Hospital Medicine

Readmission rates have been used by payers to administer financial incentives or penalties to hospitals as a measure of quality. The Centers for Medicare and Medicaid Services (CMS) reduces payments to hospitals with excess readmissions for adult Medicare patients.¹ Although the Medicare readmission penalties do not apply to children, several state Medicaid agencies have adopted policies to reduce reimbursement for hospitals with higher than expected readmission rates. These Medicaid programs often use potentially preventable readmission (PPR) rates calculated with proprietary software.² As a result of these incentives and with a goal of improving care, many children’s hospitals have focused on reducing readmissions through participation in local, regional, and national collaboratives.³

Rates of unplanned readmissions in children are lower than in older adults, with all-cause 30-day pediatric readmission rates around 13%.^4-7 Even so, as many as 30% of pediatric readmissions may be potentially preventable, with the most common transition failure involving a hospital factor, such as failure to recognize worsening clinical status prior to discharge.⁸ While readmission metrics are often judged across peer institutions, little is known about national trends over time. Therefore, we sought to examine readmission rates at children’s hospitals over a six-year timeframe to determine if progress has been made toward reducing readmissions.

We utilized data from the Children’s Hospital Association Inpatient Essentials Database and included index hospitalizations from January 1, 2010 through June 30, 2016. This database contains demographic information, diagnosis and procedure codes, and All-Patient Refined Diagnosis-Related Groups (APR-DRGs; 3M Health Information Systems) to describe the principal reason for each hospitalization.⁹ We included 66 hospitals from 31 states plus the District of Columbia with complete data during the study period.

Seven-day all-cause (AC) readmission and PPR rates were calculated using the output from 3M potentially preventable readmission software (version 32). The PPR software utilizes a proprietary algorithm to designate potentially preventable readmissions based on diagnosis codes and the severity of illness (as measured by the APR-DRG severity of illness classification). We chose seven-day readmissions, as opposed to a longer window, as readmissions soon after discharge are more likely to be preventable⁸ and thus theoretically more amenable to prevention efforts. Quarterly rates were generated for each hospital and in aggregate across the population. We chose quarterly rates a priori to assess changes in rates without focusing on minor monthly fluctuations due to seasonal differences. We performed generalized linear mixed regression models with cluster adjustments at the hospital level to assess changes in readmission rates over time adjusted for case mix index, as admissions to children’s hospitals have increased in complexity over time.^10,11 We operationalized the case mix index as an average of pediatric admissions’ relative weights at each hospital for the quarter.¹² We assessed AC and PPR models separately. The average case mix index was a covariate in both regression models.

Finally, to determine if readmission reduction may be specific to particular conditions, we generated readmission rates for a select number of APR-DRGs. We focused on conditions with a very high percentage of AC readmissions classified as PPR (appendectomy, connective tissue disorders, ventricular shunt procedures, bronchiolitis, asthma, and sickle cell crisis) as well as those with a very low percentage of AC readmissions classified as PPR (gastrointestinal infections, hematologic disease, and bone marrow transplant [BMT]).⁵

We included 4.52 million admissions to the 66 included hospitals. Most hospitals (62%) were freestanding acute-care children’s hospitals. The hospitals were geographically diverse. Two-thirds had magnet status (Appendix Table 1). Appendix Table 2 displays patient/admission characteristics over time. Approximately 49% of children were non-Hispanic white, 19% were non-Hispanic black, and 19% were Hispanic. Half of the children were insured by Medicaid. These characteristics were stable over time, except case mix index, which increased during the study period (P = .04).

Across Diagnosis All-Cause and Potentially Preventable Readmission Rates

Over the study period, there were 227,378 AC seven-day readmissions (5.1% readmission rate), and 91,467 readmissions (40% of AC readmissions) were considered PPRs. Readmission rates did not vary over the study period (Figure, Panel A). The median AC seven-day readmission rate across all quarters was 5.1%, ranging from 4.3% to 5.3% (Figure, Panels A and B). The median seven-day PPR rate across all quarters was 2.5% and ranged from 2.1% to 2.5% (Figure, Panels A and C). When adjusted for case mix index, the AC rate increased slightly (on average 0.006% increase per quarter, P = .01) and PPR rates were unchanged over time (PPR model P = .14; Figure, Panel D).

Condition-Specific Readmission Rates

Of the condition-specific readmission rates, only the AC rate for BMT changed significantly, with a decrease of 0.1% per quarter, P = .048. None of the conditions had significant trends in increasing or decreasing readmission in PPR rates. Some conditions, including sickle cell and cerebrospinal fluid ventricular shunt procedures, had fluctuating readmission rates throughout the study period (Appendix Figure, Panels A-G).

Despite substantial national efforts to reduce pediatric readmissions,³ seven-day readmission rates at children’s hospitals have not decreased over six years. When individual conditions are examined, there are minor fluctuations of readmission rates over time but no clear trend of decreased readmission events.

Our results are contrary to findings in the Medicare population, where 30-day readmission rates have decreased over time.^13,14 In these analyses, we focused on seven-day readmission, as earlier pediatric readmissions are more likely to be preventable. Importantly, the majority of our included hospitals (88%) participate in the Solutions for Patient Safety collaborative, which focuses on reducing seven-day readmissions. Thus, we are confident that a concerted effort to decrease readmission has been ongoing. Further, our findings are contrary to recent analyses indicating an increase in pediatric readmission rates using the pediatric all-condition readmission rate in the National Readmission Database.¹⁵ Our analyses are distinctly different in that they allow a focus on hospital-level performance in children’s hospitals. Although in our analyses the all-cause adjusted readmission rate did increase significantly over time (0.006% a quarter or 0.024% per year), this small increase is unlikely to be clinically relevant.

There are several potential reasons for the lack of change in pediatric readmission rates despite concerted efforts to decrease readmissions. First, pediatric readmissions across all conditions are relatively infrequent compared with adult readmission rates. Extrapolating from the largest pediatric study on readmission preventability,⁸ it is estimated that only two in 100 pediatric hospitalizations results in a PPR.¹⁶ Given the lack of robust pediatric readmission prediction tools, the ability to prospectively identify children at high risk for readmission and target interventions is challenging. Second, as we have previously described, children are readmitted after hospitalization for a wide variety of conditions.⁵ Medicare readmission penalties are leveraged on specific conditions; yet, Medicaid policies include all conditions. In pediatrics, successful interventions to reduce readmissions have focused on hospitalizations for specific conditions.¹⁷ In the only two large pediatric readmission reduction trials across multiple conditions, postdischarge homecare nursing contact did not reduce reutilization.^18,19 It is challenging to decrease readmissions in heterogenous populations without a robust set of evidence-based interventions. Third, there are multiple ways to measure pediatric readmissions, and different institutions may focus on different methods. Given the proprietary nature and the reliance on retrospective administrative data, PPR rates cannot be assessed during admission and thus are not feasible as a real-time quality improvement outcome. Fourth, in contrast to other hospital quality metrics such as central line-associated bloodstream infections or catheter-associated urinary tract infection, the locus of control for readmission is not entirely within the purview of the hospital.

It is unclear what readmission rate in children is appropriate—or safe—and whether that level has already been met. National readmission prevention efforts may have collateral benefits such as improved communication, medication errors or adherence, and other important aspects of care during transitions. In this scenario, lower readmission rates may not reflect improved quality. Future research should focus on determining if and how readmission reduction efforts are helping to ease the transition to home. Alternatively, research should determine if there are better interventions to assist with transition challenges which should receive resources divested from failing readmission reduction efforts.

Using administrative data, we are limited in delineating truly preventable readmissions from nonpreventable readmissions. Nevertheless, we chose to focus on the PPR and AC metrics, as these are the most policy-relevant metrics. Additionally, we examined aggregate rates of readmission across a cohort of hospitals and did not assess for within-hospital changes in readmission rates. Thus, it is possible (and likely) that some hospitals saw improvements and others saw increases in readmission rates during the study period. We are unable to examine readmission rates at hospitals based on investment in readmission reduction efforts or individual state Medicaid reimbursement policies. Finally, we are unable to assess readmissions to other institutions; however, it is unlikely that readmissions to other hospitals have decreased significantly when readmissions to the discharging hospital have not changed.

Pediatric readmissions at children’s hospitals have not decreased in the past six years, despite widespread readmission reduction efforts. Readmission rates for individual conditions have fluctuated but have not decreased.

Disclosures

Dr. Auger reports grants from AHRQ, during the conduct of the study. Drs. Harris, Gay, Teufel, McLead, Neuman, Peltz, Morse, Del Beccaro, Simon, Argawal, and Fieldston have nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine.

Funding

Dr. Auger’s research is funded by a K08 award from the Agency for Healthcare Research and Quality (1K08HS024735-01A).

Readmission rates have been used by payers to administer financial incentives or penalties to hospitals as a measure of quality. The Centers for Medicare and Medicaid Services (CMS) reduces payments to hospitals with excess readmissions for adult Medicare patients.¹ Although the Medicare readmission penalties do not apply to children, several state Medicaid agencies have adopted policies to reduce reimbursement for hospitals with higher than expected readmission rates. These Medicaid programs often use potentially preventable readmission (PPR) rates calculated with proprietary software.² As a result of these incentives and with a goal of improving care, many children’s hospitals have focused on reducing readmissions through participation in local, regional, and national collaboratives.³

Rates of unplanned readmissions in children are lower than in older adults, with all-cause 30-day pediatric readmission rates around 13%.^4-7 Even so, as many as 30% of pediatric readmissions may be potentially preventable, with the most common transition failure involving a hospital factor, such as failure to recognize worsening clinical status prior to discharge.⁸ While readmission metrics are often judged across peer institutions, little is known about national trends over time. Therefore, we sought to examine readmission rates at children’s hospitals over a six-year timeframe to determine if progress has been made toward reducing readmissions.

We utilized data from the Children’s Hospital Association Inpatient Essentials Database and included index hospitalizations from January 1, 2010 through June 30, 2016. This database contains demographic information, diagnosis and procedure codes, and All-Patient Refined Diagnosis-Related Groups (APR-DRGs; 3M Health Information Systems) to describe the principal reason for each hospitalization.⁹ We included 66 hospitals from 31 states plus the District of Columbia with complete data during the study period.

Seven-day all-cause (AC) readmission and PPR rates were calculated using the output from 3M potentially preventable readmission software (version 32). The PPR software utilizes a proprietary algorithm to designate potentially preventable readmissions based on diagnosis codes and the severity of illness (as measured by the APR-DRG severity of illness classification). We chose seven-day readmissions, as opposed to a longer window, as readmissions soon after discharge are more likely to be preventable⁸ and thus theoretically more amenable to prevention efforts. Quarterly rates were generated for each hospital and in aggregate across the population. We chose quarterly rates a priori to assess changes in rates without focusing on minor monthly fluctuations due to seasonal differences. We performed generalized linear mixed regression models with cluster adjustments at the hospital level to assess changes in readmission rates over time adjusted for case mix index, as admissions to children’s hospitals have increased in complexity over time.^10,11 We operationalized the case mix index as an average of pediatric admissions’ relative weights at each hospital for the quarter.¹² We assessed AC and PPR models separately. The average case mix index was a covariate in both regression models.

Finally, to determine if readmission reduction may be specific to particular conditions, we generated readmission rates for a select number of APR-DRGs. We focused on conditions with a very high percentage of AC readmissions classified as PPR (appendectomy, connective tissue disorders, ventricular shunt procedures, bronchiolitis, asthma, and sickle cell crisis) as well as those with a very low percentage of AC readmissions classified as PPR (gastrointestinal infections, hematologic disease, and bone marrow transplant [BMT]).⁵

We included 4.52 million admissions to the 66 included hospitals. Most hospitals (62%) were freestanding acute-care children’s hospitals. The hospitals were geographically diverse. Two-thirds had magnet status (Appendix Table 1). Appendix Table 2 displays patient/admission characteristics over time. Approximately 49% of children were non-Hispanic white, 19% were non-Hispanic black, and 19% were Hispanic. Half of the children were insured by Medicaid. These characteristics were stable over time, except case mix index, which increased during the study period (P = .04).

Across Diagnosis All-Cause and Potentially Preventable Readmission Rates

Over the study period, there were 227,378 AC seven-day readmissions (5.1% readmission rate), and 91,467 readmissions (40% of AC readmissions) were considered PPRs. Readmission rates did not vary over the study period (Figure, Panel A). The median AC seven-day readmission rate across all quarters was 5.1%, ranging from 4.3% to 5.3% (Figure, Panels A and B). The median seven-day PPR rate across all quarters was 2.5% and ranged from 2.1% to 2.5% (Figure, Panels A and C). When adjusted for case mix index, the AC rate increased slightly (on average 0.006% increase per quarter, P = .01) and PPR rates were unchanged over time (PPR model P = .14; Figure, Panel D).

Condition-Specific Readmission Rates

Of the condition-specific readmission rates, only the AC rate for BMT changed significantly, with a decrease of 0.1% per quarter, P = .048. None of the conditions had significant trends in increasing or decreasing readmission in PPR rates. Some conditions, including sickle cell and cerebrospinal fluid ventricular shunt procedures, had fluctuating readmission rates throughout the study period (Appendix Figure, Panels A-G).

Despite substantial national efforts to reduce pediatric readmissions,³ seven-day readmission rates at children’s hospitals have not decreased over six years. When individual conditions are examined, there are minor fluctuations of readmission rates over time but no clear trend of decreased readmission events.

Our results are contrary to findings in the Medicare population, where 30-day readmission rates have decreased over time.^13,14 In these analyses, we focused on seven-day readmission, as earlier pediatric readmissions are more likely to be preventable. Importantly, the majority of our included hospitals (88%) participate in the Solutions for Patient Safety collaborative, which focuses on reducing seven-day readmissions. Thus, we are confident that a concerted effort to decrease readmission has been ongoing. Further, our findings are contrary to recent analyses indicating an increase in pediatric readmission rates using the pediatric all-condition readmission rate in the National Readmission Database.¹⁵ Our analyses are distinctly different in that they allow a focus on hospital-level performance in children’s hospitals. Although in our analyses the all-cause adjusted readmission rate did increase significantly over time (0.006% a quarter or 0.024% per year), this small increase is unlikely to be clinically relevant.

There are several potential reasons for the lack of change in pediatric readmission rates despite concerted efforts to decrease readmissions. First, pediatric readmissions across all conditions are relatively infrequent compared with adult readmission rates. Extrapolating from the largest pediatric study on readmission preventability,⁸ it is estimated that only two in 100 pediatric hospitalizations results in a PPR.¹⁶ Given the lack of robust pediatric readmission prediction tools, the ability to prospectively identify children at high risk for readmission and target interventions is challenging. Second, as we have previously described, children are readmitted after hospitalization for a wide variety of conditions.⁵ Medicare readmission penalties are leveraged on specific conditions; yet, Medicaid policies include all conditions. In pediatrics, successful interventions to reduce readmissions have focused on hospitalizations for specific conditions.¹⁷ In the only two large pediatric readmission reduction trials across multiple conditions, postdischarge homecare nursing contact did not reduce reutilization.^18,19 It is challenging to decrease readmissions in heterogenous populations without a robust set of evidence-based interventions. Third, there are multiple ways to measure pediatric readmissions, and different institutions may focus on different methods. Given the proprietary nature and the reliance on retrospective administrative data, PPR rates cannot be assessed during admission and thus are not feasible as a real-time quality improvement outcome. Fourth, in contrast to other hospital quality metrics such as central line-associated bloodstream infections or catheter-associated urinary tract infection, the locus of control for readmission is not entirely within the purview of the hospital.

It is unclear what readmission rate in children is appropriate—or safe—and whether that level has already been met. National readmission prevention efforts may have collateral benefits such as improved communication, medication errors or adherence, and other important aspects of care during transitions. In this scenario, lower readmission rates may not reflect improved quality. Future research should focus on determining if and how readmission reduction efforts are helping to ease the transition to home. Alternatively, research should determine if there are better interventions to assist with transition challenges which should receive resources divested from failing readmission reduction efforts.

Using administrative data, we are limited in delineating truly preventable readmissions from nonpreventable readmissions. Nevertheless, we chose to focus on the PPR and AC metrics, as these are the most policy-relevant metrics. Additionally, we examined aggregate rates of readmission across a cohort of hospitals and did not assess for within-hospital changes in readmission rates. Thus, it is possible (and likely) that some hospitals saw improvements and others saw increases in readmission rates during the study period. We are unable to examine readmission rates at hospitals based on investment in readmission reduction efforts or individual state Medicaid reimbursement policies. Finally, we are unable to assess readmissions to other institutions; however, it is unlikely that readmissions to other hospitals have decreased significantly when readmissions to the discharging hospital have not changed.

Pediatric readmissions at children’s hospitals have not decreased in the past six years, despite widespread readmission reduction efforts. Readmission rates for individual conditions have fluctuated but have not decreased.

Disclosures

Dr. Auger reports grants from AHRQ, during the conduct of the study. Drs. Harris, Gay, Teufel, McLead, Neuman, Peltz, Morse, Del Beccaro, Simon, Argawal, and Fieldston have nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine.

Funding

Dr. Auger’s research is funded by a K08 award from the Agency for Healthcare Research and Quality (1K08HS024735-01A).

Readmission rates have been used by payers to administer financial incentives or penalties to hospitals as a measure of quality. The Centers for Medicare and Medicaid Services (CMS) reduces payments to hospitals with excess readmissions for adult Medicare patients.¹ Although the Medicare readmission penalties do not apply to children, several state Medicaid agencies have adopted policies to reduce reimbursement for hospitals with higher than expected readmission rates. These Medicaid programs often use potentially preventable readmission (PPR) rates calculated with proprietary software.² As a result of these incentives and with a goal of improving care, many children’s hospitals have focused on reducing readmissions through participation in local, regional, and national collaboratives.³

Rates of unplanned readmissions in children are lower than in older adults, with all-cause 30-day pediatric readmission rates around 13%.^4-7 Even so, as many as 30% of pediatric readmissions may be potentially preventable, with the most common transition failure involving a hospital factor, such as failure to recognize worsening clinical status prior to discharge.⁸ While readmission metrics are often judged across peer institutions, little is known about national trends over time. Therefore, we sought to examine readmission rates at children’s hospitals over a six-year timeframe to determine if progress has been made toward reducing readmissions.

We utilized data from the Children’s Hospital Association Inpatient Essentials Database and included index hospitalizations from January 1, 2010 through June 30, 2016. This database contains demographic information, diagnosis and procedure codes, and All-Patient Refined Diagnosis-Related Groups (APR-DRGs; 3M Health Information Systems) to describe the principal reason for each hospitalization.⁹ We included 66 hospitals from 31 states plus the District of Columbia with complete data during the study period.

Seven-day all-cause (AC) readmission and PPR rates were calculated using the output from 3M potentially preventable readmission software (version 32). The PPR software utilizes a proprietary algorithm to designate potentially preventable readmissions based on diagnosis codes and the severity of illness (as measured by the APR-DRG severity of illness classification). We chose seven-day readmissions, as opposed to a longer window, as readmissions soon after discharge are more likely to be preventable⁸ and thus theoretically more amenable to prevention efforts. Quarterly rates were generated for each hospital and in aggregate across the population. We chose quarterly rates a priori to assess changes in rates without focusing on minor monthly fluctuations due to seasonal differences. We performed generalized linear mixed regression models with cluster adjustments at the hospital level to assess changes in readmission rates over time adjusted for case mix index, as admissions to children’s hospitals have increased in complexity over time.^10,11 We operationalized the case mix index as an average of pediatric admissions’ relative weights at each hospital for the quarter.¹² We assessed AC and PPR models separately. The average case mix index was a covariate in both regression models.

Finally, to determine if readmission reduction may be specific to particular conditions, we generated readmission rates for a select number of APR-DRGs. We focused on conditions with a very high percentage of AC readmissions classified as PPR (appendectomy, connective tissue disorders, ventricular shunt procedures, bronchiolitis, asthma, and sickle cell crisis) as well as those with a very low percentage of AC readmissions classified as PPR (gastrointestinal infections, hematologic disease, and bone marrow transplant [BMT]).⁵

We included 4.52 million admissions to the 66 included hospitals. Most hospitals (62%) were freestanding acute-care children’s hospitals. The hospitals were geographically diverse. Two-thirds had magnet status (Appendix Table 1). Appendix Table 2 displays patient/admission characteristics over time. Approximately 49% of children were non-Hispanic white, 19% were non-Hispanic black, and 19% were Hispanic. Half of the children were insured by Medicaid. These characteristics were stable over time, except case mix index, which increased during the study period (P = .04).

Across Diagnosis All-Cause and Potentially Preventable Readmission Rates

Over the study period, there were 227,378 AC seven-day readmissions (5.1% readmission rate), and 91,467 readmissions (40% of AC readmissions) were considered PPRs. Readmission rates did not vary over the study period (Figure, Panel A). The median AC seven-day readmission rate across all quarters was 5.1%, ranging from 4.3% to 5.3% (Figure, Panels A and B). The median seven-day PPR rate across all quarters was 2.5% and ranged from 2.1% to 2.5% (Figure, Panels A and C). When adjusted for case mix index, the AC rate increased slightly (on average 0.006% increase per quarter, P = .01) and PPR rates were unchanged over time (PPR model P = .14; Figure, Panel D).

Condition-Specific Readmission Rates

Of the condition-specific readmission rates, only the AC rate for BMT changed significantly, with a decrease of 0.1% per quarter, P = .048. None of the conditions had significant trends in increasing or decreasing readmission in PPR rates. Some conditions, including sickle cell and cerebrospinal fluid ventricular shunt procedures, had fluctuating readmission rates throughout the study period (Appendix Figure, Panels A-G).

Despite substantial national efforts to reduce pediatric readmissions,³ seven-day readmission rates at children’s hospitals have not decreased over six years. When individual conditions are examined, there are minor fluctuations of readmission rates over time but no clear trend of decreased readmission events.

Our results are contrary to findings in the Medicare population, where 30-day readmission rates have decreased over time.^13,14 In these analyses, we focused on seven-day readmission, as earlier pediatric readmissions are more likely to be preventable. Importantly, the majority of our included hospitals (88%) participate in the Solutions for Patient Safety collaborative, which focuses on reducing seven-day readmissions. Thus, we are confident that a concerted effort to decrease readmission has been ongoing. Further, our findings are contrary to recent analyses indicating an increase in pediatric readmission rates using the pediatric all-condition readmission rate in the National Readmission Database.¹⁵ Our analyses are distinctly different in that they allow a focus on hospital-level performance in children’s hospitals. Although in our analyses the all-cause adjusted readmission rate did increase significantly over time (0.006% a quarter or 0.024% per year), this small increase is unlikely to be clinically relevant.

There are several potential reasons for the lack of change in pediatric readmission rates despite concerted efforts to decrease readmissions. First, pediatric readmissions across all conditions are relatively infrequent compared with adult readmission rates. Extrapolating from the largest pediatric study on readmission preventability,⁸ it is estimated that only two in 100 pediatric hospitalizations results in a PPR.¹⁶ Given the lack of robust pediatric readmission prediction tools, the ability to prospectively identify children at high risk for readmission and target interventions is challenging. Second, as we have previously described, children are readmitted after hospitalization for a wide variety of conditions.⁵ Medicare readmission penalties are leveraged on specific conditions; yet, Medicaid policies include all conditions. In pediatrics, successful interventions to reduce readmissions have focused on hospitalizations for specific conditions.¹⁷ In the only two large pediatric readmission reduction trials across multiple conditions, postdischarge homecare nursing contact did not reduce reutilization.^18,19 It is challenging to decrease readmissions in heterogenous populations without a robust set of evidence-based interventions. Third, there are multiple ways to measure pediatric readmissions, and different institutions may focus on different methods. Given the proprietary nature and the reliance on retrospective administrative data, PPR rates cannot be assessed during admission and thus are not feasible as a real-time quality improvement outcome. Fourth, in contrast to other hospital quality metrics such as central line-associated bloodstream infections or catheter-associated urinary tract infection, the locus of control for readmission is not entirely within the purview of the hospital.

It is unclear what readmission rate in children is appropriate—or safe—and whether that level has already been met. National readmission prevention efforts may have collateral benefits such as improved communication, medication errors or adherence, and other important aspects of care during transitions. In this scenario, lower readmission rates may not reflect improved quality. Future research should focus on determining if and how readmission reduction efforts are helping to ease the transition to home. Alternatively, research should determine if there are better interventions to assist with transition challenges which should receive resources divested from failing readmission reduction efforts.

Using administrative data, we are limited in delineating truly preventable readmissions from nonpreventable readmissions. Nevertheless, we chose to focus on the PPR and AC metrics, as these are the most policy-relevant metrics. Additionally, we examined aggregate rates of readmission across a cohort of hospitals and did not assess for within-hospital changes in readmission rates. Thus, it is possible (and likely) that some hospitals saw improvements and others saw increases in readmission rates during the study period. We are unable to examine readmission rates at hospitals based on investment in readmission reduction efforts or individual state Medicaid reimbursement policies. Finally, we are unable to assess readmissions to other institutions; however, it is unlikely that readmissions to other hospitals have decreased significantly when readmissions to the discharging hospital have not changed.

Pediatric readmissions at children’s hospitals have not decreased in the past six years, despite widespread readmission reduction efforts. Readmission rates for individual conditions have fluctuated but have not decreased.

Disclosures

Dr. Auger reports grants from AHRQ, during the conduct of the study. Drs. Harris, Gay, Teufel, McLead, Neuman, Peltz, Morse, Del Beccaro, Simon, Argawal, and Fieldston have nothing to disclose. Dr. Shah is the Editor-in-Chief of the Journal of Hospital Medicine.

Funding

Dr. Auger’s research is funded by a K08 award from the Agency for Healthcare Research and Quality (1K08HS024735-01A).

Unrecognized in-hospital deterioration can result in tragic consequences for pediatric patients. The majority of deterioration events have antecedents such as increasingly abnormal vital signs and new concerns from nurses.¹ Recent meta-analyses have shown that rapid response systems (RRSs), which include trigger mechanisms such as a pediatric early warning score (PEWS), are associated with a reduced rate of arrests and in-hospital mortality.^2,3 Cardiopulmonary arrest rates are useful metrics to judge the effectiveness of the system to identify and respond to deteriorating adult patients; however, there are important challenges to their use as an outcome measure in pediatrics. Arrests, which have been relatively uncommon in pediatric patients, are now even less frequent since the adoption of a RRS in the majority of children’s hospitals.^4,5 Several innovations in these systems will be context-dependent and hence best first evaluated in a single center, where arrests outside of the intensive care unit (ICU) may occur rarely. Identification of valid, more frequent proximal measures to arrests may better identify the risk factors for deterioration. This could potentially inform quality improvement efforts to mitigate clinical deterioration.

Bonafide et al. at the Children’s Hospital of Philadelphia developed and validated the critical deterioration event (CDE) metric, demonstrating that children who were transferred to the ICU and who received noninvasive ventilation, intubation, or vasopressor initiation within 12 hours of transfer had a >13-fold increased risk of in-hospital mortality.⁶ At Cincinnati Children’s Hospital Medical Center, an additional proximal outcome measure was developed for unrecognized clinical deterioration, now termed emergency transfers (ETs).^7-9 An ET is defined as any patient transferred to the ICU where the patient received intubation, inotropes, or three or more fluid boluses in the first hour after arrival or before transfer.⁹ Improvement science work that aimed at increasing clinician situation awareness was associated with a reduction in ETs,⁸ but the association of ETs with mortality or other healthcare utilization outcomes is unknown. The objective of this study was to determine the predictive validity of an ET on in-hospital mortality, ICU length of stay (LOS), and overall hospital LOS.

We conducted a case–control study at Cincinnati Children’s Hospital, a free-standing tertiary care children’s hospital. Our center has had an ICU-based RRS in place since 2005. In 2009, we eliminated the ICU consult such that each floor-to-ICU transfer is evaluated by the RRS. Nurses calculate a Monaghan PEWS every four hours on the majority of nursing units.

Patients of all ages cared for outside of the ICU at any point in their hospitalization from January 1, 2013, to July 31, 2017, were eligible for inclusion. There were no other exclusion criteria. The ICU included both the pediatric ICU and the cardiac ICU.

Cases

We identified all ET cases from an existing situation awareness database in which each RRS call is entered by the hospital nursing supervisor, whose role includes responding to each RRS activation. If the patient transfer meets the ET criteria, the nurse indicates this in the database. Each ET entry is later confirmed for assurance purposes by the nurse leader of the RRS committee (RG). For the purposes of this study, all records were again reviewed and validated using manual chart review in the electronic health record (Epic Systems, Verona, Wisconsin).

Controls

We identified nonemergent ICU transfers to serve as controls and matched those to ET in cases to limit the impact of confounders that may increase the likelihood of both an ET and a negative outcome such as ICU mortality. We identified up to three controls for each case from our database and matched in terms of age group (within five years of age), hospital unit before transfer, and time of year (within three months of ET). These variables were chosen to adjust for the impact of age, diversity of disease (as hospital units are generally organized by organ system of illness), and seasonality on outcomes.

Outcome Measures

Posttransfer LOS in the ICU, posttransfer hospital LOS, and in-hospital mortality were the primary outcome measures. Patient demographics, specific diagnoses, and number of medical conditions were a priori defined as covariates of interest. Data for each case and control were entered into a secure, web-based Research Electronic Data Capture (REDCap) database.

Analysis

Descriptive data were summarized using counts and percentages for categorical variables and medians and ranges for continuous variables due to nonnormal distributions. Chi-square test was used to compare in-hospital mortality between the ETs and the controls. The Wilcoxon rank-sum test was used to compare LOS between ETs and controls. All data analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).

A total of 45 ETs were identified, and 110 controls were matched. Patient demographics were similar among all cases and controls (P > .05). Patients with ETs had a median age of seven years (interquartile range: 3-18 years), and 51% of them were males. The majority of patients among our examined cases were white (68%) and non-Hispanic (93%). There was no statistical difference in insurance between the ETs and the controls. When evaluating the hospital unit before the transfer, ETs occurred most commonly in the Cardiology (22%), Hematology/Oncology (22%), and Neuroscience (16%) units.

ETs stayed longer in the ICU than non-ETs [median of 4.9 days vs 2.2 days, P = .001; Figure (A)]. Similarly, ET cases had a significantly longer posttransfer hospital LOS [median of 35 days vs 21 days, P = .001; Figure (B)]. ETs had a 22% in-hospital mortality rate, compared with 9% in-hospital mortality in the matched controls (P = .02; Table).

Children who experienced an ET had a significantly longer ICU LOS, a longer posttransfer LOS, and a higher in-hospital mortality than the matched controls who were also transferred to the ICU. Researchers and improvement science teams at multiple hospitals have demonstrated that interventions targeting improved situation awareness can reduce ETs; we have demonstrated that reducing ETs may reduce subsequent adverse outcomes.^8,10

These findings provide additional support for the use of the ET metric in children’s hospitals as a proximal measure for significant clinical deterioration. We found mortality rates that were overall high for a children’s hospital (22% in ET cases and 9% among controls) compared with a national average mortality rate of 2.3% in pediatric ICUs.¹¹ This is likely due to the study sample containing a significant proportion of children with medical complexity.

Aoki et al. recently demonstrated that ETs, compared with non-ETs, were associated with longer LOS and higher mortality in a bivariate analysis.¹² In our study, we found similar results with the important addition that these findings were robust when ETs were compared with matched controls who were likely at a higher risk of poor outcomes than ICU transfers in general. In addition, we demonstrated that ETs were associated with adverse outcomes in a United States children’s hospital with a mature, long-standing RRS process. As ETs are considerably more common than cardiac and respiratory arrests, use of the ET metric in children’s hospitals may enable more rapid learning and systems improvement implementations. We also found that most of the children with ETs present from units that care for children with substantial medical complexity, including Cardiology, Hematology/Oncology, and Neurosciences. Future work should continue to examine the relationship between medical complexity and ET risk.

The ET metric is complementary to the CDE measure developed by Bonafide et al. Both metrics capture potential events of unrecognized clinical deterioration, and both offer researchers the opportunity to better understand and improve their RRSs. Both ETs and CDEs are more common than arrests, and CDEs are more common than ETs. ETs, which by definition occur in the first hour of ICU care, are likely a more specific measure of unrecognized clinical deterioration. CDEs will capture therapies that may have been started up to 12 hours after transfer and thus are possibly more sensitive to identify unrecognized clinical deterioration. However, CDEs also may encompass some patients who arrived at the ICU after prompt recognition and then had a subacute deterioration in the ICU.

The maturity of the RRS and the bandwidth of teams to collect data may inform which metric(s) are best for individual centers. As ETs are less common and likely more specific to unrecognized clinical deterioration, they might be the first tracked as a center improves its RRS through QI methods. Alternatively, CDEs may be a useful metric for centers where unrecognized clinical deterioration is less common or in research studies where this more common outcome would lead to more power to detect the effect of interventions to improve care.

Our study had several limitations. Data collection was confined to one tertiary care children’s hospital with a high burden of complex cardiac and oncology care. The results may not generalize well to children hospitalized in smaller or community hospitals or in hospitals without a mature RRS. There is also the possibility of misclassification of covariates and outcomes, but any misclassification would likely be nondifferential and bias toward the null. Matching was not possible based on exact diagnosis, and the unit is a good but imperfect proxy for diagnosis grouping. At our center, overflow of patients into the Cardiology and Hematology/Oncology units is uncommon, mitigating this partially, although residual confounding may remain. The finding that ETs are associated with adverse outcomes does not necessarily mean that these events were preventable; however, it is important and encouraging that the rate of ETs has been reduced at two centers using improvement science interventions.^8,10

Patients who experienced an ET had a significantly higher likelihood of in-hospital mortality, spent more time in the ICU, and had a longer hospital LOS posttransfer than matched controls. The use of the ET metric in children’s hospitals would allow for further analysis of such patients in hopes of identifying clinical characteristics that serve as predictors of deterioration. This may facilitate better risk stratification in the clinical system as well as enable more rapid learning and systems improvements targeted toward preventing unrecognized clinical deterioration.

Disclosures

Dr. Hussain, Dr. Sosa, Dr. Ambroggio, and Mrs. Gallagher have nothing to disclose. Patrick Brady reports grants from the Agency for Healthcare Research and Quality, outside the submitted work. The authors certify that this submission is not under review by any other publication. The author team has no conflicts of interest to disclose.

Funding

Ms. Hussain was supported by the Society of Hospital Medicine’s Student Hospitalist Scholar Grant Program in 2017. Dr. Brady receives career development support from AHRQ K08-HS023827. The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the SHM, AHRQ, or NIH.

Unrecognized in-hospital deterioration can result in tragic consequences for pediatric patients. The majority of deterioration events have antecedents such as increasingly abnormal vital signs and new concerns from nurses.¹ Recent meta-analyses have shown that rapid response systems (RRSs), which include trigger mechanisms such as a pediatric early warning score (PEWS), are associated with a reduced rate of arrests and in-hospital mortality.^2,3 Cardiopulmonary arrest rates are useful metrics to judge the effectiveness of the system to identify and respond to deteriorating adult patients; however, there are important challenges to their use as an outcome measure in pediatrics. Arrests, which have been relatively uncommon in pediatric patients, are now even less frequent since the adoption of a RRS in the majority of children’s hospitals.^4,5 Several innovations in these systems will be context-dependent and hence best first evaluated in a single center, where arrests outside of the intensive care unit (ICU) may occur rarely. Identification of valid, more frequent proximal measures to arrests may better identify the risk factors for deterioration. This could potentially inform quality improvement efforts to mitigate clinical deterioration.

Bonafide et al. at the Children’s Hospital of Philadelphia developed and validated the critical deterioration event (CDE) metric, demonstrating that children who were transferred to the ICU and who received noninvasive ventilation, intubation, or vasopressor initiation within 12 hours of transfer had a >13-fold increased risk of in-hospital mortality.⁶ At Cincinnati Children’s Hospital Medical Center, an additional proximal outcome measure was developed for unrecognized clinical deterioration, now termed emergency transfers (ETs).^7-9 An ET is defined as any patient transferred to the ICU where the patient received intubation, inotropes, or three or more fluid boluses in the first hour after arrival or before transfer.⁹ Improvement science work that aimed at increasing clinician situation awareness was associated with a reduction in ETs,⁸ but the association of ETs with mortality or other healthcare utilization outcomes is unknown. The objective of this study was to determine the predictive validity of an ET on in-hospital mortality, ICU length of stay (LOS), and overall hospital LOS.

We conducted a case–control study at Cincinnati Children’s Hospital, a free-standing tertiary care children’s hospital. Our center has had an ICU-based RRS in place since 2005. In 2009, we eliminated the ICU consult such that each floor-to-ICU transfer is evaluated by the RRS. Nurses calculate a Monaghan PEWS every four hours on the majority of nursing units.

Patients of all ages cared for outside of the ICU at any point in their hospitalization from January 1, 2013, to July 31, 2017, were eligible for inclusion. There were no other exclusion criteria. The ICU included both the pediatric ICU and the cardiac ICU.

Cases

We identified all ET cases from an existing situation awareness database in which each RRS call is entered by the hospital nursing supervisor, whose role includes responding to each RRS activation. If the patient transfer meets the ET criteria, the nurse indicates this in the database. Each ET entry is later confirmed for assurance purposes by the nurse leader of the RRS committee (RG). For the purposes of this study, all records were again reviewed and validated using manual chart review in the electronic health record (Epic Systems, Verona, Wisconsin).

Controls

We identified nonemergent ICU transfers to serve as controls and matched those to ET in cases to limit the impact of confounders that may increase the likelihood of both an ET and a negative outcome such as ICU mortality. We identified up to three controls for each case from our database and matched in terms of age group (within five years of age), hospital unit before transfer, and time of year (within three months of ET). These variables were chosen to adjust for the impact of age, diversity of disease (as hospital units are generally organized by organ system of illness), and seasonality on outcomes.

Outcome Measures

Posttransfer LOS in the ICU, posttransfer hospital LOS, and in-hospital mortality were the primary outcome measures. Patient demographics, specific diagnoses, and number of medical conditions were a priori defined as covariates of interest. Data for each case and control were entered into a secure, web-based Research Electronic Data Capture (REDCap) database.

Analysis

Descriptive data were summarized using counts and percentages for categorical variables and medians and ranges for continuous variables due to nonnormal distributions. Chi-square test was used to compare in-hospital mortality between the ETs and the controls. The Wilcoxon rank-sum test was used to compare LOS between ETs and controls. All data analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).

A total of 45 ETs were identified, and 110 controls were matched. Patient demographics were similar among all cases and controls (P > .05). Patients with ETs had a median age of seven years (interquartile range: 3-18 years), and 51% of them were males. The majority of patients among our examined cases were white (68%) and non-Hispanic (93%). There was no statistical difference in insurance between the ETs and the controls. When evaluating the hospital unit before the transfer, ETs occurred most commonly in the Cardiology (22%), Hematology/Oncology (22%), and Neuroscience (16%) units.

ETs stayed longer in the ICU than non-ETs [median of 4.9 days vs 2.2 days, P = .001; Figure (A)]. Similarly, ET cases had a significantly longer posttransfer hospital LOS [median of 35 days vs 21 days, P = .001; Figure (B)]. ETs had a 22% in-hospital mortality rate, compared with 9% in-hospital mortality in the matched controls (P = .02; Table).

Children who experienced an ET had a significantly longer ICU LOS, a longer posttransfer LOS, and a higher in-hospital mortality than the matched controls who were also transferred to the ICU. Researchers and improvement science teams at multiple hospitals have demonstrated that interventions targeting improved situation awareness can reduce ETs; we have demonstrated that reducing ETs may reduce subsequent adverse outcomes.^8,10

These findings provide additional support for the use of the ET metric in children’s hospitals as a proximal measure for significant clinical deterioration. We found mortality rates that were overall high for a children’s hospital (22% in ET cases and 9% among controls) compared with a national average mortality rate of 2.3% in pediatric ICUs.¹¹ This is likely due to the study sample containing a significant proportion of children with medical complexity.

Aoki et al. recently demonstrated that ETs, compared with non-ETs, were associated with longer LOS and higher mortality in a bivariate analysis.¹² In our study, we found similar results with the important addition that these findings were robust when ETs were compared with matched controls who were likely at a higher risk of poor outcomes than ICU transfers in general. In addition, we demonstrated that ETs were associated with adverse outcomes in a United States children’s hospital with a mature, long-standing RRS process. As ETs are considerably more common than cardiac and respiratory arrests, use of the ET metric in children’s hospitals may enable more rapid learning and systems improvement implementations. We also found that most of the children with ETs present from units that care for children with substantial medical complexity, including Cardiology, Hematology/Oncology, and Neurosciences. Future work should continue to examine the relationship between medical complexity and ET risk.

The ET metric is complementary to the CDE measure developed by Bonafide et al. Both metrics capture potential events of unrecognized clinical deterioration, and both offer researchers the opportunity to better understand and improve their RRSs. Both ETs and CDEs are more common than arrests, and CDEs are more common than ETs. ETs, which by definition occur in the first hour of ICU care, are likely a more specific measure of unrecognized clinical deterioration. CDEs will capture therapies that may have been started up to 12 hours after transfer and thus are possibly more sensitive to identify unrecognized clinical deterioration. However, CDEs also may encompass some patients who arrived at the ICU after prompt recognition and then had a subacute deterioration in the ICU.

The maturity of the RRS and the bandwidth of teams to collect data may inform which metric(s) are best for individual centers. As ETs are less common and likely more specific to unrecognized clinical deterioration, they might be the first tracked as a center improves its RRS through QI methods. Alternatively, CDEs may be a useful metric for centers where unrecognized clinical deterioration is less common or in research studies where this more common outcome would lead to more power to detect the effect of interventions to improve care.

Our study had several limitations. Data collection was confined to one tertiary care children’s hospital with a high burden of complex cardiac and oncology care. The results may not generalize well to children hospitalized in smaller or community hospitals or in hospitals without a mature RRS. There is also the possibility of misclassification of covariates and outcomes, but any misclassification would likely be nondifferential and bias toward the null. Matching was not possible based on exact diagnosis, and the unit is a good but imperfect proxy for diagnosis grouping. At our center, overflow of patients into the Cardiology and Hematology/Oncology units is uncommon, mitigating this partially, although residual confounding may remain. The finding that ETs are associated with adverse outcomes does not necessarily mean that these events were preventable; however, it is important and encouraging that the rate of ETs has been reduced at two centers using improvement science interventions.^8,10

Patients who experienced an ET had a significantly higher likelihood of in-hospital mortality, spent more time in the ICU, and had a longer hospital LOS posttransfer than matched controls. The use of the ET metric in children’s hospitals would allow for further analysis of such patients in hopes of identifying clinical characteristics that serve as predictors of deterioration. This may facilitate better risk stratification in the clinical system as well as enable more rapid learning and systems improvements targeted toward preventing unrecognized clinical deterioration.

Disclosures

Dr. Hussain, Dr. Sosa, Dr. Ambroggio, and Mrs. Gallagher have nothing to disclose. Patrick Brady reports grants from the Agency for Healthcare Research and Quality, outside the submitted work. The authors certify that this submission is not under review by any other publication. The author team has no conflicts of interest to disclose.

Funding

Ms. Hussain was supported by the Society of Hospital Medicine’s Student Hospitalist Scholar Grant Program in 2017. Dr. Brady receives career development support from AHRQ K08-HS023827. The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the SHM, AHRQ, or NIH.

Unrecognized in-hospital deterioration can result in tragic consequences for pediatric patients. The majority of deterioration events have antecedents such as increasingly abnormal vital signs and new concerns from nurses.¹ Recent meta-analyses have shown that rapid response systems (RRSs), which include trigger mechanisms such as a pediatric early warning score (PEWS), are associated with a reduced rate of arrests and in-hospital mortality.^2,3 Cardiopulmonary arrest rates are useful metrics to judge the effectiveness of the system to identify and respond to deteriorating adult patients; however, there are important challenges to their use as an outcome measure in pediatrics. Arrests, which have been relatively uncommon in pediatric patients, are now even less frequent since the adoption of a RRS in the majority of children’s hospitals.^4,5 Several innovations in these systems will be context-dependent and hence best first evaluated in a single center, where arrests outside of the intensive care unit (ICU) may occur rarely. Identification of valid, more frequent proximal measures to arrests may better identify the risk factors for deterioration. This could potentially inform quality improvement efforts to mitigate clinical deterioration.

Bonafide et al. at the Children’s Hospital of Philadelphia developed and validated the critical deterioration event (CDE) metric, demonstrating that children who were transferred to the ICU and who received noninvasive ventilation, intubation, or vasopressor initiation within 12 hours of transfer had a >13-fold increased risk of in-hospital mortality.⁶ At Cincinnati Children’s Hospital Medical Center, an additional proximal outcome measure was developed for unrecognized clinical deterioration, now termed emergency transfers (ETs).^7-9 An ET is defined as any patient transferred to the ICU where the patient received intubation, inotropes, or three or more fluid boluses in the first hour after arrival or before transfer.⁹ Improvement science work that aimed at increasing clinician situation awareness was associated with a reduction in ETs,⁸ but the association of ETs with mortality or other healthcare utilization outcomes is unknown. The objective of this study was to determine the predictive validity of an ET on in-hospital mortality, ICU length of stay (LOS), and overall hospital LOS.

We conducted a case–control study at Cincinnati Children’s Hospital, a free-standing tertiary care children’s hospital. Our center has had an ICU-based RRS in place since 2005. In 2009, we eliminated the ICU consult such that each floor-to-ICU transfer is evaluated by the RRS. Nurses calculate a Monaghan PEWS every four hours on the majority of nursing units.

Patients of all ages cared for outside of the ICU at any point in their hospitalization from January 1, 2013, to July 31, 2017, were eligible for inclusion. There were no other exclusion criteria. The ICU included both the pediatric ICU and the cardiac ICU.

Cases

We identified all ET cases from an existing situation awareness database in which each RRS call is entered by the hospital nursing supervisor, whose role includes responding to each RRS activation. If the patient transfer meets the ET criteria, the nurse indicates this in the database. Each ET entry is later confirmed for assurance purposes by the nurse leader of the RRS committee (RG). For the purposes of this study, all records were again reviewed and validated using manual chart review in the electronic health record (Epic Systems, Verona, Wisconsin).

Controls

We identified nonemergent ICU transfers to serve as controls and matched those to ET in cases to limit the impact of confounders that may increase the likelihood of both an ET and a negative outcome such as ICU mortality. We identified up to three controls for each case from our database and matched in terms of age group (within five years of age), hospital unit before transfer, and time of year (within three months of ET). These variables were chosen to adjust for the impact of age, diversity of disease (as hospital units are generally organized by organ system of illness), and seasonality on outcomes.

Outcome Measures

Posttransfer LOS in the ICU, posttransfer hospital LOS, and in-hospital mortality were the primary outcome measures. Patient demographics, specific diagnoses, and number of medical conditions were a priori defined as covariates of interest. Data for each case and control were entered into a secure, web-based Research Electronic Data Capture (REDCap) database.

Analysis

Descriptive data were summarized using counts and percentages for categorical variables and medians and ranges for continuous variables due to nonnormal distributions. Chi-square test was used to compare in-hospital mortality between the ETs and the controls. The Wilcoxon rank-sum test was used to compare LOS between ETs and controls. All data analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).

A total of 45 ETs were identified, and 110 controls were matched. Patient demographics were similar among all cases and controls (P > .05). Patients with ETs had a median age of seven years (interquartile range: 3-18 years), and 51% of them were males. The majority of patients among our examined cases were white (68%) and non-Hispanic (93%). There was no statistical difference in insurance between the ETs and the controls. When evaluating the hospital unit before the transfer, ETs occurred most commonly in the Cardiology (22%), Hematology/Oncology (22%), and Neuroscience (16%) units.

ETs stayed longer in the ICU than non-ETs [median of 4.9 days vs 2.2 days, P = .001; Figure (A)]. Similarly, ET cases had a significantly longer posttransfer hospital LOS [median of 35 days vs 21 days, P = .001; Figure (B)]. ETs had a 22% in-hospital mortality rate, compared with 9% in-hospital mortality in the matched controls (P = .02; Table).

Children who experienced an ET had a significantly longer ICU LOS, a longer posttransfer LOS, and a higher in-hospital mortality than the matched controls who were also transferred to the ICU. Researchers and improvement science teams at multiple hospitals have demonstrated that interventions targeting improved situation awareness can reduce ETs; we have demonstrated that reducing ETs may reduce subsequent adverse outcomes.^8,10

These findings provide additional support for the use of the ET metric in children’s hospitals as a proximal measure for significant clinical deterioration. We found mortality rates that were overall high for a children’s hospital (22% in ET cases and 9% among controls) compared with a national average mortality rate of 2.3% in pediatric ICUs.¹¹ This is likely due to the study sample containing a significant proportion of children with medical complexity.

Aoki et al. recently demonstrated that ETs, compared with non-ETs, were associated with longer LOS and higher mortality in a bivariate analysis.¹² In our study, we found similar results with the important addition that these findings were robust when ETs were compared with matched controls who were likely at a higher risk of poor outcomes than ICU transfers in general. In addition, we demonstrated that ETs were associated with adverse outcomes in a United States children’s hospital with a mature, long-standing RRS process. As ETs are considerably more common than cardiac and respiratory arrests, use of the ET metric in children’s hospitals may enable more rapid learning and systems improvement implementations. We also found that most of the children with ETs present from units that care for children with substantial medical complexity, including Cardiology, Hematology/Oncology, and Neurosciences. Future work should continue to examine the relationship between medical complexity and ET risk.

The ET metric is complementary to the CDE measure developed by Bonafide et al. Both metrics capture potential events of unrecognized clinical deterioration, and both offer researchers the opportunity to better understand and improve their RRSs. Both ETs and CDEs are more common than arrests, and CDEs are more common than ETs. ETs, which by definition occur in the first hour of ICU care, are likely a more specific measure of unrecognized clinical deterioration. CDEs will capture therapies that may have been started up to 12 hours after transfer and thus are possibly more sensitive to identify unrecognized clinical deterioration. However, CDEs also may encompass some patients who arrived at the ICU after prompt recognition and then had a subacute deterioration in the ICU.

The maturity of the RRS and the bandwidth of teams to collect data may inform which metric(s) are best for individual centers. As ETs are less common and likely more specific to unrecognized clinical deterioration, they might be the first tracked as a center improves its RRS through QI methods. Alternatively, CDEs may be a useful metric for centers where unrecognized clinical deterioration is less common or in research studies where this more common outcome would lead to more power to detect the effect of interventions to improve care.

Our study had several limitations. Data collection was confined to one tertiary care children’s hospital with a high burden of complex cardiac and oncology care. The results may not generalize well to children hospitalized in smaller or community hospitals or in hospitals without a mature RRS. There is also the possibility of misclassification of covariates and outcomes, but any misclassification would likely be nondifferential and bias toward the null. Matching was not possible based on exact diagnosis, and the unit is a good but imperfect proxy for diagnosis grouping. At our center, overflow of patients into the Cardiology and Hematology/Oncology units is uncommon, mitigating this partially, although residual confounding may remain. The finding that ETs are associated with adverse outcomes does not necessarily mean that these events were preventable; however, it is important and encouraging that the rate of ETs has been reduced at two centers using improvement science interventions.^8,10

Patients who experienced an ET had a significantly higher likelihood of in-hospital mortality, spent more time in the ICU, and had a longer hospital LOS posttransfer than matched controls. The use of the ET metric in children’s hospitals would allow for further analysis of such patients in hopes of identifying clinical characteristics that serve as predictors of deterioration. This may facilitate better risk stratification in the clinical system as well as enable more rapid learning and systems improvements targeted toward preventing unrecognized clinical deterioration.

Disclosures

Dr. Hussain, Dr. Sosa, Dr. Ambroggio, and Mrs. Gallagher have nothing to disclose. Patrick Brady reports grants from the Agency for Healthcare Research and Quality, outside the submitted work. The authors certify that this submission is not under review by any other publication. The author team has no conflicts of interest to disclose.

Funding

Ms. Hussain was supported by the Society of Hospital Medicine’s Student Hospitalist Scholar Grant Program in 2017. Dr. Brady receives career development support from AHRQ K08-HS023827. The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the SHM, AHRQ, or NIH.

Recently released guidelines on safe opioid prescribing draw attention to the fact that physicians have the ability to curb the opioid epidemic through better adherence to prescribing guidelines and limiting opioid use when not clinically indicated.^1,2 A consensus statement from the Society of Hospital Medicine includes 16 recommendations for improving the safety of opioid use in hospitalized patients, one of which is to use the oral route of administration whenever possible, reserving intravenous (IV) administration for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal (GI) malabsorption, or when immediate pain control and/or rapid dose titration is necessary.² This recommendation was based on an increased risk of side effects, adverse events, and medication errors with IV compared with oral formulations.^3-5 Furthermore, the reinforcement from opioids is inversely related to the rate of onset of action, and therefore opioids administered by an IV route may be more likely to lead to addiction.^6-8

Choosing oral over IV opioids has several additional advantages. The cost of the IV formulation is more than oral; at our institution, the cost of IV morphine is 2.5-4.6 times greater than oral. Additional costs associated with IV administration include nursing time and equipment. Overall, transitioning patients from IV to oral medications could considerably lower costs of care.⁹ Ongoing need for an IV line may also lead to avoidable complications, including patient discomfort, infection, and thrombophlebitis. In addition, the recent national shortage of IV opioids has necessitated better stewardship of IV opioids.

Despite this recommendation, our observations suggest that patients often continue receiving IV opioids longer than clinically indicated. The goal of this study was to identify the incidence of potentially inappropriate IV opioid use in hospitalized patients.

The present study was an observational study seeking to quantify the burden of potentially inappropriate IV opioid use and characteristics predicting potentially inappropriate use in the inpatient setting at a large academic medical center in Boston, Massachusetts, using retrospective review of medical records.

Definition of Potentially Inappropriate Use and Study Sample

We identified all hospitalizations during the month of February 2017 with any order for IV opioids using pharmacy charge data and performed chart reviews in this sample until we reached our prespecified study sample of 200 hospitalizations meeting inclusion/exclusion criteria further defined below.

We defined potentially inappropriate use of IV opioids as use of IV opioids for greater than 24 hours in a patient who could receive oral medications (evidenced by receipt of other orally administered medications during the same 24-hour period) and was not mechanically ventilated. This definition is consistent with recommendations in the recently released consensus statement from the Society of Hospital Medicine.² We selected a time frame of 24 hours because IV pain medications may be indicated for initial immediate pain control and rapid dose titration; however, 24 hours should be sufficient time to determine opioid needs and transition to an oral regimen in patients without contraindications. After an initial IV dose, additional IV doses within 24 hours were considered appropriate, whereas IV doses thereafter were considered potentially inappropriate unless the patient had nil per os status, including medications. All IV opioids administered within 24 hours of a surgery or procedure were considered appropriate. Because it may be appropriate to continue IV opioids beyond 24 hours in patients with an active cancer diagnosis, in patients who have chosen comfort measures only, or in patients with GI dysfunction (including conditions such as small bowel obstruction, colitis, pancreatitis), we excluded these populations from the study sample. Patients admitted to the hospital for less than 24 hours were also excluded from the study, because they would not be at risk for the outcome of potentially inappropriate use. Doses of IV opioids administered for respiratory distress were considered to be appropriate. Given difficulty in identifying the appropriate time to transition from patient-controlled analgesia (PCA) to IV or per os (PO) opioids, days spent receiving opioids by PCA or continuous IV drip were excluded from the analysis.

We used Fisher’s exact test or the Chi-square test (in the setting of a multicategory variable) to calculate bivariable P values. We used multivariable logistic regression to identify independent predictors of receipt of at least one dose of potentially inappropriate IV opioids, using the hospitalization as the unit of analysis.

Of 630 hospitalizations with at least one order for IV opioids over a one-month period, we reviewed 502 charts, from which we excluded 76 hospitalizations with an active cancer diagnosis, 30 with comfort-focused care, 115 with GI dysfunction, and 108 with a hospitalization less than 24 hours in duration, resulting in 200 hospitalizations included in this analysis (some patients met multiple exclusion criteria). Table 1 outlines characteristics of the study population, stratified by appropriateness of IV opioid use. The study population was predominately white and had an average age of 56.3 years. The majority of patients were on a surgical service. Hydromorphone was the most commonly administered opioid. There were significant differences in the percentage of doses considered inappropriate between different types of opioids (P < .001), with morphine having the highest proportion of doses considered potentially inappropriate (Table 2).

Thirty-one percent of the cohort was administered at least one potentially inappropriate dose of IV opioids. A total of 432 of 1,319 (33%) IV doses were considered potentially inappropriate.

Predictors of Potentially Inappropriate Use

No significant associations were observed between potentially inappropriate IV opioid administration and age, sex, or admitting service (Table 1). Patients with an ethnicity described as other, unknown, or declined were less likely to have potentially inappropriate use.

In this cohort of medical and surgical inpatients, we found that almost one-third received at least one potentially inappropriate IV opioid administration during their hospitalization, and one-third of all IV opioid administrations were potentially inappropriate based on current recommendations defining the appropriate use of IV versus oral opioids. Although this is a single-center analysis, to our knowledge, this is the first study to ascertain the rate of potentially inappropriate IV opioid administration in hospitalized patients. Our findings suggest that quality improvement initiatives are necessary to promote more guideline-concordant care in this realm.

Several factors may contribute to overuse. Requests from patients for immediate pain relief may at times drive prescription of the IV formulation. In addition, patients may expect the IV formulation because of precedents from prior interactions with the healthcare system. Both of these situations may be opportunities for patient education about the equivalent bioavailability of oral and IV formulations in patients with a functioning GI tract, as well as the relatively small difference in rate of onset between the two routes of administration (generally 15-20 minutes). When a patient’s pain is well controlled with IV medications, physicians may also fail to recognize the need to transition to PO medications, further prolonging unnecessary use. Finally, in patients with multiple, complex, or deteriorating medical conditions, transitioning to oral opioids may be deprioritized for the sake of addressing more urgent medical concerns.

This study highlights the potential for transitioning more patients to oral opioids, which should be feasible in the inpatient setting, where pain needs can often be anticipated in advance and oral medications can be administered earlier to overcome the short delay in the onset of action between the oral and IV routes. Oral medications also have the advantage of a longer duration of effect, which may provide overall improved pain control. At our institution, a recent shortage of IV opioids (which occurred after the data collection period for this study) and subsequent efforts to limit IV opioid use (via computerized prompts and active pharmacist consultation) resulted in an immediate 50% reduction in the daily number of IV opioid administrations, further supporting our conclusion that there is an opportunity to decrease inappropriate use of IV opioids.

There were no specific patient factors that contributed to potentially inappropriate use. Although the ethnicity category of other/unknown/declined was significantly less likely to receive opioids potentially inappropriately, given the heterogeneity of this group, it is difficult to draw conclusions on the clinical significance of this finding. Morphine was significantly more likely than other opioids to be administered inappropriately.

There are several limitations of this study. Because this was a retrospective review, our criteria for appropriate use may have resulted in some misclassification; as a result, we can comment only on potentially inappropriate use rather than on definitively inappropriate use. We attempted to use a conservative definition of appropriateness by automatically assuming all doses in the first 24 hours of administration to be appropriate, which could have resulted in underestimating potentially inappropriate use. Nonetheless, there may be instances in which a patient had suspected malabsorption that was not captured or a fluctuating ability to receive oral medications within a given 24-hour period (due to nausea, for example), resulting in outcome misclassification. In addition, we did not correlate findings with patient-reported pain scores. Because there is no clearly defined pain threshold at which IV opioids are indicated, we did not believe that would be useful in clarifying appropriate versus inappropriate use. That said, we believe that, most of the time, pain medications should be able to be titrated appropriately within 24 hours to avoid the need for immediate pain relief with IV opioids thereafter. Although there may be instances of patients who have breakthrough pain severe enough to require IV opioids despite adequate titration of oral medications, we believe this is likely to represent a small number of our population that received potentially inappropriate use. It is worth noting that even if we overestimated by 50%, such that the true rate of potentially inappropriate IV administrations is 15%, we believe this would still be a ripe target for quality improvement initiatives, given that tens of millions of hospitalized patients receive opioids each year in the United States.¹⁰ Finally, we were unable to quantify the number of providers involved in decision making for these patients, and the single-center nature and short time frame of the study limit generalizability; our analysis should be replicated at other hospitals.

In conclusion, in this sample of 200 medical and surgical hospitalizations receiving IV opioids at a large academic medical center, we identified potentially inappropriate IV administration in 31%, suggesting potential to improve value through improving prescribing practices.

Disclosures

None of the authors have conflicts to disclose.

Funding

Dr. Herzig is funded by grant number K23AG042459 from the National Institute on Aging and R01HS026215 from the Agency for Healthcare Research and Quality. The manuscript contents are solely the responsibility of the authors and do not necessarily represent the views of the funding organizations.

Recently released guidelines on safe opioid prescribing draw attention to the fact that physicians have the ability to curb the opioid epidemic through better adherence to prescribing guidelines and limiting opioid use when not clinically indicated.^1,2 A consensus statement from the Society of Hospital Medicine includes 16 recommendations for improving the safety of opioid use in hospitalized patients, one of which is to use the oral route of administration whenever possible, reserving intravenous (IV) administration for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal (GI) malabsorption, or when immediate pain control and/or rapid dose titration is necessary.² This recommendation was based on an increased risk of side effects, adverse events, and medication errors with IV compared with oral formulations.^3-5 Furthermore, the reinforcement from opioids is inversely related to the rate of onset of action, and therefore opioids administered by an IV route may be more likely to lead to addiction.^6-8

Choosing oral over IV opioids has several additional advantages. The cost of the IV formulation is more than oral; at our institution, the cost of IV morphine is 2.5-4.6 times greater than oral. Additional costs associated with IV administration include nursing time and equipment. Overall, transitioning patients from IV to oral medications could considerably lower costs of care.⁹ Ongoing need for an IV line may also lead to avoidable complications, including patient discomfort, infection, and thrombophlebitis. In addition, the recent national shortage of IV opioids has necessitated better stewardship of IV opioids.

Despite this recommendation, our observations suggest that patients often continue receiving IV opioids longer than clinically indicated. The goal of this study was to identify the incidence of potentially inappropriate IV opioid use in hospitalized patients.

The present study was an observational study seeking to quantify the burden of potentially inappropriate IV opioid use and characteristics predicting potentially inappropriate use in the inpatient setting at a large academic medical center in Boston, Massachusetts, using retrospective review of medical records.

Definition of Potentially Inappropriate Use and Study Sample

We identified all hospitalizations during the month of February 2017 with any order for IV opioids using pharmacy charge data and performed chart reviews in this sample until we reached our prespecified study sample of 200 hospitalizations meeting inclusion/exclusion criteria further defined below.

We defined potentially inappropriate use of IV opioids as use of IV opioids for greater than 24 hours in a patient who could receive oral medications (evidenced by receipt of other orally administered medications during the same 24-hour period) and was not mechanically ventilated. This definition is consistent with recommendations in the recently released consensus statement from the Society of Hospital Medicine.² We selected a time frame of 24 hours because IV pain medications may be indicated for initial immediate pain control and rapid dose titration; however, 24 hours should be sufficient time to determine opioid needs and transition to an oral regimen in patients without contraindications. After an initial IV dose, additional IV doses within 24 hours were considered appropriate, whereas IV doses thereafter were considered potentially inappropriate unless the patient had nil per os status, including medications. All IV opioids administered within 24 hours of a surgery or procedure were considered appropriate. Because it may be appropriate to continue IV opioids beyond 24 hours in patients with an active cancer diagnosis, in patients who have chosen comfort measures only, or in patients with GI dysfunction (including conditions such as small bowel obstruction, colitis, pancreatitis), we excluded these populations from the study sample. Patients admitted to the hospital for less than 24 hours were also excluded from the study, because they would not be at risk for the outcome of potentially inappropriate use. Doses of IV opioids administered for respiratory distress were considered to be appropriate. Given difficulty in identifying the appropriate time to transition from patient-controlled analgesia (PCA) to IV or per os (PO) opioids, days spent receiving opioids by PCA or continuous IV drip were excluded from the analysis.

We used Fisher’s exact test or the Chi-square test (in the setting of a multicategory variable) to calculate bivariable P values. We used multivariable logistic regression to identify independent predictors of receipt of at least one dose of potentially inappropriate IV opioids, using the hospitalization as the unit of analysis.

Of 630 hospitalizations with at least one order for IV opioids over a one-month period, we reviewed 502 charts, from which we excluded 76 hospitalizations with an active cancer diagnosis, 30 with comfort-focused care, 115 with GI dysfunction, and 108 with a hospitalization less than 24 hours in duration, resulting in 200 hospitalizations included in this analysis (some patients met multiple exclusion criteria). Table 1 outlines characteristics of the study population, stratified by appropriateness of IV opioid use. The study population was predominately white and had an average age of 56.3 years. The majority of patients were on a surgical service. Hydromorphone was the most commonly administered opioid. There were significant differences in the percentage of doses considered inappropriate between different types of opioids (P < .001), with morphine having the highest proportion of doses considered potentially inappropriate (Table 2).

Thirty-one percent of the cohort was administered at least one potentially inappropriate dose of IV opioids. A total of 432 of 1,319 (33%) IV doses were considered potentially inappropriate.

Predictors of Potentially Inappropriate Use

No significant associations were observed between potentially inappropriate IV opioid administration and age, sex, or admitting service (Table 1). Patients with an ethnicity described as other, unknown, or declined were less likely to have potentially inappropriate use.

In this cohort of medical and surgical inpatients, we found that almost one-third received at least one potentially inappropriate IV opioid administration during their hospitalization, and one-third of all IV opioid administrations were potentially inappropriate based on current recommendations defining the appropriate use of IV versus oral opioids. Although this is a single-center analysis, to our knowledge, this is the first study to ascertain the rate of potentially inappropriate IV opioid administration in hospitalized patients. Our findings suggest that quality improvement initiatives are necessary to promote more guideline-concordant care in this realm.

Several factors may contribute to overuse. Requests from patients for immediate pain relief may at times drive prescription of the IV formulation. In addition, patients may expect the IV formulation because of precedents from prior interactions with the healthcare system. Both of these situations may be opportunities for patient education about the equivalent bioavailability of oral and IV formulations in patients with a functioning GI tract, as well as the relatively small difference in rate of onset between the two routes of administration (generally 15-20 minutes). When a patient’s pain is well controlled with IV medications, physicians may also fail to recognize the need to transition to PO medications, further prolonging unnecessary use. Finally, in patients with multiple, complex, or deteriorating medical conditions, transitioning to oral opioids may be deprioritized for the sake of addressing more urgent medical concerns.

This study highlights the potential for transitioning more patients to oral opioids, which should be feasible in the inpatient setting, where pain needs can often be anticipated in advance and oral medications can be administered earlier to overcome the short delay in the onset of action between the oral and IV routes. Oral medications also have the advantage of a longer duration of effect, which may provide overall improved pain control. At our institution, a recent shortage of IV opioids (which occurred after the data collection period for this study) and subsequent efforts to limit IV opioid use (via computerized prompts and active pharmacist consultation) resulted in an immediate 50% reduction in the daily number of IV opioid administrations, further supporting our conclusion that there is an opportunity to decrease inappropriate use of IV opioids.

There were no specific patient factors that contributed to potentially inappropriate use. Although the ethnicity category of other/unknown/declined was significantly less likely to receive opioids potentially inappropriately, given the heterogeneity of this group, it is difficult to draw conclusions on the clinical significance of this finding. Morphine was significantly more likely than other opioids to be administered inappropriately.

There are several limitations of this study. Because this was a retrospective review, our criteria for appropriate use may have resulted in some misclassification; as a result, we can comment only on potentially inappropriate use rather than on definitively inappropriate use. We attempted to use a conservative definition of appropriateness by automatically assuming all doses in the first 24 hours of administration to be appropriate, which could have resulted in underestimating potentially inappropriate use. Nonetheless, there may be instances in which a patient had suspected malabsorption that was not captured or a fluctuating ability to receive oral medications within a given 24-hour period (due to nausea, for example), resulting in outcome misclassification. In addition, we did not correlate findings with patient-reported pain scores. Because there is no clearly defined pain threshold at which IV opioids are indicated, we did not believe that would be useful in clarifying appropriate versus inappropriate use. That said, we believe that, most of the time, pain medications should be able to be titrated appropriately within 24 hours to avoid the need for immediate pain relief with IV opioids thereafter. Although there may be instances of patients who have breakthrough pain severe enough to require IV opioids despite adequate titration of oral medications, we believe this is likely to represent a small number of our population that received potentially inappropriate use. It is worth noting that even if we overestimated by 50%, such that the true rate of potentially inappropriate IV administrations is 15%, we believe this would still be a ripe target for quality improvement initiatives, given that tens of millions of hospitalized patients receive opioids each year in the United States.¹⁰ Finally, we were unable to quantify the number of providers involved in decision making for these patients, and the single-center nature and short time frame of the study limit generalizability; our analysis should be replicated at other hospitals.

In conclusion, in this sample of 200 medical and surgical hospitalizations receiving IV opioids at a large academic medical center, we identified potentially inappropriate IV administration in 31%, suggesting potential to improve value through improving prescribing practices.

Disclosures

None of the authors have conflicts to disclose.

Funding

Dr. Herzig is funded by grant number K23AG042459 from the National Institute on Aging and R01HS026215 from the Agency for Healthcare Research and Quality. The manuscript contents are solely the responsibility of the authors and do not necessarily represent the views of the funding organizations.

Recently released guidelines on safe opioid prescribing draw attention to the fact that physicians have the ability to curb the opioid epidemic through better adherence to prescribing guidelines and limiting opioid use when not clinically indicated.^1,2 A consensus statement from the Society of Hospital Medicine includes 16 recommendations for improving the safety of opioid use in hospitalized patients, one of which is to use the oral route of administration whenever possible, reserving intravenous (IV) administration for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal (GI) malabsorption, or when immediate pain control and/or rapid dose titration is necessary.² This recommendation was based on an increased risk of side effects, adverse events, and medication errors with IV compared with oral formulations.^3-5 Furthermore, the reinforcement from opioids is inversely related to the rate of onset of action, and therefore opioids administered by an IV route may be more likely to lead to addiction.^6-8

Choosing oral over IV opioids has several additional advantages. The cost of the IV formulation is more than oral; at our institution, the cost of IV morphine is 2.5-4.6 times greater than oral. Additional costs associated with IV administration include nursing time and equipment. Overall, transitioning patients from IV to oral medications could considerably lower costs of care.⁹ Ongoing need for an IV line may also lead to avoidable complications, including patient discomfort, infection, and thrombophlebitis. In addition, the recent national shortage of IV opioids has necessitated better stewardship of IV opioids.

Despite this recommendation, our observations suggest that patients often continue receiving IV opioids longer than clinically indicated. The goal of this study was to identify the incidence of potentially inappropriate IV opioid use in hospitalized patients.

The present study was an observational study seeking to quantify the burden of potentially inappropriate IV opioid use and characteristics predicting potentially inappropriate use in the inpatient setting at a large academic medical center in Boston, Massachusetts, using retrospective review of medical records.

Definition of Potentially Inappropriate Use and Study Sample

We identified all hospitalizations during the month of February 2017 with any order for IV opioids using pharmacy charge data and performed chart reviews in this sample until we reached our prespecified study sample of 200 hospitalizations meeting inclusion/exclusion criteria further defined below.

We defined potentially inappropriate use of IV opioids as use of IV opioids for greater than 24 hours in a patient who could receive oral medications (evidenced by receipt of other orally administered medications during the same 24-hour period) and was not mechanically ventilated. This definition is consistent with recommendations in the recently released consensus statement from the Society of Hospital Medicine.² We selected a time frame of 24 hours because IV pain medications may be indicated for initial immediate pain control and rapid dose titration; however, 24 hours should be sufficient time to determine opioid needs and transition to an oral regimen in patients without contraindications. After an initial IV dose, additional IV doses within 24 hours were considered appropriate, whereas IV doses thereafter were considered potentially inappropriate unless the patient had nil per os status, including medications. All IV opioids administered within 24 hours of a surgery or procedure were considered appropriate. Because it may be appropriate to continue IV opioids beyond 24 hours in patients with an active cancer diagnosis, in patients who have chosen comfort measures only, or in patients with GI dysfunction (including conditions such as small bowel obstruction, colitis, pancreatitis), we excluded these populations from the study sample. Patients admitted to the hospital for less than 24 hours were also excluded from the study, because they would not be at risk for the outcome of potentially inappropriate use. Doses of IV opioids administered for respiratory distress were considered to be appropriate. Given difficulty in identifying the appropriate time to transition from patient-controlled analgesia (PCA) to IV or per os (PO) opioids, days spent receiving opioids by PCA or continuous IV drip were excluded from the analysis.

We used Fisher’s exact test or the Chi-square test (in the setting of a multicategory variable) to calculate bivariable P values. We used multivariable logistic regression to identify independent predictors of receipt of at least one dose of potentially inappropriate IV opioids, using the hospitalization as the unit of analysis.

Of 630 hospitalizations with at least one order for IV opioids over a one-month period, we reviewed 502 charts, from which we excluded 76 hospitalizations with an active cancer diagnosis, 30 with comfort-focused care, 115 with GI dysfunction, and 108 with a hospitalization less than 24 hours in duration, resulting in 200 hospitalizations included in this analysis (some patients met multiple exclusion criteria). Table 1 outlines characteristics of the study population, stratified by appropriateness of IV opioid use. The study population was predominately white and had an average age of 56.3 years. The majority of patients were on a surgical service. Hydromorphone was the most commonly administered opioid. There were significant differences in the percentage of doses considered inappropriate between different types of opioids (P < .001), with morphine having the highest proportion of doses considered potentially inappropriate (Table 2).

Thirty-one percent of the cohort was administered at least one potentially inappropriate dose of IV opioids. A total of 432 of 1,319 (33%) IV doses were considered potentially inappropriate.

Predictors of Potentially Inappropriate Use

No significant associations were observed between potentially inappropriate IV opioid administration and age, sex, or admitting service (Table 1). Patients with an ethnicity described as other, unknown, or declined were less likely to have potentially inappropriate use.

In this cohort of medical and surgical inpatients, we found that almost one-third received at least one potentially inappropriate IV opioid administration during their hospitalization, and one-third of all IV opioid administrations were potentially inappropriate based on current recommendations defining the appropriate use of IV versus oral opioids. Although this is a single-center analysis, to our knowledge, this is the first study to ascertain the rate of potentially inappropriate IV opioid administration in hospitalized patients. Our findings suggest that quality improvement initiatives are necessary to promote more guideline-concordant care in this realm.

Several factors may contribute to overuse. Requests from patients for immediate pain relief may at times drive prescription of the IV formulation. In addition, patients may expect the IV formulation because of precedents from prior interactions with the healthcare system. Both of these situations may be opportunities for patient education about the equivalent bioavailability of oral and IV formulations in patients with a functioning GI tract, as well as the relatively small difference in rate of onset between the two routes of administration (generally 15-20 minutes). When a patient’s pain is well controlled with IV medications, physicians may also fail to recognize the need to transition to PO medications, further prolonging unnecessary use. Finally, in patients with multiple, complex, or deteriorating medical conditions, transitioning to oral opioids may be deprioritized for the sake of addressing more urgent medical concerns.

This study highlights the potential for transitioning more patients to oral opioids, which should be feasible in the inpatient setting, where pain needs can often be anticipated in advance and oral medications can be administered earlier to overcome the short delay in the onset of action between the oral and IV routes. Oral medications also have the advantage of a longer duration of effect, which may provide overall improved pain control. At our institution, a recent shortage of IV opioids (which occurred after the data collection period for this study) and subsequent efforts to limit IV opioid use (via computerized prompts and active pharmacist consultation) resulted in an immediate 50% reduction in the daily number of IV opioid administrations, further supporting our conclusion that there is an opportunity to decrease inappropriate use of IV opioids.

There were no specific patient factors that contributed to potentially inappropriate use. Although the ethnicity category of other/unknown/declined was significantly less likely to receive opioids potentially inappropriately, given the heterogeneity of this group, it is difficult to draw conclusions on the clinical significance of this finding. Morphine was significantly more likely than other opioids to be administered inappropriately.

There are several limitations of this study. Because this was a retrospective review, our criteria for appropriate use may have resulted in some misclassification; as a result, we can comment only on potentially inappropriate use rather than on definitively inappropriate use. We attempted to use a conservative definition of appropriateness by automatically assuming all doses in the first 24 hours of administration to be appropriate, which could have resulted in underestimating potentially inappropriate use. Nonetheless, there may be instances in which a patient had suspected malabsorption that was not captured or a fluctuating ability to receive oral medications within a given 24-hour period (due to nausea, for example), resulting in outcome misclassification. In addition, we did not correlate findings with patient-reported pain scores. Because there is no clearly defined pain threshold at which IV opioids are indicated, we did not believe that would be useful in clarifying appropriate versus inappropriate use. That said, we believe that, most of the time, pain medications should be able to be titrated appropriately within 24 hours to avoid the need for immediate pain relief with IV opioids thereafter. Although there may be instances of patients who have breakthrough pain severe enough to require IV opioids despite adequate titration of oral medications, we believe this is likely to represent a small number of our population that received potentially inappropriate use. It is worth noting that even if we overestimated by 50%, such that the true rate of potentially inappropriate IV administrations is 15%, we believe this would still be a ripe target for quality improvement initiatives, given that tens of millions of hospitalized patients receive opioids each year in the United States.¹⁰ Finally, we were unable to quantify the number of providers involved in decision making for these patients, and the single-center nature and short time frame of the study limit generalizability; our analysis should be replicated at other hospitals.

In conclusion, in this sample of 200 medical and surgical hospitalizations receiving IV opioids at a large academic medical center, we identified potentially inappropriate IV administration in 31%, suggesting potential to improve value through improving prescribing practices.

Disclosures

None of the authors have conflicts to disclose.

Funding

Dr. Herzig is funded by grant number K23AG042459 from the National Institute on Aging and R01HS026215 from the Agency for Healthcare Research and Quality. The manuscript contents are solely the responsibility of the authors and do not necessarily represent the views of the funding organizations.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.

No. After thoracentesis, chest radiography or another lung imaging study should be done only if pneumothorax is suspected, if thoracentesis requires more than 1 attempt, if the patient is on mechanical ventilation or has pre-existing lung disease, or if a large volume (> 1,500 mL) of fluid is removed. Radiography is also usually not necessary after diagnostic thoracentesis in a patient breathing spontaneously. In most cases, pneumothorax found incidentally after thoracentesis does not require decompression and can be managed supportively.

WHAT ARE THE RISKS OF THORACENTESIS?

Thoracentesis is a minimally invasive procedure usually performed at the bedside that involves insertion of a needle into the pleural cavity for drainage of fluid.¹ Diagnostic thoracentesis should be done in most cases of a new pleural effusion unless the effusion is small and with a clear diagnosis, or in cases of typical heart failure.

Therapeutic thoracentesis, often called large-volume thoracentesis, aims to improve symptoms such as dyspnea attributed to the pleural effusion by removing at least 1 L of pleural fluid. The presence of active respiratory symptoms and suspicion of infected pleural effusion should lead to thoracentesis as soon as possible.

Complications of thoracentesis may be benign, such as pain and anxiety associated with the procedure and external bleeding at the site of needle insertion. Pneumothorax is the most common serious procedural complication and the principal reason to order postprocedural chest radiography.¹ Less common complications include hemothorax, re-expansion pulmonary edema, infection, subdiaphragmatic organ puncture, and procedure-related death. Bleeding complications and hemothorax are rare even in patients with underlying coagulopathy.²

Point-of-care pleural ultrasonography is now considered the standard of care to guide optimal needle location for the procedure and to exclude other conditions that can mimic pleural effusion on chest radiography, such as lung consolidation and atelectasis.³ High proficiency in the use of preprocedural point-of-care ultrasonography reduces the rate of procedural complications, though it does not eliminate the risk entirely.^3,4

Factors associated with higher rates of complications include lack of operator proficiency, poor understanding of the anatomy, poor patient positioning, poor patient cooperation with the procedure, lack of availability of bedside ultrasonography, and drainage of more than 1,500 mL of fluid. Addressing these factors has been shown to decrease the risk of pneumothorax and infection.^1–5

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

Several early studies have examined the incidence of pneumothorax after thoracentesis. Lack of ultrasonography use likely explains a higher incidence of complications in early studies: rates of pneumothorax after thoracentesis without ultrasonographic guidance ranged from 5.2% to 26%.^6,7

Gervais et al⁸ analyzed thoracentesis with ultrasonographic guidance in 434 patients, 92 of whom were intubated, and reported that pneumothorax occurred in 10 patients, of whom 6 were intubated. Two of the intubated patients required chest tubes. Other studies have confirmed the low incidence of pneumothorax in patients undergoing thoracentesis, with rates such as 0.61%,¹ 5%,9 and 4%.¹⁰

The major predictor of postprocedural pneumothorax was the presence of symptoms such as chest pain and dyspnea. No intervention was necessary for most cases of pneumothorax in asymptomatic patients. The more widespread use of procedural ultrasonography may explain some discrepancies between the early^5,6 and more recent studies.^1,8–10

Several studies have demonstrated that postprocedural radiography is unnecessary unless a complication is suspected based on the patient’s symptoms or the need to demonstrate lung re-expansion.^1,4,9,10 Clinical suspicion and the patient’s symptoms are the major predictors of procedure-related pneumothorax requiring treatment with a chest tube. Otherwise, incidentally discovered pneumothorax can usually be observed and managed supportively.

Major causes of pneumothorax in patients undergoing thoracentesis are direct puncture during needle or catheter insertion, the introduction of air through the needle or catheter into the pleural cavity, and the inability of the ipsilateral lung to fully expand after drainage of a large volume of fluid, known as pneumothorax ex vacuo.⁵

Pneumothorax ex vacuo may be seen in patients with medical conditions such as endobronchial obstruction, pleural scarring from long-standing pleural effusion, and lung malignancy, all of which can impair the lung’s ability to expand after removal of a large volume of pleural fluid. It is believed that transient parenchymal pleural fistulae form if the lung cannot expand, causing air leakage into the pleural cavity.^5,8,9 Pleural manometry to monitor changes in pleural pressure and elastance can decrease the rates of pneumothorax ex vacuo in patients with the above risk factors.⁵

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

Current literature suggests that imaging to evaluate for postprocedural complications should be done if there is suspicion of a complication, if thoracentesis required multiple attempts, if the procedure caused aspiration of air, if the patient has advanced lung disease, if the patient is scheduled to undergo thoracic radiation, if the patient is on mechanical ventilation, and after therapeutic thoracentesis if a large volume of fluid is removed.^1–10 Routine chest radiography after thoracentesis is not supported in the literature in the absence of these risk factors.

Some practitioners order chest imaging after therapeutic thoracentesis to assess for residual pleural fluid and for visualization of other abnormalities previously hidden by pleural effusion, rather than simply to exclude postprocedural pneumothorax. Alternatively, postprocedural bedside pleural ultrasonography with recording of images can be done to assess for complications and residual pleural fluid volume without exposing the patient to radiation.¹¹

Needle decompression and chest tube insertion should be considered in patients with tension pneumothorax, large pneumothorax (distance from the chest wall to the visceral pleural line of at least 2 cm), mechanical ventilation, progressing pneumothorax, and symptoms.

KEY POINTS

• Pneumothorax is a rare complication of thoracentesis when performed by a skilled operator using ultrasonographic guidance.
• Mechanisms behind the occurrence of pneumothorax are direct lung puncture, introduction of air into the pleural cavity, and pneumothorax ex vacuo.
• In asymptomatic patients, pneumothorax after thoracentesis rarely requires intervention beyond supportive care and close observation.
• Factors such as multiple thoracentesis attempts, symptoms, clinical suspicion, air aspiration during thoracentesis, presence of previous lung disease, and removal of a large volume of fluid may require postprocedural lung imaging (eg, bedside ultrasonography, radiography).

No. After thoracentesis, chest radiography or another lung imaging study should be done only if pneumothorax is suspected, if thoracentesis requires more than 1 attempt, if the patient is on mechanical ventilation or has pre-existing lung disease, or if a large volume (> 1,500 mL) of fluid is removed. Radiography is also usually not necessary after diagnostic thoracentesis in a patient breathing spontaneously. In most cases, pneumothorax found incidentally after thoracentesis does not require decompression and can be managed supportively.

WHAT ARE THE RISKS OF THORACENTESIS?

Thoracentesis is a minimally invasive procedure usually performed at the bedside that involves insertion of a needle into the pleural cavity for drainage of fluid.¹ Diagnostic thoracentesis should be done in most cases of a new pleural effusion unless the effusion is small and with a clear diagnosis, or in cases of typical heart failure.

Therapeutic thoracentesis, often called large-volume thoracentesis, aims to improve symptoms such as dyspnea attributed to the pleural effusion by removing at least 1 L of pleural fluid. The presence of active respiratory symptoms and suspicion of infected pleural effusion should lead to thoracentesis as soon as possible.

Complications of thoracentesis may be benign, such as pain and anxiety associated with the procedure and external bleeding at the site of needle insertion. Pneumothorax is the most common serious procedural complication and the principal reason to order postprocedural chest radiography.¹ Less common complications include hemothorax, re-expansion pulmonary edema, infection, subdiaphragmatic organ puncture, and procedure-related death. Bleeding complications and hemothorax are rare even in patients with underlying coagulopathy.²

Point-of-care pleural ultrasonography is now considered the standard of care to guide optimal needle location for the procedure and to exclude other conditions that can mimic pleural effusion on chest radiography, such as lung consolidation and atelectasis.³ High proficiency in the use of preprocedural point-of-care ultrasonography reduces the rate of procedural complications, though it does not eliminate the risk entirely.^3,4

Factors associated with higher rates of complications include lack of operator proficiency, poor understanding of the anatomy, poor patient positioning, poor patient cooperation with the procedure, lack of availability of bedside ultrasonography, and drainage of more than 1,500 mL of fluid. Addressing these factors has been shown to decrease the risk of pneumothorax and infection.^1–5

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

Several early studies have examined the incidence of pneumothorax after thoracentesis. Lack of ultrasonography use likely explains a higher incidence of complications in early studies: rates of pneumothorax after thoracentesis without ultrasonographic guidance ranged from 5.2% to 26%.^6,7

Gervais et al⁸ analyzed thoracentesis with ultrasonographic guidance in 434 patients, 92 of whom were intubated, and reported that pneumothorax occurred in 10 patients, of whom 6 were intubated. Two of the intubated patients required chest tubes. Other studies have confirmed the low incidence of pneumothorax in patients undergoing thoracentesis, with rates such as 0.61%,¹ 5%,9 and 4%.¹⁰

The major predictor of postprocedural pneumothorax was the presence of symptoms such as chest pain and dyspnea. No intervention was necessary for most cases of pneumothorax in asymptomatic patients. The more widespread use of procedural ultrasonography may explain some discrepancies between the early^5,6 and more recent studies.^1,8–10

Several studies have demonstrated that postprocedural radiography is unnecessary unless a complication is suspected based on the patient’s symptoms or the need to demonstrate lung re-expansion.^1,4,9,10 Clinical suspicion and the patient’s symptoms are the major predictors of procedure-related pneumothorax requiring treatment with a chest tube. Otherwise, incidentally discovered pneumothorax can usually be observed and managed supportively.

Major causes of pneumothorax in patients undergoing thoracentesis are direct puncture during needle or catheter insertion, the introduction of air through the needle or catheter into the pleural cavity, and the inability of the ipsilateral lung to fully expand after drainage of a large volume of fluid, known as pneumothorax ex vacuo.⁵

Pneumothorax ex vacuo may be seen in patients with medical conditions such as endobronchial obstruction, pleural scarring from long-standing pleural effusion, and lung malignancy, all of which can impair the lung’s ability to expand after removal of a large volume of pleural fluid. It is believed that transient parenchymal pleural fistulae form if the lung cannot expand, causing air leakage into the pleural cavity.^5,8,9 Pleural manometry to monitor changes in pleural pressure and elastance can decrease the rates of pneumothorax ex vacuo in patients with the above risk factors.⁵

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

Current literature suggests that imaging to evaluate for postprocedural complications should be done if there is suspicion of a complication, if thoracentesis required multiple attempts, if the procedure caused aspiration of air, if the patient has advanced lung disease, if the patient is scheduled to undergo thoracic radiation, if the patient is on mechanical ventilation, and after therapeutic thoracentesis if a large volume of fluid is removed.^1–10 Routine chest radiography after thoracentesis is not supported in the literature in the absence of these risk factors.

Some practitioners order chest imaging after therapeutic thoracentesis to assess for residual pleural fluid and for visualization of other abnormalities previously hidden by pleural effusion, rather than simply to exclude postprocedural pneumothorax. Alternatively, postprocedural bedside pleural ultrasonography with recording of images can be done to assess for complications and residual pleural fluid volume without exposing the patient to radiation.¹¹

Needle decompression and chest tube insertion should be considered in patients with tension pneumothorax, large pneumothorax (distance from the chest wall to the visceral pleural line of at least 2 cm), mechanical ventilation, progressing pneumothorax, and symptoms.

KEY POINTS

• Pneumothorax is a rare complication of thoracentesis when performed by a skilled operator using ultrasonographic guidance.
• Mechanisms behind the occurrence of pneumothorax are direct lung puncture, introduction of air into the pleural cavity, and pneumothorax ex vacuo.
• In asymptomatic patients, pneumothorax after thoracentesis rarely requires intervention beyond supportive care and close observation.
• Factors such as multiple thoracentesis attempts, symptoms, clinical suspicion, air aspiration during thoracentesis, presence of previous lung disease, and removal of a large volume of fluid may require postprocedural lung imaging (eg, bedside ultrasonography, radiography).

No. After thoracentesis, chest radiography or another lung imaging study should be done only if pneumothorax is suspected, if thoracentesis requires more than 1 attempt, if the patient is on mechanical ventilation or has pre-existing lung disease, or if a large volume (> 1,500 mL) of fluid is removed. Radiography is also usually not necessary after diagnostic thoracentesis in a patient breathing spontaneously. In most cases, pneumothorax found incidentally after thoracentesis does not require decompression and can be managed supportively.

WHAT ARE THE RISKS OF THORACENTESIS?

Thoracentesis is a minimally invasive procedure usually performed at the bedside that involves insertion of a needle into the pleural cavity for drainage of fluid.¹ Diagnostic thoracentesis should be done in most cases of a new pleural effusion unless the effusion is small and with a clear diagnosis, or in cases of typical heart failure.

Therapeutic thoracentesis, often called large-volume thoracentesis, aims to improve symptoms such as dyspnea attributed to the pleural effusion by removing at least 1 L of pleural fluid. The presence of active respiratory symptoms and suspicion of infected pleural effusion should lead to thoracentesis as soon as possible.

Complications of thoracentesis may be benign, such as pain and anxiety associated with the procedure and external bleeding at the site of needle insertion. Pneumothorax is the most common serious procedural complication and the principal reason to order postprocedural chest radiography.¹ Less common complications include hemothorax, re-expansion pulmonary edema, infection, subdiaphragmatic organ puncture, and procedure-related death. Bleeding complications and hemothorax are rare even in patients with underlying coagulopathy.²

Point-of-care pleural ultrasonography is now considered the standard of care to guide optimal needle location for the procedure and to exclude other conditions that can mimic pleural effusion on chest radiography, such as lung consolidation and atelectasis.³ High proficiency in the use of preprocedural point-of-care ultrasonography reduces the rate of procedural complications, though it does not eliminate the risk entirely.^3,4

Factors associated with higher rates of complications include lack of operator proficiency, poor understanding of the anatomy, poor patient positioning, poor patient cooperation with the procedure, lack of availability of bedside ultrasonography, and drainage of more than 1,500 mL of fluid. Addressing these factors has been shown to decrease the risk of pneumothorax and infection.^1–5

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

Several early studies have examined the incidence of pneumothorax after thoracentesis. Lack of ultrasonography use likely explains a higher incidence of complications in early studies: rates of pneumothorax after thoracentesis without ultrasonographic guidance ranged from 5.2% to 26%.^6,7

Gervais et al⁸ analyzed thoracentesis with ultrasonographic guidance in 434 patients, 92 of whom were intubated, and reported that pneumothorax occurred in 10 patients, of whom 6 were intubated. Two of the intubated patients required chest tubes. Other studies have confirmed the low incidence of pneumothorax in patients undergoing thoracentesis, with rates such as 0.61%,¹ 5%,9 and 4%.¹⁰

The major predictor of postprocedural pneumothorax was the presence of symptoms such as chest pain and dyspnea. No intervention was necessary for most cases of pneumothorax in asymptomatic patients. The more widespread use of procedural ultrasonography may explain some discrepancies between the early^5,6 and more recent studies.^1,8–10

Several studies have demonstrated that postprocedural radiography is unnecessary unless a complication is suspected based on the patient’s symptoms or the need to demonstrate lung re-expansion.^1,4,9,10 Clinical suspicion and the patient’s symptoms are the major predictors of procedure-related pneumothorax requiring treatment with a chest tube. Otherwise, incidentally discovered pneumothorax can usually be observed and managed supportively.

Major causes of pneumothorax in patients undergoing thoracentesis are direct puncture during needle or catheter insertion, the introduction of air through the needle or catheter into the pleural cavity, and the inability of the ipsilateral lung to fully expand after drainage of a large volume of fluid, known as pneumothorax ex vacuo.⁵

Pneumothorax ex vacuo may be seen in patients with medical conditions such as endobronchial obstruction, pleural scarring from long-standing pleural effusion, and lung malignancy, all of which can impair the lung’s ability to expand after removal of a large volume of pleural fluid. It is believed that transient parenchymal pleural fistulae form if the lung cannot expand, causing air leakage into the pleural cavity.^5,8,9 Pleural manometry to monitor changes in pleural pressure and elastance can decrease the rates of pneumothorax ex vacuo in patients with the above risk factors.⁵

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

Current literature suggests that imaging to evaluate for postprocedural complications should be done if there is suspicion of a complication, if thoracentesis required multiple attempts, if the procedure caused aspiration of air, if the patient has advanced lung disease, if the patient is scheduled to undergo thoracic radiation, if the patient is on mechanical ventilation, and after therapeutic thoracentesis if a large volume of fluid is removed.^1–10 Routine chest radiography after thoracentesis is not supported in the literature in the absence of these risk factors.

Some practitioners order chest imaging after therapeutic thoracentesis to assess for residual pleural fluid and for visualization of other abnormalities previously hidden by pleural effusion, rather than simply to exclude postprocedural pneumothorax. Alternatively, postprocedural bedside pleural ultrasonography with recording of images can be done to assess for complications and residual pleural fluid volume without exposing the patient to radiation.¹¹

Needle decompression and chest tube insertion should be considered in patients with tension pneumothorax, large pneumothorax (distance from the chest wall to the visceral pleural line of at least 2 cm), mechanical ventilation, progressing pneumothorax, and symptoms.

KEY POINTS

• Pneumothorax is a rare complication of thoracentesis when performed by a skilled operator using ultrasonographic guidance.
• Mechanisms behind the occurrence of pneumothorax are direct lung puncture, introduction of air into the pleural cavity, and pneumothorax ex vacuo.
• In asymptomatic patients, pneumothorax after thoracentesis rarely requires intervention beyond supportive care and close observation.
• Factors such as multiple thoracentesis attempts, symptoms, clinical suspicion, air aspiration during thoracentesis, presence of previous lung disease, and removal of a large volume of fluid may require postprocedural lung imaging (eg, bedside ultrasonography, radiography).

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

“If it is true that the full humanity of women is not our culture, then we can and must make it our culture.”
—Chimamanda Ngozi Adichie

A young boy is on the way home from soccer when a driver hits his car head-on. His father dies immediately, but the boy survives. The boy is transported to the hospital and immediately rushed into the OR. The surgeon takes one look at him and says, “I can’t operate on this patient. He’s my son!” The riddle asks: If the father is dead, who is the surgeon?

Struggling to realize that the surgeon is a mom highlights the depth of gender bias in medicine. Gender bias leads to inequities which are magnified when compounded with differences in race, ethnicity, sexual orientation, gender identity and/or socioeconomic status. The recent National Academies report described the toll of gender inequities, including sexual harassment, and their impact on women in medicine.¹ But like this riddle, the focus was directed towards those at the top of the hierarchy: physicians. It is undeniable that women physicians suffer the effects of inequities, but why exclude other women in healthcare? For example, over 90% of nurses are female, yet male nurses make higher salaries with lower degrees.² If we only focus on physicians, we risk ignoring a problem faced by the entirety of our workforce.

Healthcare is a team sport. The practice of hospital medicine is a prime example of how each team member brings critical value. One would never be able to run an effective code without excellent nursing or successfully intubate a patient without a skilled respiratory therapist. Yet, when it comes to conversations about gender bias and sexual harassment, we rarely work together. The work of equity in healthcare must therefore become more like a lattice than a ladder, with many of us advocating for or with one another.

As hospital medicine has grown, hospitalists have become genuine agents of change. Therefore, this change too, must begin with hospitalists. As leaders in healthcare, we must advocate for equity for all, from the lab technician to the CEO. We must engage and respond when direct care workers (often minorities), face gender or racial bias. In short, if we see something, we must say something.

To create a culture of inclusivity and intersectionality in healthcare, we suggest the following:

• Unite healthcare workers across fields. View your fellow healthcare worker as a team member, not as a subordinate or ancillary staff. Ask them what their experiences regarding inequity have been. See things from their perspective.
• Be a champion for those affected by harassment and inequity. Offer direct support to anyone affected by harassment or inequity. Accompany them to human resources or use your influence to advocate for gender-based salary audits.
• Raise awareness and knowledge. Know the resources in your institution and share them with others. Encourage teams to discuss the impact of microaggressions and implicit bias together as opposed to in role-specific groups. Use communication to lend allyship and support. If you see microaggressions based on gender or race, inquire by asking “I’m curious...why would you say that?” or share the impact a statement has on you by noting “The comment doesn’t just affect one person, it affects all of us.”

People create culture. Meaningful cultural change must be inclusive and intersectional. Historically, movements focused on equity have failed to be inclusive, leading to certain groups feeling marginalized. The time has come to affect change in healthcare across all differences. Whether in the role of physician, nurse, advanced practice provider, or paramedical staff, it’s time to stand together and say: “time is up.”

Disclosures

Dr Kass and Dr. Acholonu are founding members of TIME’S UP Healthcare

“If it is true that the full humanity of women is not our culture, then we can and must make it our culture.”
—Chimamanda Ngozi Adichie

A young boy is on the way home from soccer when a driver hits his car head-on. His father dies immediately, but the boy survives. The boy is transported to the hospital and immediately rushed into the OR. The surgeon takes one look at him and says, “I can’t operate on this patient. He’s my son!” The riddle asks: If the father is dead, who is the surgeon?

Struggling to realize that the surgeon is a mom highlights the depth of gender bias in medicine. Gender bias leads to inequities which are magnified when compounded with differences in race, ethnicity, sexual orientation, gender identity and/or socioeconomic status. The recent National Academies report described the toll of gender inequities, including sexual harassment, and their impact on women in medicine.¹ But like this riddle, the focus was directed towards those at the top of the hierarchy: physicians. It is undeniable that women physicians suffer the effects of inequities, but why exclude other women in healthcare? For example, over 90% of nurses are female, yet male nurses make higher salaries with lower degrees.² If we only focus on physicians, we risk ignoring a problem faced by the entirety of our workforce.

Healthcare is a team sport. The practice of hospital medicine is a prime example of how each team member brings critical value. One would never be able to run an effective code without excellent nursing or successfully intubate a patient without a skilled respiratory therapist. Yet, when it comes to conversations about gender bias and sexual harassment, we rarely work together. The work of equity in healthcare must therefore become more like a lattice than a ladder, with many of us advocating for or with one another.

As hospital medicine has grown, hospitalists have become genuine agents of change. Therefore, this change too, must begin with hospitalists. As leaders in healthcare, we must advocate for equity for all, from the lab technician to the CEO. We must engage and respond when direct care workers (often minorities), face gender or racial bias. In short, if we see something, we must say something.

To create a culture of inclusivity and intersectionality in healthcare, we suggest the following:

• Unite healthcare workers across fields. View your fellow healthcare worker as a team member, not as a subordinate or ancillary staff. Ask them what their experiences regarding inequity have been. See things from their perspective.
• Be a champion for those affected by harassment and inequity. Offer direct support to anyone affected by harassment or inequity. Accompany them to human resources or use your influence to advocate for gender-based salary audits.
• Raise awareness and knowledge. Know the resources in your institution and share them with others. Encourage teams to discuss the impact of microaggressions and implicit bias together as opposed to in role-specific groups. Use communication to lend allyship and support. If you see microaggressions based on gender or race, inquire by asking “I’m curious...why would you say that?” or share the impact a statement has on you by noting “The comment doesn’t just affect one person, it affects all of us.”

People create culture. Meaningful cultural change must be inclusive and intersectional. Historically, movements focused on equity have failed to be inclusive, leading to certain groups feeling marginalized. The time has come to affect change in healthcare across all differences. Whether in the role of physician, nurse, advanced practice provider, or paramedical staff, it’s time to stand together and say: “time is up.”

Disclosures

Dr Kass and Dr. Acholonu are founding members of TIME’S UP Healthcare

“If it is true that the full humanity of women is not our culture, then we can and must make it our culture.”
—Chimamanda Ngozi Adichie

A young boy is on the way home from soccer when a driver hits his car head-on. His father dies immediately, but the boy survives. The boy is transported to the hospital and immediately rushed into the OR. The surgeon takes one look at him and says, “I can’t operate on this patient. He’s my son!” The riddle asks: If the father is dead, who is the surgeon?

Struggling to realize that the surgeon is a mom highlights the depth of gender bias in medicine. Gender bias leads to inequities which are magnified when compounded with differences in race, ethnicity, sexual orientation, gender identity and/or socioeconomic status. The recent National Academies report described the toll of gender inequities, including sexual harassment, and their impact on women in medicine.¹ But like this riddle, the focus was directed towards those at the top of the hierarchy: physicians. It is undeniable that women physicians suffer the effects of inequities, but why exclude other women in healthcare? For example, over 90% of nurses are female, yet male nurses make higher salaries with lower degrees.² If we only focus on physicians, we risk ignoring a problem faced by the entirety of our workforce.

Healthcare is a team sport. The practice of hospital medicine is a prime example of how each team member brings critical value. One would never be able to run an effective code without excellent nursing or successfully intubate a patient without a skilled respiratory therapist. Yet, when it comes to conversations about gender bias and sexual harassment, we rarely work together. The work of equity in healthcare must therefore become more like a lattice than a ladder, with many of us advocating for or with one another.

As hospital medicine has grown, hospitalists have become genuine agents of change. Therefore, this change too, must begin with hospitalists. As leaders in healthcare, we must advocate for equity for all, from the lab technician to the CEO. We must engage and respond when direct care workers (often minorities), face gender or racial bias. In short, if we see something, we must say something.

To create a culture of inclusivity and intersectionality in healthcare, we suggest the following:

• Unite healthcare workers across fields. View your fellow healthcare worker as a team member, not as a subordinate or ancillary staff. Ask them what their experiences regarding inequity have been. See things from their perspective.
• Be a champion for those affected by harassment and inequity. Offer direct support to anyone affected by harassment or inequity. Accompany them to human resources or use your influence to advocate for gender-based salary audits.
• Raise awareness and knowledge. Know the resources in your institution and share them with others. Encourage teams to discuss the impact of microaggressions and implicit bias together as opposed to in role-specific groups. Use communication to lend allyship and support. If you see microaggressions based on gender or race, inquire by asking “I’m curious...why would you say that?” or share the impact a statement has on you by noting “The comment doesn’t just affect one person, it affects all of us.”

People create culture. Meaningful cultural change must be inclusive and intersectional. Historically, movements focused on equity have failed to be inclusive, leading to certain groups feeling marginalized. The time has come to affect change in healthcare across all differences. Whether in the role of physician, nurse, advanced practice provider, or paramedical staff, it’s time to stand together and say: “time is up.”

Disclosures

Dr Kass and Dr. Acholonu are founding members of TIME’S UP Healthcare

We appreciate the comments and interest of Al-Sharefi and colleagues who highlight the use of glucose-only infusion in the management of hyperkalemia.¹ The incidence of hypoglycemia following hyperkalemia treatment with insulin/dextrose is high and measures to reduce this should be pursued.² However, evidence of the efficacy of glucose-only infusions on lowering potassium in heterogeneous inpatient populations is lacking. The small study by Chothia et al demonstrated potassium lowering efficacy in ten clinically stable patients without diabetes receiving chronic hemodialysis.³ In contrast, multiple observational studies consistently show a clinically significant effect of insulin/dextrose on potassium lowering across different populations.⁴

Importantly, inpatient hyperglycemia is associated with increased morbidity and mortality and occurs in those with preexisting diabetes and also those without, due to stress hyperglycemia from acute illness, medication or nutrition support.⁵ Determining intact insulin sensitivity during acute illness is not straightforward and deciding on the appropriateness of glucose-only hyperkalemia treatment compared with insulin/dextrose would be challenging. With the rising prevalence of diabetes in the inpatient setting (>30% in our study), the number of eligible individuals for glucose-only treatment would be small and does not justify the use of two separate hyperkalemia treatment protocols.

Given the potential life-threatening consequences of hyperkalemia, rapid potassium lowering is a priority. For glucose-only infusions to be applied, there needs to be more convincing evidence across more representative inpatient populations to ensure efficacy.

Disclosures

The authors have nothing to disclose.

We appreciate the comments and interest of Al-Sharefi and colleagues who highlight the use of glucose-only infusion in the management of hyperkalemia.¹ The incidence of hypoglycemia following hyperkalemia treatment with insulin/dextrose is high and measures to reduce this should be pursued.² However, evidence of the efficacy of glucose-only infusions on lowering potassium in heterogeneous inpatient populations is lacking. The small study by Chothia et al demonstrated potassium lowering efficacy in ten clinically stable patients without diabetes receiving chronic hemodialysis.³ In contrast, multiple observational studies consistently show a clinically significant effect of insulin/dextrose on potassium lowering across different populations.⁴

Importantly, inpatient hyperglycemia is associated with increased morbidity and mortality and occurs in those with preexisting diabetes and also those without, due to stress hyperglycemia from acute illness, medication or nutrition support.⁵ Determining intact insulin sensitivity during acute illness is not straightforward and deciding on the appropriateness of glucose-only hyperkalemia treatment compared with insulin/dextrose would be challenging. With the rising prevalence of diabetes in the inpatient setting (>30% in our study), the number of eligible individuals for glucose-only treatment would be small and does not justify the use of two separate hyperkalemia treatment protocols.

Given the potential life-threatening consequences of hyperkalemia, rapid potassium lowering is a priority. For glucose-only infusions to be applied, there needs to be more convincing evidence across more representative inpatient populations to ensure efficacy.

Disclosures

The authors have nothing to disclose.

We appreciate the comments and interest of Al-Sharefi and colleagues who highlight the use of glucose-only infusion in the management of hyperkalemia.¹ The incidence of hypoglycemia following hyperkalemia treatment with insulin/dextrose is high and measures to reduce this should be pursued.² However, evidence of the efficacy of glucose-only infusions on lowering potassium in heterogeneous inpatient populations is lacking. The small study by Chothia et al demonstrated potassium lowering efficacy in ten clinically stable patients without diabetes receiving chronic hemodialysis.³ In contrast, multiple observational studies consistently show a clinically significant effect of insulin/dextrose on potassium lowering across different populations.⁴

Importantly, inpatient hyperglycemia is associated with increased morbidity and mortality and occurs in those with preexisting diabetes and also those without, due to stress hyperglycemia from acute illness, medication or nutrition support.⁵ Determining intact insulin sensitivity during acute illness is not straightforward and deciding on the appropriateness of glucose-only hyperkalemia treatment compared with insulin/dextrose would be challenging. With the rising prevalence of diabetes in the inpatient setting (>30% in our study), the number of eligible individuals for glucose-only treatment would be small and does not justify the use of two separate hyperkalemia treatment protocols.

Given the potential life-threatening consequences of hyperkalemia, rapid potassium lowering is a priority. For glucose-only infusions to be applied, there needs to be more convincing evidence across more representative inpatient populations to ensure efficacy.

Disclosures

The authors have nothing to disclose.