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
Laboratory Exams before the study
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.
Spontaneous pain, hyperalgesia, mechanical allodynia, and other signs and symptoms associated with CRPS will be determined. The subject will be evaluated to determine the need to continue the hospitalization, the CRPS symptoms, and the need to continue with the pain control by the treating physician. If the subject meets the hospital release criteria, he/she will be sent home. If the patient requires continued hospitalization, he/she will be transferred to a floor and the medical attention and standard nursing care will continue until the patient meets the criteria for their release.
The protocol requires a hospital stay of seven days, as long as there are no adverse events or complications. The hospital stay consists of five (5) days in ICU level in a state of induced coma, immediately followed by two (2) days of post-therapy observation.
After the release from the hospital for each patient, a summary of the treatment, status and condition of the patient will be prepared and submitted to the DSMB and Dr. Kirkpatrick. Any concerns of this DSMB will be discussed with the Main Researcher, and if deemed necessary, modifications to the protocol will be submitted for approval of IRB and carried out.
After the release from HSJ, the subjects will be evaluated as outpatients at the USF Pain Management Clinic in Tampa, Florida at one month. For this visit, the subjects will
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submit again to the same battery of tests that they received before the hospitalization, as well as other diagnostic services and tests related to the CRPS symptoms.
3.5 Scheduling of Data Gathering in ICU Before Participating in the Study:
Basal metabolic panel (electrolytes, NU, Ca, Na, creatinine, glucose), BHC, hepatic enzymes, CPK, EGO (collected in a sterile container):
Thorax x-ray and EKG
A duplex ultrasound test before treatment to verify a normal deep venous system.
Chronic Smokers: Patients older than 30 years are excluded from the study. Research for subjects age 30 and younger. They will have to try to stop smoking and have a “Simple Spirometry”. This test is necessary before evaluating the patient for CRPS treatment. The test can be performed in most hospitals. Patients must call their local hospital and ask for the Pulmonary Function laboratory. The Procedure invoiced by the code in the U.S. is #94010 and the retail price is $378. In the event of any doubt, have the pneumologist call Dr. Kirkpatrick.
3.6 Neuropsychological Test
Cognitive Test
RBANS Test
RBANS is a short test, individually administered, which helps determine the
neuropsychological state of adults ages 20-89 years who have a neuropsychological
injury or illness or illnesses such as dementia, cranial injury or emboli. The test is a
timed exercise of “connecting the dots” that helps evaluate the psychomotor abilities.
The test is designed for use in research studies by non-psychiatric staff that evaluates
patient performance in five areas: Recent memory, late memory, spatial-visual ability,
attention and language.
3.7 Long-term Follow-up
Follow-up Visit at one month
The neuropsychological tests for cognitive function will be conducted before the
ketamine infusion and at 1 month after the release from HSJ. Subjects will be evaluated
as outpatients by Dr. Kirkpatrick and Dr. Hoffman. Ketamine side effects such as
vertigo, muscle weakness, fatigue, and anxiety will be documented during the
ambulatory patient visit. Utilization of opiates by the subjects will be documented (with
the intrathecal morphine pump) for pain management before participating in the study
and at one month after study participation.
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Subjects will be supervised for daily life activity changes. They will be asked to classify their social and professional rehabilitation as complete, significant improvement, unchanged, slightly worse or significantly worse during the ambulatory patient visit.
Follow-up at Two Years
Patients will advise Dr. Kirkpatrick at 6 months, 12 and 24 months to evaluate the
following clinical parameters:
The patient will be asked to classify whether his/her social and professional
rehabilitation is complete, significant improvement, unchanged, slight deterioration, or significant deterioration.
4.0 Importance of the Study
The results of the first series of 10 subjects conducted in Germany suggest that the ketamine-midazolam anesthesia can be achieved safely and can be efficient in severe generalized CRPS where all other conventional therapies have failed. Absent an efficient treatment for severe generalized CRPS, the ketamine-midazolam anesthesia could become an option for treatment that offers significant pain relief for considerable periods of time. We expect that this research will save lives restoring hope in patients who otherwise could be contemplating suicide.
Side effects, the main infectious complications related to intensive care, can be
controlled with antibiotic therapy. Thus far in Germany no long-term emotional,
cognitive or medical complication has been observed in any of the subjects treated.
However, due to potentially serious complications, only those subjects for whom all conventional treatments have failed will be selected.
Future challenges will be the strategies to maintain the success of the initial treatment, define the ideal patient profiles, perfect the ideal time for the treatment and determine the minimum efficient dosage and duration of the treatment. Also, this study may help determine if there is a role for the ketamine-midazolam anesthesia in patients with less severe forms of CRPS. For example, could a shorter duration of ketamine infusion at high doses provide remission in a subgroup of patients with less severe CRPS?
Freeman and other clinical researchers have argued that the placebo-controlled trials are necessary for the evaluation of new low-risk therapies where it is observed that the response to the placebo is an important variable in evaluating a therapy in a particular stage of the illness. [9] This model study will serve to support a request for subsidy to the NIH when determining the optimal primary final point of efficacy in a statistically larger, randomized, controlled trial. The active control could be an intravenous analgesic that has a completely different action mechanism than ketamine such as fentanyl.
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5.0 References
1. Baron R, Janig W. Complex Regional Pain Syndrome: explained mystery? Lancet Neurol 2 (2003) 687-97.
2. Bandyk DF, Johnson BL, Kirkpatrick AF, Novotney ML, Back MR, Schmacht DC,. Surgical sympathectomy for reflex sympathetic dystrophy syndromes. J Vasc Surg 35:269-77, 2002.
3. Cace SP, Mantyh PW. Molecular dynamics of pain command. Nature Review 2 (2001) 83-91.
4. Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med 343 (2000) 1765-1768.
5. Woolf CJ, Salter MW. Neuronal Plasticity: Increasing the gain in pain. Science 288 (2000) 1765-1768.
6. Kiefer T, Rohr P, Unertl K, Altemeyer K, Grothusen J, Schwartzman the R.
Ketamine-Midazolam Anesthesia for Rebel CRPS-I. 10 World Congress on Pain, San Diego, CA, August 17-22, 2002.
Available on the Internet:
http://www.rsdfoundation.org/en/en_research_updates.html
7. Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut REF., Sub-anesthetic ketamine infusion therapy: A retrospective analysis of a new therapeutic approach to the complex regional pain syndrome. Pain Medicine 5 (2004) 263-275.
8. Bruehl S, Harden RN, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M. External approval of the 1ASP diagnosis criterion for the Complex Regional Pain Syndrome and the proposed research diagnosis criterion. International Association for the Study of Pain 81 (1999) 147-54.
9. Freeman, T.B., Vawter, D.E, Leaverton, P.E., Godbold, J.H., Hauser, R.A., Goetz, C.G., Olanow, C.W. Placebo-controlled surgical trials. N. Engl. J. Med 341 (1999) 988- 992.
CO-RESEARCHERS
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PAIN MEDICINE
Co-researcher Dr. Anthony Kirkpatrick, MD, PhD, is the President of the Scientific Consulting Committee for the International Research Foundation for RSD / CRPS. A list of the members of its committee is available at:
Dr. Kirkpatrick also has a PhD degree in pharmacology and has administered thousands of doses of ketamine-midazolam for general anesthesia and conscious sedation.
He was responsible for developing a new system of medication administration and obtaining the approval of the FDA in the United States to try the medication
administration system on humans. This unique technology is being applied in
liposoluble medication and to cause a less lipidic load in dilutants and make the
preparations of medications that resist bacterial growth. To date (2006), more than $45 million have been spent in the commercialization of this technology.
Also, he has directed national clinical trials in the United States that bore the approval of the FDA of esmolol, a medication used to control heart rate for short periods of time.
A copy of Dr. Kirkpatrick’s CV is available at:
http://rsdhealthcare.org/Kirkpatrick_CV.html
Co-researcher Dr. Robert J. Schwartzman, has directed research on CRPS for over 30 years. He is a co-researcher in the study of coma with ketamine in Germany. He is a professor and Chairman of Neurology at Drexel University, School of Medicine,
Philadelphia, Pennsylvania.
Currently, he conducts the follow-up of about 30 patients in the U.S., who have
undergone the coma with ketamine study in Germany. He supports the use of low doses of ketamine in reinforcement infusions to maintain the beneficial effects of the coma with ketamine, especially in patients who have suffered re-injury.
Dr. Schwartzman recently appeared in a medical report on the study of coma with ketamine prepared by CNN news.
CNN NEWS
http://www.rsdfoundation.org/en/CNN_RSD.htm
CLINICAL PSYCHOLOGY
The protocol requires an important pre- and post-study neuropsychological intervention evaluation (cognitive function). Co-researcher Richard Hoffman, PhD, is a clinical
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psychologist who has treated hundreds of patients with CRPS. It is possible to include upon request a DVD of Dr. Hoffman treating children with CRPS. A shorter version of the DVD is available on the Internet at:
http://www.rsdfoundation.org/en/en_furtherchildren.html
CLINICAL RESEARCH
Co-researcher Dr. Thomas Freeman, is recognized internationally for his work in the area of high-risk brain research. He was the first in the world in demonstrating that fetal grafts survive in the human brain. He has defended the use of placebo and/or active controls in low-risk studies in the New England Journal of Medicine. [9] Such study designs are now accepted by the FDA, NIH, and in Europe. Dr. Freeman has received extensive financing from NIH to support his work. At SFU, he is a professor of neurosurgery and medical director of the Center for Aging and Brain Repair.
COORDINATOR OF CLINICAL RESEARCH
Deborah Scott, BA, CCRC, South Florida University, Tampa, Florida, U.S.A.
She has the following credentials:
Psychology: Florida University, 1981
Certified coordinator of clinical research (CCRC) for the Association of Clinical
Research Professionals (ACRP)
10-year experience in coordinating clinical trials.
Experience with NIH trials, trials sponsored by pharmaceutical and device companies.
IRB in continuous education for protection in humans.
CONSULTANTS
Srinivasa N. Raja, MD, is a professor of Anesthesiology and director of Pain Research at the Pain Division in the Department of Anesthesiology and Critical Care Medicine at Johns Hopkins University, School of Medicine in Baltimore, Maryland.
The efforts of Dr. Raja’s research are directed toward understanding the peripheral and central mechanisms of neuropathic pain and determining the role of the sympathetic nervous system in mediating or maintaining the chronic pain states. He is also directing the clinical trials to develop better pharmacological strategies for the treatment of neuropathic pain states such as complex regional pain syndromes. He is part of the Editing Committee of ANESTHESIOLOGY.
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Dr. Dennis F. Bandyk, is a professor of Surgery and Director of the Division of
Vascular and Endovascular Surgery at the Southern Florida University. He has
experience in the CRPS ailment and has performed the surgical sympathectomies for untreatable CRPS that have a sympathetic predominance based on a series of diagnostic/therapeutic sympathetic blockages.
Peter Rohr, MD, is a professor in the Department of Anesthesiology and Critical
Medicine at Klinikum Saarbrücken in the Teaching Hospital of Saarland Saarbrüecken University, Germany. He is the Main Researcher in the study of coma with ketamine in Germany.
HOSPITAL AND PROFESSIONAL FEES EXPENSES
The basic costs involved for a five-day (5) hospitalization in the Intensive Care Unit and subsequent care at HSJ. These charges will include but may not be limited to the following:
Charge for Admission to the ICU
Respiratory Therapy Service HSJ:
The ICU ventilator and daily respiratory
consultations
intravenous Medications:
• Infusion of Ketamine
• Infusion of Midazolam
• Antibiotics
• Bronchial dilators
• Vessel-active agents for treatment of high/low blood pressure
Anesthesia service for intubation, placement of intravenous lines, extubation and critical care
Enteral nutrition
intravenous liquids and electrolyte infusions
Laboratories:
• Arterial blood gases.
• Laboratory tests will be performed to monitor the subject.
• Thorax x-ray.
• Simple initial abdomen x-ray to confirm placement of enteral tube
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HSJ has drafted the following financial obligations:
If you decide to take part in this study, you must sign this consent form. You will also have to agree to pay all medical treatments involved in the study. You will be provided the name of a financial counselor at San Jose Hospital who will assist you in setting the payment date for this procedure.
Financial options that San Jose Hospital has for patients:
Option 1.
• SOLE amount of $29,000 U.S. dollars
• Includes: hospital costs, the first reinforcement with ketamine, medications as
well as medical fees.
• The amounts are subject to change, by written notification, either by e-mail or any other means of communication.
• The expenses of any complication will be covered by this amount.
Option 2
• Patient makes a pre-payment of $22,000 US Dollars, but at the end of the service he/she must pay the full amount of the charges with a discount benefit according to the following ranges:
From to Discount
$1 - $15,000 10%
$15,001 - $30,000 12%
$30,001 And More 15%
• Expenses for any complication will have to be covered by the patient.
• With this option the doctors’ fees are NOT included in the hospital price.
They must be covered with a pre-payment of $7,000 U.S. dollars with no
discount.
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Summary:
Prior to scheduling the admission to the hospital, an appointment will be scheduled with a SJH Financial Counselor to arrange for payment of the fees. This person can be located by notifying Dr. Cantú. The SJH financial counselor assumes the primary responsibility to explain the hospital charges to you.
All necessary supplies and medications associated with these procedures will be
included in the study charges. These items will include ketamine, midazolam, clonidine, intravenous supplies, etc.
During the planning process, the routine hospital admission processing will be
completed.
Additional visits related to the study may incur inconvenient travel and costs.
There is no sufficient clinical data to be able to request clinical subsidies. The real ethical question is: is it more ethical to charge the patients or not conduct the study (meaning, moreover, not offering the opportunity to participate?). Especially in this development stage of this study, the focus is in providing all the available information to assist the IRB members and others to integrally evaluate the risks and benefits of the study, and evaluate whether all reasonable steps have been carried out to minimize the risks to participants consistent with the solid research design and protect the participants against the possible vulnerabilities.
APPENDIX
1. Proposal of Experimental Revision of CRPS Diagnostic Criteria.
2. Description of the neuropsychological evaluation.
3. Video information disclosure agreement.
4. Neuropsychological data on nine subjects.
5. Upon completing the first research subject, the following recommendations for
improvement were made:
6. After completing the first research subject the following recommendations were made for improvement:
I. Physician
II. Care Needs of the Patient and his Family
APPENDIX 1
Proposal of experimental revision of CRPS diagnostic criteria.
New Proposed Criteria for CRPS Research [Bruehl, Harden, Galer, el al. Duela 1999;81 :147-154]
(1) Continuous pain that is not proportional to the causing event.
(2) Must report at least one symptom in each of the four following categories:
Sensitive: the hyperesthesia reports.
Vasomotor: reports of asymmetry in temperature and/or changes in skin color and/or asymmetry in skin coloration
Sudomotor/edema: report of edema and/or perspiration changes and/or perspiration asymmetry
Motor/trophic: reports of a decrease in range of movement and/or motor disorder
(weakness, trembling, distonia) and/or trophic changes (hair, fingernails, skin).
(3) Must show at least one sign in two or more of the following categories:
Sensitive: evidence of hiperalgesia (to the touch with a pin) and/or allodynia (with a soft touch)
Vasomotor: evidence in asymmetry of the temperature and/or changes in skin color and/or asymmetry.
Sudomotor / edema: evidence of edema and/or changes in perspiration and/or
asymmetry in perspiration.
Motor / trophic: evidence of a decrease in range of movement and/or motor disorder (weakness, trembling, distonia) and/or trophic changes (hair, skin, fingernails).
APPENDIX 2
Description of the Neuropsychological Tests
NOTE: The Florida Psychology Council prohibits the distribution of testing materials to persons who are not psychologists. However, any or all of the testing materials can be sent to the psychologist selected by the IRB. All selected tests are standardized and well accepted and are evaluation indicators that are frequently used. Repeatable battery for Evaluation of the Neuropsychological State (RBANS)
RBANS is a short test, individually administered, which helps determine the
neuropsychological state of adults ages 20-89 years who have a neuropsychologicalinjury or illness or illnesses such as dementia, cranial injury or embolism. The test is a timed exercise of “connecting the dots” that helps evaluate the psychomotor abilities.
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The test is designed for use in research studies by non-psychiatric staff that evaluates patient performance in five areas: Recent memory, late memory, spatial-visual ability, attention and language.
APPENDIX 3
Videotaped information disclosure agreement.
Disclosure of information for photographing and news media
Date: ___________
Researcher: Dr. Fernando Cantú Flores
Name of interviewee: __________________________________
Address of interviewee: ________________________________ Telephone
I, ________________________________________, hereby authorize and grant my permission to the San Jose Technological Hospital of Monterrey to use the safeguarded health information protected in an audio- and video-recorded format for the use of consent-provided procedure documentation.
I understand that this authorization is with the sole purpose of recording the consent provided procedures for the study entitled: A Pilot Study of Infusion of Ketamine for Five days for the Untreatable Complex regional Pain Syndrome. I understand that this recording will include personal health information, and I freely provide my consent for the use and disclosure of this information to the researchers, physicians, and personnel that is conducting and directing this research. I understand that this information may be
seen by other persons, including but not limited to:
The research team, including the Main Researcher, Dr. Fernando Cantú Flores, study coordinator, research nurses, and all the other research personnel. The whole medical team personnel and other SJH staff treating and providing me with care as part of this research.
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Any federal, state, local government agency regulating this research. This includes the (FDA) and the Health Department (DHHS).
Members of all the councils directed by the Research Division of SJH supervising this research, including but not limited to the IRB Members of the Privacy Council of SJH.
Personnel at the Research Office of SJH, Division of Research Compliance of SJH, and other SJH offices supervising this research.
Safety and Monitoring Council and its staff.
The Main Researcher is authorized to release the information on the video to the other persons when he so deems appropriate.
I understand that I will receive a copy of this video for my own review. I have been informed of the context and use of my information or image and the type of audiovisual recording that will be taken. I acknowledge that I am providing my consent voluntarily for this recording to be taken, and waive my confidentiality rights, and that this permission is in no way a condition for treatment, payment, or eligibility for any benefit. I understand that this consent may be revoked in writing whenever I desire so.
Signature of the person who will be videotaped:
______________________________________________ Date: __________
Signature of witness:
_
_____________________________________________ Date: __________
Signature of the main researcher:
APPENDIX 4
Neuropsychological tests on nine subjects
Introduction
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More than providing a “typical” profile for the RSD patients, our intention was to
compare functioning after the deep anesthesia with ketamine. For this reason, we will discuss changes, if any, in functioning.
Methods
A total of nine patients were identified (8 women, 1 man) ages 19 to 44 years (median 29.1) by the treating neurologist (RJS) with RSD criteria, and candidates for deep anesthesia with ketamine were considered. The patients were referred to the base neuropsychological test prior to receiving this treatment. In table 1 the demographic data of the patients can be observed. After an interview with a certified neuropsychologist (SK), a brief W and G neuropsychological battery was administered to all the patients. All the patients returned for the follow-up interview, reminder letter and tests, which were conducted with the same battery of exams (unless otherwise indicated), approximately six weeks after termination of the treatment.
Table 1
To watch this film you must have QuickTime™ and a TIFF decompressor (uncompressed)
Neurological Tests:
The following psychological and neuropsychological measurements were utilized to determine the cognitive function in multiple dominions (a more detailed description of these measurements can be found in appendix A): Intellectual functions and academic abilities (base): Subtest of information and vocabulary,
Subtests of the Wechsler - III
adult intelligence scale (WAIS-III), wide-range accomplishment - 3 test; Executive
Speed of Functions/Processing:
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Codification subtest of the WAIS-III, controlled oral test of the digit symbol of word association;
Attention: Palm Subtest of the WAIS-III, Connors continuous function test
(CPT) of digits; Memory: History I of logical memory; Wechsler Scale III memory
Subtest, Hopkins verbal learning test; Motor Functions: Lightly tapping with finger,
squeeze strength; Affection and personality: Tincture Barrel Depression Inventory (BDI), Inventory of the characteristics of the state of anxiety; Pain: McGill pain questionnaire; Personality: Minnesota Multiphasic - 2 personality inventory (MMPI-2), alternate versions were utilized when available.
Organization and data Analysis
Whenever possible, scores were converted to z score equivalents, and a median z score was calculated for each ability. Such conversion was possible for process speed ability, motor function and anxiety. Also converted to z scores were the digit space performance (attention control); however, the total alteration index of the CPT (attention control) prohibited the calculation of score for only one ability. So, the attention measurements were analyzed separately. For memory, the number of the addition of the units remembered for learning and late memory of both memory tests were calculated and then formulated as percentage of the possible total of 11 units-SPSS. 0 (SPSS Inc.) was utilized in all the analyses and the results were considered significant if p was less than 0.5. The differences in each ability were evaluated using t tests.
On the J and 3 scales. These same scales tended to demonstrate the majority of the improvements (according to what was indicated by lower counts) after treatment.
Classifying the magnitude of change revealed that most of the patients showed a change of less than 5 T in any direction on the majority of the MMPI-2 scales (middle and right of the table). The increase in this range reduced 10 T further the frequency of the change.
Discussion:
New patients were evaluated with a battery of neuropsychological and personality tests before and after treatment with deep anesthesia with ketamine. Compared to their base calculations before the treatment, there was no alteration in the attention, processing speed, memory, manual speed tests, or in the character and personality tests. Whenever significant changes occurred, this was typically indicative of improvement in functioning. Character and personality continued to be stable in the before and after tests. There was a significant decline in the pain index of a questionnaire.
The deep anesthesia with ketamine has been effective in treating the untreatable, severe pain that is refractory to other interventions. The results of this study do not demonstrate any adverse effect in the neuro-cognitive, memory or emotional function as a result of
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this treatment, and it suggests a positive relation between the pain relief and
improvement of functions in these behavior controls.
APPENDIX 5
Upon completion for the first research subject, the following recommendations for
improvement have been made:
I. Medical
II. Care needs of the patient and family
Medical
Revised 9/30/06
1. Companions in Mexico: At least 2 companions are needed in Monterrey, Mexico, while patient is hospitalized.
2. Ketamine emergence: If possible, a companion needs to be present at all times in the ICU while hallucinations/paranoia exist during the ketamine emergence. The companion must provide the patient with constant verbal assurance. However, there will be occasions when the companion must leave the ICU temporarily for proper care of the patient.
3. Nursing care: Nurses must explain the medications that will be administered and make better visual contact with the patient. Patients tend to experience paranoia when emerging from the ketamine and need to be reassured by the nursing staff.
4. Bearing weight: The research patient must avoid bearing weight as much as possible for at least two weeks after the ketamine emergence. CRPS could be reactivated due to re-injury. Patient must be encouraged to perform exercises in a temperature-controlled swimming pool while in Monterrey. If needed, the patient will require a “personal trainer” to help him/her safely enter and exit the temperature-controlled swimming pool.
Fortunately, on September 29, 2006, Dr. Cantú located a temperature-controlled
swimming pool for persons with disabilities at no charge for the research subjects. It would be a nice courtesy or gesture to give a gratitude/recognition plaque to this place from the Foundation.
Here is an example of the plaque:
http://www.rsdfoundation.org/test/DrBerde.html
5. Chronic Smokers: Patients older than 30 years are excluded. Research subjects age 30 or younger must try to quit smoking and undergo a “simple spirometry”. This test is
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necessary prior to evaluating the patient for CRPS treatment. This test can be conducted in most hospitals.
Patients must call their local hospital and ask for the Pulmonary Function laboratory.
The Procedure invoiced by the code in the U.S. is #94010, and the “retail” price is $378.
For any questions, the pneumologist in charge of the patient may call Dr. Kirkpatrick.
6. Physical Therapy: exercise in a temperature-controlled swimming pool is
recommended, not formal physical therapy. A physical therapist must be specially trained for treating patients with CRPS, otherwise there is great risk of injuring the patient (See article #4 above).
7. Ketamine reinforcements at low doses: On September 30, 2006, Dr. Kirkpatrick had a conference with the Main Researcher, Dr. Meter Rohr, in Germany. They agreed that the research patients must avoid trauma/pain for at least 3 months after the coma
with ketamine. They also agreed that a reinforcement of 2 hours with a low dose of ketamine every 14 days for 3 months is a reasonable protocol. However, we do not know what is the optimal regime for the ketamine reinforcements. More patients have to be studied to arrive at this determination.
Below is a network address for a study on the median life for eliminating the
intravenous ketamine. The ½ period or beta median life had a range of 3 hours (normal volunteers) at 5 hours (ICU patients). Therefore, do not expect a constant level (peak) in the blood until after a constant infusion of ketamine for approximately 4-5 median lives or at least 12 hours. The need for a loading dose (bolus injections) of intravenous ketamine should be awaited for up to 12 hours to obtain a proper clinical response from the time the constant infusion of ketamine is initiated.
A good initial infusion rate of intravenous ketamine for reinforcements at low doses in an adult weighing 70 Kg. is 100 mg/hour.
http://bja.oxfordjournals.org/cgi/content/full/90/2/155
8. Thorax X-Rays: One routine thorax x-ray per day is needed in the ICU.
9. Patient’s representative: The patient’s representative must have a cell phone
available and working at all times while in Mexico.
10. Feeding tube and constipation test: In Germany, the GI feeding tube performance is first tested with tea. If the GI tract functions normally with the tea test, routine nutritional feeding is initiated. During the 5-day coma with ketamine, patients will be given a laxative medication through the feeding tube to avoid constipation. Generally, this laxative treatment will be carried out once a day at around 8 P.M.
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11. Duration of the stay: If there is a complication, such as re-injury, the stay in
Mexico may be longer than one week after the hospital release for observation and possible treatment.
12. CRPS prevention: A typical medication protocol that we use to prevent CRPS after a surgical trauma.
• Acetaminophen 1000 mg (Tylenol)
• Loading dose of celecoxib 400 mgs (Celebrex)
• Gabapentina 300 mg (Neurontin)
II. Comfort needs of the patient and family:
Recognition to nursing for an outstanding care: Nurses Silvia, Norma and
Lupita had an exceptional performance in the ICU. They need to be recognized for the exceptional nursing care. It would be a nice gesture a recognition plaque from the Foundation presented by the General Director of the San Jose Hospital.
Transportation: A GPS is recommended with a rented automobile for the family while in Monterrey. It might be difficult to obtain a taxi after 8 P.M. at the hospital.
Special equipment: A video camera is recommended to document the clinical course, and also Internet access. Internet access is free at the business centers of many hotels in Monterrey.
The medical team: The patient must be introduced to the “Team” upon admission to the hospital.
For example:
To Dr. Fernando Cantú: Main Researcher
To Dr. Javier Valero Gómez: Medical Director, San Jose Hospital
ICU physicians
Infectologists
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Laboratory Exams before the study
The admission laboratory exams must be completed in the country of origin.
The laboratory results will be reported to Dr. Kirkpatrick and brought to Dr. Cantú upon arriving in Monterrey. These exams include:
• Basal metabolic panel (electrolytes, BUN, Ca, Na, glucose, creatinine), BHC,
hepatic enzymes, CPK, EGO (routine urine analysis);
• Thorax Tele (Chest X-Ray) and EKG;
• Doppler ultrasound test before treatment to verify a normal deep venous system.
Chronic Smokers: Patients older than 30 years are excluded.
Research subjects age 30
or younger must try to quit smoking and undergo a “simple spirometry”. This test is necessary prior to evaluating the patient for his protocol with CRPS. This test can be conducted in most hospitals. Patients must call their local hospital and ask for the pulmonary function laboratory. The code for the invoicing procedure in the U.S. is #94010, and the price is around $378. Should you have any questions; the pneumologist will have to contact Dr. Kirkpatrick.
Financial Arrangements: Steve Altmiller and Dr. Kirkpatrick will assist in preparing the best financial arrangements with the hospital and doctors for the following research subjects.
A financial arrangement must be structured that encourages teamwork, Dr. Fernando Cantú being the main researcher. The financial arrangement has to also encourage San Jose Hospital’s leading care. Furthermore, they will also work jointly to improve the CONSENT document for the following patient under study.
NOTE: Some medical insurance companies in the U.S. will pay medical expenses if the medical assistance is part of a research protocol in another country. Coverage of the medical insurance is particularly appropriate when there are no other reasonable options for treatment available to the patient and when the condition of the patient is deteriorating day by day. Prior to entering the study, research subjects are encouraged to confirm with their insurance company to find out if there is coverage while receiving medical assistance as part of a research protocol in another country.
6. Arrangements at home and hotel: The family needs to make arrangements for hydrotherapy at home before returning from Mexico. They will also have to consider hotel lodging and wheelchair needs while in Monterrey, Mexico.