Clinical Review

Orlando Regional Medical Center (ORMC) is an urban, academic, Level 1 trauma center with an ED that treats in excess of 85,000 patients each year. There are more than 4,500 annual trauma admissions, including penetrating and blunt mechanism injuries. We have a 3-year emergency medicine (EM) residency program, originally established in 1986, that now has 14 residents per year. The events that we experienced on the early morning of June 12, 2016 were tragic and unexpected and tested our community, our teams, and our organization. The following is a description of activity perspectives, personal reflections and feelings, and important lessons learned from which other EDs may benefit.

Prehospital/Rescue Period

The prehospital approach to a mass-casualty incident (MCI) caused by gunfire has changed significantly over the last decade, with lessons gleaned from the experience of military and domestic attacks. The Orange County (Florida) Emergency Medical Services (EMS) System, including the agencies involved in the response to the June 12, 2016 Pulse nightclub shooting incident (Orlando Fire Department, Rural Metro Ambulance, and Orange County Fire Rescue), have trained specifically on the evolving priorities during an active shooter incident. This includes targeted hemorrhage control, swift extrication, minimal interventions, and immediate transport to the appropriate receiving center. In June 2015, 1 year prior to the Pulse nightclub shooting, a protocol variance was written by medical directors, explaining that “EMS providers may engage in initial patient care with only the supplies deemed absolutely necessary for rapid evaluation and removal into a safe triage zone.” This variance applies when there is an active shooter scenario. In addition, in 2014, 2015, and 2016, we conducted large scale, multiagency community exercises, encompassing shooting/active shooter scenarios and drills.

On June 12, 2016, EMS units were on scene of the Pulse nightclub in downtown Orlando less than 5 minutes after shooting began. It became immediately obvious that additional resources would be necessary. Soon after the incident, an MCI alert was activated from the Orlando Fire Department Communications Center, utilizing a software system to notify area hospitals and the medical directors that up to 20 patients had been shot, and requesting status on bed availability. Christopher L. Hunter, MD, PhD, one of our associate EMS medical directors, was working in the ED at a hospital several miles away from the incident and began coordinating efforts to distribute patients to the appropriate destination via radio and phone communication between the scene, the communications center, and the trauma center.

On scene, a group of law enforcement officers were engaging the shooter while others assisted in extracting victims from the club and surrounding area. Injured victims were brought to a casualty collection point, under cover, across the street and were transported as units became available. Initially, law enforcement vehicles and ambulances would make the two-block drive from the scene to ORMC carrying as many patients as they safely could, and return immediately after offload. Per previous training, minimal interventions were performed, and unlike standard procedure, EMS could offer no prearrival report to the hospital. The decision was made to triage only patients meeting Florida’s state trauma alert criteria to ORMC, and funnel other patients to nearby nontrauma centers. Dr Hunter attempted to notify the hospitals of patients as they were transported off the scene; however, the extremely short transport times made this process difficult.

Over the course of the incident, on-scene commands designated a casualty collection point, a transport unit staging area, and a hospital liaison. Emergency medical service responders cooperated with law enforcement to transport injured patients throughout the response. By the end of the event, nearly 100 EMS providers utilizing dozens of vehicles had responded to the scene.

The ED Period

The overnight shift of Saturday, June 11 was slower than usual in the ORMC ED, and triage housed the typical Saturday-night complaints. One of our mid-level providers, Brian Clayton, ARNP, worked in the fast track pod treating lower acuity illnesses, while the four senior residents discussed who might receive the honor of leaving early. Even the senior attending, Gary A. Parrish, MD, wrapped up his patients and was ready to leave right on time. The 11:00 pm to 7:00 am attending, Kathryn  J. Bondani, MD, was looking forward to an easy shift with four graduating senior residents. We had just called in an order from a popular nearby sandwich shop when suddenly, a slew of police cars flew past the hospital—not unusual given our proximity to downtown. The radio squawked “Multiple gunshots wounds en route.” Someone said “a club downtown got shot up.” In anticipation of multiple patient arrivals, resident Amanda M. Stone, MD, and the attending hurried to the trauma/ressuscitation bay. Another resident, Amanda F. Tarkowski, MD, called the trauma attending to rally his team downstairs, informing him that “A club downtown has a shooter and we have multiple patients with a 2-minute ETA.” Multiple gunshot wounds (GSWs) at once is not unusual for our Level 1 trauma center.

The first patient arrived shortly after 2:00 am and had multiple GSWs to the abdomen, but was awake and talking. He was mildly tachycardic, but his blood pressure (BP) was stable. We all gaped at the fist-sized wound on his back—some of us had never seen a GSW like this before. It was apparent that he needed to go to the operating room, but before preparations could be made, three more patients rolled into the ED. Instead of our usual organized, methodical EMS report, these patients were dropped off by a police pickup truck and rolled in on our own stretchers by nurses and technicians. Soon, all six of our trauma bays were filled with critical patients. Christopher H. Ponder, MD, recalled, “I heard an overhead page for ‘all available trauma nurses to the trauma bay’ shortly followed by a more concerned-sounding ‘all available staff to the trauma bay.’” All four senior EM residents, both EM attendings, the trauma attending, four trauma residents, multiple ED nurses, technicians, and various ancillary staff quickly descended on the patients. Chest tubes were placed, and multiple patients were intubated. Several thoracotomies were performed at the initial point when the team was unaware of the exact number of patients who would ultimately follow. Blood bags were hung and tranexamic acid was administered liberally. Unfortunately, some of these initial attempts were unsuccessful, as the first wave contained the most critically injured patients.

We barely had time to reflect on the dead as more patients filled the hallways. In the midst of all of this, triage decisions came quickly—awake and talking patients with an acceptable BP were moved out of the trauma bay in favor of less stable patients. Intubation and chest-tube placement decisions were made instantly. There was no time for routine X-rays or laboratory evaluation. Nurses, technicians, and doctors crowded the trauma bay desperately trying to stabilize the critically injured. Vital signs were taken manually. Dr Ponder called his colleague Thomas N. Smith, MD, who was also a graduating senior EM resident, and who happened to be staffing the children’s ED across the street that night. “Is there any way you can make it over here right now?” he shouted into the phone. Dr Smith quickly grabbed several trauma supplies and hitched a ride with security to the ORMC ED to assist. He was confronted with the scene of the previously mentioned “first wave” and grabbed an ultrasound machine to help triage these unfortunate patients. In addition to Dr Smith, unit clerks continued making calls to additional off-duty medical, nursing, and support staff. Critical care attendings and fellows responded from upstairs to assist in the ED. The Hospital Incident Command System (HICS) was initiated to provide hospital and corporate coordination of services. Timothy B. Bullard, MD, another EM attending physician and medical staff director of HICS, was en route to the ED to assist in the response.

Amidst the overwhelming mass of mortally and critically wounded patients, we were told stories of terror from just down the road. The sense of horror was almost contagious, and we all wondered if the violence would spread to the hospital.

About an hour into the ordeal, we heard another page overhead “Code Silver, ED Triage. Code Silver, ED Triage.” Everyone in the trauma bay froze. We heard someone shout from the hallway “Shots fired in triage!” After a few seconds, those nearest the trauma bay doors pushed them shut. One of the trauma surgeons shouted, “Keep caring for your patients, push the portable X-ray machines in front of the doors.” That is exactly what happened, and we worked in the barricaded trauma room for the longest few minutes of the night. We would later learn that this report was false, but fearing for our own lives as well as the lives of our patients is an experience that few, if any, of us had previously been through. The fact that we continued to work in such a situation illustrates everyone’s dedication to their patients and mission.

After the first wave of patients, it was clear that reassessing patients was now our greatest challenge. There were multiple patients with stable vital signs but who had GSWs to the abdomen, pelvis, and thorax and required surgery. Having realized that the ultrasound machine and focused assessment with sonography for trauma (FAST) examinations were the most practical rapid imaging modality, Drs Tarkowski, Ponder, and Smith grabbed the machine and went from room to room repeating the FAST examinations, vital signs, and assessments for missed wounds. A portable computer allowed us to order X-ray orders for patients with extremity wounds. Several patients who initially had negative FASTs had a repeat examination that was positive for free fluid. The operating room triage list shuffled based on these examinations.

At this point, there seemed to be a never-ending list of “Doe” names on the electronic medical record (EMR) tracking board. Tracking the location of patients was a dynamic process, and updating the tracking board was difficult. Patients were continually cycled in and out of the trauma bay, shuffled in and out of treatment rooms, lined up in the hallways, and transported up to the intensive care unit (ICU). Some of those “Doe” names belonged to patients who had succumbed to their injuries. Some patients had empty, bloody charts next to them on their stretcher. Every patient had a wristband. Dr Tarkowski improvised a rapid documentation system using quarter sheets of scrap paper that were taped either to the stretcher or door with a patient name, brief list of injuries, FAST examination result, pending tests, and medications given. This system was an efficient way of identifying which patients had been evaluated, what had been done, and what was pending.

While we were “rounding” on our patients, down the street, law enforcement had broken down the club’s wall, and a second wave of patients began to arrive. Two residents completed the secondary evaluations while the other three resuscitated new patients. The second wave seemed like a repeat of the first. Several extremity-only injuries were triaged directly to the hallways to be seen by the two residents outside of the trauma bay. By this time, the orthopedic surgery service had come down to the ED and was washing out wounds, splinting, and making plans for surgery. The internal medicine service and the medical critical care team were helping reassess patients as well.

There were many emotional moments. Dr Ponder remembered, “One of the first few patients I saw was pulseless, and as I went to start chest compressions, I was stopped by a trauma surgeon who said, ‘He’s gone, focus on the ones we can help.’ That’s when I realized the gravity of our situation. For almost 2 hours, each resident cycled through patients.” Dr Stone recounted, “I just went down the line of patients, from head of the bed to head of the bed, some patients still on EMS stretchers, intubating many of them. It was surreal to see that many severely injured in one place.” Tory L. Weatherford, MD, recalled, “It was controlled chaos. My training kicked in, and it became about just trying to do anything possible to help.”

Dr Bondani, the overnight attending, said she does not remember many specifics from the event. “Faces and injuries blurred together. I remember looking in one young man’s eyes and telling him, ‘We are going to help you, just hang in there,’ and telling another panicking woman, ‘You’re talking, you can feel pain, you’re alive. Calm down.’ It was organized chaos as we swept from patient to patient moving as quickly as possible. Your training kicks in and you do what needs to be done in the moment.”

We were fortunate to have the EM team we did, and to be in the place that we were. On duty, we had five senior graduating residents, essentially with attending-level skills and training, who had been together since day one. “We gave everything we had; there was no time to stop. We went where our hands could be helpful—it didn’t matter if it was your traditional role or not,” said Dr Weatherford.

Dr Tarkowski remembered what it was like leaving the walls of the ED later that morning. “Leaving the hospital didn’t feel like a success. We knew the work we did was good, that we did everything we could, but it didn’t feel like it. It felt heavy. It felt empty.” Afterward, the emotional toll set in. We gathered up the names of the deceased and looked at a status board littered with “Doe” names, and we tried hard not to break down at the violence and the pain we witnessed.

Immediate Recovery Period (Prehospital Setting)

In the aftermath of the initial rescue operation, stabilization of injured victims, and demobilization of resources, a second “event” unfolded—hundreds of family members flooded to ORMC looking for unaccounted loved ones. At this point, there were dozens of deceased and critically injured patients who remained unidentified, and addressing the needs of both the victims and the families was becoming overwhelming. With the cooperation of federal, state, county, city, and private resources, a family reunification center (FRC; a family staging area/family reception center) was created and managed initially within the hospital. At this site, grief counselors, victim advocates, law enforcement and medical examiner’s officials, hospital chaplains, and translators gathered with the loved ones of those missing to synchronize efforts to identify and reunite them. The Emergency Operations Center quickly created a telephone hotline and Web site to guide those in need to this resource. Food and housing for those in need were provided by the generosity of our community—which cannot be overstated in the wake of this tragedy. As days passed, the FRC transitioned to a new location as the Orlando United Assistance Center, and will continue to serve as a navigation point for those who are and will be affected by the event for months to come.

Hospital Incident Command System

The HICS was activated shortly past 3:00 am, just after the initial wave of victims flooded our ED and the gravity of the situation became apparent. The ED and trauma services were already near full staff due to timing, rapid response, and communication between the traumatologists, as well as a bit of luck. Because of the time of the disaster, our normal notification process for incident command and all personnel was severely limited. In retrospect, this turned out to be a blessing. While everyone who normally would respond to HICS was not available, individuals serving in key positions were reached by personal phone calls and were on-site quickly. One of the main functions of HICS is to control the internal chaos that arises when a disaster occurs and all personnel want to assist in some manner. We have spent hours during drills crafting communications that target key personnel necessary to meet the mission, while controlling well-intentioned but unnecessary personnel. In our drills, this is not an issue because everyone knows the exercise is not reality; however, in a real disaster, everyone wants to help. This was confirmed by the guilt that so many of our team members expressed at not being involved that Sunday.

With an initial skeleton crew in incident command, it was easy to focus on the immediate needs of patient care. The strong leadership and cool heads of our incident command leadership led to rapid role definition and responsibility, and set forth an easy path for execution. Hospital command personnel adapted their usual roles and performed functions and assignments as needed. Many HICS staff had direct face-to-face contact with frontline providers in the ED and other vital areas. This was possible because of the close proximity of the hospital command headquarters to the ED. The need for additional resources was rapidly identified, and the hospital command leaders assumed direct responsibility for procuring them instead of delegating. A great example of this was when Orlando Health’s chief executive officer and chief operating officer went to our nearby hospitals to gather additional chest tubes after learning that we were running in short supply. Their main responsibilities lay ahead of them, and they were willing to help in any manner they could at the time. Some of the medical personnel were able to switch roles and pitch in to treat the second wave of victims that arrived at around 5:00 am.

As the flow of victims to the ED subsided and order began to be restored, HICS shifted gears and took on a much broader role: coordinating activities with multiple agencies, including local law enforcement, the Federal Bureau of Investigation, news media, and an array of patient and family services. Again, the timing of this tragic event allowed the needs and functions of our hospital command to concentrate the focus in a more structured manner than might have been possible during regular operational hours.

Lessons Learned and Recommendations

As with any MCI, it is important to perform after-incident debriefings to reflect upon the prehospital, ED, and hospital care to assess for areas in need of improvement. Obviously, depending on the number and type of patients who are received and the resources available at the institution, such events can stress EDs that are already at or above their capacity. At the time of this writing (less than 2 months after the incident), although we are still in the early stages of our post-incident debriefing process, we offer the following suggestions and recommendations that we believe will be a benefit to other institutions faced with similar challenges.

Dedicated Disaster Preparedness Program

Depending on the size of the institution and whether or not it is a trauma-receiving center, it is vitally important to have a team of individuals dedicated to the development and maintenance of a disaster readiness program. Eric Alberts, manager of Emergency Preparedness at Orlando Heath, emphasized the need to harness and leverage preparedness efforts and relationships with community partners, law enforcement, and EMS. In addition, he noted that these trained individuals can provide education and coordination for mass-casualty drills, assist in developing and maintaining policies and protocols, and coordinate with hospital incident command during actual events.

Practice, Practice, Practice

In order for medical staff, nursing staff, and support personnel to understand their roles and responsibilities if an MCI occurs, they must practice simulated drills. Tabletop and full-scale emergency intake drills, with a range of scenarios occurring at different times of the day and night, will improve teamwork and coordination. At least once a year, a large, full-scale community exercise that involves scene casualty collection points, law enforcement and EMS involvement, multiple EDs, and hospital-wide integration will educate staff members on their duties. There should be enough patients in these drills to stress the entire system—both ED and in-hospital. Physician involvement in these exercises is crucial. In March 2016, a full-scale community exercise was performed in the Central Florida area in which more than 500 volunteers, 50 agencies, and 15 hospitals participated. A segment of that exercise involved an active shooter impersonating a patient brought to the ED. We feel this recent exercise, and others like it, were helpful in managing our actual mass casualty event.

Notification

When the shootings at the Pulse nightclub started, we were advised that there might be as many as 20 victims, but over the next few hours, we received more than twice as many injured patients. In any scenario where it is felt additional ED resources and personnel are needed, it is advantageous to begin the notification process as early as possible. Ideally, there are redundant methods in place to notify in-house and off-duty personnel, preferably in a multilayered system of electronic and voice communications that provides feedback as to staff availability. During daytime hours, it is easier for off-duty staff to learn of an event through news and social media. However, during early morning hours, such as when these shootings occurred, it may be difficult to notify sleeping staff that they are needed. With the trend of using mobile devices instead of landline phones, and with the ability to silence those devices during nighttime sleep hours, it has become increasingly difficult to “break through” the silence. In our event, group e-mail notifications were activated, but individual phone calls were also required. Initially, some calls to staff went to voice mail rather than being
answered directly.

Communication

Communication is an area of opportunity for improvement in almost any mass-casualty event. Redundant methods of electronic, voice, telephone, and radio communications are crucial for personnel to coordinate efforts. It is imperative that HICS and ED personnel receive updates about events on the scene and the status of potential incoming patients. An infrastructure of communications is paramount for the coordination that is needed between prehospital, ED, and in-house resources.

Throughput

Facilitating ED and hospital throughput and improving operational efficiencies are regular topics of discussion in most busy EDs. However, when it becomes necessary to intake large numbers of patients in an ED within a short period of time, the need to move patients out of the department intensifies. In many cases, to continue intake of patients, it will be necessary to quickly find areas outside of the ED—such as operating rooms, ICUs, and general floors—to transport patients to. At our facility, we normally have two operating rooms staffed throughout the night for traumas. On the night of the shootings, a total of six operating rooms were activated quickly to manage the penetrating injuries of these patients. Previously admitted medical patients were retrieved by in-house nursing staff to free up ED beds.

Media

It is important to recognize the intense social, print, online, and television media exposure that will occur with such tragedies, and have personnel and systems in place to manage it. The Pulse nightclub is located only a few short blocks south of ORMC, and the majority of all injured patients, including those with the most severe injuries, presented to our facility. As a result, the intense media coverage at our hospital physically overlapped the intense media coverage at the scene. Nearby businesses were shut down, access to several main thoroughfare roads were blocked, and some individuals mistakenly thought the hospital was closed. Our media relations department felt the most efficient way to manage information dissemination was to hold a “presser”—a press conference with a few of the health professionals involved in the care of the patients. The press conference helped to relieve some of the media presence and pressure, and provided welcomed transparency to the community.

Expect the Unexpected

Even when physicians and staff conduct regular training exercises and are familiar with policies and procedures, the controlled chaos that is typical of a true mass-casualty event will likely result in some unexpected occurrences. After injured patients began arriving at our ED, during a period when patient influx and medical care was intense, there was a brief time when we were concerned an active shooter was also in our ED. Since the mass shootings were only a few blocks from the ED, and we did not know the scope or number of shooters, it was a reasonable assumption that a perpetrator could present to the ED as a patient or active shooter. During an event such as this, it is the practice at ORMC to have security officers place the facility on lockdown; however; the added concern that an active shooter was physically present in the ED required additional law enforcement officers to methodically search the entire facility until the threat of a shooter was eliminated. Although this did not directly impact patient care, it did create another level of complexity and stress to the already challenging situation.

Emotional Impact

One should not underestimate the emotional impact of a mass-casualty event. Emergency physicians and personnel are well equipped to manage illness, injury, and death. However, an event of this magnitude, with the number and manner of injuries and deaths that presented to our ED, along with the closeness to a scene of bloodshed where many young lives were taken in a senseless act of violence, will likely have a lasting impression on many staff members. Any institution encountering such an event should have behavioral health and support counselors readily available as soon as possible.

Conclusion

When patients present in truckloads, as they did in our ambulance bay in the early hours of June 12, an ED may be inundated with injured patients without notice or preparation. Teams need to trust their instincts, their training, and one another. It is unlikely that your normal ED practice patterns will be sufficient to take care of a large surge of patients, and you will need to turn to your ingenuity, creativity, and resourcefulness to do what you think is best to save the lives of as many patients as possible. As Sarah Duran, BSN, the trauma nurse who was working as the ED charge nurse the night of the shootings, stated, “I don’t think anyone can fully prepare for anything on the scale of what happened in Orlando, but with a good foundation of protocols in place, strong set of staff, constant vigilance, and great teamwork, any hospital can be successful in handling a mass casualty incident.”

Orlando Regional Medical Center (ORMC) is an urban, academic, Level 1 trauma center with an ED that treats in excess of 85,000 patients each year. There are more than 4,500 annual trauma admissions, including penetrating and blunt mechanism injuries. We have a 3-year emergency medicine (EM) residency program, originally established in 1986, that now has 14 residents per year. The events that we experienced on the early morning of June 12, 2016 were tragic and unexpected and tested our community, our teams, and our organization. The following is a description of activity perspectives, personal reflections and feelings, and important lessons learned from which other EDs may benefit.

Prehospital/Rescue Period

The prehospital approach to a mass-casualty incident (MCI) caused by gunfire has changed significantly over the last decade, with lessons gleaned from the experience of military and domestic attacks. The Orange County (Florida) Emergency Medical Services (EMS) System, including the agencies involved in the response to the June 12, 2016 Pulse nightclub shooting incident (Orlando Fire Department, Rural Metro Ambulance, and Orange County Fire Rescue), have trained specifically on the evolving priorities during an active shooter incident. This includes targeted hemorrhage control, swift extrication, minimal interventions, and immediate transport to the appropriate receiving center. In June 2015, 1 year prior to the Pulse nightclub shooting, a protocol variance was written by medical directors, explaining that “EMS providers may engage in initial patient care with only the supplies deemed absolutely necessary for rapid evaluation and removal into a safe triage zone.” This variance applies when there is an active shooter scenario. In addition, in 2014, 2015, and 2016, we conducted large scale, multiagency community exercises, encompassing shooting/active shooter scenarios and drills.

On June 12, 2016, EMS units were on scene of the Pulse nightclub in downtown Orlando less than 5 minutes after shooting began. It became immediately obvious that additional resources would be necessary. Soon after the incident, an MCI alert was activated from the Orlando Fire Department Communications Center, utilizing a software system to notify area hospitals and the medical directors that up to 20 patients had been shot, and requesting status on bed availability. Christopher L. Hunter, MD, PhD, one of our associate EMS medical directors, was working in the ED at a hospital several miles away from the incident and began coordinating efforts to distribute patients to the appropriate destination via radio and phone communication between the scene, the communications center, and the trauma center.

On scene, a group of law enforcement officers were engaging the shooter while others assisted in extracting victims from the club and surrounding area. Injured victims were brought to a casualty collection point, under cover, across the street and were transported as units became available. Initially, law enforcement vehicles and ambulances would make the two-block drive from the scene to ORMC carrying as many patients as they safely could, and return immediately after offload. Per previous training, minimal interventions were performed, and unlike standard procedure, EMS could offer no prearrival report to the hospital. The decision was made to triage only patients meeting Florida’s state trauma alert criteria to ORMC, and funnel other patients to nearby nontrauma centers. Dr Hunter attempted to notify the hospitals of patients as they were transported off the scene; however, the extremely short transport times made this process difficult.

Over the course of the incident, on-scene commands designated a casualty collection point, a transport unit staging area, and a hospital liaison. Emergency medical service responders cooperated with law enforcement to transport injured patients throughout the response. By the end of the event, nearly 100 EMS providers utilizing dozens of vehicles had responded to the scene.

The ED Period

The overnight shift of Saturday, June 11 was slower than usual in the ORMC ED, and triage housed the typical Saturday-night complaints. One of our mid-level providers, Brian Clayton, ARNP, worked in the fast track pod treating lower acuity illnesses, while the four senior residents discussed who might receive the honor of leaving early. Even the senior attending, Gary A. Parrish, MD, wrapped up his patients and was ready to leave right on time. The 11:00 pm to 7:00 am attending, Kathryn  J. Bondani, MD, was looking forward to an easy shift with four graduating senior residents. We had just called in an order from a popular nearby sandwich shop when suddenly, a slew of police cars flew past the hospital—not unusual given our proximity to downtown. The radio squawked “Multiple gunshots wounds en route.” Someone said “a club downtown got shot up.” In anticipation of multiple patient arrivals, resident Amanda M. Stone, MD, and the attending hurried to the trauma/ressuscitation bay. Another resident, Amanda F. Tarkowski, MD, called the trauma attending to rally his team downstairs, informing him that “A club downtown has a shooter and we have multiple patients with a 2-minute ETA.” Multiple gunshot wounds (GSWs) at once is not unusual for our Level 1 trauma center.

The first patient arrived shortly after 2:00 am and had multiple GSWs to the abdomen, but was awake and talking. He was mildly tachycardic, but his blood pressure (BP) was stable. We all gaped at the fist-sized wound on his back—some of us had never seen a GSW like this before. It was apparent that he needed to go to the operating room, but before preparations could be made, three more patients rolled into the ED. Instead of our usual organized, methodical EMS report, these patients were dropped off by a police pickup truck and rolled in on our own stretchers by nurses and technicians. Soon, all six of our trauma bays were filled with critical patients. Christopher H. Ponder, MD, recalled, “I heard an overhead page for ‘all available trauma nurses to the trauma bay’ shortly followed by a more concerned-sounding ‘all available staff to the trauma bay.’” All four senior EM residents, both EM attendings, the trauma attending, four trauma residents, multiple ED nurses, technicians, and various ancillary staff quickly descended on the patients. Chest tubes were placed, and multiple patients were intubated. Several thoracotomies were performed at the initial point when the team was unaware of the exact number of patients who would ultimately follow. Blood bags were hung and tranexamic acid was administered liberally. Unfortunately, some of these initial attempts were unsuccessful, as the first wave contained the most critically injured patients.

We barely had time to reflect on the dead as more patients filled the hallways. In the midst of all of this, triage decisions came quickly—awake and talking patients with an acceptable BP were moved out of the trauma bay in favor of less stable patients. Intubation and chest-tube placement decisions were made instantly. There was no time for routine X-rays or laboratory evaluation. Nurses, technicians, and doctors crowded the trauma bay desperately trying to stabilize the critically injured. Vital signs were taken manually. Dr Ponder called his colleague Thomas N. Smith, MD, who was also a graduating senior EM resident, and who happened to be staffing the children’s ED across the street that night. “Is there any way you can make it over here right now?” he shouted into the phone. Dr Smith quickly grabbed several trauma supplies and hitched a ride with security to the ORMC ED to assist. He was confronted with the scene of the previously mentioned “first wave” and grabbed an ultrasound machine to help triage these unfortunate patients. In addition to Dr Smith, unit clerks continued making calls to additional off-duty medical, nursing, and support staff. Critical care attendings and fellows responded from upstairs to assist in the ED. The Hospital Incident Command System (HICS) was initiated to provide hospital and corporate coordination of services. Timothy B. Bullard, MD, another EM attending physician and medical staff director of HICS, was en route to the ED to assist in the response.

Amidst the overwhelming mass of mortally and critically wounded patients, we were told stories of terror from just down the road. The sense of horror was almost contagious, and we all wondered if the violence would spread to the hospital.

About an hour into the ordeal, we heard another page overhead “Code Silver, ED Triage. Code Silver, ED Triage.” Everyone in the trauma bay froze. We heard someone shout from the hallway “Shots fired in triage!” After a few seconds, those nearest the trauma bay doors pushed them shut. One of the trauma surgeons shouted, “Keep caring for your patients, push the portable X-ray machines in front of the doors.” That is exactly what happened, and we worked in the barricaded trauma room for the longest few minutes of the night. We would later learn that this report was false, but fearing for our own lives as well as the lives of our patients is an experience that few, if any, of us had previously been through. The fact that we continued to work in such a situation illustrates everyone’s dedication to their patients and mission.

After the first wave of patients, it was clear that reassessing patients was now our greatest challenge. There were multiple patients with stable vital signs but who had GSWs to the abdomen, pelvis, and thorax and required surgery. Having realized that the ultrasound machine and focused assessment with sonography for trauma (FAST) examinations were the most practical rapid imaging modality, Drs Tarkowski, Ponder, and Smith grabbed the machine and went from room to room repeating the FAST examinations, vital signs, and assessments for missed wounds. A portable computer allowed us to order X-ray orders for patients with extremity wounds. Several patients who initially had negative FASTs had a repeat examination that was positive for free fluid. The operating room triage list shuffled based on these examinations.

At this point, there seemed to be a never-ending list of “Doe” names on the electronic medical record (EMR) tracking board. Tracking the location of patients was a dynamic process, and updating the tracking board was difficult. Patients were continually cycled in and out of the trauma bay, shuffled in and out of treatment rooms, lined up in the hallways, and transported up to the intensive care unit (ICU). Some of those “Doe” names belonged to patients who had succumbed to their injuries. Some patients had empty, bloody charts next to them on their stretcher. Every patient had a wristband. Dr Tarkowski improvised a rapid documentation system using quarter sheets of scrap paper that were taped either to the stretcher or door with a patient name, brief list of injuries, FAST examination result, pending tests, and medications given. This system was an efficient way of identifying which patients had been evaluated, what had been done, and what was pending.

While we were “rounding” on our patients, down the street, law enforcement had broken down the club’s wall, and a second wave of patients began to arrive. Two residents completed the secondary evaluations while the other three resuscitated new patients. The second wave seemed like a repeat of the first. Several extremity-only injuries were triaged directly to the hallways to be seen by the two residents outside of the trauma bay. By this time, the orthopedic surgery service had come down to the ED and was washing out wounds, splinting, and making plans for surgery. The internal medicine service and the medical critical care team were helping reassess patients as well.

There were many emotional moments. Dr Ponder remembered, “One of the first few patients I saw was pulseless, and as I went to start chest compressions, I was stopped by a trauma surgeon who said, ‘He’s gone, focus on the ones we can help.’ That’s when I realized the gravity of our situation. For almost 2 hours, each resident cycled through patients.” Dr Stone recounted, “I just went down the line of patients, from head of the bed to head of the bed, some patients still on EMS stretchers, intubating many of them. It was surreal to see that many severely injured in one place.” Tory L. Weatherford, MD, recalled, “It was controlled chaos. My training kicked in, and it became about just trying to do anything possible to help.”

Dr Bondani, the overnight attending, said she does not remember many specifics from the event. “Faces and injuries blurred together. I remember looking in one young man’s eyes and telling him, ‘We are going to help you, just hang in there,’ and telling another panicking woman, ‘You’re talking, you can feel pain, you’re alive. Calm down.’ It was organized chaos as we swept from patient to patient moving as quickly as possible. Your training kicks in and you do what needs to be done in the moment.”

We were fortunate to have the EM team we did, and to be in the place that we were. On duty, we had five senior graduating residents, essentially with attending-level skills and training, who had been together since day one. “We gave everything we had; there was no time to stop. We went where our hands could be helpful—it didn’t matter if it was your traditional role or not,” said Dr Weatherford.

Dr Tarkowski remembered what it was like leaving the walls of the ED later that morning. “Leaving the hospital didn’t feel like a success. We knew the work we did was good, that we did everything we could, but it didn’t feel like it. It felt heavy. It felt empty.” Afterward, the emotional toll set in. We gathered up the names of the deceased and looked at a status board littered with “Doe” names, and we tried hard not to break down at the violence and the pain we witnessed.

Immediate Recovery Period (Prehospital Setting)

In the aftermath of the initial rescue operation, stabilization of injured victims, and demobilization of resources, a second “event” unfolded—hundreds of family members flooded to ORMC looking for unaccounted loved ones. At this point, there were dozens of deceased and critically injured patients who remained unidentified, and addressing the needs of both the victims and the families was becoming overwhelming. With the cooperation of federal, state, county, city, and private resources, a family reunification center (FRC; a family staging area/family reception center) was created and managed initially within the hospital. At this site, grief counselors, victim advocates, law enforcement and medical examiner’s officials, hospital chaplains, and translators gathered with the loved ones of those missing to synchronize efforts to identify and reunite them. The Emergency Operations Center quickly created a telephone hotline and Web site to guide those in need to this resource. Food and housing for those in need were provided by the generosity of our community—which cannot be overstated in the wake of this tragedy. As days passed, the FRC transitioned to a new location as the Orlando United Assistance Center, and will continue to serve as a navigation point for those who are and will be affected by the event for months to come.

Hospital Incident Command System

The HICS was activated shortly past 3:00 am, just after the initial wave of victims flooded our ED and the gravity of the situation became apparent. The ED and trauma services were already near full staff due to timing, rapid response, and communication between the traumatologists, as well as a bit of luck. Because of the time of the disaster, our normal notification process for incident command and all personnel was severely limited. In retrospect, this turned out to be a blessing. While everyone who normally would respond to HICS was not available, individuals serving in key positions were reached by personal phone calls and were on-site quickly. One of the main functions of HICS is to control the internal chaos that arises when a disaster occurs and all personnel want to assist in some manner. We have spent hours during drills crafting communications that target key personnel necessary to meet the mission, while controlling well-intentioned but unnecessary personnel. In our drills, this is not an issue because everyone knows the exercise is not reality; however, in a real disaster, everyone wants to help. This was confirmed by the guilt that so many of our team members expressed at not being involved that Sunday.

With an initial skeleton crew in incident command, it was easy to focus on the immediate needs of patient care. The strong leadership and cool heads of our incident command leadership led to rapid role definition and responsibility, and set forth an easy path for execution. Hospital command personnel adapted their usual roles and performed functions and assignments as needed. Many HICS staff had direct face-to-face contact with frontline providers in the ED and other vital areas. This was possible because of the close proximity of the hospital command headquarters to the ED. The need for additional resources was rapidly identified, and the hospital command leaders assumed direct responsibility for procuring them instead of delegating. A great example of this was when Orlando Health’s chief executive officer and chief operating officer went to our nearby hospitals to gather additional chest tubes after learning that we were running in short supply. Their main responsibilities lay ahead of them, and they were willing to help in any manner they could at the time. Some of the medical personnel were able to switch roles and pitch in to treat the second wave of victims that arrived at around 5:00 am.

As the flow of victims to the ED subsided and order began to be restored, HICS shifted gears and took on a much broader role: coordinating activities with multiple agencies, including local law enforcement, the Federal Bureau of Investigation, news media, and an array of patient and family services. Again, the timing of this tragic event allowed the needs and functions of our hospital command to concentrate the focus in a more structured manner than might have been possible during regular operational hours.

Lessons Learned and Recommendations

As with any MCI, it is important to perform after-incident debriefings to reflect upon the prehospital, ED, and hospital care to assess for areas in need of improvement. Obviously, depending on the number and type of patients who are received and the resources available at the institution, such events can stress EDs that are already at or above their capacity. At the time of this writing (less than 2 months after the incident), although we are still in the early stages of our post-incident debriefing process, we offer the following suggestions and recommendations that we believe will be a benefit to other institutions faced with similar challenges.

Dedicated Disaster Preparedness Program

Depending on the size of the institution and whether or not it is a trauma-receiving center, it is vitally important to have a team of individuals dedicated to the development and maintenance of a disaster readiness program. Eric Alberts, manager of Emergency Preparedness at Orlando Heath, emphasized the need to harness and leverage preparedness efforts and relationships with community partners, law enforcement, and EMS. In addition, he noted that these trained individuals can provide education and coordination for mass-casualty drills, assist in developing and maintaining policies and protocols, and coordinate with hospital incident command during actual events.

Practice, Practice, Practice

In order for medical staff, nursing staff, and support personnel to understand their roles and responsibilities if an MCI occurs, they must practice simulated drills. Tabletop and full-scale emergency intake drills, with a range of scenarios occurring at different times of the day and night, will improve teamwork and coordination. At least once a year, a large, full-scale community exercise that involves scene casualty collection points, law enforcement and EMS involvement, multiple EDs, and hospital-wide integration will educate staff members on their duties. There should be enough patients in these drills to stress the entire system—both ED and in-hospital. Physician involvement in these exercises is crucial. In March 2016, a full-scale community exercise was performed in the Central Florida area in which more than 500 volunteers, 50 agencies, and 15 hospitals participated. A segment of that exercise involved an active shooter impersonating a patient brought to the ED. We feel this recent exercise, and others like it, were helpful in managing our actual mass casualty event.

Notification

When the shootings at the Pulse nightclub started, we were advised that there might be as many as 20 victims, but over the next few hours, we received more than twice as many injured patients. In any scenario where it is felt additional ED resources and personnel are needed, it is advantageous to begin the notification process as early as possible. Ideally, there are redundant methods in place to notify in-house and off-duty personnel, preferably in a multilayered system of electronic and voice communications that provides feedback as to staff availability. During daytime hours, it is easier for off-duty staff to learn of an event through news and social media. However, during early morning hours, such as when these shootings occurred, it may be difficult to notify sleeping staff that they are needed. With the trend of using mobile devices instead of landline phones, and with the ability to silence those devices during nighttime sleep hours, it has become increasingly difficult to “break through” the silence. In our event, group e-mail notifications were activated, but individual phone calls were also required. Initially, some calls to staff went to voice mail rather than being
answered directly.

Communication

Communication is an area of opportunity for improvement in almost any mass-casualty event. Redundant methods of electronic, voice, telephone, and radio communications are crucial for personnel to coordinate efforts. It is imperative that HICS and ED personnel receive updates about events on the scene and the status of potential incoming patients. An infrastructure of communications is paramount for the coordination that is needed between prehospital, ED, and in-house resources.

Throughput

Facilitating ED and hospital throughput and improving operational efficiencies are regular topics of discussion in most busy EDs. However, when it becomes necessary to intake large numbers of patients in an ED within a short period of time, the need to move patients out of the department intensifies. In many cases, to continue intake of patients, it will be necessary to quickly find areas outside of the ED—such as operating rooms, ICUs, and general floors—to transport patients to. At our facility, we normally have two operating rooms staffed throughout the night for traumas. On the night of the shootings, a total of six operating rooms were activated quickly to manage the penetrating injuries of these patients. Previously admitted medical patients were retrieved by in-house nursing staff to free up ED beds.

Media

It is important to recognize the intense social, print, online, and television media exposure that will occur with such tragedies, and have personnel and systems in place to manage it. The Pulse nightclub is located only a few short blocks south of ORMC, and the majority of all injured patients, including those with the most severe injuries, presented to our facility. As a result, the intense media coverage at our hospital physically overlapped the intense media coverage at the scene. Nearby businesses were shut down, access to several main thoroughfare roads were blocked, and some individuals mistakenly thought the hospital was closed. Our media relations department felt the most efficient way to manage information dissemination was to hold a “presser”—a press conference with a few of the health professionals involved in the care of the patients. The press conference helped to relieve some of the media presence and pressure, and provided welcomed transparency to the community.

Expect the Unexpected

Even when physicians and staff conduct regular training exercises and are familiar with policies and procedures, the controlled chaos that is typical of a true mass-casualty event will likely result in some unexpected occurrences. After injured patients began arriving at our ED, during a period when patient influx and medical care was intense, there was a brief time when we were concerned an active shooter was also in our ED. Since the mass shootings were only a few blocks from the ED, and we did not know the scope or number of shooters, it was a reasonable assumption that a perpetrator could present to the ED as a patient or active shooter. During an event such as this, it is the practice at ORMC to have security officers place the facility on lockdown; however; the added concern that an active shooter was physically present in the ED required additional law enforcement officers to methodically search the entire facility until the threat of a shooter was eliminated. Although this did not directly impact patient care, it did create another level of complexity and stress to the already challenging situation.

Emotional Impact

One should not underestimate the emotional impact of a mass-casualty event. Emergency physicians and personnel are well equipped to manage illness, injury, and death. However, an event of this magnitude, with the number and manner of injuries and deaths that presented to our ED, along with the closeness to a scene of bloodshed where many young lives were taken in a senseless act of violence, will likely have a lasting impression on many staff members. Any institution encountering such an event should have behavioral health and support counselors readily available as soon as possible.

Conclusion

When patients present in truckloads, as they did in our ambulance bay in the early hours of June 12, an ED may be inundated with injured patients without notice or preparation. Teams need to trust their instincts, their training, and one another. It is unlikely that your normal ED practice patterns will be sufficient to take care of a large surge of patients, and you will need to turn to your ingenuity, creativity, and resourcefulness to do what you think is best to save the lives of as many patients as possible. As Sarah Duran, BSN, the trauma nurse who was working as the ED charge nurse the night of the shootings, stated, “I don’t think anyone can fully prepare for anything on the scale of what happened in Orlando, but with a good foundation of protocols in place, strong set of staff, constant vigilance, and great teamwork, any hospital can be successful in handling a mass casualty incident.”

Orlando Regional Medical Center (ORMC) is an urban, academic, Level 1 trauma center with an ED that treats in excess of 85,000 patients each year. There are more than 4,500 annual trauma admissions, including penetrating and blunt mechanism injuries. We have a 3-year emergency medicine (EM) residency program, originally established in 1986, that now has 14 residents per year. The events that we experienced on the early morning of June 12, 2016 were tragic and unexpected and tested our community, our teams, and our organization. The following is a description of activity perspectives, personal reflections and feelings, and important lessons learned from which other EDs may benefit.

Prehospital/Rescue Period

The prehospital approach to a mass-casualty incident (MCI) caused by gunfire has changed significantly over the last decade, with lessons gleaned from the experience of military and domestic attacks. The Orange County (Florida) Emergency Medical Services (EMS) System, including the agencies involved in the response to the June 12, 2016 Pulse nightclub shooting incident (Orlando Fire Department, Rural Metro Ambulance, and Orange County Fire Rescue), have trained specifically on the evolving priorities during an active shooter incident. This includes targeted hemorrhage control, swift extrication, minimal interventions, and immediate transport to the appropriate receiving center. In June 2015, 1 year prior to the Pulse nightclub shooting, a protocol variance was written by medical directors, explaining that “EMS providers may engage in initial patient care with only the supplies deemed absolutely necessary for rapid evaluation and removal into a safe triage zone.” This variance applies when there is an active shooter scenario. In addition, in 2014, 2015, and 2016, we conducted large scale, multiagency community exercises, encompassing shooting/active shooter scenarios and drills.

On June 12, 2016, EMS units were on scene of the Pulse nightclub in downtown Orlando less than 5 minutes after shooting began. It became immediately obvious that additional resources would be necessary. Soon after the incident, an MCI alert was activated from the Orlando Fire Department Communications Center, utilizing a software system to notify area hospitals and the medical directors that up to 20 patients had been shot, and requesting status on bed availability. Christopher L. Hunter, MD, PhD, one of our associate EMS medical directors, was working in the ED at a hospital several miles away from the incident and began coordinating efforts to distribute patients to the appropriate destination via radio and phone communication between the scene, the communications center, and the trauma center.

On scene, a group of law enforcement officers were engaging the shooter while others assisted in extracting victims from the club and surrounding area. Injured victims were brought to a casualty collection point, under cover, across the street and were transported as units became available. Initially, law enforcement vehicles and ambulances would make the two-block drive from the scene to ORMC carrying as many patients as they safely could, and return immediately after offload. Per previous training, minimal interventions were performed, and unlike standard procedure, EMS could offer no prearrival report to the hospital. The decision was made to triage only patients meeting Florida’s state trauma alert criteria to ORMC, and funnel other patients to nearby nontrauma centers. Dr Hunter attempted to notify the hospitals of patients as they were transported off the scene; however, the extremely short transport times made this process difficult.

Over the course of the incident, on-scene commands designated a casualty collection point, a transport unit staging area, and a hospital liaison. Emergency medical service responders cooperated with law enforcement to transport injured patients throughout the response. By the end of the event, nearly 100 EMS providers utilizing dozens of vehicles had responded to the scene.

The ED Period

The overnight shift of Saturday, June 11 was slower than usual in the ORMC ED, and triage housed the typical Saturday-night complaints. One of our mid-level providers, Brian Clayton, ARNP, worked in the fast track pod treating lower acuity illnesses, while the four senior residents discussed who might receive the honor of leaving early. Even the senior attending, Gary A. Parrish, MD, wrapped up his patients and was ready to leave right on time. The 11:00 pm to 7:00 am attending, Kathryn  J. Bondani, MD, was looking forward to an easy shift with four graduating senior residents. We had just called in an order from a popular nearby sandwich shop when suddenly, a slew of police cars flew past the hospital—not unusual given our proximity to downtown. The radio squawked “Multiple gunshots wounds en route.” Someone said “a club downtown got shot up.” In anticipation of multiple patient arrivals, resident Amanda M. Stone, MD, and the attending hurried to the trauma/ressuscitation bay. Another resident, Amanda F. Tarkowski, MD, called the trauma attending to rally his team downstairs, informing him that “A club downtown has a shooter and we have multiple patients with a 2-minute ETA.” Multiple gunshot wounds (GSWs) at once is not unusual for our Level 1 trauma center.

The first patient arrived shortly after 2:00 am and had multiple GSWs to the abdomen, but was awake and talking. He was mildly tachycardic, but his blood pressure (BP) was stable. We all gaped at the fist-sized wound on his back—some of us had never seen a GSW like this before. It was apparent that he needed to go to the operating room, but before preparations could be made, three more patients rolled into the ED. Instead of our usual organized, methodical EMS report, these patients were dropped off by a police pickup truck and rolled in on our own stretchers by nurses and technicians. Soon, all six of our trauma bays were filled with critical patients. Christopher H. Ponder, MD, recalled, “I heard an overhead page for ‘all available trauma nurses to the trauma bay’ shortly followed by a more concerned-sounding ‘all available staff to the trauma bay.’” All four senior EM residents, both EM attendings, the trauma attending, four trauma residents, multiple ED nurses, technicians, and various ancillary staff quickly descended on the patients. Chest tubes were placed, and multiple patients were intubated. Several thoracotomies were performed at the initial point when the team was unaware of the exact number of patients who would ultimately follow. Blood bags were hung and tranexamic acid was administered liberally. Unfortunately, some of these initial attempts were unsuccessful, as the first wave contained the most critically injured patients.

We barely had time to reflect on the dead as more patients filled the hallways. In the midst of all of this, triage decisions came quickly—awake and talking patients with an acceptable BP were moved out of the trauma bay in favor of less stable patients. Intubation and chest-tube placement decisions were made instantly. There was no time for routine X-rays or laboratory evaluation. Nurses, technicians, and doctors crowded the trauma bay desperately trying to stabilize the critically injured. Vital signs were taken manually. Dr Ponder called his colleague Thomas N. Smith, MD, who was also a graduating senior EM resident, and who happened to be staffing the children’s ED across the street that night. “Is there any way you can make it over here right now?” he shouted into the phone. Dr Smith quickly grabbed several trauma supplies and hitched a ride with security to the ORMC ED to assist. He was confronted with the scene of the previously mentioned “first wave” and grabbed an ultrasound machine to help triage these unfortunate patients. In addition to Dr Smith, unit clerks continued making calls to additional off-duty medical, nursing, and support staff. Critical care attendings and fellows responded from upstairs to assist in the ED. The Hospital Incident Command System (HICS) was initiated to provide hospital and corporate coordination of services. Timothy B. Bullard, MD, another EM attending physician and medical staff director of HICS, was en route to the ED to assist in the response.

Amidst the overwhelming mass of mortally and critically wounded patients, we were told stories of terror from just down the road. The sense of horror was almost contagious, and we all wondered if the violence would spread to the hospital.

About an hour into the ordeal, we heard another page overhead “Code Silver, ED Triage. Code Silver, ED Triage.” Everyone in the trauma bay froze. We heard someone shout from the hallway “Shots fired in triage!” After a few seconds, those nearest the trauma bay doors pushed them shut. One of the trauma surgeons shouted, “Keep caring for your patients, push the portable X-ray machines in front of the doors.” That is exactly what happened, and we worked in the barricaded trauma room for the longest few minutes of the night. We would later learn that this report was false, but fearing for our own lives as well as the lives of our patients is an experience that few, if any, of us had previously been through. The fact that we continued to work in such a situation illustrates everyone’s dedication to their patients and mission.

After the first wave of patients, it was clear that reassessing patients was now our greatest challenge. There were multiple patients with stable vital signs but who had GSWs to the abdomen, pelvis, and thorax and required surgery. Having realized that the ultrasound machine and focused assessment with sonography for trauma (FAST) examinations were the most practical rapid imaging modality, Drs Tarkowski, Ponder, and Smith grabbed the machine and went from room to room repeating the FAST examinations, vital signs, and assessments for missed wounds. A portable computer allowed us to order X-ray orders for patients with extremity wounds. Several patients who initially had negative FASTs had a repeat examination that was positive for free fluid. The operating room triage list shuffled based on these examinations.

At this point, there seemed to be a never-ending list of “Doe” names on the electronic medical record (EMR) tracking board. Tracking the location of patients was a dynamic process, and updating the tracking board was difficult. Patients were continually cycled in and out of the trauma bay, shuffled in and out of treatment rooms, lined up in the hallways, and transported up to the intensive care unit (ICU). Some of those “Doe” names belonged to patients who had succumbed to their injuries. Some patients had empty, bloody charts next to them on their stretcher. Every patient had a wristband. Dr Tarkowski improvised a rapid documentation system using quarter sheets of scrap paper that were taped either to the stretcher or door with a patient name, brief list of injuries, FAST examination result, pending tests, and medications given. This system was an efficient way of identifying which patients had been evaluated, what had been done, and what was pending.

While we were “rounding” on our patients, down the street, law enforcement had broken down the club’s wall, and a second wave of patients began to arrive. Two residents completed the secondary evaluations while the other three resuscitated new patients. The second wave seemed like a repeat of the first. Several extremity-only injuries were triaged directly to the hallways to be seen by the two residents outside of the trauma bay. By this time, the orthopedic surgery service had come down to the ED and was washing out wounds, splinting, and making plans for surgery. The internal medicine service and the medical critical care team were helping reassess patients as well.

There were many emotional moments. Dr Ponder remembered, “One of the first few patients I saw was pulseless, and as I went to start chest compressions, I was stopped by a trauma surgeon who said, ‘He’s gone, focus on the ones we can help.’ That’s when I realized the gravity of our situation. For almost 2 hours, each resident cycled through patients.” Dr Stone recounted, “I just went down the line of patients, from head of the bed to head of the bed, some patients still on EMS stretchers, intubating many of them. It was surreal to see that many severely injured in one place.” Tory L. Weatherford, MD, recalled, “It was controlled chaos. My training kicked in, and it became about just trying to do anything possible to help.”

Dr Bondani, the overnight attending, said she does not remember many specifics from the event. “Faces and injuries blurred together. I remember looking in one young man’s eyes and telling him, ‘We are going to help you, just hang in there,’ and telling another panicking woman, ‘You’re talking, you can feel pain, you’re alive. Calm down.’ It was organized chaos as we swept from patient to patient moving as quickly as possible. Your training kicks in and you do what needs to be done in the moment.”

We were fortunate to have the EM team we did, and to be in the place that we were. On duty, we had five senior graduating residents, essentially with attending-level skills and training, who had been together since day one. “We gave everything we had; there was no time to stop. We went where our hands could be helpful—it didn’t matter if it was your traditional role or not,” said Dr Weatherford.

Dr Tarkowski remembered what it was like leaving the walls of the ED later that morning. “Leaving the hospital didn’t feel like a success. We knew the work we did was good, that we did everything we could, but it didn’t feel like it. It felt heavy. It felt empty.” Afterward, the emotional toll set in. We gathered up the names of the deceased and looked at a status board littered with “Doe” names, and we tried hard not to break down at the violence and the pain we witnessed.

Immediate Recovery Period (Prehospital Setting)

In the aftermath of the initial rescue operation, stabilization of injured victims, and demobilization of resources, a second “event” unfolded—hundreds of family members flooded to ORMC looking for unaccounted loved ones. At this point, there were dozens of deceased and critically injured patients who remained unidentified, and addressing the needs of both the victims and the families was becoming overwhelming. With the cooperation of federal, state, county, city, and private resources, a family reunification center (FRC; a family staging area/family reception center) was created and managed initially within the hospital. At this site, grief counselors, victim advocates, law enforcement and medical examiner’s officials, hospital chaplains, and translators gathered with the loved ones of those missing to synchronize efforts to identify and reunite them. The Emergency Operations Center quickly created a telephone hotline and Web site to guide those in need to this resource. Food and housing for those in need were provided by the generosity of our community—which cannot be overstated in the wake of this tragedy. As days passed, the FRC transitioned to a new location as the Orlando United Assistance Center, and will continue to serve as a navigation point for those who are and will be affected by the event for months to come.

Hospital Incident Command System

The HICS was activated shortly past 3:00 am, just after the initial wave of victims flooded our ED and the gravity of the situation became apparent. The ED and trauma services were already near full staff due to timing, rapid response, and communication between the traumatologists, as well as a bit of luck. Because of the time of the disaster, our normal notification process for incident command and all personnel was severely limited. In retrospect, this turned out to be a blessing. While everyone who normally would respond to HICS was not available, individuals serving in key positions were reached by personal phone calls and were on-site quickly. One of the main functions of HICS is to control the internal chaos that arises when a disaster occurs and all personnel want to assist in some manner. We have spent hours during drills crafting communications that target key personnel necessary to meet the mission, while controlling well-intentioned but unnecessary personnel. In our drills, this is not an issue because everyone knows the exercise is not reality; however, in a real disaster, everyone wants to help. This was confirmed by the guilt that so many of our team members expressed at not being involved that Sunday.

With an initial skeleton crew in incident command, it was easy to focus on the immediate needs of patient care. The strong leadership and cool heads of our incident command leadership led to rapid role definition and responsibility, and set forth an easy path for execution. Hospital command personnel adapted their usual roles and performed functions and assignments as needed. Many HICS staff had direct face-to-face contact with frontline providers in the ED and other vital areas. This was possible because of the close proximity of the hospital command headquarters to the ED. The need for additional resources was rapidly identified, and the hospital command leaders assumed direct responsibility for procuring them instead of delegating. A great example of this was when Orlando Health’s chief executive officer and chief operating officer went to our nearby hospitals to gather additional chest tubes after learning that we were running in short supply. Their main responsibilities lay ahead of them, and they were willing to help in any manner they could at the time. Some of the medical personnel were able to switch roles and pitch in to treat the second wave of victims that arrived at around 5:00 am.

As the flow of victims to the ED subsided and order began to be restored, HICS shifted gears and took on a much broader role: coordinating activities with multiple agencies, including local law enforcement, the Federal Bureau of Investigation, news media, and an array of patient and family services. Again, the timing of this tragic event allowed the needs and functions of our hospital command to concentrate the focus in a more structured manner than might have been possible during regular operational hours.

Lessons Learned and Recommendations

As with any MCI, it is important to perform after-incident debriefings to reflect upon the prehospital, ED, and hospital care to assess for areas in need of improvement. Obviously, depending on the number and type of patients who are received and the resources available at the institution, such events can stress EDs that are already at or above their capacity. At the time of this writing (less than 2 months after the incident), although we are still in the early stages of our post-incident debriefing process, we offer the following suggestions and recommendations that we believe will be a benefit to other institutions faced with similar challenges.

Dedicated Disaster Preparedness Program

Depending on the size of the institution and whether or not it is a trauma-receiving center, it is vitally important to have a team of individuals dedicated to the development and maintenance of a disaster readiness program. Eric Alberts, manager of Emergency Preparedness at Orlando Heath, emphasized the need to harness and leverage preparedness efforts and relationships with community partners, law enforcement, and EMS. In addition, he noted that these trained individuals can provide education and coordination for mass-casualty drills, assist in developing and maintaining policies and protocols, and coordinate with hospital incident command during actual events.

Practice, Practice, Practice

In order for medical staff, nursing staff, and support personnel to understand their roles and responsibilities if an MCI occurs, they must practice simulated drills. Tabletop and full-scale emergency intake drills, with a range of scenarios occurring at different times of the day and night, will improve teamwork and coordination. At least once a year, a large, full-scale community exercise that involves scene casualty collection points, law enforcement and EMS involvement, multiple EDs, and hospital-wide integration will educate staff members on their duties. There should be enough patients in these drills to stress the entire system—both ED and in-hospital. Physician involvement in these exercises is crucial. In March 2016, a full-scale community exercise was performed in the Central Florida area in which more than 500 volunteers, 50 agencies, and 15 hospitals participated. A segment of that exercise involved an active shooter impersonating a patient brought to the ED. We feel this recent exercise, and others like it, were helpful in managing our actual mass casualty event.

Notification

When the shootings at the Pulse nightclub started, we were advised that there might be as many as 20 victims, but over the next few hours, we received more than twice as many injured patients. In any scenario where it is felt additional ED resources and personnel are needed, it is advantageous to begin the notification process as early as possible. Ideally, there are redundant methods in place to notify in-house and off-duty personnel, preferably in a multilayered system of electronic and voice communications that provides feedback as to staff availability. During daytime hours, it is easier for off-duty staff to learn of an event through news and social media. However, during early morning hours, such as when these shootings occurred, it may be difficult to notify sleeping staff that they are needed. With the trend of using mobile devices instead of landline phones, and with the ability to silence those devices during nighttime sleep hours, it has become increasingly difficult to “break through” the silence. In our event, group e-mail notifications were activated, but individual phone calls were also required. Initially, some calls to staff went to voice mail rather than being
answered directly.

Communication

Communication is an area of opportunity for improvement in almost any mass-casualty event. Redundant methods of electronic, voice, telephone, and radio communications are crucial for personnel to coordinate efforts. It is imperative that HICS and ED personnel receive updates about events on the scene and the status of potential incoming patients. An infrastructure of communications is paramount for the coordination that is needed between prehospital, ED, and in-house resources.

Throughput

Facilitating ED and hospital throughput and improving operational efficiencies are regular topics of discussion in most busy EDs. However, when it becomes necessary to intake large numbers of patients in an ED within a short period of time, the need to move patients out of the department intensifies. In many cases, to continue intake of patients, it will be necessary to quickly find areas outside of the ED—such as operating rooms, ICUs, and general floors—to transport patients to. At our facility, we normally have two operating rooms staffed throughout the night for traumas. On the night of the shootings, a total of six operating rooms were activated quickly to manage the penetrating injuries of these patients. Previously admitted medical patients were retrieved by in-house nursing staff to free up ED beds.

Media

It is important to recognize the intense social, print, online, and television media exposure that will occur with such tragedies, and have personnel and systems in place to manage it. The Pulse nightclub is located only a few short blocks south of ORMC, and the majority of all injured patients, including those with the most severe injuries, presented to our facility. As a result, the intense media coverage at our hospital physically overlapped the intense media coverage at the scene. Nearby businesses were shut down, access to several main thoroughfare roads were blocked, and some individuals mistakenly thought the hospital was closed. Our media relations department felt the most efficient way to manage information dissemination was to hold a “presser”—a press conference with a few of the health professionals involved in the care of the patients. The press conference helped to relieve some of the media presence and pressure, and provided welcomed transparency to the community.

Expect the Unexpected

Even when physicians and staff conduct regular training exercises and are familiar with policies and procedures, the controlled chaos that is typical of a true mass-casualty event will likely result in some unexpected occurrences. After injured patients began arriving at our ED, during a period when patient influx and medical care was intense, there was a brief time when we were concerned an active shooter was also in our ED. Since the mass shootings were only a few blocks from the ED, and we did not know the scope or number of shooters, it was a reasonable assumption that a perpetrator could present to the ED as a patient or active shooter. During an event such as this, it is the practice at ORMC to have security officers place the facility on lockdown; however; the added concern that an active shooter was physically present in the ED required additional law enforcement officers to methodically search the entire facility until the threat of a shooter was eliminated. Although this did not directly impact patient care, it did create another level of complexity and stress to the already challenging situation.

Emotional Impact

One should not underestimate the emotional impact of a mass-casualty event. Emergency physicians and personnel are well equipped to manage illness, injury, and death. However, an event of this magnitude, with the number and manner of injuries and deaths that presented to our ED, along with the closeness to a scene of bloodshed where many young lives were taken in a senseless act of violence, will likely have a lasting impression on many staff members. Any institution encountering such an event should have behavioral health and support counselors readily available as soon as possible.

Conclusion

When patients present in truckloads, as they did in our ambulance bay in the early hours of June 12, an ED may be inundated with injured patients without notice or preparation. Teams need to trust their instincts, their training, and one another. It is unlikely that your normal ED practice patterns will be sufficient to take care of a large surge of patients, and you will need to turn to your ingenuity, creativity, and resourcefulness to do what you think is best to save the lives of as many patients as possible. As Sarah Duran, BSN, the trauma nurse who was working as the ED charge nurse the night of the shootings, stated, “I don’t think anyone can fully prepare for anything on the scale of what happened in Orlando, but with a good foundation of protocols in place, strong set of staff, constant vigilance, and great teamwork, any hospital can be successful in handling a mass casualty incident.”

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

From the Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia (Dr. Scott), School of Medicine, The University of Queensland, Herston Road, Brisbane, Australia (Dr. Scott), Centre of Research Excellence in Quality & Safety in Integrated Primary-Secondary Care, The University of Queensland, Herston Road, Brisbane, Australia (Ms. Anderson), and Charming Institute, Camp Hill, Brisbane, Queensland, Australia (Dr. Freeman).

Abstract

• Objective: To review the adverse drug events (ADEs) risk of polypharmacy; the process of deprescribing and evidence of efficacy in reducing inappropriate polypharmacy; the enablers and barriers to deprescribing; and patient and system of care level strategies that can be employed to enhance deprescribing.
• Methods: Literature review.
• Results: Inappropriate polypharmacy, especially in older people, imposes a significant burden of ADEs, ill health, disability, hospitalization and even death. The single most important predictor of inappropriate prescribing and risk of ADEs in older patients is the number of prescribed medicines. Deprescribing is the process of systematically reviewing, identifying, and discontinuing potentially inappropriate medicines (PIMs), aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies, and deprescribing protocols have been developed and validated for clinical use. Barriers and enablers to deprescribing by individual prescribers center on 4 themes: (1) raising awareness of the prevalence and characteristics of PIMs; (2) overcoming clinical inertia whereby discontinuing medicines is seen as being a low value proposition compared to maintaining the status quo; (3) increasing skills and competence (self-efficacy) in deprescribing; and (4) countering external and logistical factors that impede the process.
• Conclusion: In optimizing the scale and effects of deprescribing in clinical practice, strategies that promote depresribing will need to be applied at both the level of individual patient–prescriber encounters and systems of care.

In developed countries in the modern era, about 30% of patients aged 65 years or older are prescribed 5 or more medicines [1]. Over the past decade, the prevalence of polypharmacy (use of > 5 prescription drugs) in the adult population of the United States has doubled from 8.2% in 1999–2000 to 15% in 2011–2012 [2]. While many patients may benefit from such polypharmacy [3] (defined here as 5 or more regularly prescribed medicines), it comes with increased risk of adverse drug events (ADEs) in older people [4] due to physiological changes of aging that alter pharmacokinetic and pharmacodynamic responses to medicines [5]. Approximately 1 in 5 medicines commonly used in older people may be inappropriate [6], rising to a third among those living in residential aged care facilities [7]. Among nursing home residents with advanced dementia, more than half receive at least 1 medicine with questionable benefit [8]. Approximately 50% of hospitalized nursing home or ambulatory care patients receive 1 or more unnecessary medicines [9]. Observational studies have documented ADEs in at least 15% of older patients, contributing to ill health [10], disability [11], hospitalization [12] and readmissions [13], increased length of stay, and, in some cases, death [14]. This high level of iatrogenic harm from potentially inappropriate medicines (PIMs) mandates a response from clinicians responsible for managing medicines.

In this narrative review, we aim to detail the ADE risk of polypharmacy, the process of deprescribing and evidence of its efficacy in reducing potentially inappropriate polypharmacy, the enablers and barriers to deprescribing, and patient and system of care level strategies that can be employed in enhancing deprescribing.

Polypharmacy As a Risk Factor for Medicine-Related Harm

The number of medicines a patient is taking is the single most important predictor of medicine-related harm [15]. One report estimated the risk of ADEs as a contributory cause of patients presenting acutely to hospital emergency departments to be 13% for 2 drugs, 38% for 4 drugs, and 82% for 7 drugs or more [16]. The more medicines an individual takes, the greater their risk of experiencing an adverse drug reaction, a drug-drug interaction, a drug-disease interaction, cascade prescribing (where more medicines are added to counteract side effects of existing medicines), nonadherence, and drug errors (wrong drug, wrong dose, missed doses, erroneous dosing frequency) [17–20]. Once the number of regular medicines rises above 5 (commonly regarded as the threshold for defining polypharmacy), observational data suggest that additional medicines independently increase the risk of frailty, falling, and hospital admission [21].

The benefits of many medicines in frail older people remain unquantified. As many as 50% of clinical trials have a specific upper age limit and approximately 80% of clinical trials exclude people with comorbidities [22,23]. Single-disease treatment guidelines based on such trials are often extrapolated to older people with multimorbidity despite an absence of evidence for benefit [24] and with little consideration of the potential burdens and harms of polypharmacy resulting from treating multiple diseases in the one patient [25]. By contrast, the risks from many medicines in older people are well known. Older people are at high risk of ADEs and toxicity due to reduced renal and liver function and age-related changes in physiological reserve, body composition, and cellular metabolism [26]. While the adverse effects of polypharmacy or of comorbidities targeted for treatment are difficult to separate, the burden of medicine-induced decline in function and quality of life is becoming better defined and appreciated [27].

Defining Evidence-Based Deprescribing

While many definitions have been proposed [28], we define evidence-based deprescribing as follows: the active process of systematically reviewing medicines being used by individual patients and, using best available evidence, identifying and discontinuing those associated with unfavorable risk–benefit trade-offs within the context of illness severity, advanced age, multi-morbidity, physical and emotional capacity, life expectancy, care goals, and personal preferences [29]. An enlarging body of research has demonstrated the feasibility, safety and patient benefit of deprescribing, as discussed further below. It employs evidence-based frameworks that assist the prescriber [30] and are patient-centered [31].

Importantly, deprescribing should be seen as part of the good prescribing continuum, which spans medicine initiation, titrating, changing, or adding medicines, and switching or ceasing medicines. Deprescribing is not about denying effective treatment to eligible patients. It is a positive, patient-centered intervention, with inherent uncertainties, and requires shared decision-making, informed patient consent and close monitoring of effects [32]. Deprescribing involves diagnosing a problem (use of a PIM), making a therapeutic decision (withdrawing it with close follow-up) and altering the natural history of the problem (reducing incidence of medicine-related adverse events).

Our definition of evidence-based deprescribing is a form of direct deprescribing applied at the level of the individual patient-prescriber/pharmacist encounter. Direct deprescribing uses explicit, systematic processes (such as using an algorithm or structured deprescribing framework or guide) applied by individual prescribers (or pharmacists) to the medicine regimens of individual patients (ie, at the patient level), and which targets either specific classes of medicines or all medicines that are potentially inappropriate. This is in contrast to indirect deprescribing, which uses more generic, programmatic strategies aimed at prescribers as a whole (ie, at the population or system level) and which seek to improve quality use of medicines in general, including both underuse and overuse of medicines. Indirect deprescribing entails a broader aim of medicines optimization in which deprescribing is a possible outcome but not necessarily the sole focus. Such strategies include pharmacist or physician medicine reviews, education programs for clinicians and/or patients, academic detailing, audit and feedback, geriatric assessment, multidisciplinary teams, prescribing restrictions, and government policies, all of which aim to reduce the overall burden of PIMs among broad groups of patients. While intuitively the 2 approaches in combination should exert synergistic effects superior to those of either by itself, this has not been studied.

Evidence For Deprescribing

Indirect Deprescribing

Overall, the research into indirect interventions has been highly heterogenous in terms of interventions and measures of medicine use. Research has often been of low to moderate quality, focused more on changes to prescribing patterns and less on clinical outcomes, been of short duration, and produced mixed results [33]. In a 2013 systematic review of 36 studies involving different interventions involving frail older patients in various settings, 22 of 26 quantitative studies reported statistically significant reductions in the proportions of medicines deemed unnecessary (defined using various criteria), ranging from 3 to 20 percentage points [34]. A more recent review of 20 trials of pharmacist-led reviews in both inpatient and outpatient settings reported a small reduction in the mean number of prescribed medicines (–0.48, 95% confidence interval [CI] –0.89 to –0.07) but no effects on mortality or readmissions, although unplanned hospitalizations were reduced in patients with heart failure [35]. A 2012 review of 10 controlled and 20 randomized studies revealed statistically significant reductions in the number of medicines in most of the controlled studies, although mixed results in the randomized studies [36]. Another 2012 review of 10 studies of different designs concluded that interventions were beneficial in reducing potentially inappropriate prescribing and medicine-related problems [37]. A 2013 review of 15 studies of academic detailing of family physicians showed a modest decline in the number of medications of certain classes such as benzodiazepines and nonsteroidal anti-inflammatory drugs [38]. Another 2013 review restricted to 8 randomized trials of various interventions involving nursing home patients suggested medicine-related problems were more frequently identified and resolved, together with improvement in medicine appropriateness [39]. In 2 randomized trials conducted in aged care facilities and centered on educational interventions, one aimed at prescribers [40] and the other at nursing staff [41],the number of potentially harmful medicines and days in hospital was significantly reduced [40,41], combined with slower declines in health-related quality of life [40]. In a randomized trial, patient education provided through community pharmacists led to a 77% reduction in benzodiazepine use among chronic users at 6 months with no withdrawal seizures or other ill effects [42].

Direct Deprescribing Targeting Specific Classes of Medicines

The evidence base for direct patient-level deprescribing is more rigorous as it pertains to specific classes of medicines. A 2008 systematic review of 31 trials (15 randomized, 16 observational) that withdrew a single class of medicine in older people demonstrated that, with appropriate patient selection and education coupled with careful withdrawal and close monitoring, antihypertensive agents, psychotropic medicines, and benzodiazepines could be discontinued without harm in 20% to 100% of patients, although psychotropics showed a high post-trial rate of recommencement [43]. Another review of 9 randomized trials demonstrated the safety of withdrawing antipsychotic agents that had been used continuously for behavioural and psychological symptoms in more than 80% of subjects with dementia [44]. In an observational study, cessation of inappropriate antihypertensives was associated with fewer cardiovascular events and deaths over a 5-year follow-up period [45]. A recent randomized trial of statin withdrawal in patients with advanced illness and of whom half had a prognosis of less than 12 months demonstrated improved quality of life and no increased risk of cardiovascular events over the following 60 days [46].

Direct Deprescribing Targeting All Medicines

The evidence base for direct patient-level deprescribing that assesses all medicines, not just specific medicine classes, features several high-quality observational studies and controlled trials, and subgroup findings from a recent comprehensive systematic review. In this review of 132 studies, which included 56 randomized controlled trials [47], mortality was shown in randomized trials to be decreased by 38% as a result of direct (ie, patient-level) deprescribing interventions. However, this effect was not seen in studies of indirect deprescribing comprising mainly generic educational interventions. While space prevents a detailed analysis of all relevant trials, some of the more commonly cited sentinel studies are mentioned here.

In a controlled trial involving 190 patients in aged care facilities, a structured approach to deprescribing (Good Palliative–Geriatric Practice algorithm) resulted in 63% of patients having, on average, 2.8 medicines per patient discontinued, and was associated with a halving in both annual mortality and referrals to acute care hospitals [48]. In another prospective uncontrolled study, the same approach applied to a cohort of 70 community-dwelling older patients resulted in an average of 4.4 medicines prescribed to 64 patients being recommended for discontinuation, of which 81% were successfully discontinued, with 88% of patients reporting global improvements in health [49]. In a prospective cohort study of 50 older hospitalized patients receiving a median of 10 regular medicines on admission, a formal deprescribing process led to the cessation of just over 1 in 3 medicines by discharge, representing 4 fewer medicines per patient [50]. During a median follow-up period of just over 2.5 months for 39 patients, less than 5% of ceased medicines were recommenced in 3 patients for relapsing symptoms, with no deaths or acute presentations to hospital attributable to cessation of medicines. A multidisciplinary hospital clinic for older patients over a 3-month period achieved cessation of 22% of medicines in 17 patients without ill effect [51].

Two randomized studies used the Screening Tool of Older People’s Prescriptions (STOPP) to reduce the use of PIMs in older hospital inpatients [52,53]. One reported significantly reduced PIMs use in the intervention group at discharge and 6 months post-discharge, no change in the rate of hospital readmission, and non-significant reductions in falls, all cause-mortality, and primary care visits during the 6-month follow-up period [52]. The second study reported reduced PIMs use in the intervention group of frail older patients on discharge, although the proportion of people prescribed at least 1 PIM was not altered [53].

Recently, a randomized trial of a deprescribing intervention applied to aged care residents resulted in successful discontinuation of 207 (59%) of 348 medicines targeted for deprescribing, and a mean reduction of 2 medicines per patient at 12 months compared to none in controls, with no differences in mortality or hospital admissions [54]. The evidence for direct deprescribing is limited by relatively few high-quality randomized trials, small patient samples, short duration of follow-up, selection of specific subsets of patients, and the absence of comprehensive re-prescribing data and clinical outcomes.

Methods Used for Direct Deprescribing

At the level of individual patient care, various instruments have been developed to assist the deprescribing process. Screening tools or criteria such as the Beers criteria and STOPP tool help identify medicines more likely than not to be inappropriate for a given set of circumstances and are widely used by research pharmacists. Deprescribing guidelines directed at particular medications (or drug classes) [55], or specific patient populations [56], can identify clinical scenarios where a particular drug is likely to be inappropriate, and how to safely wean or discontinue it.

In applying a more nuanced, patient-centered approach to deprescribing, structured guides comprising algorithms, flowcharts, or tables describe sequential steps in deciding which medications used by an individual patient should be targeted for discontinuation after due attention to all relevant factors. Such guides prompt a more systematic appraisal of all medications being used. In a recent review of 7 structured guides that had undergone some form of efficacy testing [59], the strongest evidence of efficacy and clinician acceptability was seen for the Good Palliative–Geriatric Practice algorithm [48] (Figure) and the CEASE protocol [29,30,50,60] (Table). Both have been subject to a process of development and refinement over months to years involving multiple clinician prescribers and pharmacists. 

Clinical Circumstances Conducive to Deprescribing

Deprescribing should be especially considered in any older patient presenting with a new symptom or clinical syndrome suggestive of adverse medicine effects. The advent of advanced or end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all cares marks a stage of a person’s life when limited life expectancy and changed goals of care call for a re-appraisal of the benefits of current medicines. Lack of response in controlling symptoms despite optimal adherence and dosing or conversely the absence of symptoms for long periods of time should challenge the need for ongoing regular use of medicines. Similarly, the lack of verification, or indeed repudiation, of past diagnostic labels which gave rise to indications for medicines in the first place should prompt consideration of discontinuation. Patients receiving single medicines or combinations of medicines, both of which are high risk, should attract attention [63], as should use of preventive medicines for scenarios associated with no increased disease risk despite medicine cessation (eg, ceasing alendronate after 5 years of treatment results in no increase in osteoporotic fracture risk over the ensuing 5 years [64]; ceasing statins for primary prevention after a prolonged period results in no increase in cardiovascular events 8 years after discontinuation [65]). Evidence that has emerged that strongly contradicts previously held beliefs as to the indications for certain medicines (eg, aspirin as primary prevention of cardiovascular disease) should lead to a higher frequency of their discontinuation. Finally, medicines which impose demands on patients which they deem intolerable in terms of dietary and lifestyle restrictions, adverse side effects, medicine monitoring (such as warfarin), financial cost, or any other reason likely to result in nonadherence, should be considered candidates for deprescribing [25].

Barriers to Deprescribing

The most effective strategy to reducing potentially inappropriate polypharmacy is for doctors to prescribe and patients to consume fewer medicines. Unfortunately, both doctors and patients often lack confidence about when and how to cease medicines [66–69]. In a recent systematic review comprised mostly of studies involving general practitioners in primary care [66], 4 themes emerged. First, prescribers may be unaware of their own instances of inappropriate prescribing in older people until this is pointed out to them. Poor insight may be attributable in part to insufficient education in geriatric pharmacology. Second, clinical inertia manifesting as failure to act despite an awareness of PIMs may arise from deprescribing being viewed as a risky affair [70], with doctors fearful of provoking withdrawal syndromes or disease complications, and damaging their reputation and relationships with patients or colleagues in the process. Continuing inappropriate medicines is reinforced by prescriber beliefs that to do so is a safer or kinder course of action for the patient. Third, self-perceptions of being ill-equipped, in terms of the necessary knowledge and skills, to deprescribe appropriately (lack of self-efficacy) may be a barrier, even if one accepts the need for deprescribing. Information deficits around benefit-harm trade-offs of particular drugs and alternative treatments (both drug and non-drug), especially for older, frail, multi-morbid patients, contribute to the problem. Confidence to deprescribe is further undermined by the lack of clear documentation regarding reasons drugs were originally prescribed by other doctors, outcomes of past trials of discontinuation, and current patient care goals. Fourth, several external or logistical constraints may hamper deprescribing efforts such as perceived patient unwillingness to deprescribe certain medicines, lack of prescriber time, poor remuneration, and community and professional attitudes toward more rather than less use of medicines.

Deprescribing in hospital settings led by specialists appears to be no better than in general practice, although it has been less well studied. While an episode of acute inpatient care may afford an opportunity to review and reduce medicine lists, studies suggest the opposite occurs. In a New Zealand audit of 424 patients of mean age 80 years admitted acutely to a medical unit, chronically administered medications increased during hospital stay from a mean of 6.6 to 7.7 [71]. Similarly, in an Australian study investigating medication changes for 1220 patients of mean age 81 years admitted to general medical units of 11 acute care hospitals, the mean number of regularly administered medications rose from 7.1 on admission to 7.6 at discharge [72]. It is likely the same drivers behind failure to deprescribe in primary care also operate in secondary and tertiary care settings. Part of the problem is under-recognition of medicine-related geriatric syndromes on the part of hospital physicians and pharmacists [73].

Patients in both the community and residential aged care facilities frequently express a desire to have their medicines reduced in number, especially if advised by their treating clinician [74,75]. Having said this, many remain wary of discontinuing specific medicines [67], sharing the same fears of evoking withdrawal syndromes or disease relapse as do prescribers, and recounting the strong advice of past specialists to never withhold any medicines without first seeking their advice.

A challenge for all involved in deprescribing is gaining agreement on what are the most important factors that determine when, how, and in whom deprescribing should be conducted. Recent qualitative studies suggest that doctors, pharmacists, nursing staff, and patients and their families, while in broad agreement that deprescribing is worthwhile, often differ in their perspectives on what takes priority in selecting medicines for deprescribing in individual patients, and how it should be done and by whom [76,77].

Strategies That May Facilitate Deprescribing

While deprescribing presents some challenges, there are several strategies that can facilitate it at both the level of individual clinical encounters and at the level of whole populations and systems of care.

Individual Clinical Encounters

Within individual clinician–patient encounters, patients should be empowered to ask their doctors and pharmacists the following questions:

• What are my treatment options (including non-medicine options) for my condition?
• What are the possible benefits and harms of each medicine?
• What might be reasonable grounds for stopping a medicine?

In turn, doctors and pharmacists should ask in a nonjudgmental fashion, at every encounter, whether patients are experiencing any side effects, administration and monitoring problems, or other barriers to adherence associated with any of their medicines.

The issue of deprescribing should be framed as an attempt to alleviate symptoms (of drug toxicity), improve quality of life (from drug-induced disability), and lessen the risk of morbid events (especially ADEs) in the future. Compelling evidence that identifies circumstances in which medicines can be safely withdrawn while reducing the risk of ADEs needs to be emphasized. Specialists must play a sentinel leadership role in advising and authorizing other health professionals to deprescribe in situations where benefits of medications they have prescribed are no longer outweighed by the harms [60,78].

In language they can understand, patients should be informed of the benefit–harm trade-offs specific to them of continuing or discontinuing a particular medicine, as far as these can be specified. Patients often overestimate the benefits and underestimate the harms of treatments [79]. Providing such personalised information can substantially alter perceptions of risk and change attitudes towards discontinuation [80]. Eliciting patients’ beliefs about the necessity for each individual medicine and spending time, using an empathic manner, to dispel or qualify those at odds with evidence and clinical judgement renders deprescribing more acceptable to patients.

In estimating treatment benefit–harm trade-offs in individual patients, disease risk prediction tools (http://www.medal.org/), evidence tables [81,82], and decision aids are increasingly available. Prognostication tools (http://eprognosis.ucsf.edu) combined with trial-based time-to-event data can be used to determine if medicine-specific time until benefit exceeds remaining life span.

Deprescribing is best performed by reducing medicines one at a time over several encounters with the same overseeing generalist clinician with whom patients have established a trusting and collaborative relationship. This provides repeated opportunities to discuss and assuage any fears of discontinuing a medicine, and to adjust the deprescribing plan according to changes in clinical circumstances and revised treatment goals. Practice-based pharmacists can review patients’ medicine lists and apply screening criteria to identify medicines more likely to be unnecessary or harmful, which then helps initiate and guide deprescribing. Integrating a structured deprescribing protocol—and reminders to use it—into electronic health records, and providing decision support and data collection for future reference, reduce the cognitive burden on prescribers [83]. Practical guidance in how to safely wean and cease particular classes of medicines in older people can be accessed from various sources [84,85]. Seeking input from clinical pharmacologists, pharmacists, nurses, and other salient care providers on a case-by-case basis in the form of interactive case conferences provides support, seeks consensus, and shares the risk and responsibility for deprescribing recommendations [86].

System of Care

The success of deprescribing efforts in realizing better population health will be compromised unless all key stakeholders involved in quality use of medicines commit to operationalizing deprescribing strategies at the system of care level. Position statements on deprescribing in multi-morbid populations should be formulated and promulgated by all professional societies of prescribers (primary care, specialists, pharmacists, dentists, nurse practitioners). Professional development programs as well as undergraduate, graduate, and postgraduate courses in medicine, pharmacy, and nursing should include training in deprescribing as a core curricular element.

Researchers seeking funding and/or ethics approval for research projects involving medicines should be required to collect, analyze, and report data on the frequency of, and reasons for, withdrawal of drugs in trial subjects. This helps build the evidence base of medicine-related harm. In turn, government funders of research should require more researchers to design and conduct clinical trials that recruit multi-morbid patients, including specific subgroups (eg, patients with dementia), and aim to define medicine benefits and harms using patient risk stratification methods. Pharmaceutical companies should sponsor research on how to deprescribe their medicines within trials that also aim to assess efficacy and safety. Medicine regulatory authorities such as the Food and Drug Administration should mandate that this information be supplied at the time the company submits their application to have the medicine approved and listed for public subsidy. Trialists should adopt the word “deprescribing” in abstract titles for research on prescriber-initiated medicine discontinuation so that relevant articles can be more accurately indexed in, and retrieved from, bibliographic databases using recently formulated medical subject headings in Medline (“depresciptions”).

Editors of medical journals should promote a deprescribing agenda as a quality and safety issue for patient care, with the “Less is More” series in JAMA Internal Medicine and “Too much medicine” series in BMJ being good examples. Clinical guideline developers should formulate treatment recommendations specific to the needs of multi-morbid patients which acknowledge the limited evidence base for many medicines in such populations. These should take account of commonly encountered clinical scenarios where disease-specific medicines may engender greater risk of harm, and provide cautionary notes regarding initiation and discontinuation of medicines associated with high-risk.

Pharmacists need to instruct patients in how to identify medicine-induced harm and side effects, and how to collaborate with their prescribing clinicians in safely discontinuing high-risk medicines. Ideally, patients being admitted to residential aged care facilities should have their medicine lists reviewed by a pharmacist in flagging medicines eligible for deprescribing. Organizations and services responsible for providing quality use of medicines information (medicines handbooks, prescribing guidelines, drug safety bulletins) should describe when and how deprescribing should be performed in regards to specific medicines. This information should be cross-referenced to clinical guidelines and position statements dealing with the same medicine. Vendors of medicine prescribing software should be encouraged to incorporate flags and alerts which prompt prescribers to consider medicine cessation in high-risk patients.

Government and statutory bodies with responsibility for health care (health departments, quality and safety commissions, practice accreditation services, health care standard–setting bodies) should fund more research to develop and evaluate medicine safety standards aimed at reducing inappropriate use of medicines. Accreditation procedures for hospitals and primary care organizations should mandate the adoption of professional development and quality measurement systems that support and monitor patients receiving multiple medicines. Organizations responsible for conducting pharmacovigilance studies should issue medicine-specific deprescribing alerts whenever their data suggest higher than expected incidence of medicine-related adverse events in older populations receiving such medicines.

Conclusion

Inappropriate medicine use and polypharmacy is a growing issue among older and multi-morbid patients. The cumulative evidence of the safety and benefits of deprescribing argues for its adoption on the part of all prescribers, as well as its support by pharmacists and others responsible for optimizing use of medicines. Widespread implementation within routine care of an evidence-based approach to deprescribing in all patients receiving polypharmacy has its challenges, but also considerable potential to relieve unnecessary suffering and disability. More high quality research is needed in defining the circumstances under which deprescribing confers maximal benefit in terms of improved clinical outcomes.

Corresponding author: Ian A. Scott, Dept. of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Brisbane, Australia 4102, [email protected].

Financial disclosures: None.

From the Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia (Dr. Scott), School of Medicine, The University of Queensland, Herston Road, Brisbane, Australia (Dr. Scott), Centre of Research Excellence in Quality & Safety in Integrated Primary-Secondary Care, The University of Queensland, Herston Road, Brisbane, Australia (Ms. Anderson), and Charming Institute, Camp Hill, Brisbane, Queensland, Australia (Dr. Freeman).

Abstract

• Objective: To review the adverse drug events (ADEs) risk of polypharmacy; the process of deprescribing and evidence of efficacy in reducing inappropriate polypharmacy; the enablers and barriers to deprescribing; and patient and system of care level strategies that can be employed to enhance deprescribing.
• Methods: Literature review.
• Results: Inappropriate polypharmacy, especially in older people, imposes a significant burden of ADEs, ill health, disability, hospitalization and even death. The single most important predictor of inappropriate prescribing and risk of ADEs in older patients is the number of prescribed medicines. Deprescribing is the process of systematically reviewing, identifying, and discontinuing potentially inappropriate medicines (PIMs), aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies, and deprescribing protocols have been developed and validated for clinical use. Barriers and enablers to deprescribing by individual prescribers center on 4 themes: (1) raising awareness of the prevalence and characteristics of PIMs; (2) overcoming clinical inertia whereby discontinuing medicines is seen as being a low value proposition compared to maintaining the status quo; (3) increasing skills and competence (self-efficacy) in deprescribing; and (4) countering external and logistical factors that impede the process.
• Conclusion: In optimizing the scale and effects of deprescribing in clinical practice, strategies that promote depresribing will need to be applied at both the level of individual patient–prescriber encounters and systems of care.

In developed countries in the modern era, about 30% of patients aged 65 years or older are prescribed 5 or more medicines [1]. Over the past decade, the prevalence of polypharmacy (use of > 5 prescription drugs) in the adult population of the United States has doubled from 8.2% in 1999–2000 to 15% in 2011–2012 [2]. While many patients may benefit from such polypharmacy [3] (defined here as 5 or more regularly prescribed medicines), it comes with increased risk of adverse drug events (ADEs) in older people [4] due to physiological changes of aging that alter pharmacokinetic and pharmacodynamic responses to medicines [5]. Approximately 1 in 5 medicines commonly used in older people may be inappropriate [6], rising to a third among those living in residential aged care facilities [7]. Among nursing home residents with advanced dementia, more than half receive at least 1 medicine with questionable benefit [8]. Approximately 50% of hospitalized nursing home or ambulatory care patients receive 1 or more unnecessary medicines [9]. Observational studies have documented ADEs in at least 15% of older patients, contributing to ill health [10], disability [11], hospitalization [12] and readmissions [13], increased length of stay, and, in some cases, death [14]. This high level of iatrogenic harm from potentially inappropriate medicines (PIMs) mandates a response from clinicians responsible for managing medicines.

In this narrative review, we aim to detail the ADE risk of polypharmacy, the process of deprescribing and evidence of its efficacy in reducing potentially inappropriate polypharmacy, the enablers and barriers to deprescribing, and patient and system of care level strategies that can be employed in enhancing deprescribing.

Polypharmacy As a Risk Factor for Medicine-Related Harm

The number of medicines a patient is taking is the single most important predictor of medicine-related harm [15]. One report estimated the risk of ADEs as a contributory cause of patients presenting acutely to hospital emergency departments to be 13% for 2 drugs, 38% for 4 drugs, and 82% for 7 drugs or more [16]. The more medicines an individual takes, the greater their risk of experiencing an adverse drug reaction, a drug-drug interaction, a drug-disease interaction, cascade prescribing (where more medicines are added to counteract side effects of existing medicines), nonadherence, and drug errors (wrong drug, wrong dose, missed doses, erroneous dosing frequency) [17–20]. Once the number of regular medicines rises above 5 (commonly regarded as the threshold for defining polypharmacy), observational data suggest that additional medicines independently increase the risk of frailty, falling, and hospital admission [21].

The benefits of many medicines in frail older people remain unquantified. As many as 50% of clinical trials have a specific upper age limit and approximately 80% of clinical trials exclude people with comorbidities [22,23]. Single-disease treatment guidelines based on such trials are often extrapolated to older people with multimorbidity despite an absence of evidence for benefit [24] and with little consideration of the potential burdens and harms of polypharmacy resulting from treating multiple diseases in the one patient [25]. By contrast, the risks from many medicines in older people are well known. Older people are at high risk of ADEs and toxicity due to reduced renal and liver function and age-related changes in physiological reserve, body composition, and cellular metabolism [26]. While the adverse effects of polypharmacy or of comorbidities targeted for treatment are difficult to separate, the burden of medicine-induced decline in function and quality of life is becoming better defined and appreciated [27].

Defining Evidence-Based Deprescribing

While many definitions have been proposed [28], we define evidence-based deprescribing as follows: the active process of systematically reviewing medicines being used by individual patients and, using best available evidence, identifying and discontinuing those associated with unfavorable risk–benefit trade-offs within the context of illness severity, advanced age, multi-morbidity, physical and emotional capacity, life expectancy, care goals, and personal preferences [29]. An enlarging body of research has demonstrated the feasibility, safety and patient benefit of deprescribing, as discussed further below. It employs evidence-based frameworks that assist the prescriber [30] and are patient-centered [31].

Importantly, deprescribing should be seen as part of the good prescribing continuum, which spans medicine initiation, titrating, changing, or adding medicines, and switching or ceasing medicines. Deprescribing is not about denying effective treatment to eligible patients. It is a positive, patient-centered intervention, with inherent uncertainties, and requires shared decision-making, informed patient consent and close monitoring of effects [32]. Deprescribing involves diagnosing a problem (use of a PIM), making a therapeutic decision (withdrawing it with close follow-up) and altering the natural history of the problem (reducing incidence of medicine-related adverse events).

Our definition of evidence-based deprescribing is a form of direct deprescribing applied at the level of the individual patient-prescriber/pharmacist encounter. Direct deprescribing uses explicit, systematic processes (such as using an algorithm or structured deprescribing framework or guide) applied by individual prescribers (or pharmacists) to the medicine regimens of individual patients (ie, at the patient level), and which targets either specific classes of medicines or all medicines that are potentially inappropriate. This is in contrast to indirect deprescribing, which uses more generic, programmatic strategies aimed at prescribers as a whole (ie, at the population or system level) and which seek to improve quality use of medicines in general, including both underuse and overuse of medicines. Indirect deprescribing entails a broader aim of medicines optimization in which deprescribing is a possible outcome but not necessarily the sole focus. Such strategies include pharmacist or physician medicine reviews, education programs for clinicians and/or patients, academic detailing, audit and feedback, geriatric assessment, multidisciplinary teams, prescribing restrictions, and government policies, all of which aim to reduce the overall burden of PIMs among broad groups of patients. While intuitively the 2 approaches in combination should exert synergistic effects superior to those of either by itself, this has not been studied.

Evidence For Deprescribing

Indirect Deprescribing

Overall, the research into indirect interventions has been highly heterogenous in terms of interventions and measures of medicine use. Research has often been of low to moderate quality, focused more on changes to prescribing patterns and less on clinical outcomes, been of short duration, and produced mixed results [33]. In a 2013 systematic review of 36 studies involving different interventions involving frail older patients in various settings, 22 of 26 quantitative studies reported statistically significant reductions in the proportions of medicines deemed unnecessary (defined using various criteria), ranging from 3 to 20 percentage points [34]. A more recent review of 20 trials of pharmacist-led reviews in both inpatient and outpatient settings reported a small reduction in the mean number of prescribed medicines (–0.48, 95% confidence interval [CI] –0.89 to –0.07) but no effects on mortality or readmissions, although unplanned hospitalizations were reduced in patients with heart failure [35]. A 2012 review of 10 controlled and 20 randomized studies revealed statistically significant reductions in the number of medicines in most of the controlled studies, although mixed results in the randomized studies [36]. Another 2012 review of 10 studies of different designs concluded that interventions were beneficial in reducing potentially inappropriate prescribing and medicine-related problems [37]. A 2013 review of 15 studies of academic detailing of family physicians showed a modest decline in the number of medications of certain classes such as benzodiazepines and nonsteroidal anti-inflammatory drugs [38]. Another 2013 review restricted to 8 randomized trials of various interventions involving nursing home patients suggested medicine-related problems were more frequently identified and resolved, together with improvement in medicine appropriateness [39]. In 2 randomized trials conducted in aged care facilities and centered on educational interventions, one aimed at prescribers [40] and the other at nursing staff [41],the number of potentially harmful medicines and days in hospital was significantly reduced [40,41], combined with slower declines in health-related quality of life [40]. In a randomized trial, patient education provided through community pharmacists led to a 77% reduction in benzodiazepine use among chronic users at 6 months with no withdrawal seizures or other ill effects [42].

Direct Deprescribing Targeting Specific Classes of Medicines

The evidence base for direct patient-level deprescribing is more rigorous as it pertains to specific classes of medicines. A 2008 systematic review of 31 trials (15 randomized, 16 observational) that withdrew a single class of medicine in older people demonstrated that, with appropriate patient selection and education coupled with careful withdrawal and close monitoring, antihypertensive agents, psychotropic medicines, and benzodiazepines could be discontinued without harm in 20% to 100% of patients, although psychotropics showed a high post-trial rate of recommencement [43]. Another review of 9 randomized trials demonstrated the safety of withdrawing antipsychotic agents that had been used continuously for behavioural and psychological symptoms in more than 80% of subjects with dementia [44]. In an observational study, cessation of inappropriate antihypertensives was associated with fewer cardiovascular events and deaths over a 5-year follow-up period [45]. A recent randomized trial of statin withdrawal in patients with advanced illness and of whom half had a prognosis of less than 12 months demonstrated improved quality of life and no increased risk of cardiovascular events over the following 60 days [46].

Direct Deprescribing Targeting All Medicines

The evidence base for direct patient-level deprescribing that assesses all medicines, not just specific medicine classes, features several high-quality observational studies and controlled trials, and subgroup findings from a recent comprehensive systematic review. In this review of 132 studies, which included 56 randomized controlled trials [47], mortality was shown in randomized trials to be decreased by 38% as a result of direct (ie, patient-level) deprescribing interventions. However, this effect was not seen in studies of indirect deprescribing comprising mainly generic educational interventions. While space prevents a detailed analysis of all relevant trials, some of the more commonly cited sentinel studies are mentioned here.

In a controlled trial involving 190 patients in aged care facilities, a structured approach to deprescribing (Good Palliative–Geriatric Practice algorithm) resulted in 63% of patients having, on average, 2.8 medicines per patient discontinued, and was associated with a halving in both annual mortality and referrals to acute care hospitals [48]. In another prospective uncontrolled study, the same approach applied to a cohort of 70 community-dwelling older patients resulted in an average of 4.4 medicines prescribed to 64 patients being recommended for discontinuation, of which 81% were successfully discontinued, with 88% of patients reporting global improvements in health [49]. In a prospective cohort study of 50 older hospitalized patients receiving a median of 10 regular medicines on admission, a formal deprescribing process led to the cessation of just over 1 in 3 medicines by discharge, representing 4 fewer medicines per patient [50]. During a median follow-up period of just over 2.5 months for 39 patients, less than 5% of ceased medicines were recommenced in 3 patients for relapsing symptoms, with no deaths or acute presentations to hospital attributable to cessation of medicines. A multidisciplinary hospital clinic for older patients over a 3-month period achieved cessation of 22% of medicines in 17 patients without ill effect [51].

Two randomized studies used the Screening Tool of Older People’s Prescriptions (STOPP) to reduce the use of PIMs in older hospital inpatients [52,53]. One reported significantly reduced PIMs use in the intervention group at discharge and 6 months post-discharge, no change in the rate of hospital readmission, and non-significant reductions in falls, all cause-mortality, and primary care visits during the 6-month follow-up period [52]. The second study reported reduced PIMs use in the intervention group of frail older patients on discharge, although the proportion of people prescribed at least 1 PIM was not altered [53].

Recently, a randomized trial of a deprescribing intervention applied to aged care residents resulted in successful discontinuation of 207 (59%) of 348 medicines targeted for deprescribing, and a mean reduction of 2 medicines per patient at 12 months compared to none in controls, with no differences in mortality or hospital admissions [54]. The evidence for direct deprescribing is limited by relatively few high-quality randomized trials, small patient samples, short duration of follow-up, selection of specific subsets of patients, and the absence of comprehensive re-prescribing data and clinical outcomes.

Methods Used for Direct Deprescribing

At the level of individual patient care, various instruments have been developed to assist the deprescribing process. Screening tools or criteria such as the Beers criteria and STOPP tool help identify medicines more likely than not to be inappropriate for a given set of circumstances and are widely used by research pharmacists. Deprescribing guidelines directed at particular medications (or drug classes) [55], or specific patient populations [56], can identify clinical scenarios where a particular drug is likely to be inappropriate, and how to safely wean or discontinue it.

In applying a more nuanced, patient-centered approach to deprescribing, structured guides comprising algorithms, flowcharts, or tables describe sequential steps in deciding which medications used by an individual patient should be targeted for discontinuation after due attention to all relevant factors. Such guides prompt a more systematic appraisal of all medications being used. In a recent review of 7 structured guides that had undergone some form of efficacy testing [59], the strongest evidence of efficacy and clinician acceptability was seen for the Good Palliative–Geriatric Practice algorithm [48] (Figure) and the CEASE protocol [29,30,50,60] (Table). Both have been subject to a process of development and refinement over months to years involving multiple clinician prescribers and pharmacists. 

Clinical Circumstances Conducive to Deprescribing

Deprescribing should be especially considered in any older patient presenting with a new symptom or clinical syndrome suggestive of adverse medicine effects. The advent of advanced or end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all cares marks a stage of a person’s life when limited life expectancy and changed goals of care call for a re-appraisal of the benefits of current medicines. Lack of response in controlling symptoms despite optimal adherence and dosing or conversely the absence of symptoms for long periods of time should challenge the need for ongoing regular use of medicines. Similarly, the lack of verification, or indeed repudiation, of past diagnostic labels which gave rise to indications for medicines in the first place should prompt consideration of discontinuation. Patients receiving single medicines or combinations of medicines, both of which are high risk, should attract attention [63], as should use of preventive medicines for scenarios associated with no increased disease risk despite medicine cessation (eg, ceasing alendronate after 5 years of treatment results in no increase in osteoporotic fracture risk over the ensuing 5 years [64]; ceasing statins for primary prevention after a prolonged period results in no increase in cardiovascular events 8 years after discontinuation [65]). Evidence that has emerged that strongly contradicts previously held beliefs as to the indications for certain medicines (eg, aspirin as primary prevention of cardiovascular disease) should lead to a higher frequency of their discontinuation. Finally, medicines which impose demands on patients which they deem intolerable in terms of dietary and lifestyle restrictions, adverse side effects, medicine monitoring (such as warfarin), financial cost, or any other reason likely to result in nonadherence, should be considered candidates for deprescribing [25].

Barriers to Deprescribing

The most effective strategy to reducing potentially inappropriate polypharmacy is for doctors to prescribe and patients to consume fewer medicines. Unfortunately, both doctors and patients often lack confidence about when and how to cease medicines [66–69]. In a recent systematic review comprised mostly of studies involving general practitioners in primary care [66], 4 themes emerged. First, prescribers may be unaware of their own instances of inappropriate prescribing in older people until this is pointed out to them. Poor insight may be attributable in part to insufficient education in geriatric pharmacology. Second, clinical inertia manifesting as failure to act despite an awareness of PIMs may arise from deprescribing being viewed as a risky affair [70], with doctors fearful of provoking withdrawal syndromes or disease complications, and damaging their reputation and relationships with patients or colleagues in the process. Continuing inappropriate medicines is reinforced by prescriber beliefs that to do so is a safer or kinder course of action for the patient. Third, self-perceptions of being ill-equipped, in terms of the necessary knowledge and skills, to deprescribe appropriately (lack of self-efficacy) may be a barrier, even if one accepts the need for deprescribing. Information deficits around benefit-harm trade-offs of particular drugs and alternative treatments (both drug and non-drug), especially for older, frail, multi-morbid patients, contribute to the problem. Confidence to deprescribe is further undermined by the lack of clear documentation regarding reasons drugs were originally prescribed by other doctors, outcomes of past trials of discontinuation, and current patient care goals. Fourth, several external or logistical constraints may hamper deprescribing efforts such as perceived patient unwillingness to deprescribe certain medicines, lack of prescriber time, poor remuneration, and community and professional attitudes toward more rather than less use of medicines.

Deprescribing in hospital settings led by specialists appears to be no better than in general practice, although it has been less well studied. While an episode of acute inpatient care may afford an opportunity to review and reduce medicine lists, studies suggest the opposite occurs. In a New Zealand audit of 424 patients of mean age 80 years admitted acutely to a medical unit, chronically administered medications increased during hospital stay from a mean of 6.6 to 7.7 [71]. Similarly, in an Australian study investigating medication changes for 1220 patients of mean age 81 years admitted to general medical units of 11 acute care hospitals, the mean number of regularly administered medications rose from 7.1 on admission to 7.6 at discharge [72]. It is likely the same drivers behind failure to deprescribe in primary care also operate in secondary and tertiary care settings. Part of the problem is under-recognition of medicine-related geriatric syndromes on the part of hospital physicians and pharmacists [73].

Patients in both the community and residential aged care facilities frequently express a desire to have their medicines reduced in number, especially if advised by their treating clinician [74,75]. Having said this, many remain wary of discontinuing specific medicines [67], sharing the same fears of evoking withdrawal syndromes or disease relapse as do prescribers, and recounting the strong advice of past specialists to never withhold any medicines without first seeking their advice.

A challenge for all involved in deprescribing is gaining agreement on what are the most important factors that determine when, how, and in whom deprescribing should be conducted. Recent qualitative studies suggest that doctors, pharmacists, nursing staff, and patients and their families, while in broad agreement that deprescribing is worthwhile, often differ in their perspectives on what takes priority in selecting medicines for deprescribing in individual patients, and how it should be done and by whom [76,77].

Strategies That May Facilitate Deprescribing

While deprescribing presents some challenges, there are several strategies that can facilitate it at both the level of individual clinical encounters and at the level of whole populations and systems of care.

Individual Clinical Encounters

Within individual clinician–patient encounters, patients should be empowered to ask their doctors and pharmacists the following questions:

• What are my treatment options (including non-medicine options) for my condition?
• What are the possible benefits and harms of each medicine?
• What might be reasonable grounds for stopping a medicine?

In turn, doctors and pharmacists should ask in a nonjudgmental fashion, at every encounter, whether patients are experiencing any side effects, administration and monitoring problems, or other barriers to adherence associated with any of their medicines.

The issue of deprescribing should be framed as an attempt to alleviate symptoms (of drug toxicity), improve quality of life (from drug-induced disability), and lessen the risk of morbid events (especially ADEs) in the future. Compelling evidence that identifies circumstances in which medicines can be safely withdrawn while reducing the risk of ADEs needs to be emphasized. Specialists must play a sentinel leadership role in advising and authorizing other health professionals to deprescribe in situations where benefits of medications they have prescribed are no longer outweighed by the harms [60,78].

In language they can understand, patients should be informed of the benefit–harm trade-offs specific to them of continuing or discontinuing a particular medicine, as far as these can be specified. Patients often overestimate the benefits and underestimate the harms of treatments [79]. Providing such personalised information can substantially alter perceptions of risk and change attitudes towards discontinuation [80]. Eliciting patients’ beliefs about the necessity for each individual medicine and spending time, using an empathic manner, to dispel or qualify those at odds with evidence and clinical judgement renders deprescribing more acceptable to patients.

In estimating treatment benefit–harm trade-offs in individual patients, disease risk prediction tools (http://www.medal.org/), evidence tables [81,82], and decision aids are increasingly available. Prognostication tools (http://eprognosis.ucsf.edu) combined with trial-based time-to-event data can be used to determine if medicine-specific time until benefit exceeds remaining life span.

Deprescribing is best performed by reducing medicines one at a time over several encounters with the same overseeing generalist clinician with whom patients have established a trusting and collaborative relationship. This provides repeated opportunities to discuss and assuage any fears of discontinuing a medicine, and to adjust the deprescribing plan according to changes in clinical circumstances and revised treatment goals. Practice-based pharmacists can review patients’ medicine lists and apply screening criteria to identify medicines more likely to be unnecessary or harmful, which then helps initiate and guide deprescribing. Integrating a structured deprescribing protocol—and reminders to use it—into electronic health records, and providing decision support and data collection for future reference, reduce the cognitive burden on prescribers [83]. Practical guidance in how to safely wean and cease particular classes of medicines in older people can be accessed from various sources [84,85]. Seeking input from clinical pharmacologists, pharmacists, nurses, and other salient care providers on a case-by-case basis in the form of interactive case conferences provides support, seeks consensus, and shares the risk and responsibility for deprescribing recommendations [86].

System of Care

The success of deprescribing efforts in realizing better population health will be compromised unless all key stakeholders involved in quality use of medicines commit to operationalizing deprescribing strategies at the system of care level. Position statements on deprescribing in multi-morbid populations should be formulated and promulgated by all professional societies of prescribers (primary care, specialists, pharmacists, dentists, nurse practitioners). Professional development programs as well as undergraduate, graduate, and postgraduate courses in medicine, pharmacy, and nursing should include training in deprescribing as a core curricular element.

Researchers seeking funding and/or ethics approval for research projects involving medicines should be required to collect, analyze, and report data on the frequency of, and reasons for, withdrawal of drugs in trial subjects. This helps build the evidence base of medicine-related harm. In turn, government funders of research should require more researchers to design and conduct clinical trials that recruit multi-morbid patients, including specific subgroups (eg, patients with dementia), and aim to define medicine benefits and harms using patient risk stratification methods. Pharmaceutical companies should sponsor research on how to deprescribe their medicines within trials that also aim to assess efficacy and safety. Medicine regulatory authorities such as the Food and Drug Administration should mandate that this information be supplied at the time the company submits their application to have the medicine approved and listed for public subsidy. Trialists should adopt the word “deprescribing” in abstract titles for research on prescriber-initiated medicine discontinuation so that relevant articles can be more accurately indexed in, and retrieved from, bibliographic databases using recently formulated medical subject headings in Medline (“depresciptions”).

Editors of medical journals should promote a deprescribing agenda as a quality and safety issue for patient care, with the “Less is More” series in JAMA Internal Medicine and “Too much medicine” series in BMJ being good examples. Clinical guideline developers should formulate treatment recommendations specific to the needs of multi-morbid patients which acknowledge the limited evidence base for many medicines in such populations. These should take account of commonly encountered clinical scenarios where disease-specific medicines may engender greater risk of harm, and provide cautionary notes regarding initiation and discontinuation of medicines associated with high-risk.

Pharmacists need to instruct patients in how to identify medicine-induced harm and side effects, and how to collaborate with their prescribing clinicians in safely discontinuing high-risk medicines. Ideally, patients being admitted to residential aged care facilities should have their medicine lists reviewed by a pharmacist in flagging medicines eligible for deprescribing. Organizations and services responsible for providing quality use of medicines information (medicines handbooks, prescribing guidelines, drug safety bulletins) should describe when and how deprescribing should be performed in regards to specific medicines. This information should be cross-referenced to clinical guidelines and position statements dealing with the same medicine. Vendors of medicine prescribing software should be encouraged to incorporate flags and alerts which prompt prescribers to consider medicine cessation in high-risk patients.

Government and statutory bodies with responsibility for health care (health departments, quality and safety commissions, practice accreditation services, health care standard–setting bodies) should fund more research to develop and evaluate medicine safety standards aimed at reducing inappropriate use of medicines. Accreditation procedures for hospitals and primary care organizations should mandate the adoption of professional development and quality measurement systems that support and monitor patients receiving multiple medicines. Organizations responsible for conducting pharmacovigilance studies should issue medicine-specific deprescribing alerts whenever their data suggest higher than expected incidence of medicine-related adverse events in older populations receiving such medicines.

Conclusion

Inappropriate medicine use and polypharmacy is a growing issue among older and multi-morbid patients. The cumulative evidence of the safety and benefits of deprescribing argues for its adoption on the part of all prescribers, as well as its support by pharmacists and others responsible for optimizing use of medicines. Widespread implementation within routine care of an evidence-based approach to deprescribing in all patients receiving polypharmacy has its challenges, but also considerable potential to relieve unnecessary suffering and disability. More high quality research is needed in defining the circumstances under which deprescribing confers maximal benefit in terms of improved clinical outcomes.

Corresponding author: Ian A. Scott, Dept. of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Brisbane, Australia 4102, [email protected].

Financial disclosures: None.

From the Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia (Dr. Scott), School of Medicine, The University of Queensland, Herston Road, Brisbane, Australia (Dr. Scott), Centre of Research Excellence in Quality & Safety in Integrated Primary-Secondary Care, The University of Queensland, Herston Road, Brisbane, Australia (Ms. Anderson), and Charming Institute, Camp Hill, Brisbane, Queensland, Australia (Dr. Freeman).

Abstract

• Objective: To review the adverse drug events (ADEs) risk of polypharmacy; the process of deprescribing and evidence of efficacy in reducing inappropriate polypharmacy; the enablers and barriers to deprescribing; and patient and system of care level strategies that can be employed to enhance deprescribing.
• Methods: Literature review.
• Results: Inappropriate polypharmacy, especially in older people, imposes a significant burden of ADEs, ill health, disability, hospitalization and even death. The single most important predictor of inappropriate prescribing and risk of ADEs in older patients is the number of prescribed medicines. Deprescribing is the process of systematically reviewing, identifying, and discontinuing potentially inappropriate medicines (PIMs), aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies, and deprescribing protocols have been developed and validated for clinical use. Barriers and enablers to deprescribing by individual prescribers center on 4 themes: (1) raising awareness of the prevalence and characteristics of PIMs; (2) overcoming clinical inertia whereby discontinuing medicines is seen as being a low value proposition compared to maintaining the status quo; (3) increasing skills and competence (self-efficacy) in deprescribing; and (4) countering external and logistical factors that impede the process.
• Conclusion: In optimizing the scale and effects of deprescribing in clinical practice, strategies that promote depresribing will need to be applied at both the level of individual patient–prescriber encounters and systems of care.

In developed countries in the modern era, about 30% of patients aged 65 years or older are prescribed 5 or more medicines [1]. Over the past decade, the prevalence of polypharmacy (use of > 5 prescription drugs) in the adult population of the United States has doubled from 8.2% in 1999–2000 to 15% in 2011–2012 [2]. While many patients may benefit from such polypharmacy [3] (defined here as 5 or more regularly prescribed medicines), it comes with increased risk of adverse drug events (ADEs) in older people [4] due to physiological changes of aging that alter pharmacokinetic and pharmacodynamic responses to medicines [5]. Approximately 1 in 5 medicines commonly used in older people may be inappropriate [6], rising to a third among those living in residential aged care facilities [7]. Among nursing home residents with advanced dementia, more than half receive at least 1 medicine with questionable benefit [8]. Approximately 50% of hospitalized nursing home or ambulatory care patients receive 1 or more unnecessary medicines [9]. Observational studies have documented ADEs in at least 15% of older patients, contributing to ill health [10], disability [11], hospitalization [12] and readmissions [13], increased length of stay, and, in some cases, death [14]. This high level of iatrogenic harm from potentially inappropriate medicines (PIMs) mandates a response from clinicians responsible for managing medicines.

In this narrative review, we aim to detail the ADE risk of polypharmacy, the process of deprescribing and evidence of its efficacy in reducing potentially inappropriate polypharmacy, the enablers and barriers to deprescribing, and patient and system of care level strategies that can be employed in enhancing deprescribing.

Polypharmacy As a Risk Factor for Medicine-Related Harm

The number of medicines a patient is taking is the single most important predictor of medicine-related harm [15]. One report estimated the risk of ADEs as a contributory cause of patients presenting acutely to hospital emergency departments to be 13% for 2 drugs, 38% for 4 drugs, and 82% for 7 drugs or more [16]. The more medicines an individual takes, the greater their risk of experiencing an adverse drug reaction, a drug-drug interaction, a drug-disease interaction, cascade prescribing (where more medicines are added to counteract side effects of existing medicines), nonadherence, and drug errors (wrong drug, wrong dose, missed doses, erroneous dosing frequency) [17–20]. Once the number of regular medicines rises above 5 (commonly regarded as the threshold for defining polypharmacy), observational data suggest that additional medicines independently increase the risk of frailty, falling, and hospital admission [21].

The benefits of many medicines in frail older people remain unquantified. As many as 50% of clinical trials have a specific upper age limit and approximately 80% of clinical trials exclude people with comorbidities [22,23]. Single-disease treatment guidelines based on such trials are often extrapolated to older people with multimorbidity despite an absence of evidence for benefit [24] and with little consideration of the potential burdens and harms of polypharmacy resulting from treating multiple diseases in the one patient [25]. By contrast, the risks from many medicines in older people are well known. Older people are at high risk of ADEs and toxicity due to reduced renal and liver function and age-related changes in physiological reserve, body composition, and cellular metabolism [26]. While the adverse effects of polypharmacy or of comorbidities targeted for treatment are difficult to separate, the burden of medicine-induced decline in function and quality of life is becoming better defined and appreciated [27].

Defining Evidence-Based Deprescribing

While many definitions have been proposed [28], we define evidence-based deprescribing as follows: the active process of systematically reviewing medicines being used by individual patients and, using best available evidence, identifying and discontinuing those associated with unfavorable risk–benefit trade-offs within the context of illness severity, advanced age, multi-morbidity, physical and emotional capacity, life expectancy, care goals, and personal preferences [29]. An enlarging body of research has demonstrated the feasibility, safety and patient benefit of deprescribing, as discussed further below. It employs evidence-based frameworks that assist the prescriber [30] and are patient-centered [31].

Importantly, deprescribing should be seen as part of the good prescribing continuum, which spans medicine initiation, titrating, changing, or adding medicines, and switching or ceasing medicines. Deprescribing is not about denying effective treatment to eligible patients. It is a positive, patient-centered intervention, with inherent uncertainties, and requires shared decision-making, informed patient consent and close monitoring of effects [32]. Deprescribing involves diagnosing a problem (use of a PIM), making a therapeutic decision (withdrawing it with close follow-up) and altering the natural history of the problem (reducing incidence of medicine-related adverse events).

Our definition of evidence-based deprescribing is a form of direct deprescribing applied at the level of the individual patient-prescriber/pharmacist encounter. Direct deprescribing uses explicit, systematic processes (such as using an algorithm or structured deprescribing framework or guide) applied by individual prescribers (or pharmacists) to the medicine regimens of individual patients (ie, at the patient level), and which targets either specific classes of medicines or all medicines that are potentially inappropriate. This is in contrast to indirect deprescribing, which uses more generic, programmatic strategies aimed at prescribers as a whole (ie, at the population or system level) and which seek to improve quality use of medicines in general, including both underuse and overuse of medicines. Indirect deprescribing entails a broader aim of medicines optimization in which deprescribing is a possible outcome but not necessarily the sole focus. Such strategies include pharmacist or physician medicine reviews, education programs for clinicians and/or patients, academic detailing, audit and feedback, geriatric assessment, multidisciplinary teams, prescribing restrictions, and government policies, all of which aim to reduce the overall burden of PIMs among broad groups of patients. While intuitively the 2 approaches in combination should exert synergistic effects superior to those of either by itself, this has not been studied.

Evidence For Deprescribing

Indirect Deprescribing

Overall, the research into indirect interventions has been highly heterogenous in terms of interventions and measures of medicine use. Research has often been of low to moderate quality, focused more on changes to prescribing patterns and less on clinical outcomes, been of short duration, and produced mixed results [33]. In a 2013 systematic review of 36 studies involving different interventions involving frail older patients in various settings, 22 of 26 quantitative studies reported statistically significant reductions in the proportions of medicines deemed unnecessary (defined using various criteria), ranging from 3 to 20 percentage points [34]. A more recent review of 20 trials of pharmacist-led reviews in both inpatient and outpatient settings reported a small reduction in the mean number of prescribed medicines (–0.48, 95% confidence interval [CI] –0.89 to –0.07) but no effects on mortality or readmissions, although unplanned hospitalizations were reduced in patients with heart failure [35]. A 2012 review of 10 controlled and 20 randomized studies revealed statistically significant reductions in the number of medicines in most of the controlled studies, although mixed results in the randomized studies [36]. Another 2012 review of 10 studies of different designs concluded that interventions were beneficial in reducing potentially inappropriate prescribing and medicine-related problems [37]. A 2013 review of 15 studies of academic detailing of family physicians showed a modest decline in the number of medications of certain classes such as benzodiazepines and nonsteroidal anti-inflammatory drugs [38]. Another 2013 review restricted to 8 randomized trials of various interventions involving nursing home patients suggested medicine-related problems were more frequently identified and resolved, together with improvement in medicine appropriateness [39]. In 2 randomized trials conducted in aged care facilities and centered on educational interventions, one aimed at prescribers [40] and the other at nursing staff [41],the number of potentially harmful medicines and days in hospital was significantly reduced [40,41], combined with slower declines in health-related quality of life [40]. In a randomized trial, patient education provided through community pharmacists led to a 77% reduction in benzodiazepine use among chronic users at 6 months with no withdrawal seizures or other ill effects [42].

Direct Deprescribing Targeting Specific Classes of Medicines

The evidence base for direct patient-level deprescribing is more rigorous as it pertains to specific classes of medicines. A 2008 systematic review of 31 trials (15 randomized, 16 observational) that withdrew a single class of medicine in older people demonstrated that, with appropriate patient selection and education coupled with careful withdrawal and close monitoring, antihypertensive agents, psychotropic medicines, and benzodiazepines could be discontinued without harm in 20% to 100% of patients, although psychotropics showed a high post-trial rate of recommencement [43]. Another review of 9 randomized trials demonstrated the safety of withdrawing antipsychotic agents that had been used continuously for behavioural and psychological symptoms in more than 80% of subjects with dementia [44]. In an observational study, cessation of inappropriate antihypertensives was associated with fewer cardiovascular events and deaths over a 5-year follow-up period [45]. A recent randomized trial of statin withdrawal in patients with advanced illness and of whom half had a prognosis of less than 12 months demonstrated improved quality of life and no increased risk of cardiovascular events over the following 60 days [46].

Direct Deprescribing Targeting All Medicines

The evidence base for direct patient-level deprescribing that assesses all medicines, not just specific medicine classes, features several high-quality observational studies and controlled trials, and subgroup findings from a recent comprehensive systematic review. In this review of 132 studies, which included 56 randomized controlled trials [47], mortality was shown in randomized trials to be decreased by 38% as a result of direct (ie, patient-level) deprescribing interventions. However, this effect was not seen in studies of indirect deprescribing comprising mainly generic educational interventions. While space prevents a detailed analysis of all relevant trials, some of the more commonly cited sentinel studies are mentioned here.

In a controlled trial involving 190 patients in aged care facilities, a structured approach to deprescribing (Good Palliative–Geriatric Practice algorithm) resulted in 63% of patients having, on average, 2.8 medicines per patient discontinued, and was associated with a halving in both annual mortality and referrals to acute care hospitals [48]. In another prospective uncontrolled study, the same approach applied to a cohort of 70 community-dwelling older patients resulted in an average of 4.4 medicines prescribed to 64 patients being recommended for discontinuation, of which 81% were successfully discontinued, with 88% of patients reporting global improvements in health [49]. In a prospective cohort study of 50 older hospitalized patients receiving a median of 10 regular medicines on admission, a formal deprescribing process led to the cessation of just over 1 in 3 medicines by discharge, representing 4 fewer medicines per patient [50]. During a median follow-up period of just over 2.5 months for 39 patients, less than 5% of ceased medicines were recommenced in 3 patients for relapsing symptoms, with no deaths or acute presentations to hospital attributable to cessation of medicines. A multidisciplinary hospital clinic for older patients over a 3-month period achieved cessation of 22% of medicines in 17 patients without ill effect [51].

Two randomized studies used the Screening Tool of Older People’s Prescriptions (STOPP) to reduce the use of PIMs in older hospital inpatients [52,53]. One reported significantly reduced PIMs use in the intervention group at discharge and 6 months post-discharge, no change in the rate of hospital readmission, and non-significant reductions in falls, all cause-mortality, and primary care visits during the 6-month follow-up period [52]. The second study reported reduced PIMs use in the intervention group of frail older patients on discharge, although the proportion of people prescribed at least 1 PIM was not altered [53].

Recently, a randomized trial of a deprescribing intervention applied to aged care residents resulted in successful discontinuation of 207 (59%) of 348 medicines targeted for deprescribing, and a mean reduction of 2 medicines per patient at 12 months compared to none in controls, with no differences in mortality or hospital admissions [54]. The evidence for direct deprescribing is limited by relatively few high-quality randomized trials, small patient samples, short duration of follow-up, selection of specific subsets of patients, and the absence of comprehensive re-prescribing data and clinical outcomes.

Methods Used for Direct Deprescribing

At the level of individual patient care, various instruments have been developed to assist the deprescribing process. Screening tools or criteria such as the Beers criteria and STOPP tool help identify medicines more likely than not to be inappropriate for a given set of circumstances and are widely used by research pharmacists. Deprescribing guidelines directed at particular medications (or drug classes) [55], or specific patient populations [56], can identify clinical scenarios where a particular drug is likely to be inappropriate, and how to safely wean or discontinue it.

In applying a more nuanced, patient-centered approach to deprescribing, structured guides comprising algorithms, flowcharts, or tables describe sequential steps in deciding which medications used by an individual patient should be targeted for discontinuation after due attention to all relevant factors. Such guides prompt a more systematic appraisal of all medications being used. In a recent review of 7 structured guides that had undergone some form of efficacy testing [59], the strongest evidence of efficacy and clinician acceptability was seen for the Good Palliative–Geriatric Practice algorithm [48] (Figure) and the CEASE protocol [29,30,50,60] (Table). Both have been subject to a process of development and refinement over months to years involving multiple clinician prescribers and pharmacists. 

Clinical Circumstances Conducive to Deprescribing

Deprescribing should be especially considered in any older patient presenting with a new symptom or clinical syndrome suggestive of adverse medicine effects. The advent of advanced or end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all cares marks a stage of a person’s life when limited life expectancy and changed goals of care call for a re-appraisal of the benefits of current medicines. Lack of response in controlling symptoms despite optimal adherence and dosing or conversely the absence of symptoms for long periods of time should challenge the need for ongoing regular use of medicines. Similarly, the lack of verification, or indeed repudiation, of past diagnostic labels which gave rise to indications for medicines in the first place should prompt consideration of discontinuation. Patients receiving single medicines or combinations of medicines, both of which are high risk, should attract attention [63], as should use of preventive medicines for scenarios associated with no increased disease risk despite medicine cessation (eg, ceasing alendronate after 5 years of treatment results in no increase in osteoporotic fracture risk over the ensuing 5 years [64]; ceasing statins for primary prevention after a prolonged period results in no increase in cardiovascular events 8 years after discontinuation [65]). Evidence that has emerged that strongly contradicts previously held beliefs as to the indications for certain medicines (eg, aspirin as primary prevention of cardiovascular disease) should lead to a higher frequency of their discontinuation. Finally, medicines which impose demands on patients which they deem intolerable in terms of dietary and lifestyle restrictions, adverse side effects, medicine monitoring (such as warfarin), financial cost, or any other reason likely to result in nonadherence, should be considered candidates for deprescribing [25].

Barriers to Deprescribing

The most effective strategy to reducing potentially inappropriate polypharmacy is for doctors to prescribe and patients to consume fewer medicines. Unfortunately, both doctors and patients often lack confidence about when and how to cease medicines [66–69]. In a recent systematic review comprised mostly of studies involving general practitioners in primary care [66], 4 themes emerged. First, prescribers may be unaware of their own instances of inappropriate prescribing in older people until this is pointed out to them. Poor insight may be attributable in part to insufficient education in geriatric pharmacology. Second, clinical inertia manifesting as failure to act despite an awareness of PIMs may arise from deprescribing being viewed as a risky affair [70], with doctors fearful of provoking withdrawal syndromes or disease complications, and damaging their reputation and relationships with patients or colleagues in the process. Continuing inappropriate medicines is reinforced by prescriber beliefs that to do so is a safer or kinder course of action for the patient. Third, self-perceptions of being ill-equipped, in terms of the necessary knowledge and skills, to deprescribe appropriately (lack of self-efficacy) may be a barrier, even if one accepts the need for deprescribing. Information deficits around benefit-harm trade-offs of particular drugs and alternative treatments (both drug and non-drug), especially for older, frail, multi-morbid patients, contribute to the problem. Confidence to deprescribe is further undermined by the lack of clear documentation regarding reasons drugs were originally prescribed by other doctors, outcomes of past trials of discontinuation, and current patient care goals. Fourth, several external or logistical constraints may hamper deprescribing efforts such as perceived patient unwillingness to deprescribe certain medicines, lack of prescriber time, poor remuneration, and community and professional attitudes toward more rather than less use of medicines.

Deprescribing in hospital settings led by specialists appears to be no better than in general practice, although it has been less well studied. While an episode of acute inpatient care may afford an opportunity to review and reduce medicine lists, studies suggest the opposite occurs. In a New Zealand audit of 424 patients of mean age 80 years admitted acutely to a medical unit, chronically administered medications increased during hospital stay from a mean of 6.6 to 7.7 [71]. Similarly, in an Australian study investigating medication changes for 1220 patients of mean age 81 years admitted to general medical units of 11 acute care hospitals, the mean number of regularly administered medications rose from 7.1 on admission to 7.6 at discharge [72]. It is likely the same drivers behind failure to deprescribe in primary care also operate in secondary and tertiary care settings. Part of the problem is under-recognition of medicine-related geriatric syndromes on the part of hospital physicians and pharmacists [73].

Patients in both the community and residential aged care facilities frequently express a desire to have their medicines reduced in number, especially if advised by their treating clinician [74,75]. Having said this, many remain wary of discontinuing specific medicines [67], sharing the same fears of evoking withdrawal syndromes or disease relapse as do prescribers, and recounting the strong advice of past specialists to never withhold any medicines without first seeking their advice.

A challenge for all involved in deprescribing is gaining agreement on what are the most important factors that determine when, how, and in whom deprescribing should be conducted. Recent qualitative studies suggest that doctors, pharmacists, nursing staff, and patients and their families, while in broad agreement that deprescribing is worthwhile, often differ in their perspectives on what takes priority in selecting medicines for deprescribing in individual patients, and how it should be done and by whom [76,77].

Strategies That May Facilitate Deprescribing

While deprescribing presents some challenges, there are several strategies that can facilitate it at both the level of individual clinical encounters and at the level of whole populations and systems of care.

Individual Clinical Encounters

Within individual clinician–patient encounters, patients should be empowered to ask their doctors and pharmacists the following questions:

• What are my treatment options (including non-medicine options) for my condition?
• What are the possible benefits and harms of each medicine?
• What might be reasonable grounds for stopping a medicine?

In turn, doctors and pharmacists should ask in a nonjudgmental fashion, at every encounter, whether patients are experiencing any side effects, administration and monitoring problems, or other barriers to adherence associated with any of their medicines.

The issue of deprescribing should be framed as an attempt to alleviate symptoms (of drug toxicity), improve quality of life (from drug-induced disability), and lessen the risk of morbid events (especially ADEs) in the future. Compelling evidence that identifies circumstances in which medicines can be safely withdrawn while reducing the risk of ADEs needs to be emphasized. Specialists must play a sentinel leadership role in advising and authorizing other health professionals to deprescribe in situations where benefits of medications they have prescribed are no longer outweighed by the harms [60,78].

In language they can understand, patients should be informed of the benefit–harm trade-offs specific to them of continuing or discontinuing a particular medicine, as far as these can be specified. Patients often overestimate the benefits and underestimate the harms of treatments [79]. Providing such personalised information can substantially alter perceptions of risk and change attitudes towards discontinuation [80]. Eliciting patients’ beliefs about the necessity for each individual medicine and spending time, using an empathic manner, to dispel or qualify those at odds with evidence and clinical judgement renders deprescribing more acceptable to patients.

In estimating treatment benefit–harm trade-offs in individual patients, disease risk prediction tools (http://www.medal.org/), evidence tables [81,82], and decision aids are increasingly available. Prognostication tools (http://eprognosis.ucsf.edu) combined with trial-based time-to-event data can be used to determine if medicine-specific time until benefit exceeds remaining life span.

Deprescribing is best performed by reducing medicines one at a time over several encounters with the same overseeing generalist clinician with whom patients have established a trusting and collaborative relationship. This provides repeated opportunities to discuss and assuage any fears of discontinuing a medicine, and to adjust the deprescribing plan according to changes in clinical circumstances and revised treatment goals. Practice-based pharmacists can review patients’ medicine lists and apply screening criteria to identify medicines more likely to be unnecessary or harmful, which then helps initiate and guide deprescribing. Integrating a structured deprescribing protocol—and reminders to use it—into electronic health records, and providing decision support and data collection for future reference, reduce the cognitive burden on prescribers [83]. Practical guidance in how to safely wean and cease particular classes of medicines in older people can be accessed from various sources [84,85]. Seeking input from clinical pharmacologists, pharmacists, nurses, and other salient care providers on a case-by-case basis in the form of interactive case conferences provides support, seeks consensus, and shares the risk and responsibility for deprescribing recommendations [86].

System of Care

The success of deprescribing efforts in realizing better population health will be compromised unless all key stakeholders involved in quality use of medicines commit to operationalizing deprescribing strategies at the system of care level. Position statements on deprescribing in multi-morbid populations should be formulated and promulgated by all professional societies of prescribers (primary care, specialists, pharmacists, dentists, nurse practitioners). Professional development programs as well as undergraduate, graduate, and postgraduate courses in medicine, pharmacy, and nursing should include training in deprescribing as a core curricular element.

Researchers seeking funding and/or ethics approval for research projects involving medicines should be required to collect, analyze, and report data on the frequency of, and reasons for, withdrawal of drugs in trial subjects. This helps build the evidence base of medicine-related harm. In turn, government funders of research should require more researchers to design and conduct clinical trials that recruit multi-morbid patients, including specific subgroups (eg, patients with dementia), and aim to define medicine benefits and harms using patient risk stratification methods. Pharmaceutical companies should sponsor research on how to deprescribe their medicines within trials that also aim to assess efficacy and safety. Medicine regulatory authorities such as the Food and Drug Administration should mandate that this information be supplied at the time the company submits their application to have the medicine approved and listed for public subsidy. Trialists should adopt the word “deprescribing” in abstract titles for research on prescriber-initiated medicine discontinuation so that relevant articles can be more accurately indexed in, and retrieved from, bibliographic databases using recently formulated medical subject headings in Medline (“depresciptions”).

Editors of medical journals should promote a deprescribing agenda as a quality and safety issue for patient care, with the “Less is More” series in JAMA Internal Medicine and “Too much medicine” series in BMJ being good examples. Clinical guideline developers should formulate treatment recommendations specific to the needs of multi-morbid patients which acknowledge the limited evidence base for many medicines in such populations. These should take account of commonly encountered clinical scenarios where disease-specific medicines may engender greater risk of harm, and provide cautionary notes regarding initiation and discontinuation of medicines associated with high-risk.

Pharmacists need to instruct patients in how to identify medicine-induced harm and side effects, and how to collaborate with their prescribing clinicians in safely discontinuing high-risk medicines. Ideally, patients being admitted to residential aged care facilities should have their medicine lists reviewed by a pharmacist in flagging medicines eligible for deprescribing. Organizations and services responsible for providing quality use of medicines information (medicines handbooks, prescribing guidelines, drug safety bulletins) should describe when and how deprescribing should be performed in regards to specific medicines. This information should be cross-referenced to clinical guidelines and position statements dealing with the same medicine. Vendors of medicine prescribing software should be encouraged to incorporate flags and alerts which prompt prescribers to consider medicine cessation in high-risk patients.

Government and statutory bodies with responsibility for health care (health departments, quality and safety commissions, practice accreditation services, health care standard–setting bodies) should fund more research to develop and evaluate medicine safety standards aimed at reducing inappropriate use of medicines. Accreditation procedures for hospitals and primary care organizations should mandate the adoption of professional development and quality measurement systems that support and monitor patients receiving multiple medicines. Organizations responsible for conducting pharmacovigilance studies should issue medicine-specific deprescribing alerts whenever their data suggest higher than expected incidence of medicine-related adverse events in older populations receiving such medicines.

Conclusion

Inappropriate medicine use and polypharmacy is a growing issue among older and multi-morbid patients. The cumulative evidence of the safety and benefits of deprescribing argues for its adoption on the part of all prescribers, as well as its support by pharmacists and others responsible for optimizing use of medicines. Widespread implementation within routine care of an evidence-based approach to deprescribing in all patients receiving polypharmacy has its challenges, but also considerable potential to relieve unnecessary suffering and disability. More high quality research is needed in defining the circumstances under which deprescribing confers maximal benefit in terms of improved clinical outcomes.

Corresponding author: Ian A. Scott, Dept. of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Brisbane, Australia 4102, [email protected].

Financial disclosures: None.