Clinical Guideline Highlights

Alcohol is the most common substance implicated in hospitalizations for substance use disorders,¹ and as a result, hospitalists commonly diagnose and manage alcohol withdrawal syndrome (AWS) in the inpatient medical setting. The 2020 guidelines of the American Society of Addiction Medicine (ASAM) provide updated recommendations for the diagnosis, monitoring, and treatment of patients hospitalized with AWS, which we have condensed to emphasize key changes from the last update² and clarify ongoing areas of uncertainty. 

Diagnosis

Recommendation 1. All inpatients who have used alcohol recently or regularly should be risk-stratified for AWS, regardless of whether or not they have suggestive symptoms (recommendations I.3, I.4, I.5, II.10). The Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) identifies patients at risk for AWS, and the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) identifies those at risk for severe or complicated AWS, which includes seizures and alcohol withdrawal delirium (formerly delirium tremens). The guideline emphasizes use of these tools rather than simply initiating Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) monitoring on all such patients to diagnose AWS, as CIWA-Ar was developed for monitoring response to treatment, not diagnosis (recommendation I.6). 

Treating Mild/Moderate or Uncomplicated AWS

Recommendation 2. Because of their proven track record of reducing the incidence of seizure and alcohol withdrawal delirium, benzodiazepines remain the recommended first-line therapy (recommendations V.13, V.16). Symptom-triggered administration of benzodiazepines (via CIWA-Ar) is recommended over fixed-dose administration because the former is associated with shorter length of stay and lower cumulative benzodiazepine administration^3,4 (recommendation V.23). Patients with mild AWS who are at low risk for severe or complicated withdrawal should be monitored for up to 36 hours for the development of worsening symptoms (recommendation V.1). For patients with high CIWA-Ar scores or who are at increased risk for severe or complicated AWS, frequent administration of moderate to high doses of a long-acting benzodiazepine early in AWS treatment (a practice called frontloading) is recommended to quickly control symptoms and prevent clinical worsening. This approach has been shown to reduce the incidence of seizures and alcohol withdrawal delirium (recommendations V.14, V.19, V.24).

Carbamazepine or gabapentin may be used in mild or moderate AWS if benzodiazepines are contraindicated; however, neither agent is recommended as first-line therapy because a clear reduction in seizure and withdrawal delirium has not been established (recommendation V.16). Alpha-2 agonists (eg, clonidine, dexmedetomidine) may be used to treat persistent autonomic hyperactivity or anxiety when these are not adequately controlled by benzodiazepines alone (recommendation V.36).

Treating Severe or Complicated AWS

Recommendation 3. The guideline defines severe AWS as withdrawal with severe signs and symptoms, and complicated AWS as withdrawal accompanied by seizures or delirium (Appendix Table⁵). The development of complications warrants prompt treatment. Patients who experience seizure should receive a fast-acting benzodiazepine (eg, intravenous [IV] diazepam or lorazepam) (recommendation VI.4). Patients with withdrawal delirium should receive a benzodiazepine (preferably parenterally) dosed to achieve light sedation. Clinicians should be prepared for the possibility that large doses may be required and to monitor patients for oversedation and respiratory depression (recommendations VI.13, VI.17). Antipsychotics may be used as adjuncts when withdrawal delirium or other symptoms, such as hallucinosis, are not adequately controlled by benzodiazepines alone, but should not be used as monotherapy (recommendation VI.20). The guideline emphasizes that alpha-2 agonists should not be used to treat withdrawal delirium (recommendation VI.21), but they may be used as adjuncts for resistant alcohol withdrawal in the intensive care unit (ICU) (recommendations VI.27, VI.29). Phenobarbital is an acceptable alternative to benzodiazepines for severe withdrawal (recommendation V.17); however, the guideline recommends that clinicians should be experienced in its use.

Treating Wernicke Encephalopathy

Recommendation 4. Thiamine should be administered to prevent Wernicke encephalopathy (WE), with parenteral formulations recommended in patients with malnutrition, severe/complicated withdrawal, or requiring ICU-level care (recommendations V.7, V.8). In particular, all patients admitted to an ICU for AWS should receive thiamine, as diagnosis of WE is often difficult in this population. Although there is no consensus on the required dose of thiamine to treat WE, 100 mg IV or intramuscularly (IM) daily for 3 to 5 days is commonly administered (recommendation V.7). Because of a lack of evidence of harm, thiamine may be given before, after, or concurrently with glucose or dextrose (recommendation V.7). The guideline does not make a specific recommendation regarding how to risk-stratify patients for WE.

Treating Underlying Alcohol Use Disorder 

Recommendation 5. Hospitalization for AWS is an important opportunity to engage patients in treatment for alcohol use disorder (AUD), including pharmacotherapy and connection with outpatient providers (recommendation V.12). The guideline emphasizes that treatment for AUD should be initiated concomitantly with AWS management whenever possible but does not make recommendations regarding specific pharmacotherapies.

This guideline was authored by a committee of emergency medicine physicians, psychiatrists, and internists using the Department of Veterans Affairs/Department of Defense guidelines and the RAND/UCLA appropriateness method to combine the scientific literature with expert opinion. The result is a series of recommendations for physicians, physician assistants, nurse practitioners, and pharmacists that are not rated by strength; an assessment of the quality of the supporting evidence is available in an appendix. Four of the nine guideline committee members reported significant financial relationships with industry and other entities relevant to these guidelines.

Despite concern about oversedation from phenobarbital raised in small case series,⁶ observational studies comparing phenobarbital with benzodiazepines suggest phenobarbital has similar efficacy for treating AWS and that oversedation is rare.^7-9 Large randomized controlled trials in this area are lacking; however, at least one small randomized controlled trial¹⁰ among patients with AWS presenting to emergency departments supports the safety and efficacy of phenobarbital when used in combination with benzodiazepines. Given the growing body of evidence supporting the safety of phenobarbital, we believe a stronger recommendation for use in patients presenting with alcohol withdrawal delirium or treatment-resistant alcohol withdrawal is warranted. The guidelines also suggest that only “experienced clinicians” use phenobarbital for AWS, which may suppress appropriate use. Nationally, phenobarbital use for AWS remains low.¹¹Finally, although the guideline recommends initiation of treatment for AUD, specific recommendations for pharmacotherapy are not provided. Three medications currently have approval from the US Food and Drug Administration for treatment of AUD: acamprosate, naltrexone, and disulfiram. Large randomized controlled trials support the safety and efficacy of acamprosate and naltrexone, with or without counselling, in the treatment of AUD,¹² and disulfiram may be appropriate for selected highly motivated patients. We believe more specific recommendations to assist in choosing among these options would be useful.

More data are needed on the safety and efficacy of phenobarbital in patients with AWS, as well as comparative effectiveness against benzodiazepines. Recruitment is ongoing for a single clinical trial comparing the effect of phenobarbital and lorazepam on length of stay among patients in the ICU with AWS (NCT04156464); to date, no randomized trials of phenobarbital have been conducted in medical inpatients with AWS. In addition, gaps in the literature exist regarding benzodiazepine selection, and head-to-head comparisons of symptom-triggered usage of different benzodiazepines are lacking.

Alcohol is the most common substance implicated in hospitalizations for substance use disorders,¹ and as a result, hospitalists commonly diagnose and manage alcohol withdrawal syndrome (AWS) in the inpatient medical setting. The 2020 guidelines of the American Society of Addiction Medicine (ASAM) provide updated recommendations for the diagnosis, monitoring, and treatment of patients hospitalized with AWS, which we have condensed to emphasize key changes from the last update² and clarify ongoing areas of uncertainty. 

Diagnosis

Recommendation 1. All inpatients who have used alcohol recently or regularly should be risk-stratified for AWS, regardless of whether or not they have suggestive symptoms (recommendations I.3, I.4, I.5, II.10). The Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) identifies patients at risk for AWS, and the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) identifies those at risk for severe or complicated AWS, which includes seizures and alcohol withdrawal delirium (formerly delirium tremens). The guideline emphasizes use of these tools rather than simply initiating Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) monitoring on all such patients to diagnose AWS, as CIWA-Ar was developed for monitoring response to treatment, not diagnosis (recommendation I.6). 

Treating Mild/Moderate or Uncomplicated AWS

Recommendation 2. Because of their proven track record of reducing the incidence of seizure and alcohol withdrawal delirium, benzodiazepines remain the recommended first-line therapy (recommendations V.13, V.16). Symptom-triggered administration of benzodiazepines (via CIWA-Ar) is recommended over fixed-dose administration because the former is associated with shorter length of stay and lower cumulative benzodiazepine administration^3,4 (recommendation V.23). Patients with mild AWS who are at low risk for severe or complicated withdrawal should be monitored for up to 36 hours for the development of worsening symptoms (recommendation V.1). For patients with high CIWA-Ar scores or who are at increased risk for severe or complicated AWS, frequent administration of moderate to high doses of a long-acting benzodiazepine early in AWS treatment (a practice called frontloading) is recommended to quickly control symptoms and prevent clinical worsening. This approach has been shown to reduce the incidence of seizures and alcohol withdrawal delirium (recommendations V.14, V.19, V.24).

Carbamazepine or gabapentin may be used in mild or moderate AWS if benzodiazepines are contraindicated; however, neither agent is recommended as first-line therapy because a clear reduction in seizure and withdrawal delirium has not been established (recommendation V.16). Alpha-2 agonists (eg, clonidine, dexmedetomidine) may be used to treat persistent autonomic hyperactivity or anxiety when these are not adequately controlled by benzodiazepines alone (recommendation V.36).

Treating Severe or Complicated AWS

Recommendation 3. The guideline defines severe AWS as withdrawal with severe signs and symptoms, and complicated AWS as withdrawal accompanied by seizures or delirium (Appendix Table⁵). The development of complications warrants prompt treatment. Patients who experience seizure should receive a fast-acting benzodiazepine (eg, intravenous [IV] diazepam or lorazepam) (recommendation VI.4). Patients with withdrawal delirium should receive a benzodiazepine (preferably parenterally) dosed to achieve light sedation. Clinicians should be prepared for the possibility that large doses may be required and to monitor patients for oversedation and respiratory depression (recommendations VI.13, VI.17). Antipsychotics may be used as adjuncts when withdrawal delirium or other symptoms, such as hallucinosis, are not adequately controlled by benzodiazepines alone, but should not be used as monotherapy (recommendation VI.20). The guideline emphasizes that alpha-2 agonists should not be used to treat withdrawal delirium (recommendation VI.21), but they may be used as adjuncts for resistant alcohol withdrawal in the intensive care unit (ICU) (recommendations VI.27, VI.29). Phenobarbital is an acceptable alternative to benzodiazepines for severe withdrawal (recommendation V.17); however, the guideline recommends that clinicians should be experienced in its use.

Treating Wernicke Encephalopathy

Recommendation 4. Thiamine should be administered to prevent Wernicke encephalopathy (WE), with parenteral formulations recommended in patients with malnutrition, severe/complicated withdrawal, or requiring ICU-level care (recommendations V.7, V.8). In particular, all patients admitted to an ICU for AWS should receive thiamine, as diagnosis of WE is often difficult in this population. Although there is no consensus on the required dose of thiamine to treat WE, 100 mg IV or intramuscularly (IM) daily for 3 to 5 days is commonly administered (recommendation V.7). Because of a lack of evidence of harm, thiamine may be given before, after, or concurrently with glucose or dextrose (recommendation V.7). The guideline does not make a specific recommendation regarding how to risk-stratify patients for WE.

Treating Underlying Alcohol Use Disorder 

Recommendation 5. Hospitalization for AWS is an important opportunity to engage patients in treatment for alcohol use disorder (AUD), including pharmacotherapy and connection with outpatient providers (recommendation V.12). The guideline emphasizes that treatment for AUD should be initiated concomitantly with AWS management whenever possible but does not make recommendations regarding specific pharmacotherapies.

This guideline was authored by a committee of emergency medicine physicians, psychiatrists, and internists using the Department of Veterans Affairs/Department of Defense guidelines and the RAND/UCLA appropriateness method to combine the scientific literature with expert opinion. The result is a series of recommendations for physicians, physician assistants, nurse practitioners, and pharmacists that are not rated by strength; an assessment of the quality of the supporting evidence is available in an appendix. Four of the nine guideline committee members reported significant financial relationships with industry and other entities relevant to these guidelines.

Despite concern about oversedation from phenobarbital raised in small case series,⁶ observational studies comparing phenobarbital with benzodiazepines suggest phenobarbital has similar efficacy for treating AWS and that oversedation is rare.^7-9 Large randomized controlled trials in this area are lacking; however, at least one small randomized controlled trial¹⁰ among patients with AWS presenting to emergency departments supports the safety and efficacy of phenobarbital when used in combination with benzodiazepines. Given the growing body of evidence supporting the safety of phenobarbital, we believe a stronger recommendation for use in patients presenting with alcohol withdrawal delirium or treatment-resistant alcohol withdrawal is warranted. The guidelines also suggest that only “experienced clinicians” use phenobarbital for AWS, which may suppress appropriate use. Nationally, phenobarbital use for AWS remains low.¹¹Finally, although the guideline recommends initiation of treatment for AUD, specific recommendations for pharmacotherapy are not provided. Three medications currently have approval from the US Food and Drug Administration for treatment of AUD: acamprosate, naltrexone, and disulfiram. Large randomized controlled trials support the safety and efficacy of acamprosate and naltrexone, with or without counselling, in the treatment of AUD,¹² and disulfiram may be appropriate for selected highly motivated patients. We believe more specific recommendations to assist in choosing among these options would be useful.

More data are needed on the safety and efficacy of phenobarbital in patients with AWS, as well as comparative effectiveness against benzodiazepines. Recruitment is ongoing for a single clinical trial comparing the effect of phenobarbital and lorazepam on length of stay among patients in the ICU with AWS (NCT04156464); to date, no randomized trials of phenobarbital have been conducted in medical inpatients with AWS. In addition, gaps in the literature exist regarding benzodiazepine selection, and head-to-head comparisons of symptom-triggered usage of different benzodiazepines are lacking.

Alcohol is the most common substance implicated in hospitalizations for substance use disorders,¹ and as a result, hospitalists commonly diagnose and manage alcohol withdrawal syndrome (AWS) in the inpatient medical setting. The 2020 guidelines of the American Society of Addiction Medicine (ASAM) provide updated recommendations for the diagnosis, monitoring, and treatment of patients hospitalized with AWS, which we have condensed to emphasize key changes from the last update² and clarify ongoing areas of uncertainty. 

Diagnosis

Recommendation 1. All inpatients who have used alcohol recently or regularly should be risk-stratified for AWS, regardless of whether or not they have suggestive symptoms (recommendations I.3, I.4, I.5, II.10). The Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) identifies patients at risk for AWS, and the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) identifies those at risk for severe or complicated AWS, which includes seizures and alcohol withdrawal delirium (formerly delirium tremens). The guideline emphasizes use of these tools rather than simply initiating Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) monitoring on all such patients to diagnose AWS, as CIWA-Ar was developed for monitoring response to treatment, not diagnosis (recommendation I.6). 

Treating Mild/Moderate or Uncomplicated AWS

Recommendation 2. Because of their proven track record of reducing the incidence of seizure and alcohol withdrawal delirium, benzodiazepines remain the recommended first-line therapy (recommendations V.13, V.16). Symptom-triggered administration of benzodiazepines (via CIWA-Ar) is recommended over fixed-dose administration because the former is associated with shorter length of stay and lower cumulative benzodiazepine administration^3,4 (recommendation V.23). Patients with mild AWS who are at low risk for severe or complicated withdrawal should be monitored for up to 36 hours for the development of worsening symptoms (recommendation V.1). For patients with high CIWA-Ar scores or who are at increased risk for severe or complicated AWS, frequent administration of moderate to high doses of a long-acting benzodiazepine early in AWS treatment (a practice called frontloading) is recommended to quickly control symptoms and prevent clinical worsening. This approach has been shown to reduce the incidence of seizures and alcohol withdrawal delirium (recommendations V.14, V.19, V.24).

Carbamazepine or gabapentin may be used in mild or moderate AWS if benzodiazepines are contraindicated; however, neither agent is recommended as first-line therapy because a clear reduction in seizure and withdrawal delirium has not been established (recommendation V.16). Alpha-2 agonists (eg, clonidine, dexmedetomidine) may be used to treat persistent autonomic hyperactivity or anxiety when these are not adequately controlled by benzodiazepines alone (recommendation V.36).

Treating Severe or Complicated AWS

Recommendation 3. The guideline defines severe AWS as withdrawal with severe signs and symptoms, and complicated AWS as withdrawal accompanied by seizures or delirium (Appendix Table⁵). The development of complications warrants prompt treatment. Patients who experience seizure should receive a fast-acting benzodiazepine (eg, intravenous [IV] diazepam or lorazepam) (recommendation VI.4). Patients with withdrawal delirium should receive a benzodiazepine (preferably parenterally) dosed to achieve light sedation. Clinicians should be prepared for the possibility that large doses may be required and to monitor patients for oversedation and respiratory depression (recommendations VI.13, VI.17). Antipsychotics may be used as adjuncts when withdrawal delirium or other symptoms, such as hallucinosis, are not adequately controlled by benzodiazepines alone, but should not be used as monotherapy (recommendation VI.20). The guideline emphasizes that alpha-2 agonists should not be used to treat withdrawal delirium (recommendation VI.21), but they may be used as adjuncts for resistant alcohol withdrawal in the intensive care unit (ICU) (recommendations VI.27, VI.29). Phenobarbital is an acceptable alternative to benzodiazepines for severe withdrawal (recommendation V.17); however, the guideline recommends that clinicians should be experienced in its use.

Treating Wernicke Encephalopathy

Recommendation 4. Thiamine should be administered to prevent Wernicke encephalopathy (WE), with parenteral formulations recommended in patients with malnutrition, severe/complicated withdrawal, or requiring ICU-level care (recommendations V.7, V.8). In particular, all patients admitted to an ICU for AWS should receive thiamine, as diagnosis of WE is often difficult in this population. Although there is no consensus on the required dose of thiamine to treat WE, 100 mg IV or intramuscularly (IM) daily for 3 to 5 days is commonly administered (recommendation V.7). Because of a lack of evidence of harm, thiamine may be given before, after, or concurrently with glucose or dextrose (recommendation V.7). The guideline does not make a specific recommendation regarding how to risk-stratify patients for WE.

Treating Underlying Alcohol Use Disorder 

Recommendation 5. Hospitalization for AWS is an important opportunity to engage patients in treatment for alcohol use disorder (AUD), including pharmacotherapy and connection with outpatient providers (recommendation V.12). The guideline emphasizes that treatment for AUD should be initiated concomitantly with AWS management whenever possible but does not make recommendations regarding specific pharmacotherapies.

This guideline was authored by a committee of emergency medicine physicians, psychiatrists, and internists using the Department of Veterans Affairs/Department of Defense guidelines and the RAND/UCLA appropriateness method to combine the scientific literature with expert opinion. The result is a series of recommendations for physicians, physician assistants, nurse practitioners, and pharmacists that are not rated by strength; an assessment of the quality of the supporting evidence is available in an appendix. Four of the nine guideline committee members reported significant financial relationships with industry and other entities relevant to these guidelines.

Despite concern about oversedation from phenobarbital raised in small case series,⁶ observational studies comparing phenobarbital with benzodiazepines suggest phenobarbital has similar efficacy for treating AWS and that oversedation is rare.^7-9 Large randomized controlled trials in this area are lacking; however, at least one small randomized controlled trial¹⁰ among patients with AWS presenting to emergency departments supports the safety and efficacy of phenobarbital when used in combination with benzodiazepines. Given the growing body of evidence supporting the safety of phenobarbital, we believe a stronger recommendation for use in patients presenting with alcohol withdrawal delirium or treatment-resistant alcohol withdrawal is warranted. The guidelines also suggest that only “experienced clinicians” use phenobarbital for AWS, which may suppress appropriate use. Nationally, phenobarbital use for AWS remains low.¹¹Finally, although the guideline recommends initiation of treatment for AUD, specific recommendations for pharmacotherapy are not provided. Three medications currently have approval from the US Food and Drug Administration for treatment of AUD: acamprosate, naltrexone, and disulfiram. Large randomized controlled trials support the safety and efficacy of acamprosate and naltrexone, with or without counselling, in the treatment of AUD,¹² and disulfiram may be appropriate for selected highly motivated patients. We believe more specific recommendations to assist in choosing among these options would be useful.

More data are needed on the safety and efficacy of phenobarbital in patients with AWS, as well as comparative effectiveness against benzodiazepines. Recruitment is ongoing for a single clinical trial comparing the effect of phenobarbital and lorazepam on length of stay among patients in the ICU with AWS (NCT04156464); to date, no randomized trials of phenobarbital have been conducted in medical inpatients with AWS. In addition, gaps in the literature exist regarding benzodiazepine selection, and head-to-head comparisons of symptom-triggered usage of different benzodiazepines are lacking.

Upper gastrointestinal bleeding (UGIB) is defined as a bleed originating from the esophagus, stomach, or duodenum. Approximately 80% of patients with UGIB presenting to the emergency department are admitted to the hospital, accounting for more than 200,000 hospital admissions and 4000 in-hospital deaths per year.¹ In this article, we highlight 9 of the 16 recommendations from the 2021 American College of Gastroenterology (ACG) guidelines that are most pertinent to the hospitalist, presented in sections corresponding to the stages of inpatient clinical management.

Initial Triage

Recommendation 1. Patients with UGIB presenting to the emergency department who are classified as very low risk, defined as a risk assessment score with ≤1% false-negative rate for the outcome of hospital-based intervention or death (ie, Glasgow-Blatchford score of 0-1), should be discharged with outpatient follow-up rather than admitted to the hospital (conditional recommendation, very-low-quality evidence). The Glasgow-Blatchford score is an effective risk-assessment tool that can classify patients at high risk for death or needing a hospital-based intervention (eg, endoscopy or blood transfusion) with a sensitivity of 99%.² Triage decisions should incorporate other patient factors, such as age, comorbidities, and reliability of close follow-up after discharge.

Pre-endoscopy Management

Recommendation 2. A restrictive threshold for red blood cell transfusion of 7 g/dL is recommended for patients with UGIB (conditional recommendation, low-quality evidence) as it appears to reduce death and further bleeding.³ It is reasonable to transfuse patients with preexisting cardiovascular disease whose hemoglobin is below 8 g/dL. For patients who are exsanguinating with hemodynamic instability, it is reasonable to transfuse before the hemoglobin reaches 7 g/dL.

Recommendation 3. An infusion of erythromycin is recommended before endoscopy in patients with UGIB (conditional recommendation, very-low-quality evidence). Erythromycin (250 mg intravenously [IV]) improves endoscopic visualization and diagnostic accuracy by moving the blood and clot out of the upper GI tract. A meta-analysis showed a reduction of need for repeat endoscopy (odds ratio [OR], 0.51; 95% CI, 0.34-0.77) and length of hospitalization (mean difference, –1.75 d).⁴

Recommendation 4. There is no consensus for or against pre-endoscopic proton pump inhibitor (PPI) therapy for patients with UGIB, owing to overall limited available data.

Recommendation 5. Patients hospitalized for UGIB should undergo endoscopy within 24 hours of presentation (conditional recommendation, very-low-quality evidence). Performing endoscopy within 24 hours, rather than 12 hours, of presentation demonstrated a potential trend toward decreased length of stay, mortality, and need for surgery. The potential harm in performing earlier endoscopy was attributed to inadequate resuscitation and insufficient optimization of active comorbidities.

Post-endoscopy Management

Recommendation 6. High-dose PPI therapy should be given for 3 days after successful endoscopic hemostatic therapy of a bleeding ulcer (strong recommendation, moderate- to high-quality evidence). When compared with placebo, there is an absolute risk reduction of 3% in mortality and 10% in further bleeding when administering continuous (80 mg bolus with 8 mg/h infusion) or intermittent high-dose PPI therapy (80 mg bolus with 40 mg 2-4 times daily thereafter) for 3 days after endoscopic therapy.^5,6 Cost and ease of administration should be considered when choosing between intermittent or continuous PPI therapy. Oral PPI therapy may be appropriate for patients who are able to tolerate oral intake (no nausea, vomiting, dysphagia, or somnolence).

Recommendation 7. High-risk patients (defined as a Rockall score of ≥6 ) with UGIB due to ulcers who received endoscopic hemostatic therapy followed by short-term high-dose PPI therapy in hospital should be continued on twice-daily PPI therapy until 2 weeks after index endoscopy (conditional recommendation, low-quality evidence). A randomized controlled trial of high-risk patients showed significantly lower recurrence of bleeding with twice-daily vs once daily PPI.⁷ It remains uncertain whether patients benefit from PPI therapy beyond 4 weeks.

Rebleeding Management

Recommendation 8. Patients with recurrent bleeding after endoscopic therapy for a bleeding ulcer should undergo repeat endoscopic therapy rather than surgery or transcatheter arterial embolization (TAE) (conditional recommendation, low-quality evidence for comparison with surgery, very-low-quality evidence for comparison with TAE). In a small randomized controlled trial of repeat endoscopy vs surgery in patients with rebleeding after initial successful endoscopic treatment, there were more subsequent bleeding episodes in the repeat endoscopy group, but no significant difference in mortality and length of stay.⁸ The repeat endoscopy group had fewer complications, though, and a successful treatment rate of 75%. Because of the lack of high-quality studies in support of TAE and the known safety and efficacy of repeat endoscopy, repeat endoscopy is preferred over TAE for recurrent UGIB.

Recommendation 9. Patients with bleeding ulcers who have failed repeat endoscopic therapy should be treated with TAE (conditional recommendation, very-low-quality evidence). Based on a meta-analysis, when comparing TAE with surgery in patients with UGIB who fail endoscopic therapy, overall mortality was the same, and TAE patients had fewer complications and shorter hospital stays despite having a higher risk of further bleeding.⁹

The guidelines were formulated by panel members with input from the ACG Practice Parameters Committee using the population, intervention, comparator, and outcome (PICO) format to frame each question. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the strength of the recommendation and the quality of evidence.

Most of the recommendations are conditional and/or based on low-quality or very-low-quality evidence. Although randomized control trials were sought, observational studies were sometimes included when randomized controlled trials were lacking. The literature review process appeared to focus on the primary outcome of further bleeding, which, although critical in patients with UGIB, could have limited the scope of evidence used in making the recommendations. It was stated that studies identified as relevant to the panel members or authors were considered for review without mentioning any standardized approach. The composition of the panel members was not discussed, and it is uncertain whether the guidelines underwent any formal peer-review process. Furthermore, although competing interests were declared, the panel did not discuss how conflicts were managed and what potential impact they had in the guideline recommendations. Finally, some of the recommendations (eg, TAE) will depend on local expertise and may not be available at all medical centers.

Further study is needed to address the integration of risk-assessment tools into electronic health records to assist with timely decisions on managing patients with acute UGIB, to clarify the role for pre-endoscopic PPI therapy, and to specify fluid resuscitation and blood pressure goals in patients with more severe bleeding episodes and determine whether a subset of patients might benefit from very-early endoscopy (the 2012 ACG guidelines suggested that endoscopy within 12 hours may be considered in patients with high-risk clinical features such as hemodynamic instability or cirrhosis).

Glasgow-Blatchford Score (https://www.mdcalc.com/glasgow-blatchford-bleeding-score-gbs)

Rockall Score (https://www.mdcalc.com/rockall-score-upper-gi-bleeding-pre-endoscopy)

Upper gastrointestinal bleeding (UGIB) is defined as a bleed originating from the esophagus, stomach, or duodenum. Approximately 80% of patients with UGIB presenting to the emergency department are admitted to the hospital, accounting for more than 200,000 hospital admissions and 4000 in-hospital deaths per year.¹ In this article, we highlight 9 of the 16 recommendations from the 2021 American College of Gastroenterology (ACG) guidelines that are most pertinent to the hospitalist, presented in sections corresponding to the stages of inpatient clinical management.

Initial Triage

Recommendation 1. Patients with UGIB presenting to the emergency department who are classified as very low risk, defined as a risk assessment score with ≤1% false-negative rate for the outcome of hospital-based intervention or death (ie, Glasgow-Blatchford score of 0-1), should be discharged with outpatient follow-up rather than admitted to the hospital (conditional recommendation, very-low-quality evidence). The Glasgow-Blatchford score is an effective risk-assessment tool that can classify patients at high risk for death or needing a hospital-based intervention (eg, endoscopy or blood transfusion) with a sensitivity of 99%.² Triage decisions should incorporate other patient factors, such as age, comorbidities, and reliability of close follow-up after discharge.

Pre-endoscopy Management

Recommendation 2. A restrictive threshold for red blood cell transfusion of 7 g/dL is recommended for patients with UGIB (conditional recommendation, low-quality evidence) as it appears to reduce death and further bleeding.³ It is reasonable to transfuse patients with preexisting cardiovascular disease whose hemoglobin is below 8 g/dL. For patients who are exsanguinating with hemodynamic instability, it is reasonable to transfuse before the hemoglobin reaches 7 g/dL.

Recommendation 3. An infusion of erythromycin is recommended before endoscopy in patients with UGIB (conditional recommendation, very-low-quality evidence). Erythromycin (250 mg intravenously [IV]) improves endoscopic visualization and diagnostic accuracy by moving the blood and clot out of the upper GI tract. A meta-analysis showed a reduction of need for repeat endoscopy (odds ratio [OR], 0.51; 95% CI, 0.34-0.77) and length of hospitalization (mean difference, –1.75 d).⁴

Recommendation 4. There is no consensus for or against pre-endoscopic proton pump inhibitor (PPI) therapy for patients with UGIB, owing to overall limited available data.

Recommendation 5. Patients hospitalized for UGIB should undergo endoscopy within 24 hours of presentation (conditional recommendation, very-low-quality evidence). Performing endoscopy within 24 hours, rather than 12 hours, of presentation demonstrated a potential trend toward decreased length of stay, mortality, and need for surgery. The potential harm in performing earlier endoscopy was attributed to inadequate resuscitation and insufficient optimization of active comorbidities.

Post-endoscopy Management

Recommendation 6. High-dose PPI therapy should be given for 3 days after successful endoscopic hemostatic therapy of a bleeding ulcer (strong recommendation, moderate- to high-quality evidence). When compared with placebo, there is an absolute risk reduction of 3% in mortality and 10% in further bleeding when administering continuous (80 mg bolus with 8 mg/h infusion) or intermittent high-dose PPI therapy (80 mg bolus with 40 mg 2-4 times daily thereafter) for 3 days after endoscopic therapy.^5,6 Cost and ease of administration should be considered when choosing between intermittent or continuous PPI therapy. Oral PPI therapy may be appropriate for patients who are able to tolerate oral intake (no nausea, vomiting, dysphagia, or somnolence).

Recommendation 7. High-risk patients (defined as a Rockall score of ≥6 ) with UGIB due to ulcers who received endoscopic hemostatic therapy followed by short-term high-dose PPI therapy in hospital should be continued on twice-daily PPI therapy until 2 weeks after index endoscopy (conditional recommendation, low-quality evidence). A randomized controlled trial of high-risk patients showed significantly lower recurrence of bleeding with twice-daily vs once daily PPI.⁷ It remains uncertain whether patients benefit from PPI therapy beyond 4 weeks.

Rebleeding Management

Recommendation 8. Patients with recurrent bleeding after endoscopic therapy for a bleeding ulcer should undergo repeat endoscopic therapy rather than surgery or transcatheter arterial embolization (TAE) (conditional recommendation, low-quality evidence for comparison with surgery, very-low-quality evidence for comparison with TAE). In a small randomized controlled trial of repeat endoscopy vs surgery in patients with rebleeding after initial successful endoscopic treatment, there were more subsequent bleeding episodes in the repeat endoscopy group, but no significant difference in mortality and length of stay.⁸ The repeat endoscopy group had fewer complications, though, and a successful treatment rate of 75%. Because of the lack of high-quality studies in support of TAE and the known safety and efficacy of repeat endoscopy, repeat endoscopy is preferred over TAE for recurrent UGIB.

Recommendation 9. Patients with bleeding ulcers who have failed repeat endoscopic therapy should be treated with TAE (conditional recommendation, very-low-quality evidence). Based on a meta-analysis, when comparing TAE with surgery in patients with UGIB who fail endoscopic therapy, overall mortality was the same, and TAE patients had fewer complications and shorter hospital stays despite having a higher risk of further bleeding.⁹

The guidelines were formulated by panel members with input from the ACG Practice Parameters Committee using the population, intervention, comparator, and outcome (PICO) format to frame each question. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the strength of the recommendation and the quality of evidence.

Most of the recommendations are conditional and/or based on low-quality or very-low-quality evidence. Although randomized control trials were sought, observational studies were sometimes included when randomized controlled trials were lacking. The literature review process appeared to focus on the primary outcome of further bleeding, which, although critical in patients with UGIB, could have limited the scope of evidence used in making the recommendations. It was stated that studies identified as relevant to the panel members or authors were considered for review without mentioning any standardized approach. The composition of the panel members was not discussed, and it is uncertain whether the guidelines underwent any formal peer-review process. Furthermore, although competing interests were declared, the panel did not discuss how conflicts were managed and what potential impact they had in the guideline recommendations. Finally, some of the recommendations (eg, TAE) will depend on local expertise and may not be available at all medical centers.

Further study is needed to address the integration of risk-assessment tools into electronic health records to assist with timely decisions on managing patients with acute UGIB, to clarify the role for pre-endoscopic PPI therapy, and to specify fluid resuscitation and blood pressure goals in patients with more severe bleeding episodes and determine whether a subset of patients might benefit from very-early endoscopy (the 2012 ACG guidelines suggested that endoscopy within 12 hours may be considered in patients with high-risk clinical features such as hemodynamic instability or cirrhosis).

Glasgow-Blatchford Score (https://www.mdcalc.com/glasgow-blatchford-bleeding-score-gbs)

Rockall Score (https://www.mdcalc.com/rockall-score-upper-gi-bleeding-pre-endoscopy)

Upper gastrointestinal bleeding (UGIB) is defined as a bleed originating from the esophagus, stomach, or duodenum. Approximately 80% of patients with UGIB presenting to the emergency department are admitted to the hospital, accounting for more than 200,000 hospital admissions and 4000 in-hospital deaths per year.¹ In this article, we highlight 9 of the 16 recommendations from the 2021 American College of Gastroenterology (ACG) guidelines that are most pertinent to the hospitalist, presented in sections corresponding to the stages of inpatient clinical management.

Initial Triage

Recommendation 1. Patients with UGIB presenting to the emergency department who are classified as very low risk, defined as a risk assessment score with ≤1% false-negative rate for the outcome of hospital-based intervention or death (ie, Glasgow-Blatchford score of 0-1), should be discharged with outpatient follow-up rather than admitted to the hospital (conditional recommendation, very-low-quality evidence). The Glasgow-Blatchford score is an effective risk-assessment tool that can classify patients at high risk for death or needing a hospital-based intervention (eg, endoscopy or blood transfusion) with a sensitivity of 99%.² Triage decisions should incorporate other patient factors, such as age, comorbidities, and reliability of close follow-up after discharge.

Pre-endoscopy Management

Recommendation 2. A restrictive threshold for red blood cell transfusion of 7 g/dL is recommended for patients with UGIB (conditional recommendation, low-quality evidence) as it appears to reduce death and further bleeding.³ It is reasonable to transfuse patients with preexisting cardiovascular disease whose hemoglobin is below 8 g/dL. For patients who are exsanguinating with hemodynamic instability, it is reasonable to transfuse before the hemoglobin reaches 7 g/dL.

Recommendation 3. An infusion of erythromycin is recommended before endoscopy in patients with UGIB (conditional recommendation, very-low-quality evidence). Erythromycin (250 mg intravenously [IV]) improves endoscopic visualization and diagnostic accuracy by moving the blood and clot out of the upper GI tract. A meta-analysis showed a reduction of need for repeat endoscopy (odds ratio [OR], 0.51; 95% CI, 0.34-0.77) and length of hospitalization (mean difference, –1.75 d).⁴

Recommendation 4. There is no consensus for or against pre-endoscopic proton pump inhibitor (PPI) therapy for patients with UGIB, owing to overall limited available data.

Recommendation 5. Patients hospitalized for UGIB should undergo endoscopy within 24 hours of presentation (conditional recommendation, very-low-quality evidence). Performing endoscopy within 24 hours, rather than 12 hours, of presentation demonstrated a potential trend toward decreased length of stay, mortality, and need for surgery. The potential harm in performing earlier endoscopy was attributed to inadequate resuscitation and insufficient optimization of active comorbidities.

Post-endoscopy Management

Recommendation 6. High-dose PPI therapy should be given for 3 days after successful endoscopic hemostatic therapy of a bleeding ulcer (strong recommendation, moderate- to high-quality evidence). When compared with placebo, there is an absolute risk reduction of 3% in mortality and 10% in further bleeding when administering continuous (80 mg bolus with 8 mg/h infusion) or intermittent high-dose PPI therapy (80 mg bolus with 40 mg 2-4 times daily thereafter) for 3 days after endoscopic therapy.^5,6 Cost and ease of administration should be considered when choosing between intermittent or continuous PPI therapy. Oral PPI therapy may be appropriate for patients who are able to tolerate oral intake (no nausea, vomiting, dysphagia, or somnolence).

Recommendation 7. High-risk patients (defined as a Rockall score of ≥6 ) with UGIB due to ulcers who received endoscopic hemostatic therapy followed by short-term high-dose PPI therapy in hospital should be continued on twice-daily PPI therapy until 2 weeks after index endoscopy (conditional recommendation, low-quality evidence). A randomized controlled trial of high-risk patients showed significantly lower recurrence of bleeding with twice-daily vs once daily PPI.⁷ It remains uncertain whether patients benefit from PPI therapy beyond 4 weeks.

Rebleeding Management

Recommendation 8. Patients with recurrent bleeding after endoscopic therapy for a bleeding ulcer should undergo repeat endoscopic therapy rather than surgery or transcatheter arterial embolization (TAE) (conditional recommendation, low-quality evidence for comparison with surgery, very-low-quality evidence for comparison with TAE). In a small randomized controlled trial of repeat endoscopy vs surgery in patients with rebleeding after initial successful endoscopic treatment, there were more subsequent bleeding episodes in the repeat endoscopy group, but no significant difference in mortality and length of stay.⁸ The repeat endoscopy group had fewer complications, though, and a successful treatment rate of 75%. Because of the lack of high-quality studies in support of TAE and the known safety and efficacy of repeat endoscopy, repeat endoscopy is preferred over TAE for recurrent UGIB.

Recommendation 9. Patients with bleeding ulcers who have failed repeat endoscopic therapy should be treated with TAE (conditional recommendation, very-low-quality evidence). Based on a meta-analysis, when comparing TAE with surgery in patients with UGIB who fail endoscopic therapy, overall mortality was the same, and TAE patients had fewer complications and shorter hospital stays despite having a higher risk of further bleeding.⁹

The guidelines were formulated by panel members with input from the ACG Practice Parameters Committee using the population, intervention, comparator, and outcome (PICO) format to frame each question. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the strength of the recommendation and the quality of evidence.

Most of the recommendations are conditional and/or based on low-quality or very-low-quality evidence. Although randomized control trials were sought, observational studies were sometimes included when randomized controlled trials were lacking. The literature review process appeared to focus on the primary outcome of further bleeding, which, although critical in patients with UGIB, could have limited the scope of evidence used in making the recommendations. It was stated that studies identified as relevant to the panel members or authors were considered for review without mentioning any standardized approach. The composition of the panel members was not discussed, and it is uncertain whether the guidelines underwent any formal peer-review process. Furthermore, although competing interests were declared, the panel did not discuss how conflicts were managed and what potential impact they had in the guideline recommendations. Finally, some of the recommendations (eg, TAE) will depend on local expertise and may not be available at all medical centers.

Further study is needed to address the integration of risk-assessment tools into electronic health records to assist with timely decisions on managing patients with acute UGIB, to clarify the role for pre-endoscopic PPI therapy, and to specify fluid resuscitation and blood pressure goals in patients with more severe bleeding episodes and determine whether a subset of patients might benefit from very-early endoscopy (the 2012 ACG guidelines suggested that endoscopy within 12 hours may be considered in patients with high-risk clinical features such as hemodynamic instability or cirrhosis).

Glasgow-Blatchford Score (https://www.mdcalc.com/glasgow-blatchford-bleeding-score-gbs)

Rockall Score (https://www.mdcalc.com/rockall-score-upper-gi-bleeding-pre-endoscopy)

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Asthma is a heterogeneous condition characterized by airway hyperresponsiveness and obstruction, with associated airway inflammation and remodeling.² Asthma affects 25 million people in the United States and 334 million people worldwide, with significant healthcare disparities across race and ethnicity.^2-6 Asthma is the third most common reason for hospitalizations in pediatrics, accounting for 180,000 annual hospitalizations for children and adults.^3,7 In 2020, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel provided a focused update to the Asthma Management Guidelines, centered on six topics with sufficient new evidence. The management of status asthmaticus was not included in this update. We spotlight four of the recommendations applicable to the practice of pediatric hospital medicine.

Recommendation 1. Children 0 to 4 years old with recurrent wheezing triggered by a respiratory tract infection (RTI) and no wheezing between infections should receive a short course of daily inhaled corticosteroids (ICS) at the onset of a RTI, with an as-needed short-acting beta agonist (SABA) for quick-relief therapy compared to SABA alone (evidence quality: high; recommendation strength: conditional).

Recurrent wheezing is defined as clinically significant periods of wheezing that are reversible or consistent with bronchospasm and as ≥3 episodes in a lifetime or 2 episodes in the past year. It is important to adhere to this definition to prevent inappropriate use of ICS for bronchiolitis. This treatment is associated with a reduction of use of systemic steroids (relative risk [RR], 0.67; 95% CI, 0.46-0.98) without a statistical decrease in acute care visits (RR, 0.90; 95% CI, 0.77-1.05) or hospitalizations (RR, 0.77; 95% CI, 0.06-9.68). Improved transition of care is essential between the primary care provider, hospitalist, and family to ensure an understanding of how/when to initiate ICS at the onset of a RTI. Potential harms include effect on growth and overprescribing. Growth should be monitored because data are conflicting.

Recommendation 2. Individuals ages 12 years and older with mild persistent asthma should use as-needed SABA and may use either daily low-dose ICS or as-needed ICS when symptoms flare (evidence quality: moderate; recommendation strength: conditional).

In intermittent therapy, patients take a SABA followed by an ICS as needed for acute asthma symptoms. This recommendation is driven by asthma-control and quality-of-life outcomes, with caregivers reporting that intermittent dosing could “offer flexibility and potentially reduce side effects.” There were no differences between management regimens with respect to systemic steroid use (RR, 0.70; 95% CI, 0.30-1.64) or urgent care visits (RR, 0.25; 95% CI, 0.05-1.16). Differing perception of symptoms by individuals may lead to undertreating or overtreating, and intermittent administration makes it challenging for clinicians to assess the need to adjust therapy.

Recommendation 3. Children 4 years and older with moderate to severe persistent asthma should use ICS-formoterol in a single inhaler used as both daily controller and reliever therapy compared to either (a) higher-dose ICS as daily controller therapy and SABA for quick-relief therapy or (b) a same-dose ICS-long-acting beta agonist (LABA) as daily controller therapy and SABA for quick-relief therapy (evidence quality: high for ages ≥12 years, moderate for ages 4-11 years; recommendation strength: strong).

For children 4 years and older, it is recommended to use “single maintenance and reliever therapy” (SMART) with a single-inhaler containing either low- or medium-dose ICS and formoterol when stepping up from Step 2 (daily low-dose ICS and as-needed SABA) to Step 3 (daily and as-needed low-dose ICS-formoterol) and Step 4 (daily and as-needed medium-dose ICS-formoterol). It is preferred to use this single inhaler as needed when symptoms flare rather than an additional as-needed SABA. However, this may be impractical if insurance does not cover multiple prescriptions per month. Formoterol is specified because it is the only LABA studied. Studies have shown reductions in hospitalizations, systemic corticosteroids, and ED visits with this regimen. “ICS-formoterol should be administered as maintenance therapy with 1-2 puffs once to twice daily and 1-2 puffs as needed for asthma symptoms. The maximum number of puffs per day is 12 (54 mcg formoterol) for individuals ages 12 years and older and 8 (36 mcg formoterol) for children ages 4-11 years.”¹

Recommendation 4. If individuals with asthma have symptoms related to indoor allergens, confirmed by history or allergy testing, they should use a multicomponent allergen-specific mitigation intervention. Allergen mitigation interventions should not be a part of routine asthma management for individuals with asthma who do not have symptoms related to exposure to specific indoor allergens (evidence quality: low; recommendation strength: conditional).

Providers often emphasize exposure to potential indoor allergens such as carpets and pets when taking an asthma history and counsel removal of these triggers. However, all recommendations related to allergies in the 2020 updates have low-moderate evidence quality and conditional recommendation strength. Hospitalists should instead focus their questions on allergy symptoms and triggers and recommend multicomponent mitigation intervention only if there is a confirmed allergy history. Families should continue routine good practices such as house cleaning and laundering, but other interventions are not evidence-based.

Methods

The Expert Panel included a diverse group of clinicians, a pharmacist, and health policy experts. In 2015, a needs assessment identified 6 out of 17 priority topics with sufficient new information for updates. Key questions were drafted, and systematic reviews were published through 2018. The Expert Panel made its recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The Expert Panel informed its recommendations with input from focus groups, including individuals with asthma and caregivers. The NHLBI posted the draft report for public review, and comments were considered. We believe these methods effectively developed evidence-based recommendations, and the diversity of stakeholders increases the value of this guideline. However, the infrequency of updates limits the utility of the NHLBI guidelines as compared with annual GINA (Global Initiative for Asthma) updates.

There are important considerations in assessing these guidelines. Specifically, the validity of systemic steroid courses as an outcome for children ages 0 to 4 years is controversial. Second, the studies cited in defense of intermittent ICS use in children >12 years of age excluded pediatric patients and did not include readmissions as a primary outcome, which is of particular interest to the hospitalist.

Potential Conflicts for Guideline Authors

The Expert Panel reported all potential conflicts of interest (COIs), which were rated by the Expert Panel Chair and Journal of Allergy and Clinical Immunology editors. Individuals with high COIs were excluded from the Expert Panel. Those with moderate COIs were recused for that topic. Low COIs were not related to the guideline.

Generalizability of the Guideline

These guidelines are based on systematic reviews with large sample sizes and patients of all ages. They are generalizable. However, the authors recognize that variations in asthma require individualized approaches. They identify this as a reason for the lack of strong recommendations for asthma standards of care.

Biologics have progressed considerably since revision of the guidelines. The 2020 guidelines did not address these to prevent delay of the guideline release, but recommendations should be included in future guidelines. Future studies should address healthcare disparities in asthma, barriers to equitable care, and how to eliminate them, as guided by the President’s Task Force.⁸ Status asthmaticus should be included in future updates.

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.

Invasive bacterial infections (IBI; ie, bacterial meningitis, bacteremia) are an uncommon but potentially devastating occurrence in young febrile infants. The challenge for clinicians is that physical examination cannot reliably exclude such infections. Thus, these infants have historically received comprehensive emergency department evaluation, including routine cerebrospinal fluid (CSF) assessment, and, often, required hospitalization for parenteral antibiotic administration while awaiting CSF culture results. The new American Academy of Pediatrics (AAP) guidelines were necessary given changing bacteriology, advances in diagnostic testing, greater insight into the differential risk of poor outcomes by site of infection, and better appreciation of the potential harms of unnecessary care and interventions.¹ The 21 recommendations apply to well-appearing febrile infants 8 to 60 days of age, with recommendations stratified by age group, and exclude infants with certain conditions, including prematurity, focal bacterial infection, congenital or chromosomal abnormalities, and bronchiolitis. Four key recommendations are highlighted.

Recommendation 1: Diagnostic evaluation. For all age groups, blood culture and urinalysis (UA) are routinely recommended. For infants 8 to 21 days old, urine culture is routinely recommended. For older infants, urine culture is recommended if the UA is positive. All specimens for culture should be obtained via catheterization or suprapubic aspiration.

Infants 8 to 21 days old

• May assess inflammatory markers (grade B, weak).
• Should obtain CSF for analysis and culture (grade A, strong).

Infants 22 to 28 days old

• Should assess inflammatory markers (grade B, strong).
• May obtain CSF for analysis and culture even if no inflammatory marker obtained is abnormal (grade B, moderate).
• Should obtain CSF for analysis and culture if any inflammatory marker obtained is abnormal (procalcitonin >0.5 ng/mL [preferred]; C-reactive protein >20 mg/L; absolute neutrophil count >4000-5200/mm³; or temperature >38.5 °C) (grade B, moderate).

Infants 29 to 60 days old

• Should assess inflammatory markers (grade B, moderate).
• May obtain CSF for analysis and culture if any inflammatory marker is abnormal, (grade C, weak).
• Need not obtain CSF for analysis if all inflammatory markers obtained are normal (grade B, moderate).

Recommendation 2: Initial disposition decision

Infants 8 to 21 days old

• Admit (grade B, moderate).

Infants 22 to 28 days old

• Admit if CSF analysis is abnormal, UA is positive (A, strong), or if CSF is not obtained or is uninterpretable (grade B, weak).
• May manage at home if UA is normal, inflammatory markers are normal, CSF is normal or enterovirus positive, family has received verbal and written home monitoring instructions for concerning signs that should prompt immediate return for care, follow-up plan for reevaluation in 24 hours is in place, and means of communication for change in clinical status has been established (grade B, moderate).

Infants 29 to 60 days old

• Admit if CSF analysis is abnormal (grade A strong).
• May hospitalize if any inflammatory marker obtained is abnormal (grade B, moderate).
• Should manage at home if all the following are present: CSF is normal, if obtained; UA is negative; all inflammatory markers obtained are normal; teaching is complete; follow-up plan for reevaluation in 24 hours is in place; and means of communication for change in clinical status has been established (grade B, moderate).

Recommendation 3: Empiric antimicrobial treatment

Infants 8 to 21 days old

• Should initiate parenteral antimicrobial therapy (grade A, strong).
• This recommendation is based on the high prevalence of IBIs in this age category, and IBI may be present despite a negative UA and/or normal inflammatory markers.

Infants 22 to 28 days old

• Should initiate parenteral antimicrobial therapy if either CSF analysis suggests bacterial meningitis or UA is positive (grade A, strong).
• May administer parenteral antimicrobial therapy if any inflammatory marker is abnormal (grade B, moderate).
• May administer parenteral antimicrobial therapy even if everything is reassuring (grade B, weak).
• Should administer parenteral antimicrobial therapy to infant who will be managed at home even if all evaluation is reassuring (grade C, moderate).

Infants 29 to 60 days old

• Should start parenteral antimicrobials if CSF analysis suggests bacterial meningitis (grade A, strong).
• May use parenteral antimicrobials if any inflammatory marker is abnormal (grade B, moderate).
• Should initiate oral antimicrobial therapy if CSF is normal (if obtained), UA is positive, and no inflammatory markers obtained are abnormal (grade B, strong).
• Need not start antimicrobials if CSF is normal or enterovirus positive, UA is negative, and no inflammatory marker obtained is abnormal (grade B, moderate).

Recommendation 4: Hospital discharge decision

Infants 8 to 21 days old AND Infants 22 to 28 days ol

• Discontinue antibiotics and discharge infant when culture results are negative for 24 to 36 hours (or positive only for contaminants), the infant is well or improving, and there are no other reasons for hospitalization (grade B, strong).

Infants 29 to 60 days old

• Although no specific parameters are given for infants without UTI, presumably the discharge criteria for younger infants would also apply for this group.
• For infants with UTI, discharge if blood and CSF cultures are negative, infant is well or improving, and no other reasons for hospitalization remain (grade B, strong).

The guideline provides opportunities for safely doing less in a vulnerable population. For example, infants with UTIs may be managed differently (eg, often with oral antibiotics) from those with IBIs, which represents an important change from conventional practice.² Additional strengths are the incorporation of procalcitonin, which has emerged as the most accurate marker for risk stratification;³ and deemphasis of complete blood count results.

Multiple exclusions for relatively common scenarios represent missed opportunities for a more complete set of recommendations for the febrile infant population. The decision to exclude infants in the first week of life is perplexing since infants 0 to 7 days old will receive CSF analysis, require admission, and generally be managed comparably to infants 8 to 21 days old. Infants with bronchiolitis are excluded; the absence of uniform guidance may perpetuate variability in management within and across institutions. Finally, exclusion of infants in whom perinatal or congenital herpes simplex virus is a consideration is not ideal. The requirement to consult separate guidance for herpes simplex virus evaluation fragments decision-making and may lead to inadvertent omissions of critical tests or treatment in at-risk infants.

Methods in Preparing the Guideline

The guideline working group included stakeholders from multiple specialties including general pediatrics, emergency medicine, hospital medicine, infectious diseases, and family medicine. In addition to published studies, the committee considered an Agency for Healthcare Research and Quality commissioned systematic review, as well as analyses of additional data solicited from previously published peer-reviewed studies. Once recommendations were formulated, additional input from physician focus groups and parents was solicited. Recommendations were rated based on strength of available evidence (A, B, C, D, X) as well as assessment of the benefit/harm profile (strong, moderate, weak).

Sources of Potential Conflicts of Interest or Bias

The guideline writing group was predominantly male, though we note that the broader working group was diverse in gender and specialty. No significant conflicts of interest were noted.

Generalizability

The complexity of this guideline, including age stratification, multiple exclusions, and multistep processes could lead to challenges in implementation; a health information technology application (app) could substantially ease the difficulty of implementation at the point of care.

Additional areas in need of guidance include neonates with bronchiolitis and fever and neonates with focal infection. For the former, there is an abundance of evidence;⁴ what is needed is consensus. For the latter, additional study is needed such as the role of inflammatory markers in stratifying infants with focal infection who need additional evaluation prior to treatment.

Sickle cell disease (SCD) affects an estimated 100,000 people in the United States.¹ Pain is the most common complication of SCD and the primary reason patients with SCD seek medical attention.² In 2016, three-fourths of the approximately 130,000 SCD-related hospitalizations in the United States involved pain crises.³ When managing patients with SCD and chronic pain, an individualized and interdisciplinary approach is crucial. In 2020, the American Society of Hematology (ASH) developed guidelines reflecting the latest evidence in managing acute and chronic pain in adult and pediatric patients with SCD. The ASH guidelines provide 18 recommendations; here, we highlight the 8 recommendations most pertinent to the hospitalist.

Acute Pain

Acute pain in the guideline is defined as pain that results in an unplanned visit to an acute care center for treatment.

Recommendation 1. For adult and pediatric patients presenting to an acute care setting with SCD-related acute pain, the ASH guideline panel recommends rapid (ie, within 1 hour of arrival at the emergency department [ED]) assessment and administration of analgesia, with reassessments every 30-60 minutes to optimize pain control (Strong recommendation; low certainty in the evidence about effects).

Although the perceived benefits are unclear due to insufficient evidence, the panel agrees that delaying pain management results in undeniable harm to patients. Hence, this recommendation was deemed both acceptable and ethical. Rapid evaluation also allows for earlier identification and treatment of other potential SCD-related complications.

Recommendation 2. For adult and pediatric patients presenting to an acute care setting with SCD-associated pain for whom opioid therapy is indicated, the ASH guideline panel suggests tailored opioid dosing based on consideration of baseline opioid therapy and prior effective therapy. (For adults: conditional recommendation; moderate certainty in the evidence about effects. For children: conditional recommendation; low certainty in the evidence about effects).

One randomized controlled trial examined patient-specific opioid dosing (based on current chronic opioid therapy [COT] and previously known effective acute pain management) vs weight-based dosing in the ED and found that participants randomized into the patient-specific protocol had a greater reduction in pain and decreased rate of hospital admission.⁴

The panel acknowledges that intravenous patient-controlled opioid analgesia is generally the standard of care at most institutions. However, no clear data address whether continuous opioid infusion in addition to on-demand dosing is beneficial.

Recommendation 3. For adult and pediatric patients with acute pain related to SCD, the ASH guideline panel suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids (Conditional recommendation; very low certainty in the evidence about effects).

The use of NSAIDs for managing pain in hospitalized patients with SCD has been associated with a reduction in the use of opioids in the inpatient setting and decreased lengths of stay.⁵ The potential harms of NSAIDs, including renal and gastrointestinal toxicity, however, should be factored into the decision-making as the risks may outweigh the potential benefits.

Recommendation 4. For adult and pediatric patients with SCD hospitalized for acute pain, the ASH guideline panel suggests a subanesthetic (analgesic) infusion of ketamine as adjunctive treatment of pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects). The guideline panel also suggests regional anesthesia for localized pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects).

Studies have demonstrated reduced pain and opioid utilization in individuals who received adjuvant ketamine infusions⁶ or regional anesthesia (ie, epidural).⁷ Feasibility, however, is limited to centers that have the appropriate experience and expertise with these interventions.

Recommendation 5. For adult and pediatric patients who have recurrent acute pain associated with SCD, the ASH guideline panel suggests against chronic monthly transfusion therapy as a first-line strategy to prevent or reduce recurrent acute pain episodes (Conditional recommendation; low certainty in the evidence about effects). The evidence for monthly transfusions in preventing recurrent pain is limited. There is, however, a moderate risk of harm, including iron overload and transfusion reactions, in addition to substantial burden and costs.

Chronic Pain

Chronic pain in the guideline is defined as ongoing pain present on most days over the past 6 months.

Recommendation 6. For adult patients with SCD who have chronic pain from the SCD-related identifiable cause avascular necrosis (AVN) of the bone, the ASH guideline panel suggests the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) or NSAIDs in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). For patients with no identifiable cause beyond SCD, the guideline panel suggests SNRIs, tricyclic antidepressants, or gabapentinoids for pain management (Conditional recommendation; very low certainty in the evidence about effects). Given the lack of direct evidence, indirect evidence was used to formulate these recommendations. For pain associated with AVN, data were extrapolated from literature on osteoarthritis, a form of degenerative arthropathy. For pain without an identifiable cause, evidence was taken from studies on fibromyalgia, a condition the panel felt most closely aligned with chronic pain related to SCD.

No recommendations were made for pediatric patients as the indirect evidence base only addressed adult patients.

Recommendation 7. For adult and pediatric patients with SCD and emerging and/or recently developed chronic pain, the ASH guideline panel does not recommend initiating COT unless pain is refractory to multiple other treatment modalities (Conditional recommendation; very low certainty in the evidence about effects). For patients receiving COT who are functioning well and have perceived benefit, the ASH guideline panel suggests shared decision-making for continuation of COT (Conditional recommendation; very low certainty in the evidence about effects).

High-quality data on the benefit of long-term COT in individuals with chronic noncancer pain are lacking. The panel maintains that the decision to initiate or continue COT should be individualized after weighing appropriate risks and benefits.

Recommendation 8. For adult and pediatric patients with chronic pain related to SCD, the panel suggests cognitive and behavioral pain management strategies in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). Cognitive behavioral therapy may decrease overall pain intensity and improve coping skills.⁸ The panel agrees that medications alone may not be effective in reducing the burden of chronic pain in adult and pediatric patients with SCD.

The guidelines were created by a multidisciplinary panel that included physicians from hematology, pain medicine, psychiatry, and emergency medicine, a doctoral nurse practitioner, and two patient representatives. The Mayo Evidence-Based Practice Research Program supported the guideline-development process. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess evidence and make recommendations.

High-quality data in treating acute and chronic pain in both adult and pediatric patients with SCD are limited. As such, the majority of recommendations in these guidelines are conditional. The panel included studies that were indirectly related to SCD based on consensus (eg, inferred data from disease processes thought to be similar to SCD). One panelist disclosed receiving direct payments from a company that could be affected by these guidelines; however, it was deemed that the conflict was unlikely to have influenced any recommendations.

The panel acknowledges that further investigation is needed for both nonpharmacologic and pharmacologic modalities in treating acute and chronic pain related to SCD. Examples include evaluating the comparative-effectiveness of COT vs nonopioid pharmacotherapy, the benefits and harms of continuous opioid infusions in acute pain crises, and the impact of chronic transfusions on acute and chronic pain.

Sickle cell disease (SCD) affects an estimated 100,000 people in the United States.¹ Pain is the most common complication of SCD and the primary reason patients with SCD seek medical attention.² In 2016, three-fourths of the approximately 130,000 SCD-related hospitalizations in the United States involved pain crises.³ When managing patients with SCD and chronic pain, an individualized and interdisciplinary approach is crucial. In 2020, the American Society of Hematology (ASH) developed guidelines reflecting the latest evidence in managing acute and chronic pain in adult and pediatric patients with SCD. The ASH guidelines provide 18 recommendations; here, we highlight the 8 recommendations most pertinent to the hospitalist.

Acute Pain

Acute pain in the guideline is defined as pain that results in an unplanned visit to an acute care center for treatment.

Recommendation 1. For adult and pediatric patients presenting to an acute care setting with SCD-related acute pain, the ASH guideline panel recommends rapid (ie, within 1 hour of arrival at the emergency department [ED]) assessment and administration of analgesia, with reassessments every 30-60 minutes to optimize pain control (Strong recommendation; low certainty in the evidence about effects).

Although the perceived benefits are unclear due to insufficient evidence, the panel agrees that delaying pain management results in undeniable harm to patients. Hence, this recommendation was deemed both acceptable and ethical. Rapid evaluation also allows for earlier identification and treatment of other potential SCD-related complications.

Recommendation 2. For adult and pediatric patients presenting to an acute care setting with SCD-associated pain for whom opioid therapy is indicated, the ASH guideline panel suggests tailored opioid dosing based on consideration of baseline opioid therapy and prior effective therapy. (For adults: conditional recommendation; moderate certainty in the evidence about effects. For children: conditional recommendation; low certainty in the evidence about effects).

One randomized controlled trial examined patient-specific opioid dosing (based on current chronic opioid therapy [COT] and previously known effective acute pain management) vs weight-based dosing in the ED and found that participants randomized into the patient-specific protocol had a greater reduction in pain and decreased rate of hospital admission.⁴

The panel acknowledges that intravenous patient-controlled opioid analgesia is generally the standard of care at most institutions. However, no clear data address whether continuous opioid infusion in addition to on-demand dosing is beneficial.

Recommendation 3. For adult and pediatric patients with acute pain related to SCD, the ASH guideline panel suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids (Conditional recommendation; very low certainty in the evidence about effects).

The use of NSAIDs for managing pain in hospitalized patients with SCD has been associated with a reduction in the use of opioids in the inpatient setting and decreased lengths of stay.⁵ The potential harms of NSAIDs, including renal and gastrointestinal toxicity, however, should be factored into the decision-making as the risks may outweigh the potential benefits.

Recommendation 4. For adult and pediatric patients with SCD hospitalized for acute pain, the ASH guideline panel suggests a subanesthetic (analgesic) infusion of ketamine as adjunctive treatment of pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects). The guideline panel also suggests regional anesthesia for localized pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects).

Studies have demonstrated reduced pain and opioid utilization in individuals who received adjuvant ketamine infusions⁶ or regional anesthesia (ie, epidural).⁷ Feasibility, however, is limited to centers that have the appropriate experience and expertise with these interventions.

Recommendation 5. For adult and pediatric patients who have recurrent acute pain associated with SCD, the ASH guideline panel suggests against chronic monthly transfusion therapy as a first-line strategy to prevent or reduce recurrent acute pain episodes (Conditional recommendation; low certainty in the evidence about effects). The evidence for monthly transfusions in preventing recurrent pain is limited. There is, however, a moderate risk of harm, including iron overload and transfusion reactions, in addition to substantial burden and costs.

Chronic Pain

Chronic pain in the guideline is defined as ongoing pain present on most days over the past 6 months.

Recommendation 6. For adult patients with SCD who have chronic pain from the SCD-related identifiable cause avascular necrosis (AVN) of the bone, the ASH guideline panel suggests the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) or NSAIDs in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). For patients with no identifiable cause beyond SCD, the guideline panel suggests SNRIs, tricyclic antidepressants, or gabapentinoids for pain management (Conditional recommendation; very low certainty in the evidence about effects). Given the lack of direct evidence, indirect evidence was used to formulate these recommendations. For pain associated with AVN, data were extrapolated from literature on osteoarthritis, a form of degenerative arthropathy. For pain without an identifiable cause, evidence was taken from studies on fibromyalgia, a condition the panel felt most closely aligned with chronic pain related to SCD.

No recommendations were made for pediatric patients as the indirect evidence base only addressed adult patients.

Recommendation 7. For adult and pediatric patients with SCD and emerging and/or recently developed chronic pain, the ASH guideline panel does not recommend initiating COT unless pain is refractory to multiple other treatment modalities (Conditional recommendation; very low certainty in the evidence about effects). For patients receiving COT who are functioning well and have perceived benefit, the ASH guideline panel suggests shared decision-making for continuation of COT (Conditional recommendation; very low certainty in the evidence about effects).

High-quality data on the benefit of long-term COT in individuals with chronic noncancer pain are lacking. The panel maintains that the decision to initiate or continue COT should be individualized after weighing appropriate risks and benefits.

Recommendation 8. For adult and pediatric patients with chronic pain related to SCD, the panel suggests cognitive and behavioral pain management strategies in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). Cognitive behavioral therapy may decrease overall pain intensity and improve coping skills.⁸ The panel agrees that medications alone may not be effective in reducing the burden of chronic pain in adult and pediatric patients with SCD.

The guidelines were created by a multidisciplinary panel that included physicians from hematology, pain medicine, psychiatry, and emergency medicine, a doctoral nurse practitioner, and two patient representatives. The Mayo Evidence-Based Practice Research Program supported the guideline-development process. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess evidence and make recommendations.

High-quality data in treating acute and chronic pain in both adult and pediatric patients with SCD are limited. As such, the majority of recommendations in these guidelines are conditional. The panel included studies that were indirectly related to SCD based on consensus (eg, inferred data from disease processes thought to be similar to SCD). One panelist disclosed receiving direct payments from a company that could be affected by these guidelines; however, it was deemed that the conflict was unlikely to have influenced any recommendations.

The panel acknowledges that further investigation is needed for both nonpharmacologic and pharmacologic modalities in treating acute and chronic pain related to SCD. Examples include evaluating the comparative-effectiveness of COT vs nonopioid pharmacotherapy, the benefits and harms of continuous opioid infusions in acute pain crises, and the impact of chronic transfusions on acute and chronic pain.

Sickle cell disease (SCD) affects an estimated 100,000 people in the United States.¹ Pain is the most common complication of SCD and the primary reason patients with SCD seek medical attention.² In 2016, three-fourths of the approximately 130,000 SCD-related hospitalizations in the United States involved pain crises.³ When managing patients with SCD and chronic pain, an individualized and interdisciplinary approach is crucial. In 2020, the American Society of Hematology (ASH) developed guidelines reflecting the latest evidence in managing acute and chronic pain in adult and pediatric patients with SCD. The ASH guidelines provide 18 recommendations; here, we highlight the 8 recommendations most pertinent to the hospitalist.

Acute Pain

Acute pain in the guideline is defined as pain that results in an unplanned visit to an acute care center for treatment.

Recommendation 1. For adult and pediatric patients presenting to an acute care setting with SCD-related acute pain, the ASH guideline panel recommends rapid (ie, within 1 hour of arrival at the emergency department [ED]) assessment and administration of analgesia, with reassessments every 30-60 minutes to optimize pain control (Strong recommendation; low certainty in the evidence about effects).

Although the perceived benefits are unclear due to insufficient evidence, the panel agrees that delaying pain management results in undeniable harm to patients. Hence, this recommendation was deemed both acceptable and ethical. Rapid evaluation also allows for earlier identification and treatment of other potential SCD-related complications.

Recommendation 2. For adult and pediatric patients presenting to an acute care setting with SCD-associated pain for whom opioid therapy is indicated, the ASH guideline panel suggests tailored opioid dosing based on consideration of baseline opioid therapy and prior effective therapy. (For adults: conditional recommendation; moderate certainty in the evidence about effects. For children: conditional recommendation; low certainty in the evidence about effects).

One randomized controlled trial examined patient-specific opioid dosing (based on current chronic opioid therapy [COT] and previously known effective acute pain management) vs weight-based dosing in the ED and found that participants randomized into the patient-specific protocol had a greater reduction in pain and decreased rate of hospital admission.⁴

The panel acknowledges that intravenous patient-controlled opioid analgesia is generally the standard of care at most institutions. However, no clear data address whether continuous opioid infusion in addition to on-demand dosing is beneficial.

Recommendation 3. For adult and pediatric patients with acute pain related to SCD, the ASH guideline panel suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids (Conditional recommendation; very low certainty in the evidence about effects).

The use of NSAIDs for managing pain in hospitalized patients with SCD has been associated with a reduction in the use of opioids in the inpatient setting and decreased lengths of stay.⁵ The potential harms of NSAIDs, including renal and gastrointestinal toxicity, however, should be factored into the decision-making as the risks may outweigh the potential benefits.

Recommendation 4. For adult and pediatric patients with SCD hospitalized for acute pain, the ASH guideline panel suggests a subanesthetic (analgesic) infusion of ketamine as adjunctive treatment of pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects). The guideline panel also suggests regional anesthesia for localized pain refractory or not effectively treated with opioids alone (Conditional recommendation; very low certainty in the evidence about effects).

Studies have demonstrated reduced pain and opioid utilization in individuals who received adjuvant ketamine infusions⁶ or regional anesthesia (ie, epidural).⁷ Feasibility, however, is limited to centers that have the appropriate experience and expertise with these interventions.

Recommendation 5. For adult and pediatric patients who have recurrent acute pain associated with SCD, the ASH guideline panel suggests against chronic monthly transfusion therapy as a first-line strategy to prevent or reduce recurrent acute pain episodes (Conditional recommendation; low certainty in the evidence about effects). The evidence for monthly transfusions in preventing recurrent pain is limited. There is, however, a moderate risk of harm, including iron overload and transfusion reactions, in addition to substantial burden and costs.

Chronic Pain

Chronic pain in the guideline is defined as ongoing pain present on most days over the past 6 months.

Recommendation 6. For adult patients with SCD who have chronic pain from the SCD-related identifiable cause avascular necrosis (AVN) of the bone, the ASH guideline panel suggests the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) or NSAIDs in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). For patients with no identifiable cause beyond SCD, the guideline panel suggests SNRIs, tricyclic antidepressants, or gabapentinoids for pain management (Conditional recommendation; very low certainty in the evidence about effects). Given the lack of direct evidence, indirect evidence was used to formulate these recommendations. For pain associated with AVN, data were extrapolated from literature on osteoarthritis, a form of degenerative arthropathy. For pain without an identifiable cause, evidence was taken from studies on fibromyalgia, a condition the panel felt most closely aligned with chronic pain related to SCD.

No recommendations were made for pediatric patients as the indirect evidence base only addressed adult patients.

Recommendation 7. For adult and pediatric patients with SCD and emerging and/or recently developed chronic pain, the ASH guideline panel does not recommend initiating COT unless pain is refractory to multiple other treatment modalities (Conditional recommendation; very low certainty in the evidence about effects). For patients receiving COT who are functioning well and have perceived benefit, the ASH guideline panel suggests shared decision-making for continuation of COT (Conditional recommendation; very low certainty in the evidence about effects).

High-quality data on the benefit of long-term COT in individuals with chronic noncancer pain are lacking. The panel maintains that the decision to initiate or continue COT should be individualized after weighing appropriate risks and benefits.

Recommendation 8. For adult and pediatric patients with chronic pain related to SCD, the panel suggests cognitive and behavioral pain management strategies in the context of a comprehensive disease and pain management plan (Conditional recommendation; very low certainty in the evidence about effects). Cognitive behavioral therapy may decrease overall pain intensity and improve coping skills.⁸ The panel agrees that medications alone may not be effective in reducing the burden of chronic pain in adult and pediatric patients with SCD.

The guidelines were created by a multidisciplinary panel that included physicians from hematology, pain medicine, psychiatry, and emergency medicine, a doctoral nurse practitioner, and two patient representatives. The Mayo Evidence-Based Practice Research Program supported the guideline-development process. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess evidence and make recommendations.

High-quality data in treating acute and chronic pain in both adult and pediatric patients with SCD are limited. As such, the majority of recommendations in these guidelines are conditional. The panel included studies that were indirectly related to SCD based on consensus (eg, inferred data from disease processes thought to be similar to SCD). One panelist disclosed receiving direct payments from a company that could be affected by these guidelines; however, it was deemed that the conflict was unlikely to have influenced any recommendations.

The panel acknowledges that further investigation is needed for both nonpharmacologic and pharmacologic modalities in treating acute and chronic pain related to SCD. Examples include evaluating the comparative-effectiveness of COT vs nonopioid pharmacotherapy, the benefits and harms of continuous opioid infusions in acute pain crises, and the impact of chronic transfusions on acute and chronic pain.

Anaphylaxis, an acute, life-threatening allergic response, affects multiple organ systems and manifests variably. Anaphylaxis is likely taking place if one or more of the following occurs: (a) sudden- onset skin and mucosal tissue swelling, (b) skin and mucosal abnormalities or respiratory or gastrointestinal symptoms after exposure to an allergen, or (c) reduced blood pressure after exposure to an allergen. With an estimated lifetime prevalence of up to 5.1%, it is a significant cause of morbidity in adults and children.¹ The 2020 anaphylaxis practice parameter update provides recommendations on treatment, prevention, and assessment of biphasic symptom risk in patients experiencing anaphylaxis.² The guideline provides five key recommendations and four good-practice statements, which we have consolidated into five recommendations for this update.

Recommendation 1. All patients with suspected or confirmed anaphylaxis should be treated with epinephrine. (Good-practice statement)

Self-injectable epinephrine is the first-line treatment for anaphylaxis, with weight-based dosing of 0.15 mg/kg for children weighing less than 30 kg and 0.30 mg/kg for children weighing more than 30 kg and adults. Delayed administration of epinephrine can increase anaphylaxis-associated morbidity and mortality. After epinephrine administration, patients should be observed in a healthcare setting for symptom resolution.

Recommendation 2. For all patients, clinicians should assess the risk for developing biphasic anaphylaxis. (Conditional recommendation, very low quality of evidence)

Biphasic anaphylaxis is defined as the return of anaphylaxis symptoms after an asymptomatic period of at least 1 hour, all during a single instance of anaphylaxis. Biphasic anaphylaxis occurs in up to 20% of patients.³ Biphasic anaphylaxis is more likely among patients receiving repeated doses of epinephrine (odds ratio [OR], 4.82; 95% CI, 2.70-8.58), delayed epinephrine administration greater than 60 minutes (OR, 2.29; 95% CI, 1.09-4.79), or a severe initial presentation (OR, 4.82; 95% CI, 1.23-3.61).² The presence of any of these risk factors raises the risk for developing biphasic anaphylaxis by 17%.⁴ Severe anaphylaxis is characterized by life-threatening symptoms, including loss of consciousness, syncope or dizziness, hypotension, cardiovascular system collapse, or neurologic dysfunction from hypoperfusion or hypoxia after exposure to an allergen.⁵

Other risk factors for biphasic anaphylaxis in all ages include a widened pulse pressure, unknown anaphylaxis trigger, and cutaneous signs and symptoms. Drug triggers are also a risk factor in pediatric patients.²

Recommendation 3. All patients with anaphylaxis and risk factors for biphasic anaphylaxis should undergo extended clinical observation in a setting capable of managing anaphylaxis. (Conditional recommendation, very low quality of evidence)

All patients should be monitored for resolution of symptoms prior to discharge, regardless of age or severity at onset. Patients with all three of the following can be discharged 1 hour after symptom resolution because these three factors together have a 95% negative predictive value for biphasic anaphylaxis: nonsevere anaphylaxis, prompt response to epinephrine, and access to medical care.⁵ In contrast, extended observation of at least 6 hours should be offered to patients with increased risk of biphasic reactions. Patients who have potentially fatal underlying illnesses (eg, severe respiratory or cardiac disease), poor access to emergency medical services, poor self-management skills, or inability to access epinephrine should also be considered for extended observation or hospitalization. Evidence is lacking to define the optimal observation time because extended biphasic reactions can occur from 1 to 78 hours after initial anaphylaxis symptoms.⁶

Given the lack of specific evidence around length of observation, there is an opportunity for shared decision-making. Every patient should receive education regarding trigger avoidance, reasons to seek care or activate emergency medical services, and warning signs of biphasic anaphylaxis. Additionally, self-injectable epinephrine and an action plan detailing how and when to administer the epinephrine should be provided. Patients with anaphylaxis should follow up with an allergist.

Recommendation 4. Administration of glucocorticoids or antihistamines for prevention of biphasic anaphylaxis is not recommended. (Conditional recommendation, very low quality of evidence)

This guideline discourages glucocorticoids and antihistamines as a primary treatment as it may delay epinephrine administration. Despite treating the cutaneous manifestations of anaphylaxis, antihistamines fail to treat the life-threatening cardiovascular and respiratory symptoms. No clear evidence exists on whether antihistamines or glucocorticoids prevent biphasic anaphylaxis.

Recommendation 5. In adult patients receiving chemotherapy, premedication with antihistamine and/or glucocorticoid should be used to prevent anaphylaxis or infusion-related reactions for some chemotherapeutic agents in patients with no previous reaction to the drug. (Conditional recommendation, very low quality of evidence)

Premedication with antihistamines and/or glucocorticoids was associated with 51% reduced odds for anaphylaxis and infusion-related reactions to certain chemotherapy agents (pegaspargase, docetaxel, carboplatin, oxaliplatin, and rituximab) in adults who had not previously experienced a reaction to the drug (OR, 0.49; 95% CI, 0.37-0.66).² However, this same benefit was not found with other chemotherapy agents for patients without a prior allergic reaction to the agent, which allows clinicians to defer premedication. The benefit of premedication with antihistamines and/or glucocorticoids to patients with prior anaphylactic reactions to chemotherapy agents was not evaluated in this guideline, nor was the role premedication plays in desensitization to chemotherapy.

This guideline was created by a panel of allergists, clinical immunologists, and methodologists using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest (COI) were disclosed by all panel members according to the American Academy of Allergy, Asthma, and Immunology (AAAAI) guidelines. The inclusion of many observational studies and meta-analyses improves the generalizability of the guideline. The authors highlighted the low certainty of evidence due to the lack of randomized controlled trials and significant heterogeneity of the included studies.

Some recommendations in the guideline have implications for costs of care. A recent economic analysis looked at cost-effectiveness for extended observation for anaphylaxis and found it was cost-effective only when patients were at increased risk for biphasic anaphylaxis.⁷ Although Recommendation 4 advises against the use of glucocorticoids for prevention of biphasic anaphylaxis, one retrospective cohort study demonstrated that glucocorticoid use was associated with decreased length of stay in children admitted with anaphylaxis.⁸ Therefore, the recommendation to avoid glucocorticoids for prevention of biphasic anaphylaxis could possibly increase hospital length of stay for children. The usefulness of dexamethasone to prevent biphasic anaphylaxis in children 3 to 14 months old is being evaluated in a randomized trial (ClinicalTrials.gov, NCT03523221).

Future research should better characterize risk factors for biphasic reactions to aid in clinical triage and diagnosis. Additional studies are needed to determine the optimal observation duration for patients experiencing anaphylactic reactions or requiring multiple doses of epinephrine. The role of premedication in patients receiving chemotherapy is poorly described, with few studies evaluating the benefit of premedication in patients with previous anaphylactic reactions.

Anaphylaxis, an acute, life-threatening allergic response, affects multiple organ systems and manifests variably. Anaphylaxis is likely taking place if one or more of the following occurs: (a) sudden- onset skin and mucosal tissue swelling, (b) skin and mucosal abnormalities or respiratory or gastrointestinal symptoms after exposure to an allergen, or (c) reduced blood pressure after exposure to an allergen. With an estimated lifetime prevalence of up to 5.1%, it is a significant cause of morbidity in adults and children.¹ The 2020 anaphylaxis practice parameter update provides recommendations on treatment, prevention, and assessment of biphasic symptom risk in patients experiencing anaphylaxis.² The guideline provides five key recommendations and four good-practice statements, which we have consolidated into five recommendations for this update.

Recommendation 1. All patients with suspected or confirmed anaphylaxis should be treated with epinephrine. (Good-practice statement)

Self-injectable epinephrine is the first-line treatment for anaphylaxis, with weight-based dosing of 0.15 mg/kg for children weighing less than 30 kg and 0.30 mg/kg for children weighing more than 30 kg and adults. Delayed administration of epinephrine can increase anaphylaxis-associated morbidity and mortality. After epinephrine administration, patients should be observed in a healthcare setting for symptom resolution.

Recommendation 2. For all patients, clinicians should assess the risk for developing biphasic anaphylaxis. (Conditional recommendation, very low quality of evidence)

Biphasic anaphylaxis is defined as the return of anaphylaxis symptoms after an asymptomatic period of at least 1 hour, all during a single instance of anaphylaxis. Biphasic anaphylaxis occurs in up to 20% of patients.³ Biphasic anaphylaxis is more likely among patients receiving repeated doses of epinephrine (odds ratio [OR], 4.82; 95% CI, 2.70-8.58), delayed epinephrine administration greater than 60 minutes (OR, 2.29; 95% CI, 1.09-4.79), or a severe initial presentation (OR, 4.82; 95% CI, 1.23-3.61).² The presence of any of these risk factors raises the risk for developing biphasic anaphylaxis by 17%.⁴ Severe anaphylaxis is characterized by life-threatening symptoms, including loss of consciousness, syncope or dizziness, hypotension, cardiovascular system collapse, or neurologic dysfunction from hypoperfusion or hypoxia after exposure to an allergen.⁵

Other risk factors for biphasic anaphylaxis in all ages include a widened pulse pressure, unknown anaphylaxis trigger, and cutaneous signs and symptoms. Drug triggers are also a risk factor in pediatric patients.²

Recommendation 3. All patients with anaphylaxis and risk factors for biphasic anaphylaxis should undergo extended clinical observation in a setting capable of managing anaphylaxis. (Conditional recommendation, very low quality of evidence)

All patients should be monitored for resolution of symptoms prior to discharge, regardless of age or severity at onset. Patients with all three of the following can be discharged 1 hour after symptom resolution because these three factors together have a 95% negative predictive value for biphasic anaphylaxis: nonsevere anaphylaxis, prompt response to epinephrine, and access to medical care.⁵ In contrast, extended observation of at least 6 hours should be offered to patients with increased risk of biphasic reactions. Patients who have potentially fatal underlying illnesses (eg, severe respiratory or cardiac disease), poor access to emergency medical services, poor self-management skills, or inability to access epinephrine should also be considered for extended observation or hospitalization. Evidence is lacking to define the optimal observation time because extended biphasic reactions can occur from 1 to 78 hours after initial anaphylaxis symptoms.⁶

Given the lack of specific evidence around length of observation, there is an opportunity for shared decision-making. Every patient should receive education regarding trigger avoidance, reasons to seek care or activate emergency medical services, and warning signs of biphasic anaphylaxis. Additionally, self-injectable epinephrine and an action plan detailing how and when to administer the epinephrine should be provided. Patients with anaphylaxis should follow up with an allergist.

Recommendation 4. Administration of glucocorticoids or antihistamines for prevention of biphasic anaphylaxis is not recommended. (Conditional recommendation, very low quality of evidence)

This guideline discourages glucocorticoids and antihistamines as a primary treatment as it may delay epinephrine administration. Despite treating the cutaneous manifestations of anaphylaxis, antihistamines fail to treat the life-threatening cardiovascular and respiratory symptoms. No clear evidence exists on whether antihistamines or glucocorticoids prevent biphasic anaphylaxis.

Recommendation 5. In adult patients receiving chemotherapy, premedication with antihistamine and/or glucocorticoid should be used to prevent anaphylaxis or infusion-related reactions for some chemotherapeutic agents in patients with no previous reaction to the drug. (Conditional recommendation, very low quality of evidence)

Premedication with antihistamines and/or glucocorticoids was associated with 51% reduced odds for anaphylaxis and infusion-related reactions to certain chemotherapy agents (pegaspargase, docetaxel, carboplatin, oxaliplatin, and rituximab) in adults who had not previously experienced a reaction to the drug (OR, 0.49; 95% CI, 0.37-0.66).² However, this same benefit was not found with other chemotherapy agents for patients without a prior allergic reaction to the agent, which allows clinicians to defer premedication. The benefit of premedication with antihistamines and/or glucocorticoids to patients with prior anaphylactic reactions to chemotherapy agents was not evaluated in this guideline, nor was the role premedication plays in desensitization to chemotherapy.

This guideline was created by a panel of allergists, clinical immunologists, and methodologists using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest (COI) were disclosed by all panel members according to the American Academy of Allergy, Asthma, and Immunology (AAAAI) guidelines. The inclusion of many observational studies and meta-analyses improves the generalizability of the guideline. The authors highlighted the low certainty of evidence due to the lack of randomized controlled trials and significant heterogeneity of the included studies.

Some recommendations in the guideline have implications for costs of care. A recent economic analysis looked at cost-effectiveness for extended observation for anaphylaxis and found it was cost-effective only when patients were at increased risk for biphasic anaphylaxis.⁷ Although Recommendation 4 advises against the use of glucocorticoids for prevention of biphasic anaphylaxis, one retrospective cohort study demonstrated that glucocorticoid use was associated with decreased length of stay in children admitted with anaphylaxis.⁸ Therefore, the recommendation to avoid glucocorticoids for prevention of biphasic anaphylaxis could possibly increase hospital length of stay for children. The usefulness of dexamethasone to prevent biphasic anaphylaxis in children 3 to 14 months old is being evaluated in a randomized trial (ClinicalTrials.gov, NCT03523221).

Future research should better characterize risk factors for biphasic reactions to aid in clinical triage and diagnosis. Additional studies are needed to determine the optimal observation duration for patients experiencing anaphylactic reactions or requiring multiple doses of epinephrine. The role of premedication in patients receiving chemotherapy is poorly described, with few studies evaluating the benefit of premedication in patients with previous anaphylactic reactions.

Anaphylaxis, an acute, life-threatening allergic response, affects multiple organ systems and manifests variably. Anaphylaxis is likely taking place if one or more of the following occurs: (a) sudden- onset skin and mucosal tissue swelling, (b) skin and mucosal abnormalities or respiratory or gastrointestinal symptoms after exposure to an allergen, or (c) reduced blood pressure after exposure to an allergen. With an estimated lifetime prevalence of up to 5.1%, it is a significant cause of morbidity in adults and children.¹ The 2020 anaphylaxis practice parameter update provides recommendations on treatment, prevention, and assessment of biphasic symptom risk in patients experiencing anaphylaxis.² The guideline provides five key recommendations and four good-practice statements, which we have consolidated into five recommendations for this update.

Recommendation 1. All patients with suspected or confirmed anaphylaxis should be treated with epinephrine. (Good-practice statement)

Self-injectable epinephrine is the first-line treatment for anaphylaxis, with weight-based dosing of 0.15 mg/kg for children weighing less than 30 kg and 0.30 mg/kg for children weighing more than 30 kg and adults. Delayed administration of epinephrine can increase anaphylaxis-associated morbidity and mortality. After epinephrine administration, patients should be observed in a healthcare setting for symptom resolution.

Recommendation 2. For all patients, clinicians should assess the risk for developing biphasic anaphylaxis. (Conditional recommendation, very low quality of evidence)

Biphasic anaphylaxis is defined as the return of anaphylaxis symptoms after an asymptomatic period of at least 1 hour, all during a single instance of anaphylaxis. Biphasic anaphylaxis occurs in up to 20% of patients.³ Biphasic anaphylaxis is more likely among patients receiving repeated doses of epinephrine (odds ratio [OR], 4.82; 95% CI, 2.70-8.58), delayed epinephrine administration greater than 60 minutes (OR, 2.29; 95% CI, 1.09-4.79), or a severe initial presentation (OR, 4.82; 95% CI, 1.23-3.61).² The presence of any of these risk factors raises the risk for developing biphasic anaphylaxis by 17%.⁴ Severe anaphylaxis is characterized by life-threatening symptoms, including loss of consciousness, syncope or dizziness, hypotension, cardiovascular system collapse, or neurologic dysfunction from hypoperfusion or hypoxia after exposure to an allergen.⁵

Other risk factors for biphasic anaphylaxis in all ages include a widened pulse pressure, unknown anaphylaxis trigger, and cutaneous signs and symptoms. Drug triggers are also a risk factor in pediatric patients.²

Recommendation 3. All patients with anaphylaxis and risk factors for biphasic anaphylaxis should undergo extended clinical observation in a setting capable of managing anaphylaxis. (Conditional recommendation, very low quality of evidence)

All patients should be monitored for resolution of symptoms prior to discharge, regardless of age or severity at onset. Patients with all three of the following can be discharged 1 hour after symptom resolution because these three factors together have a 95% negative predictive value for biphasic anaphylaxis: nonsevere anaphylaxis, prompt response to epinephrine, and access to medical care.⁵ In contrast, extended observation of at least 6 hours should be offered to patients with increased risk of biphasic reactions. Patients who have potentially fatal underlying illnesses (eg, severe respiratory or cardiac disease), poor access to emergency medical services, poor self-management skills, or inability to access epinephrine should also be considered for extended observation or hospitalization. Evidence is lacking to define the optimal observation time because extended biphasic reactions can occur from 1 to 78 hours after initial anaphylaxis symptoms.⁶

Given the lack of specific evidence around length of observation, there is an opportunity for shared decision-making. Every patient should receive education regarding trigger avoidance, reasons to seek care or activate emergency medical services, and warning signs of biphasic anaphylaxis. Additionally, self-injectable epinephrine and an action plan detailing how and when to administer the epinephrine should be provided. Patients with anaphylaxis should follow up with an allergist.

Recommendation 4. Administration of glucocorticoids or antihistamines for prevention of biphasic anaphylaxis is not recommended. (Conditional recommendation, very low quality of evidence)

This guideline discourages glucocorticoids and antihistamines as a primary treatment as it may delay epinephrine administration. Despite treating the cutaneous manifestations of anaphylaxis, antihistamines fail to treat the life-threatening cardiovascular and respiratory symptoms. No clear evidence exists on whether antihistamines or glucocorticoids prevent biphasic anaphylaxis.

Recommendation 5. In adult patients receiving chemotherapy, premedication with antihistamine and/or glucocorticoid should be used to prevent anaphylaxis or infusion-related reactions for some chemotherapeutic agents in patients with no previous reaction to the drug. (Conditional recommendation, very low quality of evidence)

Premedication with antihistamines and/or glucocorticoids was associated with 51% reduced odds for anaphylaxis and infusion-related reactions to certain chemotherapy agents (pegaspargase, docetaxel, carboplatin, oxaliplatin, and rituximab) in adults who had not previously experienced a reaction to the drug (OR, 0.49; 95% CI, 0.37-0.66).² However, this same benefit was not found with other chemotherapy agents for patients without a prior allergic reaction to the agent, which allows clinicians to defer premedication. The benefit of premedication with antihistamines and/or glucocorticoids to patients with prior anaphylactic reactions to chemotherapy agents was not evaluated in this guideline, nor was the role premedication plays in desensitization to chemotherapy.

This guideline was created by a panel of allergists, clinical immunologists, and methodologists using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach to draft recommendations. Conflicts of interest (COI) were disclosed by all panel members according to the American Academy of Allergy, Asthma, and Immunology (AAAAI) guidelines. The inclusion of many observational studies and meta-analyses improves the generalizability of the guideline. The authors highlighted the low certainty of evidence due to the lack of randomized controlled trials and significant heterogeneity of the included studies.

Some recommendations in the guideline have implications for costs of care. A recent economic analysis looked at cost-effectiveness for extended observation for anaphylaxis and found it was cost-effective only when patients were at increased risk for biphasic anaphylaxis.⁷ Although Recommendation 4 advises against the use of glucocorticoids for prevention of biphasic anaphylaxis, one retrospective cohort study demonstrated that glucocorticoid use was associated with decreased length of stay in children admitted with anaphylaxis.⁸ Therefore, the recommendation to avoid glucocorticoids for prevention of biphasic anaphylaxis could possibly increase hospital length of stay for children. The usefulness of dexamethasone to prevent biphasic anaphylaxis in children 3 to 14 months old is being evaluated in a randomized trial (ClinicalTrials.gov, NCT03523221).

Future research should better characterize risk factors for biphasic reactions to aid in clinical triage and diagnosis. Additional studies are needed to determine the optimal observation duration for patients experiencing anaphylactic reactions or requiring multiple doses of epinephrine. The role of premedication in patients receiving chemotherapy is poorly described, with few studies evaluating the benefit of premedication in patients with previous anaphylactic reactions.

Osteoporosis is the most prevalent bone disease and a leading cause of morbidity and mortality in older people. According to the National Health and Nutrition Examination Survey, from 2005-2010, there were an estimated 10.2 million adults 50 years and older with osteoporosis and 43.4 million more with low bone mass in the United States.¹ Osteoporotic fracture is a leading cause of hospitalization in the United States for women 55 years or older, ahead of heart attacks, stroke, and breast cancer.² Despite elucidation of the pathogenesis of osteoporosis and the advent of effective and widely available therapies, a “treatment gap” separates the many patients who warrant therapy from the few who receive it. Systematic improvement strategies, such as coordinator-based fracture liaison services, have had a positive impact on addressing this treatment gap.³ There is an opportunity for hospitalists to further narrow this treatment gap.

The American Society of Bone and Mineral Research, in conjunction with the Center for Medical Technology Policy, developed consensus clinical recommendations to address secondary fracture prevention for people 65 years or older who have experienced a hip or vertebral fracture.⁴ We address six of the fundamental and two of the supplemental recommendations as they apply to the practice of hospital medicine.

Recommendations 1 and 2

Communicate key information to the patient and their usual healthcare provider. Patients 65 years or older with a hip or vertebral fracture likely have osteoporosis and are at high risk for subsequent fractures, which can lead to a decline in function and an increase in mortality. Patients must be counseled regarding their diagnosis, their risks, and the actions they can take to manage their disease. Primary care providers must be notified of the occurrence of the fracture, the diagnosis of osteoporosis, and the plans for management.

We recommend hospitalists act as leading advocates for at-risk patients to ensure that this communication occurs during hospitalization. We encourage hospitals and institutions to adopt systematic interventions to facilitate postdischarge care for these patients. These may include implementing a fracture liaison service, with multidisciplinary secondary fracture–prevention strategies using physicians, pharmacists, nurses, social workers, and case managers for care coordination and treatment initiation.

Elderly patients with osteoporotic fragility fractures are at risk for further morbidity and mortality. Coordination of care between the inpatient care team and the primary care provider is necessary to reduce this risk. In addition to verbal communication and especially when verbal communication is not feasible, discharge documents provided to patients and outpatient providers should clearly identify the occurrence of a hip or vertebral fracture and a discharge diagnosis of osteoporosis if not previously documented, regardless of bone mineral density (BMD) results or lack of testing.

Recommendation 3

Regularly assess fall risk. Patients 65 years or older with a current or prior hip or vertebral fracture must be regularly assessed for risk of falls. Hospitalists can assess patients’ ongoing risk for falls at time of admission or during hospitalization. Risk factors include prior falls; advanced age; visual, auditory, or cognitive impairment; decreased muscle strength; gait and balance impairment; diabetes mellitus; use of multiple medications, and others.⁵ Specialist evaluation by a physical therapist or a physiatrist should be considered. Active medications should be reviewed for adverse effects and interactions. The use of diuretics, antipsychotics, antidepressants, benzodiazepines, antiepileptics, and opioids should be minimized.

Recommendations 4, 5, 6, and 11

Offer pharmacologic therapy and initiate calcium and vitamin D supplementation. Recommendations 4 through 6 and 11 advocate pharmacologic interventions including bisphosphonates, denosumab, vitamin D, and/or calcium to reduce the risk of future fractures. Bisphosphonates are the cornerstone of pharmacologic therapy for secondary fracture prevention. The efficacy of these agents for prevention of subsequent fractures outweighs the potential for interference in healing of surgically repaired bones.⁶ Oral bisphosphonate therapy should be initiated in the hospital or at discharge. Parenteral bisphosphonates and denosumab may be utilized in patients unable to tolerate or absorb oral bisphosphonates due to esophageal or other gastrointestinal disease. Initiation of these agents should be delayed until after vitamin D and calcium supplementation have been administered for 2 weeks after the fracture to reduce the risk of precipitating hypocalcemia, and they should not be used in patients with confirmed hypocalcemia until that is resolved. BMD measurement is not necessary prior to pharmacologic therapy initiation because the risk of fracture is elevated for these patients regardless of BMD. Patients without significant dental disease or planned oral or maxillofacial procedures may begin bisphosphonate therapy prior to a full dental assessment because risk of osteonecrosis of the jaw is low.

The guidelines recommend people 65 years or older with a hip or vertebral fracture receive daily supplementation of at least 800 IU vitamin D. Patients unable to achieve an intake of 1,200 mg/day of calcium from food sources should receive daily calcium supplementation. The effect of vitamin D monotherapy on fracture risk is not clear; however, strong evidence suggests that fracture risk is reduced when individuals at high risk of deficiency receive supplementation with vitamin D and calcium. Calcium supplementation alone has not demonstrated reduction in fracture risk. Total daily calcium intake above 1,500 mg has not been shown to provide additional benefit and is potentially harmful.

Recommendation 9

Counsel patients on lifestyle modifications and consider physical therapy. Tobacco has a deleterious effect on bone density and increases risk for osteoporotic fragility fracture.⁷ Hospitalists should obtain tobacco use history from all patients with an osteoporotic fracture and provide tobacco cessation counseling when appropriate. Excessive alcohol consumption increases the risk of fall injuries.⁸ Hospitalists should counsel patients to limit alcohol intake to a maximum of two drinks a day for men and one drink a day for women.

Weight-bearing and strength-training exercises, particularly those involving balance and trunk muscle strength, are associated with reduction in fall-risk. Exercise must be tailored to the patient’s physical capacity. Hospitalists may partner with physical therapists or physiatrists to facilitate development of an exercise plan to maximize benefit and minimize risk of injury.

We found this document to be highly informative and well cited, with ample evidence to support the recommendations.

Methods in Preparing Guidelines

The multistakeholder coalition did not employ a rigorous and standardized methodology for the guideline, such as GRADE (Grading of Recommendations Assessment, Development, and Evaluation); hence, no assessment of evidence quality, benefits and harms of an intervention, or resource use was provided.

Potential Conflicts for Guideline Authors

Eight guideline authors have pharmaceutical relationships with the manufacturer of one of the medications listed on the guidelines (Amgen-denosumab, Novartis-zoledronic acid). There are no disclosures reported from the multistakeholder coalition members who are not listed as guideline authors.

We anticipate future studies may report outcomes focused on secondary prevention of fractures. Additionally, we would like to see new studies investigating patient-centered outcomes such as improvement in functional status and ambulatory independence based on improved postfracture medical therapies. We see an opportunity for studies assessing real-world outcomes to inform future recommendations, particularly after widespread implementation of secondary fracture prevention therapy either initiated during hospitalization or purposefully planned for after discharge.

We would like to see more trial data comparing the safety and cost-effectiveness of first-line therapy, namely oral bisphosphonates, to alternative treatments, particularly parenteral agents, which may improve treatment compliance because of the convenience in dosing frequency.

Osteoporosis is the most prevalent bone disease and a leading cause of morbidity and mortality in older people. According to the National Health and Nutrition Examination Survey, from 2005-2010, there were an estimated 10.2 million adults 50 years and older with osteoporosis and 43.4 million more with low bone mass in the United States.¹ Osteoporotic fracture is a leading cause of hospitalization in the United States for women 55 years or older, ahead of heart attacks, stroke, and breast cancer.² Despite elucidation of the pathogenesis of osteoporosis and the advent of effective and widely available therapies, a “treatment gap” separates the many patients who warrant therapy from the few who receive it. Systematic improvement strategies, such as coordinator-based fracture liaison services, have had a positive impact on addressing this treatment gap.³ There is an opportunity for hospitalists to further narrow this treatment gap.

The American Society of Bone and Mineral Research, in conjunction with the Center for Medical Technology Policy, developed consensus clinical recommendations to address secondary fracture prevention for people 65 years or older who have experienced a hip or vertebral fracture.⁴ We address six of the fundamental and two of the supplemental recommendations as they apply to the practice of hospital medicine.

Recommendations 1 and 2

Communicate key information to the patient and their usual healthcare provider. Patients 65 years or older with a hip or vertebral fracture likely have osteoporosis and are at high risk for subsequent fractures, which can lead to a decline in function and an increase in mortality. Patients must be counseled regarding their diagnosis, their risks, and the actions they can take to manage their disease. Primary care providers must be notified of the occurrence of the fracture, the diagnosis of osteoporosis, and the plans for management.

We recommend hospitalists act as leading advocates for at-risk patients to ensure that this communication occurs during hospitalization. We encourage hospitals and institutions to adopt systematic interventions to facilitate postdischarge care for these patients. These may include implementing a fracture liaison service, with multidisciplinary secondary fracture–prevention strategies using physicians, pharmacists, nurses, social workers, and case managers for care coordination and treatment initiation.

Elderly patients with osteoporotic fragility fractures are at risk for further morbidity and mortality. Coordination of care between the inpatient care team and the primary care provider is necessary to reduce this risk. In addition to verbal communication and especially when verbal communication is not feasible, discharge documents provided to patients and outpatient providers should clearly identify the occurrence of a hip or vertebral fracture and a discharge diagnosis of osteoporosis if not previously documented, regardless of bone mineral density (BMD) results or lack of testing.

Recommendation 3

Regularly assess fall risk. Patients 65 years or older with a current or prior hip or vertebral fracture must be regularly assessed for risk of falls. Hospitalists can assess patients’ ongoing risk for falls at time of admission or during hospitalization. Risk factors include prior falls; advanced age; visual, auditory, or cognitive impairment; decreased muscle strength; gait and balance impairment; diabetes mellitus; use of multiple medications, and others.⁵ Specialist evaluation by a physical therapist or a physiatrist should be considered. Active medications should be reviewed for adverse effects and interactions. The use of diuretics, antipsychotics, antidepressants, benzodiazepines, antiepileptics, and opioids should be minimized.

Recommendations 4, 5, 6, and 11

Offer pharmacologic therapy and initiate calcium and vitamin D supplementation. Recommendations 4 through 6 and 11 advocate pharmacologic interventions including bisphosphonates, denosumab, vitamin D, and/or calcium to reduce the risk of future fractures. Bisphosphonates are the cornerstone of pharmacologic therapy for secondary fracture prevention. The efficacy of these agents for prevention of subsequent fractures outweighs the potential for interference in healing of surgically repaired bones.⁶ Oral bisphosphonate therapy should be initiated in the hospital or at discharge. Parenteral bisphosphonates and denosumab may be utilized in patients unable to tolerate or absorb oral bisphosphonates due to esophageal or other gastrointestinal disease. Initiation of these agents should be delayed until after vitamin D and calcium supplementation have been administered for 2 weeks after the fracture to reduce the risk of precipitating hypocalcemia, and they should not be used in patients with confirmed hypocalcemia until that is resolved. BMD measurement is not necessary prior to pharmacologic therapy initiation because the risk of fracture is elevated for these patients regardless of BMD. Patients without significant dental disease or planned oral or maxillofacial procedures may begin bisphosphonate therapy prior to a full dental assessment because risk of osteonecrosis of the jaw is low.

The guidelines recommend people 65 years or older with a hip or vertebral fracture receive daily supplementation of at least 800 IU vitamin D. Patients unable to achieve an intake of 1,200 mg/day of calcium from food sources should receive daily calcium supplementation. The effect of vitamin D monotherapy on fracture risk is not clear; however, strong evidence suggests that fracture risk is reduced when individuals at high risk of deficiency receive supplementation with vitamin D and calcium. Calcium supplementation alone has not demonstrated reduction in fracture risk. Total daily calcium intake above 1,500 mg has not been shown to provide additional benefit and is potentially harmful.

Recommendation 9

Counsel patients on lifestyle modifications and consider physical therapy. Tobacco has a deleterious effect on bone density and increases risk for osteoporotic fragility fracture.⁷ Hospitalists should obtain tobacco use history from all patients with an osteoporotic fracture and provide tobacco cessation counseling when appropriate. Excessive alcohol consumption increases the risk of fall injuries.⁸ Hospitalists should counsel patients to limit alcohol intake to a maximum of two drinks a day for men and one drink a day for women.

Weight-bearing and strength-training exercises, particularly those involving balance and trunk muscle strength, are associated with reduction in fall-risk. Exercise must be tailored to the patient’s physical capacity. Hospitalists may partner with physical therapists or physiatrists to facilitate development of an exercise plan to maximize benefit and minimize risk of injury.

We found this document to be highly informative and well cited, with ample evidence to support the recommendations.

Methods in Preparing Guidelines

The multistakeholder coalition did not employ a rigorous and standardized methodology for the guideline, such as GRADE (Grading of Recommendations Assessment, Development, and Evaluation); hence, no assessment of evidence quality, benefits and harms of an intervention, or resource use was provided.

Potential Conflicts for Guideline Authors

Eight guideline authors have pharmaceutical relationships with the manufacturer of one of the medications listed on the guidelines (Amgen-denosumab, Novartis-zoledronic acid). There are no disclosures reported from the multistakeholder coalition members who are not listed as guideline authors.

We anticipate future studies may report outcomes focused on secondary prevention of fractures. Additionally, we would like to see new studies investigating patient-centered outcomes such as improvement in functional status and ambulatory independence based on improved postfracture medical therapies. We see an opportunity for studies assessing real-world outcomes to inform future recommendations, particularly after widespread implementation of secondary fracture prevention therapy either initiated during hospitalization or purposefully planned for after discharge.

We would like to see more trial data comparing the safety and cost-effectiveness of first-line therapy, namely oral bisphosphonates, to alternative treatments, particularly parenteral agents, which may improve treatment compliance because of the convenience in dosing frequency.

Osteoporosis is the most prevalent bone disease and a leading cause of morbidity and mortality in older people. According to the National Health and Nutrition Examination Survey, from 2005-2010, there were an estimated 10.2 million adults 50 years and older with osteoporosis and 43.4 million more with low bone mass in the United States.¹ Osteoporotic fracture is a leading cause of hospitalization in the United States for women 55 years or older, ahead of heart attacks, stroke, and breast cancer.² Despite elucidation of the pathogenesis of osteoporosis and the advent of effective and widely available therapies, a “treatment gap” separates the many patients who warrant therapy from the few who receive it. Systematic improvement strategies, such as coordinator-based fracture liaison services, have had a positive impact on addressing this treatment gap.³ There is an opportunity for hospitalists to further narrow this treatment gap.

The American Society of Bone and Mineral Research, in conjunction with the Center for Medical Technology Policy, developed consensus clinical recommendations to address secondary fracture prevention for people 65 years or older who have experienced a hip or vertebral fracture.⁴ We address six of the fundamental and two of the supplemental recommendations as they apply to the practice of hospital medicine.

Recommendations 1 and 2

Communicate key information to the patient and their usual healthcare provider. Patients 65 years or older with a hip or vertebral fracture likely have osteoporosis and are at high risk for subsequent fractures, which can lead to a decline in function and an increase in mortality. Patients must be counseled regarding their diagnosis, their risks, and the actions they can take to manage their disease. Primary care providers must be notified of the occurrence of the fracture, the diagnosis of osteoporosis, and the plans for management.

We recommend hospitalists act as leading advocates for at-risk patients to ensure that this communication occurs during hospitalization. We encourage hospitals and institutions to adopt systematic interventions to facilitate postdischarge care for these patients. These may include implementing a fracture liaison service, with multidisciplinary secondary fracture–prevention strategies using physicians, pharmacists, nurses, social workers, and case managers for care coordination and treatment initiation.

Elderly patients with osteoporotic fragility fractures are at risk for further morbidity and mortality. Coordination of care between the inpatient care team and the primary care provider is necessary to reduce this risk. In addition to verbal communication and especially when verbal communication is not feasible, discharge documents provided to patients and outpatient providers should clearly identify the occurrence of a hip or vertebral fracture and a discharge diagnosis of osteoporosis if not previously documented, regardless of bone mineral density (BMD) results or lack of testing.

Recommendation 3

Regularly assess fall risk. Patients 65 years or older with a current or prior hip or vertebral fracture must be regularly assessed for risk of falls. Hospitalists can assess patients’ ongoing risk for falls at time of admission or during hospitalization. Risk factors include prior falls; advanced age; visual, auditory, or cognitive impairment; decreased muscle strength; gait and balance impairment; diabetes mellitus; use of multiple medications, and others.⁵ Specialist evaluation by a physical therapist or a physiatrist should be considered. Active medications should be reviewed for adverse effects and interactions. The use of diuretics, antipsychotics, antidepressants, benzodiazepines, antiepileptics, and opioids should be minimized.

Recommendations 4, 5, 6, and 11

Offer pharmacologic therapy and initiate calcium and vitamin D supplementation. Recommendations 4 through 6 and 11 advocate pharmacologic interventions including bisphosphonates, denosumab, vitamin D, and/or calcium to reduce the risk of future fractures. Bisphosphonates are the cornerstone of pharmacologic therapy for secondary fracture prevention. The efficacy of these agents for prevention of subsequent fractures outweighs the potential for interference in healing of surgically repaired bones.⁶ Oral bisphosphonate therapy should be initiated in the hospital or at discharge. Parenteral bisphosphonates and denosumab may be utilized in patients unable to tolerate or absorb oral bisphosphonates due to esophageal or other gastrointestinal disease. Initiation of these agents should be delayed until after vitamin D and calcium supplementation have been administered for 2 weeks after the fracture to reduce the risk of precipitating hypocalcemia, and they should not be used in patients with confirmed hypocalcemia until that is resolved. BMD measurement is not necessary prior to pharmacologic therapy initiation because the risk of fracture is elevated for these patients regardless of BMD. Patients without significant dental disease or planned oral or maxillofacial procedures may begin bisphosphonate therapy prior to a full dental assessment because risk of osteonecrosis of the jaw is low.

The guidelines recommend people 65 years or older with a hip or vertebral fracture receive daily supplementation of at least 800 IU vitamin D. Patients unable to achieve an intake of 1,200 mg/day of calcium from food sources should receive daily calcium supplementation. The effect of vitamin D monotherapy on fracture risk is not clear; however, strong evidence suggests that fracture risk is reduced when individuals at high risk of deficiency receive supplementation with vitamin D and calcium. Calcium supplementation alone has not demonstrated reduction in fracture risk. Total daily calcium intake above 1,500 mg has not been shown to provide additional benefit and is potentially harmful.

Recommendation 9

Counsel patients on lifestyle modifications and consider physical therapy. Tobacco has a deleterious effect on bone density and increases risk for osteoporotic fragility fracture.⁷ Hospitalists should obtain tobacco use history from all patients with an osteoporotic fracture and provide tobacco cessation counseling when appropriate. Excessive alcohol consumption increases the risk of fall injuries.⁸ Hospitalists should counsel patients to limit alcohol intake to a maximum of two drinks a day for men and one drink a day for women.

Weight-bearing and strength-training exercises, particularly those involving balance and trunk muscle strength, are associated with reduction in fall-risk. Exercise must be tailored to the patient’s physical capacity. Hospitalists may partner with physical therapists or physiatrists to facilitate development of an exercise plan to maximize benefit and minimize risk of injury.

We found this document to be highly informative and well cited, with ample evidence to support the recommendations.

Methods in Preparing Guidelines

The multistakeholder coalition did not employ a rigorous and standardized methodology for the guideline, such as GRADE (Grading of Recommendations Assessment, Development, and Evaluation); hence, no assessment of evidence quality, benefits and harms of an intervention, or resource use was provided.

Potential Conflicts for Guideline Authors

Eight guideline authors have pharmaceutical relationships with the manufacturer of one of the medications listed on the guidelines (Amgen-denosumab, Novartis-zoledronic acid). There are no disclosures reported from the multistakeholder coalition members who are not listed as guideline authors.

We anticipate future studies may report outcomes focused on secondary prevention of fractures. Additionally, we would like to see new studies investigating patient-centered outcomes such as improvement in functional status and ambulatory independence based on improved postfracture medical therapies. We see an opportunity for studies assessing real-world outcomes to inform future recommendations, particularly after widespread implementation of secondary fracture prevention therapy either initiated during hospitalization or purposefully planned for after discharge.

We would like to see more trial data comparing the safety and cost-effectiveness of first-line therapy, namely oral bisphosphonates, to alternative treatments, particularly parenteral agents, which may improve treatment compliance because of the convenience in dosing frequency.