Clinical Guideline Highlights

Clostridium difficile (name changed to Clostridioides difficile [CDI]) are a major public health problem, with 500,000 infections annually in the United States, 15,000-30,000 associated deaths, and acute care costs exceeding $4.8 billion. The recent clinical practice guideline for CDI provides recommendations about the epidemiology, diagnosis, treatment, prevention, and environmental management. A total of 52 recommendations are included, and we will review 11 with pertinence to pediatrics in this highlight.

Recommendation 1. In infants ≤12 months of age, testing for CDI should never be routinely recommended because of the high prevalence of asymptomatic carriage of toxigenic C. difficile in infants (strong recommendation, moderate quality of evidence).

Recommendation 2. In children 1-2 years of age, testing should not be routinely performed unless other causes have been excluded (weak recommendation, low quality of evidence).Recommendation 3. In children ≥2 years of age, testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease) or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics) (weak recommendation, moderate quality of evidence).

The rate of C. difficile colonization among asymptomatic infants can exceed 40%. This rate declines over the first year but remains 15% at 12 months of age.¹ Therefore, the guideline recommends against routinely testing infants ≤12 months of age as a positive test probably reflects colonization rather than disease. Testing in infants is recommended only when other causes have been excluded and a concern for pseudomembranous colitis, toxic megacolon, or clinically significant diarrhea exists.

The rate of asymptomatic colonization remains elevated in the second year of life. By 2-3 years, the rate is 1%-3% which is similar to that in healthy adults. However, the role of C. difficile in community-onset diarrhea in otherwise healthy children is controversial. In a study of 100 hospitalized children aged <2 years with CDI and diarrhea, all had resolution of diarrhea regardless of whether therapy was administered.² Another study found an alternative pathogen in >50% of hospitalized children with CDI.³ Therefore, the guideline recommends against testing in children aged 1-2 years unless other causes have been excluded and in children aged >2 years only when they have prolonged or worsening diarrhea along with risk factors or exposures.

Recommendation 4. In institutions without specific required criteria for stool submissions, use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin, GDH plus toxin arbitrated by nucleic-acid amplification tests [NAAT], or NAAT plus toxin) rather than a NAAT alone (weak recommendation, low quality of evidence).

Recommendation 5. In institutions with specific required criteria for stool submissions, use a NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin, GDH plus toxin arbitrated by NAAT, or NAAT plus toxin) rather than a toxin test alone (weak recommendation, low quality of evidence).

There are a variety of testing approaches for CDI and recommendations vary based on local practice. If laboratories accept all stools, a more specific approach is recommended, including a toxin test as part of a multistep algorithm to limit false positives. If laboratories first screen for symptoms and antibiotic exposure before accepting stool samples, a more sensitive approach is recommended including NAAT alone or a multistep algorithm rather than toxin alone.

Infection Prevention and Control

Recommendation 6. There is insufficient evidence for discontinuation of PPIs (proton pump inhibitors) as a measure for preventing CDI (no recommendation).

The guideline acknowledges data suggesting an association between PPI use and CDI, but not a causal relationship. Due to the lack of high-quality evidence, it does not recommend stopping PPIs to prevent CDI.

Recommendation 7. There are insufficient data to recommend probiotics for primary prevention of CDI outside of clinical trials (no recommendation).

The guideline notes that although several meta-analyses indicate that probiotics may prevent CDI; however there were limitations, including a high incidence of CDI in placebo arms and differences in probiotic formulations and duration of use, leading to insufficient data to recommend probiotic use to prevent CDI.

Treatment

Recommendation 8. Either per os (PO) metronidazole or PO vancomycin is recommended for an initial episode or first recurrence of nonsevere pediatric CDI (weak recommendation, low quality of evidence).

Data assessing the optimal treatment for nonsevere pediatric CDI are limited. Emerging data support the use of vancomycin,⁴ which is now recommended for initial episodes of CDI in adults. However, there are insufficient data to recommend vancomycin over metronidazole for nonsevere pediatric CDI; therefore, either option is recommended.

Recommendation 9. For children with an initial episode of severe CDI, oral vancomycin with or without IV metronidazole is recommended over metronidazole alone (strong recommendation, moderate quality of evidence).

Recommendation 10. For children with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole (weak recommendation, low quality of evidence).

There is no well-designed trial comparing metronidazole and vancomycin for severe or recurrent pediatric CDI. For children previously treated with metronidazole, vancomycin is recommended based on adult literature.⁴ For children previously treated with metronidazole and vancomycin, an extended course of tapered or pulse regimen vancomycin or vancomycin followed by rifaximin is recommended.

Recommendations must weigh potential harms. Metronidazole has been associated with neuropathies,⁵ cramping, and nausea. PO vancomycin has poor enteral absorption, minimizing systemic effects. Both vancomycin and metronidazole may promote carriage of resistant enterococci.

Recommendation 11. Fecal microbiota transplantation (FMT) should be considered for pediatric patients with multiple recurrences of CDI following standard treatments (weak recommendation, very low quality of evidence).

There are no robust data examining the effectiveness of pediatric FMT. Recommendations are guided by adult studies. Limited evidence suggests that FMT can be effective in children with multiple recurrent CDI.⁶ Concerns include procedure-related risks, transmission of resistant organisms and blood-borne pathogens, and induced metabolic or immunologic disorders.

Methods in Preparing a Guideline

The strength of a guideline includes representation from a diverse panel, including the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America, the American Society of Health-Systems Pharmacists, the Society of Infectious Diseases Pharmacists, and the Pediatric Infectious Diseases Society.

The panel utilized the Grading of Recommendations Assessment, Development, and Evaluation system to weigh the strength and quality of evidence.

From a pediatric perspective, the current guideline added pediatric-specific recommendations based on a comprehensive review of the literature from 1977 to 2016. The strength of these recommendations is somewhat limited by the lack of well-designed pediatric studies. An additional limitation is that treatment recommendations are based on illness severity, although the definitions used to classify severity are not pediatric-specific and are based on unvalidated expert opinion.

Sources of Potential Conflicts or Interest or Bias

The panel complied with the IDSA policy on conflicts of interest and disclosed any interest that might be construed as a conflict, regardless of relevancy. These were evaluated by the IDSA Standards and Practice Guidelines Committee.

Generalizability

Guideline generalizability may be impacted by testing availabilities within a particular setting. Cost factors and local formularies may also limit treatment options within a given setting.

Areas in Need of Future Study

Research gaps exist regarding at what age C. difficile is pathogenic given the prevalence of asymptomatic carriage. Future studies can also focus on a newly available molecular polymerase chain reaction test platform that detects C. difficile.⁷

There is limited pediatric evidence to recommend metronidazole versus vancomycin in children, particularly in nonsevere cases. There is also an opportunity to further explore alternative therapies, including fidaxomicin (not currently approved for children) and bezlotoxumab, a new agent approved as adult adjunctive therapy.⁸

Clostridium difficile (name changed to Clostridioides difficile [CDI]) are a major public health problem, with 500,000 infections annually in the United States, 15,000-30,000 associated deaths, and acute care costs exceeding $4.8 billion. The recent clinical practice guideline for CDI provides recommendations about the epidemiology, diagnosis, treatment, prevention, and environmental management. A total of 52 recommendations are included, and we will review 11 with pertinence to pediatrics in this highlight.

Recommendation 1. In infants ≤12 months of age, testing for CDI should never be routinely recommended because of the high prevalence of asymptomatic carriage of toxigenic C. difficile in infants (strong recommendation, moderate quality of evidence).

Recommendation 2. In children 1-2 years of age, testing should not be routinely performed unless other causes have been excluded (weak recommendation, low quality of evidence).Recommendation 3. In children ≥2 years of age, testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease) or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics) (weak recommendation, moderate quality of evidence).

The rate of C. difficile colonization among asymptomatic infants can exceed 40%. This rate declines over the first year but remains 15% at 12 months of age.¹ Therefore, the guideline recommends against routinely testing infants ≤12 months of age as a positive test probably reflects colonization rather than disease. Testing in infants is recommended only when other causes have been excluded and a concern for pseudomembranous colitis, toxic megacolon, or clinically significant diarrhea exists.

The rate of asymptomatic colonization remains elevated in the second year of life. By 2-3 years, the rate is 1%-3% which is similar to that in healthy adults. However, the role of C. difficile in community-onset diarrhea in otherwise healthy children is controversial. In a study of 100 hospitalized children aged <2 years with CDI and diarrhea, all had resolution of diarrhea regardless of whether therapy was administered.² Another study found an alternative pathogen in >50% of hospitalized children with CDI.³ Therefore, the guideline recommends against testing in children aged 1-2 years unless other causes have been excluded and in children aged >2 years only when they have prolonged or worsening diarrhea along with risk factors or exposures.

Recommendation 4. In institutions without specific required criteria for stool submissions, use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin, GDH plus toxin arbitrated by nucleic-acid amplification tests [NAAT], or NAAT plus toxin) rather than a NAAT alone (weak recommendation, low quality of evidence).

Recommendation 5. In institutions with specific required criteria for stool submissions, use a NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin, GDH plus toxin arbitrated by NAAT, or NAAT plus toxin) rather than a toxin test alone (weak recommendation, low quality of evidence).

There are a variety of testing approaches for CDI and recommendations vary based on local practice. If laboratories accept all stools, a more specific approach is recommended, including a toxin test as part of a multistep algorithm to limit false positives. If laboratories first screen for symptoms and antibiotic exposure before accepting stool samples, a more sensitive approach is recommended including NAAT alone or a multistep algorithm rather than toxin alone.

Infection Prevention and Control

Recommendation 6. There is insufficient evidence for discontinuation of PPIs (proton pump inhibitors) as a measure for preventing CDI (no recommendation).

The guideline acknowledges data suggesting an association between PPI use and CDI, but not a causal relationship. Due to the lack of high-quality evidence, it does not recommend stopping PPIs to prevent CDI.

Recommendation 7. There are insufficient data to recommend probiotics for primary prevention of CDI outside of clinical trials (no recommendation).

The guideline notes that although several meta-analyses indicate that probiotics may prevent CDI; however there were limitations, including a high incidence of CDI in placebo arms and differences in probiotic formulations and duration of use, leading to insufficient data to recommend probiotic use to prevent CDI.

Treatment

Recommendation 8. Either per os (PO) metronidazole or PO vancomycin is recommended for an initial episode or first recurrence of nonsevere pediatric CDI (weak recommendation, low quality of evidence).

Data assessing the optimal treatment for nonsevere pediatric CDI are limited. Emerging data support the use of vancomycin,⁴ which is now recommended for initial episodes of CDI in adults. However, there are insufficient data to recommend vancomycin over metronidazole for nonsevere pediatric CDI; therefore, either option is recommended.

Recommendation 9. For children with an initial episode of severe CDI, oral vancomycin with or without IV metronidazole is recommended over metronidazole alone (strong recommendation, moderate quality of evidence).

Recommendation 10. For children with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole (weak recommendation, low quality of evidence).

There is no well-designed trial comparing metronidazole and vancomycin for severe or recurrent pediatric CDI. For children previously treated with metronidazole, vancomycin is recommended based on adult literature.⁴ For children previously treated with metronidazole and vancomycin, an extended course of tapered or pulse regimen vancomycin or vancomycin followed by rifaximin is recommended.

Recommendations must weigh potential harms. Metronidazole has been associated with neuropathies,⁵ cramping, and nausea. PO vancomycin has poor enteral absorption, minimizing systemic effects. Both vancomycin and metronidazole may promote carriage of resistant enterococci.

Recommendation 11. Fecal microbiota transplantation (FMT) should be considered for pediatric patients with multiple recurrences of CDI following standard treatments (weak recommendation, very low quality of evidence).

There are no robust data examining the effectiveness of pediatric FMT. Recommendations are guided by adult studies. Limited evidence suggests that FMT can be effective in children with multiple recurrent CDI.⁶ Concerns include procedure-related risks, transmission of resistant organisms and blood-borne pathogens, and induced metabolic or immunologic disorders.

Methods in Preparing a Guideline

The strength of a guideline includes representation from a diverse panel, including the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America, the American Society of Health-Systems Pharmacists, the Society of Infectious Diseases Pharmacists, and the Pediatric Infectious Diseases Society.

The panel utilized the Grading of Recommendations Assessment, Development, and Evaluation system to weigh the strength and quality of evidence.

From a pediatric perspective, the current guideline added pediatric-specific recommendations based on a comprehensive review of the literature from 1977 to 2016. The strength of these recommendations is somewhat limited by the lack of well-designed pediatric studies. An additional limitation is that treatment recommendations are based on illness severity, although the definitions used to classify severity are not pediatric-specific and are based on unvalidated expert opinion.

Sources of Potential Conflicts or Interest or Bias

The panel complied with the IDSA policy on conflicts of interest and disclosed any interest that might be construed as a conflict, regardless of relevancy. These were evaluated by the IDSA Standards and Practice Guidelines Committee.

Generalizability

Guideline generalizability may be impacted by testing availabilities within a particular setting. Cost factors and local formularies may also limit treatment options within a given setting.

Areas in Need of Future Study

Research gaps exist regarding at what age C. difficile is pathogenic given the prevalence of asymptomatic carriage. Future studies can also focus on a newly available molecular polymerase chain reaction test platform that detects C. difficile.⁷

There is limited pediatric evidence to recommend metronidazole versus vancomycin in children, particularly in nonsevere cases. There is also an opportunity to further explore alternative therapies, including fidaxomicin (not currently approved for children) and bezlotoxumab, a new agent approved as adult adjunctive therapy.⁸

Clostridium difficile (name changed to Clostridioides difficile [CDI]) are a major public health problem, with 500,000 infections annually in the United States, 15,000-30,000 associated deaths, and acute care costs exceeding $4.8 billion. The recent clinical practice guideline for CDI provides recommendations about the epidemiology, diagnosis, treatment, prevention, and environmental management. A total of 52 recommendations are included, and we will review 11 with pertinence to pediatrics in this highlight.

Recommendation 1. In infants ≤12 months of age, testing for CDI should never be routinely recommended because of the high prevalence of asymptomatic carriage of toxigenic C. difficile in infants (strong recommendation, moderate quality of evidence).

Recommendation 2. In children 1-2 years of age, testing should not be routinely performed unless other causes have been excluded (weak recommendation, low quality of evidence).Recommendation 3. In children ≥2 years of age, testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease) or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics) (weak recommendation, moderate quality of evidence).

The rate of C. difficile colonization among asymptomatic infants can exceed 40%. This rate declines over the first year but remains 15% at 12 months of age.¹ Therefore, the guideline recommends against routinely testing infants ≤12 months of age as a positive test probably reflects colonization rather than disease. Testing in infants is recommended only when other causes have been excluded and a concern for pseudomembranous colitis, toxic megacolon, or clinically significant diarrhea exists.

The rate of asymptomatic colonization remains elevated in the second year of life. By 2-3 years, the rate is 1%-3% which is similar to that in healthy adults. However, the role of C. difficile in community-onset diarrhea in otherwise healthy children is controversial. In a study of 100 hospitalized children aged <2 years with CDI and diarrhea, all had resolution of diarrhea regardless of whether therapy was administered.² Another study found an alternative pathogen in >50% of hospitalized children with CDI.³ Therefore, the guideline recommends against testing in children aged 1-2 years unless other causes have been excluded and in children aged >2 years only when they have prolonged or worsening diarrhea along with risk factors or exposures.

Recommendation 4. In institutions without specific required criteria for stool submissions, use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin, GDH plus toxin arbitrated by nucleic-acid amplification tests [NAAT], or NAAT plus toxin) rather than a NAAT alone (weak recommendation, low quality of evidence).

Recommendation 5. In institutions with specific required criteria for stool submissions, use a NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin, GDH plus toxin arbitrated by NAAT, or NAAT plus toxin) rather than a toxin test alone (weak recommendation, low quality of evidence).

There are a variety of testing approaches for CDI and recommendations vary based on local practice. If laboratories accept all stools, a more specific approach is recommended, including a toxin test as part of a multistep algorithm to limit false positives. If laboratories first screen for symptoms and antibiotic exposure before accepting stool samples, a more sensitive approach is recommended including NAAT alone or a multistep algorithm rather than toxin alone.

Infection Prevention and Control

Recommendation 6. There is insufficient evidence for discontinuation of PPIs (proton pump inhibitors) as a measure for preventing CDI (no recommendation).

The guideline acknowledges data suggesting an association between PPI use and CDI, but not a causal relationship. Due to the lack of high-quality evidence, it does not recommend stopping PPIs to prevent CDI.

Recommendation 7. There are insufficient data to recommend probiotics for primary prevention of CDI outside of clinical trials (no recommendation).

The guideline notes that although several meta-analyses indicate that probiotics may prevent CDI; however there were limitations, including a high incidence of CDI in placebo arms and differences in probiotic formulations and duration of use, leading to insufficient data to recommend probiotic use to prevent CDI.

Treatment

Recommendation 8. Either per os (PO) metronidazole or PO vancomycin is recommended for an initial episode or first recurrence of nonsevere pediatric CDI (weak recommendation, low quality of evidence).

Data assessing the optimal treatment for nonsevere pediatric CDI are limited. Emerging data support the use of vancomycin,⁴ which is now recommended for initial episodes of CDI in adults. However, there are insufficient data to recommend vancomycin over metronidazole for nonsevere pediatric CDI; therefore, either option is recommended.

Recommendation 9. For children with an initial episode of severe CDI, oral vancomycin with or without IV metronidazole is recommended over metronidazole alone (strong recommendation, moderate quality of evidence).

Recommendation 10. For children with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole (weak recommendation, low quality of evidence).

There is no well-designed trial comparing metronidazole and vancomycin for severe or recurrent pediatric CDI. For children previously treated with metronidazole, vancomycin is recommended based on adult literature.⁴ For children previously treated with metronidazole and vancomycin, an extended course of tapered or pulse regimen vancomycin or vancomycin followed by rifaximin is recommended.

Recommendations must weigh potential harms. Metronidazole has been associated with neuropathies,⁵ cramping, and nausea. PO vancomycin has poor enteral absorption, minimizing systemic effects. Both vancomycin and metronidazole may promote carriage of resistant enterococci.

Recommendation 11. Fecal microbiota transplantation (FMT) should be considered for pediatric patients with multiple recurrences of CDI following standard treatments (weak recommendation, very low quality of evidence).

There are no robust data examining the effectiveness of pediatric FMT. Recommendations are guided by adult studies. Limited evidence suggests that FMT can be effective in children with multiple recurrent CDI.⁶ Concerns include procedure-related risks, transmission of resistant organisms and blood-borne pathogens, and induced metabolic or immunologic disorders.

Methods in Preparing a Guideline

The strength of a guideline includes representation from a diverse panel, including the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America, the American Society of Health-Systems Pharmacists, the Society of Infectious Diseases Pharmacists, and the Pediatric Infectious Diseases Society.

The panel utilized the Grading of Recommendations Assessment, Development, and Evaluation system to weigh the strength and quality of evidence.

From a pediatric perspective, the current guideline added pediatric-specific recommendations based on a comprehensive review of the literature from 1977 to 2016. The strength of these recommendations is somewhat limited by the lack of well-designed pediatric studies. An additional limitation is that treatment recommendations are based on illness severity, although the definitions used to classify severity are not pediatric-specific and are based on unvalidated expert opinion.

Sources of Potential Conflicts or Interest or Bias

The panel complied with the IDSA policy on conflicts of interest and disclosed any interest that might be construed as a conflict, regardless of relevancy. These were evaluated by the IDSA Standards and Practice Guidelines Committee.

Generalizability

Guideline generalizability may be impacted by testing availabilities within a particular setting. Cost factors and local formularies may also limit treatment options within a given setting.

Areas in Need of Future Study

Research gaps exist regarding at what age C. difficile is pathogenic given the prevalence of asymptomatic carriage. Future studies can also focus on a newly available molecular polymerase chain reaction test platform that detects C. difficile.⁷

There is limited pediatric evidence to recommend metronidazole versus vancomycin in children, particularly in nonsevere cases. There is also an opportunity to further explore alternative therapies, including fidaxomicin (not currently approved for children) and bezlotoxumab, a new agent approved as adult adjunctive therapy.⁸

Clostridium difficile, now referred to as Clostridioides difficile (C. difficile), is the most commonly identified cause of healthcare-associated infection among adults in the United States.¹ Because C. difficile infection results in significant mortality and inpatient costs, its persistence threatens to undermine patient safety and the value of healthcare delivery.¹ A standardized, evidence-based approach to diagnosis and management is crucial. However, inconsistencies remain with regard to the appropriate threshold for testing, the type of diagnostic tests used, and treatment. Knowledge of these areas has progressed since the publication of the previous C. difficile guidelines in 2010. These guidelines contain 53 recommendations across 35 sections based on a systematic weighting of the strength of recommendation and quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we have chosen to highlight five of these recommendations most relevant to hospitalists.

Recommendation 1. Patients with unexplained and new-onset ≥3 unformed stools within 24 hours are the preferred target population for testing for C. difficile infection (weak recommendation, very low quality of evidence). Do not perform repeat testing (within seven days) during the same episode of diarrhea and do not test stool from asymptomatic patients (strong recommendation, moderate quality of evidence).

In the recent past, healthcare facilities employed C. difficile tests with limited sensitivity, leading to frequent and repeat testing of hospitalized patients. Excess testing puts patients at risk for false positive results and unnecessary or prolonged treatment courses. Proper testing requires consideration of pretest probability, including analysis of the alternative causes of diarrhea. Duration of hospitalization and antibiotic exposure are the most significant modifiable risk factors for C. difficile infection in adult inpatients.² Laxative use within the previous 48 hours, enteral tube feeding, and underlying medical conditions, such as inflammatory bowel disease (IBD), are common causes of improper testing.³ This decision may be difficult, as some underlying causes of diarrhea, such as IBD and enteral tube feeding, also increase the risk of C. difficile infection.³ Laboratories can help by rejecting specimens that are not liquid or soft and employing a multistep algorithm using a combination of nucleic acid testing, antigen testing, and toxin detection to maximize sensitivity and specificity. Because recurrent C. difficile infection is relatively common, repeat testing is appropriate only for recurrence of symptoms following successful treatment and should focus on detection of C. difficile toxin because the persistence of the organism itself can occur after successful treatment.⁴

Recommendation 2. Either vancomycin (125 mg orally four times per day for 10 days) or fidaxomicin (200 mg twice daily for 10 days) is recommended over metronidazole for an initial episode of nonsevere or severe C. difficile infection (strong recommendation, high quality of evidence). For fulminant C. difficile infection, the regimen of choice is a vancomycin dosage of 500 mg orally four times per day (per rectum every six hours if with ileus) in addition to intravenous metronidazole (strong recommendation, moderate quality of evidence).

For several decades now, metronidazole has been the primary antibiotic agent for initial treatment of nonsevere C. difficile infection. Two recent randomized, placebo-controlled trials, however, have found oral vancomycin to be superior to metronidazole for producing a clinical cure and resolution of diarrhea without recurrence.^5,6 Oral vancomycin remains the treatment of choice for severe C. difficile infection. Fidaxomicin, a recently FDA-approved antibiotic, can also be used as initial treatment in place of oral vancomycin. One study found fidaxomicin to be superior to oral vancomycin for producing a sustained clinical response, that is, resolution of diarrhea at the end of treatment without recurrence 25 days later.⁷ Fulminant disease, which is characterized by hypotension or shock, ileus, or megacolon, requires a higher dose of oral vancomycin (or vancomycin enema if with ileus) in addition to intravenous metronidazole.

Recommendation 3. Treat a first recurrence of C. difficile infection with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin or metronidazole (weak recommendation, low quality of evidence).

Despite the improved treatment response with oral vancomycin, one in four patients will experience recurrence. For a first recurrence of C. difficile infection after a 10-day course of oral vancomycin, an extended taper or pulsed course of vancomycin should be attempted. Various regimens have been tried and found to be effective. For a second recurrence, providers can consider addition of rifaximin following oral vancomycin. Fecal microbiota transplantation is recommended for patients with multiple recurrences of C. difficile infection who have failed these antibiotic treatments.

Recommendation 4. Minimize the frequency and duration of high-risk antibiotic therapy (based on local epidemiology) and the number of antibiotic agents prescribed to reduce C. difficile infection risk (strong recommendation, moderate quality of evidence).

Antibiotic stewardship is a necessary component of any successful effort to reduce C. difficile infections. Antibiotic stewardship programs, which are now commonplace in US hospitals, largely rely on educational initiatives or committee-based order review. Hospitalists should take a structured approach emphasizing the four critical questions of antibiotic prescribing: Does this infection require antibiotics? Have I ordered appropriate cultures and the correct empiric therapy? Can I stop, narrow, or switch to oral agents? Finally, what duration of therapy is needed at discharge?⁸ Initial efforts should focus on the restriction of fluoroquinolones, clindamycin, and cephalosporins (except for surgical antibiotic prophylaxis) given their known risk to cause C. difficile infection.

Recommendation 5. Contact precautions should be maintained for at least 48 hours after diarrhea has resolved (weak recommendation, low quality of evidence).

Although C. difficile is undetectable in stool samples from most patients by the time diarrhea has resolved, skin and environmental contaminations remain high. No studies demonstrating a benefit to further extending contact precautions beyond 48 hours after resolution of diarrhea are yet available.

Methods in Preparing Guidelines

The guideline committee consisted of an interdisciplinary team of healthcare providers with extensive experience in the diagnosis, infection control, treatment, and management of C. difficile. The literature search accessed five different databases (Medline, Embase, Cochrane, Health Technology Assessment, and Database of Abstracts of Reviews and Effects), relevant journals, conference proceedings, and regulatory websites published over the search period of 2009-2016.

A major strength of these guidelines is the extensive work that went into their preparation. The committee reviewed over 14,000 pieces of literature and performed a detailed analysis of each one to determine the quality of evidence in support of each recommendation.

Sources of Potential Conflict of Interest or Bias

To reduce bias, the committee’s work was funded by Infectious Disease Society of America and Society for Healthcare Epidemiology of America. Some authors received funding for work outside of this guideline by companies that manufacture diagnostic assays, vancomycin, and fidaxomicin. These potential conflicts were listed at the end of the article.

Generalizability of the Guideline

Not all studies included in the guideline contain exclusively hospitalized patients, but much of the guideline content is applicable to hospitalized patients. Because C. difficile infection is such a widespread public health problem and these guidelines represent a significant update in knowledge since 2010, the specific recommendations highlighted in this review will impact numerous hospitalists, regardless of the practice setting.

Areas in Need of Future Study

Based on the current literature, as well as statements in the guideline, we expect future guidance around potential screening for and isolation of asymptomatic carriers, including closer guidance on stool transplantation focusing on timing and route, as further data emerge in these areas.

Other Resources

• Grading of Recommendations Assessment, Development, and Evaluation system (http://www.gradeworkinggroup.org)
• Universal Screening for C. difficile in a Tertiary Hospital: risk factors for carriage and clinical disease (Color/Blackhttps://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(19)30048-5/fulltext)
• Effectiveness of Isolating Clostridium Difficile Asymptomatic Carriers on the Incidence of Infections (Color/Blackhttps://clinicaltrials.gov/ct2/show/NCT03223415)
• Effect of Detecting and Isolating Clostridium difficile Carriers at Hospital Admission on the Incidence of C difficile Infections (Color/Blackhttps://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2516765)
• Clinical Trial Testing Fecal Microbiota Transplant for Recurrent Diarrheal Disease Begins (Color/Blackhttps://www.nih.gov/news-events/news-releases/clinical-trial-testing-fecal-microbiota-transplant-recurrent-diarrheal-disease-begins)

Clostridium difficile, now referred to as Clostridioides difficile (C. difficile), is the most commonly identified cause of healthcare-associated infection among adults in the United States.¹ Because C. difficile infection results in significant mortality and inpatient costs, its persistence threatens to undermine patient safety and the value of healthcare delivery.¹ A standardized, evidence-based approach to diagnosis and management is crucial. However, inconsistencies remain with regard to the appropriate threshold for testing, the type of diagnostic tests used, and treatment. Knowledge of these areas has progressed since the publication of the previous C. difficile guidelines in 2010. These guidelines contain 53 recommendations across 35 sections based on a systematic weighting of the strength of recommendation and quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we have chosen to highlight five of these recommendations most relevant to hospitalists.

Recommendation 1. Patients with unexplained and new-onset ≥3 unformed stools within 24 hours are the preferred target population for testing for C. difficile infection (weak recommendation, very low quality of evidence). Do not perform repeat testing (within seven days) during the same episode of diarrhea and do not test stool from asymptomatic patients (strong recommendation, moderate quality of evidence).

In the recent past, healthcare facilities employed C. difficile tests with limited sensitivity, leading to frequent and repeat testing of hospitalized patients. Excess testing puts patients at risk for false positive results and unnecessary or prolonged treatment courses. Proper testing requires consideration of pretest probability, including analysis of the alternative causes of diarrhea. Duration of hospitalization and antibiotic exposure are the most significant modifiable risk factors for C. difficile infection in adult inpatients.² Laxative use within the previous 48 hours, enteral tube feeding, and underlying medical conditions, such as inflammatory bowel disease (IBD), are common causes of improper testing.³ This decision may be difficult, as some underlying causes of diarrhea, such as IBD and enteral tube feeding, also increase the risk of C. difficile infection.³ Laboratories can help by rejecting specimens that are not liquid or soft and employing a multistep algorithm using a combination of nucleic acid testing, antigen testing, and toxin detection to maximize sensitivity and specificity. Because recurrent C. difficile infection is relatively common, repeat testing is appropriate only for recurrence of symptoms following successful treatment and should focus on detection of C. difficile toxin because the persistence of the organism itself can occur after successful treatment.⁴

Recommendation 2. Either vancomycin (125 mg orally four times per day for 10 days) or fidaxomicin (200 mg twice daily for 10 days) is recommended over metronidazole for an initial episode of nonsevere or severe C. difficile infection (strong recommendation, high quality of evidence). For fulminant C. difficile infection, the regimen of choice is a vancomycin dosage of 500 mg orally four times per day (per rectum every six hours if with ileus) in addition to intravenous metronidazole (strong recommendation, moderate quality of evidence).

For several decades now, metronidazole has been the primary antibiotic agent for initial treatment of nonsevere C. difficile infection. Two recent randomized, placebo-controlled trials, however, have found oral vancomycin to be superior to metronidazole for producing a clinical cure and resolution of diarrhea without recurrence.^5,6 Oral vancomycin remains the treatment of choice for severe C. difficile infection. Fidaxomicin, a recently FDA-approved antibiotic, can also be used as initial treatment in place of oral vancomycin. One study found fidaxomicin to be superior to oral vancomycin for producing a sustained clinical response, that is, resolution of diarrhea at the end of treatment without recurrence 25 days later.⁷ Fulminant disease, which is characterized by hypotension or shock, ileus, or megacolon, requires a higher dose of oral vancomycin (or vancomycin enema if with ileus) in addition to intravenous metronidazole.

Recommendation 3. Treat a first recurrence of C. difficile infection with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin or metronidazole (weak recommendation, low quality of evidence).

Despite the improved treatment response with oral vancomycin, one in four patients will experience recurrence. For a first recurrence of C. difficile infection after a 10-day course of oral vancomycin, an extended taper or pulsed course of vancomycin should be attempted. Various regimens have been tried and found to be effective. For a second recurrence, providers can consider addition of rifaximin following oral vancomycin. Fecal microbiota transplantation is recommended for patients with multiple recurrences of C. difficile infection who have failed these antibiotic treatments.

Recommendation 4. Minimize the frequency and duration of high-risk antibiotic therapy (based on local epidemiology) and the number of antibiotic agents prescribed to reduce C. difficile infection risk (strong recommendation, moderate quality of evidence).

Antibiotic stewardship is a necessary component of any successful effort to reduce C. difficile infections. Antibiotic stewardship programs, which are now commonplace in US hospitals, largely rely on educational initiatives or committee-based order review. Hospitalists should take a structured approach emphasizing the four critical questions of antibiotic prescribing: Does this infection require antibiotics? Have I ordered appropriate cultures and the correct empiric therapy? Can I stop, narrow, or switch to oral agents? Finally, what duration of therapy is needed at discharge?⁸ Initial efforts should focus on the restriction of fluoroquinolones, clindamycin, and cephalosporins (except for surgical antibiotic prophylaxis) given their known risk to cause C. difficile infection.

Recommendation 5. Contact precautions should be maintained for at least 48 hours after diarrhea has resolved (weak recommendation, low quality of evidence).

Although C. difficile is undetectable in stool samples from most patients by the time diarrhea has resolved, skin and environmental contaminations remain high. No studies demonstrating a benefit to further extending contact precautions beyond 48 hours after resolution of diarrhea are yet available.

Methods in Preparing Guidelines

The guideline committee consisted of an interdisciplinary team of healthcare providers with extensive experience in the diagnosis, infection control, treatment, and management of C. difficile. The literature search accessed five different databases (Medline, Embase, Cochrane, Health Technology Assessment, and Database of Abstracts of Reviews and Effects), relevant journals, conference proceedings, and regulatory websites published over the search period of 2009-2016.

A major strength of these guidelines is the extensive work that went into their preparation. The committee reviewed over 14,000 pieces of literature and performed a detailed analysis of each one to determine the quality of evidence in support of each recommendation.

Sources of Potential Conflict of Interest or Bias

To reduce bias, the committee’s work was funded by Infectious Disease Society of America and Society for Healthcare Epidemiology of America. Some authors received funding for work outside of this guideline by companies that manufacture diagnostic assays, vancomycin, and fidaxomicin. These potential conflicts were listed at the end of the article.

Generalizability of the Guideline

Not all studies included in the guideline contain exclusively hospitalized patients, but much of the guideline content is applicable to hospitalized patients. Because C. difficile infection is such a widespread public health problem and these guidelines represent a significant update in knowledge since 2010, the specific recommendations highlighted in this review will impact numerous hospitalists, regardless of the practice setting.

Areas in Need of Future Study

Based on the current literature, as well as statements in the guideline, we expect future guidance around potential screening for and isolation of asymptomatic carriers, including closer guidance on stool transplantation focusing on timing and route, as further data emerge in these areas.

Other Resources

• Grading of Recommendations Assessment, Development, and Evaluation system (http://www.gradeworkinggroup.org)
• Universal Screening for C. difficile in a Tertiary Hospital: risk factors for carriage and clinical disease (Color/Blackhttps://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(19)30048-5/fulltext)
• Effectiveness of Isolating Clostridium Difficile Asymptomatic Carriers on the Incidence of Infections (Color/Blackhttps://clinicaltrials.gov/ct2/show/NCT03223415)
• Effect of Detecting and Isolating Clostridium difficile Carriers at Hospital Admission on the Incidence of C difficile Infections (Color/Blackhttps://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2516765)
• Clinical Trial Testing Fecal Microbiota Transplant for Recurrent Diarrheal Disease Begins (Color/Blackhttps://www.nih.gov/news-events/news-releases/clinical-trial-testing-fecal-microbiota-transplant-recurrent-diarrheal-disease-begins)

Clostridium difficile, now referred to as Clostridioides difficile (C. difficile), is the most commonly identified cause of healthcare-associated infection among adults in the United States.¹ Because C. difficile infection results in significant mortality and inpatient costs, its persistence threatens to undermine patient safety and the value of healthcare delivery.¹ A standardized, evidence-based approach to diagnosis and management is crucial. However, inconsistencies remain with regard to the appropriate threshold for testing, the type of diagnostic tests used, and treatment. Knowledge of these areas has progressed since the publication of the previous C. difficile guidelines in 2010. These guidelines contain 53 recommendations across 35 sections based on a systematic weighting of the strength of recommendation and quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we have chosen to highlight five of these recommendations most relevant to hospitalists.

Recommendation 1. Patients with unexplained and new-onset ≥3 unformed stools within 24 hours are the preferred target population for testing for C. difficile infection (weak recommendation, very low quality of evidence). Do not perform repeat testing (within seven days) during the same episode of diarrhea and do not test stool from asymptomatic patients (strong recommendation, moderate quality of evidence).

In the recent past, healthcare facilities employed C. difficile tests with limited sensitivity, leading to frequent and repeat testing of hospitalized patients. Excess testing puts patients at risk for false positive results and unnecessary or prolonged treatment courses. Proper testing requires consideration of pretest probability, including analysis of the alternative causes of diarrhea. Duration of hospitalization and antibiotic exposure are the most significant modifiable risk factors for C. difficile infection in adult inpatients.² Laxative use within the previous 48 hours, enteral tube feeding, and underlying medical conditions, such as inflammatory bowel disease (IBD), are common causes of improper testing.³ This decision may be difficult, as some underlying causes of diarrhea, such as IBD and enteral tube feeding, also increase the risk of C. difficile infection.³ Laboratories can help by rejecting specimens that are not liquid or soft and employing a multistep algorithm using a combination of nucleic acid testing, antigen testing, and toxin detection to maximize sensitivity and specificity. Because recurrent C. difficile infection is relatively common, repeat testing is appropriate only for recurrence of symptoms following successful treatment and should focus on detection of C. difficile toxin because the persistence of the organism itself can occur after successful treatment.⁴

Recommendation 2. Either vancomycin (125 mg orally four times per day for 10 days) or fidaxomicin (200 mg twice daily for 10 days) is recommended over metronidazole for an initial episode of nonsevere or severe C. difficile infection (strong recommendation, high quality of evidence). For fulminant C. difficile infection, the regimen of choice is a vancomycin dosage of 500 mg orally four times per day (per rectum every six hours if with ileus) in addition to intravenous metronidazole (strong recommendation, moderate quality of evidence).

For several decades now, metronidazole has been the primary antibiotic agent for initial treatment of nonsevere C. difficile infection. Two recent randomized, placebo-controlled trials, however, have found oral vancomycin to be superior to metronidazole for producing a clinical cure and resolution of diarrhea without recurrence.^5,6 Oral vancomycin remains the treatment of choice for severe C. difficile infection. Fidaxomicin, a recently FDA-approved antibiotic, can also be used as initial treatment in place of oral vancomycin. One study found fidaxomicin to be superior to oral vancomycin for producing a sustained clinical response, that is, resolution of diarrhea at the end of treatment without recurrence 25 days later.⁷ Fulminant disease, which is characterized by hypotension or shock, ileus, or megacolon, requires a higher dose of oral vancomycin (or vancomycin enema if with ileus) in addition to intravenous metronidazole.

Recommendation 3. Treat a first recurrence of C. difficile infection with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin or metronidazole (weak recommendation, low quality of evidence).

Despite the improved treatment response with oral vancomycin, one in four patients will experience recurrence. For a first recurrence of C. difficile infection after a 10-day course of oral vancomycin, an extended taper or pulsed course of vancomycin should be attempted. Various regimens have been tried and found to be effective. For a second recurrence, providers can consider addition of rifaximin following oral vancomycin. Fecal microbiota transplantation is recommended for patients with multiple recurrences of C. difficile infection who have failed these antibiotic treatments.

Recommendation 4. Minimize the frequency and duration of high-risk antibiotic therapy (based on local epidemiology) and the number of antibiotic agents prescribed to reduce C. difficile infection risk (strong recommendation, moderate quality of evidence).

Antibiotic stewardship is a necessary component of any successful effort to reduce C. difficile infections. Antibiotic stewardship programs, which are now commonplace in US hospitals, largely rely on educational initiatives or committee-based order review. Hospitalists should take a structured approach emphasizing the four critical questions of antibiotic prescribing: Does this infection require antibiotics? Have I ordered appropriate cultures and the correct empiric therapy? Can I stop, narrow, or switch to oral agents? Finally, what duration of therapy is needed at discharge?⁸ Initial efforts should focus on the restriction of fluoroquinolones, clindamycin, and cephalosporins (except for surgical antibiotic prophylaxis) given their known risk to cause C. difficile infection.

Recommendation 5. Contact precautions should be maintained for at least 48 hours after diarrhea has resolved (weak recommendation, low quality of evidence).

Although C. difficile is undetectable in stool samples from most patients by the time diarrhea has resolved, skin and environmental contaminations remain high. No studies demonstrating a benefit to further extending contact precautions beyond 48 hours after resolution of diarrhea are yet available.

Methods in Preparing Guidelines

The guideline committee consisted of an interdisciplinary team of healthcare providers with extensive experience in the diagnosis, infection control, treatment, and management of C. difficile. The literature search accessed five different databases (Medline, Embase, Cochrane, Health Technology Assessment, and Database of Abstracts of Reviews and Effects), relevant journals, conference proceedings, and regulatory websites published over the search period of 2009-2016.

A major strength of these guidelines is the extensive work that went into their preparation. The committee reviewed over 14,000 pieces of literature and performed a detailed analysis of each one to determine the quality of evidence in support of each recommendation.

Sources of Potential Conflict of Interest or Bias

To reduce bias, the committee’s work was funded by Infectious Disease Society of America and Society for Healthcare Epidemiology of America. Some authors received funding for work outside of this guideline by companies that manufacture diagnostic assays, vancomycin, and fidaxomicin. These potential conflicts were listed at the end of the article.

Generalizability of the Guideline

Not all studies included in the guideline contain exclusively hospitalized patients, but much of the guideline content is applicable to hospitalized patients. Because C. difficile infection is such a widespread public health problem and these guidelines represent a significant update in knowledge since 2010, the specific recommendations highlighted in this review will impact numerous hospitalists, regardless of the practice setting.

Areas in Need of Future Study

Based on the current literature, as well as statements in the guideline, we expect future guidance around potential screening for and isolation of asymptomatic carriers, including closer guidance on stool transplantation focusing on timing and route, as further data emerge in these areas.

Other Resources

• Grading of Recommendations Assessment, Development, and Evaluation system (http://www.gradeworkinggroup.org)
• Universal Screening for C. difficile in a Tertiary Hospital: risk factors for carriage and clinical disease (Color/Blackhttps://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(19)30048-5/fulltext)
• Effectiveness of Isolating Clostridium Difficile Asymptomatic Carriers on the Incidence of Infections (Color/Blackhttps://clinicaltrials.gov/ct2/show/NCT03223415)
• Effect of Detecting and Isolating Clostridium difficile Carriers at Hospital Admission on the Incidence of C difficile Infections (Color/Blackhttps://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2516765)
• Clinical Trial Testing Fecal Microbiota Transplant for Recurrent Diarrheal Disease Begins (Color/Blackhttps://www.nih.gov/news-events/news-releases/clinical-trial-testing-fecal-microbiota-transplant-recurrent-diarrheal-disease-begins)

Pediatric acute pancreatitis is being diagnosed more commonly, affecting approximately one per 10,000 children annually with an estimated inpatient cost burden of $200 million per year.^1,2 Common causes of pediatric acute pancreatitis include systemic illness, biliary disease, trauma, and medications; 13%-34% of cases are idiopathic.¹ Currently, substantial variation exists in the clinical management of this condition.^3,4 Hospitalists should familiarize themselves with the current literature, including the recent practice guideline by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).²

(Evidence quality: not graded, recommendation by expert consensus)

Recommendation 1. Diagnosis of acute pancreatitis in pediatric patients requires at least two of the following symptoms: abdominal pain compatible with acute pancreatitis, serum amylase and/or lipase values >3 times the upper limits of normal, and imaging findings consistent with acute pancreatitis.The most common symptoms of acute pancreatitis in children are epigastric or diffuse abdominal pain, vomiting, and irritability. Presentation varies by age, and diagnosis requires a high index of suspicion. Significant elevations in amylase and lipase levels are typically detected early in the disease course. The guideline does not specify a preferred serum biomarker in the diagnosis of pancreatitis but notes that lipase is more sensitive and specific than amylase, rises within 6 hours of symptoms, and stays elevated longer. Amylase levels rise faster but often normalize by 24 hours of symptom onset. Amylase and lipase can originate from extrapancreatic sources and may be elevated during acute illness in the absence of pancreatitis.

Laboratory testing to investigate the etiology of acute pancreatitis should include hepatic enzymes, bilirubin, triglyceride, and calcium levels. Although not typically necessary for diagnosis, imaging may demonstrate pancreatic edema or peripancreatic fluid, confirm disease complications, and identify obstructive causes. Transabdominal ultrasonography is indicated if biliary pancreatitis is suspected. Contrast-enhanced computed tomography should be considered for patients with severe presentation or deteriorating condition. Magnetic resonance cholangiopancreatography is useful in detecting pancreaticobiliary abnormalities.

Recommendation 2. Children with acute pancreatitis should be initially resuscitated with crystalloids, either with lactated Ringer’s or normal saline in the acute setting. These children should be provided 1.5-2 times maintenance intravenous fluids with monitoring of urine output over the next 24-48 hours.

Fluid resuscitation and maintenance are the current mainstays of therapy for pancreatitis. Prompt fluid administration corrects hypovolemia and may prevent potential complications. Early, aggressive fluid replacement in adults reduces the incidence of systemic inflammatory response syndrome and organ failure. Limited pediatric studies support correction of hypovolemia and/or circulatory compromise using 10-20 ml/kg boluses of isotonic crystalloid fluid. Although the literature is sparse regarding the rate of continued fluid replacement, the committee recommends patients receive 1.5-2 times maintenance intravenous fluid (IVF) with normal saline plus 5% dextrose for the first 24-48 hours. The rate of IVF administration should be adjusted based on volume status and urine output. IVF should be discontinued once the patient is able to maintain adequate hydration enterally. Cardiac, renal, and pulmonary complications of pancreatitis often present within the first 48 hours of illness and should prompt close monitoring with assessment of vital signs every four hours. The committee recommends monitoring serum electrolytes and renal function in the first 48 hours but does not offer guidance regarding the frequency of laboratory testing or the value of trending serum biomarkers.

Recommendation 3. Except in the presence of direct contraindications to use the gut, children with mild acute pancreatitis may benefit from early (within 48-72 hours of presentation) oral and enteral nutrition to decrease the length of stay (LOS) and the risk of organ dysfunction.

Adult studies suggest early enteral nutrition decreases complications and reduces LOS. Initiating enteral nutrition within 48 hours in children may have similar benefits. Several small pediatric studies have demonstrated a reduced LOS with early enteral feeds without an increase in complications. In a retrospective single-center study, children who were fed within the first 48 hours and received 1.5-2 times maintenance IVF had shorter LOS, less frequent intensive care admissions, and reduced severity of illness compared with those who were kept nil per os for the first 48 hours.⁵ Nasogastric or nasojejunal feeds may be initiated if a patient is unable to tolerate oral feeding. Parenteral nutrition should be reserved for children in whom enteral nutrition cannot be initiated within five to seven days.

Recommendation 4. Intravenous morphine or other opioids should be used for acute pancreatitis pain not responding to acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs).

Abdominal pain is the most common presenting symptom of pancreatitis, and pain control is an essential component of supportive care. There are no randomized trials identifying an optimal pain management regimen. The committee recommends the use of opioids for pain not controlled with acetaminophen and NSAIDs. Refractory pain may necessitate consultation with an acute pain specialist.

Recommendation 5. Routine use of prophylactic antibiotics, protease inhibitors, antioxidants, and probiotics is not recommended in acute pancreatitis.

Adult literature does not support routine use of antibiotics in acute pancreatitis, but their use may be beneficial in severe or recalcitrant cases. Pediatric literature neither confirms nor refutes this finding. The guideline does not recommend the use of antibiotics without signs of infection. Limited adult studies have shown protease inhibitors, antioxidants, and probiotics to be beneficial; however, no pediatric data support their use.

This guideline also discusses interventional and surgical procedures. Of note, biliary tract disease may necessitate endoscopic retrograde cholangiopancreatography or cholecystectomy. Such procedures should be considered in conjunction with subspecialty input.²

Methods in Preparing Guideline

The guideline development committee, funded by the NASPGHAN and the National Institutes of Diabetes and Digestive and Kidney Diseases, was composed of members of the NASPGHAN Pancreas Committee and included gastroenterologists from multiple sites.² Topics were selected via group discussion, and Medline searches included both adult and pediatric literature. Preliminary recommendations were presented at the 2016 World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Following revision, the 24 authors voted on each recommendation using a five-point Likert scale. A recommendation passed if 75% of the participants either agreed or strongly agreed with it. The authors reported no conflicts of interest.

Although the literature review was comprehensive, it lacked prospective pediatric studies and many of the recommendations were derived from adult research. The committee originally intended to grade the quality of evidence; however, the pediatric specific literature was underpowered and retrospective. Therefore, the committee opted to use consensus voting. The authors note that had the group used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, it would have returned grades of “low” or “very low” quality evidence.² The Hungarian Pancreatic Study Group and the European Pancreatic Club published a consensus guideline on the management of pediatric acute pancreatitis shortly after the NASPGHAN guideline, which offers similar conclusions.^2,6 The strength and generalizability of the NASPGHAN guideline are limited by its overreliance on adult literature, expert consensus, and small, retrospective pediatric studies to guide care.

This guideline highlights the need for pediatric research to guide the management of acute pancreatitis. The etiologies of pancreatitis in children are distinct from adults, where alcohol abuse and biliary disease are significant contributors.¹ Furthermore, age and environmental factors influence the presentation and clinical course.¹ Robust, prospective studies are needed to better understand the treatment outcomes of pediatric pancreatitis. Areas of further research include pediatric pancreatic severity scoring, ideal fluid composition and administration rate, enteral feed timing, optimal pain control, laboratory monitoring frequency, and adjuvant therapies.

Disclosures

Dr. Wall has nothing to disclose.

Pediatric acute pancreatitis is being diagnosed more commonly, affecting approximately one per 10,000 children annually with an estimated inpatient cost burden of $200 million per year.^1,2 Common causes of pediatric acute pancreatitis include systemic illness, biliary disease, trauma, and medications; 13%-34% of cases are idiopathic.¹ Currently, substantial variation exists in the clinical management of this condition.^3,4 Hospitalists should familiarize themselves with the current literature, including the recent practice guideline by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).²

(Evidence quality: not graded, recommendation by expert consensus)

Recommendation 1. Diagnosis of acute pancreatitis in pediatric patients requires at least two of the following symptoms: abdominal pain compatible with acute pancreatitis, serum amylase and/or lipase values >3 times the upper limits of normal, and imaging findings consistent with acute pancreatitis.The most common symptoms of acute pancreatitis in children are epigastric or diffuse abdominal pain, vomiting, and irritability. Presentation varies by age, and diagnosis requires a high index of suspicion. Significant elevations in amylase and lipase levels are typically detected early in the disease course. The guideline does not specify a preferred serum biomarker in the diagnosis of pancreatitis but notes that lipase is more sensitive and specific than amylase, rises within 6 hours of symptoms, and stays elevated longer. Amylase levels rise faster but often normalize by 24 hours of symptom onset. Amylase and lipase can originate from extrapancreatic sources and may be elevated during acute illness in the absence of pancreatitis.

Laboratory testing to investigate the etiology of acute pancreatitis should include hepatic enzymes, bilirubin, triglyceride, and calcium levels. Although not typically necessary for diagnosis, imaging may demonstrate pancreatic edema or peripancreatic fluid, confirm disease complications, and identify obstructive causes. Transabdominal ultrasonography is indicated if biliary pancreatitis is suspected. Contrast-enhanced computed tomography should be considered for patients with severe presentation or deteriorating condition. Magnetic resonance cholangiopancreatography is useful in detecting pancreaticobiliary abnormalities.

Recommendation 2. Children with acute pancreatitis should be initially resuscitated with crystalloids, either with lactated Ringer’s or normal saline in the acute setting. These children should be provided 1.5-2 times maintenance intravenous fluids with monitoring of urine output over the next 24-48 hours.

Fluid resuscitation and maintenance are the current mainstays of therapy for pancreatitis. Prompt fluid administration corrects hypovolemia and may prevent potential complications. Early, aggressive fluid replacement in adults reduces the incidence of systemic inflammatory response syndrome and organ failure. Limited pediatric studies support correction of hypovolemia and/or circulatory compromise using 10-20 ml/kg boluses of isotonic crystalloid fluid. Although the literature is sparse regarding the rate of continued fluid replacement, the committee recommends patients receive 1.5-2 times maintenance intravenous fluid (IVF) with normal saline plus 5% dextrose for the first 24-48 hours. The rate of IVF administration should be adjusted based on volume status and urine output. IVF should be discontinued once the patient is able to maintain adequate hydration enterally. Cardiac, renal, and pulmonary complications of pancreatitis often present within the first 48 hours of illness and should prompt close monitoring with assessment of vital signs every four hours. The committee recommends monitoring serum electrolytes and renal function in the first 48 hours but does not offer guidance regarding the frequency of laboratory testing or the value of trending serum biomarkers.

Recommendation 3. Except in the presence of direct contraindications to use the gut, children with mild acute pancreatitis may benefit from early (within 48-72 hours of presentation) oral and enteral nutrition to decrease the length of stay (LOS) and the risk of organ dysfunction.

Adult studies suggest early enteral nutrition decreases complications and reduces LOS. Initiating enteral nutrition within 48 hours in children may have similar benefits. Several small pediatric studies have demonstrated a reduced LOS with early enteral feeds without an increase in complications. In a retrospective single-center study, children who were fed within the first 48 hours and received 1.5-2 times maintenance IVF had shorter LOS, less frequent intensive care admissions, and reduced severity of illness compared with those who were kept nil per os for the first 48 hours.⁵ Nasogastric or nasojejunal feeds may be initiated if a patient is unable to tolerate oral feeding. Parenteral nutrition should be reserved for children in whom enteral nutrition cannot be initiated within five to seven days.

Recommendation 4. Intravenous morphine or other opioids should be used for acute pancreatitis pain not responding to acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs).

Abdominal pain is the most common presenting symptom of pancreatitis, and pain control is an essential component of supportive care. There are no randomized trials identifying an optimal pain management regimen. The committee recommends the use of opioids for pain not controlled with acetaminophen and NSAIDs. Refractory pain may necessitate consultation with an acute pain specialist.

Recommendation 5. Routine use of prophylactic antibiotics, protease inhibitors, antioxidants, and probiotics is not recommended in acute pancreatitis.

Adult literature does not support routine use of antibiotics in acute pancreatitis, but their use may be beneficial in severe or recalcitrant cases. Pediatric literature neither confirms nor refutes this finding. The guideline does not recommend the use of antibiotics without signs of infection. Limited adult studies have shown protease inhibitors, antioxidants, and probiotics to be beneficial; however, no pediatric data support their use.

This guideline also discusses interventional and surgical procedures. Of note, biliary tract disease may necessitate endoscopic retrograde cholangiopancreatography or cholecystectomy. Such procedures should be considered in conjunction with subspecialty input.²

Methods in Preparing Guideline

The guideline development committee, funded by the NASPGHAN and the National Institutes of Diabetes and Digestive and Kidney Diseases, was composed of members of the NASPGHAN Pancreas Committee and included gastroenterologists from multiple sites.² Topics were selected via group discussion, and Medline searches included both adult and pediatric literature. Preliminary recommendations were presented at the 2016 World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Following revision, the 24 authors voted on each recommendation using a five-point Likert scale. A recommendation passed if 75% of the participants either agreed or strongly agreed with it. The authors reported no conflicts of interest.

Although the literature review was comprehensive, it lacked prospective pediatric studies and many of the recommendations were derived from adult research. The committee originally intended to grade the quality of evidence; however, the pediatric specific literature was underpowered and retrospective. Therefore, the committee opted to use consensus voting. The authors note that had the group used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, it would have returned grades of “low” or “very low” quality evidence.² The Hungarian Pancreatic Study Group and the European Pancreatic Club published a consensus guideline on the management of pediatric acute pancreatitis shortly after the NASPGHAN guideline, which offers similar conclusions.^2,6 The strength and generalizability of the NASPGHAN guideline are limited by its overreliance on adult literature, expert consensus, and small, retrospective pediatric studies to guide care.

This guideline highlights the need for pediatric research to guide the management of acute pancreatitis. The etiologies of pancreatitis in children are distinct from adults, where alcohol abuse and biliary disease are significant contributors.¹ Furthermore, age and environmental factors influence the presentation and clinical course.¹ Robust, prospective studies are needed to better understand the treatment outcomes of pediatric pancreatitis. Areas of further research include pediatric pancreatic severity scoring, ideal fluid composition and administration rate, enteral feed timing, optimal pain control, laboratory monitoring frequency, and adjuvant therapies.

Disclosures

Dr. Wall has nothing to disclose.

Pediatric acute pancreatitis is being diagnosed more commonly, affecting approximately one per 10,000 children annually with an estimated inpatient cost burden of $200 million per year.^1,2 Common causes of pediatric acute pancreatitis include systemic illness, biliary disease, trauma, and medications; 13%-34% of cases are idiopathic.¹ Currently, substantial variation exists in the clinical management of this condition.^3,4 Hospitalists should familiarize themselves with the current literature, including the recent practice guideline by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).²

(Evidence quality: not graded, recommendation by expert consensus)

Recommendation 1. Diagnosis of acute pancreatitis in pediatric patients requires at least two of the following symptoms: abdominal pain compatible with acute pancreatitis, serum amylase and/or lipase values >3 times the upper limits of normal, and imaging findings consistent with acute pancreatitis.The most common symptoms of acute pancreatitis in children are epigastric or diffuse abdominal pain, vomiting, and irritability. Presentation varies by age, and diagnosis requires a high index of suspicion. Significant elevations in amylase and lipase levels are typically detected early in the disease course. The guideline does not specify a preferred serum biomarker in the diagnosis of pancreatitis but notes that lipase is more sensitive and specific than amylase, rises within 6 hours of symptoms, and stays elevated longer. Amylase levels rise faster but often normalize by 24 hours of symptom onset. Amylase and lipase can originate from extrapancreatic sources and may be elevated during acute illness in the absence of pancreatitis.

Laboratory testing to investigate the etiology of acute pancreatitis should include hepatic enzymes, bilirubin, triglyceride, and calcium levels. Although not typically necessary for diagnosis, imaging may demonstrate pancreatic edema or peripancreatic fluid, confirm disease complications, and identify obstructive causes. Transabdominal ultrasonography is indicated if biliary pancreatitis is suspected. Contrast-enhanced computed tomography should be considered for patients with severe presentation or deteriorating condition. Magnetic resonance cholangiopancreatography is useful in detecting pancreaticobiliary abnormalities.

Recommendation 2. Children with acute pancreatitis should be initially resuscitated with crystalloids, either with lactated Ringer’s or normal saline in the acute setting. These children should be provided 1.5-2 times maintenance intravenous fluids with monitoring of urine output over the next 24-48 hours.

Fluid resuscitation and maintenance are the current mainstays of therapy for pancreatitis. Prompt fluid administration corrects hypovolemia and may prevent potential complications. Early, aggressive fluid replacement in adults reduces the incidence of systemic inflammatory response syndrome and organ failure. Limited pediatric studies support correction of hypovolemia and/or circulatory compromise using 10-20 ml/kg boluses of isotonic crystalloid fluid. Although the literature is sparse regarding the rate of continued fluid replacement, the committee recommends patients receive 1.5-2 times maintenance intravenous fluid (IVF) with normal saline plus 5% dextrose for the first 24-48 hours. The rate of IVF administration should be adjusted based on volume status and urine output. IVF should be discontinued once the patient is able to maintain adequate hydration enterally. Cardiac, renal, and pulmonary complications of pancreatitis often present within the first 48 hours of illness and should prompt close monitoring with assessment of vital signs every four hours. The committee recommends monitoring serum electrolytes and renal function in the first 48 hours but does not offer guidance regarding the frequency of laboratory testing or the value of trending serum biomarkers.

Recommendation 3. Except in the presence of direct contraindications to use the gut, children with mild acute pancreatitis may benefit from early (within 48-72 hours of presentation) oral and enteral nutrition to decrease the length of stay (LOS) and the risk of organ dysfunction.

Adult studies suggest early enteral nutrition decreases complications and reduces LOS. Initiating enteral nutrition within 48 hours in children may have similar benefits. Several small pediatric studies have demonstrated a reduced LOS with early enteral feeds without an increase in complications. In a retrospective single-center study, children who were fed within the first 48 hours and received 1.5-2 times maintenance IVF had shorter LOS, less frequent intensive care admissions, and reduced severity of illness compared with those who were kept nil per os for the first 48 hours.⁵ Nasogastric or nasojejunal feeds may be initiated if a patient is unable to tolerate oral feeding. Parenteral nutrition should be reserved for children in whom enteral nutrition cannot be initiated within five to seven days.

Recommendation 4. Intravenous morphine or other opioids should be used for acute pancreatitis pain not responding to acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs).

Abdominal pain is the most common presenting symptom of pancreatitis, and pain control is an essential component of supportive care. There are no randomized trials identifying an optimal pain management regimen. The committee recommends the use of opioids for pain not controlled with acetaminophen and NSAIDs. Refractory pain may necessitate consultation with an acute pain specialist.

Recommendation 5. Routine use of prophylactic antibiotics, protease inhibitors, antioxidants, and probiotics is not recommended in acute pancreatitis.

Adult literature does not support routine use of antibiotics in acute pancreatitis, but their use may be beneficial in severe or recalcitrant cases. Pediatric literature neither confirms nor refutes this finding. The guideline does not recommend the use of antibiotics without signs of infection. Limited adult studies have shown protease inhibitors, antioxidants, and probiotics to be beneficial; however, no pediatric data support their use.

This guideline also discusses interventional and surgical procedures. Of note, biliary tract disease may necessitate endoscopic retrograde cholangiopancreatography or cholecystectomy. Such procedures should be considered in conjunction with subspecialty input.²

Methods in Preparing Guideline

The guideline development committee, funded by the NASPGHAN and the National Institutes of Diabetes and Digestive and Kidney Diseases, was composed of members of the NASPGHAN Pancreas Committee and included gastroenterologists from multiple sites.² Topics were selected via group discussion, and Medline searches included both adult and pediatric literature. Preliminary recommendations were presented at the 2016 World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Following revision, the 24 authors voted on each recommendation using a five-point Likert scale. A recommendation passed if 75% of the participants either agreed or strongly agreed with it. The authors reported no conflicts of interest.

Although the literature review was comprehensive, it lacked prospective pediatric studies and many of the recommendations were derived from adult research. The committee originally intended to grade the quality of evidence; however, the pediatric specific literature was underpowered and retrospective. Therefore, the committee opted to use consensus voting. The authors note that had the group used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, it would have returned grades of “low” or “very low” quality evidence.² The Hungarian Pancreatic Study Group and the European Pancreatic Club published a consensus guideline on the management of pediatric acute pancreatitis shortly after the NASPGHAN guideline, which offers similar conclusions.^2,6 The strength and generalizability of the NASPGHAN guideline are limited by its overreliance on adult literature, expert consensus, and small, retrospective pediatric studies to guide care.

This guideline highlights the need for pediatric research to guide the management of acute pancreatitis. The etiologies of pancreatitis in children are distinct from adults, where alcohol abuse and biliary disease are significant contributors.¹ Furthermore, age and environmental factors influence the presentation and clinical course.¹ Robust, prospective studies are needed to better understand the treatment outcomes of pediatric pancreatitis. Areas of further research include pediatric pancreatic severity scoring, ideal fluid composition and administration rate, enteral feed timing, optimal pain control, laboratory monitoring frequency, and adjuvant therapies.

Disclosures

Dr. Wall has nothing to disclose.

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

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

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

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

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

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

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

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

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

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

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

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

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

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

Recommendations for Patients on Anticoagulation Undergoing Procedures

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

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

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

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

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

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

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

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

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

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

Methods in Preparing Guidelines

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

Sources of Potential Conflict of Interest

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

Generalizability

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

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

Disclosures

The authors have nothing to disclose.

Funding

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

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

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

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

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

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

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

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

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

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

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

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

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

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

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

Recommendations for Patients on Anticoagulation Undergoing Procedures

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

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

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

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

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

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

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

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

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

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

Methods in Preparing Guidelines

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

Sources of Potential Conflict of Interest

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

Generalizability

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

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

Disclosures

The authors have nothing to disclose.

Funding

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

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

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

Initial Anticoagulant Dosing, Monitoring, and Medication Interactions

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

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

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

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

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

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

Recommendations for Ongoing Outpatient Monitoring upon Discharge from the Hospital

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

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

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

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

Recommendations for Patients on Anticoagulation Undergoing Procedures

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

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

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

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

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

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

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

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

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

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

Methods in Preparing Guidelines

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

Sources of Potential Conflict of Interest

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

Generalizability

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

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

Disclosures

The authors have nothing to disclose.

Funding

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

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

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

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

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

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

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

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

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

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

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

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

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

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

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

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

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

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

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

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

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

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

Disclosures

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

Funding

No funding was secured for this study.

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

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

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

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

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

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

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

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

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

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

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

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

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

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

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

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

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

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

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

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

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

Disclosures

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

Funding

No funding was secured for this study.

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

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

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

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

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

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

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

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

Pediatric Patients with Symptomatic CVAD-Related Thrombosis

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

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

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

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

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

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

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

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

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

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

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

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

Disclosures

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

Funding

No funding was secured for this study.

Hospitalized patients often receive intravenous fluids (IVF) when they cannot meet physiologic needs through oral intake in the setting of medical or surgical illness. Prescribing the optimal IVF solution to the appropriate patient is a complex decision and often occurs without the same degree of institutionalized restrictions or guidance developed for other inpatient pharmacologic agents. There is wide variation in clinical utilization of IVF due to the lack of data to guide decision making.¹ When data do exist, they typically focus on a limited number of clinical situations.² Thus, even though IVF are often considered low-risk, the frequency and lack of consistency with which they are used can result in errors, complications, and over-use of medical resources.³

(Evidence quality: not described in the guideline, recommendation strength: not described in the guideline)

Recommendation 1

To aid in fluid management and avoid complications, the guidelines recommend that patients on IVF require careful assessment of volume status, including a detailed history, physical exam, clinical monitoring, and daily labs.²

Clinical history should focus on understanding fluid losses and intake; physical exam should include vital signs, evidence of orthostatic hypotension, capillary refill, jugular venous pulsation, and assessment for pulmonary edema. Subsequent clinical monitoring should include fluid balance (Ins and Outs) and daily weights. All patients starting or continuing IVF should have a basic metabolic panel at least daily according to the guidelines, though the authors note this frequency may be too high for some patients and needs further study.²

Recommendation 2

The guidelines describe four types of IV fluids that can be administered: crystalloids, balanced crystalloids, glucose solutions, and non blood-product colloids.²

Crystalloids include isotonic saline with 154 millimoles (mmol) of sodium and chloride. Balanced crystalloids, such as lactated Ringer’s solution, are more physiologic, with less sodium and chloride, and the addition of magnesium, potassium, and calcium. Glucose solutions are quickly metabolized and, thus, are an effective way to deliver free water. Non blood-product colloids include particles that are retained within the circulation, including proteins such as human albumin.

Recommendation 3

For each indication to administer IVF, the guidelines recommend the following formulations and considerations:²

For general resuscitation, use crystalloids with sodium content of 130-154 mmol, delivered in a bolus of at least 500 milliliters (mL) over 15 minutes or less. For sepsis, infuse at least 30 mL/kg.⁴ For routine maintenance, restrict the volume to 25-30 mL/kg/day of water, and include 1 mmol/kg/day of potassium, sodium, and chloride along with 50-100 g/day of glucose to prevent starvation ketosis, though glucose should be avoided in most diabetic patients. With obesity, adjust the IVF to ideal body weight, and for patients who are older, frail, or admitted with renal or cardiac impairment, consider prescribing a lower range of fluid (20-25 mL/kg/day). For redistribution or replacement, use sodium chloride or balanced crystalloids or consider colloids, which have a theoretical advantage in expanding intravascular volume while limiting interstitial edema. Note that colloids are more expensive, and definitive evidence supporting increased efficacy is lacking. Clinicians should monitor closely for hypovolemia, hypervolemia, and electrolyte abnormalities, particularly hypo- and hypernatremia that carry associated mental status implications and risk of central pontine myelinolysis. The inadvertent overuse of IVF is common in hospital settings, particularly when maintenance fluids are not discontinued upon patient improvement or when patients move between care areas. Thus, regular clinical reassessment of volume status is important.

Recommendation 4

In both noncritically ill and critically ill hospitalized patients, there is a benefit to using balanced crystalloids compared to isotonic saline in preventing major adverse kidney events and death.^5,6

Two important studies in 2018 added new information to the existing NICE guidelines, addressing the previously unanswered question of the benefits of balanced crystalloids versus isotonic saline, one among non-critically ill patients and the other among critically ill patients.^5,6 Prior data suggested that the use of isotonic saline is associated with multiple complications, including hyperchloremic metabolic acidosis, acute kidney injury, and death. In the non-critically ill population, the use of balanced crystalloids resulted in lower incidence of major adverse kidney events (absolute difference of 0.9%), but did not change the number of hospital days (the primary outcome).⁵ In the critically ill population the use of balanced crystalloids resulted in lower rates of death, new renal replacement therapy, or persistent renal dysfunction,⁶ and the authors found preferential use of balanced crystalloids could prevent one out of every 94 patients admitted to the ICU from experiencing these adverse outcomes. Given the similar cost associated with isotonic saline and balanced crystalloids, these new findings suggest hospitalists should select balanced crystalloids if there is no compelling clinical reason to use isotonic saline.

While conflicts of interest are often a concern in clinical guidelines due to influence by pharmaceutical, device, and specialty interests, the United Kingdom’s National Clinical Guideline Centre (NGC), which developed the NICE guidelines, is hosted by the Royal College of Physicians and has governance partnerships with the Royal College of Surgeons of England, Royal College of General Practitioners, and Royal College of Nursing. Each guideline produced by the NGC is overseen by an independent guideline committee comprised of healthcare professionals and patient representatives, and as a result, concern for conflicts of interest is low.

The NICE guidelines were created by a multidisciplinary team from multiple clinical specialties, and reviewed evidence addressing both clinical and health economic outcomes. Importantly, data from randomized controlled studies was relatively limited. The data excluded patients under 16 years of age, pregnant women, and those with severe liver or renal disease, diabetes or burns, as well as those in intensive care settings. Unfortunately, many medical patients cared for by hospitalists fall into one or more of these categories, limiting applicability of the guidelines.

Two important studies in 2018 added new information to the existing NICE guidelines, as outlined in Recommendation 4.^5,6 Both of these studies occurred at a single institution, limiting their generalizability, though each study included a diverse patient population. In the ICU study, treating clinicians were aware of the composition of the assigned crystalloid so the decision to initiate renal-replacement therapy may have been susceptible to treatment bias. In addition, censoring of data collection at hospital discharge may have underestimated the true incidence of death at 30 days and overestimated persistent renal dysfunction at 30 days. Importantly, the trial design did not allow comparison of lactated Ringer’s solution versus Plasma-Lyte. The non-ICU study evaluated patients who began treatment in the emergency department and were subsequently admitted to non-ICU inpatient units—a population that mirrors much of hospitalist practice, however the un-blinded design makes bias a concern. Finally, lactated Ringer’s solution represented more than 95% of the balanced crystalloids used in the trial, so additional study is required to compare Plasma-Lyte with both saline and lactated Ringer’s solution.

More evidence is needed to better understand the appropriate use of IVF in specific clinical scenarios, including to determine if balanced solutions, as compared with isotonic saline, are superior across a spectrum of clinical conditions. For patients with an indication for maintenance fluid administration, determining if a higher sodium content reduces the risk of hyponatremia without increasing the risk of volume overload will help guide practice. Finally, more comprehensive study of the incidence of overuse and complications as a consequence of IVF, as well as the optimal frequency of lab monitoring, is needed to guide understanding of how practicing hospitalists and health systems can help reduce harm and waste

Disclosures

The authors have nothing to disclose.

Hospitalized patients often receive intravenous fluids (IVF) when they cannot meet physiologic needs through oral intake in the setting of medical or surgical illness. Prescribing the optimal IVF solution to the appropriate patient is a complex decision and often occurs without the same degree of institutionalized restrictions or guidance developed for other inpatient pharmacologic agents. There is wide variation in clinical utilization of IVF due to the lack of data to guide decision making.¹ When data do exist, they typically focus on a limited number of clinical situations.² Thus, even though IVF are often considered low-risk, the frequency and lack of consistency with which they are used can result in errors, complications, and over-use of medical resources.³

(Evidence quality: not described in the guideline, recommendation strength: not described in the guideline)

Recommendation 1

To aid in fluid management and avoid complications, the guidelines recommend that patients on IVF require careful assessment of volume status, including a detailed history, physical exam, clinical monitoring, and daily labs.²

Clinical history should focus on understanding fluid losses and intake; physical exam should include vital signs, evidence of orthostatic hypotension, capillary refill, jugular venous pulsation, and assessment for pulmonary edema. Subsequent clinical monitoring should include fluid balance (Ins and Outs) and daily weights. All patients starting or continuing IVF should have a basic metabolic panel at least daily according to the guidelines, though the authors note this frequency may be too high for some patients and needs further study.²

Recommendation 2

The guidelines describe four types of IV fluids that can be administered: crystalloids, balanced crystalloids, glucose solutions, and non blood-product colloids.²

Crystalloids include isotonic saline with 154 millimoles (mmol) of sodium and chloride. Balanced crystalloids, such as lactated Ringer’s solution, are more physiologic, with less sodium and chloride, and the addition of magnesium, potassium, and calcium. Glucose solutions are quickly metabolized and, thus, are an effective way to deliver free water. Non blood-product colloids include particles that are retained within the circulation, including proteins such as human albumin.

Recommendation 3

For each indication to administer IVF, the guidelines recommend the following formulations and considerations:²

For general resuscitation, use crystalloids with sodium content of 130-154 mmol, delivered in a bolus of at least 500 milliliters (mL) over 15 minutes or less. For sepsis, infuse at least 30 mL/kg.⁴ For routine maintenance, restrict the volume to 25-30 mL/kg/day of water, and include 1 mmol/kg/day of potassium, sodium, and chloride along with 50-100 g/day of glucose to prevent starvation ketosis, though glucose should be avoided in most diabetic patients. With obesity, adjust the IVF to ideal body weight, and for patients who are older, frail, or admitted with renal or cardiac impairment, consider prescribing a lower range of fluid (20-25 mL/kg/day). For redistribution or replacement, use sodium chloride or balanced crystalloids or consider colloids, which have a theoretical advantage in expanding intravascular volume while limiting interstitial edema. Note that colloids are more expensive, and definitive evidence supporting increased efficacy is lacking. Clinicians should monitor closely for hypovolemia, hypervolemia, and electrolyte abnormalities, particularly hypo- and hypernatremia that carry associated mental status implications and risk of central pontine myelinolysis. The inadvertent overuse of IVF is common in hospital settings, particularly when maintenance fluids are not discontinued upon patient improvement or when patients move between care areas. Thus, regular clinical reassessment of volume status is important.

Recommendation 4

In both noncritically ill and critically ill hospitalized patients, there is a benefit to using balanced crystalloids compared to isotonic saline in preventing major adverse kidney events and death.^5,6

Two important studies in 2018 added new information to the existing NICE guidelines, addressing the previously unanswered question of the benefits of balanced crystalloids versus isotonic saline, one among non-critically ill patients and the other among critically ill patients.^5,6 Prior data suggested that the use of isotonic saline is associated with multiple complications, including hyperchloremic metabolic acidosis, acute kidney injury, and death. In the non-critically ill population, the use of balanced crystalloids resulted in lower incidence of major adverse kidney events (absolute difference of 0.9%), but did not change the number of hospital days (the primary outcome).⁵ In the critically ill population the use of balanced crystalloids resulted in lower rates of death, new renal replacement therapy, or persistent renal dysfunction,⁶ and the authors found preferential use of balanced crystalloids could prevent one out of every 94 patients admitted to the ICU from experiencing these adverse outcomes. Given the similar cost associated with isotonic saline and balanced crystalloids, these new findings suggest hospitalists should select balanced crystalloids if there is no compelling clinical reason to use isotonic saline.

While conflicts of interest are often a concern in clinical guidelines due to influence by pharmaceutical, device, and specialty interests, the United Kingdom’s National Clinical Guideline Centre (NGC), which developed the NICE guidelines, is hosted by the Royal College of Physicians and has governance partnerships with the Royal College of Surgeons of England, Royal College of General Practitioners, and Royal College of Nursing. Each guideline produced by the NGC is overseen by an independent guideline committee comprised of healthcare professionals and patient representatives, and as a result, concern for conflicts of interest is low.

The NICE guidelines were created by a multidisciplinary team from multiple clinical specialties, and reviewed evidence addressing both clinical and health economic outcomes. Importantly, data from randomized controlled studies was relatively limited. The data excluded patients under 16 years of age, pregnant women, and those with severe liver or renal disease, diabetes or burns, as well as those in intensive care settings. Unfortunately, many medical patients cared for by hospitalists fall into one or more of these categories, limiting applicability of the guidelines.

Two important studies in 2018 added new information to the existing NICE guidelines, as outlined in Recommendation 4.^5,6 Both of these studies occurred at a single institution, limiting their generalizability, though each study included a diverse patient population. In the ICU study, treating clinicians were aware of the composition of the assigned crystalloid so the decision to initiate renal-replacement therapy may have been susceptible to treatment bias. In addition, censoring of data collection at hospital discharge may have underestimated the true incidence of death at 30 days and overestimated persistent renal dysfunction at 30 days. Importantly, the trial design did not allow comparison of lactated Ringer’s solution versus Plasma-Lyte. The non-ICU study evaluated patients who began treatment in the emergency department and were subsequently admitted to non-ICU inpatient units—a population that mirrors much of hospitalist practice, however the un-blinded design makes bias a concern. Finally, lactated Ringer’s solution represented more than 95% of the balanced crystalloids used in the trial, so additional study is required to compare Plasma-Lyte with both saline and lactated Ringer’s solution.

More evidence is needed to better understand the appropriate use of IVF in specific clinical scenarios, including to determine if balanced solutions, as compared with isotonic saline, are superior across a spectrum of clinical conditions. For patients with an indication for maintenance fluid administration, determining if a higher sodium content reduces the risk of hyponatremia without increasing the risk of volume overload will help guide practice. Finally, more comprehensive study of the incidence of overuse and complications as a consequence of IVF, as well as the optimal frequency of lab monitoring, is needed to guide understanding of how practicing hospitalists and health systems can help reduce harm and waste

Disclosures

The authors have nothing to disclose.

Hospitalized patients often receive intravenous fluids (IVF) when they cannot meet physiologic needs through oral intake in the setting of medical or surgical illness. Prescribing the optimal IVF solution to the appropriate patient is a complex decision and often occurs without the same degree of institutionalized restrictions or guidance developed for other inpatient pharmacologic agents. There is wide variation in clinical utilization of IVF due to the lack of data to guide decision making.¹ When data do exist, they typically focus on a limited number of clinical situations.² Thus, even though IVF are often considered low-risk, the frequency and lack of consistency with which they are used can result in errors, complications, and over-use of medical resources.³

(Evidence quality: not described in the guideline, recommendation strength: not described in the guideline)

Recommendation 1

To aid in fluid management and avoid complications, the guidelines recommend that patients on IVF require careful assessment of volume status, including a detailed history, physical exam, clinical monitoring, and daily labs.²

Clinical history should focus on understanding fluid losses and intake; physical exam should include vital signs, evidence of orthostatic hypotension, capillary refill, jugular venous pulsation, and assessment for pulmonary edema. Subsequent clinical monitoring should include fluid balance (Ins and Outs) and daily weights. All patients starting or continuing IVF should have a basic metabolic panel at least daily according to the guidelines, though the authors note this frequency may be too high for some patients and needs further study.²

Recommendation 2

The guidelines describe four types of IV fluids that can be administered: crystalloids, balanced crystalloids, glucose solutions, and non blood-product colloids.²

Crystalloids include isotonic saline with 154 millimoles (mmol) of sodium and chloride. Balanced crystalloids, such as lactated Ringer’s solution, are more physiologic, with less sodium and chloride, and the addition of magnesium, potassium, and calcium. Glucose solutions are quickly metabolized and, thus, are an effective way to deliver free water. Non blood-product colloids include particles that are retained within the circulation, including proteins such as human albumin.

Recommendation 3

For each indication to administer IVF, the guidelines recommend the following formulations and considerations:²

For general resuscitation, use crystalloids with sodium content of 130-154 mmol, delivered in a bolus of at least 500 milliliters (mL) over 15 minutes or less. For sepsis, infuse at least 30 mL/kg.⁴ For routine maintenance, restrict the volume to 25-30 mL/kg/day of water, and include 1 mmol/kg/day of potassium, sodium, and chloride along with 50-100 g/day of glucose to prevent starvation ketosis, though glucose should be avoided in most diabetic patients. With obesity, adjust the IVF to ideal body weight, and for patients who are older, frail, or admitted with renal or cardiac impairment, consider prescribing a lower range of fluid (20-25 mL/kg/day). For redistribution or replacement, use sodium chloride or balanced crystalloids or consider colloids, which have a theoretical advantage in expanding intravascular volume while limiting interstitial edema. Note that colloids are more expensive, and definitive evidence supporting increased efficacy is lacking. Clinicians should monitor closely for hypovolemia, hypervolemia, and electrolyte abnormalities, particularly hypo- and hypernatremia that carry associated mental status implications and risk of central pontine myelinolysis. The inadvertent overuse of IVF is common in hospital settings, particularly when maintenance fluids are not discontinued upon patient improvement or when patients move between care areas. Thus, regular clinical reassessment of volume status is important.

Recommendation 4

In both noncritically ill and critically ill hospitalized patients, there is a benefit to using balanced crystalloids compared to isotonic saline in preventing major adverse kidney events and death.^5,6

Two important studies in 2018 added new information to the existing NICE guidelines, addressing the previously unanswered question of the benefits of balanced crystalloids versus isotonic saline, one among non-critically ill patients and the other among critically ill patients.^5,6 Prior data suggested that the use of isotonic saline is associated with multiple complications, including hyperchloremic metabolic acidosis, acute kidney injury, and death. In the non-critically ill population, the use of balanced crystalloids resulted in lower incidence of major adverse kidney events (absolute difference of 0.9%), but did not change the number of hospital days (the primary outcome).⁵ In the critically ill population the use of balanced crystalloids resulted in lower rates of death, new renal replacement therapy, or persistent renal dysfunction,⁶ and the authors found preferential use of balanced crystalloids could prevent one out of every 94 patients admitted to the ICU from experiencing these adverse outcomes. Given the similar cost associated with isotonic saline and balanced crystalloids, these new findings suggest hospitalists should select balanced crystalloids if there is no compelling clinical reason to use isotonic saline.

While conflicts of interest are often a concern in clinical guidelines due to influence by pharmaceutical, device, and specialty interests, the United Kingdom’s National Clinical Guideline Centre (NGC), which developed the NICE guidelines, is hosted by the Royal College of Physicians and has governance partnerships with the Royal College of Surgeons of England, Royal College of General Practitioners, and Royal College of Nursing. Each guideline produced by the NGC is overseen by an independent guideline committee comprised of healthcare professionals and patient representatives, and as a result, concern for conflicts of interest is low.

The NICE guidelines were created by a multidisciplinary team from multiple clinical specialties, and reviewed evidence addressing both clinical and health economic outcomes. Importantly, data from randomized controlled studies was relatively limited. The data excluded patients under 16 years of age, pregnant women, and those with severe liver or renal disease, diabetes or burns, as well as those in intensive care settings. Unfortunately, many medical patients cared for by hospitalists fall into one or more of these categories, limiting applicability of the guidelines.

Two important studies in 2018 added new information to the existing NICE guidelines, as outlined in Recommendation 4.^5,6 Both of these studies occurred at a single institution, limiting their generalizability, though each study included a diverse patient population. In the ICU study, treating clinicians were aware of the composition of the assigned crystalloid so the decision to initiate renal-replacement therapy may have been susceptible to treatment bias. In addition, censoring of data collection at hospital discharge may have underestimated the true incidence of death at 30 days and overestimated persistent renal dysfunction at 30 days. Importantly, the trial design did not allow comparison of lactated Ringer’s solution versus Plasma-Lyte. The non-ICU study evaluated patients who began treatment in the emergency department and were subsequently admitted to non-ICU inpatient units—a population that mirrors much of hospitalist practice, however the un-blinded design makes bias a concern. Finally, lactated Ringer’s solution represented more than 95% of the balanced crystalloids used in the trial, so additional study is required to compare Plasma-Lyte with both saline and lactated Ringer’s solution.

More evidence is needed to better understand the appropriate use of IVF in specific clinical scenarios, including to determine if balanced solutions, as compared with isotonic saline, are superior across a spectrum of clinical conditions. For patients with an indication for maintenance fluid administration, determining if a higher sodium content reduces the risk of hyponatremia without increasing the risk of volume overload will help guide practice. Finally, more comprehensive study of the incidence of overuse and complications as a consequence of IVF, as well as the optimal frequency of lab monitoring, is needed to guide understanding of how practicing hospitalists and health systems can help reduce harm and waste

Disclosures

The authors have nothing to disclose.

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.

Hospitalized children with inadequate fluid intake are often administered maintenance intravenous fluids (IVFs) to support metabolic needs and sensible losses. Historically, hypotonic IVFs have been the standard, based on theoretical water and electrolyte requirements for estimated energy expenditure.¹ However, when combined with increased levels of arginine vasopressin (AVP) seen in acutely ill children which impairs free-water excretion,² hypotonic IVF can result in hyponatremia. The recently published guideline by the American Academy of Pediatrics (AAP)³ is the first to provide an evidence-based recommendation on the use of maintenance IVF therapy in children.

Patients between the ages of 28 days and 18 years should receive isotonic solutions with appropriate potassium chloride and dextrose for maintenance IVFs (evidence quality: high; recommendation strength: strong)

Isotonic fluids, such as 0.9% NaCl (normal saline), Hartmann solution and PlasmaLyte, contain a sodium concentration similar to that of plasma (135-144 mEq/L). Lactated Ringer solution (LR) is near-isotonic (sodium 130 mEq/L), but was not used in any of the reviewed studies and therefore not included in the recommendation. Excluded are patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, severe burns, or patients in the neonatal intensive care unit.

The primary benefit of the AAP recommendation is the reduced risk of iatrogenic hyponatremia and its associated sequelae, including complications or impact on cost of care. The number needed to treat with isotonic fluids was 7.5 to prevent any hyponatremia and 27.8 to prevent moderate hyponatremia (<130 mEq/L). Increases in readmission rates, length of stay, and cost of hospitalization have been reported in a recent meta-analysis reviewing the economic burden of hyponatremia in both adults and children.⁴

Potential harms from the use of isotonic fluids include hypernatremia, hyperchloremic metabolic acidosis, and fluid overload, although available data have not demonstrated an increased risk of these complications. In light of a recent normal saline (NS) shortage in the United States, limited availability is also a consideration. Plasmalyte is more costly than NS and is currently incompatible with the addition of dextrose.

Methods in Preparing Guideline

The guideline development committee included broad representation by pediatric experts in primary care, hospital medicine, emergency medicine, critical care medicine, nephrology, anesthesiology, surgery and quality improvement, as well as a guideline methodologist/informatician and epidemiologist.

Search strategies from recently published systematic reviews of clinical trials comparing isotonic with hypotonic maintenance IVFs were used to identify studies eligible for inclusion. A total of 17 studies with 2,455 total patients were initially identified and included. One additional study meeting inclusion criteria was found after the committee convened and excluded from the guideline.⁵ Three reviewers from the subcommittee performed a structured critical appraisal of each article. The methods of each trial were assessed for risk-of-bias in multiple domains, including randomization, allocation concealment, performance, detection, attrition and reporting. Forest plots were generated using random-effects models and Mantel-Haenzel statistics with the outcome of hyponatremia. The guideline underwent review by various stakeholders including AAP councils, committees, and sections, and individuals considered experts in the field.

A strength of the guideline is the high quality of the evidence and the consistent findings. All of the included studies were randomized clinical trials and the number of included patients was large. Of the 17 included studies, 16 reported a risk ratio favoring isotonic fluids over hypotonic fluids in the prevention of developing hyponatremia; the results of the study that favored hypotonic fluids were not statistically significant on their own. A sensitivity analysis was performed to exclude one study with a 20% weight, determined by multiple factors such as sample size, confidence interval, and an unusually high rate of hyponatremia in the isotonic and hypotonic fluids groups (33.3 % and 70%, respectively).⁶ After exclusion, there was no change in the overall estimated risk in hypotonic fluids leading to hyponatremia. Only one trial had two sources of high risk of bias (allocation concealment, attrition) and the remaining had only low or unclear risk of biases in the various domains.

The study that was excluded due to its late identification similarly shows increased risk of hyponatremia in groups administered hypotonic fluids (risk ratio 6.5-8.5), and would likely not affect the estimated risk.⁵

Despite differences in types of patients enrolled, rate of administered fluids, type of IVF, frequency of lab testing, and study duration, the I² (degree of heterogeneity) of the forest plot of all included studies remained low at 14% and the increased risk of hyponatremia from hypotonic fluids remained consistent.

Due to study design differences, a limitation of the guideline is that no recommendation is made regarding the type of isotonic fluids and the rate of IVF administration. Additionally, due to the low frequency of clinically significant sequelae of hyponatremia, such as hyponatremic encephalopathy, it remains uncertain how many patients would need to be treated with isotonic fluids to prevent a rare but potentially devastating event.

Sources of Potential Conflict of Interest or Bias

The guideline was developed and funded by the AAP. A formal conflict of interest management policy was followed, and subcommittee members had no conflicts of interests or financial relationships relevant to the guideline to disclose.

Generalizability

Given the large number of patients included in the studies and heterogeneity of the population included, the recommendation applies to most patients cared for by pediatric hospitalists. Several patient exclusions relevant to the pediatric hospitalist deserve mention: neonates, kidney disease, and voluminous diarrhea. Neonates under the age of 28 days, including febrile neonates, are excluded from the guideline because of the immature concentrating abilities of neonatal kidneys. Patients with renal impairment were excluded from the guideline recommendation because several studies excluded patients with kidney disease. Hospitalists often care for children who sustain prerenal acute kidney injury from severe dehydration. In this condition, the kidney conserves water through the release of AVP. While an excluded population, these patients would be even more susceptible to develop hyponatremia if administered hypotonic fluids. Patients with “voluminous diarrhea” are excluded from the guideline because those with gastroenteritis with ongoing losses may require IVFs at rates higher than maintenance, and are particularly vulnerable to electrolyte derangements. The guideline, however, does not define voluminous diarrhea, leaving it to the discretion of the treating clinician.

Finally, it is critical to mention that IVF should be considered a therapy to be judiciously used, and discontinued when possible. While the guideline addresses the choice of fluid composition, alternatives to orally or enterally hydrate a patient are always preferred.

While the guideline strongly recommends isotonic fluids for maintenance therapy, the choice of isotonic fluid remains with the clinician. Most included studies used NS for their isotonic groups, but Hartmann’s solution and Plasmalyte were represented in a few studies. LR, one of the more widely used balanced solutions, though slightly hypotonic (130 mEq/L), was not studied. The exclusion of LR from the included studies is unfortunate, as the benefit of balanced solutions compared to NS after significant fluid resuscitation has been shown in the setting of severe sepsis and shock.⁷ Hyperchloremic metabolic acidosis after fluid resuscitation with NS has raised concern about continuing NS as maintenance fluid and possibly worsening acidosis or hyperchloremia and its adverse effects.⁸ Further studies on the potential benefit of LR as maintenance fluid, or the potential harms of unbalanced solutions as maintenance fluids in the setting of significant resuscitation are needed.

Disclosures

The authors have nothing to disclose.

As part of the Journal of Hospital Medicine’s^® commitment to our readership, we are excited to announce innovative new review formats, designed for busy hospitalists. The state of knowledge in our field is changing rapidly, and the 21^st century poses a conundrum to clinicians in the form of increasingly complex studies and guidelines amidst ever-decreasing time to digest them. As a result, it can be challenging for hospitalists to access and interpret recently published research to inform their clinical practice. Because we are committed to practical innovation for hospitalists, starting in 2019, JHM will offer focused yet informative content that places important advances into relevant clinical or methodological context and provides our readers with information that is accessible, meaningful, and actionable—all in a more concise format.

Our new Clinical Guideline Highlights for the Hospitalist is a brief, targeted review of recently published clinical guidelines, distilling the major recommendations relevant to hospital medicine and placing them in context of the available evidence. This review format also offers a critique of gaps in the literature and notes areas ripe for future study. In this issue, we debut two articles using this new approach—one aimed at adult hospitalists and the other at pediatric hospitalists—regarding recently published studies and guidelines about maintenance intravenous fluids.^1-5

In 2019, we will also introduce a second new format, called Progress Notes. These reviews will be shorter than JHM’s traditional review format, and will accept two types of articles: clinical and methodological. The clinical Progress Notes will provide an update on the last several years of evidence related to diagnosis, treatment, risk stratification, and/or prevention of a clinical problem highly pertinent to hospitalists. The methodological Progress Notes will provide our readers with insight into the application of quantitative, qualitative, and quality improvement methods commonly used in work published in this journal. Our aim is to use Progress Notes as a way to enhance both clinical practice and scholarship efforts by our readers.

Finally, we will introduce “Hospital Medicine: The Year in Review,” an annual feature that concisely compiles and critiques the top articles in both adult and pediatric hospital medicine over the past year. The “Year in Review” will serve as a written corollary to the popular “Updates in Hospital Medicine” presentation at the Society of Hospital Medicine annual meeting, and will highlight important research that advanced our field or provided us a fresh perspective on hospitalist practice.

As we introduce these new review formats, it is important to note that JHM will continue to accept traditional, long-form reviews on any topic relevant to hospitalists, with a preference for rigorous systematic reviews or meta-analyses. Equally important is that JHM’s overarching commitment remains unchanged: support clinicians, leaders, and scholars in our field in their pursuit of delivering evidence-based, high-value clinical care. We hope you enjoy these new article formats and we look forward to your feedback.

Disclosures

The authors declare they have no conflicts of interest/competing interests.

As part of the Journal of Hospital Medicine’s^® commitment to our readership, we are excited to announce innovative new review formats, designed for busy hospitalists. The state of knowledge in our field is changing rapidly, and the 21^st century poses a conundrum to clinicians in the form of increasingly complex studies and guidelines amidst ever-decreasing time to digest them. As a result, it can be challenging for hospitalists to access and interpret recently published research to inform their clinical practice. Because we are committed to practical innovation for hospitalists, starting in 2019, JHM will offer focused yet informative content that places important advances into relevant clinical or methodological context and provides our readers with information that is accessible, meaningful, and actionable—all in a more concise format.

Our new Clinical Guideline Highlights for the Hospitalist is a brief, targeted review of recently published clinical guidelines, distilling the major recommendations relevant to hospital medicine and placing them in context of the available evidence. This review format also offers a critique of gaps in the literature and notes areas ripe for future study. In this issue, we debut two articles using this new approach—one aimed at adult hospitalists and the other at pediatric hospitalists—regarding recently published studies and guidelines about maintenance intravenous fluids.^1-5

In 2019, we will also introduce a second new format, called Progress Notes. These reviews will be shorter than JHM’s traditional review format, and will accept two types of articles: clinical and methodological. The clinical Progress Notes will provide an update on the last several years of evidence related to diagnosis, treatment, risk stratification, and/or prevention of a clinical problem highly pertinent to hospitalists. The methodological Progress Notes will provide our readers with insight into the application of quantitative, qualitative, and quality improvement methods commonly used in work published in this journal. Our aim is to use Progress Notes as a way to enhance both clinical practice and scholarship efforts by our readers.

Finally, we will introduce “Hospital Medicine: The Year in Review,” an annual feature that concisely compiles and critiques the top articles in both adult and pediatric hospital medicine over the past year. The “Year in Review” will serve as a written corollary to the popular “Updates in Hospital Medicine” presentation at the Society of Hospital Medicine annual meeting, and will highlight important research that advanced our field or provided us a fresh perspective on hospitalist practice.

As we introduce these new review formats, it is important to note that JHM will continue to accept traditional, long-form reviews on any topic relevant to hospitalists, with a preference for rigorous systematic reviews or meta-analyses. Equally important is that JHM’s overarching commitment remains unchanged: support clinicians, leaders, and scholars in our field in their pursuit of delivering evidence-based, high-value clinical care. We hope you enjoy these new article formats and we look forward to your feedback.

Disclosures

The authors declare they have no conflicts of interest/competing interests.

As part of the Journal of Hospital Medicine’s^® commitment to our readership, we are excited to announce innovative new review formats, designed for busy hospitalists. The state of knowledge in our field is changing rapidly, and the 21^st century poses a conundrum to clinicians in the form of increasingly complex studies and guidelines amidst ever-decreasing time to digest them. As a result, it can be challenging for hospitalists to access and interpret recently published research to inform their clinical practice. Because we are committed to practical innovation for hospitalists, starting in 2019, JHM will offer focused yet informative content that places important advances into relevant clinical or methodological context and provides our readers with information that is accessible, meaningful, and actionable—all in a more concise format.

Our new Clinical Guideline Highlights for the Hospitalist is a brief, targeted review of recently published clinical guidelines, distilling the major recommendations relevant to hospital medicine and placing them in context of the available evidence. This review format also offers a critique of gaps in the literature and notes areas ripe for future study. In this issue, we debut two articles using this new approach—one aimed at adult hospitalists and the other at pediatric hospitalists—regarding recently published studies and guidelines about maintenance intravenous fluids.^1-5

In 2019, we will also introduce a second new format, called Progress Notes. These reviews will be shorter than JHM’s traditional review format, and will accept two types of articles: clinical and methodological. The clinical Progress Notes will provide an update on the last several years of evidence related to diagnosis, treatment, risk stratification, and/or prevention of a clinical problem highly pertinent to hospitalists. The methodological Progress Notes will provide our readers with insight into the application of quantitative, qualitative, and quality improvement methods commonly used in work published in this journal. Our aim is to use Progress Notes as a way to enhance both clinical practice and scholarship efforts by our readers.

Finally, we will introduce “Hospital Medicine: The Year in Review,” an annual feature that concisely compiles and critiques the top articles in both adult and pediatric hospital medicine over the past year. The “Year in Review” will serve as a written corollary to the popular “Updates in Hospital Medicine” presentation at the Society of Hospital Medicine annual meeting, and will highlight important research that advanced our field or provided us a fresh perspective on hospitalist practice.

As we introduce these new review formats, it is important to note that JHM will continue to accept traditional, long-form reviews on any topic relevant to hospitalists, with a preference for rigorous systematic reviews or meta-analyses. Equally important is that JHM’s overarching commitment remains unchanged: support clinicians, leaders, and scholars in our field in their pursuit of delivering evidence-based, high-value clinical care. We hope you enjoy these new article formats and we look forward to your feedback.

Disclosures

The authors declare they have no conflicts of interest/competing interests.