Polypharmacy, the practice of taking multiple medications to manage health conditions, is common for children. Many children today have a higher burden chronic illness and an increasing number of pharmaceuticals—often delivered in various doses throughout the day. Polypharmacy has been linked to a variety of pediatric and adult outcomes, including medication errors and readmission.^1-3 Consequently, the Society of Hospital Medicine recognizes polypharmacy as a risk factor for readmission for adult populations.⁴ These adverse outcomes are related to both the human elements of polypharmacy (eg, cognitive burden, adherence) and the pharmacologic elements, including drug–drug interactions. For many children, the safety implications of polypharmacy may be more consequential due to the reliance of multiple caregivers to administer medications, which requires additional coordination to ensure that medications are administered and not duplicated. Dual administration of the same medication by both parents is the most common reason for pediatric calls to Poison Control Centers.⁵ Yet, there is a paucity of research in this area, with most of the pediatric literature focusing on the outpatient setting and specific populations, including epilepsy and mental health.^6-8

How providers, patients, and families translate medication lists to counts of medications—and hence the burden of polypharmacy—is not clearly or consistently described. Often in studies of polypharmacy, researchers utilize medication claims data to count the number of medications a patient has filled from the pharmacy. However, in routine clinical practice, clinicians rarely have access to medication claims and thus rely on patient or family report, which may or may not match the list of medications in the patients’ medical records.

Therefore, linking polypharmacy research to the pragmatic complexities of clinical care requires greater clarity and consistent application of concepts. At hospital discharge, families receive a list of medications to take, including home medications to resume as well as newly prescribed medications. However, not all medications are equally essential to patients’ care regarding importance of administration (eg, hydrocortisone ointment versus an anticonvulsant medication). Patients, parents, and caregivers are ultimately responsible for determining which medications to prioritize and administer.

Although there is no standard numerical definition for how to identify polypharmacy, five medications is commonly considered the threshold for polypharmacy.⁹ A recent review of the pediatric polypharmacy literature suggested a lower threshold, with any two concurrent medications for at least a day.⁷ Yet, the best approach to “count” medications at hospital discharge is unclear. The simplest method is to tally the number of medications listed in the discharge summary. However, medications are sometimes listed twice due to different dosages administered at different times. Frequently, medications are prescribed on an as-needed basis; these medications could be administered routinely or very infrequently (eg, epinephrine for anaphylaxis). Over-the-counter medications are also sometimes included in discharge summaries and consideration should be given as to whether these medications count toward measures of polypharmacy. Over-the-counter medications would not be counted by a polypharmacy measure that relies on claims data if those medications are not paid by the insurer.

We sought consensus on how to count discharge medications through a series of informal interviews with hospitalists, nurses, and parents. We asked the seemingly simple question, “How many medications is this child on?” across a variety of scenarios (Figure). For panel A, all stakeholders agreed that this medication list includes two medications. All other scenarios elicited disagreement. For panel B, many people responded three medications, but others (often physicians) counted only clindamycin and therefore responded one medication.

Disclosures

Dr. Auger has nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine. Dr. Davis has nothing to disclose. Dr. Brady reports grants from Agency for Healthcare Research and Quality, outside the submitted work.

Funding

This project is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1).

Polypharmacy, the practice of taking multiple medications to manage health conditions, is common for children. Many children today have a higher burden chronic illness and an increasing number of pharmaceuticals—often delivered in various doses throughout the day. Polypharmacy has been linked to a variety of pediatric and adult outcomes, including medication errors and readmission.^1-3 Consequently, the Society of Hospital Medicine recognizes polypharmacy as a risk factor for readmission for adult populations.⁴ These adverse outcomes are related to both the human elements of polypharmacy (eg, cognitive burden, adherence) and the pharmacologic elements, including drug–drug interactions. For many children, the safety implications of polypharmacy may be more consequential due to the reliance of multiple caregivers to administer medications, which requires additional coordination to ensure that medications are administered and not duplicated. Dual administration of the same medication by both parents is the most common reason for pediatric calls to Poison Control Centers.⁵ Yet, there is a paucity of research in this area, with most of the pediatric literature focusing on the outpatient setting and specific populations, including epilepsy and mental health.^6-8

How providers, patients, and families translate medication lists to counts of medications—and hence the burden of polypharmacy—is not clearly or consistently described. Often in studies of polypharmacy, researchers utilize medication claims data to count the number of medications a patient has filled from the pharmacy. However, in routine clinical practice, clinicians rarely have access to medication claims and thus rely on patient or family report, which may or may not match the list of medications in the patients’ medical records.

Therefore, linking polypharmacy research to the pragmatic complexities of clinical care requires greater clarity and consistent application of concepts. At hospital discharge, families receive a list of medications to take, including home medications to resume as well as newly prescribed medications. However, not all medications are equally essential to patients’ care regarding importance of administration (eg, hydrocortisone ointment versus an anticonvulsant medication). Patients, parents, and caregivers are ultimately responsible for determining which medications to prioritize and administer.

Although there is no standard numerical definition for how to identify polypharmacy, five medications is commonly considered the threshold for polypharmacy.⁹ A recent review of the pediatric polypharmacy literature suggested a lower threshold, with any two concurrent medications for at least a day.⁷ Yet, the best approach to “count” medications at hospital discharge is unclear. The simplest method is to tally the number of medications listed in the discharge summary. However, medications are sometimes listed twice due to different dosages administered at different times. Frequently, medications are prescribed on an as-needed basis; these medications could be administered routinely or very infrequently (eg, epinephrine for anaphylaxis). Over-the-counter medications are also sometimes included in discharge summaries and consideration should be given as to whether these medications count toward measures of polypharmacy. Over-the-counter medications would not be counted by a polypharmacy measure that relies on claims data if those medications are not paid by the insurer.

We sought consensus on how to count discharge medications through a series of informal interviews with hospitalists, nurses, and parents. We asked the seemingly simple question, “How many medications is this child on?” across a variety of scenarios (Figure). For panel A, all stakeholders agreed that this medication list includes two medications. All other scenarios elicited disagreement. For panel B, many people responded three medications, but others (often physicians) counted only clindamycin and therefore responded one medication.

Disclosures

Dr. Auger has nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine. Dr. Davis has nothing to disclose. Dr. Brady reports grants from Agency for Healthcare Research and Quality, outside the submitted work.

Funding

This project is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1).

Polypharmacy, the practice of taking multiple medications to manage health conditions, is common for children. Many children today have a higher burden chronic illness and an increasing number of pharmaceuticals—often delivered in various doses throughout the day. Polypharmacy has been linked to a variety of pediatric and adult outcomes, including medication errors and readmission.^1-3 Consequently, the Society of Hospital Medicine recognizes polypharmacy as a risk factor for readmission for adult populations.⁴ These adverse outcomes are related to both the human elements of polypharmacy (eg, cognitive burden, adherence) and the pharmacologic elements, including drug–drug interactions. For many children, the safety implications of polypharmacy may be more consequential due to the reliance of multiple caregivers to administer medications, which requires additional coordination to ensure that medications are administered and not duplicated. Dual administration of the same medication by both parents is the most common reason for pediatric calls to Poison Control Centers.⁵ Yet, there is a paucity of research in this area, with most of the pediatric literature focusing on the outpatient setting and specific populations, including epilepsy and mental health.^6-8

How providers, patients, and families translate medication lists to counts of medications—and hence the burden of polypharmacy—is not clearly or consistently described. Often in studies of polypharmacy, researchers utilize medication claims data to count the number of medications a patient has filled from the pharmacy. However, in routine clinical practice, clinicians rarely have access to medication claims and thus rely on patient or family report, which may or may not match the list of medications in the patients’ medical records.

Therefore, linking polypharmacy research to the pragmatic complexities of clinical care requires greater clarity and consistent application of concepts. At hospital discharge, families receive a list of medications to take, including home medications to resume as well as newly prescribed medications. However, not all medications are equally essential to patients’ care regarding importance of administration (eg, hydrocortisone ointment versus an anticonvulsant medication). Patients, parents, and caregivers are ultimately responsible for determining which medications to prioritize and administer.

Although there is no standard numerical definition for how to identify polypharmacy, five medications is commonly considered the threshold for polypharmacy.⁹ A recent review of the pediatric polypharmacy literature suggested a lower threshold, with any two concurrent medications for at least a day.⁷ Yet, the best approach to “count” medications at hospital discharge is unclear. The simplest method is to tally the number of medications listed in the discharge summary. However, medications are sometimes listed twice due to different dosages administered at different times. Frequently, medications are prescribed on an as-needed basis; these medications could be administered routinely or very infrequently (eg, epinephrine for anaphylaxis). Over-the-counter medications are also sometimes included in discharge summaries and consideration should be given as to whether these medications count toward measures of polypharmacy. Over-the-counter medications would not be counted by a polypharmacy measure that relies on claims data if those medications are not paid by the insurer.

We sought consensus on how to count discharge medications through a series of informal interviews with hospitalists, nurses, and parents. We asked the seemingly simple question, “How many medications is this child on?” across a variety of scenarios (Figure). For panel A, all stakeholders agreed that this medication list includes two medications. All other scenarios elicited disagreement. For panel B, many people responded three medications, but others (often physicians) counted only clindamycin and therefore responded one medication.

Disclosures

Dr. Auger has nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine. Dr. Davis has nothing to disclose. Dr. Brady reports grants from Agency for Healthcare Research and Quality, outside the submitted work.

Funding

This project is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1).

Anticoagulation for patients with venous thromboembolism (VTE) is associated not only with considerable benefits, including prevention of pulmonary embolus and thrombus extension, but also with potential significant risks, such as life-threatening bleeding.¹ Hospitalized patients may require anticoagulation to treat new VTE or for secondary prevention of prior events. Hospital admission is a high-risk time for anticoagulation control.² Additionally, anticoagulation has become an increasingly complex decision as the number of therapeutic agents on the market has significantly increased, coupled with medication interactions and dosing intricacies. Management is multifaceted and associated with wide variation in practice patterns.³ Thus, further evidence-based guidance for providers is necessary for the care of the hospitalized patient with VTE.

The following are 16 selected guideline recommendations most relevant to adult hospitalists.⁴ Recommendations were graded as “strong” if most individuals should follow the recommended course of action and “conditional” if different choices are appropriate for different patients.

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

(for all recommendations–evidence quality: low certainty; recommendation strength: conditional)

Recommendation 1. In obese patients receiving low molecular weight heparin (LMWH), determine the initial dose based on actual body weight rather than a fixed or “capped” maximum dose.

Recommendation 2. For obese patients or those with renal dysfunction receiving LMWH, avoid dosing based on serum antifactor Xa levels. Instead, adjust dosing based on product labeling, with appropriate dose reduction in patients with chronic kidney disease.

Recommendation 3. For patients receiving direct oral anticoagulant (DOAC) therapy, avoid measuring the anticoagulation effect during management of bleeding as there is no evidence to support a beneficial effect, and it may result in a delay in treatment.

Recommendation 4. For patients requiring administration of inhibitors or inducers of P-glycoprotein or cytochrome P450 enzymes, use LMWH or vitamin K antagonists (VKA) rather than a DOAC.

Recommendation 5. When transitioning from a DOAC to a VKA, the medications should overlap until the international normalized ratio (INR) is therapeutic instead of bridging with a heparin agent.

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

Recommendation 6. Use point-of-care INR testing by patients at home, with self-adjustment of VKA dose (evidence quality: low certainty; recommendation strength: strong).

Recommendation 7. Patients should be referred for specialized anticoagulation management rather than to their primary care provider (PCP) (evidence quality: very low certainty; recommendation strength: conditional).

Recommendation 8. Supplementary education, in addition to basic education, should be made available to patients to help improve outcomes (evidence quality: very low certainty; recommendation strength: conditional).

Hospitalists are often responsible for the coordination of care upon discharge from the hospital, including discharge teaching, subspecialty referrals, and determination of patient suitability for home monitoring and dose adjustment. The follow-up plan may depend on local systems and access. A PCP can manage anticoagulation if performed in a systematic and coordinated fashion.⁵

Recommendations for Patients on Anticoagulation Undergoing Procedures

Recommendation 9. For patients with a low or moderate risk of recurrent VTE on VKA therapy undergoing procedures, periprocedural bridging with heparin or LMWH should be avoided. This excludes patients at high risk for recurrent VTE, defined as those with recent VTE (<3 months); having a known thrombophilic abnormality such as antiphospholipid syndrome, protein C/S deficiency, or antithrombin deficiency; or high-risk patient populations by expert consensus and practice guidelines^4,6 (evidence quality: moderate certainty; recommendation strength: strong).

Recommendation 10. For patients on DOACs undergoing procedures, measurement of the anticoagulation effect of the DOAC should be avoided (evidence quality: very low certainty; recommendation strength: conditional).

Recommendations for Patients on Anticoagulation Suffering from Supratherapeutic Levels or Bleeding Complications

(for all recommendations–evidence quality: very low certainty; recommendation strength: conditional)

Recommendation 11. If a patient on VKA therapy has an INR between 4.5 and 10 without clinically relevant bleeding, the use of vitamin K therapy can be avoided in favor of temporary cessation of VKA alone.

Recommendation 12. If a patient on VKA therapy has life-threatening bleeding, four-factor prothrombin complex concentrate (PCC) should be used in addition to the cessation of VKA therapy and initiation of vitamin K therapy, over the use of fresh frozen plaza, because of the ease of administration and minimal risk of volume overload.

Recommendation 13. If a patient has life-threatening bleeding on a Xa inhibitor, the panel recommends discontinuation of the medication and the option to administer either PCC or recombinant coagulation factor Xa, as there have been no studies comparing these two strategies.

Recommendation 14. If life-threatening bleeding occurs in a patient on dabigatran, idarucizumab should be administered, if available.

Recommendation 15. In patients with bleeding while on heparin or LMWH, protamine should be administered.

Recommendation 16. Following an episode of life-threatening bleeding, anticoagulation should be resumed within 90 days, provided that the patient is at moderate to high risk for recurrent VTE, is not at high risk for recurrent bleeding, and is willing to continue anticoagulation.

Methods in Preparing Guidelines

The panel was funded by the American Society of Hematology (ASH), a nonprofit medical specialty society.⁴ The panel is multidisciplinary, including physicians and providers as well as patient representatives, and is supported by the McMaster University GRADE Center, which conducted new and updated systematic reviews of the evidence according to the “Cochrane Handbook for Systematic Reviews of Interventions.” The panel members agreed on 25 recommendations and two good practice statements. The recommendations were made available to external review by stakeholders and addressed. Comments made by 10 individuals or organizations were subsequently incorporated.

Sources of Potential Conflict of Interest

Panel members, other than patient representatives, did not receive funding, and the majority of the panel had no conflicts of interest to report. Given the minimal influence of outside parties including pharmaceutical companies, and the wide diversity of opinions sought in the creation of the guidelines, concern for conflict of interest is low.

Generalizability

These guidelines assume that the decision to anticoagulate a patient, and which agent to use, has already been made and thus do not offer further guidance on this decision. These guidelines also do not address optimal choices for anticoagulation in specific patient populations, such as patients with cancer. They are limited in scope to exclude the treatment of specific thromboembolic disease processes such as subsegmental pulmonary emboli, superficial venous thrombus, or distal vein thrombosis. Unfortunately, challenging decisions made by hospitalists frequently fall into one of these categories. Coincident with these guidelines, ASH introduced comprehensive guidelines to support basic diagnostic decisions.⁷

More evidence is needed to better understand optimal monitoring practices for patients on anticoagulation therapy, including the ideal INR monitoring frequency for patients on VKA therapy. Additionally, there is a need to better understand the difference in clinical outcomes and resources utilization when care is provided by an anticoagulation specialist as compared with a PCP. Finally, while guidelines suggest that anticoagulation should be resumed within 90 days of a life-threatening bleed, there is a need to better understand the optimal timing of a restart, as well as the patient factors to be considered in this decision.

Disclosures

The authors have nothing to disclose.

Funding

There was no funding support in the creation of this manuscript.

Anticoagulation for patients with venous thromboembolism (VTE) is associated not only with considerable benefits, including prevention of pulmonary embolus and thrombus extension, but also with potential significant risks, such as life-threatening bleeding.¹ Hospitalized patients may require anticoagulation to treat new VTE or for secondary prevention of prior events. Hospital admission is a high-risk time for anticoagulation control.² Additionally, anticoagulation has become an increasingly complex decision as the number of therapeutic agents on the market has significantly increased, coupled with medication interactions and dosing intricacies. Management is multifaceted and associated with wide variation in practice patterns.³ Thus, further evidence-based guidance for providers is necessary for the care of the hospitalized patient with VTE.

The following are 16 selected guideline recommendations most relevant to adult hospitalists.⁴ Recommendations were graded as “strong” if most individuals should follow the recommended course of action and “conditional” if different choices are appropriate for different patients.

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

(for all recommendations–evidence quality: low certainty; recommendation strength: conditional)

Recommendation 1. In obese patients receiving low molecular weight heparin (LMWH), determine the initial dose based on actual body weight rather than a fixed or “capped” maximum dose.

Recommendation 2. For obese patients or those with renal dysfunction receiving LMWH, avoid dosing based on serum antifactor Xa levels. Instead, adjust dosing based on product labeling, with appropriate dose reduction in patients with chronic kidney disease.

Recommendation 3. For patients receiving direct oral anticoagulant (DOAC) therapy, avoid measuring the anticoagulation effect during management of bleeding as there is no evidence to support a beneficial effect, and it may result in a delay in treatment.

Recommendation 4. For patients requiring administration of inhibitors or inducers of P-glycoprotein or cytochrome P450 enzymes, use LMWH or vitamin K antagonists (VKA) rather than a DOAC.

Recommendation 5. When transitioning from a DOAC to a VKA, the medications should overlap until the international normalized ratio (INR) is therapeutic instead of bridging with a heparin agent.

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

Recommendation 6. Use point-of-care INR testing by patients at home, with self-adjustment of VKA dose (evidence quality: low certainty; recommendation strength: strong).

Recommendation 7. Patients should be referred for specialized anticoagulation management rather than to their primary care provider (PCP) (evidence quality: very low certainty; recommendation strength: conditional).

Recommendation 8. Supplementary education, in addition to basic education, should be made available to patients to help improve outcomes (evidence quality: very low certainty; recommendation strength: conditional).

Hospitalists are often responsible for the coordination of care upon discharge from the hospital, including discharge teaching, subspecialty referrals, and determination of patient suitability for home monitoring and dose adjustment. The follow-up plan may depend on local systems and access. A PCP can manage anticoagulation if performed in a systematic and coordinated fashion.⁵

Recommendations for Patients on Anticoagulation Undergoing Procedures

Recommendation 9. For patients with a low or moderate risk of recurrent VTE on VKA therapy undergoing procedures, periprocedural bridging with heparin or LMWH should be avoided. This excludes patients at high risk for recurrent VTE, defined as those with recent VTE (<3 months); having a known thrombophilic abnormality such as antiphospholipid syndrome, protein C/S deficiency, or antithrombin deficiency; or high-risk patient populations by expert consensus and practice guidelines^4,6 (evidence quality: moderate certainty; recommendation strength: strong).

Recommendation 10. For patients on DOACs undergoing procedures, measurement of the anticoagulation effect of the DOAC should be avoided (evidence quality: very low certainty; recommendation strength: conditional).

Recommendations for Patients on Anticoagulation Suffering from Supratherapeutic Levels or Bleeding Complications

(for all recommendations–evidence quality: very low certainty; recommendation strength: conditional)

Recommendation 11. If a patient on VKA therapy has an INR between 4.5 and 10 without clinically relevant bleeding, the use of vitamin K therapy can be avoided in favor of temporary cessation of VKA alone.

Recommendation 12. If a patient on VKA therapy has life-threatening bleeding, four-factor prothrombin complex concentrate (PCC) should be used in addition to the cessation of VKA therapy and initiation of vitamin K therapy, over the use of fresh frozen plaza, because of the ease of administration and minimal risk of volume overload.

Recommendation 13. If a patient has life-threatening bleeding on a Xa inhibitor, the panel recommends discontinuation of the medication and the option to administer either PCC or recombinant coagulation factor Xa, as there have been no studies comparing these two strategies.

Recommendation 14. If life-threatening bleeding occurs in a patient on dabigatran, idarucizumab should be administered, if available.

Recommendation 15. In patients with bleeding while on heparin or LMWH, protamine should be administered.

Recommendation 16. Following an episode of life-threatening bleeding, anticoagulation should be resumed within 90 days, provided that the patient is at moderate to high risk for recurrent VTE, is not at high risk for recurrent bleeding, and is willing to continue anticoagulation.

Methods in Preparing Guidelines

The panel was funded by the American Society of Hematology (ASH), a nonprofit medical specialty society.⁴ The panel is multidisciplinary, including physicians and providers as well as patient representatives, and is supported by the McMaster University GRADE Center, which conducted new and updated systematic reviews of the evidence according to the “Cochrane Handbook for Systematic Reviews of Interventions.” The panel members agreed on 25 recommendations and two good practice statements. The recommendations were made available to external review by stakeholders and addressed. Comments made by 10 individuals or organizations were subsequently incorporated.

Sources of Potential Conflict of Interest

Panel members, other than patient representatives, did not receive funding, and the majority of the panel had no conflicts of interest to report. Given the minimal influence of outside parties including pharmaceutical companies, and the wide diversity of opinions sought in the creation of the guidelines, concern for conflict of interest is low.

Generalizability

These guidelines assume that the decision to anticoagulate a patient, and which agent to use, has already been made and thus do not offer further guidance on this decision. These guidelines also do not address optimal choices for anticoagulation in specific patient populations, such as patients with cancer. They are limited in scope to exclude the treatment of specific thromboembolic disease processes such as subsegmental pulmonary emboli, superficial venous thrombus, or distal vein thrombosis. Unfortunately, challenging decisions made by hospitalists frequently fall into one of these categories. Coincident with these guidelines, ASH introduced comprehensive guidelines to support basic diagnostic decisions.⁷

More evidence is needed to better understand optimal monitoring practices for patients on anticoagulation therapy, including the ideal INR monitoring frequency for patients on VKA therapy. Additionally, there is a need to better understand the difference in clinical outcomes and resources utilization when care is provided by an anticoagulation specialist as compared with a PCP. Finally, while guidelines suggest that anticoagulation should be resumed within 90 days of a life-threatening bleed, there is a need to better understand the optimal timing of a restart, as well as the patient factors to be considered in this decision.

Disclosures

The authors have nothing to disclose.

Funding

There was no funding support in the creation of this manuscript.

Anticoagulation for patients with venous thromboembolism (VTE) is associated not only with considerable benefits, including prevention of pulmonary embolus and thrombus extension, but also with potential significant risks, such as life-threatening bleeding.¹ Hospitalized patients may require anticoagulation to treat new VTE or for secondary prevention of prior events. Hospital admission is a high-risk time for anticoagulation control.² Additionally, anticoagulation has become an increasingly complex decision as the number of therapeutic agents on the market has significantly increased, coupled with medication interactions and dosing intricacies. Management is multifaceted and associated with wide variation in practice patterns.³ Thus, further evidence-based guidance for providers is necessary for the care of the hospitalized patient with VTE.

The following are 16 selected guideline recommendations most relevant to adult hospitalists.⁴ Recommendations were graded as “strong” if most individuals should follow the recommended course of action and “conditional” if different choices are appropriate for different patients.

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

(for all recommendations–evidence quality: low certainty; recommendation strength: conditional)

Recommendation 1. In obese patients receiving low molecular weight heparin (LMWH), determine the initial dose based on actual body weight rather than a fixed or “capped” maximum dose.

Recommendation 2. For obese patients or those with renal dysfunction receiving LMWH, avoid dosing based on serum antifactor Xa levels. Instead, adjust dosing based on product labeling, with appropriate dose reduction in patients with chronic kidney disease.

Recommendation 3. For patients receiving direct oral anticoagulant (DOAC) therapy, avoid measuring the anticoagulation effect during management of bleeding as there is no evidence to support a beneficial effect, and it may result in a delay in treatment.

Recommendation 4. For patients requiring administration of inhibitors or inducers of P-glycoprotein or cytochrome P450 enzymes, use LMWH or vitamin K antagonists (VKA) rather than a DOAC.

Recommendation 5. When transitioning from a DOAC to a VKA, the medications should overlap until the international normalized ratio (INR) is therapeutic instead of bridging with a heparin agent.

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

Recommendation 6. Use point-of-care INR testing by patients at home, with self-adjustment of VKA dose (evidence quality: low certainty; recommendation strength: strong).

Recommendation 7. Patients should be referred for specialized anticoagulation management rather than to their primary care provider (PCP) (evidence quality: very low certainty; recommendation strength: conditional).

Recommendation 8. Supplementary education, in addition to basic education, should be made available to patients to help improve outcomes (evidence quality: very low certainty; recommendation strength: conditional).

Hospitalists are often responsible for the coordination of care upon discharge from the hospital, including discharge teaching, subspecialty referrals, and determination of patient suitability for home monitoring and dose adjustment. The follow-up plan may depend on local systems and access. A PCP can manage anticoagulation if performed in a systematic and coordinated fashion.⁵

Recommendations for Patients on Anticoagulation Undergoing Procedures

Recommendation 9. For patients with a low or moderate risk of recurrent VTE on VKA therapy undergoing procedures, periprocedural bridging with heparin or LMWH should be avoided. This excludes patients at high risk for recurrent VTE, defined as those with recent VTE (<3 months); having a known thrombophilic abnormality such as antiphospholipid syndrome, protein C/S deficiency, or antithrombin deficiency; or high-risk patient populations by expert consensus and practice guidelines^4,6 (evidence quality: moderate certainty; recommendation strength: strong).

Recommendation 10. For patients on DOACs undergoing procedures, measurement of the anticoagulation effect of the DOAC should be avoided (evidence quality: very low certainty; recommendation strength: conditional).

Recommendations for Patients on Anticoagulation Suffering from Supratherapeutic Levels or Bleeding Complications

(for all recommendations–evidence quality: very low certainty; recommendation strength: conditional)

Recommendation 11. If a patient on VKA therapy has an INR between 4.5 and 10 without clinically relevant bleeding, the use of vitamin K therapy can be avoided in favor of temporary cessation of VKA alone.

Recommendation 12. If a patient on VKA therapy has life-threatening bleeding, four-factor prothrombin complex concentrate (PCC) should be used in addition to the cessation of VKA therapy and initiation of vitamin K therapy, over the use of fresh frozen plaza, because of the ease of administration and minimal risk of volume overload.

Recommendation 13. If a patient has life-threatening bleeding on a Xa inhibitor, the panel recommends discontinuation of the medication and the option to administer either PCC or recombinant coagulation factor Xa, as there have been no studies comparing these two strategies.

Recommendation 14. If life-threatening bleeding occurs in a patient on dabigatran, idarucizumab should be administered, if available.

Recommendation 15. In patients with bleeding while on heparin or LMWH, protamine should be administered.

Recommendation 16. Following an episode of life-threatening bleeding, anticoagulation should be resumed within 90 days, provided that the patient is at moderate to high risk for recurrent VTE, is not at high risk for recurrent bleeding, and is willing to continue anticoagulation.

Methods in Preparing Guidelines

The panel was funded by the American Society of Hematology (ASH), a nonprofit medical specialty society.⁴ The panel is multidisciplinary, including physicians and providers as well as patient representatives, and is supported by the McMaster University GRADE Center, which conducted new and updated systematic reviews of the evidence according to the “Cochrane Handbook for Systematic Reviews of Interventions.” The panel members agreed on 25 recommendations and two good practice statements. The recommendations were made available to external review by stakeholders and addressed. Comments made by 10 individuals or organizations were subsequently incorporated.

Sources of Potential Conflict of Interest

Panel members, other than patient representatives, did not receive funding, and the majority of the panel had no conflicts of interest to report. Given the minimal influence of outside parties including pharmaceutical companies, and the wide diversity of opinions sought in the creation of the guidelines, concern for conflict of interest is low.

Generalizability

These guidelines assume that the decision to anticoagulate a patient, and which agent to use, has already been made and thus do not offer further guidance on this decision. These guidelines also do not address optimal choices for anticoagulation in specific patient populations, such as patients with cancer. They are limited in scope to exclude the treatment of specific thromboembolic disease processes such as subsegmental pulmonary emboli, superficial venous thrombus, or distal vein thrombosis. Unfortunately, challenging decisions made by hospitalists frequently fall into one of these categories. Coincident with these guidelines, ASH introduced comprehensive guidelines to support basic diagnostic decisions.⁷

More evidence is needed to better understand optimal monitoring practices for patients on anticoagulation therapy, including the ideal INR monitoring frequency for patients on VKA therapy. Additionally, there is a need to better understand the difference in clinical outcomes and resources utilization when care is provided by an anticoagulation specialist as compared with a PCP. Finally, while guidelines suggest that anticoagulation should be resumed within 90 days of a life-threatening bleed, there is a need to better understand the optimal timing of a restart, as well as the patient factors to be considered in this decision.

Disclosures

The authors have nothing to disclose.

Funding

There was no funding support in the creation of this manuscript.

Venous thromboembolism (VTE) occurs uncommonly in pediatrics, affecting 0.07-0.14 per 10,000 children.^1,2 Yet, in the last 20 years, the incidence of VTE in hospitalized children has increased dramatically to approximately 58 per 10,000 admissions.³ This increase may be attributed to improved survival of very ill children, better diagnostic imaging modalities, and heightened awareness by managing physicians.³ Randomized controlled trials are lacking in pediatric thrombosis, and clinical care is based on extrapolation of adult data and expert consensus guidelines.^4,5 In 2014, the American Society of Hematology (ASH) sought to develop comprehensive guidelines on thrombosis. The pediatric VTE treatment guideline is one of six published to date.

The following are five selected guideline recommendations thought most relevant to pediatric hospitalists. Three focus on the central venous access device (CVAD), since it is the most common risk factor for pediatric VTE.¹ Recommendations were graded as “strong” if most providers, patients, and policy makers agreed with the intervention and if it was supported by credible research. Conditional recommendations had less uniform agreement with an emphasis on individualized care and weighing patients’ values and preferences.⁶

Recommendation 1. It is recommended that pediatric patients receive anticoagulation, versus no anticoagulation, for symptomatic VTE (evidence quality: low certainty; recommendation strength: strong).

There is strong indirect data in adults that symptomatic VTE requires treatment, with limited direct evidence in children. As VTE occurs most commonly in ill, hospitalized children with the potential for VTE to be life threatening, the benefit was felt to justify the strong recommendation despite low-quality evidence.

The primary benefit of anticoagulation in children with symptomatic VTE is the prevention of progressive or recurrent thrombosis with high morbidity and the prevention of life-threatening VTE. The greatest potential harm from the use of anticoagulation, particularly in very ill children, is the risk for major bleeding.⁴Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).
Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).

The panel focused on the unique features of pediatric VTE related to the heterogeneity in both the site and pathophysiology of VTE in children, such as age, presence of a CVAD, and comorbidities. There is little certainty that treating asymptomatic VTE is beneficial in the same way that treating symptomatic VTE would be in preventing recurrent thrombosis and embolization.

Until better evidence is available to guide care, the primary benefit of this recommendation is individualization of care related to each patient’s risk-benefit profile and parental preferences.

Potential problems with using this recommendation include the cost of anticoagulant drugs and major bleeding if anticoagulation is used. Potential problems with not using anticoagulation would be progressive or recurrent thromboembolism. Close monitoring of children with VTE—regardless of whether anticoagulation is prescribed—is warranted.

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

Recommendations three through five pertain to CVAD-associated thrombosis, so they are reviewed together.

Recommendation 3. No removal of a functioning CVAD is suggested if venous access is still required (evidence quality: low certainty; recommendation strength: conditional).Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).

Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

CVAD is the most common precipitating factor for pediatric VTE, particularly in neonates and older children.¹ Based on limited direct and indirect observational studies, there is low evidence of benefit for CVAD removal, but high-quality indirect evidence of harm and high cost, which the panel felt justified the strong recommendation for removing an unneeded or nonfunctioning line. If ongoing care can be safely administered without central access, removing the thrombosis stimulus is recommended. The guideline suggests keeping a functioning CVAD in a patient who requires ongoing venous access and placing high value on avoiding new line insertion when access sites may be limited to avoid the potential thrombogenic effect of new line placement.

In the limited direct and indirect observational studies identified, the optimal timing of CVAD removal is uncertain. Given the potential risk of emboli leading to pulmonary embolism or stroke, prior publications have suggested delaying removal until after three to five days of anticoagulation, particularly in children with known or potential right-to-left shunts.⁴ The risk of infection and bleeding with anticoagulation prior to CVAD removal was considered small by the panel. This recommendation is primarily based on the panel’s anecdotal experience and first principles, which is a limitation.

Methods in Preparing Guideline. The panel included pediatric experts with clinical and research expertise in the guideline topic, including nine hematologists, one intensivist, one cardiologist, one hematology pharmacist, and one anticoagulation nurse practitioner. It also included two methodologists with evidence appraisal and guideline development expertise, as well as two patient representatives.

The panel brainstormed and prioritized questions to be addressed and selected outcomes of interest for each question. The McMaster University GRADE Centre vetted and retained researchers to conduct or update systematic evidence reviews and coordinate the guideline development using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.⁶ For each guideline question, the results of systematic reviews were summarized in GRADE Evidence-to-Decision tables. The evidence quality was categorized into four levels ranging from very low to high. For each recommendation developed, the panel agreed on the evidence quality, balance of benefits and harms of compared management options with consideration of resource use, and inferences regarding the potential associated values and preferences. The panel addressed 26 questions, which generated 30 recommendations.

Draft recommendations were made available online for review by stakeholders, including allied organizations, medical professionals, patients, and the public. Revisions were made to address pertinent submitted comments, but the recommendations were not changed. After approval by ASH, the guideline was subjected to peer review by Blood Advances.

Sources of Potential Conflict of Interest or Bias. The guideline was developed and funded by ASH. All participants’ conflicts of interest were managed according to ASH policies based on recommendations of the Institute of Medicine and the Guideline International Network. A majority of the guideline panel had no conflicts. During deliberations, panelists with direct financial interests were recused from making judgments about relevant recommendations. The McMaster University-affiliated researchers had no conflicts.Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Although there is increasing interest in pediatric VTE prevention and risk assessment,⁷ there is currently limited evidence on the best ways to mitigate VTE risk or anticoagulation-associated major bleeding in hospitalized children. The relatively low incidence of VTE in children makes large randomized controlled trials difficult, but several are ongoing. The Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT) multicenter, randomized trial will inform care on the optimal duration of anticoagulation in children with a transient provoking factor,⁸ and several phase III studies are investigating the safety and efficacy of direct oral anticoagulants in children (NCT02234843, NCT02464969, NCT01895777, NCT02234843). These and future trials will better inform therapy in pediatric VTE.

Disclosures

The authors have no financial relationships or conflicts of interest relevant to this article to disclose.

Funding

No funding was secured for this study.

Venous thromboembolism (VTE) occurs uncommonly in pediatrics, affecting 0.07-0.14 per 10,000 children.^1,2 Yet, in the last 20 years, the incidence of VTE in hospitalized children has increased dramatically to approximately 58 per 10,000 admissions.³ This increase may be attributed to improved survival of very ill children, better diagnostic imaging modalities, and heightened awareness by managing physicians.³ Randomized controlled trials are lacking in pediatric thrombosis, and clinical care is based on extrapolation of adult data and expert consensus guidelines.^4,5 In 2014, the American Society of Hematology (ASH) sought to develop comprehensive guidelines on thrombosis. The pediatric VTE treatment guideline is one of six published to date.

The following are five selected guideline recommendations thought most relevant to pediatric hospitalists. Three focus on the central venous access device (CVAD), since it is the most common risk factor for pediatric VTE.¹ Recommendations were graded as “strong” if most providers, patients, and policy makers agreed with the intervention and if it was supported by credible research. Conditional recommendations had less uniform agreement with an emphasis on individualized care and weighing patients’ values and preferences.⁶

Recommendation 1. It is recommended that pediatric patients receive anticoagulation, versus no anticoagulation, for symptomatic VTE (evidence quality: low certainty; recommendation strength: strong).

There is strong indirect data in adults that symptomatic VTE requires treatment, with limited direct evidence in children. As VTE occurs most commonly in ill, hospitalized children with the potential for VTE to be life threatening, the benefit was felt to justify the strong recommendation despite low-quality evidence.

The primary benefit of anticoagulation in children with symptomatic VTE is the prevention of progressive or recurrent thrombosis with high morbidity and the prevention of life-threatening VTE. The greatest potential harm from the use of anticoagulation, particularly in very ill children, is the risk for major bleeding.⁴Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).
Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).

The panel focused on the unique features of pediatric VTE related to the heterogeneity in both the site and pathophysiology of VTE in children, such as age, presence of a CVAD, and comorbidities. There is little certainty that treating asymptomatic VTE is beneficial in the same way that treating symptomatic VTE would be in preventing recurrent thrombosis and embolization.

Until better evidence is available to guide care, the primary benefit of this recommendation is individualization of care related to each patient’s risk-benefit profile and parental preferences.

Potential problems with using this recommendation include the cost of anticoagulant drugs and major bleeding if anticoagulation is used. Potential problems with not using anticoagulation would be progressive or recurrent thromboembolism. Close monitoring of children with VTE—regardless of whether anticoagulation is prescribed—is warranted.

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

Recommendations three through five pertain to CVAD-associated thrombosis, so they are reviewed together.

Recommendation 3. No removal of a functioning CVAD is suggested if venous access is still required (evidence quality: low certainty; recommendation strength: conditional).Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).

Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

CVAD is the most common precipitating factor for pediatric VTE, particularly in neonates and older children.¹ Based on limited direct and indirect observational studies, there is low evidence of benefit for CVAD removal, but high-quality indirect evidence of harm and high cost, which the panel felt justified the strong recommendation for removing an unneeded or nonfunctioning line. If ongoing care can be safely administered without central access, removing the thrombosis stimulus is recommended. The guideline suggests keeping a functioning CVAD in a patient who requires ongoing venous access and placing high value on avoiding new line insertion when access sites may be limited to avoid the potential thrombogenic effect of new line placement.

In the limited direct and indirect observational studies identified, the optimal timing of CVAD removal is uncertain. Given the potential risk of emboli leading to pulmonary embolism or stroke, prior publications have suggested delaying removal until after three to five days of anticoagulation, particularly in children with known or potential right-to-left shunts.⁴ The risk of infection and bleeding with anticoagulation prior to CVAD removal was considered small by the panel. This recommendation is primarily based on the panel’s anecdotal experience and first principles, which is a limitation.

Methods in Preparing Guideline. The panel included pediatric experts with clinical and research expertise in the guideline topic, including nine hematologists, one intensivist, one cardiologist, one hematology pharmacist, and one anticoagulation nurse practitioner. It also included two methodologists with evidence appraisal and guideline development expertise, as well as two patient representatives.

The panel brainstormed and prioritized questions to be addressed and selected outcomes of interest for each question. The McMaster University GRADE Centre vetted and retained researchers to conduct or update systematic evidence reviews and coordinate the guideline development using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.⁶ For each guideline question, the results of systematic reviews were summarized in GRADE Evidence-to-Decision tables. The evidence quality was categorized into four levels ranging from very low to high. For each recommendation developed, the panel agreed on the evidence quality, balance of benefits and harms of compared management options with consideration of resource use, and inferences regarding the potential associated values and preferences. The panel addressed 26 questions, which generated 30 recommendations.

Draft recommendations were made available online for review by stakeholders, including allied organizations, medical professionals, patients, and the public. Revisions were made to address pertinent submitted comments, but the recommendations were not changed. After approval by ASH, the guideline was subjected to peer review by Blood Advances.

Sources of Potential Conflict of Interest or Bias. The guideline was developed and funded by ASH. All participants’ conflicts of interest were managed according to ASH policies based on recommendations of the Institute of Medicine and the Guideline International Network. A majority of the guideline panel had no conflicts. During deliberations, panelists with direct financial interests were recused from making judgments about relevant recommendations. The McMaster University-affiliated researchers had no conflicts.Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Although there is increasing interest in pediatric VTE prevention and risk assessment,⁷ there is currently limited evidence on the best ways to mitigate VTE risk or anticoagulation-associated major bleeding in hospitalized children. The relatively low incidence of VTE in children makes large randomized controlled trials difficult, but several are ongoing. The Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT) multicenter, randomized trial will inform care on the optimal duration of anticoagulation in children with a transient provoking factor,⁸ and several phase III studies are investigating the safety and efficacy of direct oral anticoagulants in children (NCT02234843, NCT02464969, NCT01895777, NCT02234843). These and future trials will better inform therapy in pediatric VTE.

Disclosures

The authors have no financial relationships or conflicts of interest relevant to this article to disclose.

Funding

No funding was secured for this study.

Venous thromboembolism (VTE) occurs uncommonly in pediatrics, affecting 0.07-0.14 per 10,000 children.^1,2 Yet, in the last 20 years, the incidence of VTE in hospitalized children has increased dramatically to approximately 58 per 10,000 admissions.³ This increase may be attributed to improved survival of very ill children, better diagnostic imaging modalities, and heightened awareness by managing physicians.³ Randomized controlled trials are lacking in pediatric thrombosis, and clinical care is based on extrapolation of adult data and expert consensus guidelines.^4,5 In 2014, the American Society of Hematology (ASH) sought to develop comprehensive guidelines on thrombosis. The pediatric VTE treatment guideline is one of six published to date.

The following are five selected guideline recommendations thought most relevant to pediatric hospitalists. Three focus on the central venous access device (CVAD), since it is the most common risk factor for pediatric VTE.¹ Recommendations were graded as “strong” if most providers, patients, and policy makers agreed with the intervention and if it was supported by credible research. Conditional recommendations had less uniform agreement with an emphasis on individualized care and weighing patients’ values and preferences.⁶

Recommendation 1. It is recommended that pediatric patients receive anticoagulation, versus no anticoagulation, for symptomatic VTE (evidence quality: low certainty; recommendation strength: strong).

There is strong indirect data in adults that symptomatic VTE requires treatment, with limited direct evidence in children. As VTE occurs most commonly in ill, hospitalized children with the potential for VTE to be life threatening, the benefit was felt to justify the strong recommendation despite low-quality evidence.

The primary benefit of anticoagulation in children with symptomatic VTE is the prevention of progressive or recurrent thrombosis with high morbidity and the prevention of life-threatening VTE. The greatest potential harm from the use of anticoagulation, particularly in very ill children, is the risk for major bleeding.⁴Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).
Recommendation 2. Children with asymptomatic VTE can be managed with or without anticoagulation (evidence quality: poor; recommendation strength: conditional).

The panel focused on the unique features of pediatric VTE related to the heterogeneity in both the site and pathophysiology of VTE in children, such as age, presence of a CVAD, and comorbidities. There is little certainty that treating asymptomatic VTE is beneficial in the same way that treating symptomatic VTE would be in preventing recurrent thrombosis and embolization.

Until better evidence is available to guide care, the primary benefit of this recommendation is individualization of care related to each patient’s risk-benefit profile and parental preferences.

Potential problems with using this recommendation include the cost of anticoagulant drugs and major bleeding if anticoagulation is used. Potential problems with not using anticoagulation would be progressive or recurrent thromboembolism. Close monitoring of children with VTE—regardless of whether anticoagulation is prescribed—is warranted.

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

Recommendations three through five pertain to CVAD-associated thrombosis, so they are reviewed together.

Recommendation 3. No removal of a functioning CVAD is suggested if venous access is still required (evidence quality: low certainty; recommendation strength: conditional).Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

Recommendation 4. It is recommended to remove a nonfunctioning or unneeded CVAD (evidence quality: low certainty; recommendation strength: strong).

Recommendation 5. It is suggested to delay CVAD removal until after initiation of anticoagulation (days), rather than immediate removal if the CVAD is nonfunctioning or no longer needed (evidence quality: low certainty; recommendation strength: conditional).

CVAD is the most common precipitating factor for pediatric VTE, particularly in neonates and older children.¹ Based on limited direct and indirect observational studies, there is low evidence of benefit for CVAD removal, but high-quality indirect evidence of harm and high cost, which the panel felt justified the strong recommendation for removing an unneeded or nonfunctioning line. If ongoing care can be safely administered without central access, removing the thrombosis stimulus is recommended. The guideline suggests keeping a functioning CVAD in a patient who requires ongoing venous access and placing high value on avoiding new line insertion when access sites may be limited to avoid the potential thrombogenic effect of new line placement.

In the limited direct and indirect observational studies identified, the optimal timing of CVAD removal is uncertain. Given the potential risk of emboli leading to pulmonary embolism or stroke, prior publications have suggested delaying removal until after three to five days of anticoagulation, particularly in children with known or potential right-to-left shunts.⁴ The risk of infection and bleeding with anticoagulation prior to CVAD removal was considered small by the panel. This recommendation is primarily based on the panel’s anecdotal experience and first principles, which is a limitation.

Methods in Preparing Guideline. The panel included pediatric experts with clinical and research expertise in the guideline topic, including nine hematologists, one intensivist, one cardiologist, one hematology pharmacist, and one anticoagulation nurse practitioner. It also included two methodologists with evidence appraisal and guideline development expertise, as well as two patient representatives.

The panel brainstormed and prioritized questions to be addressed and selected outcomes of interest for each question. The McMaster University GRADE Centre vetted and retained researchers to conduct or update systematic evidence reviews and coordinate the guideline development using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.⁶ For each guideline question, the results of systematic reviews were summarized in GRADE Evidence-to-Decision tables. The evidence quality was categorized into four levels ranging from very low to high. For each recommendation developed, the panel agreed on the evidence quality, balance of benefits and harms of compared management options with consideration of resource use, and inferences regarding the potential associated values and preferences. The panel addressed 26 questions, which generated 30 recommendations.

Draft recommendations were made available online for review by stakeholders, including allied organizations, medical professionals, patients, and the public. Revisions were made to address pertinent submitted comments, but the recommendations were not changed. After approval by ASH, the guideline was subjected to peer review by Blood Advances.

Sources of Potential Conflict of Interest or Bias. The guideline was developed and funded by ASH. All participants’ conflicts of interest were managed according to ASH policies based on recommendations of the Institute of Medicine and the Guideline International Network. A majority of the guideline panel had no conflicts. During deliberations, panelists with direct financial interests were recused from making judgments about relevant recommendations. The McMaster University-affiliated researchers had no conflicts.Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Generalizability. While this guideline included 30 recommendations, the ones highlighted apply to the most commonly seen pediatric VTE cases in hospital medicine. ASH emphasized that these guidelines should not be construed as the standard of care, but as a guide to help clinicians make treatment decisions for children with VTE and to enable them to individualize care when needed. The greatest limitation of this guideline is the lack of strong direct supporting evidence in pediatric VTE management.

Although there is increasing interest in pediatric VTE prevention and risk assessment,⁷ there is currently limited evidence on the best ways to mitigate VTE risk or anticoagulation-associated major bleeding in hospitalized children. The relatively low incidence of VTE in children makes large randomized controlled trials difficult, but several are ongoing. The Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT) multicenter, randomized trial will inform care on the optimal duration of anticoagulation in children with a transient provoking factor,⁸ and several phase III studies are investigating the safety and efficacy of direct oral anticoagulants in children (NCT02234843, NCT02464969, NCT01895777, NCT02234843). These and future trials will better inform therapy in pediatric VTE.

Disclosures

The authors have no financial relationships or conflicts of interest relevant to this article to disclose.

Funding

No funding was secured for this study.

“I think healthcare is more about love than most other things”
—Don Berwick

Dr. Berwick speaks of the relationship between the doctor and the patient and family. I believe this relationship is sacred. My job as CEO of Blue Cross North Carolina is hard. But it was so much harder on a recent weekend to give a new diagnosis of a certainly fatal disease of a less than 1-year old child to her parents and discuss palliative care options. I cried and they cried. Being a leader, particularly in healthcare, requires us to maintain sight of what is important and return to those things often as we lead.

Growing up, my parents stressed two things: service and education. I decided early on that I wanted to improve our health care system. I have had a sometimes-winding path to this goal - including work as a consultant, medical school and residency, an RWJ Clinical Scholar, clinical work as a pediatric hospitalist and two tours through government as a White House Fellow, the Centers for Medicare and Medicaid Services (CMS) as Chief Medical Officer, Deputy Administrator and leader of the CMS Innovation Center. With each step I have used five criteria that have allowed me to consider decisions while staying true to myself and my mission.

First, Family. My wife and I have four children, age 10 and under. I put them first as I make decisions.

Second, Impact. Better quality, lower costs, and exceptional experience for populations of people. The triple aim, as we better know it.

Third, People. In the beginning, I took jobs to work with specific mentors. Now, I look carefully at the people and culture where I serve to assess fit and how I could uniquely add value.

Fourth, Learning. How much will I learn every day? When I interviewed for my current job, I told them that they could hire an insurance executive who would be better on day one than me, but if they wanted someone who would improve every day and try to make a model of health transformation and a model health plan for the nation, then they should choose me.

Fifth, Joy in Work. Self-explanatory.

We also have a family mission statement, which was my wife’s good idea. We wrote it together right after we were married. It is too personal to share in detail, but it talks about family, public service, commitment to community, life balance, faith, etc. It is short but to the point and has guided us well.

At some point, you will have someone more senior than you who says you must do A before B and then C. My advice: ignore them. Choose your own path. During my journey, I was encouraged to go down a traditional academic path. I did not do it. Yet, somehow, I was elected to the National Academy of Medicine before I turned 40. It was poignant because it was almost the only accomplishment that my father (a PhD scientist), who passed away before I was elected, would have understood.

So please, decide on your criteria and mission for career and life. Write them down, share them if you wish. Then follow them! Passionately! When things are going well, review them. Are you still aligned with what is important to you? When you are at a crossroads to make a decision, review them again. They should help guide your choice.

I often get asked “what keeps me up at night?” Honestly, nothing as I fall asleep in 10 seconds or less. But if something did, it is the fact that I am always worried that someone is falling through the cracks and getting suboptimal care. We must continue to strive to build a more highly reliable health system that delivers better quality, lower costs, and exceptional experience to all people. We cannot do that without great leaders. So, choose your own path, use your mission as a guide and lead focused on a better health system for all!

Disclosures

Dr. Conway has nothing to disclose.

“I think healthcare is more about love than most other things”
—Don Berwick

Dr. Berwick speaks of the relationship between the doctor and the patient and family. I believe this relationship is sacred. My job as CEO of Blue Cross North Carolina is hard. But it was so much harder on a recent weekend to give a new diagnosis of a certainly fatal disease of a less than 1-year old child to her parents and discuss palliative care options. I cried and they cried. Being a leader, particularly in healthcare, requires us to maintain sight of what is important and return to those things often as we lead.

Growing up, my parents stressed two things: service and education. I decided early on that I wanted to improve our health care system. I have had a sometimes-winding path to this goal - including work as a consultant, medical school and residency, an RWJ Clinical Scholar, clinical work as a pediatric hospitalist and two tours through government as a White House Fellow, the Centers for Medicare and Medicaid Services (CMS) as Chief Medical Officer, Deputy Administrator and leader of the CMS Innovation Center. With each step I have used five criteria that have allowed me to consider decisions while staying true to myself and my mission.

First, Family. My wife and I have four children, age 10 and under. I put them first as I make decisions.

Second, Impact. Better quality, lower costs, and exceptional experience for populations of people. The triple aim, as we better know it.

Third, People. In the beginning, I took jobs to work with specific mentors. Now, I look carefully at the people and culture where I serve to assess fit and how I could uniquely add value.

Fourth, Learning. How much will I learn every day? When I interviewed for my current job, I told them that they could hire an insurance executive who would be better on day one than me, but if they wanted someone who would improve every day and try to make a model of health transformation and a model health plan for the nation, then they should choose me.

Fifth, Joy in Work. Self-explanatory.

We also have a family mission statement, which was my wife’s good idea. We wrote it together right after we were married. It is too personal to share in detail, but it talks about family, public service, commitment to community, life balance, faith, etc. It is short but to the point and has guided us well.

At some point, you will have someone more senior than you who says you must do A before B and then C. My advice: ignore them. Choose your own path. During my journey, I was encouraged to go down a traditional academic path. I did not do it. Yet, somehow, I was elected to the National Academy of Medicine before I turned 40. It was poignant because it was almost the only accomplishment that my father (a PhD scientist), who passed away before I was elected, would have understood.

So please, decide on your criteria and mission for career and life. Write them down, share them if you wish. Then follow them! Passionately! When things are going well, review them. Are you still aligned with what is important to you? When you are at a crossroads to make a decision, review them again. They should help guide your choice.

I often get asked “what keeps me up at night?” Honestly, nothing as I fall asleep in 10 seconds or less. But if something did, it is the fact that I am always worried that someone is falling through the cracks and getting suboptimal care. We must continue to strive to build a more highly reliable health system that delivers better quality, lower costs, and exceptional experience to all people. We cannot do that without great leaders. So, choose your own path, use your mission as a guide and lead focused on a better health system for all!

Disclosures

Dr. Conway has nothing to disclose.

“I think healthcare is more about love than most other things”
—Don Berwick

Dr. Berwick speaks of the relationship between the doctor and the patient and family. I believe this relationship is sacred. My job as CEO of Blue Cross North Carolina is hard. But it was so much harder on a recent weekend to give a new diagnosis of a certainly fatal disease of a less than 1-year old child to her parents and discuss palliative care options. I cried and they cried. Being a leader, particularly in healthcare, requires us to maintain sight of what is important and return to those things often as we lead.

Growing up, my parents stressed two things: service and education. I decided early on that I wanted to improve our health care system. I have had a sometimes-winding path to this goal - including work as a consultant, medical school and residency, an RWJ Clinical Scholar, clinical work as a pediatric hospitalist and two tours through government as a White House Fellow, the Centers for Medicare and Medicaid Services (CMS) as Chief Medical Officer, Deputy Administrator and leader of the CMS Innovation Center. With each step I have used five criteria that have allowed me to consider decisions while staying true to myself and my mission.

First, Family. My wife and I have four children, age 10 and under. I put them first as I make decisions.

Second, Impact. Better quality, lower costs, and exceptional experience for populations of people. The triple aim, as we better know it.

Third, People. In the beginning, I took jobs to work with specific mentors. Now, I look carefully at the people and culture where I serve to assess fit and how I could uniquely add value.

Fourth, Learning. How much will I learn every day? When I interviewed for my current job, I told them that they could hire an insurance executive who would be better on day one than me, but if they wanted someone who would improve every day and try to make a model of health transformation and a model health plan for the nation, then they should choose me.

Fifth, Joy in Work. Self-explanatory.

We also have a family mission statement, which was my wife’s good idea. We wrote it together right after we were married. It is too personal to share in detail, but it talks about family, public service, commitment to community, life balance, faith, etc. It is short but to the point and has guided us well.

At some point, you will have someone more senior than you who says you must do A before B and then C. My advice: ignore them. Choose your own path. During my journey, I was encouraged to go down a traditional academic path. I did not do it. Yet, somehow, I was elected to the National Academy of Medicine before I turned 40. It was poignant because it was almost the only accomplishment that my father (a PhD scientist), who passed away before I was elected, would have understood.

So please, decide on your criteria and mission for career and life. Write them down, share them if you wish. Then follow them! Passionately! When things are going well, review them. Are you still aligned with what is important to you? When you are at a crossroads to make a decision, review them again. They should help guide your choice.

I often get asked “what keeps me up at night?” Honestly, nothing as I fall asleep in 10 seconds or less. But if something did, it is the fact that I am always worried that someone is falling through the cracks and getting suboptimal care. We must continue to strive to build a more highly reliable health system that delivers better quality, lower costs, and exceptional experience to all people. We cannot do that without great leaders. So, choose your own path, use your mission as a guide and lead focused on a better health system for all!

Disclosures

Dr. Conway has nothing to disclose.

Hospitalizations are disruptive, stressful, and costly for patients and families.^1-5 Hospital readmissions subject families to the additional morbidity inherent to hospitalization and place patients at additional risk of hospital-acquired conditions or other harm.^6-9 In pediatrics, hospital readmissions are common for specific conditions;¹⁰ with rates varying across institutions;^10,11 and as many as one-third of unplanned pediatric readmissions are potentially preventable.¹²

Reducing pediatric readmissions requires a deeper understanding of the mechanisms through which readmissions occur. Medical complexity—specifically chronic conditions and use of medical technology—is associated with increased risk of readmission.^13,14 Polypharmacy at discharge has also been associated with readmission.^15,16 However, prior studies on polypharmacy and readmission risk examined the count of total medications and did not consider the nuances of scheduled versus as-needed medications, or the frequency of doses. These nuances may be critical to caregivers as discharge medical complexity can be overwhelming, even in diagnoses which are not traditionally considered complex.¹⁷ Finally, of potentially greater importance than medical complexity at discharge is a change in medical complexity during a hospitalization—for example, new diagnoses or new technologies that require additional education in hospital and management at home.

We sought to further understand the relationship between discharge medical complexity and readmission risk with regards to polypharmacy and home healthcare referrals at discharge. Specifically, we hypothesized that a change in medical complexity during an admission—ie, a new chronic diagnosis or new technology—would be a more prominent risk factor for readmission than discharge complexity alone. We examined these factors in the context of length of stay (LOS) since this is a marker of in-hospital severity of illness and a potentially modifiable function of time allowed for in-hospital teaching and discharge preparation.

We conducted a retrospective, case-control study of pediatric hospitalizations at one tertiary care children’s hospital. Children <18 years were eligible for inclusion. Normal birth hospitalizations were excluded. We randomly selected one hospitalization from each child as the index visit. We identified cases, hospitalizations at C.S. Mott Children’s Hospital between 2008 and 2012 with a subsequent unplanned 30-day readmission,¹⁸ and matched them one to one with hospitalizations at the same hospital during the same period without subsequent readmission. We matched cases to controls based on the month of admission to account for seasonality of certain illnesses. We also matched on distance and direction from the hospital to the patient’s home to account for the potential to have readmissions to other institutions. We utilized both distance and direction recognizing that a family living 30 miles in one direction would be closer to an urban area with access to more facilities, as opposed to 30 miles in another direction in a rural area without additional access. We subsequently performed medical record review to abstract relevant covariates.

Primary Predictors

Medical Complexity Models (Models 1 and 2):

We evaluated three attributes of discharge medical complexity abstracted by medical record review—discharge medications, technology assistance (ie, tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, central line), and the need for home healthcare after discharge. We counted discharge medications based on the number of medications listed on the discharge summary separated into scheduled or as needed.¹⁹ We also considered the number of scheduled doses to be administered in a 24-hour period (see Appendix methods for more information on counting discharge medications). For assistance by technology, we considered the presence of tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, and central lines. While we describe these technologies separately, for multivariable analyses we considered the presence of any of the four types of technology.

Change in Medical Complexity Models (Models 3 and 4)

We examined two aspects of change in medical complexity—the presence of a new complex chronic condition (CCC)²⁰ diagnosed during the hospitalization, and a new reliance on medical technology. The presence of new CCC was determined by comparing discharge diagnoses to past medical history abstracted by medical record review. A new CCC was defined as any complex chronic condition that was captured in the discharge diagnoses but was not evident in the past medical history. By definition, all CCCs coded during birth hospitalization (eg, at discharge from the neonatal intensive care unit) were assigned to “new” CCC. We calculated a kappa statistic to determine interrater reliability in determining the designation of new CCC. A sensitivity analysis examining these birth CCCs was also performed comparing no new CCC, new CCC, and new CCC after birth hospitalization. The methods appendix provides additional information on considering new CCCs. New technology, abstracted from chart review, was defined as technology placed during hospitalization that remained in place at discharge. If a child with existing technology had additional technology placed during the hospitalization (eg, a new tracheostomy in a child with a previously placed enteral feeding tube), the encounter was considered as having new technology placed.

Covariates

We created different sets of multivariable models to account for patient/hospitalization characteristics. In Models 1 and 3, we examined the primary predictors adjusting for patient characteristics (age, race/ethnicity, sex, and insurance). In Models 2 and 4, we added the index hospitalization LOS into the multivariable models adjusting for patient characteristics. We chose to add LOS in a second set of models because it is a potentially important confounder in readmission risk: discharge timing is a modifiable factor dependent on both physiologic recovery and the medical team’s perception of caregiver’s readiness for discharge. We elected to present models with and without LOS since LOS is also a marker of illness severity while in the hospital and is linked to discharge complexity.

Statistical Analysis

A review of 600 cases and 600 controls yields 89% power to detect statistical significance for covariates with an odds ratio of 1.25 (β = 0.22) if the candidate covariate has low to moderate correlation with other covariates (<0.3). If a candidate covariate has a moderate correlation with other covariates (0.6), we have 89% power to detect an odds ratio of 1.35 (β = 0.30).²¹ We calculated odds of 30-days unplanned readmission using conditional logistic regression to account for matched case-control design. All the analyses were performed using STATA 13 (Stata Corp., College Station, Texas).

Of the 41,422 eligible index hospitalizations during the study period, 9.4% resulted in a 30-day unplanned readmission. After randomly selecting one hospitalization per child, there were 781 eligible cases. We subsequent matched all but one eligible case to a control. We randomly selected encounters for medical record review, reviewing a total of 1,212 encounters. After excluding pairs with incomplete records, we included 595 cases and 595 controls in this analysis (Figure). Patient/hospitalization characteristics are displayed in Table 1. The most frequent primary discharge diagnoses are displayed in Appendix Table 1.

Models of Medical Complexity at Discharge

Polypharmacy after discharge was common for both readmitted and nonreadmitted patients. Children who experienced unplanned readmission in 30 days were discharged with a median of four different scheduled medications (interquartile range [IQR] 2,7) which translated into a median of six (IQR 3,12) scheduled doses in a 24-hour period. In comparison, children without an unplanned readmission had a median of two different scheduled medications (IQR 1,3) with a median of three (IQR 0,7) scheduled doses in a 24-hour period. Medical technology was more common in case children (42%) than in control children (14%). Central lines and enteral tubes were the most common forms of medical technology in both cases and controls. Home health referral was common in both cases (44%) and controls (23%; Table 1).

Change in Medical Complexity Models

The adjudication of new CCCs had good reliability (Κ = 0.72). New CCCs occurred in 18% and new technologies occurred in 17% of cases. Comparatively, new CCCs occurred in 10% and new technologies in 7% of hospitalizations in control children (Table 1). In bivariate analyses, both aspects of change in medical complexity were associated with higher odds of readmission (Table 2). In multivariate analysis with patient characteristics (Model 3; Table 3), all aspects of change in complexity were associated with elevated odds of readmission. A new CCC was associated with higher odds of readmission (adjusted OR (AOR) 1.75, 95% CI: 1.11-2.75) as was new technology during admission (AOR 1.84, 95%CI: 1.09-3.10). Furthermore, the odds of readmission for medical complexity variables (polypharmacy and home healthcare need) remained largely unchanged when adding the change in medical complexity variables (ie, comparing Model 1 and Model 3). However, when accounting for LOS (Model 4), neither the acquisition of a new CCC nor the addition of new technology was associated with readmission. The most common form of new technology was central line followed by nonsurgically placed enteral tube (Appendix Table 2). Finally, in sensitivity analyses (results not detailed), separating new CCC acquired at birth and new CCCs in nonbirth hospitalizations, compared to hospitalizations with no new CCC, yielded similar results as the primary analyses.

We examined multiple attributes of polypharmacy—the number of scheduled medications, number of as-needed medications, and number of scheduled doses per 24 hours. Interestingly, only the scheduled medications (count of medication and number of doses) were associated with elevated readmission risk. As-needed medications have heterogeneity in the level of importance from critical (eg, seizure rescue) to discretionary (eg, antipyretics, creams). The burden of managing these types of medications may still be high (ie, parents must decide when to administer a critical medication); however, this burden does not translate into increased readmission risk in this population.

Not surprisingly, greater medical complexity—as defined by higher numbers of scheduled discharge medications and technology assistance—is associated with 30-day readmission risk. Our analyses do not allow us to determine how much of the increased risk is due to additional care burden and risks of polypharmacy versus the inherent increase in complexity and severity of illness for which polypharmacy is a marker. Tailoring discharge regimens to the realities of daily life, with the goal of “minimally disruptive medicine”^22,23 (eg, integrating manageable discharge medication routines into school and work schedules), is not a common feature of pediatric discharge planning. For adult patients with complex medical conditions, tailoring medication regimens in a minimally disruptive way is known to improve outcomes.²⁴ Similarly, adopting minimally disruptive techniques to integrate the polypharmacy inherent in discharge could potentially mitigate some of the readmission risks for children and adolescents.

Contrary to our hypothesis, new technologies and new diagnoses did not confer additional readmission risk when accounting for LOS and patient characteristics. One potential explanation is varying risks conveyed by different types of new technologies placed during hospitalization. Central lines, the most common form of new technology, is associated with higher odds of reutilization in unadjusted analyses. However, the second most common form of new technology, nonsurgically placed enteral feeding tube, was not. Further analyses of the differential effects of new technology should be further examined in larger datasets. Additionally, the lack of additional readmission risk from new technology may relate to additional teaching and support provided to families of patients undergoing unfamiliar procedures offsets the risks inherent of greater complexity. If so, it may be that the more intensive teaching and postdischarge support provided to families with new technology or a new diagnosis could be replicated through refresher teaching during hospitalizations, when a patient’s state of health is status quo for the family (ie, the child was admitted and discharged with the same technology and diagnoses). This notion is supported by prior work that demonstrated successful readmission reduction interventions for children with chronic conditions often rely on enhanced education or coaching.^25,26

We elected to present models both with and without LOS as a confounder because it is a potentially modifiable attribute of hospitalization. Change in medical complexity aspects were significantly associated with readmission in multivariable models without LOS. However, with the addition of LOS, they were no longer significant. Thus, the readmission risk of new complexity is accounted for by the readmission risk inherent in a longer LOS. This finding prompts additional questions that merit further study: is it that LOS is a general marker for heightened complexity, or is it that a longer LOS can modify readmission risk through additional in-hospital care and time for enhanced education?

Our study has several strengths. We were able to discern true complexity at the time of discharge through medical record review. For example, if a child had a peripherally inserted central catheter placed during hospitalization, it cannot be ascertained through administrative data without medical record review if the technology was removed or in place at discharge. Likewise, medical record review allows for identification of medical technology which is not surgically implanted (eg, nasogastric feeding tubes). Given the “fog” families report as part of their in-hospital experience and its threats to education and postdischarge contingency planning,¹⁷ we felt it important to evaluate medical technology regardless of whether or not it was surgically placed. Additionally, the more detailed and nuanced understanding gained of polypharmacy burden can better inform both risk prediction models and interventions to improve the transition from hospital to home.

This study should also be considered in the context of several limitations. First, the data was from a single children’s hospital, so the generalizability of our findings is uncertain. Second, we utilized a novel method for counting new CCCs which compared information collected for clinical purposes (eg, obtaining a past medical history) with data collected for billing purposes (ie, discharge diagnoses). This comparison of information collected for different purposes potentially introduced uncertainty in the classification of diagnoses as new or not new; however, the interrater reliability for adjudicating new diagnoses suggests that the process was reasonably reliable. Third, we did not have access to other hospitals where readmissions could have occurred. While this is a common limitation for readmission studies,^{10,12,14,15,18,27-29} we attempted to mitigate any differential risk of being readmitted to other institutions by matching on distance and direction from the hospital. Of note, it is possible that children with medical complexity may be more willing to travel further to the hospital of their choice; thus our matching may be imperfect. However, there is no established method available to identify preadmission medical complexity through administrative data. Finally, the case-control method of the study makes estimating the true incidence of a variety of elements of medical complexity challenging. For example, it is difficult to tell how often children are discharged on five or more medications from a population standpoint when this practice was quite common for cases. Likewise, the true incidence of new technologies and new CCCs is challenging to estimate.

Medical complexity at discharge is associated with pediatric readmission risk. Contrary to our hypothesis, the addition of new technologies and new CCC diagnoses are not associated with pediatric readmission, after accounting for patient and hospitalization factors including LOS. The dynamics of LOS as a risk factor for readmission for children with medical complexity are likely multifaceted and merit further investigation in a multi-institutional study.

Disclosures

The authors report no potential conflicts of interest.

Funding

This work was supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1) and a grant from the Blue Cross Blue Shield of Michigan Foundation.

Hospitalizations are disruptive, stressful, and costly for patients and families.^1-5 Hospital readmissions subject families to the additional morbidity inherent to hospitalization and place patients at additional risk of hospital-acquired conditions or other harm.^6-9 In pediatrics, hospital readmissions are common for specific conditions;¹⁰ with rates varying across institutions;^10,11 and as many as one-third of unplanned pediatric readmissions are potentially preventable.¹²

Reducing pediatric readmissions requires a deeper understanding of the mechanisms through which readmissions occur. Medical complexity—specifically chronic conditions and use of medical technology—is associated with increased risk of readmission.^13,14 Polypharmacy at discharge has also been associated with readmission.^15,16 However, prior studies on polypharmacy and readmission risk examined the count of total medications and did not consider the nuances of scheduled versus as-needed medications, or the frequency of doses. These nuances may be critical to caregivers as discharge medical complexity can be overwhelming, even in diagnoses which are not traditionally considered complex.¹⁷ Finally, of potentially greater importance than medical complexity at discharge is a change in medical complexity during a hospitalization—for example, new diagnoses or new technologies that require additional education in hospital and management at home.

We sought to further understand the relationship between discharge medical complexity and readmission risk with regards to polypharmacy and home healthcare referrals at discharge. Specifically, we hypothesized that a change in medical complexity during an admission—ie, a new chronic diagnosis or new technology—would be a more prominent risk factor for readmission than discharge complexity alone. We examined these factors in the context of length of stay (LOS) since this is a marker of in-hospital severity of illness and a potentially modifiable function of time allowed for in-hospital teaching and discharge preparation.

We conducted a retrospective, case-control study of pediatric hospitalizations at one tertiary care children’s hospital. Children <18 years were eligible for inclusion. Normal birth hospitalizations were excluded. We randomly selected one hospitalization from each child as the index visit. We identified cases, hospitalizations at C.S. Mott Children’s Hospital between 2008 and 2012 with a subsequent unplanned 30-day readmission,¹⁸ and matched them one to one with hospitalizations at the same hospital during the same period without subsequent readmission. We matched cases to controls based on the month of admission to account for seasonality of certain illnesses. We also matched on distance and direction from the hospital to the patient’s home to account for the potential to have readmissions to other institutions. We utilized both distance and direction recognizing that a family living 30 miles in one direction would be closer to an urban area with access to more facilities, as opposed to 30 miles in another direction in a rural area without additional access. We subsequently performed medical record review to abstract relevant covariates.

Primary Predictors

Medical Complexity Models (Models 1 and 2):

We evaluated three attributes of discharge medical complexity abstracted by medical record review—discharge medications, technology assistance (ie, tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, central line), and the need for home healthcare after discharge. We counted discharge medications based on the number of medications listed on the discharge summary separated into scheduled or as needed.¹⁹ We also considered the number of scheduled doses to be administered in a 24-hour period (see Appendix methods for more information on counting discharge medications). For assistance by technology, we considered the presence of tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, and central lines. While we describe these technologies separately, for multivariable analyses we considered the presence of any of the four types of technology.

Change in Medical Complexity Models (Models 3 and 4)

We examined two aspects of change in medical complexity—the presence of a new complex chronic condition (CCC)²⁰ diagnosed during the hospitalization, and a new reliance on medical technology. The presence of new CCC was determined by comparing discharge diagnoses to past medical history abstracted by medical record review. A new CCC was defined as any complex chronic condition that was captured in the discharge diagnoses but was not evident in the past medical history. By definition, all CCCs coded during birth hospitalization (eg, at discharge from the neonatal intensive care unit) were assigned to “new” CCC. We calculated a kappa statistic to determine interrater reliability in determining the designation of new CCC. A sensitivity analysis examining these birth CCCs was also performed comparing no new CCC, new CCC, and new CCC after birth hospitalization. The methods appendix provides additional information on considering new CCCs. New technology, abstracted from chart review, was defined as technology placed during hospitalization that remained in place at discharge. If a child with existing technology had additional technology placed during the hospitalization (eg, a new tracheostomy in a child with a previously placed enteral feeding tube), the encounter was considered as having new technology placed.

Covariates

We created different sets of multivariable models to account for patient/hospitalization characteristics. In Models 1 and 3, we examined the primary predictors adjusting for patient characteristics (age, race/ethnicity, sex, and insurance). In Models 2 and 4, we added the index hospitalization LOS into the multivariable models adjusting for patient characteristics. We chose to add LOS in a second set of models because it is a potentially important confounder in readmission risk: discharge timing is a modifiable factor dependent on both physiologic recovery and the medical team’s perception of caregiver’s readiness for discharge. We elected to present models with and without LOS since LOS is also a marker of illness severity while in the hospital and is linked to discharge complexity.

Statistical Analysis

A review of 600 cases and 600 controls yields 89% power to detect statistical significance for covariates with an odds ratio of 1.25 (β = 0.22) if the candidate covariate has low to moderate correlation with other covariates (<0.3). If a candidate covariate has a moderate correlation with other covariates (0.6), we have 89% power to detect an odds ratio of 1.35 (β = 0.30).²¹ We calculated odds of 30-days unplanned readmission using conditional logistic regression to account for matched case-control design. All the analyses were performed using STATA 13 (Stata Corp., College Station, Texas).

Of the 41,422 eligible index hospitalizations during the study period, 9.4% resulted in a 30-day unplanned readmission. After randomly selecting one hospitalization per child, there were 781 eligible cases. We subsequent matched all but one eligible case to a control. We randomly selected encounters for medical record review, reviewing a total of 1,212 encounters. After excluding pairs with incomplete records, we included 595 cases and 595 controls in this analysis (Figure). Patient/hospitalization characteristics are displayed in Table 1. The most frequent primary discharge diagnoses are displayed in Appendix Table 1.

Models of Medical Complexity at Discharge

Polypharmacy after discharge was common for both readmitted and nonreadmitted patients. Children who experienced unplanned readmission in 30 days were discharged with a median of four different scheduled medications (interquartile range [IQR] 2,7) which translated into a median of six (IQR 3,12) scheduled doses in a 24-hour period. In comparison, children without an unplanned readmission had a median of two different scheduled medications (IQR 1,3) with a median of three (IQR 0,7) scheduled doses in a 24-hour period. Medical technology was more common in case children (42%) than in control children (14%). Central lines and enteral tubes were the most common forms of medical technology in both cases and controls. Home health referral was common in both cases (44%) and controls (23%; Table 1).

Change in Medical Complexity Models

The adjudication of new CCCs had good reliability (Κ = 0.72). New CCCs occurred in 18% and new technologies occurred in 17% of cases. Comparatively, new CCCs occurred in 10% and new technologies in 7% of hospitalizations in control children (Table 1). In bivariate analyses, both aspects of change in medical complexity were associated with higher odds of readmission (Table 2). In multivariate analysis with patient characteristics (Model 3; Table 3), all aspects of change in complexity were associated with elevated odds of readmission. A new CCC was associated with higher odds of readmission (adjusted OR (AOR) 1.75, 95% CI: 1.11-2.75) as was new technology during admission (AOR 1.84, 95%CI: 1.09-3.10). Furthermore, the odds of readmission for medical complexity variables (polypharmacy and home healthcare need) remained largely unchanged when adding the change in medical complexity variables (ie, comparing Model 1 and Model 3). However, when accounting for LOS (Model 4), neither the acquisition of a new CCC nor the addition of new technology was associated with readmission. The most common form of new technology was central line followed by nonsurgically placed enteral tube (Appendix Table 2). Finally, in sensitivity analyses (results not detailed), separating new CCC acquired at birth and new CCCs in nonbirth hospitalizations, compared to hospitalizations with no new CCC, yielded similar results as the primary analyses.

We examined multiple attributes of polypharmacy—the number of scheduled medications, number of as-needed medications, and number of scheduled doses per 24 hours. Interestingly, only the scheduled medications (count of medication and number of doses) were associated with elevated readmission risk. As-needed medications have heterogeneity in the level of importance from critical (eg, seizure rescue) to discretionary (eg, antipyretics, creams). The burden of managing these types of medications may still be high (ie, parents must decide when to administer a critical medication); however, this burden does not translate into increased readmission risk in this population.

Not surprisingly, greater medical complexity—as defined by higher numbers of scheduled discharge medications and technology assistance—is associated with 30-day readmission risk. Our analyses do not allow us to determine how much of the increased risk is due to additional care burden and risks of polypharmacy versus the inherent increase in complexity and severity of illness for which polypharmacy is a marker. Tailoring discharge regimens to the realities of daily life, with the goal of “minimally disruptive medicine”^22,23 (eg, integrating manageable discharge medication routines into school and work schedules), is not a common feature of pediatric discharge planning. For adult patients with complex medical conditions, tailoring medication regimens in a minimally disruptive way is known to improve outcomes.²⁴ Similarly, adopting minimally disruptive techniques to integrate the polypharmacy inherent in discharge could potentially mitigate some of the readmission risks for children and adolescents.

Contrary to our hypothesis, new technologies and new diagnoses did not confer additional readmission risk when accounting for LOS and patient characteristics. One potential explanation is varying risks conveyed by different types of new technologies placed during hospitalization. Central lines, the most common form of new technology, is associated with higher odds of reutilization in unadjusted analyses. However, the second most common form of new technology, nonsurgically placed enteral feeding tube, was not. Further analyses of the differential effects of new technology should be further examined in larger datasets. Additionally, the lack of additional readmission risk from new technology may relate to additional teaching and support provided to families of patients undergoing unfamiliar procedures offsets the risks inherent of greater complexity. If so, it may be that the more intensive teaching and postdischarge support provided to families with new technology or a new diagnosis could be replicated through refresher teaching during hospitalizations, when a patient’s state of health is status quo for the family (ie, the child was admitted and discharged with the same technology and diagnoses). This notion is supported by prior work that demonstrated successful readmission reduction interventions for children with chronic conditions often rely on enhanced education or coaching.^25,26

We elected to present models both with and without LOS as a confounder because it is a potentially modifiable attribute of hospitalization. Change in medical complexity aspects were significantly associated with readmission in multivariable models without LOS. However, with the addition of LOS, they were no longer significant. Thus, the readmission risk of new complexity is accounted for by the readmission risk inherent in a longer LOS. This finding prompts additional questions that merit further study: is it that LOS is a general marker for heightened complexity, or is it that a longer LOS can modify readmission risk through additional in-hospital care and time for enhanced education?

Our study has several strengths. We were able to discern true complexity at the time of discharge through medical record review. For example, if a child had a peripherally inserted central catheter placed during hospitalization, it cannot be ascertained through administrative data without medical record review if the technology was removed or in place at discharge. Likewise, medical record review allows for identification of medical technology which is not surgically implanted (eg, nasogastric feeding tubes). Given the “fog” families report as part of their in-hospital experience and its threats to education and postdischarge contingency planning,¹⁷ we felt it important to evaluate medical technology regardless of whether or not it was surgically placed. Additionally, the more detailed and nuanced understanding gained of polypharmacy burden can better inform both risk prediction models and interventions to improve the transition from hospital to home.

This study should also be considered in the context of several limitations. First, the data was from a single children’s hospital, so the generalizability of our findings is uncertain. Second, we utilized a novel method for counting new CCCs which compared information collected for clinical purposes (eg, obtaining a past medical history) with data collected for billing purposes (ie, discharge diagnoses). This comparison of information collected for different purposes potentially introduced uncertainty in the classification of diagnoses as new or not new; however, the interrater reliability for adjudicating new diagnoses suggests that the process was reasonably reliable. Third, we did not have access to other hospitals where readmissions could have occurred. While this is a common limitation for readmission studies,^{10,12,14,15,18,27-29} we attempted to mitigate any differential risk of being readmitted to other institutions by matching on distance and direction from the hospital. Of note, it is possible that children with medical complexity may be more willing to travel further to the hospital of their choice; thus our matching may be imperfect. However, there is no established method available to identify preadmission medical complexity through administrative data. Finally, the case-control method of the study makes estimating the true incidence of a variety of elements of medical complexity challenging. For example, it is difficult to tell how often children are discharged on five or more medications from a population standpoint when this practice was quite common for cases. Likewise, the true incidence of new technologies and new CCCs is challenging to estimate.

Medical complexity at discharge is associated with pediatric readmission risk. Contrary to our hypothesis, the addition of new technologies and new CCC diagnoses are not associated with pediatric readmission, after accounting for patient and hospitalization factors including LOS. The dynamics of LOS as a risk factor for readmission for children with medical complexity are likely multifaceted and merit further investigation in a multi-institutional study.

Disclosures

The authors report no potential conflicts of interest.

Funding

This work was supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1) and a grant from the Blue Cross Blue Shield of Michigan Foundation.

Hospitalizations are disruptive, stressful, and costly for patients and families.^1-5 Hospital readmissions subject families to the additional morbidity inherent to hospitalization and place patients at additional risk of hospital-acquired conditions or other harm.^6-9 In pediatrics, hospital readmissions are common for specific conditions;¹⁰ with rates varying across institutions;^10,11 and as many as one-third of unplanned pediatric readmissions are potentially preventable.¹²

Reducing pediatric readmissions requires a deeper understanding of the mechanisms through which readmissions occur. Medical complexity—specifically chronic conditions and use of medical technology—is associated with increased risk of readmission.^13,14 Polypharmacy at discharge has also been associated with readmission.^15,16 However, prior studies on polypharmacy and readmission risk examined the count of total medications and did not consider the nuances of scheduled versus as-needed medications, or the frequency of doses. These nuances may be critical to caregivers as discharge medical complexity can be overwhelming, even in diagnoses which are not traditionally considered complex.¹⁷ Finally, of potentially greater importance than medical complexity at discharge is a change in medical complexity during a hospitalization—for example, new diagnoses or new technologies that require additional education in hospital and management at home.

We sought to further understand the relationship between discharge medical complexity and readmission risk with regards to polypharmacy and home healthcare referrals at discharge. Specifically, we hypothesized that a change in medical complexity during an admission—ie, a new chronic diagnosis or new technology—would be a more prominent risk factor for readmission than discharge complexity alone. We examined these factors in the context of length of stay (LOS) since this is a marker of in-hospital severity of illness and a potentially modifiable function of time allowed for in-hospital teaching and discharge preparation.

We conducted a retrospective, case-control study of pediatric hospitalizations at one tertiary care children’s hospital. Children <18 years were eligible for inclusion. Normal birth hospitalizations were excluded. We randomly selected one hospitalization from each child as the index visit. We identified cases, hospitalizations at C.S. Mott Children’s Hospital between 2008 and 2012 with a subsequent unplanned 30-day readmission,¹⁸ and matched them one to one with hospitalizations at the same hospital during the same period without subsequent readmission. We matched cases to controls based on the month of admission to account for seasonality of certain illnesses. We also matched on distance and direction from the hospital to the patient’s home to account for the potential to have readmissions to other institutions. We utilized both distance and direction recognizing that a family living 30 miles in one direction would be closer to an urban area with access to more facilities, as opposed to 30 miles in another direction in a rural area without additional access. We subsequently performed medical record review to abstract relevant covariates.

Primary Predictors

Medical Complexity Models (Models 1 and 2):

We evaluated three attributes of discharge medical complexity abstracted by medical record review—discharge medications, technology assistance (ie, tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, central line), and the need for home healthcare after discharge. We counted discharge medications based on the number of medications listed on the discharge summary separated into scheduled or as needed.¹⁹ We also considered the number of scheduled doses to be administered in a 24-hour period (see Appendix methods for more information on counting discharge medications). For assistance by technology, we considered the presence of tracheostomy, cerebral spinal fluid ventricular shunt, enteral feeding tube, and central lines. While we describe these technologies separately, for multivariable analyses we considered the presence of any of the four types of technology.

Change in Medical Complexity Models (Models 3 and 4)

We examined two aspects of change in medical complexity—the presence of a new complex chronic condition (CCC)²⁰ diagnosed during the hospitalization, and a new reliance on medical technology. The presence of new CCC was determined by comparing discharge diagnoses to past medical history abstracted by medical record review. A new CCC was defined as any complex chronic condition that was captured in the discharge diagnoses but was not evident in the past medical history. By definition, all CCCs coded during birth hospitalization (eg, at discharge from the neonatal intensive care unit) were assigned to “new” CCC. We calculated a kappa statistic to determine interrater reliability in determining the designation of new CCC. A sensitivity analysis examining these birth CCCs was also performed comparing no new CCC, new CCC, and new CCC after birth hospitalization. The methods appendix provides additional information on considering new CCCs. New technology, abstracted from chart review, was defined as technology placed during hospitalization that remained in place at discharge. If a child with existing technology had additional technology placed during the hospitalization (eg, a new tracheostomy in a child with a previously placed enteral feeding tube), the encounter was considered as having new technology placed.

Covariates

We created different sets of multivariable models to account for patient/hospitalization characteristics. In Models 1 and 3, we examined the primary predictors adjusting for patient characteristics (age, race/ethnicity, sex, and insurance). In Models 2 and 4, we added the index hospitalization LOS into the multivariable models adjusting for patient characteristics. We chose to add LOS in a second set of models because it is a potentially important confounder in readmission risk: discharge timing is a modifiable factor dependent on both physiologic recovery and the medical team’s perception of caregiver’s readiness for discharge. We elected to present models with and without LOS since LOS is also a marker of illness severity while in the hospital and is linked to discharge complexity.

Statistical Analysis

A review of 600 cases and 600 controls yields 89% power to detect statistical significance for covariates with an odds ratio of 1.25 (β = 0.22) if the candidate covariate has low to moderate correlation with other covariates (<0.3). If a candidate covariate has a moderate correlation with other covariates (0.6), we have 89% power to detect an odds ratio of 1.35 (β = 0.30).²¹ We calculated odds of 30-days unplanned readmission using conditional logistic regression to account for matched case-control design. All the analyses were performed using STATA 13 (Stata Corp., College Station, Texas).

Of the 41,422 eligible index hospitalizations during the study period, 9.4% resulted in a 30-day unplanned readmission. After randomly selecting one hospitalization per child, there were 781 eligible cases. We subsequent matched all but one eligible case to a control. We randomly selected encounters for medical record review, reviewing a total of 1,212 encounters. After excluding pairs with incomplete records, we included 595 cases and 595 controls in this analysis (Figure). Patient/hospitalization characteristics are displayed in Table 1. The most frequent primary discharge diagnoses are displayed in Appendix Table 1.

Models of Medical Complexity at Discharge

Polypharmacy after discharge was common for both readmitted and nonreadmitted patients. Children who experienced unplanned readmission in 30 days were discharged with a median of four different scheduled medications (interquartile range [IQR] 2,7) which translated into a median of six (IQR 3,12) scheduled doses in a 24-hour period. In comparison, children without an unplanned readmission had a median of two different scheduled medications (IQR 1,3) with a median of three (IQR 0,7) scheduled doses in a 24-hour period. Medical technology was more common in case children (42%) than in control children (14%). Central lines and enteral tubes were the most common forms of medical technology in both cases and controls. Home health referral was common in both cases (44%) and controls (23%; Table 1).

Change in Medical Complexity Models

The adjudication of new CCCs had good reliability (Κ = 0.72). New CCCs occurred in 18% and new technologies occurred in 17% of cases. Comparatively, new CCCs occurred in 10% and new technologies in 7% of hospitalizations in control children (Table 1). In bivariate analyses, both aspects of change in medical complexity were associated with higher odds of readmission (Table 2). In multivariate analysis with patient characteristics (Model 3; Table 3), all aspects of change in complexity were associated with elevated odds of readmission. A new CCC was associated with higher odds of readmission (adjusted OR (AOR) 1.75, 95% CI: 1.11-2.75) as was new technology during admission (AOR 1.84, 95%CI: 1.09-3.10). Furthermore, the odds of readmission for medical complexity variables (polypharmacy and home healthcare need) remained largely unchanged when adding the change in medical complexity variables (ie, comparing Model 1 and Model 3). However, when accounting for LOS (Model 4), neither the acquisition of a new CCC nor the addition of new technology was associated with readmission. The most common form of new technology was central line followed by nonsurgically placed enteral tube (Appendix Table 2). Finally, in sensitivity analyses (results not detailed), separating new CCC acquired at birth and new CCCs in nonbirth hospitalizations, compared to hospitalizations with no new CCC, yielded similar results as the primary analyses.

We examined multiple attributes of polypharmacy—the number of scheduled medications, number of as-needed medications, and number of scheduled doses per 24 hours. Interestingly, only the scheduled medications (count of medication and number of doses) were associated with elevated readmission risk. As-needed medications have heterogeneity in the level of importance from critical (eg, seizure rescue) to discretionary (eg, antipyretics, creams). The burden of managing these types of medications may still be high (ie, parents must decide when to administer a critical medication); however, this burden does not translate into increased readmission risk in this population.

Not surprisingly, greater medical complexity—as defined by higher numbers of scheduled discharge medications and technology assistance—is associated with 30-day readmission risk. Our analyses do not allow us to determine how much of the increased risk is due to additional care burden and risks of polypharmacy versus the inherent increase in complexity and severity of illness for which polypharmacy is a marker. Tailoring discharge regimens to the realities of daily life, with the goal of “minimally disruptive medicine”^22,23 (eg, integrating manageable discharge medication routines into school and work schedules), is not a common feature of pediatric discharge planning. For adult patients with complex medical conditions, tailoring medication regimens in a minimally disruptive way is known to improve outcomes.²⁴ Similarly, adopting minimally disruptive techniques to integrate the polypharmacy inherent in discharge could potentially mitigate some of the readmission risks for children and adolescents.

Contrary to our hypothesis, new technologies and new diagnoses did not confer additional readmission risk when accounting for LOS and patient characteristics. One potential explanation is varying risks conveyed by different types of new technologies placed during hospitalization. Central lines, the most common form of new technology, is associated with higher odds of reutilization in unadjusted analyses. However, the second most common form of new technology, nonsurgically placed enteral feeding tube, was not. Further analyses of the differential effects of new technology should be further examined in larger datasets. Additionally, the lack of additional readmission risk from new technology may relate to additional teaching and support provided to families of patients undergoing unfamiliar procedures offsets the risks inherent of greater complexity. If so, it may be that the more intensive teaching and postdischarge support provided to families with new technology or a new diagnosis could be replicated through refresher teaching during hospitalizations, when a patient’s state of health is status quo for the family (ie, the child was admitted and discharged with the same technology and diagnoses). This notion is supported by prior work that demonstrated successful readmission reduction interventions for children with chronic conditions often rely on enhanced education or coaching.^25,26

We elected to present models both with and without LOS as a confounder because it is a potentially modifiable attribute of hospitalization. Change in medical complexity aspects were significantly associated with readmission in multivariable models without LOS. However, with the addition of LOS, they were no longer significant. Thus, the readmission risk of new complexity is accounted for by the readmission risk inherent in a longer LOS. This finding prompts additional questions that merit further study: is it that LOS is a general marker for heightened complexity, or is it that a longer LOS can modify readmission risk through additional in-hospital care and time for enhanced education?

Our study has several strengths. We were able to discern true complexity at the time of discharge through medical record review. For example, if a child had a peripherally inserted central catheter placed during hospitalization, it cannot be ascertained through administrative data without medical record review if the technology was removed or in place at discharge. Likewise, medical record review allows for identification of medical technology which is not surgically implanted (eg, nasogastric feeding tubes). Given the “fog” families report as part of their in-hospital experience and its threats to education and postdischarge contingency planning,¹⁷ we felt it important to evaluate medical technology regardless of whether or not it was surgically placed. Additionally, the more detailed and nuanced understanding gained of polypharmacy burden can better inform both risk prediction models and interventions to improve the transition from hospital to home.

This study should also be considered in the context of several limitations. First, the data was from a single children’s hospital, so the generalizability of our findings is uncertain. Second, we utilized a novel method for counting new CCCs which compared information collected for clinical purposes (eg, obtaining a past medical history) with data collected for billing purposes (ie, discharge diagnoses). This comparison of information collected for different purposes potentially introduced uncertainty in the classification of diagnoses as new or not new; however, the interrater reliability for adjudicating new diagnoses suggests that the process was reasonably reliable. Third, we did not have access to other hospitals where readmissions could have occurred. While this is a common limitation for readmission studies,^{10,12,14,15,18,27-29} we attempted to mitigate any differential risk of being readmitted to other institutions by matching on distance and direction from the hospital. Of note, it is possible that children with medical complexity may be more willing to travel further to the hospital of their choice; thus our matching may be imperfect. However, there is no established method available to identify preadmission medical complexity through administrative data. Finally, the case-control method of the study makes estimating the true incidence of a variety of elements of medical complexity challenging. For example, it is difficult to tell how often children are discharged on five or more medications from a population standpoint when this practice was quite common for cases. Likewise, the true incidence of new technologies and new CCCs is challenging to estimate.

Medical complexity at discharge is associated with pediatric readmission risk. Contrary to our hypothesis, the addition of new technologies and new CCC diagnoses are not associated with pediatric readmission, after accounting for patient and hospitalization factors including LOS. The dynamics of LOS as a risk factor for readmission for children with medical complexity are likely multifaceted and merit further investigation in a multi-institutional study.

Disclosures

The authors report no potential conflicts of interest.

Funding

This work was supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1) and a grant from the Blue Cross Blue Shield of Michigan Foundation.

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

A proposal by the Centers for Medicare & Medicaid Services to require full price transparency, including the disclosure of both list prices and payer-negotiated prices, is already receiving pushback.

Ivary/Thinkstock

Rick Pollack, president and CEO of the American Hospital Association, said in a statement that “mandating disclosure of negotiated rates between insurers and hospitals is the wrong approach,” adding that it “could seriously limit the choices available to patients in the private market and fuel anticompetitive behavior among commercial health insurers in an already highly concentrated insurance industry.”

The requirement for hospital price transparency was posted online July 29 as part of the proposed annual update to the hospital outpatient prospective payment system (OPPS) for 2020. It is scheduled for publication in the Federal Register on Aug. 9.

CMS is proposing, beginning in calendar year 2020, that hospitals make publicly available their “standard charges,” defined as the gross – or list – price of for all services provided by the hospital, as well as payer-specific negotiated prices. To allow for price comparisons, prices would be posted on the Internet in a machine-readable file that includes common billing or accounting codes and a description of the item of service being delivered.

Additionally, hospitals must make payer-specific negotiated prices for “shoppable” services, defined as services that can be scheduled in advance – such as x-rays, outpatient visits, imaging and laboratory tests, or bundled services like a cesarean delivery with pre- and postdelivery care – in a consumer-friendly manner.

“As deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” CMS Administrator Seema Verma said during a July 29 press conference. “In fact, a recent poll showed that the majority of Americans have tried to get pricing information before getting care, but have found it challenging to find that information.”

She noted that patients may see prices that range from 150% of Medicare rates to more than 400% for the same service.

Hospitals will need to display at least 300 shoppable services, including 70 that are CMS selected and 230 that are hospital selected, according to a fact sheet outlining this and other proposed OPPS updates for 2020.

“If a hospital does not provide one or more of the 70 CMS selected shoppable services, the hospital must select additional shoppable services such that the total number of shoppable services is at least 300,” the fact sheet states.

Information on pricing will be required to be updated at least annually.

CMS is including enforcement tools as part of the proposal, including fines to hospitals for noncompliance.

“Price transparency creates a marketplace where providers compete on the basis of cost and quality that will lower cost,” Ms. Verma said.

However, that notion has been challenged by America’s Health Insurance Plans (AHIP).

Matt Eyles, president and CEO of AHIP said in a statement that “multiple experts, including the Federal Trade Commission, agree that disclosing privately negotiated rates will make it harder to bargain for lower rates, creating a floor, not a ceiling, for the prices that hospitals would be willing to accept. Publicly disclosing competitively negotiated, proprietary rates will push prices and premiums higher, not lower, for consumers, patients, and taxpayers.”

Mr. Pollack of the American Hospital Association agreed. “While we support transparency, [this] proposal misses the mark, exceeds the Administration’s legal authority, and should be abandoned.”

Ms. Verma said she believed the agency had legal authority to impose this requirement and is not worried about possible lawsuits that could challenge this provision.

“This administration is not afraid of those things,” she said. “We are not about protecting the status quo when it doesn’t work for patients.”

gtwachtman@mdedge.com

A proposal by the Centers for Medicare & Medicaid Services to require full price transparency, including the disclosure of both list prices and payer-negotiated prices, is already receiving pushback.

Ivary/Thinkstock

Rick Pollack, president and CEO of the American Hospital Association, said in a statement that “mandating disclosure of negotiated rates between insurers and hospitals is the wrong approach,” adding that it “could seriously limit the choices available to patients in the private market and fuel anticompetitive behavior among commercial health insurers in an already highly concentrated insurance industry.”

The requirement for hospital price transparency was posted online July 29 as part of the proposed annual update to the hospital outpatient prospective payment system (OPPS) for 2020. It is scheduled for publication in the Federal Register on Aug. 9.

CMS is proposing, beginning in calendar year 2020, that hospitals make publicly available their “standard charges,” defined as the gross – or list – price of for all services provided by the hospital, as well as payer-specific negotiated prices. To allow for price comparisons, prices would be posted on the Internet in a machine-readable file that includes common billing or accounting codes and a description of the item of service being delivered.

Additionally, hospitals must make payer-specific negotiated prices for “shoppable” services, defined as services that can be scheduled in advance – such as x-rays, outpatient visits, imaging and laboratory tests, or bundled services like a cesarean delivery with pre- and postdelivery care – in a consumer-friendly manner.

“As deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” CMS Administrator Seema Verma said during a July 29 press conference. “In fact, a recent poll showed that the majority of Americans have tried to get pricing information before getting care, but have found it challenging to find that information.”

She noted that patients may see prices that range from 150% of Medicare rates to more than 400% for the same service.

Hospitals will need to display at least 300 shoppable services, including 70 that are CMS selected and 230 that are hospital selected, according to a fact sheet outlining this and other proposed OPPS updates for 2020.

“If a hospital does not provide one or more of the 70 CMS selected shoppable services, the hospital must select additional shoppable services such that the total number of shoppable services is at least 300,” the fact sheet states.

Information on pricing will be required to be updated at least annually.

CMS is including enforcement tools as part of the proposal, including fines to hospitals for noncompliance.

“Price transparency creates a marketplace where providers compete on the basis of cost and quality that will lower cost,” Ms. Verma said.

However, that notion has been challenged by America’s Health Insurance Plans (AHIP).

Matt Eyles, president and CEO of AHIP said in a statement that “multiple experts, including the Federal Trade Commission, agree that disclosing privately negotiated rates will make it harder to bargain for lower rates, creating a floor, not a ceiling, for the prices that hospitals would be willing to accept. Publicly disclosing competitively negotiated, proprietary rates will push prices and premiums higher, not lower, for consumers, patients, and taxpayers.”

Mr. Pollack of the American Hospital Association agreed. “While we support transparency, [this] proposal misses the mark, exceeds the Administration’s legal authority, and should be abandoned.”

Ms. Verma said she believed the agency had legal authority to impose this requirement and is not worried about possible lawsuits that could challenge this provision.

“This administration is not afraid of those things,” she said. “We are not about protecting the status quo when it doesn’t work for patients.”

gtwachtman@mdedge.com

A proposal by the Centers for Medicare & Medicaid Services to require full price transparency, including the disclosure of both list prices and payer-negotiated prices, is already receiving pushback.

Ivary/Thinkstock

Rick Pollack, president and CEO of the American Hospital Association, said in a statement that “mandating disclosure of negotiated rates between insurers and hospitals is the wrong approach,” adding that it “could seriously limit the choices available to patients in the private market and fuel anticompetitive behavior among commercial health insurers in an already highly concentrated insurance industry.”

The requirement for hospital price transparency was posted online July 29 as part of the proposed annual update to the hospital outpatient prospective payment system (OPPS) for 2020. It is scheduled for publication in the Federal Register on Aug. 9.

CMS is proposing, beginning in calendar year 2020, that hospitals make publicly available their “standard charges,” defined as the gross – or list – price of for all services provided by the hospital, as well as payer-specific negotiated prices. To allow for price comparisons, prices would be posted on the Internet in a machine-readable file that includes common billing or accounting codes and a description of the item of service being delivered.

Additionally, hospitals must make payer-specific negotiated prices for “shoppable” services, defined as services that can be scheduled in advance – such as x-rays, outpatient visits, imaging and laboratory tests, or bundled services like a cesarean delivery with pre- and postdelivery care – in a consumer-friendly manner.

“As deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” CMS Administrator Seema Verma said during a July 29 press conference. “In fact, a recent poll showed that the majority of Americans have tried to get pricing information before getting care, but have found it challenging to find that information.”

She noted that patients may see prices that range from 150% of Medicare rates to more than 400% for the same service.

Hospitals will need to display at least 300 shoppable services, including 70 that are CMS selected and 230 that are hospital selected, according to a fact sheet outlining this and other proposed OPPS updates for 2020.

“If a hospital does not provide one or more of the 70 CMS selected shoppable services, the hospital must select additional shoppable services such that the total number of shoppable services is at least 300,” the fact sheet states.

Information on pricing will be required to be updated at least annually.

CMS is including enforcement tools as part of the proposal, including fines to hospitals for noncompliance.

“Price transparency creates a marketplace where providers compete on the basis of cost and quality that will lower cost,” Ms. Verma said.

However, that notion has been challenged by America’s Health Insurance Plans (AHIP).

Matt Eyles, president and CEO of AHIP said in a statement that “multiple experts, including the Federal Trade Commission, agree that disclosing privately negotiated rates will make it harder to bargain for lower rates, creating a floor, not a ceiling, for the prices that hospitals would be willing to accept. Publicly disclosing competitively negotiated, proprietary rates will push prices and premiums higher, not lower, for consumers, patients, and taxpayers.”

Mr. Pollack of the American Hospital Association agreed. “While we support transparency, [this] proposal misses the mark, exceeds the Administration’s legal authority, and should be abandoned.”

Ms. Verma said she believed the agency had legal authority to impose this requirement and is not worried about possible lawsuits that could challenge this provision.

“This administration is not afraid of those things,” she said. “We are not about protecting the status quo when it doesn’t work for patients.”

gtwachtman@mdedge.com

Trial results suggest African children with uncomplicated, severe anemia may not require immediate blood transfusion, and the volume of transfusion may only matter in the context of fever.

roobcio/Thinkstock

The TRACT trial showed no significant differences in 28-day mortality or other clinical outcomes between children who received immediate transfusions and those who did not.

Similarly, there was no significant difference in 28-day mortality among children who received transfusions of 20 mL/kg and those who received transfusions of 30 mL/kg. There was evidence to suggest a higher transfusion volume may benefit children without fevers, but this was an exploratory endpoint. The findings were published in the New England Journal of Medicine.

These results suggest “there is no credible reason to transfuse immediately or to transfuse a higher volume of blood, at least in pediatric populations in regions such as these two sub-Saharan countries [Uganda and Malawi],” Julie R. Ingelfinger, MD, of Massachusetts General Hospital in Boston, wrote in an accompanying editorial, also published in the New England Journal of Medicine (2019;381:475-6).

“The possible effect of higher volume transfusion in patients with fever may trigger additional and potentially useful studies,” she added.

Immediate transfusion

One goal of the TRACT trial was to determine if blood transfusion is the best treatment for children with severe anemia. With this in mind, Kathryn Maitland, MD, PhD, of Imperial College London and colleagues evaluated 1,565 Ugandan and Malawian children with uncomplicated, severe anemia. The patients’ median age was 26 months, and 984 (62.9%) had malaria.

The children were randomized to immediate transfusion (n = 778) or no immediate transfusion (n = 787). Children who did not have an immediate transfusion (control group) could receive a transfusion if they exhibited new signs of clinical severity or had their hemoglobin decrease to below 4 g/dL.

All children in the immediate-transfusion group received a transfusion, as did 386 (49.0%) in the control group. The median time to transfusion was 1.3 hours in the immediate group and 24.9 hours in the control group. The mean total blood volume transfused per child was 314 plus or minus 228 mL and 142 plus or minus 224, respectively. The follow-up period was 180 days, and 4.5% of patients (n = 71) were lost to follow-up.

The researchers found no significant difference between the treatment groups with regard to mortality, other clinical outcomes, or the cost of care.

The 28-day mortality rate was 0.9% in the immediate-transfusion group and 1.7% in the control group (hazard ratio, 0.54; 95% confidence interval, 0.22-1.36; P = .19). The 180-day mortality was 4.5% and 6.0%, respectively (HR, 0.75; 95% CI, 0.48-1.15).
 

Transfusion volume

To assess the effects of transfusion volume, Dr. Maitland and colleagues evaluated 3,196 Ugandan and Malawian children with severe anemia. The median age of the children was 37 months, and 2,050 (64.1%) had malaria.

The children received a transfusion of 30 mL/kg (n = 1,592) or 20 mL/kg (n = 1,596) at a median of 1.2 hours after randomization. Some children – 197 in the 30-mL/kg group and 300 in the 20-mL/kg group – received additional transfusions. The mean volume of total blood transfused per child was 475 plus or minus 385 mL, and 353 plus or minus 348 mL, respectively.

Overall, there was no significant between-group difference with regard to mortality. The 28-day mortality rate was 3.4% in the 30 mL/kg group and 4.5% in the 20 mL/kg group (HR = 0.76; 95% CI, 0.54 to 1.08; P = .12).

However, the 28-day mortality rate did differ according to the presence of fever at screening. The mortality rate was lower in the 30 mL/kg group for children without fevers (HR = 0.43; 95% CI, 0.27 to 0.69) but higher in the 30 mL/kg group for febrile children (HR = 1.91; 95% CI, 1.04 to 3.49).

For other outcomes, including readmissions and serious adverse events, the researchers found no significant between-group differences.

This trial was supported by a grant from the United Kingdom Medical Research Council through a concordat with the Department for International Development. One researcher has a Wellcome Senior Research Fellowship, and another is a National Institute for Health Research Senior Investigator. Dr. Ingelfinger is a deputy editor at the New England Journal of Medicine. No other relevant conflicts of interest were reported.

jensmith@mdedge.com

SOURCES: Maitland K et al. N Engl J Med. 2019;381:407-19. Maitland K et al. N Engl J Med. 2019;381:420-31.


 

Trial results suggest African children with uncomplicated, severe anemia may not require immediate blood transfusion, and the volume of transfusion may only matter in the context of fever.

roobcio/Thinkstock

The TRACT trial showed no significant differences in 28-day mortality or other clinical outcomes between children who received immediate transfusions and those who did not.

Similarly, there was no significant difference in 28-day mortality among children who received transfusions of 20 mL/kg and those who received transfusions of 30 mL/kg. There was evidence to suggest a higher transfusion volume may benefit children without fevers, but this was an exploratory endpoint. The findings were published in the New England Journal of Medicine.

These results suggest “there is no credible reason to transfuse immediately or to transfuse a higher volume of blood, at least in pediatric populations in regions such as these two sub-Saharan countries [Uganda and Malawi],” Julie R. Ingelfinger, MD, of Massachusetts General Hospital in Boston, wrote in an accompanying editorial, also published in the New England Journal of Medicine (2019;381:475-6).

“The possible effect of higher volume transfusion in patients with fever may trigger additional and potentially useful studies,” she added.

Immediate transfusion

One goal of the TRACT trial was to determine if blood transfusion is the best treatment for children with severe anemia. With this in mind, Kathryn Maitland, MD, PhD, of Imperial College London and colleagues evaluated 1,565 Ugandan and Malawian children with uncomplicated, severe anemia. The patients’ median age was 26 months, and 984 (62.9%) had malaria.

The children were randomized to immediate transfusion (n = 778) or no immediate transfusion (n = 787). Children who did not have an immediate transfusion (control group) could receive a transfusion if they exhibited new signs of clinical severity or had their hemoglobin decrease to below 4 g/dL.

All children in the immediate-transfusion group received a transfusion, as did 386 (49.0%) in the control group. The median time to transfusion was 1.3 hours in the immediate group and 24.9 hours in the control group. The mean total blood volume transfused per child was 314 plus or minus 228 mL and 142 plus or minus 224, respectively. The follow-up period was 180 days, and 4.5% of patients (n = 71) were lost to follow-up.

The researchers found no significant difference between the treatment groups with regard to mortality, other clinical outcomes, or the cost of care.

The 28-day mortality rate was 0.9% in the immediate-transfusion group and 1.7% in the control group (hazard ratio, 0.54; 95% confidence interval, 0.22-1.36; P = .19). The 180-day mortality was 4.5% and 6.0%, respectively (HR, 0.75; 95% CI, 0.48-1.15).
 

Transfusion volume

To assess the effects of transfusion volume, Dr. Maitland and colleagues evaluated 3,196 Ugandan and Malawian children with severe anemia. The median age of the children was 37 months, and 2,050 (64.1%) had malaria.

The children received a transfusion of 30 mL/kg (n = 1,592) or 20 mL/kg (n = 1,596) at a median of 1.2 hours after randomization. Some children – 197 in the 30-mL/kg group and 300 in the 20-mL/kg group – received additional transfusions. The mean volume of total blood transfused per child was 475 plus or minus 385 mL, and 353 plus or minus 348 mL, respectively.

Overall, there was no significant between-group difference with regard to mortality. The 28-day mortality rate was 3.4% in the 30 mL/kg group and 4.5% in the 20 mL/kg group (HR = 0.76; 95% CI, 0.54 to 1.08; P = .12).

However, the 28-day mortality rate did differ according to the presence of fever at screening. The mortality rate was lower in the 30 mL/kg group for children without fevers (HR = 0.43; 95% CI, 0.27 to 0.69) but higher in the 30 mL/kg group for febrile children (HR = 1.91; 95% CI, 1.04 to 3.49).

For other outcomes, including readmissions and serious adverse events, the researchers found no significant between-group differences.

This trial was supported by a grant from the United Kingdom Medical Research Council through a concordat with the Department for International Development. One researcher has a Wellcome Senior Research Fellowship, and another is a National Institute for Health Research Senior Investigator. Dr. Ingelfinger is a deputy editor at the New England Journal of Medicine. No other relevant conflicts of interest were reported.

jensmith@mdedge.com

SOURCES: Maitland K et al. N Engl J Med. 2019;381:407-19. Maitland K et al. N Engl J Med. 2019;381:420-31.


 

Trial results suggest African children with uncomplicated, severe anemia may not require immediate blood transfusion, and the volume of transfusion may only matter in the context of fever.

roobcio/Thinkstock

The TRACT trial showed no significant differences in 28-day mortality or other clinical outcomes between children who received immediate transfusions and those who did not.

Similarly, there was no significant difference in 28-day mortality among children who received transfusions of 20 mL/kg and those who received transfusions of 30 mL/kg. There was evidence to suggest a higher transfusion volume may benefit children without fevers, but this was an exploratory endpoint. The findings were published in the New England Journal of Medicine.

These results suggest “there is no credible reason to transfuse immediately or to transfuse a higher volume of blood, at least in pediatric populations in regions such as these two sub-Saharan countries [Uganda and Malawi],” Julie R. Ingelfinger, MD, of Massachusetts General Hospital in Boston, wrote in an accompanying editorial, also published in the New England Journal of Medicine (2019;381:475-6).

“The possible effect of higher volume transfusion in patients with fever may trigger additional and potentially useful studies,” she added.

Immediate transfusion

One goal of the TRACT trial was to determine if blood transfusion is the best treatment for children with severe anemia. With this in mind, Kathryn Maitland, MD, PhD, of Imperial College London and colleagues evaluated 1,565 Ugandan and Malawian children with uncomplicated, severe anemia. The patients’ median age was 26 months, and 984 (62.9%) had malaria.

The children were randomized to immediate transfusion (n = 778) or no immediate transfusion (n = 787). Children who did not have an immediate transfusion (control group) could receive a transfusion if they exhibited new signs of clinical severity or had their hemoglobin decrease to below 4 g/dL.

All children in the immediate-transfusion group received a transfusion, as did 386 (49.0%) in the control group. The median time to transfusion was 1.3 hours in the immediate group and 24.9 hours in the control group. The mean total blood volume transfused per child was 314 plus or minus 228 mL and 142 plus or minus 224, respectively. The follow-up period was 180 days, and 4.5% of patients (n = 71) were lost to follow-up.

The researchers found no significant difference between the treatment groups with regard to mortality, other clinical outcomes, or the cost of care.

The 28-day mortality rate was 0.9% in the immediate-transfusion group and 1.7% in the control group (hazard ratio, 0.54; 95% confidence interval, 0.22-1.36; P = .19). The 180-day mortality was 4.5% and 6.0%, respectively (HR, 0.75; 95% CI, 0.48-1.15).
 

Transfusion volume

To assess the effects of transfusion volume, Dr. Maitland and colleagues evaluated 3,196 Ugandan and Malawian children with severe anemia. The median age of the children was 37 months, and 2,050 (64.1%) had malaria.

The children received a transfusion of 30 mL/kg (n = 1,592) or 20 mL/kg (n = 1,596) at a median of 1.2 hours after randomization. Some children – 197 in the 30-mL/kg group and 300 in the 20-mL/kg group – received additional transfusions. The mean volume of total blood transfused per child was 475 plus or minus 385 mL, and 353 plus or minus 348 mL, respectively.

Overall, there was no significant between-group difference with regard to mortality. The 28-day mortality rate was 3.4% in the 30 mL/kg group and 4.5% in the 20 mL/kg group (HR = 0.76; 95% CI, 0.54 to 1.08; P = .12).

However, the 28-day mortality rate did differ according to the presence of fever at screening. The mortality rate was lower in the 30 mL/kg group for children without fevers (HR = 0.43; 95% CI, 0.27 to 0.69) but higher in the 30 mL/kg group for febrile children (HR = 1.91; 95% CI, 1.04 to 3.49).

For other outcomes, including readmissions and serious adverse events, the researchers found no significant between-group differences.

This trial was supported by a grant from the United Kingdom Medical Research Council through a concordat with the Department for International Development. One researcher has a Wellcome Senior Research Fellowship, and another is a National Institute for Health Research Senior Investigator. Dr. Ingelfinger is a deputy editor at the New England Journal of Medicine. No other relevant conflicts of interest were reported.

jensmith@mdedge.com

SOURCES: Maitland K et al. N Engl J Med. 2019;381:407-19. Maitland K et al. N Engl J Med. 2019;381:420-31.


 

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

lfranki@mdedge.com

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

lfranki@mdedge.com

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

lfranki@mdedge.com

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

jremaly@mdedge.com

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

jremaly@mdedge.com

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

jremaly@mdedge.com

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.