Lawrence Park, AM, MD presented to the U.S. Food and Drug Administration Neurological Devices Panel examining the reclassification of electroconvulsive therapy (ECT) devices on January 27, 2011. These are his remarks describing a research literature review of the risks and primary side effects of ECT, as published in the public record of the meeting.
Key risks are defined as substantial risks of device use that could significantly influence the risk/benefit profile of the device. Mitigating factors may potentially serve as regulatory controls to adequately reduce the risk of device use such that a reasonable assurance of safety and effectiveness can be demonstrated for the device.
Like the determination of potentially significant adverse events discussed in the safety review, the identification of key risks is based on similar criteria, that is, they are substantiated by a comprehensive review of all sources of data, there is sufficient evidence of significant frequency and severity, and there’s evidence of being associated with ECT device use. […]
The key risks of ECT are presented in this slide and reorganized into three different main categories.
The first category, medical and physical risks includes adverse reaction to anesthetic agents and neuromuscular blocking agents, alterations in blood pressure, cardiovascular complications, death, dental and oral trauma, pain and discomfort, physical trauma, prolonged seizures, pulmonary complications, skin burns, and stroke. The other two main categories include cognitive and memory dysfunction, and device malfunction. […]
Again, here’s the list of proposed key risks. The Panel will be asked if this is a complete and accurate list of the key risks presented by ECT and asked to comment on whether you disagree with the inclusion of any of these risks or whether you believe any other risks are among the key risks presented by ECT.
Key Risks and Mitigating Factors of ECT
I’ll now present an examination of each key risk and potential mitigating factors by reviewing this table which goes over the next three slides.
Adverse reactions to anesthesia are rare but potentially severe complications associated with ECT. These reactions are related to the use of anesthetic agents and neuromuscular blocking agents to which patients may have rare but potentially severe reactions. Potential mitigating factors may consist of pre-ECT assessment, including pertinent medical and surgical history, family history of reaction to anesthetic agents, physical exam, as well as appropriate procedure monitoring and clinical management to any reaction that may arise.
Alterations in blood pressure are common but typically benign complications associated ECT. Hypertension as well as hypotension may be associated with ECT treatment. Potential mitigating factors include pre-ECT assessment of medical, particularly cardiovascular status, appropriate procedure monitoring, and clinical management.
Cardiovascular complications are uncommon but potentially severe complications of ECT treatment. They most commonly include arrhythmias and/or ischemia. Cardiovascular complications are one of the most frequent causes of morbidity and mortality associated with ECT. Potential mitigating factors for cardiovascular complications include pre-ECT assessment which may include blood pressure assessment, pre-ECT electrocardiogram, echocardiogram or Holter monitoring, appropriate procedure monitoring, and clinical management.
Death is a rare but severe outcome of ECT treatment. It is a result of various complications of ECT such as reactions to anesthesia, cardiovascular complications, pulmonary complications, or stroke. Potential mitigating factors include those proposed for each of these key risks.
Dental and oral trauma including dental fractures, dislocations, lacerations, and prosthetic damage are uncommon complications of ECT and are generally of mild to moderate severity. Potential mitigating factors may include pre-ECT dental assessment, removal of prostheses, as well as the use of mouth protection or bite blocks during the procedure.
Pain and discomfort are common but generally mild to moderate complications of ECT. They are typically treated with the use of as-needed analgesic medication.
Physical trauma associated with ECT, they include fractures and soft tissue injury. Physical trauma usually occurs as a consequence of significant muscle contraction during the treatment. Though more prevalent in previous years of ECT use, in current practice, this key risk is uncommon. Potential mitigating factors to prevent or reduce the severity of physical trauma include the use of general anesthetic agents and neuromuscular blocking agents. 189
Prolonged seizures are an uncommon and moderate to severe complication of ECT. Status epilepticus may ensue if prolonged seizures are not properly treated. Potential mitigating factors include an appropriate pre-ECT neurological assessment as well as EEG monitoring during the procedure and the availability of rapid treatment of prolonged seizures should they occur.
Pulmonary complications, such as prolonged apnea or aspiration, are rare but potentially severe complications of ECT. With cardiovascular complications, they represent one of the most common causes of morbidity and mortality associated with ECT. Potential mitigating factors include appropriate pre-ECT assessment of pulmonary function, pre- ECT tests such as chest x-ray and pulmonary function test, and appropriate monitoring and clinical management before, during, and after the procedure.
Skin burns are uncommon and typically mild complications of ECT. They most commonly occur when there’s poor contact of the electrode with the skin surface resulting in high impedance in the electrical circuit. Skin burns may be mitigated by proper skin preparation, electrode contact, including the use of conductivity gel.
Stroke is a rare and potentially severe complication that may be associated with ECT. Potential mitigating factors include pre-ECT assessment of risk factors for stroke, including possible neuroimaging or cardiovascular and neurovascular assessment when appropriate, appropriate procedure monitoring, and clinical management during the treatment.
The issue of inadequate informed consent processes and/or forced treatment has been raised in the public docket, in the MAUDE database, and in the published literature. Critics of the informed consent process claim that if individuals are inadequately or inaccurately informed of the risks of ECT, the risk/benefit assessment is altered.
One potential mitigating factor for inadequate consent is the requirement of a more rigorous informed consent process. Such a process would help to ensure that the patient is making a fully informed decision about receiving treatment. The process would consist of outlining a more rigorous consent process in the user labeling of the device that would require the use of an additional checklist in addition to standard written informed consent procedure. This checklist would contain all known risks of device usage, the likelihood of occurrence, and the potential severity.
During the process, the treating physician and patient would be required to review each item with both parties signing off to acknowledge discussion of the item. This checklist could then be kept with the standard written informed consent documentation, and the criteria for patient capacity to consent to treatment and perform the acceptance of risk through this process would remain unchanged. Acceptance of risk checklist may be a useful special control for addressing the risks of ECT device use. Within FDA, there’s precedence for requiring such additional informed consent requirements.
Please keep this discussion of key risks and potential mitigating factors in mind in your deliberations of the following question regarding whether the medical and physical risks of ECT can be adequately mitigated. […]
Cognitive and Memory Problems with ECT
A second area of key risks associated with ECT use is cognitive and memory dysfunction. The FDA review found that ECT is likely associated with immediate general cognitive and memory dysfunction. Cognitive dysfunction is represented by disorientation. Disorientation appears to be transient and generally resolves in a matter of minutes after the procedure.
Memory dysfunction in general largely resolves in the days to weeks after the completion of a course of ECT. However, in certain domains, particularly in anterograde verbal memory and retrograde autobiographical memory, deficits may be more prominent and/or persistent. While anterograde memory deficits may resolve in the days to weeks after ECT, autobiographical memory deficits may be more persistent. Per Dr. Como’s and Dr. Krulewitch’s presentations, at one to two weeks post-ECT, there is evidence that suggests that autobiographical memory performance is approximately 76 to 77 percent of baseline performance for right unilateral treatment and 58 to 67 percent for bilateral treatment. Limited evidence suggests that ECT memory deficits may approach baseline at six months.
In terms of mitigating factors, studies have demonstrated that potential mitigating factors for reducing the occurrence and risk of memory and cognitive adverse events might include exclusive use of square wave, direct current, brief pulse stimulus, use of ultrabrief pulse, 0.3 milliseconds stimulus, exclusive use of unilateral nondominant electrode placement, use of bifrontal electrode placement, or limiting ECT administration to twice per week.
When the onset of memory and cognitive function are noted during the course of ECT, other mitigating strategies may include switching from bilateral to unilateral treatments, decreasing energy dose or employing ultrabrief pulse stimulus. Identification of safe stimulation parameters in the device labeling to inform practitioners of safe device use may serve as an additional mitigating factor.
Please keep this discussion in mind in your deliberations of the following Panel question regarding mitigating the risks of adverse cognitive and memory adverse events, by employing physician labeling recommendations for exclusive use of brief pulse, that is 1 to 1.5 millisecond waveform stimulus; use of ultrabrief pulse, 0.3 millisecond stimulus; exclusive use of unilateral nondominant electrode placement; use of bifrontal electrode placement; limiting frequency of treatment to a maximum of twice weekly during a course of ECT; and monitoring cognitive status prior to ECT and throughout the course of treatment.
Also patient labeling requiring the use of a checklist of all known risks of ECT, with each item to be signed off by both patient and physician prior to initiating treatment or requirement of further premarket studies, either preclinical, bench or animal testing, or clinical studies for significant changes in device technology or new indications for use.
Please discuss each of these potential controls and whether it, either alone or in combination with others, adequate mitigates the cognitive and memory risks of ECT.
ECT Device Malfunction
My only device malfunction was identified as the third category of key risks of ECT devices. The proper functioning of all devices, not only ECT devices, is typically mitigated by generally accepted manufacturing and safety standards. These include general controls, such as good manufacturing practices and quality system regulations as described in the Code of Federal Regulations, as well as through adherence in international safety standards of medical devices such as the International Electrotechnical Commission, for example, IEC 60601-1-1 for medical electrical system safety requirements, and electromagnetic compatibility.
In summary, the objective of this Panel meeting is to gain expert recommendations on the question of whether ECT devices should be classified as Class II or Class III for each of the currently cleared indications. To review the classifications, Class II devices cannot be classified into Class I because general controls themselves are insufficient to provide reasonable assurance of the safety and effectiveness of the device, and there’s sufficient information to establish special controls to provide such assurance. Class III devices are those for which general and special controls cannot be established and therefore provide reasonable assurance of the safety and effectiveness of the device, and therefore premarket approval is required.