changes in airway integrity and respiration[xiii] nor clinically important incidence or severity of adverse events.[xiv] Only high and/or rapid IV administration predicted an increased risk of agitation.[xv],[xvi]

Ketamine use in the United States is far less frequent than elsewhere. This is likely due, in large part, to wariness over emergence reactions that sometimes follow the use of this phencyclidine derivative.[xvii],[xviii] The experience has limited use of the drug despite the fact that in all but a few cases[xix],[xx],[xxi] out of the many hundreds of thousands[xxii],[xxiii] in which use has been reported, the effects have been transient and typically resolve within 30-120 minutes.[xxiv],[xxv] Ketamine is the number one agent used to sedate children in the emergency room and is frequently used in dental offices.

In addition to its widespread dissociative use, ketamine has a long clinical history of off-label use as an analgesic. It has been used as a treatment for a wide spectrum of pain syndromes, including neuropathic pain, phantom limb pain, postoperative pain, acute traumatic pain, complex regional pain syndrome and breakthrough and regional chronic pain.[xxvi],[xxvii],[xxviii],[xxix] In some neurological ICUs, ketamine has been used in cases of prolonged status epilepticus in order to protect neurons from glutamatergic damage.[xxx]  Finally, ketamine has been known to have bronchodilatory effects and to be used in the treatment of bronchospasm.[xxxi]

 

THE JEKYLL AND HYDE QUESTION OF KETAMINE: neurotoxic or neuroprotective

The effect of ketamine on neurons has been confusing. While ketamine is known for its neuroprotective properties, it is also known to cause irreversible neuronal degeneration. While the exact mechanisms which define these dichotomous effects are not fully understood, it is clear that degree of exposure is the primary cause and age of the subject is secondary.

Two different types of neurodegeneration result from NMDA blockade: apoptosis and excitotoxicity. Windows of vulnerability for these two events occur during neurogenesis and from adolescence forward, respectively. The potential for apoptotic effects closes with the end of neurogenesis.[xxxii] In the human, literature puts this developmental period between 152 days post conception to a maximum of 3.5 years.[xxxiii],[xxxiv],[xxxv],[xxxvi],[xxxvii] However, even during this extremely vulnerable time, apoptosis is dose dependent. Only at supraclinical doses (perhaps 20 the maximum dose level used in our study) does it occur. [xxxviii],[xxxix]

Neurons are vulnerable to necrotic excitotoxicity starting in adolescence.[xl] However, the dose level at which this occurs is shown to be between 100 and 500 times the maximum dose level that will be used in our study and it has been shown not to occur at lower doses.[xli],[xlii],[xliii],[xliv],[xlv]

Since children in the Ketamine Clinical study will be between the ages of 6 and 12, not only do they avoid both windows of vulnerability, but more importantly, they will receive an administration of drug which is well below the threshold in which any neuronal degeneration occurs.

In contrast to the neurodegenerative effects described above, low doses of ketamine have been known to encourage cell growth. The benefit of this for people who have suffered neuronal atrophy as the result of chronic stress and depression is borne out by the recent behavioral studies mentioned above. Recent studies have begun to shed light on the mechanisms of action although there is still much to uncover. It has been shown that NMDA blockade by very low doses of ketamine results in increased mTOR activity, the direct result of which is the strengthening and improved synaptic connectivity in neurons.[xlvi],[xlvii],[xlviii]

The reason why extremely low doses of ketamine result in this effect may derive from two important actions of NMDA blockade. First, at low doses, the scarce but dominating extrasynaptic NMDA receptors (which when activated by glutamate shut down cell growth[xlix],[l]) are blocked to a greater proportion than the abundant NMDA receptors found in the synapse (which when activated by glutamate initiate a pro-growth cascade which includes, among other things, activation of mTOR [li],[lii]).[liii] In a hyperglutamatergic tonic condition, as may be the case for conditions such as depression and bipolar disorder, this would reverse the direction towards cell growth.[liv] Second, it is known that administration of an NMDA inhibitor results in a release of glutamate into the synapse. This additional burst optimizes the receptive, pro-growth condition.[lv]

For a more complete discussion of these effects, click here.

 

OVERDOSE INFORMATION:

The several documented cases of unintentional ketamine overdose, up to 100 times that required, have been followed by prolonged, but complete, recovery.[lvi] Median lethal dose of intraperitoneal ketamine hydrochloride is 224 mg/kg in rats and 229 mg/kg in mice.[lvii] In guinea pigs, the LD50 of ketamine hydrochloride ranges from 351 to 373 mg/kg when given by intramuscular injection with 10 mg/kg of xylazine (a short-acting sedative).[lviii]

 

ADVERSE EVENTS and SIDE EFFECTS ASSOCIATED WITH THE MEDICAL USE OF KETAMINE:

Emergence from ketamine sedation causes the well known psychotomimetic effects associated with the drug. The percentage of children who experience emergence phenomena or recovery agitation is much smaller than that of adults and almost no children express or exhibit distress from them when emerging from ketamine sedation.[lix],[lx] While reports of recovery agitation are not infrequent (app. 20%), the event was only judged moderate to severe in 1.6% of the cases.[lxi] In one trial in which the reaction was quantified, the investigators found that the median agitation score was 5 out of 100.[lxii] It is worth noting here that these observations pertain to the use of ketamine to achieve complete, rather than partial dissociation as the case will be for our study.

Since ketamine does not depress the respiratory system it does not require respiratory support. While some adverse respiratory events have been documented, the incidence and nature of these events are not of clinical importance. A 2009 meta-analysis of 8,282 pediatric ketamine sedation cases found  incidence of airway malalignment and respiratory depression together was 2.8% (234 cases), apnea was 0.8% (63 cases) and laryngospasm was 0.3% (22 cases).[lxiii] The commensurate corrective action required for these kinds of advents was recorded in an earlier study of 1,022 cases. In that study, for the 7 cases of airway complications, repositioning of the head alleviated partial obstruction and no assisted ventilation was performed. In the seven cases of transient laryngospasm, apnea or respiratory depression, none of the cases required endotracheal intubation and all cases were completed with uneventful recovery.[lxiv]  We are not aware of any instances of adverse respiratory events in children in which an intranasal administration of ketamine is used.[lxv],[lxvi],[lxvii]

The presence of lower urinary tract symptoms (LUTS) associated with ketamine use has garnered recent attention and concern in the urological community. Our review of the literature indicates that LUTS follows extremely high doses of ketamine (between hundreds and thousands of times higher than the doses in the study), typically over a long period of time and during which medical attention is not sought despite the presence of symptoms. A 2012 study reported that daily administration of 600mg ketamine in pain management did not lead to symptom onset.[lxviii]

Other side effects of ketamine include nausea, vomiting, fatigue and headache.

Despite the phencyclidine characteristic of ketamine, ketamine does not create a physical addiction.[lxix]


 

ADDITIONAL SOURCES OF INFORMATION

 

JBRF Research

The published papers that substantiate the FOH profile can be found on our website at:

http://www.jbrf.org/publications-by-jbrf-researchers/

or you can go directly to the three most relevant articles:

http://www.jbrf.org/wp-content/uploads/2012/03/Fear-of-Harm-a-possible-JAD.pdf

http://www.jbrf.org/wp-content/uploads/2012/03/A-strategy-for-identifying-phenotypic-subtypes-Concordance-of-symptom-dimensions-between-sibling-pairs-who-met-screening-criteria-for-a-genetic-linkage-study-of-childhood-onset-bipolar-disorder-using-the-Child-Bipolar-Questionnaire.pdf

http://www.jbrf.org/wp-content/uploads/2012/03/The-child-bipolar-questionnaire-A-dimensional-approach-to-screening-for-pediatric-bipolar-disorder.pdf

 

Dr. Papolos maintains his own website; http://bipolarchild.com/ .  Of particular note is the BLOG which contains stories directly from some of the patients who have used ketamine as well as stories from their parents. http://bipolarchild.com/important-information-on-this-site/

 

Three interviews on the Coffee Klatch, a blog talk radio program can be found at: http://www.jbrf.org/category/media-coverage/ .  Scroll down through the page to get to all three.

 

Other Scholarly Research

Published studies conducted by Carlos Zarate of NIMH on the use of ketamine to treat mood disorder can be found at:

http://archpsyc.ama-assn.org/cgi/content/abstract/63/8/856

http://archpsyc.ama-assn.org/cgi/content/abstract/67/8/793

 

The following article reviews the studies listed just above:

http://www.primarypsychiatry.com/aspx/article_pf.aspx?articleid=1522

 

Additionally, an effort to extend the Zarate findings into a treatment protocol is discussed in the following articles:

http://neuro.psychiatryonline.org/article.aspx?articleid=104296

http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=260

 

Popular Media Coverage

Three interviews on the Coffee Klatch, a blog talk radio program, in which Dr. Papolos speaks about the condition, can be found at:

http://www.jbrf.org/category/media-coverage/ .  Scroll down through the page to get to all three.

 

Bloomberg and NPR

http://www.bloomberg.com/news/2012-07-08/special-k-for-depression-renews-hope-in-hallucinogens.html

http://www.npr.org/blogs/health/2012/01/30/145992588/could-a-club-drug-offer-almost-immediate-relief-from-depression

http://www.npr.org/blogs/health/2012/01/31/146096540/i-wanted-to-live-new-depression-drugs-offer-hope-for-toughest-cases

 

 

 

REPRINT OF CLEARANCE CRITERIA ON THE MEDICAL RELEASE FORM

Tests required:

  • EKG with rhythm strip
  • CBC
  • Chem Screen Panel
  • Urinalysis

 

Test Results:

Results of EKG____________________________________________________________

Results of CBC____________________________________________________________

Results of Chem Screen Panel________________________________________________

Results of Urinalysis________________________________________________________

 

Health Checklist:

Does the patient have any illnesses or conditions for which (s)he receives or should receive regular care? ______yes   ______no

If yes, please specify __________________________________________________

Does the patient have frequent sinus congestion?  ______yes ______no

If yes, is the congestions treated with a steroidal inhaler? ______yes ______no

Does the patient have any drug sensitivities?  ______yes ______no

If yes, please specify __________________________________________________

Has the patient had a physical exam within the last four months in which all body systems were examined?  ______yes ______no

If yes, were there any abnormal findings?  ______yes ______no

If yes, what were they? __________________________________________

Has the patient suffered from sexual abuse: ______yes ______no

If yes, please indicate the following:

Between the ages of:

1-3:   none  ______  rare ______  sometimes _______  often_______

3-6:   none  ______  rare ______  sometimes _______  often_______

6-9:   none  ______  rare ______  sometimes _______  often_______

9-12: none  ______  rare ______  sometimes _______  often_______

Has the patient suffered from physical abuse: ______yes ______no

If yes, please indicate the following:

Between the ages of:

1-3:   none  ______  rare ______  sometimes _______  often_______

3-6:   none  ______  rare ______  sometimes _______  often_______

6-9:   none  ______  rare ______  sometimes _______  often_______

9-12: none  ______  rare ______  sometimes _______  often_______

 

 

Please check which, if any, of the following apply:

_____Endocrine or neurological illness;

_____History of chronic lower urinary tract symptoms

_____Previous history of closed head injury, current head injury associated with possible intracranial hypertension, central nervous system masses, abnormalities, or hydrocephalus, ever had loss of consciousness;

_____Previous history of glaucoma or acute globe injury

_____Abnormal nasal physiology which would not allow for adequate medication delivery;

_____Meets DSM-IV criteria for Mental Retardation;

_____The presence of any abnormal laboratory findings or serious medical disorder or condition including: clinically significant organ system dysfunction; significant endocrine disease, including diabetes mellitus; hypothyroidism; cardiovascular disease (myocardial ischemia, heart failure, arrhythmias); coagulopathy; significant anemia; significant acute infection; glaucoma; dehydration; epilepsy; any intra-abdominal or intrathoracic surgery or limb amputation within the prior 6 months; any diagnosed cardiac condition causing documented hemodynamic compromise or dysfunction of the SA or AV node; any diagnosed respiratory condition causing documented or clinically recognized hypoxia (e.g., chronic obstructive or restrictive pulmonary disease); body weight approximately < 80% or > 120% ideal body weight; or any medical condition known to interfere with cognitive performance; medication-related exclusions include narcotic therapy, chronic acetaminophen use, acute sedative hypnotic withdrawal, corticosteroid or spironolactone therapy, regularly dosed narcotics or any other sedative therapy or medication that interferes with SA or AV node function or could be considered contraindicated with the sedative properties of ketamine.

 

 

 



[i] Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000;47(4):351-354.

 

[ii] Zarate CA, Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. Aug 2006;63(8):856-864.

[iii] Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. Aug 2010;67(8):793-802.

[iv] Krystal JH. Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Med Wkly. Apr 21 2007;137(15-16):215-216.

[v] Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. Sep 1 2009;66(5):522-526.

[vi] Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA, Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. Jan 15 2009;65(2):181-184.

[vii] Liebrenz M, Borgeat A, Leisinger R, Stohler R. Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Swiss Med Wkly. Apr 21 2007;137(15-16):234-236.

[viii] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

[ix] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

[x] Green SM, Krauss B. The semantics of ketamine. Ann Emerg Med. Nov 2000;36(5):480-482.

[xi] Green SM, Krauss B. The semantics of ketamine. Ann Emerg Med. Nov 2000;36(5):480-482.

[xii] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

[xiii] Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. Aug 2009;54(2):158-168 e151-154.

[xiv] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xv] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xvi] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

[xvii] Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111-125.

[xviii] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

[xix] Fine J, Finestone SC. Sensory disturbances following ketamine anesthesia: recurrent hallucinations. Anesth Analg. May-Jun 1973;52(3):428-430.

[xx] Meyers EF, Charles P. Prolonged adverse reactions to ketamine in children. Anesthesiology. Jul 1978;49(1):39-40.

[xxi] Perel A, Davidson JT. Recurrent hallucinations following ketamine. Anaesthesia. Oct 1976;31(8):1081-1083.

[xxii] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xxiii] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xxiv] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xxv] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xxvi] Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. Mar 2004;108(1-2):17-27.

[xxvii] Innovative Drug Delivery Systems I. Investigator’s Brochure, v7, PMI-100/150 (intranasal ketamine 100 – 150 mg/mL)1995.

[xxviii] Huge V, Lauchart M, Magerl W, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. Apr 2010;14(4):387-394.

[xxix] Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. Apr 2005;8(2):175-179.

[xxx] Borris DJ, Bertram EH, Kapur J. Ketamine controls prolonged status epilepticus. Epilepsy research. 2000;42(2):117-122.

[xxxi] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xxxii] Olney JW, Wozniak DF, Jevtovic-Todorovic V, et al. (2002) Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol; 12:488-498.

[xxxiii] Dobbing J, Sands J. (1979) Comparative aspects of the brain growth spurt. Early Human Development; 311:79-83.

[xxxiv] Romijn H, Hofman M, Gramsbergen A. (1991) At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev; 26(1):61-67.

[xxxv] Clancy B, Kersh B, Hyde J, et al.(2007) Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics 5:79-94.

[xxxvi] http://translatingtime.org/public/index  retrieved from the web 10/18/2012

[xxxvii] Watson R, DeSsso J, Hurtt M, Cappon G. (2006) Postnatal growth and morphological development of the brain: a species comparison. Birth Defects Research (Part B) 77:471-484.

[xxxviii] Huang L, Liu Y, Jin W, et al. (2012) Detamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment throught the PKCy-ERK signaling pathway in the developing brain.

[xxxix] Bosnjak ZJ, Yan Y, Canfield S, et al. Ketamine induces toxicity in human neurons differentiated from embryonic stem cells via mitochondrial apoptosis pathway. Curr Drug Saf. 7(2):106-119.

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