RESEARCH PROTOCOL
THIS FORM IS PROVIDED ONLY AS A GUIDE TO HELP YOU
FORMULATE THE QUESTIONS YOU MAY HAVE REGARDING THE RESEARCH STUDY
February 15, 2007
Revised: September 29, 2006
Revised: September 29, 2006.
Based on Steve Altmiller’s entry (CEO of San Juan Regional Medical Center in the U.S., and father of the first study patient in San José hospital)
TITLE OF THE RESEARCH
Pilot Study of 5-day Infusion of Ketamine for the Untreatable Complex Regional Pain Syndrome.
MAIN RESEARCHER:
Fernando Cantú, MD, Anesthesiologist and Specialist in Pain Management,
San Jose Technological Hospital of Monterrey, School of Medicine, Monterrey,
Mexico.
CO-RESEARCHERS:
Anthony Kirkpatrick MD, PhD, Anesthesiologist and Specialist in Pain Management, Southern Florida University, Tampa, Florida, U.S.A.
Richard Hoffman, PhD, Clinical Psychologist, Tampa, Florida, U.S.A.
Thomas Freeman MD, Neurosurgeon, Southern Florida University, Tampa, Florida, U.S.A.
Robert J. Schwartzman, MD, Professor and President of Neurology of the Drexel University, Philadelphia University of Medicine, Pennsylvania.
CLINICAL RESEARCH COORDINATOR
Deborah Scott, BA, CCRC,
Southern Florida University, Tampa, Florida, U.S.A.
CONSULTANTS:
Robert Taylor, MD,
Department of Neurological Surgery
Medical Director of Neurology
Intensive Care Unit
Southern Florida University
Dennis Bandyk, MD
Professor of Surgery
Study Consultant
Director of Vascular and Endovascular Surgery
Southern Florida University
Peter Rohr, MD
Department of Anesthesiology
Intensive Care Medicine
Klinikum Saarbrücken University
Saarland Saarbrüecken, Germany
Safety Committee
Dr. Javier Valero Gómez
Medical Director
San Jose Technological Hospital of Monterrey
Dr. Rodolfo J. Treviño Pérez
Pediatric Intensive Care
San Jose Technological Hospital of Monterrey
Dr. Fernando Castilleja
Intensive Care Medicine
San Jose Technological Hospital of Monterrey
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INDEX
Introduction 1.0
• CRPS 1.1
• Ketamine 1.2
• Open-protocol Trial in Germany 1.3
• Dr. Kirkpatrick and research in Germany 1.4
• Update of the study in Germany 1.5
The proposed study 2.0
• Protocol objectives 2.1
Design of the study 3.0
• Criteria for inclusion 3.1
• Criteria for exclusion 3.2
• Potential risks for patients 3.3
• Administration of the medication 3.4
• Data gathering in the ICU during the study 3.5
• Neuropsychological tests 3.6
• Long term follow-up 3.7
Importance of the Study 4.0
References 5.0
Co-researchers
Consultants
The Coordinator of the clinical Research
Monitoring data safety
Hospital expenses
1.0 Introduction
1-1 untreatable complex regional pain syndrome
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The untreatable complex regional pain syndrome (CRPS) is a severe neuropathic pain that is out of proportion to the magnitude of the initial injury. The characteristic symptoms are severe burning and deep pain that does not subside. It is associated to mechanic and thermal allodynia (defined as any type of tactile stimulation that is perceived as painful) and hyperpathia (defined as a repetitive tactile stimulation that becomes progressively more painful). Edema, autonomic deregulation, alteration of movement, atrophy and dystrophy present themselves at different degrees. Some patients experience an expansion of symptoms to large segments of their body. The painful syndrome frequently becomes “the primary relation” of the life of the affected individual. Consequences in terms of its relation to significant pain, quality of life, social factors, financial loss, and in some cases suicide are increased. [1]
CRPS can sometimes be palliated with invasive procedures, but often times it no longer responds to the blockage of nerves. In many cases the current therapies are inadequate due to the variability and lack of permanent efficacy. Alternative therapies including the use of high-risk procedures including sympathectomies and other surgical procedures are authorized. [2]
1.2 Ketamine
Hyper-regulation and central sensitization are the main neurological processes that appear to be involved in the induction and perseverance of pain of CRPS/neuropathic pain. Due to the fact that a stimulation of the receptor of the N-methyl-D-Aspartate (NMDA) appears to have an important role in the development of these phenomena, efforts have been made during the last 20 years to treat the chronic pain using an antagonist of the NMDA receptors. [3-5]
Ketamine was used for the majority of these studies as it is the most potent NMDA antagonist clinically available. Medications such as dextrometorfan, amantadine and memantine, though they are relatively safe (from the point of view of side effects in the central nervous system), have a relatively weak activity in the inhibition of the NMDA receptor and appear to have a relatively low potential to block the sensitization process.
Although experiments on animals have shown evidence that ketamine can inhibit
sensitization, the clinical utility of these results has been limited due to the lack of
important efficacy and/or the excessive side effects such as vertigo, anxiety and
hallucinations in the CNS in conscious subjects.
In the proposed study, ketamine will be used at a level of dosage and duration normally employed to treat certain patient populations. For example, the intravenous administration of ketamine for periods longer than five days is useful in providing anesthesia to burn patients requiring frequent gauze changes. Furthermore, ketamine is useful in the treatment of asthma patients when anesthesia is required for periods longer than five days due to the bronchial dilating properties of ketamine. Ketamine is also used in the ICU for long-term general anesthesia in patients with severe cranial injury, more so when low blood pressure is a potential problem.
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There is supporting data from the scientific literature that supports safety in general anesthesia with ketamine for prolonged periods of time in the ICU. This data includes a randomized double-blind study by Bourgoin et al: “Safety of sedation with ketamine in patients with severe cranial injury: A comparison with sufentanyl.” (Critic Care Medicine. 31(3):711-717, March 2003)
The subjects in the Bourgoin study were exposed to ketamine for a longer period in the ICU than the proposed period in our study. Our study requires a 5-day infusion of ketamine. The medial duration of the ketamine infusion in the Bourgoin study was 6 days. The dose of ketamine in both studies is comparable (i.e., 360-380 mg/hour).
The Bourgoin study observed the following potential advantages of ketamine over the opiates for prolonged general anesthesia in the ICU:
• Maintaining the hemodynamic state
• Control of the cerebral perfusion pressure (CPP)
• Better tolerance of the enteral nutrition
• Absence of abstinence symptoms.
1.3 Open-protocol clinical trial in Germany
An Open-protocol trial in Germany (Section 5.0, Reference 6) suggests the therapeutic efficacy of the ketamine-midazolam anesthesia in the treatment of the untreatable severe neuropathic pain due to CRPS.
The induced coma regime developed from the work of the German researchers who had previously used ketamine to treat the phantom limb pain syndrome. One of the German doctors had a relative with CRPS who was not responding to any other treatment and tried the ketamine-induced coma and it worked.
The discovery by the German team appears to be a chance finding involving a patient with pre-existing CRPS who suffered a severe cranial trauma in an automobile accident.
They were forced to induce him into a coma in order to protect the brain. When they removed the patient from the coma, the chronic pain had subsided. It had nothing to do with theory. It was a casual observation.
Anyhow, once the German team acquired safety in the new procedure, they began formally speaking about it at international meetings.
These same physicians carried out the first open-protocol study in Germany. Their study has not been published in its entirety, by a scientific report reviewed by researchers.
However, a series of ten subjects were studied and the results were published as a summary [6] which is available in APPENDIX 4 and in the Internet:
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http://www.rsdfoundation.org/en/en_research_updates.html
The subjects in the German study were recruited by Dr. Robert Schwartzman, professor and president of the school of Medicine at the Drexel University, neurology department, Philadelphia, Pennsylvania. These subjects had to have attempted and failed all reasonable treatments and the CRPS had to involve multiple limbs or be spreading rapidly. The ketamine-midazolam anesthesia studies have not been reported outside Germany.
1.4 Dr. Kirkpatrick and the study in Germany
Co-researcher Anthony F. Kirkpatrick, MD, PhD, is the president of the scientific advising committee and a consultant for the RSD/CRPS International Research
Foundation. A list of members of its committee is available in APPENDIX 5 and at:
Dr. Schwartzman and the German researchers who conducted the first clinical trials of the anesthesia with ketamine for 5 days (Dr. Ralph- Thomas Kiefer, Eberhard-Karls University, Tuebingen, and Dr. Peter Rohr, Klinikum Saarbrücken University, Saarland Saarbrüecken), are members of this committee. The design of this study will be similar to the German studies.
1.5 Update of the study in Germany
Dr. Schwartzman provided the following update and results of the first series of 10 subjects. (Personal communication: On January 6, 2005). The intensity of the pain prior to participating in the study was determined according to a numerical evaluation scale (NRS, it being 0: no pain, 10: strongest pain imaginable). All 10 subjects categorized their pain at least NRS=8 prior to participating in the study.
After awaking from the anesthesia, all subjects experienced complete pain relief. Spontaneous pain, hyperalgesia, mechanical allodynia and other signs and symptoms associated with CRPS were absent. Complete relief of all CRPS components lasted at least 2 months (an average of 3.8 months, ± 1.5) in all of them. The neuropsychological tests before and after participation in the study (intellectual function, attention, memory, process speed, motor function, and character) did not show cognitive deterioration in any fashion. The specific side effects of the ketamine included vertigo, muscular weakness, fatigue, and slight anxiety, resolved within 2-4 weeks. During the five days of the general anesthesia intervention there were temporary and reversible increments in the hepatic enzymes and CPK. There were nosocomial infections (respiratory infections -5/10, urinary tract infections -2/10). The infections required intravenous antibiotic treatment and were resolved with no incidents.
At three months, 7 subjects continued with complete pain relief, 1 subject showed minor recurring pain experienced (NRS 1-2) in the original injury site. All 7 subjects with complete pain relief had been removed from narcotic medications during participation
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in the study and did not need any pain medication. The two subjects that had a relapse of CRPS required reduced amounts of narcotics <25% of the pre-study participation levels. The subjects with recurring symptoms retained a significant relief of pain (41- 62%).
At 6 months, 5 subjects were pain free, 2 had a relapse of their original neuropathic pain (NRS <3) and a third subject had a relapse of CRPS (NRS 5-6). The subjects with recurring symptoms reported a significant relief of the pain (33-65%). The 5 subjects with complete pain relief did not require any pain medication. The symptomatic subjects had a significant reduction in medication which they were previously taking for the pain.
One subject detached himself from his intrathecal morphine pump; he was completely pain free and did not require any medication. Six subjects categorized their social and professional rehabilitation as complete, 2 with significant improvement and 2 with only minimal improvement.
Since July 5, 2005, the 5-day study with ketamine has been completed on 27 volunteers for the study in German. To date there has not been any adverse long-term event. On October 3, 2005, Dr. Schwartzman provided the classified neuropsychological data in nine subjects who entered the 5-day trial with ketamine in Germany. [Appendix 8].
These patients were evaluated with a battery of neuropsychological and personality tests before and after the treatment with ketamine anesthesia. Compared with their base calculations before the treatment, there was no reduction in the tests for attention, processing speed, memory, and manual speed, or in the character and personality tests.
Whenever there was a significant change, it was typically indicative of function
improvement. Character and personality remained stable before and after the tests.
There was significant reduction in a survey on pain index. So, deep anesthesia with ketamine during 5 days has been efficient in treating severe pain, refractory to other interventions, the results of the study in Germany suggest that there are no adverse effects in the neuro-cognitive functioning of memory or emotional state as a result of this treatment and suggests in a positive relation between pain relief and improvement in these behavioral aspects.
Upon returning to the United States from Germany, some patients have required
occasional ketamine infusions in low doses in sessions that last two to four hours
approximately to be able to maintain remission of their CRPS. Some insurance companies have been paying for the bolus infusions in low doses. Each 4-hour infusion is around $400 dollars. In a hospital setting, the charge for a 4-hour ketamine infusion might be much higher. During the infusion, patients are monitored for their heart rate, oxygen saturation, mental state, and blood pressure. Some patients report headache and nausea. Phenergan and Zofran are used to treat the nausea and Fioricet for the headaches.
Following is an update from March 8, 2006, with the results for thirty (30) research subjects reported to Dr. Kirkpatrick by Dr. Robert Schwartzman.
Nine of the 30 patients have experienced a complete and permanent remission of the previous intransigent symptoms. One of these subjects had a complete remission for nine years and the others for more than five years.
Of the remaining 21 subjects, all had at least one partial remission, seven were
completely pain free for six to seven months, after which the pain returned slowly.
Currently, ten of the subjects are being treated with sub anesthetic doses (low) of the 4-hour ketamine in an effort to reinforce the initial effect.
Pneumonia appeared in eight of the 30 subjects, and kidney infections in six, but they all responded to the treatment.
The detailed psychological tests conducted on 15 of 30 patients before and after the 5-day ketamine infusion has not shown any change in the mental function.
Dr. Schwartzman treated approximately 100 patients with sub anesthetic doses of ketamine. He found that the sub anesthetic doses help but do not cure the patients. It appears that the anesthetic doses of ketamine are required for healing.
Dr. Schwartzman and his colleagues in Germany have not had any problems with addiction related to the use of ketamine in the research subjects. He has suspended the ketamine bolus at low doses for any patient who did not have pain higher than a 3 in a pain scale of 0-10. Patients who have been pain free following a 5-day infusion find it difficult to accept a pain of 3 in the 3/10 scale. In those cases, the German researchers stop the ketamine bolus and attempt to use non-narcotic analgesics such as anti-inflammatory
medications and Neurontin.
2.0 Proposal of the Study
In this proposal, we will evaluate the use of general anesthesia with ketamine for approximately five days to evaluate the safety, tolerability and possible efficacy of this intervention for treatment of advanced CRPS in subjects for whom standard
interventions have failed (Section 3.1, Criterion for Inclusion). The study will be carried out at San Jose Technological Hospital of Monterrey.
The duration of the anesthesia with ketamine-midazolam for our study is five days based on the experience of the German researchers. Dr. Schwartzman and his German colleagues found that the objective signs of CRPS began to disappear after 3 days of the anesthesia with ketamine-midazolam and reached a plateau around day 5. These objective signs included a decrease in the inflammation, changes in skin color from blue to pink and normalization of the skin blood flow measured by a laser doppler flow meter.
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The dose of ketamine for our study is based on the experience of the German
researchers. They found that the ketamine at low doses is not effective to induce a remission in subjects with advanced, generalized CRPS. For example, in their study, four subjects were treated first with ketamine at low doses for 10 days at doses sufficiently high to cause serious side effects (hallucinations). None of these subjects benefited from ketamine at low doses and all required a ketamine-midazolam anesthesia at higher doses to acquire a remission. (Personal communication with Dr. Ralph- Thomas Kiefer on January 2, 2005) A recent report from Australia suggests that some patients with relatively light CRPS may benefit from receiving low doses of ketamine. [7] However, the authors advise that their report represents a retrospective review and that controlled studies are needed to determine the safety and efficacy of ketamine at low doses in patients with CRPS.
2.1 Objectives of the Protocol
The objective of the current protocol is to repeat and extend the observations of the study conducted in Germany. Various questions need to be addressed.
1. Are these important observations reproducible at a second center in another
country?
2. Is this therapy safe and tolerable?
3. Is any potential benefit reasonable in relation to the expected risk of a course of five days of general anesthesia?
4. Half of the subjects showed a long-term benefit (meaning pain free at 6 months) and 80% had an improvement in their social/professional reintegration. Is there an optimal group in the selection of patients with respect to the duration of the illness where more improvement can be observed?
5. Can higher doses or longer anesthesia time be more effective?
6. In subjects where therapy fails after six months, is there an effect that would allow the administration of the protocol to be repeated so that it has a longer effect?
7. Can this therapy be verified in a larger study, randomized, controlled with a placebo and active substance?
In the current study we will address the most urgent questions, those related to safety and tolerability.
Specific Objectives
To determine the safety and tolerability to a course of 5 days of anesthesia with
ketamine-midazolam in subjects with stationary CRPS and significant pain and
disability.
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3.0 Design of the Study
The design is an open-protocol pilot study, non-randomized to examine the safety, tolerability, and possible efficacy of five days of ketamine-midazolam anesthesia for CRPS.
San José Technological Hospital of Monterrey reserves their right to terminate the study whenever it so desires, should it be necessary.
A summary of the treatment and health status of the patient will be performed after each release from the hospital and it will be sent to the Data Safety and Monitoring Board (DSMB). Upon conducting the trial for the first three subjects, the DSMB will evaluate the results for safety and tolerability as well as the possible evidence of efficacy. If the Safety and Monitoring Council finds that the appropriate criteria for safety and tolerability have been met, then the trial will continue with the participation in the study for the remaining subjects.
The final primary points will be the functional capability documented by the video recording, scores of pain threshold, comparing the base scores with those conducted at one month. Changes in the objective signs of CRPS as well as normalization of the asymmetry of the skin temperature, piloerection, skin coloration, motor changes in perspiration and inflammation will be used as the secondary final points.
There is no medication-free period. Subjects will continue with their medications. The only difference is that the subject will be under the general anesthesia for five days with midazolam and ketamine. There are two exceptions:
Ketamine increases the effects of narcotics. The German researchers were on the verge of completely removing approximately 16 patients from the narcotics during the 5-day infusion. Subjects will need only common non-narcotic medications during the infusion, and if successful, also after the 5-day infusion.
Clonidine may be administered via NG at 0.1 mg TID. Clonidine is an anti-hypertension medication that might counteract the possible side effects of ketamine such as high blood pressure. Furthermore, a study on rats suggests that clonidine may have a neuroprotecting effect.
3.1 Inclusion Criteria:
• I-III physical state (NOTE: Any patient with systemic CRPS would never be
considered an ASA-1. In fact, some of these subjects might be considered ASA-
3 because of the “severe limitations in daily life activities).
• All subjects will meet the diagnostic criteria of IASP and modified criteria of
diagnostic research for CRPS. [8] The diagnostic research criteria for CRPS are
based upon the objective findings during a physical exam. (See APPENDIX 1)
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• Subjects must not have responded to all reasonable treatments. Failed treatments may include medications, nerve blocking, sympathectomy, and spinal cord stimulation.
• The participant must possess the decision-making capacity evaluated by Clinical Psychologist Richard Hoffman, (the Mac Arthur Test for Competence evaluation in Clinical Research. Sarasota, Professional Recourse Press or similar tests).
• The participant has someone whom they identify as their legal guardian in
decision making while the participant is unconscious in the ICU.
3.2 Exclusion Criteria:
• “Morbid obesity” is defined as having an IMC higher than or equal to 35.
• Actiq (Fentanyl). The German researchers found that it was difficult to remove
the subjects from this medication after an intervention with ketamine for 5 days.
• History of resistance to antibiotics.
• History of deep venous thrombosis, increase in intra-cranial pressure, increase in intra-ocular pressure, uncontrolled high blood pressure, psychosis, or anyone
with a history of ischemic cardiac illness.
• Subjects who are taking nitrates will be excluded.
• History of myocardial infarction and alcohol abuse.
• Alteration in renal or hepatic function.
• Subjects older than 65 years of age.
• History of pulmonary hypertension, existing pulmonary pathology, and any
significant medical condition that may confuse the pain conditions such as
diabetes.
• Chronic smokers older than 30 years and patients with bronchial spastic illness
are excluded.
• History of ischemic cardiac illness.
• Pregnant women or any with positive pregnancy test before the inclusion.
3.3 Potential Risks for Subjects:
• Respiratory infection.
• Urinary tract infection.
• Systemic infection due to the invasive procedures such as placement of
venous, arterial line, etc.
• Prolonged dependency on the mechanical ventilator.
• Oral-tracheal injury due to intubation and/or extubation.
• Deep venous thrombosis and pulmonary embolism.
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• Injury of major nerves due to placement of arterial line.
• Unexpected anaphylactic/anaphylactoid reaction due to study medications.
• Weight loss, abnormal appetite, and abnormal perspiration for one or more
months after the five days with general anesthesia with ketamine.
• Re-injury after onset of CRPS symptoms.
• If there are any benefits from the study of a coma with ketamine, these benefits
may not become evident for weeks or months later.
• Midazolam may cause side effects such as respiratory depression and confusion.
Most of the side effects will subside after the effect of the midazolam wears off.
Although the side effects from clonidine are not common, they may occur. The
following symptoms may be severe: dry mouth, sleepiness, vertigo, constipation,
fatigue, headache, nervousness, decrease in sexual capacity, abdominal discomfort, vomiting, exanthema, fainting, increased or decreased heart rate, irregular heart rate, edema of feet or ankles.
The specific side effects from ketamine include:
PSYCHOLOGICAL
Emergence reactions have occurred in approximately 12 percent of the patients.
Psychological manifestations vary in severity between states of sleepiness to vivid
imaginary hallucinations and delirium. In some cases these states have been
accompanied by confusion, excitement, and irrational behavior that some patients reject
as an unpleasant experience. Generally, the duration is not more than a few hours.
However, in some cases, there have been recurrences up to 48 hours after the
administration of ketamine. Residual psychological effects due to the use of ketamine are not known.
The incidence of these phenomena is less in young patients (15 years of age or younger) and older ones (older than 65 years of age). The incidence also decreases as the physician acquires more experience with the medication. The incidence of emergence phenomena also decreases with repeated exposure of the patient to ketamine.
The incidence of psychological manifestations during the emergence, especially
observations such as dreaming and delirium of the emergence, may diminish when using in conjunction with ketamine an intravenous benzodiazepine such as midazolam.
CARDIOVASCULAR
Blood pressure and heart rate frequently increase during the administration of isolated ketamine. However, low blood pressure and bradycardia have been observed.
Arrhythmia has also occurred.
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RESPIRATION
Although frequently respiration is stimulated, severe depression of respiration or apnea may occur after rapid intravenous administration of high doses of ketamine. Larynx spasm and other forms of obstruction of the air passages have occurred during anesthesia with ketamine.
EYES
Diplopia and nistagmus have been observed after the administration of ketamine. It can also cause a slight increase of intra-ocular pressure.
NEUROLOGICAL
In some patients, the increase in the skeletal-muscular tone may manifest itself by tonic and clonic movements that sometimes resemble convulsions.
GASTROINTESTINAL
Anorexia, nausea and vomiting have been observed; however, these generally are not severe and allow for the majority of patients to be able to take liquids by mouth shortly after having recovered consciousness.
GENERAL
Anaphylaxis.
Local pain and exanthema have been reported at the injection site.
Temporary erythema and/or morbiliform exanthema have been reported.
• Gastrointestinal dysfunction and/or muscle discomfort and weakness due to
the prolonged general anesthesia.
• Death
Ketamine has been approved by the FDA as an anesthetic agent for general anesthesia but has not been approved by the FDA as treatment for RSD/CRPS.
This pilot study is a high risk study involving participants. There is also a series of vulnerabilities that require special protection, such as stress, desperation, a long period of unconsciousness during the study in which the subject cannot participate in decision-making as to what he/she does or withdrawing from the study or speak for him/herself. The subject may confuse the research with the treatment, and be susceptible to underestimating the risks
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and overestimate the benefits of his/her participation. The study includes potential short and long-term physical, mental, and financial risks and they all may be serious.
The key in this pilot study, from a perspective of research ethics, is to focus on:
1) Minimizing the risks, to include considering additional protections given the
vulnerabilities of the possible participants, and
2) Insuring a firm consent process to achieve the maximum degree of understanding and voluntary participation.
The protocol includes various steps to minimize the risks:
• Participants who have not responded to all reasonable alternative treatments.
• Study one participant at a time.
• As previously mentioned, there will be an evaluation period after each patient is
released from the hospital. This process may somewhat decrease the anxiety for
the next research subject. A summary of the state and treatment of the patient
will be prepared after each release from the hospital and reported to the Safety
and Monitoring Council (DSMB). Upon completion of the trial for the first three
subjects, the Safety and Monitoring Council will evaluate the results for safety
and tolerability as well as the possible evidence of the efficacy. If the DSMB
finds that the appropriate criteria has been met for safety and tolerability, then
the trial will continue for enrollment and study of the performance for the
remaining subjects.
• A battery of tests before and during the administration of study medications, and using the DSMB.
Additional protections will include:
Dr. Fernando Cantú is the main clinical researcher identified as the primary responsible party for participants in the study in the ICU. He has had experience in Mexico using the coma protocol with ketamine in a compassionate manner.
The clinical co-researchers (Drs. Kirkpatrick, Hoffman and Freeman) of Southern
Florida University, Tampa, will be available to consult directly with Dr. Cantú.
Also, Dr. Robert Schwartzman, Professor and President of Neurology, Drexel University, Philadelphia, Pennsylvania, and Peter Rohr, MD, Klinikum Saarbrücken of the Saarland Saarbrüecken University Hospital have offered their counsel during the study.
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The following steps will offer additional protection to vulnerable participants, and insure the voluntary informed consent:
Dr. Kirkpatrick Co-researcher will be assigned the duties of contracting to help probable participants understand that the invitation is for a study and not a therapy, and to diminish the perception they may have in feeling pressured to participate. After the participant provides his/her consent to be videotaped, this interview will be videotaped.
A family member will be invited to be present and encouraged to participate during the filmed interview. The patient will have a copy of the video to evaluate during the waiting period. [See Appendix 7 for the Video Information Disclosure Agreement]
There will be a waiting period of about two weeks in the consent process. During the waiting period the participants will be encouraged to review the consent process video and invited to ask questions. The subject will be required to make his pre-payment for a single cost for hospital and medical fees.
While the participant is unconscious for five days in the ICU, someone outside the study team (i.e., a family member) will be assigned to act as the participant’s attorney.
3.4 Administration of Medication under Study:
Ketamine and midazolam will be given as a standard procedure of open protocol based upon the clinical experience in Germany with the ICU subjects. The anesthesia will be induced with intravenous ketamine (0.5-1.5 mg/Kg.) and midazolam (bolus of 2.5-6 mg) and adjusted to the deep anesthesia. Oral clonidine may be administered through the NG tube at a dose of 0.1 mg TID.
Clonidine belongs to a type of medications that not only can protect against the neurotoxic, psychometric, and cardiovascular side effects of ketamine, but can also reinforce the analgesic action of the NMDA antagonists. (7)
The anesthesia will be maintained for 5 days by the infusions of ketamine (3-7
mg/Kg./h). Midazolam (0.15-0.4 mg/Kg./h) will be utilized to attenuate the specific
psycho mimetic effects of ketamine. Based on the clinical experience of the Main
Researcher with ketamine, some subjects may require larger doses of midazolam and ketamine to maintain an adequate deep anesthesia. Mechanical ventilation will be used with tracheal intubation, the mode will be determined by the treating physician. All subjects will receive a placement of an arterial line, Foley catheter and NG tube.
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A typical sequence of placement of line/monitoring on the first day:
1. Placement of an intravenous peripheral line for the induction of general
anesthesia.
2. Intubation.
3. The arterial line.
4. The central line in the antecubital cavity for the administration of long-term
medication.
5. Feeding tube.
6. The Venoflow medians (synchronized compression device) to minimize the risk of DVT.
7. 5000 Units of Subcutaneous heparin to minimize the risk of DVT.
8. The Foley catheter.
During the study intervention in the ICU, hepatic enzymes, CPK, and thorax x-rays will be supervised. Subjects will be closely monitored for respiratory infections and urinary tract infections using the standard protocol of SJH’s ICU.
As in the study in Germany, subjects will be monitored daily for changes in the CRPS objective signs such as normalization of the skin temperature in an asymmetric manner, pilo-erection, skin coloration, motor changes in perspiration and inflammation. Some research subjects may not show permanent objective results that could be traced during the ketamine infusion.
After 5 days, the infusions will be reduced and subjects will be removed from
the mechanical ventilator. It is expected that a patient with controlled ventilation for five days may have a deficit in CO2 (producing a low respiratory flow). Furthermore, it is foreseen that the patient will be confused and unable to respond to orders during the removal process. These two factors will be taken into account when the patient is weaned off the ventilator.
A protocol of the typical removal from the ventilator:
FIO2 = 21% (room air)
Tidal volume = 6-8 ml / Kg.
CPAP = 5 centimeters H2O and 5 centimeters H2O support pressure
IMV = 6
IMV = 6
IMV = 4
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IMV = 3
IMV = 2
IMV = 1
Extubate
NOTE: The above recommendations for support of the ventilator were made by John B. Downs, MD, Professor of Anesthesiology at Southern Florida University:
The above-mentioned initial ventilating frames must produce a PaCO2 ~45 mmHg that will prevent hypoventilation during the emergence. Use the lowest FIO2 to obtain SPO2 >90%. In other words, FIO2=0.21. I would reduce the mechanical rate by increasing the cycle time. I would start at 10 seconds. (6 BPM) then proceed to 15 seconds, 20 seconds, 25 seconds, and so forth to 60 seconds as long as the SPO2 does not decrease.
Hypoventilation is not a problem as long as the FIO2 is 0.21. You cannot use the SPO2 as a ventilation indicator with any O2 supplement.
APRV is still the preferable method to ventilate and wean off the ventilator.
After awaking from the anesthesia, all subjects will be evaluated for pain relief.