From the Department of Neurology, Duke University Medical Center, Durham, NC (Dr. McFarlin), the Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA (Dr. Tulsky), Harborview Medical Center, University of Washington, Seattle, WA (Dr. Back), and Department of Medicine, University of Pittsburgh, Pittsburgh, PA (Dr. Arnold).

Abstract

• Objective: To describe the use of a cognitive map for navigating family meetings with surrogate decision makers of patients in an intensive care unit.
•  Methods: Descriptive report and discussion using an illustrative case to outline the steps in the cognitive map.
• Results: The use of cognitive maps has improved the ability of physicians to efficiently perform a specific communication skill. During a “goals of care” conversation, the cognitive map follows these steps: (1) Gather the clinical team for a pre-meeting, (2) Introduce everyone, (3) Use the “ask-tell-ask” strategy to communicate information, (4) Respond to emotion, (5) Highlight the patient’s voice, (6) Plan next steps, (7) Reflect on the meeting with the team. Providing this map of key communication skills will help faculty teach learners the core components of a family meeting.
• Conclusion: Practicing the behaviors demonstrated in the cognitive map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Key words: intensive care unit; communication; family meeting; critical illness; decision making; end of life care.

Family members of patients in the ICU value high-quality communication with the medical team. In fact, family members report that physicians’ communication skills are often more important than their medical skills [1]. Multiple professional societies, including the American Thoracic Society and the Society of Critical Care Medicine, define communication with families as a key component of high-quality critical care. Effective physician-patient communication improves measureable outcomes including decreased ICU length of stay [2] and may reduce distress amongst patients’ families [3]. The American College of Chest Physicians position statement on Palliative and End-of-Life Care for Patients with Cardiopulmonary Diseases urges physicians to develop curricula that incorporate interpersonal communication skills into training [4].

Unfortunately, such high-quality communication is not the norm. Surrogate decision makers are often displeased with the frequency of communication, the limited availability of attending physicians, and report feeling excluded from discussions [5]. When family meetings do occur, surrogate decision makers report inadequate understanding of diagnosis, prognosis, and treatment plans [6].

Physicians also find family meetings difficult. Intensivists worry that high-quality family meetings are time consuming and difficult to do in a busy ICU [7]. Critical care fellows report not feeling adequately trained to conduct family meetings [8]. It makes sense that untrained clinicians would want to avoid a conversation that is emotionally charged, particularly if one is unsure how to respond effectively.

The Case of Mr. A

Thomas A. is a 79-year-old man admitted to the medical intensive care unit 7 days earlier with a large left middle cerebral artery territory infarction. Given his decreased mental status, on admission he was intubated for airway protection. He is awake but aphasic and unable to follow any commands or move his right side. The neurology consultants do not feel this will improve. He has significant secretions and episodes of hypoxia. He has also developed acute on chronic kidney injury and may need to start dialysis. The social worker explains that his need for dialysis limits his placement options and that he will not be able to be discharged to home. Given his lack of improvement the team is concerned he will need a tracheostomy and feeding tube placed in order to safely continue this level of care. A family meeting is arranged to understand Mr. A’s goals of care.

Talking Map Basics

Before each step is discussed in detail, some definitions are needed. “Family” can be defined as anyone important enough, biologically related or not, to be present at a conversation with a clinician [10]. Second, a “family meeting” is a planned event between the family and interdisciplinary members of the ICU team as well as any other health care providers who have been involved in the patient’s care. The meeting takes place in a private space and at a time that is scheduled with the families’ needs in mind. Thus it is different from having families present on rounds or one-off meetings with particular clinicians.

Goals of care meetings are typically held when, in the clinicians’ view, the current treatments are not achieving the previously stated goals. Thus, the meeting has 2 purposes: first, to give the family the bad news that the current plan is not working and second, to develop a new plan based on the patient’s values. The family’s job, as surrogate decision maker, is to provide information about what would be most important to the patient. The clinician’s job is to suggest treatment plans that have the best probability of matching the patient’s values.

Not all of these tasks need be done at once. Some families will not be able to move from hearing bad news to making a decision without having time to first reflect and grieve. Others will need to confer with other family members privately before deciding on a plan. In many cases, a time-limited trial may be the right option with a plan for subsequent meetings. Given this, we recommend checking in with the family between each step to ensure that they feel safe moving ahead. For example, one might ask “Is it OK if we talk about what happens next?”

Talking Map Steps in Detail

1. Gather the Clinical Team for a Pre-Meeting

ICU care involves a large interdisciplinary care team. A “meeting before the meeting” with the entire clinical team is an opportunity to reach consensus on prognosis and therapeutic options, share prior interactions with family, and determine goals for the family meeting. It is also helpful to clarify team members’ roles at the meeting and to choose a primary facilitator. All of this helps to ensure that the family receives a consistent message during the meeting. The pre-meeting is also an opportunity to ask a team member to observe the communication skills of the facilitator and be prepared to give feedback after the meeting.

At this time, the team should also create the proper environment for the family meeting. This includes a quiet room free of interruptions with ample seating, available tissues, and transferred pagers and cell phones.

The intensivist and bedside nurse should always be present at the family meeting, and it is best when the same attending can be at subsequent family meetings Their consistent dual presence provides the uniform communication from the team, can reduce anxiety in family members and the collaboration reduces ICU nurse and physician burnout [11]. For illnesses that involve a specific disease or organ system, it is important to have the specialist at the meeting who can provide the appropriate expertise.

The Pre-Meeting

A family meeting was scheduled in the family meeting room for 3 pm, after morning rounds. Thirty minutes prior to the meeting the medical team, including the MICU intensivist, the bedside nurse, the neurology attending who has been involved in the care, the case manager and 2 residents sat to discuss Mr. A’s care. The neurology team confirmed that this stroke was considered very large and would result in a level of disability that could only be cared for in a nursing home and would require both a tracheostomy and feeding tube for safe care. The bedside nurse relayed that the family had asked if Mr. A. would ever recover enough to get back to his home. The neurology team shared they did not expect much improvement at all. Given the worsening renal failure and need for dialysis the case manager reminded the team that Mr. A’s nursing home placements were limited. The team decided that the intensivist would lead the meeting as she had updated various family members on rounds for the past 4 days and would be on service for another week. The team decided that their goal for the meeting was to make sure the family understands that Mr. A’s several medical illnesses portend a poor prognosis. They recognized this may be breaking bad news to the family. They also wanted to better understand what Mr. A would have thought given this situation. The residents were asked to watch for the family’s responses when the team delivered the news.

2. Introduce Everyone

Each meeting should start with formal introductions. Even if most providers know most family members it is a polite way to start the meeting. Introducing each family member present and how they know the patient provides insight into how the family is constructed and makes decisions. For example, the entire family may defer to the daughter who introduces herself as a nurse. In other situations, although there is one legal decision maker, the family may explain that they make decisions by consensus.

Each member of the treating team should also introduce themselves. Even if the clinician has been working with the family, it is polite to be formal and give your name and role. Given the number of people the family sees every day, one should not assume that the family remembers all of the clinicians.

In teaching hospitals, providers should also help the family understand their level of training. Surrogates do not always understand the different roles or level of training between students, residents and fellows, advanced practice providers, consultants and their attending physicians. Uncertainty about the roles can lead to family members feeling as though they are receiving contradictory information. Family satisfaction decreases when multiple attending physicians are involved in a patient’s care [12]. When possible, a consistent presence among providers at family meetings is always best.

3. Ask the Family's Understanding of the Situation (Ask-Tell-Ask)

Asking the family to explain the situation in their own language reveals how well they understand the medical facts and helps the medical team determine what information will be most helpful to the family. An opening statement might be “We have all seen your dad and talked to many of his providers. It would help us all be on the same page if you can you tell me what the doctors are telling you?” Starting with the family’s understanding builds trust with the medical team as it creates an opportunity for the family to lead the meeting and indicates that the team is available to listen to their concerns. Asking surrogates for their understanding allows them to tell their story and not hear a reiteration of things they already know. Providing time for the family to share their perspective of the care elicits family’s concerns.

In a large meeting, ensure that all members of the family have an opportunity to communicate their concerns. Does a particular person do all of the talking? Are there individuals that do not speak at all? One way to further understand unspoken concerns during the meeting is to ask “I notice you have been quiet, what questions do you have that I can answer?” There may be several rounds of “asking” in order to ensure all the family members’ concerns are heard. Letting the family tell what they have heard helps the clinicians get a better idea of their health literacy. Do they explain information using technical data or jargon? Finally, as the family talks the clinicians can determine how surprising the “serious news” will be to them. For example, if the family says they know their dad is doing much worse and may die, the information to be delivered can be truncated. However if family incorrectly thinks their dad is doing better or is uncertain they will be much more surprised by the serious news.

After providing time for the family to express their understanding, tell them the information the team needs to communicate. When delivering serious news it is important to focus on the key 1 to 2 points you want the family to take away from the meeting. Typically when health care professionals talk to each other, they talk about every medical detail. Families find this amount of information overwhelming and are not sure what is most important, asking “So what does that mean?” Focusing on the “headline” helps the family focus on what you think the most important piece of information is. Studies suggest that what families most want to know is what the information means for the patient’s future and what treatments are possible. After delivering the new information, stop to allow the family space to think about what you said. If you are giving serious news, you will know they have heard what you said as they will get emotional (see next step).

Checking for understanding is the final “ask” in Ask-Tell-Ask. Begin by asking “What questions do you have?” Data in primary care has shown that patients are more likely to ask questions if you ask “what questions do you have” rather than “do you have any questions?” It is important to continue to ask this question until the family has asked all their questions. Often the family’s tough questions do not come until they get more comfortable and confident in the health care team. In cases where one family member is dominant it might also help to say “What questions do others have?” Next, using techniques like the “teach back” model the physician should check in to see what the family is taking away from the conversation. If a family understands, they can “teach back” the information accurately. This “ask” can be done in a way that does not make the family feel they are being tested: “I am not always clear when I communicate. Do you mind telling me back in your own words what you thought I said so I know we are on the same page?” This also provides an opportunity to answer any new questions that arise. Hearing the information directly from the family can allow the team to clarify any misconceptions and give insight into any emotional responses that the family might have.

4. Respond to Emotion

Discussing serious news in the ICU setting naturally leads to an emotional reaction. The clinician’s ability to notice emotional cues and respond with empathy is a key communication skill in family meetings [13]. Emotional reactions impede individual’s ability to process cognitive information and make it hard to think cognitively about what should be done next.

Physicians miss opportunities to respond to emotion in family meetings [14]. Missed opportunities lead to decreased family satisfaction and may lead to treatment decisions not consistent with the wishes of their loved ones. Empathic responses improve the family-clinician relationship and helps build trust and rapport [15]. Well- placed empathic statements may help surrogates disclose concerns that help the physician better understand the goals and values of the family and patient. Families also can more fully process cognitive information when their emotional responses have been attended to.

Physicians can develop the capacity to recognize and respond to the emotional cues family members are delivering. Intensivists should actively look for the emotions, the empathic opportunity, that are displayed by the family. This emotion is the “data” that will help lead to an empathic response. A family that just received bad news typically responds by showing emotion. Clues that emotions are present include: the family asking the same questions multiple times; using emotional words such as “sad” or “frustrated;” existential questions that do not have a cognitive answer such as “Why did God let this happen?;” or non-verbal cues like tears and hand wringing.

Sometimes the emotional responses are more difficult to recognize. Families may continue to ask for more cognitive information after hearing bad news. Someone keeps asking “Why did his kidney function worsen?” or “I thought the team said the chest x-ray looked better.” It is tempting to start answering these questions with more medical facts. However, if the question comes after bad news, it is usually an expression of frustration or sadness rather than a request for more information. Rather than giving information, it might help to acknowledge this by saying “I imagine this new is overwhelming.”

5. Highlight the Patient’s Voice

Family meetings are often used to develop new treatment plans (given that the old plans are not working). In these situations, it is essential to understand what the incapacitated patient would say if they were part of the family meeting. The surrogate’s primary role is to represent the patient’s voice. To do this, surrogates need assistance in applying their critically ill loved one’s thoughts and values to complex, possibly life limiting, situations. Surrogate decision makers struggle with the decisions’ emotional impact, as well as how to reconcile their desires with their loved one’s wishes [18]. This can lead them to make decisions that conflict with the loved one’s values [19] as well as emotional sequelae such as PTSD and depression [20].

As families reflect on their loved one’s values, conflicting desires will arise. For example, someone may have wanted to live as long as possible and also values independence. Or someone may value their ability to think clearly more than being physically well but would not want to be physically dependent on artificial life support. Exploring which values would be more important can help resolve these conflicts.

Clinicians should check for understanding while family members are identifying the values of their loved ones. Providing the family with a summary of what you have heard will help ensure a more accurate understanding of these crucial issues. A summary statement might be, “It sounds like you are saying your dad really valued his independence. He enjoyed being able to take care of his loved ones and himself. Is that right?”

6. Plan Next Steps

The family meeting serves to attend to family emotion and allow space to elicit patients’ values. Following a family meeting surrogate decision makers may be able to begin to consider the next steps in their loved one’s care. If bad news was delivered they may need space to adjust to a different future than they expected. Using an empathic statement of support “We will continue to make sure we communicate with you as we work together to plan next steps” will reassure a family that they have time and space to plan for the future.

Families vary regarding how much physician input they desire in planning next steps [21]. You can explicitly ask how the team can best help the family with decisions: “Some families like to hear the options for next steps from the team and make a decision, other families like to hear a recommendation from the team. What would be the most helpful for you?” Throughout the course of an illness a surrogate’s preference for decision making may change and clinicians should be responsive to those changing needs.

If the surrogate wants a clinician’s recommendation, 3 points are worth stressing. First, the recommendation should be personalized to this patient and his values. The goal is to reveal how the understanding of the patient’s values led to the treatment plan offered. Second, the recommendation should focus primarily on what will be done to achieve the patient’s values. Focusing on what the clinicians will do may help the family feel that the clinicians are still “trying” and not abandoning their loved one. In this case, the team will continue medical care that will help the patient regain/maintain independence. Only after talking about what will be done should the clinician point out that certain interventions will not achieve the patient’s goals and thus will not be done:

“It sounds like your father really valued his independence and that this illness has really taken that away. Knowing this, would it be helpful for me to make a recommendation for next steps?” “I think we should continue providing excellent medical care for your father in hopes he can get better and go home. One the other hand, if he gets worse, we should not use therapies such as CPR or dialysis that are unlikely to help him regain his independence.”

Finally, be concrete when planning next steps. If a time-limited trial of a therapy is proposed, make sure the family understands what a successful and unsuccessful trial will look like. Make plans to meet again on a specific date in order to ensure the family understands the progress being made. If a transition to comfort care is agreed upon, ensure support of the entire family during the next hours to days and offer services such as chaplaincy or child life specialists.

A family may not agree with the recommendation and back and forth discussion can help create a plan that is in line with their understanding of the illness. Rather than convincing, a clinician should keep an open mind about why they and the surrogate disagree. Do they have different views about the patient’s future? Did the medical team misunderstand the patient’s values? Are there emotional factors that inhibit the surrogate’s ability to attend to the discussion? It is only by learning where the disagreement is that a clinician can move the conversation forward.

A surrogate may ask about a therapy that is not beneficial or may increase distress to the patient. The use of “I wish” or “I worry” statements can be helpful at these points. These specific phrases recognize the surrogate’s desire to do more but also imply that the therapies are not helpful.

“I wish that his ability to communicate and tell you what he wants would get better with a little more time as well.”

“I worry that waiting 2 more weeks for improvement will actually cause complications to occur.”

7. Reflect

Family meetings have an impact on both the family and the medical team. Following the meeting, a short debriefing with the clinical team can be helpful. Summarizing the events of the meeting ensures clarity about the treatment plan going forward. It provides team members a chance to discuss conflicts that may have arisen. It allows the participants in the meeting to reflect on what communication skills they used and how they can improve their skills going forward.

Conclusion

Family meetings with surrogate decision makers must navigate multiple agendas of the family and providers. The goal of excellent communication with surrogates in an ICU should be to understand the patient’s goals and values and seek to make treatment plans that align with their perspective. This talking map provides a conceptual framework for physicians to guide a family through these conversations. The framework creates an opportunity to focus on the patient’s values and preferences for care while allowing space to attend to emotional responses to reduce the distress inherent in surrogate decision-making. Practicing the behaviors demonstrated in the talking map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Corresponding author: Jessica McFarlin, MD, [email protected].

Funding/support: Dr. Arnold receives support though the Leo H. Criep Chair in Patient Care.

Financial disclosures: None.

From the Department of Neurology, Duke University Medical Center, Durham, NC (Dr. McFarlin), the Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA (Dr. Tulsky), Harborview Medical Center, University of Washington, Seattle, WA (Dr. Back), and Department of Medicine, University of Pittsburgh, Pittsburgh, PA (Dr. Arnold).

Abstract

• Objective: To describe the use of a cognitive map for navigating family meetings with surrogate decision makers of patients in an intensive care unit.
•  Methods: Descriptive report and discussion using an illustrative case to outline the steps in the cognitive map.
• Results: The use of cognitive maps has improved the ability of physicians to efficiently perform a specific communication skill. During a “goals of care” conversation, the cognitive map follows these steps: (1) Gather the clinical team for a pre-meeting, (2) Introduce everyone, (3) Use the “ask-tell-ask” strategy to communicate information, (4) Respond to emotion, (5) Highlight the patient’s voice, (6) Plan next steps, (7) Reflect on the meeting with the team. Providing this map of key communication skills will help faculty teach learners the core components of a family meeting.
• Conclusion: Practicing the behaviors demonstrated in the cognitive map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Key words: intensive care unit; communication; family meeting; critical illness; decision making; end of life care.

Family members of patients in the ICU value high-quality communication with the medical team. In fact, family members report that physicians’ communication skills are often more important than their medical skills [1]. Multiple professional societies, including the American Thoracic Society and the Society of Critical Care Medicine, define communication with families as a key component of high-quality critical care. Effective physician-patient communication improves measureable outcomes including decreased ICU length of stay [2] and may reduce distress amongst patients’ families [3]. The American College of Chest Physicians position statement on Palliative and End-of-Life Care for Patients with Cardiopulmonary Diseases urges physicians to develop curricula that incorporate interpersonal communication skills into training [4].

Unfortunately, such high-quality communication is not the norm. Surrogate decision makers are often displeased with the frequency of communication, the limited availability of attending physicians, and report feeling excluded from discussions [5]. When family meetings do occur, surrogate decision makers report inadequate understanding of diagnosis, prognosis, and treatment plans [6].

Physicians also find family meetings difficult. Intensivists worry that high-quality family meetings are time consuming and difficult to do in a busy ICU [7]. Critical care fellows report not feeling adequately trained to conduct family meetings [8]. It makes sense that untrained clinicians would want to avoid a conversation that is emotionally charged, particularly if one is unsure how to respond effectively.

The Case of Mr. A

Thomas A. is a 79-year-old man admitted to the medical intensive care unit 7 days earlier with a large left middle cerebral artery territory infarction. Given his decreased mental status, on admission he was intubated for airway protection. He is awake but aphasic and unable to follow any commands or move his right side. The neurology consultants do not feel this will improve. He has significant secretions and episodes of hypoxia. He has also developed acute on chronic kidney injury and may need to start dialysis. The social worker explains that his need for dialysis limits his placement options and that he will not be able to be discharged to home. Given his lack of improvement the team is concerned he will need a tracheostomy and feeding tube placed in order to safely continue this level of care. A family meeting is arranged to understand Mr. A’s goals of care.

Talking Map Basics

Before each step is discussed in detail, some definitions are needed. “Family” can be defined as anyone important enough, biologically related or not, to be present at a conversation with a clinician [10]. Second, a “family meeting” is a planned event between the family and interdisciplinary members of the ICU team as well as any other health care providers who have been involved in the patient’s care. The meeting takes place in a private space and at a time that is scheduled with the families’ needs in mind. Thus it is different from having families present on rounds or one-off meetings with particular clinicians.

Goals of care meetings are typically held when, in the clinicians’ view, the current treatments are not achieving the previously stated goals. Thus, the meeting has 2 purposes: first, to give the family the bad news that the current plan is not working and second, to develop a new plan based on the patient’s values. The family’s job, as surrogate decision maker, is to provide information about what would be most important to the patient. The clinician’s job is to suggest treatment plans that have the best probability of matching the patient’s values.

Not all of these tasks need be done at once. Some families will not be able to move from hearing bad news to making a decision without having time to first reflect and grieve. Others will need to confer with other family members privately before deciding on a plan. In many cases, a time-limited trial may be the right option with a plan for subsequent meetings. Given this, we recommend checking in with the family between each step to ensure that they feel safe moving ahead. For example, one might ask “Is it OK if we talk about what happens next?”

Talking Map Steps in Detail

1. Gather the Clinical Team for a Pre-Meeting

ICU care involves a large interdisciplinary care team. A “meeting before the meeting” with the entire clinical team is an opportunity to reach consensus on prognosis and therapeutic options, share prior interactions with family, and determine goals for the family meeting. It is also helpful to clarify team members’ roles at the meeting and to choose a primary facilitator. All of this helps to ensure that the family receives a consistent message during the meeting. The pre-meeting is also an opportunity to ask a team member to observe the communication skills of the facilitator and be prepared to give feedback after the meeting.

At this time, the team should also create the proper environment for the family meeting. This includes a quiet room free of interruptions with ample seating, available tissues, and transferred pagers and cell phones.

The intensivist and bedside nurse should always be present at the family meeting, and it is best when the same attending can be at subsequent family meetings Their consistent dual presence provides the uniform communication from the team, can reduce anxiety in family members and the collaboration reduces ICU nurse and physician burnout [11]. For illnesses that involve a specific disease or organ system, it is important to have the specialist at the meeting who can provide the appropriate expertise.

The Pre-Meeting

A family meeting was scheduled in the family meeting room for 3 pm, after morning rounds. Thirty minutes prior to the meeting the medical team, including the MICU intensivist, the bedside nurse, the neurology attending who has been involved in the care, the case manager and 2 residents sat to discuss Mr. A’s care. The neurology team confirmed that this stroke was considered very large and would result in a level of disability that could only be cared for in a nursing home and would require both a tracheostomy and feeding tube for safe care. The bedside nurse relayed that the family had asked if Mr. A. would ever recover enough to get back to his home. The neurology team shared they did not expect much improvement at all. Given the worsening renal failure and need for dialysis the case manager reminded the team that Mr. A’s nursing home placements were limited. The team decided that the intensivist would lead the meeting as she had updated various family members on rounds for the past 4 days and would be on service for another week. The team decided that their goal for the meeting was to make sure the family understands that Mr. A’s several medical illnesses portend a poor prognosis. They recognized this may be breaking bad news to the family. They also wanted to better understand what Mr. A would have thought given this situation. The residents were asked to watch for the family’s responses when the team delivered the news.

2. Introduce Everyone

Each meeting should start with formal introductions. Even if most providers know most family members it is a polite way to start the meeting. Introducing each family member present and how they know the patient provides insight into how the family is constructed and makes decisions. For example, the entire family may defer to the daughter who introduces herself as a nurse. In other situations, although there is one legal decision maker, the family may explain that they make decisions by consensus.

Each member of the treating team should also introduce themselves. Even if the clinician has been working with the family, it is polite to be formal and give your name and role. Given the number of people the family sees every day, one should not assume that the family remembers all of the clinicians.

In teaching hospitals, providers should also help the family understand their level of training. Surrogates do not always understand the different roles or level of training between students, residents and fellows, advanced practice providers, consultants and their attending physicians. Uncertainty about the roles can lead to family members feeling as though they are receiving contradictory information. Family satisfaction decreases when multiple attending physicians are involved in a patient’s care [12]. When possible, a consistent presence among providers at family meetings is always best.

3. Ask the Family's Understanding of the Situation (Ask-Tell-Ask)

Asking the family to explain the situation in their own language reveals how well they understand the medical facts and helps the medical team determine what information will be most helpful to the family. An opening statement might be “We have all seen your dad and talked to many of his providers. It would help us all be on the same page if you can you tell me what the doctors are telling you?” Starting with the family’s understanding builds trust with the medical team as it creates an opportunity for the family to lead the meeting and indicates that the team is available to listen to their concerns. Asking surrogates for their understanding allows them to tell their story and not hear a reiteration of things they already know. Providing time for the family to share their perspective of the care elicits family’s concerns.

In a large meeting, ensure that all members of the family have an opportunity to communicate their concerns. Does a particular person do all of the talking? Are there individuals that do not speak at all? One way to further understand unspoken concerns during the meeting is to ask “I notice you have been quiet, what questions do you have that I can answer?” There may be several rounds of “asking” in order to ensure all the family members’ concerns are heard. Letting the family tell what they have heard helps the clinicians get a better idea of their health literacy. Do they explain information using technical data or jargon? Finally, as the family talks the clinicians can determine how surprising the “serious news” will be to them. For example, if the family says they know their dad is doing much worse and may die, the information to be delivered can be truncated. However if family incorrectly thinks their dad is doing better or is uncertain they will be much more surprised by the serious news.

After providing time for the family to express their understanding, tell them the information the team needs to communicate. When delivering serious news it is important to focus on the key 1 to 2 points you want the family to take away from the meeting. Typically when health care professionals talk to each other, they talk about every medical detail. Families find this amount of information overwhelming and are not sure what is most important, asking “So what does that mean?” Focusing on the “headline” helps the family focus on what you think the most important piece of information is. Studies suggest that what families most want to know is what the information means for the patient’s future and what treatments are possible. After delivering the new information, stop to allow the family space to think about what you said. If you are giving serious news, you will know they have heard what you said as they will get emotional (see next step).

Checking for understanding is the final “ask” in Ask-Tell-Ask. Begin by asking “What questions do you have?” Data in primary care has shown that patients are more likely to ask questions if you ask “what questions do you have” rather than “do you have any questions?” It is important to continue to ask this question until the family has asked all their questions. Often the family’s tough questions do not come until they get more comfortable and confident in the health care team. In cases where one family member is dominant it might also help to say “What questions do others have?” Next, using techniques like the “teach back” model the physician should check in to see what the family is taking away from the conversation. If a family understands, they can “teach back” the information accurately. This “ask” can be done in a way that does not make the family feel they are being tested: “I am not always clear when I communicate. Do you mind telling me back in your own words what you thought I said so I know we are on the same page?” This also provides an opportunity to answer any new questions that arise. Hearing the information directly from the family can allow the team to clarify any misconceptions and give insight into any emotional responses that the family might have.

4. Respond to Emotion

Discussing serious news in the ICU setting naturally leads to an emotional reaction. The clinician’s ability to notice emotional cues and respond with empathy is a key communication skill in family meetings [13]. Emotional reactions impede individual’s ability to process cognitive information and make it hard to think cognitively about what should be done next.

Physicians miss opportunities to respond to emotion in family meetings [14]. Missed opportunities lead to decreased family satisfaction and may lead to treatment decisions not consistent with the wishes of their loved ones. Empathic responses improve the family-clinician relationship and helps build trust and rapport [15]. Well- placed empathic statements may help surrogates disclose concerns that help the physician better understand the goals and values of the family and patient. Families also can more fully process cognitive information when their emotional responses have been attended to.

Physicians can develop the capacity to recognize and respond to the emotional cues family members are delivering. Intensivists should actively look for the emotions, the empathic opportunity, that are displayed by the family. This emotion is the “data” that will help lead to an empathic response. A family that just received bad news typically responds by showing emotion. Clues that emotions are present include: the family asking the same questions multiple times; using emotional words such as “sad” or “frustrated;” existential questions that do not have a cognitive answer such as “Why did God let this happen?;” or non-verbal cues like tears and hand wringing.

Sometimes the emotional responses are more difficult to recognize. Families may continue to ask for more cognitive information after hearing bad news. Someone keeps asking “Why did his kidney function worsen?” or “I thought the team said the chest x-ray looked better.” It is tempting to start answering these questions with more medical facts. However, if the question comes after bad news, it is usually an expression of frustration or sadness rather than a request for more information. Rather than giving information, it might help to acknowledge this by saying “I imagine this new is overwhelming.”

5. Highlight the Patient’s Voice

Family meetings are often used to develop new treatment plans (given that the old plans are not working). In these situations, it is essential to understand what the incapacitated patient would say if they were part of the family meeting. The surrogate’s primary role is to represent the patient’s voice. To do this, surrogates need assistance in applying their critically ill loved one’s thoughts and values to complex, possibly life limiting, situations. Surrogate decision makers struggle with the decisions’ emotional impact, as well as how to reconcile their desires with their loved one’s wishes [18]. This can lead them to make decisions that conflict with the loved one’s values [19] as well as emotional sequelae such as PTSD and depression [20].

As families reflect on their loved one’s values, conflicting desires will arise. For example, someone may have wanted to live as long as possible and also values independence. Or someone may value their ability to think clearly more than being physically well but would not want to be physically dependent on artificial life support. Exploring which values would be more important can help resolve these conflicts.

Clinicians should check for understanding while family members are identifying the values of their loved ones. Providing the family with a summary of what you have heard will help ensure a more accurate understanding of these crucial issues. A summary statement might be, “It sounds like you are saying your dad really valued his independence. He enjoyed being able to take care of his loved ones and himself. Is that right?”

6. Plan Next Steps

The family meeting serves to attend to family emotion and allow space to elicit patients’ values. Following a family meeting surrogate decision makers may be able to begin to consider the next steps in their loved one’s care. If bad news was delivered they may need space to adjust to a different future than they expected. Using an empathic statement of support “We will continue to make sure we communicate with you as we work together to plan next steps” will reassure a family that they have time and space to plan for the future.

Families vary regarding how much physician input they desire in planning next steps [21]. You can explicitly ask how the team can best help the family with decisions: “Some families like to hear the options for next steps from the team and make a decision, other families like to hear a recommendation from the team. What would be the most helpful for you?” Throughout the course of an illness a surrogate’s preference for decision making may change and clinicians should be responsive to those changing needs.

If the surrogate wants a clinician’s recommendation, 3 points are worth stressing. First, the recommendation should be personalized to this patient and his values. The goal is to reveal how the understanding of the patient’s values led to the treatment plan offered. Second, the recommendation should focus primarily on what will be done to achieve the patient’s values. Focusing on what the clinicians will do may help the family feel that the clinicians are still “trying” and not abandoning their loved one. In this case, the team will continue medical care that will help the patient regain/maintain independence. Only after talking about what will be done should the clinician point out that certain interventions will not achieve the patient’s goals and thus will not be done:

“It sounds like your father really valued his independence and that this illness has really taken that away. Knowing this, would it be helpful for me to make a recommendation for next steps?” “I think we should continue providing excellent medical care for your father in hopes he can get better and go home. One the other hand, if he gets worse, we should not use therapies such as CPR or dialysis that are unlikely to help him regain his independence.”

Finally, be concrete when planning next steps. If a time-limited trial of a therapy is proposed, make sure the family understands what a successful and unsuccessful trial will look like. Make plans to meet again on a specific date in order to ensure the family understands the progress being made. If a transition to comfort care is agreed upon, ensure support of the entire family during the next hours to days and offer services such as chaplaincy or child life specialists.

A family may not agree with the recommendation and back and forth discussion can help create a plan that is in line with their understanding of the illness. Rather than convincing, a clinician should keep an open mind about why they and the surrogate disagree. Do they have different views about the patient’s future? Did the medical team misunderstand the patient’s values? Are there emotional factors that inhibit the surrogate’s ability to attend to the discussion? It is only by learning where the disagreement is that a clinician can move the conversation forward.

A surrogate may ask about a therapy that is not beneficial or may increase distress to the patient. The use of “I wish” or “I worry” statements can be helpful at these points. These specific phrases recognize the surrogate’s desire to do more but also imply that the therapies are not helpful.

“I wish that his ability to communicate and tell you what he wants would get better with a little more time as well.”

“I worry that waiting 2 more weeks for improvement will actually cause complications to occur.”

7. Reflect

Family meetings have an impact on both the family and the medical team. Following the meeting, a short debriefing with the clinical team can be helpful. Summarizing the events of the meeting ensures clarity about the treatment plan going forward. It provides team members a chance to discuss conflicts that may have arisen. It allows the participants in the meeting to reflect on what communication skills they used and how they can improve their skills going forward.

Conclusion

Family meetings with surrogate decision makers must navigate multiple agendas of the family and providers. The goal of excellent communication with surrogates in an ICU should be to understand the patient’s goals and values and seek to make treatment plans that align with their perspective. This talking map provides a conceptual framework for physicians to guide a family through these conversations. The framework creates an opportunity to focus on the patient’s values and preferences for care while allowing space to attend to emotional responses to reduce the distress inherent in surrogate decision-making. Practicing the behaviors demonstrated in the talking map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Corresponding author: Jessica McFarlin, MD, [email protected].

Funding/support: Dr. Arnold receives support though the Leo H. Criep Chair in Patient Care.

Financial disclosures: None.

From the Department of Neurology, Duke University Medical Center, Durham, NC (Dr. McFarlin), the Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA (Dr. Tulsky), Harborview Medical Center, University of Washington, Seattle, WA (Dr. Back), and Department of Medicine, University of Pittsburgh, Pittsburgh, PA (Dr. Arnold).

Abstract

• Objective: To describe the use of a cognitive map for navigating family meetings with surrogate decision makers of patients in an intensive care unit.
•  Methods: Descriptive report and discussion using an illustrative case to outline the steps in the cognitive map.
• Results: The use of cognitive maps has improved the ability of physicians to efficiently perform a specific communication skill. During a “goals of care” conversation, the cognitive map follows these steps: (1) Gather the clinical team for a pre-meeting, (2) Introduce everyone, (3) Use the “ask-tell-ask” strategy to communicate information, (4) Respond to emotion, (5) Highlight the patient’s voice, (6) Plan next steps, (7) Reflect on the meeting with the team. Providing this map of key communication skills will help faculty teach learners the core components of a family meeting.
• Conclusion: Practicing the behaviors demonstrated in the cognitive map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Key words: intensive care unit; communication; family meeting; critical illness; decision making; end of life care.

Family members of patients in the ICU value high-quality communication with the medical team. In fact, family members report that physicians’ communication skills are often more important than their medical skills [1]. Multiple professional societies, including the American Thoracic Society and the Society of Critical Care Medicine, define communication with families as a key component of high-quality critical care. Effective physician-patient communication improves measureable outcomes including decreased ICU length of stay [2] and may reduce distress amongst patients’ families [3]. The American College of Chest Physicians position statement on Palliative and End-of-Life Care for Patients with Cardiopulmonary Diseases urges physicians to develop curricula that incorporate interpersonal communication skills into training [4].

Unfortunately, such high-quality communication is not the norm. Surrogate decision makers are often displeased with the frequency of communication, the limited availability of attending physicians, and report feeling excluded from discussions [5]. When family meetings do occur, surrogate decision makers report inadequate understanding of diagnosis, prognosis, and treatment plans [6].

Physicians also find family meetings difficult. Intensivists worry that high-quality family meetings are time consuming and difficult to do in a busy ICU [7]. Critical care fellows report not feeling adequately trained to conduct family meetings [8]. It makes sense that untrained clinicians would want to avoid a conversation that is emotionally charged, particularly if one is unsure how to respond effectively.

The Case of Mr. A

Thomas A. is a 79-year-old man admitted to the medical intensive care unit 7 days earlier with a large left middle cerebral artery territory infarction. Given his decreased mental status, on admission he was intubated for airway protection. He is awake but aphasic and unable to follow any commands or move his right side. The neurology consultants do not feel this will improve. He has significant secretions and episodes of hypoxia. He has also developed acute on chronic kidney injury and may need to start dialysis. The social worker explains that his need for dialysis limits his placement options and that he will not be able to be discharged to home. Given his lack of improvement the team is concerned he will need a tracheostomy and feeding tube placed in order to safely continue this level of care. A family meeting is arranged to understand Mr. A’s goals of care.

Talking Map Basics

Before each step is discussed in detail, some definitions are needed. “Family” can be defined as anyone important enough, biologically related or not, to be present at a conversation with a clinician [10]. Second, a “family meeting” is a planned event between the family and interdisciplinary members of the ICU team as well as any other health care providers who have been involved in the patient’s care. The meeting takes place in a private space and at a time that is scheduled with the families’ needs in mind. Thus it is different from having families present on rounds or one-off meetings with particular clinicians.

Goals of care meetings are typically held when, in the clinicians’ view, the current treatments are not achieving the previously stated goals. Thus, the meeting has 2 purposes: first, to give the family the bad news that the current plan is not working and second, to develop a new plan based on the patient’s values. The family’s job, as surrogate decision maker, is to provide information about what would be most important to the patient. The clinician’s job is to suggest treatment plans that have the best probability of matching the patient’s values.

Not all of these tasks need be done at once. Some families will not be able to move from hearing bad news to making a decision without having time to first reflect and grieve. Others will need to confer with other family members privately before deciding on a plan. In many cases, a time-limited trial may be the right option with a plan for subsequent meetings. Given this, we recommend checking in with the family between each step to ensure that they feel safe moving ahead. For example, one might ask “Is it OK if we talk about what happens next?”

Talking Map Steps in Detail

1. Gather the Clinical Team for a Pre-Meeting

ICU care involves a large interdisciplinary care team. A “meeting before the meeting” with the entire clinical team is an opportunity to reach consensus on prognosis and therapeutic options, share prior interactions with family, and determine goals for the family meeting. It is also helpful to clarify team members’ roles at the meeting and to choose a primary facilitator. All of this helps to ensure that the family receives a consistent message during the meeting. The pre-meeting is also an opportunity to ask a team member to observe the communication skills of the facilitator and be prepared to give feedback after the meeting.

At this time, the team should also create the proper environment for the family meeting. This includes a quiet room free of interruptions with ample seating, available tissues, and transferred pagers and cell phones.

The intensivist and bedside nurse should always be present at the family meeting, and it is best when the same attending can be at subsequent family meetings Their consistent dual presence provides the uniform communication from the team, can reduce anxiety in family members and the collaboration reduces ICU nurse and physician burnout [11]. For illnesses that involve a specific disease or organ system, it is important to have the specialist at the meeting who can provide the appropriate expertise.

The Pre-Meeting

A family meeting was scheduled in the family meeting room for 3 pm, after morning rounds. Thirty minutes prior to the meeting the medical team, including the MICU intensivist, the bedside nurse, the neurology attending who has been involved in the care, the case manager and 2 residents sat to discuss Mr. A’s care. The neurology team confirmed that this stroke was considered very large and would result in a level of disability that could only be cared for in a nursing home and would require both a tracheostomy and feeding tube for safe care. The bedside nurse relayed that the family had asked if Mr. A. would ever recover enough to get back to his home. The neurology team shared they did not expect much improvement at all. Given the worsening renal failure and need for dialysis the case manager reminded the team that Mr. A’s nursing home placements were limited. The team decided that the intensivist would lead the meeting as she had updated various family members on rounds for the past 4 days and would be on service for another week. The team decided that their goal for the meeting was to make sure the family understands that Mr. A’s several medical illnesses portend a poor prognosis. They recognized this may be breaking bad news to the family. They also wanted to better understand what Mr. A would have thought given this situation. The residents were asked to watch for the family’s responses when the team delivered the news.

2. Introduce Everyone

Each meeting should start with formal introductions. Even if most providers know most family members it is a polite way to start the meeting. Introducing each family member present and how they know the patient provides insight into how the family is constructed and makes decisions. For example, the entire family may defer to the daughter who introduces herself as a nurse. In other situations, although there is one legal decision maker, the family may explain that they make decisions by consensus.

Each member of the treating team should also introduce themselves. Even if the clinician has been working with the family, it is polite to be formal and give your name and role. Given the number of people the family sees every day, one should not assume that the family remembers all of the clinicians.

In teaching hospitals, providers should also help the family understand their level of training. Surrogates do not always understand the different roles or level of training between students, residents and fellows, advanced practice providers, consultants and their attending physicians. Uncertainty about the roles can lead to family members feeling as though they are receiving contradictory information. Family satisfaction decreases when multiple attending physicians are involved in a patient’s care [12]. When possible, a consistent presence among providers at family meetings is always best.

3. Ask the Family's Understanding of the Situation (Ask-Tell-Ask)

Asking the family to explain the situation in their own language reveals how well they understand the medical facts and helps the medical team determine what information will be most helpful to the family. An opening statement might be “We have all seen your dad and talked to many of his providers. It would help us all be on the same page if you can you tell me what the doctors are telling you?” Starting with the family’s understanding builds trust with the medical team as it creates an opportunity for the family to lead the meeting and indicates that the team is available to listen to their concerns. Asking surrogates for their understanding allows them to tell their story and not hear a reiteration of things they already know. Providing time for the family to share their perspective of the care elicits family’s concerns.

In a large meeting, ensure that all members of the family have an opportunity to communicate their concerns. Does a particular person do all of the talking? Are there individuals that do not speak at all? One way to further understand unspoken concerns during the meeting is to ask “I notice you have been quiet, what questions do you have that I can answer?” There may be several rounds of “asking” in order to ensure all the family members’ concerns are heard. Letting the family tell what they have heard helps the clinicians get a better idea of their health literacy. Do they explain information using technical data or jargon? Finally, as the family talks the clinicians can determine how surprising the “serious news” will be to them. For example, if the family says they know their dad is doing much worse and may die, the information to be delivered can be truncated. However if family incorrectly thinks their dad is doing better or is uncertain they will be much more surprised by the serious news.

After providing time for the family to express their understanding, tell them the information the team needs to communicate. When delivering serious news it is important to focus on the key 1 to 2 points you want the family to take away from the meeting. Typically when health care professionals talk to each other, they talk about every medical detail. Families find this amount of information overwhelming and are not sure what is most important, asking “So what does that mean?” Focusing on the “headline” helps the family focus on what you think the most important piece of information is. Studies suggest that what families most want to know is what the information means for the patient’s future and what treatments are possible. After delivering the new information, stop to allow the family space to think about what you said. If you are giving serious news, you will know they have heard what you said as they will get emotional (see next step).

Checking for understanding is the final “ask” in Ask-Tell-Ask. Begin by asking “What questions do you have?” Data in primary care has shown that patients are more likely to ask questions if you ask “what questions do you have” rather than “do you have any questions?” It is important to continue to ask this question until the family has asked all their questions. Often the family’s tough questions do not come until they get more comfortable and confident in the health care team. In cases where one family member is dominant it might also help to say “What questions do others have?” Next, using techniques like the “teach back” model the physician should check in to see what the family is taking away from the conversation. If a family understands, they can “teach back” the information accurately. This “ask” can be done in a way that does not make the family feel they are being tested: “I am not always clear when I communicate. Do you mind telling me back in your own words what you thought I said so I know we are on the same page?” This also provides an opportunity to answer any new questions that arise. Hearing the information directly from the family can allow the team to clarify any misconceptions and give insight into any emotional responses that the family might have.

4. Respond to Emotion

Discussing serious news in the ICU setting naturally leads to an emotional reaction. The clinician’s ability to notice emotional cues and respond with empathy is a key communication skill in family meetings [13]. Emotional reactions impede individual’s ability to process cognitive information and make it hard to think cognitively about what should be done next.

Physicians miss opportunities to respond to emotion in family meetings [14]. Missed opportunities lead to decreased family satisfaction and may lead to treatment decisions not consistent with the wishes of their loved ones. Empathic responses improve the family-clinician relationship and helps build trust and rapport [15]. Well- placed empathic statements may help surrogates disclose concerns that help the physician better understand the goals and values of the family and patient. Families also can more fully process cognitive information when their emotional responses have been attended to.

Physicians can develop the capacity to recognize and respond to the emotional cues family members are delivering. Intensivists should actively look for the emotions, the empathic opportunity, that are displayed by the family. This emotion is the “data” that will help lead to an empathic response. A family that just received bad news typically responds by showing emotion. Clues that emotions are present include: the family asking the same questions multiple times; using emotional words such as “sad” or “frustrated;” existential questions that do not have a cognitive answer such as “Why did God let this happen?;” or non-verbal cues like tears and hand wringing.

Sometimes the emotional responses are more difficult to recognize. Families may continue to ask for more cognitive information after hearing bad news. Someone keeps asking “Why did his kidney function worsen?” or “I thought the team said the chest x-ray looked better.” It is tempting to start answering these questions with more medical facts. However, if the question comes after bad news, it is usually an expression of frustration or sadness rather than a request for more information. Rather than giving information, it might help to acknowledge this by saying “I imagine this new is overwhelming.”

5. Highlight the Patient’s Voice

Family meetings are often used to develop new treatment plans (given that the old plans are not working). In these situations, it is essential to understand what the incapacitated patient would say if they were part of the family meeting. The surrogate’s primary role is to represent the patient’s voice. To do this, surrogates need assistance in applying their critically ill loved one’s thoughts and values to complex, possibly life limiting, situations. Surrogate decision makers struggle with the decisions’ emotional impact, as well as how to reconcile their desires with their loved one’s wishes [18]. This can lead them to make decisions that conflict with the loved one’s values [19] as well as emotional sequelae such as PTSD and depression [20].

As families reflect on their loved one’s values, conflicting desires will arise. For example, someone may have wanted to live as long as possible and also values independence. Or someone may value their ability to think clearly more than being physically well but would not want to be physically dependent on artificial life support. Exploring which values would be more important can help resolve these conflicts.

Clinicians should check for understanding while family members are identifying the values of their loved ones. Providing the family with a summary of what you have heard will help ensure a more accurate understanding of these crucial issues. A summary statement might be, “It sounds like you are saying your dad really valued his independence. He enjoyed being able to take care of his loved ones and himself. Is that right?”

6. Plan Next Steps

The family meeting serves to attend to family emotion and allow space to elicit patients’ values. Following a family meeting surrogate decision makers may be able to begin to consider the next steps in their loved one’s care. If bad news was delivered they may need space to adjust to a different future than they expected. Using an empathic statement of support “We will continue to make sure we communicate with you as we work together to plan next steps” will reassure a family that they have time and space to plan for the future.

Families vary regarding how much physician input they desire in planning next steps [21]. You can explicitly ask how the team can best help the family with decisions: “Some families like to hear the options for next steps from the team and make a decision, other families like to hear a recommendation from the team. What would be the most helpful for you?” Throughout the course of an illness a surrogate’s preference for decision making may change and clinicians should be responsive to those changing needs.

If the surrogate wants a clinician’s recommendation, 3 points are worth stressing. First, the recommendation should be personalized to this patient and his values. The goal is to reveal how the understanding of the patient’s values led to the treatment plan offered. Second, the recommendation should focus primarily on what will be done to achieve the patient’s values. Focusing on what the clinicians will do may help the family feel that the clinicians are still “trying” and not abandoning their loved one. In this case, the team will continue medical care that will help the patient regain/maintain independence. Only after talking about what will be done should the clinician point out that certain interventions will not achieve the patient’s goals and thus will not be done:

“It sounds like your father really valued his independence and that this illness has really taken that away. Knowing this, would it be helpful for me to make a recommendation for next steps?” “I think we should continue providing excellent medical care for your father in hopes he can get better and go home. One the other hand, if he gets worse, we should not use therapies such as CPR or dialysis that are unlikely to help him regain his independence.”

Finally, be concrete when planning next steps. If a time-limited trial of a therapy is proposed, make sure the family understands what a successful and unsuccessful trial will look like. Make plans to meet again on a specific date in order to ensure the family understands the progress being made. If a transition to comfort care is agreed upon, ensure support of the entire family during the next hours to days and offer services such as chaplaincy or child life specialists.

A family may not agree with the recommendation and back and forth discussion can help create a plan that is in line with their understanding of the illness. Rather than convincing, a clinician should keep an open mind about why they and the surrogate disagree. Do they have different views about the patient’s future? Did the medical team misunderstand the patient’s values? Are there emotional factors that inhibit the surrogate’s ability to attend to the discussion? It is only by learning where the disagreement is that a clinician can move the conversation forward.

A surrogate may ask about a therapy that is not beneficial or may increase distress to the patient. The use of “I wish” or “I worry” statements can be helpful at these points. These specific phrases recognize the surrogate’s desire to do more but also imply that the therapies are not helpful.

“I wish that his ability to communicate and tell you what he wants would get better with a little more time as well.”

“I worry that waiting 2 more weeks for improvement will actually cause complications to occur.”

7. Reflect

Family meetings have an impact on both the family and the medical team. Following the meeting, a short debriefing with the clinical team can be helpful. Summarizing the events of the meeting ensures clarity about the treatment plan going forward. It provides team members a chance to discuss conflicts that may have arisen. It allows the participants in the meeting to reflect on what communication skills they used and how they can improve their skills going forward.

Conclusion

Family meetings with surrogate decision makers must navigate multiple agendas of the family and providers. The goal of excellent communication with surrogates in an ICU should be to understand the patient’s goals and values and seek to make treatment plans that align with their perspective. This talking map provides a conceptual framework for physicians to guide a family through these conversations. The framework creates an opportunity to focus on the patient’s values and preferences for care while allowing space to attend to emotional responses to reduce the distress inherent in surrogate decision-making. Practicing the behaviors demonstrated in the talking map may increase clinician skill during difficult conversations. Improving communication with surrogate decision makers will increase the support we offer to critically ill patients and their loved ones.

Corresponding author: Jessica McFarlin, MD, [email protected].

Funding/support: Dr. Arnold receives support though the Leo H. Criep Chair in Patient Care.

Financial disclosures: None.

Study Overview

Objective. To determine if the Dietary Approaches to Stop Hypertension (DASH) diet is effective for lowering serum uric acid (SUA) levels, and if lower sodium intake as part of the diet would have an effect on SUA.

Design. Ancillary study of a randomized, crossover feeding trial.

Setting and participants. The original DASH study was an National Institute of Health (NIH)–funded, investigator-initiated trial conducted at 4 university centers in the United States from 1997 to 1999. Participants aged 22 years or older who did not have preexisting renal insufficiency, heart disease, uncontrolled dyslipidemia, or diabetes were recruited. Those on antihypertensives, insulin, or with alcohol intake exceeding daily recommended limits for men (> 14 drinks per week) were excluded. For the current secondary analysis, only subjects from 1 center, where SUA was measured, were studied. Participants were randomized to a consume a diet consistent with the typical American diet (control diet) or a diet in line with the principles of the DASH diet. For the first 2 weeks, all groups ate the high-sodium control diet. After this 2-week run-in period, the patients in the study then ate the diet they were assigned to for 30 days. After this 30-day period, participants ate their usual home diet for 5 days. The groups were then crossed over.

Intervention. The DASH diet emphasizes fruits, vegetables, and low-fat dairy foods; includes whole grains, poultry, fish, and nuts; and contains smaller amounts of red meat, sweets, and sugar-containing beverages than the typical US diet. It also contains smaller amounts of total and saturated fat and cholesterol and larger amounts of potassium, calcium, magnesium, dietary fiber, and protein than the typical diet. Both diets contained the same number of calories overall. The diets were similar in mg/day of sodium, however, each arm was subdivided to intake either a high (4400 mg/day), intermediate (3000 mg/day), or low (1400 mg/day) level of sodium. During the study period, all food was provided for participants, including meals and snacks, and was donated by various food vendors in the United States.

Main outcome measure. SUA levels, which were measured after each change in diet and at baseline. Other measures were blood pressure, body mass index, renal function, and fasting glucose and lipids.

Main results. There were 103 participants with an average blood pressure of 139/87 mm Hg at baseline. Mean age was 51 years and about half of the patients were women. The majority of patients were overweight (mean BMI, 29.5 kg/m²) and African American (74.8%), with an average SUA level of 5.0 mg/dL. There were 8 participants with a SUA level > 7 mg/dL at baseline. Daily alcohol intake, fasting glucose and triglycerides, renal function, and blood pressure did not differ significantly between the groups. The DASH diet was effective in lowering SUA levels overall by an average of 0.35 mg/dL (P = 0.02). The sodium content had an effect on SUA levels regardless of the diet. The intermediate sodium subset of both the DASH and the control diets resulted in an overall decrease in SUA by 0.34 mg/dL, P < 0.001 (0.35 mg/dL for the DASH diet, P = 0.04; 0.33 mg/dL for the control diet, P < 0.001). There was no difference in SUA between the low- and high-sodium groups. Those participants with the highest SUA at the start of the study had the greatest reduction in SUA. For those with levels > 7 mg/dL, there was a decrease in SUA by 1.29 mg/dL. If the SUA at the start of the trial was lower, reductions were more modest. SUA was reduced by 0.76 mg/dL when the starting level was between 6 and 7 mg/dL. When the participants had a SUA between 4 and 5 mg/dL, the effect of the diet was nonexistent. Other variables such as hypertension and obesity were found not to be confounders.

Conclusion. For participants with SUA levels > 7, an average reduction in serum uric acid of 1.29 mg/dL can reasonably be expected from implementation of a DASH-type diet.

Commentary

SUA is considered an important etiologic factor in gout, but there has been little evidence for success in controlling uric acid with diet. Dietary recommendations for gout patients from the American College of Rheumatology include avoiding organ meats, high-fructose corn syrup, and alcohol in excess, and suggest that beef, lamb, pork, shellfish and sugary beverages should be limited while vegetables and nonfat dairy be encouraged [1].

The DASH diet, promoted by the National Heart, Lung, and Blood Institute to prevent and control hypertension, has been widely disseminated in the popular press and is well known to many Americans. Clinical evidence supporting DASH as first-line nonpharmacologic treatment for high blood pressure is based mainly on the results of 3 trials: DASH Trial[2], DASH-Sodium Trial [3], and PREMIER clinical trial [4]. The DASH diet, while it overlaps with the ACR recommendations of encouraging intake of vegetables and non-fat dairy and discouraging added sugars, recommends as a primary calorie source whole grains, followed by vegetables, fruits, and lean meats, poultry, or fish. One to 2 servings of nuts, seeds, or legumes is also encouraged as well as healthful fats and oils.

The authors’ hypothesis, that the DASH diet would lower uric acid levels as compared with the control diet, was affirmed, with the greater effect seen in patients with higher SUA at baseline. The authors also hypothesized that reducing sodium intake would lower uric acid levels, given its association with high blood pressure. In this study, higher levels of sodium were found to be associated with a decrease in uric acid. The reason for this is unclear and the authors speculate as to why this could be physiologically. The relationship between sodium intake and SUA level is controversial and the authors do not recommend advising anincrease in sodium in the diet to lower SUA levels based on their findings.

Long-term dietary change is not easy. It is encouraging that, according to the authors, most of the participants in the study found the DASH diet to be preferable to the typical Western control diet provided and expressed a desire to maintain the DASH style of eating. This is important to consider, as any lifestyle change must be sustained to see continued benefit. The study participants maintained a constant weight, which eliminates this potentially confounding variable as weight reduction alone leads to a reduction in SUA.

While this study showed a positive effect of implementing the DASH diet in those with elevated SUA levels, it excluded those with comorbidities often found in patients with gout, such as cardiovascular disease, diabetes, and renal impairment. This limits generalizability, as does excluding those who consume alcohol beyond the daily recommended quantities—a known risk factor for hyperuricemia. As with any dietary study, it is difficult to know for certain that participants did not eat any foods outside of the study protocol even when the food was provided.

Patients with gout and hyperuricemia are at an increased risk for cardiovascular disease and the metabolic syndrome, making lifestyle interventions and dietary counselling crucial to the global wellbeing of the patient. Overall, this randomized crossover study provides compelling evidence that the DASH diet should be recommended to patients with hyperuricemia.

Applications for Clinical Practice

For patients with borderline-high SUA (between 6–7 mg/dL), it is reasonable to encourage implementation of the DASH diet with the expectation that SUA will be lowered by about 1.29 mg/dL, getting the patient to goal SUA. As a greater benefit was seen in patients with higher levels of SUA at baseline, it is also reasonable to attempt to lower SUA with a DASH-style diet prior to pharmacologic intervention for higher SUA level if the patient is amenable to trying this tactic.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Study Overview

Objective. To determine if the Dietary Approaches to Stop Hypertension (DASH) diet is effective for lowering serum uric acid (SUA) levels, and if lower sodium intake as part of the diet would have an effect on SUA.

Design. Ancillary study of a randomized, crossover feeding trial.

Setting and participants. The original DASH study was an National Institute of Health (NIH)–funded, investigator-initiated trial conducted at 4 university centers in the United States from 1997 to 1999. Participants aged 22 years or older who did not have preexisting renal insufficiency, heart disease, uncontrolled dyslipidemia, or diabetes were recruited. Those on antihypertensives, insulin, or with alcohol intake exceeding daily recommended limits for men (> 14 drinks per week) were excluded. For the current secondary analysis, only subjects from 1 center, where SUA was measured, were studied. Participants were randomized to a consume a diet consistent with the typical American diet (control diet) or a diet in line with the principles of the DASH diet. For the first 2 weeks, all groups ate the high-sodium control diet. After this 2-week run-in period, the patients in the study then ate the diet they were assigned to for 30 days. After this 30-day period, participants ate their usual home diet for 5 days. The groups were then crossed over.

Intervention. The DASH diet emphasizes fruits, vegetables, and low-fat dairy foods; includes whole grains, poultry, fish, and nuts; and contains smaller amounts of red meat, sweets, and sugar-containing beverages than the typical US diet. It also contains smaller amounts of total and saturated fat and cholesterol and larger amounts of potassium, calcium, magnesium, dietary fiber, and protein than the typical diet. Both diets contained the same number of calories overall. The diets were similar in mg/day of sodium, however, each arm was subdivided to intake either a high (4400 mg/day), intermediate (3000 mg/day), or low (1400 mg/day) level of sodium. During the study period, all food was provided for participants, including meals and snacks, and was donated by various food vendors in the United States.

Main outcome measure. SUA levels, which were measured after each change in diet and at baseline. Other measures were blood pressure, body mass index, renal function, and fasting glucose and lipids.

Main results. There were 103 participants with an average blood pressure of 139/87 mm Hg at baseline. Mean age was 51 years and about half of the patients were women. The majority of patients were overweight (mean BMI, 29.5 kg/m²) and African American (74.8%), with an average SUA level of 5.0 mg/dL. There were 8 participants with a SUA level > 7 mg/dL at baseline. Daily alcohol intake, fasting glucose and triglycerides, renal function, and blood pressure did not differ significantly between the groups. The DASH diet was effective in lowering SUA levels overall by an average of 0.35 mg/dL (P = 0.02). The sodium content had an effect on SUA levels regardless of the diet. The intermediate sodium subset of both the DASH and the control diets resulted in an overall decrease in SUA by 0.34 mg/dL, P < 0.001 (0.35 mg/dL for the DASH diet, P = 0.04; 0.33 mg/dL for the control diet, P < 0.001). There was no difference in SUA between the low- and high-sodium groups. Those participants with the highest SUA at the start of the study had the greatest reduction in SUA. For those with levels > 7 mg/dL, there was a decrease in SUA by 1.29 mg/dL. If the SUA at the start of the trial was lower, reductions were more modest. SUA was reduced by 0.76 mg/dL when the starting level was between 6 and 7 mg/dL. When the participants had a SUA between 4 and 5 mg/dL, the effect of the diet was nonexistent. Other variables such as hypertension and obesity were found not to be confounders.

Conclusion. For participants with SUA levels > 7, an average reduction in serum uric acid of 1.29 mg/dL can reasonably be expected from implementation of a DASH-type diet.

Commentary

SUA is considered an important etiologic factor in gout, but there has been little evidence for success in controlling uric acid with diet. Dietary recommendations for gout patients from the American College of Rheumatology include avoiding organ meats, high-fructose corn syrup, and alcohol in excess, and suggest that beef, lamb, pork, shellfish and sugary beverages should be limited while vegetables and nonfat dairy be encouraged [1].

The DASH diet, promoted by the National Heart, Lung, and Blood Institute to prevent and control hypertension, has been widely disseminated in the popular press and is well known to many Americans. Clinical evidence supporting DASH as first-line nonpharmacologic treatment for high blood pressure is based mainly on the results of 3 trials: DASH Trial[2], DASH-Sodium Trial [3], and PREMIER clinical trial [4]. The DASH diet, while it overlaps with the ACR recommendations of encouraging intake of vegetables and non-fat dairy and discouraging added sugars, recommends as a primary calorie source whole grains, followed by vegetables, fruits, and lean meats, poultry, or fish. One to 2 servings of nuts, seeds, or legumes is also encouraged as well as healthful fats and oils.

The authors’ hypothesis, that the DASH diet would lower uric acid levels as compared with the control diet, was affirmed, with the greater effect seen in patients with higher SUA at baseline. The authors also hypothesized that reducing sodium intake would lower uric acid levels, given its association with high blood pressure. In this study, higher levels of sodium were found to be associated with a decrease in uric acid. The reason for this is unclear and the authors speculate as to why this could be physiologically. The relationship between sodium intake and SUA level is controversial and the authors do not recommend advising anincrease in sodium in the diet to lower SUA levels based on their findings.

Long-term dietary change is not easy. It is encouraging that, according to the authors, most of the participants in the study found the DASH diet to be preferable to the typical Western control diet provided and expressed a desire to maintain the DASH style of eating. This is important to consider, as any lifestyle change must be sustained to see continued benefit. The study participants maintained a constant weight, which eliminates this potentially confounding variable as weight reduction alone leads to a reduction in SUA.

While this study showed a positive effect of implementing the DASH diet in those with elevated SUA levels, it excluded those with comorbidities often found in patients with gout, such as cardiovascular disease, diabetes, and renal impairment. This limits generalizability, as does excluding those who consume alcohol beyond the daily recommended quantities—a known risk factor for hyperuricemia. As with any dietary study, it is difficult to know for certain that participants did not eat any foods outside of the study protocol even when the food was provided.

Patients with gout and hyperuricemia are at an increased risk for cardiovascular disease and the metabolic syndrome, making lifestyle interventions and dietary counselling crucial to the global wellbeing of the patient. Overall, this randomized crossover study provides compelling evidence that the DASH diet should be recommended to patients with hyperuricemia.

Applications for Clinical Practice

For patients with borderline-high SUA (between 6–7 mg/dL), it is reasonable to encourage implementation of the DASH diet with the expectation that SUA will be lowered by about 1.29 mg/dL, getting the patient to goal SUA. As a greater benefit was seen in patients with higher levels of SUA at baseline, it is also reasonable to attempt to lower SUA with a DASH-style diet prior to pharmacologic intervention for higher SUA level if the patient is amenable to trying this tactic.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Study Overview

Objective. To determine if the Dietary Approaches to Stop Hypertension (DASH) diet is effective for lowering serum uric acid (SUA) levels, and if lower sodium intake as part of the diet would have an effect on SUA.

Design. Ancillary study of a randomized, crossover feeding trial.

Setting and participants. The original DASH study was an National Institute of Health (NIH)–funded, investigator-initiated trial conducted at 4 university centers in the United States from 1997 to 1999. Participants aged 22 years or older who did not have preexisting renal insufficiency, heart disease, uncontrolled dyslipidemia, or diabetes were recruited. Those on antihypertensives, insulin, or with alcohol intake exceeding daily recommended limits for men (> 14 drinks per week) were excluded. For the current secondary analysis, only subjects from 1 center, where SUA was measured, were studied. Participants were randomized to a consume a diet consistent with the typical American diet (control diet) or a diet in line with the principles of the DASH diet. For the first 2 weeks, all groups ate the high-sodium control diet. After this 2-week run-in period, the patients in the study then ate the diet they were assigned to for 30 days. After this 30-day period, participants ate their usual home diet for 5 days. The groups were then crossed over.

Intervention. The DASH diet emphasizes fruits, vegetables, and low-fat dairy foods; includes whole grains, poultry, fish, and nuts; and contains smaller amounts of red meat, sweets, and sugar-containing beverages than the typical US diet. It also contains smaller amounts of total and saturated fat and cholesterol and larger amounts of potassium, calcium, magnesium, dietary fiber, and protein than the typical diet. Both diets contained the same number of calories overall. The diets were similar in mg/day of sodium, however, each arm was subdivided to intake either a high (4400 mg/day), intermediate (3000 mg/day), or low (1400 mg/day) level of sodium. During the study period, all food was provided for participants, including meals and snacks, and was donated by various food vendors in the United States.

Main outcome measure. SUA levels, which were measured after each change in diet and at baseline. Other measures were blood pressure, body mass index, renal function, and fasting glucose and lipids.

Main results. There were 103 participants with an average blood pressure of 139/87 mm Hg at baseline. Mean age was 51 years and about half of the patients were women. The majority of patients were overweight (mean BMI, 29.5 kg/m²) and African American (74.8%), with an average SUA level of 5.0 mg/dL. There were 8 participants with a SUA level > 7 mg/dL at baseline. Daily alcohol intake, fasting glucose and triglycerides, renal function, and blood pressure did not differ significantly between the groups. The DASH diet was effective in lowering SUA levels overall by an average of 0.35 mg/dL (P = 0.02). The sodium content had an effect on SUA levels regardless of the diet. The intermediate sodium subset of both the DASH and the control diets resulted in an overall decrease in SUA by 0.34 mg/dL, P < 0.001 (0.35 mg/dL for the DASH diet, P = 0.04; 0.33 mg/dL for the control diet, P < 0.001). There was no difference in SUA between the low- and high-sodium groups. Those participants with the highest SUA at the start of the study had the greatest reduction in SUA. For those with levels > 7 mg/dL, there was a decrease in SUA by 1.29 mg/dL. If the SUA at the start of the trial was lower, reductions were more modest. SUA was reduced by 0.76 mg/dL when the starting level was between 6 and 7 mg/dL. When the participants had a SUA between 4 and 5 mg/dL, the effect of the diet was nonexistent. Other variables such as hypertension and obesity were found not to be confounders.

Conclusion. For participants with SUA levels > 7, an average reduction in serum uric acid of 1.29 mg/dL can reasonably be expected from implementation of a DASH-type diet.

Commentary

SUA is considered an important etiologic factor in gout, but there has been little evidence for success in controlling uric acid with diet. Dietary recommendations for gout patients from the American College of Rheumatology include avoiding organ meats, high-fructose corn syrup, and alcohol in excess, and suggest that beef, lamb, pork, shellfish and sugary beverages should be limited while vegetables and nonfat dairy be encouraged [1].

The DASH diet, promoted by the National Heart, Lung, and Blood Institute to prevent and control hypertension, has been widely disseminated in the popular press and is well known to many Americans. Clinical evidence supporting DASH as first-line nonpharmacologic treatment for high blood pressure is based mainly on the results of 3 trials: DASH Trial[2], DASH-Sodium Trial [3], and PREMIER clinical trial [4]. The DASH diet, while it overlaps with the ACR recommendations of encouraging intake of vegetables and non-fat dairy and discouraging added sugars, recommends as a primary calorie source whole grains, followed by vegetables, fruits, and lean meats, poultry, or fish. One to 2 servings of nuts, seeds, or legumes is also encouraged as well as healthful fats and oils.

The authors’ hypothesis, that the DASH diet would lower uric acid levels as compared with the control diet, was affirmed, with the greater effect seen in patients with higher SUA at baseline. The authors also hypothesized that reducing sodium intake would lower uric acid levels, given its association with high blood pressure. In this study, higher levels of sodium were found to be associated with a decrease in uric acid. The reason for this is unclear and the authors speculate as to why this could be physiologically. The relationship between sodium intake and SUA level is controversial and the authors do not recommend advising anincrease in sodium in the diet to lower SUA levels based on their findings.

Long-term dietary change is not easy. It is encouraging that, according to the authors, most of the participants in the study found the DASH diet to be preferable to the typical Western control diet provided and expressed a desire to maintain the DASH style of eating. This is important to consider, as any lifestyle change must be sustained to see continued benefit. The study participants maintained a constant weight, which eliminates this potentially confounding variable as weight reduction alone leads to a reduction in SUA.

While this study showed a positive effect of implementing the DASH diet in those with elevated SUA levels, it excluded those with comorbidities often found in patients with gout, such as cardiovascular disease, diabetes, and renal impairment. This limits generalizability, as does excluding those who consume alcohol beyond the daily recommended quantities—a known risk factor for hyperuricemia. As with any dietary study, it is difficult to know for certain that participants did not eat any foods outside of the study protocol even when the food was provided.

Patients with gout and hyperuricemia are at an increased risk for cardiovascular disease and the metabolic syndrome, making lifestyle interventions and dietary counselling crucial to the global wellbeing of the patient. Overall, this randomized crossover study provides compelling evidence that the DASH diet should be recommended to patients with hyperuricemia.

Applications for Clinical Practice

For patients with borderline-high SUA (between 6–7 mg/dL), it is reasonable to encourage implementation of the DASH diet with the expectation that SUA will be lowered by about 1.29 mg/dL, getting the patient to goal SUA. As a greater benefit was seen in patients with higher levels of SUA at baseline, it is also reasonable to attempt to lower SUA with a DASH-style diet prior to pharmacologic intervention for higher SUA level if the patient is amenable to trying this tactic.

—Christina Downey, MD, Geisinger Medical Center, Danville, PA

Between 20% and 40% of patients with multiple myeloma (MM) have renal impairment and also may take drugs that raise the risk of venous thromboembolism (VTE). Do those factors contribute to a higher risk of arterial thrombosis in this patient group? Researchers from the University of Arkansas and Ohio State University conducted a large, retrospective, comparative case control study to find out.

Related:  Treating Patients With Multiple Myeloma in the VA

Patients were enrolled in Total Therapy protocols (TT2, TT3a, and TT3b), which tested varying combinations of thalidomide, bortezomib, lenalidomide, and dexamethasone. Of 1,148 patients, 46 (4%) had strokes, usually ischemic stroke (33 patients, or 72%). Hypercoagulability, atrial fibrillation and small-vessel occlusion were common mechanisms. Whereas other research has found a higher risk of arterial thrombosis from activated prothrombotic factors, especially during the early period of chemotherapy, in this study vascular events occurred months later.

Seven patients died in the hospital (15% compared with a national average of 5%). Although 6 of those deaths were stroke related, 36 patients  were discharged home or to a rehabilitation facility; 2 were discharged to a long-term nursing facility. During a median follow-up of 10 years, 6 patients had another stroke. The cumulative risk of recurrent stroke was 15% compared with 5% for the general population.

Related:  Link Found Between Agent Orange Exposure and Multiple Myeloma

Stage I and II cancers and renal insufficiency independently predicted stroke. Also noteworthy, according to the researchers: Patients with MM who developed renal insufficiency had worse clinical outcomes despite improvement in their renal function or lack of significant difference in their baseline renal functions between various treatment protocols. Thus, the increased risk of stroke, recurrent stroke, and mortality could partly be due to renal disease, which may or may not have resulted from myeloma.

Use of combination chemotherapy has “markedly improved” clinical outcomes for MM patients, the researchers say, but those drugs have also been associated with an increased risk of VTE, especially during the first months of chemotherapy. Thalidomide alone did not increase the risk of VTE, nor did lenalinomide on its own. However, thalidomide combined with multiagent chemotherapy increased VTE risk as much as 34% in newly diagnosed patients, and lenalinomide with dexamethasone boosted risk as high as 75%.

The researchers found no significant relationship between mortality and use of thalidomide. Median survival was 103 months for a thalidomide-based regimen and 78 months for a regimen without thalidomide.

Related: Multiple Myeloma: Updates on Diagnosis and Management

The researchers noted that the patients developed strokes despite a trend toward coagulopathy, to the extent that half were ineligible for immediate use of antiplatelet agents. The study findings “heightened our awareness,” the researchers say, that aggressive preventive measures can help reduce the incidence of stroke in patients with renal insufficiency.

Source:
Hinduja A, Limaye K, Ravilla R, et al. PLoS One. 2016;11(11): e0166627.
doi: 10.1371/journal.pone.0166627.

Between 20% and 40% of patients with multiple myeloma (MM) have renal impairment and also may take drugs that raise the risk of venous thromboembolism (VTE). Do those factors contribute to a higher risk of arterial thrombosis in this patient group? Researchers from the University of Arkansas and Ohio State University conducted a large, retrospective, comparative case control study to find out.

Related:  Treating Patients With Multiple Myeloma in the VA

Patients were enrolled in Total Therapy protocols (TT2, TT3a, and TT3b), which tested varying combinations of thalidomide, bortezomib, lenalidomide, and dexamethasone. Of 1,148 patients, 46 (4%) had strokes, usually ischemic stroke (33 patients, or 72%). Hypercoagulability, atrial fibrillation and small-vessel occlusion were common mechanisms. Whereas other research has found a higher risk of arterial thrombosis from activated prothrombotic factors, especially during the early period of chemotherapy, in this study vascular events occurred months later.

Seven patients died in the hospital (15% compared with a national average of 5%). Although 6 of those deaths were stroke related, 36 patients  were discharged home or to a rehabilitation facility; 2 were discharged to a long-term nursing facility. During a median follow-up of 10 years, 6 patients had another stroke. The cumulative risk of recurrent stroke was 15% compared with 5% for the general population.

Related:  Link Found Between Agent Orange Exposure and Multiple Myeloma

Stage I and II cancers and renal insufficiency independently predicted stroke. Also noteworthy, according to the researchers: Patients with MM who developed renal insufficiency had worse clinical outcomes despite improvement in their renal function or lack of significant difference in their baseline renal functions between various treatment protocols. Thus, the increased risk of stroke, recurrent stroke, and mortality could partly be due to renal disease, which may or may not have resulted from myeloma.

Use of combination chemotherapy has “markedly improved” clinical outcomes for MM patients, the researchers say, but those drugs have also been associated with an increased risk of VTE, especially during the first months of chemotherapy. Thalidomide alone did not increase the risk of VTE, nor did lenalinomide on its own. However, thalidomide combined with multiagent chemotherapy increased VTE risk as much as 34% in newly diagnosed patients, and lenalinomide with dexamethasone boosted risk as high as 75%.

The researchers found no significant relationship between mortality and use of thalidomide. Median survival was 103 months for a thalidomide-based regimen and 78 months for a regimen without thalidomide.

Related: Multiple Myeloma: Updates on Diagnosis and Management

The researchers noted that the patients developed strokes despite a trend toward coagulopathy, to the extent that half were ineligible for immediate use of antiplatelet agents. The study findings “heightened our awareness,” the researchers say, that aggressive preventive measures can help reduce the incidence of stroke in patients with renal insufficiency.

Source:
Hinduja A, Limaye K, Ravilla R, et al. PLoS One. 2016;11(11): e0166627.
doi: 10.1371/journal.pone.0166627.

Between 20% and 40% of patients with multiple myeloma (MM) have renal impairment and also may take drugs that raise the risk of venous thromboembolism (VTE). Do those factors contribute to a higher risk of arterial thrombosis in this patient group? Researchers from the University of Arkansas and Ohio State University conducted a large, retrospective, comparative case control study to find out.

Related:  Treating Patients With Multiple Myeloma in the VA

Patients were enrolled in Total Therapy protocols (TT2, TT3a, and TT3b), which tested varying combinations of thalidomide, bortezomib, lenalidomide, and dexamethasone. Of 1,148 patients, 46 (4%) had strokes, usually ischemic stroke (33 patients, or 72%). Hypercoagulability, atrial fibrillation and small-vessel occlusion were common mechanisms. Whereas other research has found a higher risk of arterial thrombosis from activated prothrombotic factors, especially during the early period of chemotherapy, in this study vascular events occurred months later.

Seven patients died in the hospital (15% compared with a national average of 5%). Although 6 of those deaths were stroke related, 36 patients  were discharged home or to a rehabilitation facility; 2 were discharged to a long-term nursing facility. During a median follow-up of 10 years, 6 patients had another stroke. The cumulative risk of recurrent stroke was 15% compared with 5% for the general population.

Related:  Link Found Between Agent Orange Exposure and Multiple Myeloma

Stage I and II cancers and renal insufficiency independently predicted stroke. Also noteworthy, according to the researchers: Patients with MM who developed renal insufficiency had worse clinical outcomes despite improvement in their renal function or lack of significant difference in their baseline renal functions between various treatment protocols. Thus, the increased risk of stroke, recurrent stroke, and mortality could partly be due to renal disease, which may or may not have resulted from myeloma.

Use of combination chemotherapy has “markedly improved” clinical outcomes for MM patients, the researchers say, but those drugs have also been associated with an increased risk of VTE, especially during the first months of chemotherapy. Thalidomide alone did not increase the risk of VTE, nor did lenalinomide on its own. However, thalidomide combined with multiagent chemotherapy increased VTE risk as much as 34% in newly diagnosed patients, and lenalinomide with dexamethasone boosted risk as high as 75%.

The researchers found no significant relationship between mortality and use of thalidomide. Median survival was 103 months for a thalidomide-based regimen and 78 months for a regimen without thalidomide.

Related: Multiple Myeloma: Updates on Diagnosis and Management

The researchers noted that the patients developed strokes despite a trend toward coagulopathy, to the extent that half were ineligible for immediate use of antiplatelet agents. The study findings “heightened our awareness,” the researchers say, that aggressive preventive measures can help reduce the incidence of stroke in patients with renal insufficiency.

Source:
Hinduja A, Limaye K, Ravilla R, et al. PLoS One. 2016;11(11): e0166627.
doi: 10.1371/journal.pone.0166627.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing TTP
Image by Erhabor Osaro

SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).

Earlier studies suggested that ADAMTS13 activity during remission has

limited utility in estimating relapse risk, and cognitive dysfunction

observed in TTP appears to be progressive and independent of relapses.

However, these studies were small with minimal longitudinal data.

Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.

He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.

Dr Mazepa said the objective of the study is to identify biomarkers that

predict the danger period for neurocognitive dysfunction and relapse.

“Hematologists usually do not realize the

neurocognitive dysfunction among patients with TTP, and it is important

that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in

Columbus.

“This study will be crucial in

improving our understanding of this issue.”

The consortium plans to study 100 TTP patients in remission for 3 years.

Every

3 months, patients will complete neuropsychologic testing, and

investigators will evaluate patients’ end-organ ischemic biomarkers,

ADAMTS13 activity, ultra-large von Willebrand factor levels, and

complement activation biomarkers.

In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.

Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.

The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.

Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.

In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him ([email protected]) or Dr Cataland ([email protected]).

Micrograph showing TTP
Image by Erhabor Osaro

SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).

Earlier studies suggested that ADAMTS13 activity during remission has

limited utility in estimating relapse risk, and cognitive dysfunction

observed in TTP appears to be progressive and independent of relapses.

However, these studies were small with minimal longitudinal data.

Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.

He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.

Dr Mazepa said the objective of the study is to identify biomarkers that

predict the danger period for neurocognitive dysfunction and relapse.

“Hematologists usually do not realize the

neurocognitive dysfunction among patients with TTP, and it is important

that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in

Columbus.

“This study will be crucial in

improving our understanding of this issue.”

The consortium plans to study 100 TTP patients in remission for 3 years.

Every

3 months, patients will complete neuropsychologic testing, and

investigators will evaluate patients’ end-organ ischemic biomarkers,

ADAMTS13 activity, ultra-large von Willebrand factor levels, and

complement activation biomarkers.

In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.

Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.

The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.

Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.

In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him ([email protected]) or Dr Cataland ([email protected]).

Micrograph showing TTP
Image by Erhabor Osaro

SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).

Earlier studies suggested that ADAMTS13 activity during remission has

limited utility in estimating relapse risk, and cognitive dysfunction

observed in TTP appears to be progressive and independent of relapses.

However, these studies were small with minimal longitudinal data.

Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.

He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.

Dr Mazepa said the objective of the study is to identify biomarkers that

predict the danger period for neurocognitive dysfunction and relapse.

“Hematologists usually do not realize the

neurocognitive dysfunction among patients with TTP, and it is important

that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in

Columbus.

“This study will be crucial in

improving our understanding of this issue.”

The consortium plans to study 100 TTP patients in remission for 3 years.

Every

3 months, patients will complete neuropsychologic testing, and

investigators will evaluate patients’ end-organ ischemic biomarkers,

ADAMTS13 activity, ultra-large von Willebrand factor levels, and

complement activation biomarkers.

In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.

Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.

The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.

Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.

In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him ([email protected]) or Dr Cataland ([email protected]).

Children in The Gambia
Photo by Aurimas Rimsa

New research suggests that, for young children, iron deficiency anemia offers a

greater protective effect against malaria than sickle cell trait.

The

study indicates that iron deficiency anemia can protect children age 2 and

younger from the blood stage of Plasmodium falciparum malaria, and

treating the anemia with iron supplementation removes this protective

effect.

The researchers reported these findings in EBioMedicine.

“This study is elegant in its simplicity yet remains one of the most

substantial and systematic attempts to unveil the cellular-level

relationship between anemia, iron supplementation, and malaria risk,”

said study author Carla Cerami, MD, PhD, of the Medical Research Council

Unit The Gambia in Banjul, Gambia.

For this study, she and her colleagues analyzed the red blood cells of 135 anemic children who were participating in an iron supplementation trial.

The children ranged in age from 6 months to 24 months and lived in a malaria-endemic region of The Gambia where sickle cell trait was also common.

The children received iron (12 mg/day) through micronutrient powder for 84 days, and the researchers analyzed the children’s red blood cells at baseline, day 49, and day 84.

The team conducted in vitro growth and invasion assays with P falciparum laboratory and field strains. The study’s primary endpoint was in vitro parasite growth in the children’s RBCs.

The researchers found that “anemia substantially reduced the invasion and growth of both laboratory and field strains of P falciparum.” The team noted a roughly 10% growth reduction per standard deviation shift in hemoglobin.

On a population-wide basis, anemia reduced the blood stage of malaria by 15.9%, while the sickle cell trait reduced it by 3.5%.

“Our finding that anemia offers greater natural protection against blood-stage malaria infection than sickle cell trait has led us to formulate the interesting hypothesis that the widespread prevalence of anemia in people of African descent is a genetic signature of malaria,” said study author Morgan Goheen, PhD, of University of North Carolina in Chapel Hill.

The researchers also found that deficits in invasion and growth for blood-stage P falciparum were reversed when anemic children had received 7 weeks of iron supplementation. Parasite growth was 2.4-fold higher after supplementation than it was at baseline (P<0.001).

Prior work by the same research group suggested the increased invasion and growth rates following iron supplementation are caused by the parasites’ strong preference for young red blood cells.

The researchers said these new field results consolidate the evidence that iron supplementation increases the risk of P falciparum malaria and provide support for the use of malaria prophylaxis in

conjunction with iron supplementation, especially during the early

phases of erythroid recovery.

Children in The Gambia
Photo by Aurimas Rimsa

New research suggests that, for young children, iron deficiency anemia offers a

greater protective effect against malaria than sickle cell trait.

The

study indicates that iron deficiency anemia can protect children age 2 and

younger from the blood stage of Plasmodium falciparum malaria, and

treating the anemia with iron supplementation removes this protective

effect.

The researchers reported these findings in EBioMedicine.

“This study is elegant in its simplicity yet remains one of the most

substantial and systematic attempts to unveil the cellular-level

relationship between anemia, iron supplementation, and malaria risk,”

said study author Carla Cerami, MD, PhD, of the Medical Research Council

Unit The Gambia in Banjul, Gambia.

For this study, she and her colleagues analyzed the red blood cells of 135 anemic children who were participating in an iron supplementation trial.

The children ranged in age from 6 months to 24 months and lived in a malaria-endemic region of The Gambia where sickle cell trait was also common.

The children received iron (12 mg/day) through micronutrient powder for 84 days, and the researchers analyzed the children’s red blood cells at baseline, day 49, and day 84.

The team conducted in vitro growth and invasion assays with P falciparum laboratory and field strains. The study’s primary endpoint was in vitro parasite growth in the children’s RBCs.

The researchers found that “anemia substantially reduced the invasion and growth of both laboratory and field strains of P falciparum.” The team noted a roughly 10% growth reduction per standard deviation shift in hemoglobin.

On a population-wide basis, anemia reduced the blood stage of malaria by 15.9%, while the sickle cell trait reduced it by 3.5%.

“Our finding that anemia offers greater natural protection against blood-stage malaria infection than sickle cell trait has led us to formulate the interesting hypothesis that the widespread prevalence of anemia in people of African descent is a genetic signature of malaria,” said study author Morgan Goheen, PhD, of University of North Carolina in Chapel Hill.

The researchers also found that deficits in invasion and growth for blood-stage P falciparum were reversed when anemic children had received 7 weeks of iron supplementation. Parasite growth was 2.4-fold higher after supplementation than it was at baseline (P<0.001).

Prior work by the same research group suggested the increased invasion and growth rates following iron supplementation are caused by the parasites’ strong preference for young red blood cells.

The researchers said these new field results consolidate the evidence that iron supplementation increases the risk of P falciparum malaria and provide support for the use of malaria prophylaxis in

conjunction with iron supplementation, especially during the early

phases of erythroid recovery.

Children in The Gambia
Photo by Aurimas Rimsa

New research suggests that, for young children, iron deficiency anemia offers a

greater protective effect against malaria than sickle cell trait.

The

study indicates that iron deficiency anemia can protect children age 2 and

younger from the blood stage of Plasmodium falciparum malaria, and

treating the anemia with iron supplementation removes this protective

effect.

The researchers reported these findings in EBioMedicine.

“This study is elegant in its simplicity yet remains one of the most

substantial and systematic attempts to unveil the cellular-level

relationship between anemia, iron supplementation, and malaria risk,”

said study author Carla Cerami, MD, PhD, of the Medical Research Council

Unit The Gambia in Banjul, Gambia.

For this study, she and her colleagues analyzed the red blood cells of 135 anemic children who were participating in an iron supplementation trial.

The children ranged in age from 6 months to 24 months and lived in a malaria-endemic region of The Gambia where sickle cell trait was also common.

The children received iron (12 mg/day) through micronutrient powder for 84 days, and the researchers analyzed the children’s red blood cells at baseline, day 49, and day 84.

The team conducted in vitro growth and invasion assays with P falciparum laboratory and field strains. The study’s primary endpoint was in vitro parasite growth in the children’s RBCs.

The researchers found that “anemia substantially reduced the invasion and growth of both laboratory and field strains of P falciparum.” The team noted a roughly 10% growth reduction per standard deviation shift in hemoglobin.

On a population-wide basis, anemia reduced the blood stage of malaria by 15.9%, while the sickle cell trait reduced it by 3.5%.

“Our finding that anemia offers greater natural protection against blood-stage malaria infection than sickle cell trait has led us to formulate the interesting hypothesis that the widespread prevalence of anemia in people of African descent is a genetic signature of malaria,” said study author Morgan Goheen, PhD, of University of North Carolina in Chapel Hill.

The researchers also found that deficits in invasion and growth for blood-stage P falciparum were reversed when anemic children had received 7 weeks of iron supplementation. Parasite growth was 2.4-fold higher after supplementation than it was at baseline (P<0.001).

Prior work by the same research group suggested the increased invasion and growth rates following iron supplementation are caused by the parasites’ strong preference for young red blood cells.

The researchers said these new field results consolidate the evidence that iron supplementation increases the risk of P falciparum malaria and provide support for the use of malaria prophylaxis in

conjunction with iron supplementation, especially during the early

phases of erythroid recovery.

Antihemophilic factor

The European Commission has granted marketing authorization for lonoctocog alfa (Afstyla), a recombinant factor VIII (FVIII) single-chain therapy.

Lonoctocog alfa is indicated for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.

Lonoctocog alfa is the first and only single-chain recombinant FVIII therapy for hemophilia A specifically designed to provide long-lasting protection from bleeds with 2- to 3-times weekly dosing, according to CSL Behring, the company developing the product.

The company says lonoctocog alfa uses a covalent bond that forms one structural entity—a single polypeptide chain—to improve the stability of FVIII and provide FVIII activity with the option of twice-weekly dosing.

According to CSL Behring, lonoctocog alfa will be launched in European markets in the coming months, as market access is obtained.

Lonoctocog alfa is also approved for use in the US and Canada.

Regulatory submissions for lonoctocog alfa are based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12. 

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to FVIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.*

O et al; rVIII-SingleChain, results of the pivotal efficacy data from a

phase III PK, efficacy and safety clinical study in children less than

12 years of age with severe hemophilia A; WFH 2016 World Congress, July

2016.

Antihemophilic factor

The European Commission has granted marketing authorization for lonoctocog alfa (Afstyla), a recombinant factor VIII (FVIII) single-chain therapy.

Lonoctocog alfa is indicated for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.

Lonoctocog alfa is the first and only single-chain recombinant FVIII therapy for hemophilia A specifically designed to provide long-lasting protection from bleeds with 2- to 3-times weekly dosing, according to CSL Behring, the company developing the product.

The company says lonoctocog alfa uses a covalent bond that forms one structural entity—a single polypeptide chain—to improve the stability of FVIII and provide FVIII activity with the option of twice-weekly dosing.

According to CSL Behring, lonoctocog alfa will be launched in European markets in the coming months, as market access is obtained.

Lonoctocog alfa is also approved for use in the US and Canada.

Regulatory submissions for lonoctocog alfa are based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12. 

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to FVIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.*

O et al; rVIII-SingleChain, results of the pivotal efficacy data from a

phase III PK, efficacy and safety clinical study in children less than

12 years of age with severe hemophilia A; WFH 2016 World Congress, July

2016.

Antihemophilic factor

The European Commission has granted marketing authorization for lonoctocog alfa (Afstyla), a recombinant factor VIII (FVIII) single-chain therapy.

Lonoctocog alfa is indicated for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.

Lonoctocog alfa is the first and only single-chain recombinant FVIII therapy for hemophilia A specifically designed to provide long-lasting protection from bleeds with 2- to 3-times weekly dosing, according to CSL Behring, the company developing the product.

The company says lonoctocog alfa uses a covalent bond that forms one structural entity—a single polypeptide chain—to improve the stability of FVIII and provide FVIII activity with the option of twice-weekly dosing.

According to CSL Behring, lonoctocog alfa will be launched in European markets in the coming months, as market access is obtained.

Lonoctocog alfa is also approved for use in the US and Canada.

Regulatory submissions for lonoctocog alfa are based on results from the AFFINITY clinical development program, which includes a trial of children (n=84) and a trial of adolescents and adults (n=175).

Among patients who received lonoctocog alfa prophylactically in these trials, the median annualized bleeding rate was 1.14 in the adults/adolescents and 3.69 in children younger than 12. 

In all, there were 1195 bleeding events—848 in the adults/adolescents and 347 in the children.

Ninety-four percent of bleeds in adults/adolescents and 96% of bleeds in pediatric patients were effectively controlled with no more than 2 infusions of lonoctocog alfa weekly.

Eighty-one percent of bleeds in adults/adolescents and 86% of bleeds in pediatric patients were controlled by a single infusion.

Researchers assessed safety in 258 patients from both studies. Adverse reactions occurred in 14 patients and included hypersensitivity (n=4), dizziness (n=2), paresthesia (n=1), rash (n=1), erythema (n=1), pruritus (n=1), pyrexia (n=1), injection-site pain (n=1), chills (n=1), and feeling hot (n=1).

One patient withdrew from treatment due to hypersensitivity.

None of the patients developed neutralizing antibodies to FVIII or antibodies to host cell proteins. There were no reports of anaphylaxis or thrombosis.

Results from the trial of adolescents/adults were published in Blood in August 2016. Results from the trial of children were presented at the World Federation of Hemophilia 2016 World Congress in July 2016.*

O et al; rVIII-SingleChain, results of the pivotal efficacy data from a

phase III PK, efficacy and safety clinical study in children less than

12 years of age with severe hemophilia A; WFH 2016 World Congress, July

2016.

Q)I overheard a conversation at the hospital in which one of the nephrologists told an internist that allopurinol is better than other medications for treating gout because it slows the progression of chronic kidney disease (CKD). What does the data say?

CKD is a growing problem in America; the number of adults with CKD doubled from 2000 to 2008.¹ Gout is considered an independent risk factor for CKD progression.² Some randomized controlled trials (RCTs) have shown an association between allopurinol use and decreased proteinuria.³

A recent large retrospective review of Medicare charts assessed the correlation between use and dose of allopurinol and incidence of renal failure in patients older than 65.¹ The researchers found that, compared with lower doses, allopurinol doses of 200 to 299 mg/d and > 300 mg/d were associated with a significantly lower hazard ratio for kidney failure, in a multivariate-adjusted model. The findings therefore suggest that doses > 199 mg may slow progression to kidney failure in the elderly.

Despite the strengths of this study, it is worth noting that it did not consider stage of kidney disease, nor did it distinguish comorbidities of the patients. The retrospective chart review format did not allow for identification of concurrent medication use (including OTC and herbal products).

The National Institute of Diabetes and Digestive and Kidney Diseases is currently conducting an RCT to investigate the renoprotective effects of allopurinol versus placebo in diabetic patients. (Clinical Trials.gov identifier: NCT02017171). Enrollment was completed in 2014, and results are expected in June 2019.

One important proviso about allopurinol: While it is inexpensive and generally well tolerated, prescribers should be aware of rare sensitivity reactions, particularly Stevens-Johnson syndrome. —MRS

Mary Rogers Sorey, MSN
Division of Nephrology and Hypertension at Vanderbilt University Medical Center, Nashville

Q)I overheard a conversation at the hospital in which one of the nephrologists told an internist that allopurinol is better than other medications for treating gout because it slows the progression of chronic kidney disease (CKD). What does the data say?

CKD is a growing problem in America; the number of adults with CKD doubled from 2000 to 2008.¹ Gout is considered an independent risk factor for CKD progression.² Some randomized controlled trials (RCTs) have shown an association between allopurinol use and decreased proteinuria.³

A recent large retrospective review of Medicare charts assessed the correlation between use and dose of allopurinol and incidence of renal failure in patients older than 65.¹ The researchers found that, compared with lower doses, allopurinol doses of 200 to 299 mg/d and > 300 mg/d were associated with a significantly lower hazard ratio for kidney failure, in a multivariate-adjusted model. The findings therefore suggest that doses > 199 mg may slow progression to kidney failure in the elderly.

Despite the strengths of this study, it is worth noting that it did not consider stage of kidney disease, nor did it distinguish comorbidities of the patients. The retrospective chart review format did not allow for identification of concurrent medication use (including OTC and herbal products).

The National Institute of Diabetes and Digestive and Kidney Diseases is currently conducting an RCT to investigate the renoprotective effects of allopurinol versus placebo in diabetic patients. (Clinical Trials.gov identifier: NCT02017171). Enrollment was completed in 2014, and results are expected in June 2019.

One important proviso about allopurinol: While it is inexpensive and generally well tolerated, prescribers should be aware of rare sensitivity reactions, particularly Stevens-Johnson syndrome. —MRS

Mary Rogers Sorey, MSN
Division of Nephrology and Hypertension at Vanderbilt University Medical Center, Nashville

Q)I overheard a conversation at the hospital in which one of the nephrologists told an internist that allopurinol is better than other medications for treating gout because it slows the progression of chronic kidney disease (CKD). What does the data say?

CKD is a growing problem in America; the number of adults with CKD doubled from 2000 to 2008.¹ Gout is considered an independent risk factor for CKD progression.² Some randomized controlled trials (RCTs) have shown an association between allopurinol use and decreased proteinuria.³

A recent large retrospective review of Medicare charts assessed the correlation between use and dose of allopurinol and incidence of renal failure in patients older than 65.¹ The researchers found that, compared with lower doses, allopurinol doses of 200 to 299 mg/d and > 300 mg/d were associated with a significantly lower hazard ratio for kidney failure, in a multivariate-adjusted model. The findings therefore suggest that doses > 199 mg may slow progression to kidney failure in the elderly.

Despite the strengths of this study, it is worth noting that it did not consider stage of kidney disease, nor did it distinguish comorbidities of the patients. The retrospective chart review format did not allow for identification of concurrent medication use (including OTC and herbal products).

The National Institute of Diabetes and Digestive and Kidney Diseases is currently conducting an RCT to investigate the renoprotective effects of allopurinol versus placebo in diabetic patients. (Clinical Trials.gov identifier: NCT02017171). Enrollment was completed in 2014, and results are expected in June 2019.

One important proviso about allopurinol: While it is inexpensive and generally well tolerated, prescribers should be aware of rare sensitivity reactions, particularly Stevens-Johnson syndrome. —MRS

Mary Rogers Sorey, MSN
Division of Nephrology and Hypertension at Vanderbilt University Medical Center, Nashville

Explantation of mesh used in ventral hernia repair occurs in approximately 1 of every 1,000 surgeries, but it’s a “hidden” morbidity because it almost always happens well after the 30- to 90-day window in which postoperative complications are typically reported in most registries and surveillance systems, according to a report in the Journal of the American College of Surgeons.

Mesh explantation usually occurs 1-3 years after implantation and triples the operative costs of the original ventral hernia repair. The rate of 1 per 1,000 surgeries and the massive increase in cost are comparable with those of occult injury of the common bile duct during cholecystectomy that later requires biliary reconstruction. But mesh explantation doesn’t generate the “profound attention” accorded to bile duct injury, perhaps because it develops much later in the postoperative course.

“It is surprising that mesh complications have not yet prompted similar concern,” said Kristy Kummerow Broman, MD, of the department of surgery, Vanderbilt University Medical Center, Nashville, Tenn., and her associates.

Until now, the frequency and cost of mesh explantation after ventral hernia repair in the general population have not been known. To make a reasonable estimate, the investigators constructed a cohort of 619,751 patients using information from inpatient and surgery databases for New York, California, and Florida between 2005 and 2011. Most of these were open procedures (91%), while 9% were laparoscopic.

During a mean follow-up of 3 years, 438 patients (0.7 per 1,000) underwent mesh explantation. This is a clinically significant incidence, and is likely an underestimate because ICD-9 and CPT coding for mesh removal is highly variable, Dr. Broman and her associates said.

This rate, for just three states during 3 years of follow-up, is nearly twice as high as the rate of mesh-related complications voluntarily reported to the FDA in post-marketing surveillance for the entire country during a 7-year period, they noted (J Am Coll Surg. 2017 Jan;224:35-42).

“It is paramount” that surgeons, manufacturers, and regulatory groups advocate mandatory reporting and “extend the surveillance for at least 1-3 years after implantation of a mesh device,” Dr. Broman and her associates said.

In this study, the median time to explantation was approximately 1 year (range, 2 days to 6 years), and 80% of explantations occurred within 2 years.

The median cumulative operative cost – excluding physician fees, nonsurgical medical costs, and the costs of patient disability and lost productivity – were $21,889 for patients requiring mesh explantation, compared with only $6,579 for those who did not. This finding highlights “the profound long-term implications of implantable devices in abdominal wall reconstruction,” they noted.

To put their findings in context, the investigators reviewed the literature regarding major bile duct injury during cholecystectomy. One large study on cases from 2001 to 2011 found that the rate of biliary reconstruction was comparable with that of explantation, at 0.8 to 1.1 per 1,000. Similarly, reoperation for bile duct injury approximately tripled the operative costs ($9,061 for patients who required biliary reconstruction vs $2,689 for those who didn’t). However, the $21,000 for mesh reoperation far exceeds the $9,000 for biliary reoperation.

This study was supported by the Department of Veterans Affairs, the VA Tennessee Valley Healthcare System, and the Americas Hernia Society Quality Collaborative. Dr. Broman reported having no relevant financial disclosures; her associates reported ties to Intuitive Surgical Solutions, Bard Davol, Ariste Medical, and Pfizer.

Explantation of mesh used in ventral hernia repair occurs in approximately 1 of every 1,000 surgeries, but it’s a “hidden” morbidity because it almost always happens well after the 30- to 90-day window in which postoperative complications are typically reported in most registries and surveillance systems, according to a report in the Journal of the American College of Surgeons.

Mesh explantation usually occurs 1-3 years after implantation and triples the operative costs of the original ventral hernia repair. The rate of 1 per 1,000 surgeries and the massive increase in cost are comparable with those of occult injury of the common bile duct during cholecystectomy that later requires biliary reconstruction. But mesh explantation doesn’t generate the “profound attention” accorded to bile duct injury, perhaps because it develops much later in the postoperative course.

“It is surprising that mesh complications have not yet prompted similar concern,” said Kristy Kummerow Broman, MD, of the department of surgery, Vanderbilt University Medical Center, Nashville, Tenn., and her associates.

Until now, the frequency and cost of mesh explantation after ventral hernia repair in the general population have not been known. To make a reasonable estimate, the investigators constructed a cohort of 619,751 patients using information from inpatient and surgery databases for New York, California, and Florida between 2005 and 2011. Most of these were open procedures (91%), while 9% were laparoscopic.

During a mean follow-up of 3 years, 438 patients (0.7 per 1,000) underwent mesh explantation. This is a clinically significant incidence, and is likely an underestimate because ICD-9 and CPT coding for mesh removal is highly variable, Dr. Broman and her associates said.

This rate, for just three states during 3 years of follow-up, is nearly twice as high as the rate of mesh-related complications voluntarily reported to the FDA in post-marketing surveillance for the entire country during a 7-year period, they noted (J Am Coll Surg. 2017 Jan;224:35-42).

“It is paramount” that surgeons, manufacturers, and regulatory groups advocate mandatory reporting and “extend the surveillance for at least 1-3 years after implantation of a mesh device,” Dr. Broman and her associates said.

In this study, the median time to explantation was approximately 1 year (range, 2 days to 6 years), and 80% of explantations occurred within 2 years.

The median cumulative operative cost – excluding physician fees, nonsurgical medical costs, and the costs of patient disability and lost productivity – were $21,889 for patients requiring mesh explantation, compared with only $6,579 for those who did not. This finding highlights “the profound long-term implications of implantable devices in abdominal wall reconstruction,” they noted.

To put their findings in context, the investigators reviewed the literature regarding major bile duct injury during cholecystectomy. One large study on cases from 2001 to 2011 found that the rate of biliary reconstruction was comparable with that of explantation, at 0.8 to 1.1 per 1,000. Similarly, reoperation for bile duct injury approximately tripled the operative costs ($9,061 for patients who required biliary reconstruction vs $2,689 for those who didn’t). However, the $21,000 for mesh reoperation far exceeds the $9,000 for biliary reoperation.

This study was supported by the Department of Veterans Affairs, the VA Tennessee Valley Healthcare System, and the Americas Hernia Society Quality Collaborative. Dr. Broman reported having no relevant financial disclosures; her associates reported ties to Intuitive Surgical Solutions, Bard Davol, Ariste Medical, and Pfizer.

Explantation of mesh used in ventral hernia repair occurs in approximately 1 of every 1,000 surgeries, but it’s a “hidden” morbidity because it almost always happens well after the 30- to 90-day window in which postoperative complications are typically reported in most registries and surveillance systems, according to a report in the Journal of the American College of Surgeons.

Mesh explantation usually occurs 1-3 years after implantation and triples the operative costs of the original ventral hernia repair. The rate of 1 per 1,000 surgeries and the massive increase in cost are comparable with those of occult injury of the common bile duct during cholecystectomy that later requires biliary reconstruction. But mesh explantation doesn’t generate the “profound attention” accorded to bile duct injury, perhaps because it develops much later in the postoperative course.

“It is surprising that mesh complications have not yet prompted similar concern,” said Kristy Kummerow Broman, MD, of the department of surgery, Vanderbilt University Medical Center, Nashville, Tenn., and her associates.

Until now, the frequency and cost of mesh explantation after ventral hernia repair in the general population have not been known. To make a reasonable estimate, the investigators constructed a cohort of 619,751 patients using information from inpatient and surgery databases for New York, California, and Florida between 2005 and 2011. Most of these were open procedures (91%), while 9% were laparoscopic.

During a mean follow-up of 3 years, 438 patients (0.7 per 1,000) underwent mesh explantation. This is a clinically significant incidence, and is likely an underestimate because ICD-9 and CPT coding for mesh removal is highly variable, Dr. Broman and her associates said.

This rate, for just three states during 3 years of follow-up, is nearly twice as high as the rate of mesh-related complications voluntarily reported to the FDA in post-marketing surveillance for the entire country during a 7-year period, they noted (J Am Coll Surg. 2017 Jan;224:35-42).

“It is paramount” that surgeons, manufacturers, and regulatory groups advocate mandatory reporting and “extend the surveillance for at least 1-3 years after implantation of a mesh device,” Dr. Broman and her associates said.

In this study, the median time to explantation was approximately 1 year (range, 2 days to 6 years), and 80% of explantations occurred within 2 years.

The median cumulative operative cost – excluding physician fees, nonsurgical medical costs, and the costs of patient disability and lost productivity – were $21,889 for patients requiring mesh explantation, compared with only $6,579 for those who did not. This finding highlights “the profound long-term implications of implantable devices in abdominal wall reconstruction,” they noted.

To put their findings in context, the investigators reviewed the literature regarding major bile duct injury during cholecystectomy. One large study on cases from 2001 to 2011 found that the rate of biliary reconstruction was comparable with that of explantation, at 0.8 to 1.1 per 1,000. Similarly, reoperation for bile duct injury approximately tripled the operative costs ($9,061 for patients who required biliary reconstruction vs $2,689 for those who didn’t). However, the $21,000 for mesh reoperation far exceeds the $9,000 for biliary reoperation.

This study was supported by the Department of Veterans Affairs, the VA Tennessee Valley Healthcare System, and the Americas Hernia Society Quality Collaborative. Dr. Broman reported having no relevant financial disclosures; her associates reported ties to Intuitive Surgical Solutions, Bard Davol, Ariste Medical, and Pfizer.

Compared with midweight mesh, lightweight mesh was associated with more surgical site infection and longer hospital stay following open ventral hernia repair, according to a report published in the American Journal of Surgery.

In addition, lightweight mesh was associated with greater pain, more limitation of movement, and poorer quality of life for up to 2 years after the procedure, compared with midweight mesh.

Compared with midweight mesh, lightweight mesh was associated with more surgical site infection and longer hospital stay following open ventral hernia repair, according to a report published in the American Journal of Surgery.

In addition, lightweight mesh was associated with greater pain, more limitation of movement, and poorer quality of life for up to 2 years after the procedure, compared with midweight mesh.

Compared with midweight mesh, lightweight mesh was associated with more surgical site infection and longer hospital stay following open ventral hernia repair, according to a report published in the American Journal of Surgery.

In addition, lightweight mesh was associated with greater pain, more limitation of movement, and poorer quality of life for up to 2 years after the procedure, compared with midweight mesh.