Hospitalists and other inpatient providers are familiar with hospitalizations classified observation. The Centers for Medicare & Medicaid Services (CMS) uses the “2-midnight rule” to distinguish between outpatient services (which include all observation stays) and inpatient services for most hospitalizations. The rule states that “inpatient admissions will generally be payable … if the admitting practitioner expected the patient to require a hospital stay that crossed two midnights and the medical record supports that reasonable expectation.”¹

Hospitalization under inpatient versus outpatient status is a billing distinction that can have significant financial consequences for patients, providers, and hospitals. The inpatient or outpatient observation orders written by hospitalists and other hospital-based providers direct billing based on CMS and other third-party regulation. However, providers may have variable expertise writing such orders. To audit the correct use of the visit-status orders by hospital providers, CMS uses recovery auditors (RAs), also referred to as recovery audit contractors.^2,3

Historically, RAs had up to 3 years from date of service (DOS) to perform an audit, which involves asking a hospital for a medical record for a particular stay. The audit timeline includes 45 days for hospitals to produce such documentation, and 60 days for the RA either to agree with the hospital’s billing or to make an “overpayment determination” that the hospital should have billed Medicare Part B (outpatient) instead of Part A (inpatient).^3,4 The hospital may either accept the RA decision, or contest it by using the pre-appeals discussion period or by directly entering the 5-level Medicare administrative appeals process.^3,4 Level 1 and Level 2 appeals are heard by a government contractor, Level 3 by an administrative law judge (ALJ), Level 4 by a Medicare appeals council, and Level 5 by a federal district court. These different appeal types have different deadlines (Appendix 1). The deadlines for hospitals and government responses beyond Level 1 are set by Congress and enforced by CMS,^3,4 and CMS sets discussion period timelines. Hospitals that miss an appeals deadline automatically default their appeals request, but there are no penalties for missed government deadlines.

Recently, there has been increased scrutiny of the audit-and-appeals process of outpatient and inpatient status determinations.⁵ Despite the 2-midnight rule, the Medicare Benefit Policy Manual (MBPM) retains the passage: “Physicians should use a 24-hour period as a benchmark, i.e., they should order admission for patients who are expected to need hospital care for 24 hours or more, and treat other patients on an outpatient basis.”⁶ Auditors often cite “medical necessity” in their decisions, which is not well defined in the MBPM and can be open to different interpretation. This lack of clarity likely contributed to the large number of status determination discrepancies between providers and RAs, thereby creating a federal appeals backlog that caused the Office of Medicare Hearings and Appeals to halt hospital appeals assignments⁷ and prompted an ongoing lawsuit against CMS regarding the lengthy appeals process.⁴ To address these problems and clear the appeals backlog, CMS proposed a “$0.68 settlement offer.”⁴ The settlement “offered an administrative agreement to any hospital willing to withdraw their pending appeals in exchange for timely partial payment (68% of the net allowable amount)”⁸ and paid out almost $1.5 billion to the third of eligible hospitals that accepted the offer.⁹ CMS also made programmatic improvements to the RA program.¹⁰

Despite these efforts, problems remain. On June 9, 2016, the U.S. Government Accountability Office (GAO) published Medicare Fee-for-Service: Opportunities Remain to Improve Appeals Process, citing an approximate 2000% increase in hospital inpatient appeals during the period 2010–2014 and the concern that appeals requests will continue to exceed adjudication capabilities.¹¹ On July 5, 2016, CMS issued its proposed rule for appeals reform that allows the Medicare Appeals Council (Level 4) to set precedents which would be binding at lower levels and allows senior attorneys to handle some cases and effectively increase manpower at the Level 3 (ALJ). In addition, CMS proposes to revise the method for calculating dollars at risk needed to schedule an ALJ hearing, and develop methods to better adjudicate similar claims, and other process improvements aimed at decreasing the more than 750,000 current claims awaiting ALJ decisions.¹²

We conducted a study to better understand the Medicare appeals process in the context of the proposed CMS reforms by investigating all appeals reaching Level 3 at Johns Hopkins Hospital (JHH), University of Wisconsin Hospitals and Clinics (UWHC), and University of Utah Hospital (UU). Because relatively few cases nationally are appealed beyond Level 3, the study focused on most-relevant data.³ We examined time spent at each appeal Level and whether it met federally mandated deadlines, as well as the percentage accountable to hospitals versus government contractors or ALJs. We also recorded the overturn rate at Level 3 and evaluated standardized text in de-identified decision letters to determine criteria cited by contractors in their decisions to deny hospital appeal requests.

The JHH, UWHC, and UU Institutional Review Boards did not require a review. The study included all complex Part A appeals involving DOS before October 1, 2013 and reaching Level 3 (ALJ) as of May 1, 2016.

Our general methods were described previously.² Briefly, the 3 academic medical centers are geographically diverse. JHH is in region A, UWHC in region B, and UU in region D (3 of the 4 RA regions are represented). The hospitals had different Medicare administrative contractors but the same qualified independent contractor until March 1, 2015 (Appendix 2).

Of 219 Level 3 cases, 135 (61.6%) concluded at Level 3. Of these 135 cases, 96 (71.1%) were decided in favor of the hospital, 11 (8.1%) were settled in the CMS $0.68 settlement offer, and 28 (20.7%) were unfavorable to the hospital (Table 1).

Mean total days since DOS was 1,663.3 (536.8) (mean [SD]), with median 1708 days. This included 560.4 (351.6) days between DOS and audit (median 556 days) and 891.3 (320.3) days in appeal (median 979 days). The hospitals were responsible for 29.3% of that time (260.7 [68.2] days) while government contractors were responsible for 70.7% (630.6 [277.2] days). Government contractors and ALJs met deadlines 47.7% of the time, meeting appeals deadlines 92.5% of the time for Discussion, 85.4% for Level 1, 38.8% for Level 2, and 0% for Level 3 (Table 1).

All “redetermination” (level 1 appeals letters) received at UU and UWHC, and all “reconsideration” (level 2 appeals letters) received by UU, UWHC, and JHH contained standardized time-based 24–hour benchmark text directly or referencing the MBPM containing such text, to describe criteria for inpatient status (Table 2 and Appendix 3).⁶ In total, 417 of 438 (95.2%) of Level 1 and Level 2 appeals results letters contained time-based 24-hour benchmark criteria for inpatient status despite 154 of 219 (70.3%) of denied cases exceeding a 24-hour LOS.

This study demonstrated process and timeliness concerns in the Medicare RA program for Level 3 cases at 3 academic medical centers. Although hospitals forfeit any appeal for which they miss a filing deadline, government contractors and ALJs met their deadlines less than half the time without default or penalty. Average time from the rendering of services to the conclusion of the audit-and-appeals process exceeded 4.5 years, which included an average 560 days between hospital stay and initial RA audit, and almost 900 days in appeals, with more than 70% of that time attributable to government contractors and ALJs.

Objective time-based 24-hour inpatient status criteria were referenced in 95% of decision letters, even though LOS exceeded 24 hours in more than 70% of these cases, suggesting that objective LOS data played only a small role in contractor decisions, or that contractors did not actually audit for LOS when reviewing cases. Unclear criteria likely contributed to payment denials and improper payments, despite admitting providers’ best efforts to comply with Medicare rules when writing visit-status orders. There was also a significant cost to hospitals; our prior study found that navigating the appeals process required 5 full-time equivalents per institution.²

At the 2 study hospitals with Level 3 decisions, more than two thirds of the decisions favored the hospital, suggesting the hospitals were justified in appealing RA Level 1 and Level 2 determinations. This proportion is consistent with the 43% ALJ overturn rate (including RA- and non-RA-derived appeals) cited in the recent U.S. Court of Appeals for the DC Circuit decision.⁹

This study potentially was limited by contractor and hospital use of the nonstandardized LOS calculation during the study period. That the majority of JHH and UU cases cited the 24-hour benchmark in their letters but nevertheless exceeded 24-hour LOS (using the most conservative definition of LOS) suggests contractors did not audit for or consider LOS in their decisions.

Our results support recent steps taken by CMS to reform the appeals process, including shortening the RA “look-back period” from 3 years to 6 months,¹⁰ which will markedly shorten the 560-day lag between DOS and audit found in this study. In addition, CMS has replaced RAs with beneficiary and family-centered care quality improvement organizations (BFCC-QIOs)^1,8 for initial status determination audits. Although it is too soon to tell, the hope is that BFCC-QIOs will decrease the volume of audits and denials that have overwhelmed the system and most probably contributed to process delays and the appeals backlog.

However, our data demonstrate several areas of concern not addressed in the recent GAO report¹¹ or in the rule proposed by CMS.¹² Most important, CMS could consider an appeals deadline missed by a government contractor as a decision for the hospital, in the same way a hospital’s missed deadline defaults its appeal. Such equity would ensure due process and prevent another appeals backlog. In addition, the large number of Level 3 decisions favoring hospitals suggests a need for process improvement at the Medicare administrative contractor and qualified independent contractor Level of appeals—such as mandatory review of Level 1 and Level 2 decision letters for appeals overturned at Level 3, accountability for Level 1 and Level 2 contractors with high rates of Level 3 overturn, and clarification of criteria used to judge determinations.

Medicare fraud cannot be tolerated, and a robust auditing process is essential to the integrity of the Medicare program. CMS’s current and proposed reforms may not be enough to eliminate the appeals backlog and restore a timely and fair appeals process. As CMS explores bundled payments and other reimbursement reforms, perhaps the need to distinguish observation hospital care will be eliminated. Short of that, additional actions must be taken so that a just and efficient Medicare appeals system can be realized for observation hospitalizations.

Acknowledgments

For invaluable assistance in data preparation and presentation, the authors thank Becky Borchert, RN, MS, MBA, Program Manager for Medicare/Medicaid Utilization Review, University of Wisconsin Hospital and Clinics; Carol Duhaney, Calvin Young, and Joan Kratz, RN, Johns Hopkins Hospital; and Morgan Walker and Lisa Whittaker, RN, University of Utah.

Disclosure

Nothing to report.

Hospitalists and other inpatient providers are familiar with hospitalizations classified observation. The Centers for Medicare & Medicaid Services (CMS) uses the “2-midnight rule” to distinguish between outpatient services (which include all observation stays) and inpatient services for most hospitalizations. The rule states that “inpatient admissions will generally be payable … if the admitting practitioner expected the patient to require a hospital stay that crossed two midnights and the medical record supports that reasonable expectation.”¹

Hospitalization under inpatient versus outpatient status is a billing distinction that can have significant financial consequences for patients, providers, and hospitals. The inpatient or outpatient observation orders written by hospitalists and other hospital-based providers direct billing based on CMS and other third-party regulation. However, providers may have variable expertise writing such orders. To audit the correct use of the visit-status orders by hospital providers, CMS uses recovery auditors (RAs), also referred to as recovery audit contractors.^2,3

Historically, RAs had up to 3 years from date of service (DOS) to perform an audit, which involves asking a hospital for a medical record for a particular stay. The audit timeline includes 45 days for hospitals to produce such documentation, and 60 days for the RA either to agree with the hospital’s billing or to make an “overpayment determination” that the hospital should have billed Medicare Part B (outpatient) instead of Part A (inpatient).^3,4 The hospital may either accept the RA decision, or contest it by using the pre-appeals discussion period or by directly entering the 5-level Medicare administrative appeals process.^3,4 Level 1 and Level 2 appeals are heard by a government contractor, Level 3 by an administrative law judge (ALJ), Level 4 by a Medicare appeals council, and Level 5 by a federal district court. These different appeal types have different deadlines (Appendix 1). The deadlines for hospitals and government responses beyond Level 1 are set by Congress and enforced by CMS,^3,4 and CMS sets discussion period timelines. Hospitals that miss an appeals deadline automatically default their appeals request, but there are no penalties for missed government deadlines.

Recently, there has been increased scrutiny of the audit-and-appeals process of outpatient and inpatient status determinations.⁵ Despite the 2-midnight rule, the Medicare Benefit Policy Manual (MBPM) retains the passage: “Physicians should use a 24-hour period as a benchmark, i.e., they should order admission for patients who are expected to need hospital care for 24 hours or more, and treat other patients on an outpatient basis.”⁶ Auditors often cite “medical necessity” in their decisions, which is not well defined in the MBPM and can be open to different interpretation. This lack of clarity likely contributed to the large number of status determination discrepancies between providers and RAs, thereby creating a federal appeals backlog that caused the Office of Medicare Hearings and Appeals to halt hospital appeals assignments⁷ and prompted an ongoing lawsuit against CMS regarding the lengthy appeals process.⁴ To address these problems and clear the appeals backlog, CMS proposed a “$0.68 settlement offer.”⁴ The settlement “offered an administrative agreement to any hospital willing to withdraw their pending appeals in exchange for timely partial payment (68% of the net allowable amount)”⁸ and paid out almost $1.5 billion to the third of eligible hospitals that accepted the offer.⁹ CMS also made programmatic improvements to the RA program.¹⁰

Despite these efforts, problems remain. On June 9, 2016, the U.S. Government Accountability Office (GAO) published Medicare Fee-for-Service: Opportunities Remain to Improve Appeals Process, citing an approximate 2000% increase in hospital inpatient appeals during the period 2010–2014 and the concern that appeals requests will continue to exceed adjudication capabilities.¹¹ On July 5, 2016, CMS issued its proposed rule for appeals reform that allows the Medicare Appeals Council (Level 4) to set precedents which would be binding at lower levels and allows senior attorneys to handle some cases and effectively increase manpower at the Level 3 (ALJ). In addition, CMS proposes to revise the method for calculating dollars at risk needed to schedule an ALJ hearing, and develop methods to better adjudicate similar claims, and other process improvements aimed at decreasing the more than 750,000 current claims awaiting ALJ decisions.¹²

We conducted a study to better understand the Medicare appeals process in the context of the proposed CMS reforms by investigating all appeals reaching Level 3 at Johns Hopkins Hospital (JHH), University of Wisconsin Hospitals and Clinics (UWHC), and University of Utah Hospital (UU). Because relatively few cases nationally are appealed beyond Level 3, the study focused on most-relevant data.³ We examined time spent at each appeal Level and whether it met federally mandated deadlines, as well as the percentage accountable to hospitals versus government contractors or ALJs. We also recorded the overturn rate at Level 3 and evaluated standardized text in de-identified decision letters to determine criteria cited by contractors in their decisions to deny hospital appeal requests.

The JHH, UWHC, and UU Institutional Review Boards did not require a review. The study included all complex Part A appeals involving DOS before October 1, 2013 and reaching Level 3 (ALJ) as of May 1, 2016.

Our general methods were described previously.² Briefly, the 3 academic medical centers are geographically diverse. JHH is in region A, UWHC in region B, and UU in region D (3 of the 4 RA regions are represented). The hospitals had different Medicare administrative contractors but the same qualified independent contractor until March 1, 2015 (Appendix 2).

Of 219 Level 3 cases, 135 (61.6%) concluded at Level 3. Of these 135 cases, 96 (71.1%) were decided in favor of the hospital, 11 (8.1%) were settled in the CMS $0.68 settlement offer, and 28 (20.7%) were unfavorable to the hospital (Table 1).

Mean total days since DOS was 1,663.3 (536.8) (mean [SD]), with median 1708 days. This included 560.4 (351.6) days between DOS and audit (median 556 days) and 891.3 (320.3) days in appeal (median 979 days). The hospitals were responsible for 29.3% of that time (260.7 [68.2] days) while government contractors were responsible for 70.7% (630.6 [277.2] days). Government contractors and ALJs met deadlines 47.7% of the time, meeting appeals deadlines 92.5% of the time for Discussion, 85.4% for Level 1, 38.8% for Level 2, and 0% for Level 3 (Table 1).

All “redetermination” (level 1 appeals letters) received at UU and UWHC, and all “reconsideration” (level 2 appeals letters) received by UU, UWHC, and JHH contained standardized time-based 24–hour benchmark text directly or referencing the MBPM containing such text, to describe criteria for inpatient status (Table 2 and Appendix 3).⁶ In total, 417 of 438 (95.2%) of Level 1 and Level 2 appeals results letters contained time-based 24-hour benchmark criteria for inpatient status despite 154 of 219 (70.3%) of denied cases exceeding a 24-hour LOS.

This study demonstrated process and timeliness concerns in the Medicare RA program for Level 3 cases at 3 academic medical centers. Although hospitals forfeit any appeal for which they miss a filing deadline, government contractors and ALJs met their deadlines less than half the time without default or penalty. Average time from the rendering of services to the conclusion of the audit-and-appeals process exceeded 4.5 years, which included an average 560 days between hospital stay and initial RA audit, and almost 900 days in appeals, with more than 70% of that time attributable to government contractors and ALJs.

Objective time-based 24-hour inpatient status criteria were referenced in 95% of decision letters, even though LOS exceeded 24 hours in more than 70% of these cases, suggesting that objective LOS data played only a small role in contractor decisions, or that contractors did not actually audit for LOS when reviewing cases. Unclear criteria likely contributed to payment denials and improper payments, despite admitting providers’ best efforts to comply with Medicare rules when writing visit-status orders. There was also a significant cost to hospitals; our prior study found that navigating the appeals process required 5 full-time equivalents per institution.²

At the 2 study hospitals with Level 3 decisions, more than two thirds of the decisions favored the hospital, suggesting the hospitals were justified in appealing RA Level 1 and Level 2 determinations. This proportion is consistent with the 43% ALJ overturn rate (including RA- and non-RA-derived appeals) cited in the recent U.S. Court of Appeals for the DC Circuit decision.⁹

This study potentially was limited by contractor and hospital use of the nonstandardized LOS calculation during the study period. That the majority of JHH and UU cases cited the 24-hour benchmark in their letters but nevertheless exceeded 24-hour LOS (using the most conservative definition of LOS) suggests contractors did not audit for or consider LOS in their decisions.

Our results support recent steps taken by CMS to reform the appeals process, including shortening the RA “look-back period” from 3 years to 6 months,¹⁰ which will markedly shorten the 560-day lag between DOS and audit found in this study. In addition, CMS has replaced RAs with beneficiary and family-centered care quality improvement organizations (BFCC-QIOs)^1,8 for initial status determination audits. Although it is too soon to tell, the hope is that BFCC-QIOs will decrease the volume of audits and denials that have overwhelmed the system and most probably contributed to process delays and the appeals backlog.

However, our data demonstrate several areas of concern not addressed in the recent GAO report¹¹ or in the rule proposed by CMS.¹² Most important, CMS could consider an appeals deadline missed by a government contractor as a decision for the hospital, in the same way a hospital’s missed deadline defaults its appeal. Such equity would ensure due process and prevent another appeals backlog. In addition, the large number of Level 3 decisions favoring hospitals suggests a need for process improvement at the Medicare administrative contractor and qualified independent contractor Level of appeals—such as mandatory review of Level 1 and Level 2 decision letters for appeals overturned at Level 3, accountability for Level 1 and Level 2 contractors with high rates of Level 3 overturn, and clarification of criteria used to judge determinations.

Medicare fraud cannot be tolerated, and a robust auditing process is essential to the integrity of the Medicare program. CMS’s current and proposed reforms may not be enough to eliminate the appeals backlog and restore a timely and fair appeals process. As CMS explores bundled payments and other reimbursement reforms, perhaps the need to distinguish observation hospital care will be eliminated. Short of that, additional actions must be taken so that a just and efficient Medicare appeals system can be realized for observation hospitalizations.

Acknowledgments

For invaluable assistance in data preparation and presentation, the authors thank Becky Borchert, RN, MS, MBA, Program Manager for Medicare/Medicaid Utilization Review, University of Wisconsin Hospital and Clinics; Carol Duhaney, Calvin Young, and Joan Kratz, RN, Johns Hopkins Hospital; and Morgan Walker and Lisa Whittaker, RN, University of Utah.

Disclosure

Nothing to report.

Hospitalists and other inpatient providers are familiar with hospitalizations classified observation. The Centers for Medicare & Medicaid Services (CMS) uses the “2-midnight rule” to distinguish between outpatient services (which include all observation stays) and inpatient services for most hospitalizations. The rule states that “inpatient admissions will generally be payable … if the admitting practitioner expected the patient to require a hospital stay that crossed two midnights and the medical record supports that reasonable expectation.”¹

Hospitalization under inpatient versus outpatient status is a billing distinction that can have significant financial consequences for patients, providers, and hospitals. The inpatient or outpatient observation orders written by hospitalists and other hospital-based providers direct billing based on CMS and other third-party regulation. However, providers may have variable expertise writing such orders. To audit the correct use of the visit-status orders by hospital providers, CMS uses recovery auditors (RAs), also referred to as recovery audit contractors.^2,3

Historically, RAs had up to 3 years from date of service (DOS) to perform an audit, which involves asking a hospital for a medical record for a particular stay. The audit timeline includes 45 days for hospitals to produce such documentation, and 60 days for the RA either to agree with the hospital’s billing or to make an “overpayment determination” that the hospital should have billed Medicare Part B (outpatient) instead of Part A (inpatient).^3,4 The hospital may either accept the RA decision, or contest it by using the pre-appeals discussion period or by directly entering the 5-level Medicare administrative appeals process.^3,4 Level 1 and Level 2 appeals are heard by a government contractor, Level 3 by an administrative law judge (ALJ), Level 4 by a Medicare appeals council, and Level 5 by a federal district court. These different appeal types have different deadlines (Appendix 1). The deadlines for hospitals and government responses beyond Level 1 are set by Congress and enforced by CMS,^3,4 and CMS sets discussion period timelines. Hospitals that miss an appeals deadline automatically default their appeals request, but there are no penalties for missed government deadlines.

Recently, there has been increased scrutiny of the audit-and-appeals process of outpatient and inpatient status determinations.⁵ Despite the 2-midnight rule, the Medicare Benefit Policy Manual (MBPM) retains the passage: “Physicians should use a 24-hour period as a benchmark, i.e., they should order admission for patients who are expected to need hospital care for 24 hours or more, and treat other patients on an outpatient basis.”⁶ Auditors often cite “medical necessity” in their decisions, which is not well defined in the MBPM and can be open to different interpretation. This lack of clarity likely contributed to the large number of status determination discrepancies between providers and RAs, thereby creating a federal appeals backlog that caused the Office of Medicare Hearings and Appeals to halt hospital appeals assignments⁷ and prompted an ongoing lawsuit against CMS regarding the lengthy appeals process.⁴ To address these problems and clear the appeals backlog, CMS proposed a “$0.68 settlement offer.”⁴ The settlement “offered an administrative agreement to any hospital willing to withdraw their pending appeals in exchange for timely partial payment (68% of the net allowable amount)”⁸ and paid out almost $1.5 billion to the third of eligible hospitals that accepted the offer.⁹ CMS also made programmatic improvements to the RA program.¹⁰

Despite these efforts, problems remain. On June 9, 2016, the U.S. Government Accountability Office (GAO) published Medicare Fee-for-Service: Opportunities Remain to Improve Appeals Process, citing an approximate 2000% increase in hospital inpatient appeals during the period 2010–2014 and the concern that appeals requests will continue to exceed adjudication capabilities.¹¹ On July 5, 2016, CMS issued its proposed rule for appeals reform that allows the Medicare Appeals Council (Level 4) to set precedents which would be binding at lower levels and allows senior attorneys to handle some cases and effectively increase manpower at the Level 3 (ALJ). In addition, CMS proposes to revise the method for calculating dollars at risk needed to schedule an ALJ hearing, and develop methods to better adjudicate similar claims, and other process improvements aimed at decreasing the more than 750,000 current claims awaiting ALJ decisions.¹²

We conducted a study to better understand the Medicare appeals process in the context of the proposed CMS reforms by investigating all appeals reaching Level 3 at Johns Hopkins Hospital (JHH), University of Wisconsin Hospitals and Clinics (UWHC), and University of Utah Hospital (UU). Because relatively few cases nationally are appealed beyond Level 3, the study focused on most-relevant data.³ We examined time spent at each appeal Level and whether it met federally mandated deadlines, as well as the percentage accountable to hospitals versus government contractors or ALJs. We also recorded the overturn rate at Level 3 and evaluated standardized text in de-identified decision letters to determine criteria cited by contractors in their decisions to deny hospital appeal requests.

The JHH, UWHC, and UU Institutional Review Boards did not require a review. The study included all complex Part A appeals involving DOS before October 1, 2013 and reaching Level 3 (ALJ) as of May 1, 2016.

Our general methods were described previously.² Briefly, the 3 academic medical centers are geographically diverse. JHH is in region A, UWHC in region B, and UU in region D (3 of the 4 RA regions are represented). The hospitals had different Medicare administrative contractors but the same qualified independent contractor until March 1, 2015 (Appendix 2).

Of 219 Level 3 cases, 135 (61.6%) concluded at Level 3. Of these 135 cases, 96 (71.1%) were decided in favor of the hospital, 11 (8.1%) were settled in the CMS $0.68 settlement offer, and 28 (20.7%) were unfavorable to the hospital (Table 1).

Mean total days since DOS was 1,663.3 (536.8) (mean [SD]), with median 1708 days. This included 560.4 (351.6) days between DOS and audit (median 556 days) and 891.3 (320.3) days in appeal (median 979 days). The hospitals were responsible for 29.3% of that time (260.7 [68.2] days) while government contractors were responsible for 70.7% (630.6 [277.2] days). Government contractors and ALJs met deadlines 47.7% of the time, meeting appeals deadlines 92.5% of the time for Discussion, 85.4% for Level 1, 38.8% for Level 2, and 0% for Level 3 (Table 1).

All “redetermination” (level 1 appeals letters) received at UU and UWHC, and all “reconsideration” (level 2 appeals letters) received by UU, UWHC, and JHH contained standardized time-based 24–hour benchmark text directly or referencing the MBPM containing such text, to describe criteria for inpatient status (Table 2 and Appendix 3).⁶ In total, 417 of 438 (95.2%) of Level 1 and Level 2 appeals results letters contained time-based 24-hour benchmark criteria for inpatient status despite 154 of 219 (70.3%) of denied cases exceeding a 24-hour LOS.

This study demonstrated process and timeliness concerns in the Medicare RA program for Level 3 cases at 3 academic medical centers. Although hospitals forfeit any appeal for which they miss a filing deadline, government contractors and ALJs met their deadlines less than half the time without default or penalty. Average time from the rendering of services to the conclusion of the audit-and-appeals process exceeded 4.5 years, which included an average 560 days between hospital stay and initial RA audit, and almost 900 days in appeals, with more than 70% of that time attributable to government contractors and ALJs.

Objective time-based 24-hour inpatient status criteria were referenced in 95% of decision letters, even though LOS exceeded 24 hours in more than 70% of these cases, suggesting that objective LOS data played only a small role in contractor decisions, or that contractors did not actually audit for LOS when reviewing cases. Unclear criteria likely contributed to payment denials and improper payments, despite admitting providers’ best efforts to comply with Medicare rules when writing visit-status orders. There was also a significant cost to hospitals; our prior study found that navigating the appeals process required 5 full-time equivalents per institution.²

At the 2 study hospitals with Level 3 decisions, more than two thirds of the decisions favored the hospital, suggesting the hospitals were justified in appealing RA Level 1 and Level 2 determinations. This proportion is consistent with the 43% ALJ overturn rate (including RA- and non-RA-derived appeals) cited in the recent U.S. Court of Appeals for the DC Circuit decision.⁹

This study potentially was limited by contractor and hospital use of the nonstandardized LOS calculation during the study period. That the majority of JHH and UU cases cited the 24-hour benchmark in their letters but nevertheless exceeded 24-hour LOS (using the most conservative definition of LOS) suggests contractors did not audit for or consider LOS in their decisions.

Our results support recent steps taken by CMS to reform the appeals process, including shortening the RA “look-back period” from 3 years to 6 months,¹⁰ which will markedly shorten the 560-day lag between DOS and audit found in this study. In addition, CMS has replaced RAs with beneficiary and family-centered care quality improvement organizations (BFCC-QIOs)^1,8 for initial status determination audits. Although it is too soon to tell, the hope is that BFCC-QIOs will decrease the volume of audits and denials that have overwhelmed the system and most probably contributed to process delays and the appeals backlog.

However, our data demonstrate several areas of concern not addressed in the recent GAO report¹¹ or in the rule proposed by CMS.¹² Most important, CMS could consider an appeals deadline missed by a government contractor as a decision for the hospital, in the same way a hospital’s missed deadline defaults its appeal. Such equity would ensure due process and prevent another appeals backlog. In addition, the large number of Level 3 decisions favoring hospitals suggests a need for process improvement at the Medicare administrative contractor and qualified independent contractor Level of appeals—such as mandatory review of Level 1 and Level 2 decision letters for appeals overturned at Level 3, accountability for Level 1 and Level 2 contractors with high rates of Level 3 overturn, and clarification of criteria used to judge determinations.

Medicare fraud cannot be tolerated, and a robust auditing process is essential to the integrity of the Medicare program. CMS’s current and proposed reforms may not be enough to eliminate the appeals backlog and restore a timely and fair appeals process. As CMS explores bundled payments and other reimbursement reforms, perhaps the need to distinguish observation hospital care will be eliminated. Short of that, additional actions must be taken so that a just and efficient Medicare appeals system can be realized for observation hospitalizations.

Acknowledgments

For invaluable assistance in data preparation and presentation, the authors thank Becky Borchert, RN, MS, MBA, Program Manager for Medicare/Medicaid Utilization Review, University of Wisconsin Hospital and Clinics; Carol Duhaney, Calvin Young, and Joan Kratz, RN, Johns Hopkins Hospital; and Morgan Walker and Lisa Whittaker, RN, University of Utah.

Disclosure

Nothing to report.

WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.

This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.

• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.

• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.

Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.

Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.

Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.

Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.

He reported having no financial conflicts regarding his study.

[email protected]

WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.

This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.

• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.

• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.

Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.

Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.

Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.

Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.

He reported having no financial conflicts regarding his study.

[email protected]

WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.

This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.

Bruce Jancin/Frontline Medical News

• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.

• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.

• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.

Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.

Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.

Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.

Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.

He reported having no financial conflicts regarding his study.

[email protected]

Sepsis is a leading cause of hospital mortality in the United States, contributing to up to half of all deaths.¹ If the infection is identified and treated early, however, its associated morbidity and mortality can be significantly reduced.² The 2001 sepsis guidelines define sepsis as the suspicion of infection plus meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria.³ Although the utility of SIRS criteria has been extensively debated, providers’ accuracy and agreement regarding suspicion of infection are not yet fully characterized. This is very important, as the source of infection is often not identified in patients with severe sepsis or septic shock.⁴

Although much attention recently has been given to ideal objective criteria for accurately identifying sepsis, less is known about what constitutes ideal subjective criteria and who can best make that assessment.^5-7 We conducted a study to measure providers’ agreement regarding this subjective assessment and the impact of that agreement on patient outcomes.

We performed a secondary analysis of prospectively collected data on consecutive adults hospitalized on a general medicine ward at an academic medical center between April 1, 2014 and March 31, 2015. This study was approved by the University of Chicago Institutional Review Board with a waiver of consent.

A sepsis screening tool was developed locally as part of the Surviving Sepsis Campaign Quality Improvement Learning Collaborative⁸ (Supplemental Figure). This tool was completed by bedside nurses for each patient during each shift. Bedside registered nurse (RN) suspicion of infection was deemed positive if the nurse answered yes to question 2: “Does the patient have evidence of an active infection?” We compared RN assessment with assessment by the ordering provider, a medical doctor or advanced practice professionals (MD/APP), using an existing order for antibiotics or a new order for either blood or urine cultures placed within 12 hours before nursing screen time to indicate MD/APP suspicion of infection.

All nursing screens were transcribed into an electronic database, excluding screens not performed, or missing RN suspicion of infection. For quality purposes, screening data were merged with electronic health record data to verify SIRS criteria at the time of the screens as well as the presence of culture and/or antibiotic orders preceding the screens. Outcome data were obtained from an administrative database and confirmed by chart review using the 2001 sepsis definitions.⁶ Data were de-identified and time-shifted before this analysis. SIRS-positive criteria were defined as meeting 2 or more of the following: temperature higher than 38°C or lower than 36°C; heart rate higher than 90 beats per minute; respiratory rate more than 20 breaths per minute; and white blood cell count more than 2,000/mm³ or less than 4,000/mm³.The primary clinical outcome was progression to severe sepsis or septic shock. Secondary outcomes included transfer to intensive care unit (ICU) and in-hospital mortality. Given that RN and MD/APP suspicion of infection can vary over time, only the initial screen for each patient was used in assessing progression to severe sepsis or septic shock and in-hospital mortality. All available screens were used to investigate the association between each provider’s suspicion of infection over time and ICU transfer.

Demographic characteristics were compared using the χ² test and analysis of variance, as appropriate. Provider agreement was evaluated with a weighted κ statistic. Fisher exact tests were used to compare proportions of mortality and severe sepsis/septic shock, and the McNemar test was used to compare proportions of ICU transfers. The association of outcomes based on provider agreement was evaluated with a nonparametric test for trend.

During the study period, 1386 distinct patients had 13,223 screening opportunities, with a 95.4% compliance rate. A total of 1127 screens were excluded for missing nursing documentation of suspicion of infection, leaving 1192 first screens and 11,489 total screens for analysis. Of the completed screens, 3744 (32.6%) met SIRS criteria; suspicion of infection was noted by both RN and MD/APP in 5.8% of cases, by RN only in 22.2%, by MD/APP only in 7.2%, and by neither provider in 64.7% (Figure 1). Overall agreement rate was 80.7% for suspicion of infection (κ = 0.11, P < 0.001). Demographics by subgroup are shown in the Supplemental Table. Progression to severe sepsis or shock was highest when both providers suspected infection in a SIRS-positive patient (17.7%), was substantially reduced with single-provider suspicion (6.0%), and was lowest when neither provider suspected infection (1.5%) (P < 0.001). A similar trend was found for in-hospital mortality (both providers, 6.3%; single provider, 2.7%; neither provider, 2.5%; P = 0.01). Compared with MD/APP-only suspicion, SIRS-positive patients in whom only RNs suspected infection had similar frequency of progression to severe sepsis or septic shock (6.5% vs 5.6%; P = 0.52) and higher mortality (5.0% vs 1.1%; P = 0.32), though these findings were not statistically significant.

For the 121 patients (10.2%) transferred to ICU, RNs were more likely than MD/APPs to suspect infection at all time points (Figure 2). The difference was small (P = 0.29) 48 hours before transfer (RN, 12.5%; MD/APP, 5.6%) but became more pronounced (P = 0.06) by 3 hours before transfer (RN, 46.3%; MD/APP, 33.1%). Nursing assessments were not available after transfer, but 3 hours after transfer the proportion of patients who met MD/APP suspicion-of-infection criteria (44.6%) was similar (P = 0.90) to that of the RNs 3 hours before transfer (46.3%).

Our findings reveal that bedside nurses and ordering providers routinely have discordant assessments regarding presence of infection. Specifically, when RNs are asked to screen patients on the wards, they are suspicious of infection more often than MD/APPs are, and they suspect infection earlier in ICU transfer patients. These findings have significant implications for patient care, compliance with the new national SEP-1 Centers for Medicare & Medicaid Services quality measure, and identification of appropriate patients for enrollment in sepsis-related clinical trials.

To our knowledge, this is the first study to explore agreement between bedside RN and MD/APP suspicion of infection in sepsis screening and its association with patient outcomes. Studies on nurse and physician concordance in other domains have had mixed findings.^9-11 The high discordance rate found in our study points to the highly subjective nature of suspicion of infection.

Our finding that RNs suspect infection earlier in patients transferred to ICU suggests nursing suspicion has value above and beyond current practice. A possible explanation for the higher rate of RN suspicion, and earlier RN suspicion, is that bedside nurses spend substantially more time with their patients and are more attuned to subtle changes that often occur before any objective signs of deterioration. This phenomenon is well documented and accounts for why rapid response calling criteria often include “nurse worry or concern.”^12,13 Thus, nurse intuition may be an important signal for early identification of patients at high risk for sepsis.

That about one third of all screens met SIRS criteria and that almost two thirds of those screens were not thought by RN or MD/APP to be caused by infection add to the literature demonstrating the limited value of SIRS as a screening tool for sepsis.¹⁴ To address this issue, the 2016 sepsis definitions propose using the quick Sepsis-Related Organ Failure Assessment (qSOFA) to identify patients at high risk for clinical deterioration; however, the Surviving Sepsis Campaign continues to encourage sepsis screening using the SIRS criteria.¹⁵

Limitations of this study include its lack of generalizability, as it was conducted with general medical patients at a single center. Second, we did not specifically ask the MD/APPs whether they suspected infection; instead, we relied on their ordering practices. Third, RN and MD/APP assessments were not independent, as RNs had access to MD/APP orders before making their own assessments, which could bias our results.

Discordance in provider suspicion of infection is common, with RNs documenting suspicion more often than MD/APPs, and earlier in patients transferred to ICU. Suspicion by either provider alone is associated with higher risk for sepsis progression and in-hospital mortality than is the case when neither provider suspects infection. Thus, a collaborative method that includes both RNs and MD/APPs may improve the accuracy and timing of sepsis detection on the wards.

Acknowledgments

The authors thank the members of the Surviving Sepsis Campaign (SSC) Quality Improvement Learning Collaborative at the University of Chicago for their help in data collection and review, especially Meredith Borak, Rita Lanier, Mary Ann Francisco, and Bill Marsack. The authors also thank Thomas Best and Mary-Kate Springman for their assistance in data entry and Nicole Twu for administrative support. Data from this study were provided by the Clinical Research Data Warehouse (CRDW) maintained by the Center for Research Informatics (CRI) at the University of Chicago. CRI is funded by the Biological Sciences Division of the Institute for Translational Medicine/Clinical and Translational Science Award (CTSA) (National Institutes of Health UL1 TR000430) at the University of Chicago.

Disclosures

Dr. Bhattacharjee is supported by postdoctoral training grant 4T32HS000078 from the Agency for Healthcare Research and Quality. Drs. Churpek and Edelson have a patent pending (ARCD.P0535US.P2) for risk stratification algorithms for hospitalized patients. Dr. Churpek is supported by career development award K08 HL121080 from the National Heart, Lung, and Blood Institute. Dr. Edelson has received research support from Philips Healthcare (Andover, Massachusetts), American Heart Association (Dallas, Texas), and Laerdal Medical (Stavanger, Norway) and has ownership interest in Quant HC (Chicago, Illinois), which is developing products for risk stratification of hospitalized patients. The other authors report no conflicts of interest.

Sepsis is a leading cause of hospital mortality in the United States, contributing to up to half of all deaths.¹ If the infection is identified and treated early, however, its associated morbidity and mortality can be significantly reduced.² The 2001 sepsis guidelines define sepsis as the suspicion of infection plus meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria.³ Although the utility of SIRS criteria has been extensively debated, providers’ accuracy and agreement regarding suspicion of infection are not yet fully characterized. This is very important, as the source of infection is often not identified in patients with severe sepsis or septic shock.⁴

Although much attention recently has been given to ideal objective criteria for accurately identifying sepsis, less is known about what constitutes ideal subjective criteria and who can best make that assessment.^5-7 We conducted a study to measure providers’ agreement regarding this subjective assessment and the impact of that agreement on patient outcomes.

We performed a secondary analysis of prospectively collected data on consecutive adults hospitalized on a general medicine ward at an academic medical center between April 1, 2014 and March 31, 2015. This study was approved by the University of Chicago Institutional Review Board with a waiver of consent.

A sepsis screening tool was developed locally as part of the Surviving Sepsis Campaign Quality Improvement Learning Collaborative⁸ (Supplemental Figure). This tool was completed by bedside nurses for each patient during each shift. Bedside registered nurse (RN) suspicion of infection was deemed positive if the nurse answered yes to question 2: “Does the patient have evidence of an active infection?” We compared RN assessment with assessment by the ordering provider, a medical doctor or advanced practice professionals (MD/APP), using an existing order for antibiotics or a new order for either blood or urine cultures placed within 12 hours before nursing screen time to indicate MD/APP suspicion of infection.

All nursing screens were transcribed into an electronic database, excluding screens not performed, or missing RN suspicion of infection. For quality purposes, screening data were merged with electronic health record data to verify SIRS criteria at the time of the screens as well as the presence of culture and/or antibiotic orders preceding the screens. Outcome data were obtained from an administrative database and confirmed by chart review using the 2001 sepsis definitions.⁶ Data were de-identified and time-shifted before this analysis. SIRS-positive criteria were defined as meeting 2 or more of the following: temperature higher than 38°C or lower than 36°C; heart rate higher than 90 beats per minute; respiratory rate more than 20 breaths per minute; and white blood cell count more than 2,000/mm³ or less than 4,000/mm³.The primary clinical outcome was progression to severe sepsis or septic shock. Secondary outcomes included transfer to intensive care unit (ICU) and in-hospital mortality. Given that RN and MD/APP suspicion of infection can vary over time, only the initial screen for each patient was used in assessing progression to severe sepsis or septic shock and in-hospital mortality. All available screens were used to investigate the association between each provider’s suspicion of infection over time and ICU transfer.

Demographic characteristics were compared using the χ² test and analysis of variance, as appropriate. Provider agreement was evaluated with a weighted κ statistic. Fisher exact tests were used to compare proportions of mortality and severe sepsis/septic shock, and the McNemar test was used to compare proportions of ICU transfers. The association of outcomes based on provider agreement was evaluated with a nonparametric test for trend.

During the study period, 1386 distinct patients had 13,223 screening opportunities, with a 95.4% compliance rate. A total of 1127 screens were excluded for missing nursing documentation of suspicion of infection, leaving 1192 first screens and 11,489 total screens for analysis. Of the completed screens, 3744 (32.6%) met SIRS criteria; suspicion of infection was noted by both RN and MD/APP in 5.8% of cases, by RN only in 22.2%, by MD/APP only in 7.2%, and by neither provider in 64.7% (Figure 1). Overall agreement rate was 80.7% for suspicion of infection (κ = 0.11, P < 0.001). Demographics by subgroup are shown in the Supplemental Table. Progression to severe sepsis or shock was highest when both providers suspected infection in a SIRS-positive patient (17.7%), was substantially reduced with single-provider suspicion (6.0%), and was lowest when neither provider suspected infection (1.5%) (P < 0.001). A similar trend was found for in-hospital mortality (both providers, 6.3%; single provider, 2.7%; neither provider, 2.5%; P = 0.01). Compared with MD/APP-only suspicion, SIRS-positive patients in whom only RNs suspected infection had similar frequency of progression to severe sepsis or septic shock (6.5% vs 5.6%; P = 0.52) and higher mortality (5.0% vs 1.1%; P = 0.32), though these findings were not statistically significant.

For the 121 patients (10.2%) transferred to ICU, RNs were more likely than MD/APPs to suspect infection at all time points (Figure 2). The difference was small (P = 0.29) 48 hours before transfer (RN, 12.5%; MD/APP, 5.6%) but became more pronounced (P = 0.06) by 3 hours before transfer (RN, 46.3%; MD/APP, 33.1%). Nursing assessments were not available after transfer, but 3 hours after transfer the proportion of patients who met MD/APP suspicion-of-infection criteria (44.6%) was similar (P = 0.90) to that of the RNs 3 hours before transfer (46.3%).

Our findings reveal that bedside nurses and ordering providers routinely have discordant assessments regarding presence of infection. Specifically, when RNs are asked to screen patients on the wards, they are suspicious of infection more often than MD/APPs are, and they suspect infection earlier in ICU transfer patients. These findings have significant implications for patient care, compliance with the new national SEP-1 Centers for Medicare & Medicaid Services quality measure, and identification of appropriate patients for enrollment in sepsis-related clinical trials.

To our knowledge, this is the first study to explore agreement between bedside RN and MD/APP suspicion of infection in sepsis screening and its association with patient outcomes. Studies on nurse and physician concordance in other domains have had mixed findings.^9-11 The high discordance rate found in our study points to the highly subjective nature of suspicion of infection.

Our finding that RNs suspect infection earlier in patients transferred to ICU suggests nursing suspicion has value above and beyond current practice. A possible explanation for the higher rate of RN suspicion, and earlier RN suspicion, is that bedside nurses spend substantially more time with their patients and are more attuned to subtle changes that often occur before any objective signs of deterioration. This phenomenon is well documented and accounts for why rapid response calling criteria often include “nurse worry or concern.”^12,13 Thus, nurse intuition may be an important signal for early identification of patients at high risk for sepsis.

That about one third of all screens met SIRS criteria and that almost two thirds of those screens were not thought by RN or MD/APP to be caused by infection add to the literature demonstrating the limited value of SIRS as a screening tool for sepsis.¹⁴ To address this issue, the 2016 sepsis definitions propose using the quick Sepsis-Related Organ Failure Assessment (qSOFA) to identify patients at high risk for clinical deterioration; however, the Surviving Sepsis Campaign continues to encourage sepsis screening using the SIRS criteria.¹⁵

Limitations of this study include its lack of generalizability, as it was conducted with general medical patients at a single center. Second, we did not specifically ask the MD/APPs whether they suspected infection; instead, we relied on their ordering practices. Third, RN and MD/APP assessments were not independent, as RNs had access to MD/APP orders before making their own assessments, which could bias our results.

Discordance in provider suspicion of infection is common, with RNs documenting suspicion more often than MD/APPs, and earlier in patients transferred to ICU. Suspicion by either provider alone is associated with higher risk for sepsis progression and in-hospital mortality than is the case when neither provider suspects infection. Thus, a collaborative method that includes both RNs and MD/APPs may improve the accuracy and timing of sepsis detection on the wards.

Acknowledgments

The authors thank the members of the Surviving Sepsis Campaign (SSC) Quality Improvement Learning Collaborative at the University of Chicago for their help in data collection and review, especially Meredith Borak, Rita Lanier, Mary Ann Francisco, and Bill Marsack. The authors also thank Thomas Best and Mary-Kate Springman for their assistance in data entry and Nicole Twu for administrative support. Data from this study were provided by the Clinical Research Data Warehouse (CRDW) maintained by the Center for Research Informatics (CRI) at the University of Chicago. CRI is funded by the Biological Sciences Division of the Institute for Translational Medicine/Clinical and Translational Science Award (CTSA) (National Institutes of Health UL1 TR000430) at the University of Chicago.

Disclosures

Dr. Bhattacharjee is supported by postdoctoral training grant 4T32HS000078 from the Agency for Healthcare Research and Quality. Drs. Churpek and Edelson have a patent pending (ARCD.P0535US.P2) for risk stratification algorithms for hospitalized patients. Dr. Churpek is supported by career development award K08 HL121080 from the National Heart, Lung, and Blood Institute. Dr. Edelson has received research support from Philips Healthcare (Andover, Massachusetts), American Heart Association (Dallas, Texas), and Laerdal Medical (Stavanger, Norway) and has ownership interest in Quant HC (Chicago, Illinois), which is developing products for risk stratification of hospitalized patients. The other authors report no conflicts of interest.

Sepsis is a leading cause of hospital mortality in the United States, contributing to up to half of all deaths.¹ If the infection is identified and treated early, however, its associated morbidity and mortality can be significantly reduced.² The 2001 sepsis guidelines define sepsis as the suspicion of infection plus meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria.³ Although the utility of SIRS criteria has been extensively debated, providers’ accuracy and agreement regarding suspicion of infection are not yet fully characterized. This is very important, as the source of infection is often not identified in patients with severe sepsis or septic shock.⁴

Although much attention recently has been given to ideal objective criteria for accurately identifying sepsis, less is known about what constitutes ideal subjective criteria and who can best make that assessment.^5-7 We conducted a study to measure providers’ agreement regarding this subjective assessment and the impact of that agreement on patient outcomes.

We performed a secondary analysis of prospectively collected data on consecutive adults hospitalized on a general medicine ward at an academic medical center between April 1, 2014 and March 31, 2015. This study was approved by the University of Chicago Institutional Review Board with a waiver of consent.

A sepsis screening tool was developed locally as part of the Surviving Sepsis Campaign Quality Improvement Learning Collaborative⁸ (Supplemental Figure). This tool was completed by bedside nurses for each patient during each shift. Bedside registered nurse (RN) suspicion of infection was deemed positive if the nurse answered yes to question 2: “Does the patient have evidence of an active infection?” We compared RN assessment with assessment by the ordering provider, a medical doctor or advanced practice professionals (MD/APP), using an existing order for antibiotics or a new order for either blood or urine cultures placed within 12 hours before nursing screen time to indicate MD/APP suspicion of infection.

All nursing screens were transcribed into an electronic database, excluding screens not performed, or missing RN suspicion of infection. For quality purposes, screening data were merged with electronic health record data to verify SIRS criteria at the time of the screens as well as the presence of culture and/or antibiotic orders preceding the screens. Outcome data were obtained from an administrative database and confirmed by chart review using the 2001 sepsis definitions.⁶ Data were de-identified and time-shifted before this analysis. SIRS-positive criteria were defined as meeting 2 or more of the following: temperature higher than 38°C or lower than 36°C; heart rate higher than 90 beats per minute; respiratory rate more than 20 breaths per minute; and white blood cell count more than 2,000/mm³ or less than 4,000/mm³.The primary clinical outcome was progression to severe sepsis or septic shock. Secondary outcomes included transfer to intensive care unit (ICU) and in-hospital mortality. Given that RN and MD/APP suspicion of infection can vary over time, only the initial screen for each patient was used in assessing progression to severe sepsis or septic shock and in-hospital mortality. All available screens were used to investigate the association between each provider’s suspicion of infection over time and ICU transfer.

Demographic characteristics were compared using the χ² test and analysis of variance, as appropriate. Provider agreement was evaluated with a weighted κ statistic. Fisher exact tests were used to compare proportions of mortality and severe sepsis/septic shock, and the McNemar test was used to compare proportions of ICU transfers. The association of outcomes based on provider agreement was evaluated with a nonparametric test for trend.

During the study period, 1386 distinct patients had 13,223 screening opportunities, with a 95.4% compliance rate. A total of 1127 screens were excluded for missing nursing documentation of suspicion of infection, leaving 1192 first screens and 11,489 total screens for analysis. Of the completed screens, 3744 (32.6%) met SIRS criteria; suspicion of infection was noted by both RN and MD/APP in 5.8% of cases, by RN only in 22.2%, by MD/APP only in 7.2%, and by neither provider in 64.7% (Figure 1). Overall agreement rate was 80.7% for suspicion of infection (κ = 0.11, P < 0.001). Demographics by subgroup are shown in the Supplemental Table. Progression to severe sepsis or shock was highest when both providers suspected infection in a SIRS-positive patient (17.7%), was substantially reduced with single-provider suspicion (6.0%), and was lowest when neither provider suspected infection (1.5%) (P < 0.001). A similar trend was found for in-hospital mortality (both providers, 6.3%; single provider, 2.7%; neither provider, 2.5%; P = 0.01). Compared with MD/APP-only suspicion, SIRS-positive patients in whom only RNs suspected infection had similar frequency of progression to severe sepsis or septic shock (6.5% vs 5.6%; P = 0.52) and higher mortality (5.0% vs 1.1%; P = 0.32), though these findings were not statistically significant.

For the 121 patients (10.2%) transferred to ICU, RNs were more likely than MD/APPs to suspect infection at all time points (Figure 2). The difference was small (P = 0.29) 48 hours before transfer (RN, 12.5%; MD/APP, 5.6%) but became more pronounced (P = 0.06) by 3 hours before transfer (RN, 46.3%; MD/APP, 33.1%). Nursing assessments were not available after transfer, but 3 hours after transfer the proportion of patients who met MD/APP suspicion-of-infection criteria (44.6%) was similar (P = 0.90) to that of the RNs 3 hours before transfer (46.3%).

Our findings reveal that bedside nurses and ordering providers routinely have discordant assessments regarding presence of infection. Specifically, when RNs are asked to screen patients on the wards, they are suspicious of infection more often than MD/APPs are, and they suspect infection earlier in ICU transfer patients. These findings have significant implications for patient care, compliance with the new national SEP-1 Centers for Medicare & Medicaid Services quality measure, and identification of appropriate patients for enrollment in sepsis-related clinical trials.

To our knowledge, this is the first study to explore agreement between bedside RN and MD/APP suspicion of infection in sepsis screening and its association with patient outcomes. Studies on nurse and physician concordance in other domains have had mixed findings.^9-11 The high discordance rate found in our study points to the highly subjective nature of suspicion of infection.

Our finding that RNs suspect infection earlier in patients transferred to ICU suggests nursing suspicion has value above and beyond current practice. A possible explanation for the higher rate of RN suspicion, and earlier RN suspicion, is that bedside nurses spend substantially more time with their patients and are more attuned to subtle changes that often occur before any objective signs of deterioration. This phenomenon is well documented and accounts for why rapid response calling criteria often include “nurse worry or concern.”^12,13 Thus, nurse intuition may be an important signal for early identification of patients at high risk for sepsis.

That about one third of all screens met SIRS criteria and that almost two thirds of those screens were not thought by RN or MD/APP to be caused by infection add to the literature demonstrating the limited value of SIRS as a screening tool for sepsis.¹⁴ To address this issue, the 2016 sepsis definitions propose using the quick Sepsis-Related Organ Failure Assessment (qSOFA) to identify patients at high risk for clinical deterioration; however, the Surviving Sepsis Campaign continues to encourage sepsis screening using the SIRS criteria.¹⁵

Limitations of this study include its lack of generalizability, as it was conducted with general medical patients at a single center. Second, we did not specifically ask the MD/APPs whether they suspected infection; instead, we relied on their ordering practices. Third, RN and MD/APP assessments were not independent, as RNs had access to MD/APP orders before making their own assessments, which could bias our results.

Discordance in provider suspicion of infection is common, with RNs documenting suspicion more often than MD/APPs, and earlier in patients transferred to ICU. Suspicion by either provider alone is associated with higher risk for sepsis progression and in-hospital mortality than is the case when neither provider suspects infection. Thus, a collaborative method that includes both RNs and MD/APPs may improve the accuracy and timing of sepsis detection on the wards.

Acknowledgments

The authors thank the members of the Surviving Sepsis Campaign (SSC) Quality Improvement Learning Collaborative at the University of Chicago for their help in data collection and review, especially Meredith Borak, Rita Lanier, Mary Ann Francisco, and Bill Marsack. The authors also thank Thomas Best and Mary-Kate Springman for their assistance in data entry and Nicole Twu for administrative support. Data from this study were provided by the Clinical Research Data Warehouse (CRDW) maintained by the Center for Research Informatics (CRI) at the University of Chicago. CRI is funded by the Biological Sciences Division of the Institute for Translational Medicine/Clinical and Translational Science Award (CTSA) (National Institutes of Health UL1 TR000430) at the University of Chicago.

Disclosures

Dr. Bhattacharjee is supported by postdoctoral training grant 4T32HS000078 from the Agency for Healthcare Research and Quality. Drs. Churpek and Edelson have a patent pending (ARCD.P0535US.P2) for risk stratification algorithms for hospitalized patients. Dr. Churpek is supported by career development award K08 HL121080 from the National Heart, Lung, and Blood Institute. Dr. Edelson has received research support from Philips Healthcare (Andover, Massachusetts), American Heart Association (Dallas, Texas), and Laerdal Medical (Stavanger, Norway) and has ownership interest in Quant HC (Chicago, Illinois), which is developing products for risk stratification of hospitalized patients. The other authors report no conflicts of interest.

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 50-year-old man presented to the emergency department with a 3-day-old cut on his anterior right shin. Associated redness, warmth, pain, and swelling had progressed. The patient had no history of prior DVT or pulmonary embolism (PE). His temperature was 38.5°C, and his white blood cell count of 18,000. On review of systems, he denied shortness of breath and chest pain. He was diagnosed with cellulitis and administered intravenous fluids and cefazolin. The clinician wondered whether to perform lower extremity ultrasound to rule out concurrent DVT.

WHY YOU MIGHT THINK ULTRASOUND IS HELPFUL IN RULING OUT DVT IN CELLULITIS

Lower extremity cellulitis, a common infection of the skin and subcutaneous tissues, is characterized by unilateral erythema, pain, warmth, and swelling. The infection usually follows a skin breach that allows bacteria to enter. DVT may present similarly, and symptoms can include mild leukocytosis and elevated temperature. Because of the clinical similarities, clinicians often order compression ultrasound of the extremity to rule out concurrent DVT in cellulitis. Further impetus for testing stems from fear of the potential complications of untreated DVT, including post-thrombotic syndrome, chronic venous insufficiency, and venous ulceration. A subsequent PE can be fatal, or can cause significant morbidity, including chronic VTE with associated pulmonary hypertension. An estimated quarter of all PEs present as sudden death.¹

WHY ULTRASOUND IS NOT HELPFUL IN THIS SETTING

Studies have shown that ultrasound is ordered for 16% to 73% of patients with a cellulitis diagnosis.^2,3 Although testing is commonly performed, a meta-analysis of 9 studies of cellulitis patients who underwent ultrasound testing for concurrent DVT revealed a low pooled incidence of total DVT (3.1%) and proximal DVT (2.1%).⁴ Maze et al.² retrospectively reviewed 1515 cellulitis cases (identified by International Classification of Diseases, Ninth Revision codes) at a single center in New Zealand over 3 years. Of the 1515 patients, 240 (16%) had ultrasound performed, and only 3 (1.3%) were found to have DVT. Two of the 3 had active malignancy, and the third had injected battery acid into the area. In a 5-year retrospective cohort study at a Veterans Administration hospital in Connecticut, Gunderson and Chang³ reviewed the cases of 183 patients with cellulitis and found ultrasound testing commonly performed (73% of cases) to assess for DVT. Only 1 patient (<1%) was diagnosed with new DVT in the ipsilateral leg, and acute DVT was diagnosed in the contralateral leg of 2 other patients. Overall, these studies indicate the incidence of concurrent DVT in cellulitis is low, regardless of the frequency of ultrasound testing.

Although the cost of a single ultrasound test is not prohibitive, annual total costs hospital-wide and nationally are large. In the United States, the charge for a unilateral duplex ultrasound of the extremity ranges from $260 to $1300, and there is an additional charge for interpretation by a radiologist.⁵ In a retrospective study spanning 3.5 years and involving 2 community hospitals in Michigan, an estimated $290,000 was spent on ultrasound tests defined as unnecessary for patients with cellulitis.⁶ A limitation of the study was defining a test as unnecessary based on its result being negative.

DOES WELLS SCORE WITH D-DIMER HELP DEFINE A LOW-RISK POPULATION?

The Wells clinical prediction rule is commonly used to assess the pretest probability of DVT in patients presenting with unilateral leg symptoms. The Wells score is often combined with D-dimer testing to help determine whether ultrasound is necessary. Studies of patients with suspected DVT have found that those considered low risk according to the Wells criteria had a 6.5% incidence of DVT.⁷ However, the predictive value is lower in the setting of presumed cellulitis. In a prospective cohort study of 200 patients with cellulitis, Maze et al.⁸ reported that use of the Wells score with D-dimer testing overestimated the DVT risk. D-dimer level was elevated for 74% of patients, and 20.5% were high-risk by Wells criteria. An algorithm determined that—among patients with a high-risk Wells score, a positive D-dimer result, or both—only 1 (0.5%) was diagnosed with ipsilateral DVT after ultrasound testing. Two patients were diagnosed with DVT in the contralateral leg. These results suggest that a strategy that incorporates the Wells score and D-dimer testing in the setting of acute cellulitis provides little value. The authors concluded that, in the absence of a known hypercoagulable state, ultrasound is not warranted. However, their study did not assess whether there are any specific hypercoagulable states for which further testing may be indicated.

WHEN MIGHT ULTRASOUND BE HELPFUL IN CELLULITIS?

Investigators have described possible DVT risk factors in patients with cellulitis, but definitive associations are lacking because of the insufficient number of patients studied.^8,9 The most consistently identified DVT risk factor is history of previous thromboembolism. In a retrospective analysis of patients with cellulitis, Afzal et al.⁶ found that, of the 66.8% who underwent ultrasound testing, 5.5% were identified as having concurrent DVT. The authors performed univariate analyses of 15 potential risk factors, including active malignancy, oral contraceptive pill use, recent hospitalization, and surgery. A higher incidence of DVT was found for patients with history of VTE (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.3-13.7), calf swelling (OR, 4.5; 95% CI, 1.3-15.8), CVA (OR, 3.5; 95% CI, 1.2-10.1), or hypertension (OR, 3.5; 95% CI, 0.98-12.2). Given the wide confidence intervals, paucity of studies, and lack of definitive data in the setting of cellulitis, clinicians may want to consider the risk factors established in larger trials in other settings, including known immobility (OR, <2); thrombophilia, CHF, and CVA with hemiparesis (OR, 2-9); and trauma and recent surgery (OR, >10).¹⁰

WHAT YOU SHOULD DO INSTEAD

As the incidence of concurrent VTE in patients with cellulitis is low, the essential step is to make a clear diagnosis of cellulitis based on its established signs and symptoms. A 2-center trial of 145 patients found that cellulitis was diagnosed accurately by general medicine and emergency medicine physicians 72% of the time, with evaluation by dermatologists and infectious disease specialists used as the gold standard. Only 5% of the misdiagnosed patients were diagnosed with DVT; stasis dermatitis was the most common alternative diagnosis. Taking a thorough history may elicit risk factors consistent with cellulitis, such as a recent injury with a break in the skin. On examination, cellulitis should be suspected for patients with fever and localized pain, redness, swelling, and warmth—the cardinal signs of dolor, rubor, tumor, and calor. An injury or entry site and leukocytosis also support the diagnosis of cellulitis. Distinct margins of erythema on the skin are highly suspicious for erysipelas.¹¹ Other physical findings (eg, laceration, purulent drainage, lymphangitic spread, fluctuating mass) also are consistent with a diagnosis of cellulitis.

The patient’s history is also essential in determining whether any DVT risk factors are present. Past medical history of VTE or CVA, or recent history of surgery, immobility, or trauma, should alert the clinician to the possibility of DVT. Family history of VTE increases the likelihood of DVT. Acute shortness of breath or chest pain in the setting of concerning lower extremity findings for DVT should raise concern for DVT and concurrent PE.

If the classic features of cellulitis are present, empiric antibiotics should be initiated. Routine ultrasound testing for all patients with cellulitis is of low value. However, as the incidence of DVT in this population is not negligible, those with VTE risk factors should be targeted for testing. Studies in the setting of cellulitis provide little guidance regarding specific risk factors that can be used to determine who should undergo further testing. Given this limitation, we suggest that clinicians incorporate into their decision making the well-established VTE risk factors identified for large populations studied in other settings, such as the postoperative period. Specifically, clinicians should consider ultrasound testing for patients with cellulitis and prior history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery.^10-12 Ultrasound should also be considered for patients with cellulitis that does not improve and for patients whose localized symptoms worsen despite use of antibiotics.

• Do not routinely perform ultrasound to rule out concurrent DVT in cases of cellulitis.

• Consider compression ultrasound if there is a history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery. Also consider it for patients who do not respond to antibiotics.

• In cases of cellulitis, avoid use of the Wells score alone or with D-dimer testing, as it likely overestimates the DVT risk.

The current evidence shows that, for most patients with cellulitis, routine ultrasound testing for DVT is unnecessary. Ultrasound should be considered for patients with potent VTE risk factors. If symptoms do not improve, or if they worsen despite use of antibiotics, clinicians should be alert to potential anchoring bias and consider DVT. The Wells clinical prediction rule overestimates the incidence of DVT in cellulitis and has little value in this setting.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 50-year-old man presented to the emergency department with a 3-day-old cut on his anterior right shin. Associated redness, warmth, pain, and swelling had progressed. The patient had no history of prior DVT or pulmonary embolism (PE). His temperature was 38.5°C, and his white blood cell count of 18,000. On review of systems, he denied shortness of breath and chest pain. He was diagnosed with cellulitis and administered intravenous fluids and cefazolin. The clinician wondered whether to perform lower extremity ultrasound to rule out concurrent DVT.

WHY YOU MIGHT THINK ULTRASOUND IS HELPFUL IN RULING OUT DVT IN CELLULITIS

Lower extremity cellulitis, a common infection of the skin and subcutaneous tissues, is characterized by unilateral erythema, pain, warmth, and swelling. The infection usually follows a skin breach that allows bacteria to enter. DVT may present similarly, and symptoms can include mild leukocytosis and elevated temperature. Because of the clinical similarities, clinicians often order compression ultrasound of the extremity to rule out concurrent DVT in cellulitis. Further impetus for testing stems from fear of the potential complications of untreated DVT, including post-thrombotic syndrome, chronic venous insufficiency, and venous ulceration. A subsequent PE can be fatal, or can cause significant morbidity, including chronic VTE with associated pulmonary hypertension. An estimated quarter of all PEs present as sudden death.¹

WHY ULTRASOUND IS NOT HELPFUL IN THIS SETTING

Studies have shown that ultrasound is ordered for 16% to 73% of patients with a cellulitis diagnosis.^2,3 Although testing is commonly performed, a meta-analysis of 9 studies of cellulitis patients who underwent ultrasound testing for concurrent DVT revealed a low pooled incidence of total DVT (3.1%) and proximal DVT (2.1%).⁴ Maze et al.² retrospectively reviewed 1515 cellulitis cases (identified by International Classification of Diseases, Ninth Revision codes) at a single center in New Zealand over 3 years. Of the 1515 patients, 240 (16%) had ultrasound performed, and only 3 (1.3%) were found to have DVT. Two of the 3 had active malignancy, and the third had injected battery acid into the area. In a 5-year retrospective cohort study at a Veterans Administration hospital in Connecticut, Gunderson and Chang³ reviewed the cases of 183 patients with cellulitis and found ultrasound testing commonly performed (73% of cases) to assess for DVT. Only 1 patient (<1%) was diagnosed with new DVT in the ipsilateral leg, and acute DVT was diagnosed in the contralateral leg of 2 other patients. Overall, these studies indicate the incidence of concurrent DVT in cellulitis is low, regardless of the frequency of ultrasound testing.

Although the cost of a single ultrasound test is not prohibitive, annual total costs hospital-wide and nationally are large. In the United States, the charge for a unilateral duplex ultrasound of the extremity ranges from $260 to $1300, and there is an additional charge for interpretation by a radiologist.⁵ In a retrospective study spanning 3.5 years and involving 2 community hospitals in Michigan, an estimated $290,000 was spent on ultrasound tests defined as unnecessary for patients with cellulitis.⁶ A limitation of the study was defining a test as unnecessary based on its result being negative.

DOES WELLS SCORE WITH D-DIMER HELP DEFINE A LOW-RISK POPULATION?

The Wells clinical prediction rule is commonly used to assess the pretest probability of DVT in patients presenting with unilateral leg symptoms. The Wells score is often combined with D-dimer testing to help determine whether ultrasound is necessary. Studies of patients with suspected DVT have found that those considered low risk according to the Wells criteria had a 6.5% incidence of DVT.⁷ However, the predictive value is lower in the setting of presumed cellulitis. In a prospective cohort study of 200 patients with cellulitis, Maze et al.⁸ reported that use of the Wells score with D-dimer testing overestimated the DVT risk. D-dimer level was elevated for 74% of patients, and 20.5% were high-risk by Wells criteria. An algorithm determined that—among patients with a high-risk Wells score, a positive D-dimer result, or both—only 1 (0.5%) was diagnosed with ipsilateral DVT after ultrasound testing. Two patients were diagnosed with DVT in the contralateral leg. These results suggest that a strategy that incorporates the Wells score and D-dimer testing in the setting of acute cellulitis provides little value. The authors concluded that, in the absence of a known hypercoagulable state, ultrasound is not warranted. However, their study did not assess whether there are any specific hypercoagulable states for which further testing may be indicated.

WHEN MIGHT ULTRASOUND BE HELPFUL IN CELLULITIS?

Investigators have described possible DVT risk factors in patients with cellulitis, but definitive associations are lacking because of the insufficient number of patients studied.^8,9 The most consistently identified DVT risk factor is history of previous thromboembolism. In a retrospective analysis of patients with cellulitis, Afzal et al.⁶ found that, of the 66.8% who underwent ultrasound testing, 5.5% were identified as having concurrent DVT. The authors performed univariate analyses of 15 potential risk factors, including active malignancy, oral contraceptive pill use, recent hospitalization, and surgery. A higher incidence of DVT was found for patients with history of VTE (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.3-13.7), calf swelling (OR, 4.5; 95% CI, 1.3-15.8), CVA (OR, 3.5; 95% CI, 1.2-10.1), or hypertension (OR, 3.5; 95% CI, 0.98-12.2). Given the wide confidence intervals, paucity of studies, and lack of definitive data in the setting of cellulitis, clinicians may want to consider the risk factors established in larger trials in other settings, including known immobility (OR, <2); thrombophilia, CHF, and CVA with hemiparesis (OR, 2-9); and trauma and recent surgery (OR, >10).¹⁰

WHAT YOU SHOULD DO INSTEAD

As the incidence of concurrent VTE in patients with cellulitis is low, the essential step is to make a clear diagnosis of cellulitis based on its established signs and symptoms. A 2-center trial of 145 patients found that cellulitis was diagnosed accurately by general medicine and emergency medicine physicians 72% of the time, with evaluation by dermatologists and infectious disease specialists used as the gold standard. Only 5% of the misdiagnosed patients were diagnosed with DVT; stasis dermatitis was the most common alternative diagnosis. Taking a thorough history may elicit risk factors consistent with cellulitis, such as a recent injury with a break in the skin. On examination, cellulitis should be suspected for patients with fever and localized pain, redness, swelling, and warmth—the cardinal signs of dolor, rubor, tumor, and calor. An injury or entry site and leukocytosis also support the diagnosis of cellulitis. Distinct margins of erythema on the skin are highly suspicious for erysipelas.¹¹ Other physical findings (eg, laceration, purulent drainage, lymphangitic spread, fluctuating mass) also are consistent with a diagnosis of cellulitis.

The patient’s history is also essential in determining whether any DVT risk factors are present. Past medical history of VTE or CVA, or recent history of surgery, immobility, or trauma, should alert the clinician to the possibility of DVT. Family history of VTE increases the likelihood of DVT. Acute shortness of breath or chest pain in the setting of concerning lower extremity findings for DVT should raise concern for DVT and concurrent PE.

If the classic features of cellulitis are present, empiric antibiotics should be initiated. Routine ultrasound testing for all patients with cellulitis is of low value. However, as the incidence of DVT in this population is not negligible, those with VTE risk factors should be targeted for testing. Studies in the setting of cellulitis provide little guidance regarding specific risk factors that can be used to determine who should undergo further testing. Given this limitation, we suggest that clinicians incorporate into their decision making the well-established VTE risk factors identified for large populations studied in other settings, such as the postoperative period. Specifically, clinicians should consider ultrasound testing for patients with cellulitis and prior history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery.^10-12 Ultrasound should also be considered for patients with cellulitis that does not improve and for patients whose localized symptoms worsen despite use of antibiotics.

• Do not routinely perform ultrasound to rule out concurrent DVT in cases of cellulitis.

• Consider compression ultrasound if there is a history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery. Also consider it for patients who do not respond to antibiotics.

• In cases of cellulitis, avoid use of the Wells score alone or with D-dimer testing, as it likely overestimates the DVT risk.

The current evidence shows that, for most patients with cellulitis, routine ultrasound testing for DVT is unnecessary. Ultrasound should be considered for patients with potent VTE risk factors. If symptoms do not improve, or if they worsen despite use of antibiotics, clinicians should be alert to potential anchoring bias and consider DVT. The Wells clinical prediction rule overestimates the incidence of DVT in cellulitis and has little value in this setting.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 50-year-old man presented to the emergency department with a 3-day-old cut on his anterior right shin. Associated redness, warmth, pain, and swelling had progressed. The patient had no history of prior DVT or pulmonary embolism (PE). His temperature was 38.5°C, and his white blood cell count of 18,000. On review of systems, he denied shortness of breath and chest pain. He was diagnosed with cellulitis and administered intravenous fluids and cefazolin. The clinician wondered whether to perform lower extremity ultrasound to rule out concurrent DVT.

WHY YOU MIGHT THINK ULTRASOUND IS HELPFUL IN RULING OUT DVT IN CELLULITIS

Lower extremity cellulitis, a common infection of the skin and subcutaneous tissues, is characterized by unilateral erythema, pain, warmth, and swelling. The infection usually follows a skin breach that allows bacteria to enter. DVT may present similarly, and symptoms can include mild leukocytosis and elevated temperature. Because of the clinical similarities, clinicians often order compression ultrasound of the extremity to rule out concurrent DVT in cellulitis. Further impetus for testing stems from fear of the potential complications of untreated DVT, including post-thrombotic syndrome, chronic venous insufficiency, and venous ulceration. A subsequent PE can be fatal, or can cause significant morbidity, including chronic VTE with associated pulmonary hypertension. An estimated quarter of all PEs present as sudden death.¹

WHY ULTRASOUND IS NOT HELPFUL IN THIS SETTING

Studies have shown that ultrasound is ordered for 16% to 73% of patients with a cellulitis diagnosis.^2,3 Although testing is commonly performed, a meta-analysis of 9 studies of cellulitis patients who underwent ultrasound testing for concurrent DVT revealed a low pooled incidence of total DVT (3.1%) and proximal DVT (2.1%).⁴ Maze et al.² retrospectively reviewed 1515 cellulitis cases (identified by International Classification of Diseases, Ninth Revision codes) at a single center in New Zealand over 3 years. Of the 1515 patients, 240 (16%) had ultrasound performed, and only 3 (1.3%) were found to have DVT. Two of the 3 had active malignancy, and the third had injected battery acid into the area. In a 5-year retrospective cohort study at a Veterans Administration hospital in Connecticut, Gunderson and Chang³ reviewed the cases of 183 patients with cellulitis and found ultrasound testing commonly performed (73% of cases) to assess for DVT. Only 1 patient (<1%) was diagnosed with new DVT in the ipsilateral leg, and acute DVT was diagnosed in the contralateral leg of 2 other patients. Overall, these studies indicate the incidence of concurrent DVT in cellulitis is low, regardless of the frequency of ultrasound testing.

Although the cost of a single ultrasound test is not prohibitive, annual total costs hospital-wide and nationally are large. In the United States, the charge for a unilateral duplex ultrasound of the extremity ranges from $260 to $1300, and there is an additional charge for interpretation by a radiologist.⁵ In a retrospective study spanning 3.5 years and involving 2 community hospitals in Michigan, an estimated $290,000 was spent on ultrasound tests defined as unnecessary for patients with cellulitis.⁶ A limitation of the study was defining a test as unnecessary based on its result being negative.

DOES WELLS SCORE WITH D-DIMER HELP DEFINE A LOW-RISK POPULATION?

The Wells clinical prediction rule is commonly used to assess the pretest probability of DVT in patients presenting with unilateral leg symptoms. The Wells score is often combined with D-dimer testing to help determine whether ultrasound is necessary. Studies of patients with suspected DVT have found that those considered low risk according to the Wells criteria had a 6.5% incidence of DVT.⁷ However, the predictive value is lower in the setting of presumed cellulitis. In a prospective cohort study of 200 patients with cellulitis, Maze et al.⁸ reported that use of the Wells score with D-dimer testing overestimated the DVT risk. D-dimer level was elevated for 74% of patients, and 20.5% were high-risk by Wells criteria. An algorithm determined that—among patients with a high-risk Wells score, a positive D-dimer result, or both—only 1 (0.5%) was diagnosed with ipsilateral DVT after ultrasound testing. Two patients were diagnosed with DVT in the contralateral leg. These results suggest that a strategy that incorporates the Wells score and D-dimer testing in the setting of acute cellulitis provides little value. The authors concluded that, in the absence of a known hypercoagulable state, ultrasound is not warranted. However, their study did not assess whether there are any specific hypercoagulable states for which further testing may be indicated.

WHEN MIGHT ULTRASOUND BE HELPFUL IN CELLULITIS?

Investigators have described possible DVT risk factors in patients with cellulitis, but definitive associations are lacking because of the insufficient number of patients studied.^8,9 The most consistently identified DVT risk factor is history of previous thromboembolism. In a retrospective analysis of patients with cellulitis, Afzal et al.⁶ found that, of the 66.8% who underwent ultrasound testing, 5.5% were identified as having concurrent DVT. The authors performed univariate analyses of 15 potential risk factors, including active malignancy, oral contraceptive pill use, recent hospitalization, and surgery. A higher incidence of DVT was found for patients with history of VTE (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.3-13.7), calf swelling (OR, 4.5; 95% CI, 1.3-15.8), CVA (OR, 3.5; 95% CI, 1.2-10.1), or hypertension (OR, 3.5; 95% CI, 0.98-12.2). Given the wide confidence intervals, paucity of studies, and lack of definitive data in the setting of cellulitis, clinicians may want to consider the risk factors established in larger trials in other settings, including known immobility (OR, <2); thrombophilia, CHF, and CVA with hemiparesis (OR, 2-9); and trauma and recent surgery (OR, >10).¹⁰

WHAT YOU SHOULD DO INSTEAD

As the incidence of concurrent VTE in patients with cellulitis is low, the essential step is to make a clear diagnosis of cellulitis based on its established signs and symptoms. A 2-center trial of 145 patients found that cellulitis was diagnosed accurately by general medicine and emergency medicine physicians 72% of the time, with evaluation by dermatologists and infectious disease specialists used as the gold standard. Only 5% of the misdiagnosed patients were diagnosed with DVT; stasis dermatitis was the most common alternative diagnosis. Taking a thorough history may elicit risk factors consistent with cellulitis, such as a recent injury with a break in the skin. On examination, cellulitis should be suspected for patients with fever and localized pain, redness, swelling, and warmth—the cardinal signs of dolor, rubor, tumor, and calor. An injury or entry site and leukocytosis also support the diagnosis of cellulitis. Distinct margins of erythema on the skin are highly suspicious for erysipelas.¹¹ Other physical findings (eg, laceration, purulent drainage, lymphangitic spread, fluctuating mass) also are consistent with a diagnosis of cellulitis.

The patient’s history is also essential in determining whether any DVT risk factors are present. Past medical history of VTE or CVA, or recent history of surgery, immobility, or trauma, should alert the clinician to the possibility of DVT. Family history of VTE increases the likelihood of DVT. Acute shortness of breath or chest pain in the setting of concerning lower extremity findings for DVT should raise concern for DVT and concurrent PE.

If the classic features of cellulitis are present, empiric antibiotics should be initiated. Routine ultrasound testing for all patients with cellulitis is of low value. However, as the incidence of DVT in this population is not negligible, those with VTE risk factors should be targeted for testing. Studies in the setting of cellulitis provide little guidance regarding specific risk factors that can be used to determine who should undergo further testing. Given this limitation, we suggest that clinicians incorporate into their decision making the well-established VTE risk factors identified for large populations studied in other settings, such as the postoperative period. Specifically, clinicians should consider ultrasound testing for patients with cellulitis and prior history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery.^10-12 Ultrasound should also be considered for patients with cellulitis that does not improve and for patients whose localized symptoms worsen despite use of antibiotics.

• Do not routinely perform ultrasound to rule out concurrent DVT in cases of cellulitis.

• Consider compression ultrasound if there is a history of VTE; immobility; thrombophilia, CHF, and CVA with hemiparesis; or trauma and recent surgery. Also consider it for patients who do not respond to antibiotics.

• In cases of cellulitis, avoid use of the Wells score alone or with D-dimer testing, as it likely overestimates the DVT risk.

The current evidence shows that, for most patients with cellulitis, routine ultrasound testing for DVT is unnecessary. Ultrasound should be considered for patients with potent VTE risk factors. If symptoms do not improve, or if they worsen despite use of antibiotics, clinicians should be alert to potential anchoring bias and consider DVT. The Wells clinical prediction rule overestimates the incidence of DVT in cellulitis and has little value in this setting.

Disclosure

Nothing to report.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook and don’t forget to “Like It” on Facebook or retweet it on Twitter. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

Two weeks after undergoing a below-knee amputation (BKA) and 10 days after being discharged to a skilled nursing facility (SNF), an 87-year-old man returned to the emergency department (ED) for evaluation of somnolence and altered mental state. In the ED, he was disoriented and unable to provide a detailed history.

The differential diagnosis for acute confusion and altered consciousness is broad. Initial possibilities include toxic-metabolic abnormalities, medication side effects, and infections. Urinary tract infection, pneumonia, and surgical-site infection should be assessed for first, as they are common causes of postoperative altered mentation. Next to be considered are subclinical seizure, ischemic stroke, and infectious encephalitis or meningitis, along with hemorrhagic stroke and subdural hematoma.

During initial assessment, the clinician should ascertain baseline mental state, the timeline of the change in mental status, recent medication changes, history of substance abuse, and concern about any recent trauma, such as a fall. Performing the physical examination, the clinician should assess vital signs and then focus on identifying localizing neurologic deficits.

First steps in the work-up include a complete metabolic panel, complete blood cell count, urinalysis with culture, and a urine toxicology screen. If the patient has a “toxic” appearance, blood cultures should be obtained. An electrocardiogram should be used to screen for drug toxicity or evidence of cardiac ischemia. If laboratory test results do not reveal an obvious infectious or metabolic cause, a noncontrast computed tomography (CT) of the head should be obtained. In terms of early interventions, a low glucose level should be treated with thiamine and then glucose, and naloxone should be given if there is any suspicion of narcotic overdose.

More history was obtained from the patient’s records. The BKA was performed to address a nonhealing transmetatarsal amputation. Two months earlier, the transmetatarsal amputation had been performed as treatment for a diabetic forefoot ulcer with chronic osteomyelitis. The patient’s post-BKA course was uncomplicated. He was started on intravenous (IV) ertapenem on postoperative day 1, and on postoperative day 4 was discharged to the SNF to complete a 6-week course of antibiotics for osteomyelitis. Past medical history included paroxysmal atrial fibrillation, coronary artery disease, congestive heart failure (ejection fraction 40%), and type 2 diabetes mellitus. Medications given at the SNF were oxycodone, acetaminophen, cholecalciferol, melatonin, digoxin, ondansetron, furosemide, gabapentin, correctional insulin, tamsulosin, senna, docusate, warfarin, and metoprolol. While there, the patient’s family expressed concern about his diminishing “mental ability.” They reported he had been fully alert and oriented on arrival at the SNF, and living independently with his wife before the BKA. Then, a week before the ED presentation, he started becoming more somnolent and forgetful. The gabapentin and oxycodone dosages were reduced to minimize their sedative effects, but he showed no improvement. At the SNF, a somnolence work-up was not performed.

Several of the patient’s medications can contribute to altered mental state. Ertapenem can cause seizures as well as profound mental status changes, though these are more likely in the setting of poor renal function. The mental status changes were noticed about a week into the patient’s course of antibiotics, which suggests a possible temporal correlation with the initiation of ertapenem. An electroencephalogram is required to diagnose nonconvulsive seizure activity. Narcotic overdose should still be considered, despite the recent reduction in oxycodone dosage. Digoxin toxicity, though less likely when the dose is stable and there are no changes in renal function, can cause a confused state. Concurrent use of furosemide could potentiate the toxic effects of digoxin.

Non-medication-related concerns include hypoglycemia, hyperglycemia, and, given his history of atrial fibrillation, cardioembolic stroke. Although generalized confusion is not a common manifestation of stroke, a thalamic stroke can alter mental state but be easily missed if not specifically considered. Additional lab work-up should include a digoxin level and, since he is taking warfarin, a prothrombin time/international normalized ratio (PT/INR). If the initial laboratory studies and head CT do not explain the altered mental state, magnetic resonance imaging (MRI) of the brain should be performed to further assess for stroke.

On physical examination in the ED, the patient was resting comfortably with eyes closed, and arousing to voice. He obeyed commands and participated in the examination. His Glasgow Coma Scale score was 13; temperature, 36.8°C, heart rate, 80 beats per minute; respiratory rate, 16 breaths per minute; blood pressure, 90/57 mm Hg; and 100% peripheral capillary oxygen saturation while breathing ambient air. He appeared well developed. His heart rhythm was irregularly irregular, without murmurs, rubs, or gallops. Respiratory and abdominal examination findings were normal. The left BKA incision was well approximated, with no drainage, dehiscence, fluctuance, or erythema. On neurologic examination, the patient was intermittently oriented only to self. Pupils were equal, round, and reactive to light; extraocular movements were intact; face was symmetric; tongue was midline; sensation on face was equal bilaterally; and shoulder shrug was intact. Strength was 5/5 and symmetric in the elbow and hip and 5/5 in the right knee and ankle (not tested on left because of BKA). Deep tendon reflexes were 3+ and symmetrical at the biceps, brachioradialis, and triceps tendons and 3+ in the right patellar and Achilles tendons. Sensation was intact and symmetrical in the upper and lower extremities. The patient’s speech was slow and slurred, and his answers were unrelated to the questions being asked.

The patient’s mental state is best described as lethargic. As he is only intermittently oriented, he meets the criteria for delirium. He is not obtunded or comatose, and his pupils are at least reactive, not pinpoint, so narcotic overdose is less likely. Thalamic stroke remains in the differential diagnosis; despite the seemingly symmetrical sensation examination, hemisensory deficits cannot be definitively ruled out given the patient’s mental state. A rare entity such as carcinomatosis meningitis or another diffuse, infiltrative neoplastic process could be causing his condition. However, because focal deficits other than abnormal speech and diffuse hyperreflexia are absent, toxic, infectious, or metabolic causes are more likely than structural abnormalities. Still possible is a medication toxicity, such as ertapenem toxicity or, less likely, digoxin toxicity. In terms of infectious possibilities, urinary tract infection could certainly present in this fashion, especially if the patient had a somewhat low neurologic reserve at baseline, and hypotension could be secondary to sepsis. Encephalitis or meningitis remains in the differential diagnosis, though the patient appears nontoxic, and therefore a bacterial etiology is very unlikely.

The patient’s hyperreflexia may be an important clue. Although the strength of his reflexes at baseline is unknown, seizures can cause transiently increased reflexes as well as a confused, lethargic mental state. Reflexes can also be increased by a drug overdose that has caused serotonin syndrome. Of the patient’s medications, only ondansetron can cause this reaction. Hyperthyroidism can cause brisk reflexes and confusion, though more typically it causes agitated confusion. A thyroid-stimulating hormone level should be added to the initial laboratory panel.

A complete blood count revealed white blood cell count 11.86 K/uL with neutrophilic predominance and immature granulocytes, hemoglobin 11.5 g/dL, and platelet count 323 K/uL. Serum sodium was 141 mEq/L, potassium 4.2 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, creatinine 1.14 mg/dL (prior baseline of 0.8-1.0 mg/dL), blood urea nitrogen 26 mg/dL, blood glucose 159 mg/dL, and calcium 9.1 mg/dL. His digoxin level was 1.3 ng/mL (reference range 0.5-1.9 mg/mL) and troponin was undetectable. INR was 2.7 and partial thromboplastin time (PTT) 60 seconds. Vitamin B₁₂ level was 674 pg/mL (reference range >180). A urinalysis had 1+ hyaline casts and was negative for nitrites, leukocyte esterase, blood, and bacteria. An ECG revealed atrial fibrillation with a ventricular rate of 80 beats per minute. A chest radiograph showed clear lung fields. A CT of the head without IV contrast had no evidence of an acute intracranial abnormality. In the ED, 1 liter of IV normal saline was given and blood pressure improved to 127/72 mm Hg.

The head CT does not show intracranial bleeding, and, though it is reassuring that INR is in the therapeutic range, ischemic stroke must remain in the differential diagnosis. Sepsis is less likely given that the criteria for systemic inflammatory response syndrome are not met, and hypotension was rapidly corrected with administration of IV fluids. Urinary tract infection was ruled out with the negative urinalysis. Subclinical seizures remain possible, as does medication-related or other toxicity. A medication overdose, intentional or otherwise, should also be considered.

The patient was admitted to the hospital. On reassessment by the inpatient team, he was oriented only to self, frequently falling asleep, and not recalling earlier conversations when aroused. His speech remained slurred and difficult to understand. Neurologic examination findings were unchanged since the ED examination. On additional cerebellar examination, he had dysmetria with finger-to-nose testing bilaterally and dysdiadochokinesia (impaired rapid alternating movements) of the left hand.

His handedness is not mentioned; the dysdiadochokinesia of the left hand may reflect the patient’s being right-handed, or may signify a focal cerebellar lesion. The cerebellum is also implicated by the bilateral dysmetria. Persistent somnolence in the absence of CT findings suggests a metabolic or infectious process. Metabolic processes that can cause bilateral cerebellar ataxia and somnolence include overdose of a drug or medication. Use of alcohol or a medication such as phenytoin, valproic acid, or a benzodiazepine can cause the symptoms in this case, but was not reported by the family, and there was no documentation of it in the SNF records. Wernicke encephalopathy is rare and is not well supported by the patient’s presentation but should be considered, as it can be easily treated with thiamine. Meningoencephalitis affecting the cerebellum remains possible, but infection is less likely. Both electroencephalogram and brain MRI should be performed, with a specific interest in possible cerebellar lesions. If the MRI is unremarkable, a lumbar puncture should be performed to assess opening pressure and investigate for infectious etiologies.

MRI of the brain showed age-related volume loss and nonspecific white matter disease without acute changes. Lack of a clear explanation for the neurologic findings led to suspicion of a medication side effect. Ertapenem was stopped on admission because it has been reported to rarely cause altered mental status. IV moxifloxacin was started for the osteomyelitis. Over the next 2 days, symptoms began resolving; within 24 hours of ertapenem discontinuation, the patient was awake, alert, and talkative. On examination, he remained dysarthric but was no longer dysmetric. Within 48 hours, the dysarthria was completely resolved, and he was returned to the SNF to complete a course of IV moxifloxacin.

Among elderly patients presenting to the ED, altered mental status is a common complaint, accounting for 10% to 30% of visits.¹ Medications are a common cause of altered mental status among the elderly and are responsible for 40% of delirium cases.¹ The risk of adverse drug events (ADEs) rises with the number of medications prescribed.^1-3 Among patients older than 60 years, the incidence of polypharmacy (defined as taking >5 prescription medications) increased from roughly 20% in 1999 to 40% in 2012.^4,5 The most common ADEs in the ambulatory setting (25%) are central nervous system (CNS) symptoms, including dizziness, sleep disturbances, and mood changes.⁶ A medication effect should be suspected in any elderly patient presenting with altered mental state.

The present patient developed a constellation of neurologic symptoms after starting ertapenem, one of the carbapenem antibiotics, which is a class of medications that can cause CNS ADEs. Carbapenems are renally cleared, and adjustments must be made for acute or chronic changes in kidney function. Carbapenems are associated with increased risk of seizure; the incidence of seizure with ertapenem is 0.2%.^7,8 Food and Drug Administration postmarketing reports have noted ertapenem can cause somnolence and dyskinesia,⁹ and several case reports have described ertapenem-associated CNS side effects, including psychosis and encephalopathy.^10-13 Symptoms and examination findings can include confusion, disorientation, garbled speech, dysphagia, hallucinations, miosis, myoclonus, tremor, and agitation.^10-13 Although reports of dysmetria and dysdiadochokinesia are lacking, suspicion of an ADE in this case was heightened by the timing of the exposure and the absence of alternative infectious, metabolic, and vascular explanations for bilateral cerebellar dysfunction.

The Naranjo Adverse Drug Reaction (ADR) scale may help clinicians differentiate ADEs from other etiologies of symptoms. It uses 10 weighted questions (Table) to estimate the probability that an adverse clinical event is caused by a drug reaction.¹⁴ The present case was assigned 1 point for prior reports of neurologic ADEs associated with ertapenem, 2 for the temporal association, 1 for resolution after medication withdrawal, 2 for lack of alternative causes, and 1 for objective evidence of neurologic dysfunction—for a total of 7 points, indicating ertapenem was probably the cause of the patient’s neurologic symptoms. Of 4 prior cases in which carbapenem toxicity was suspected and the Naranjo scale was used, 3 found a probable relationship, and the fourth a highly probable one.^10,12 Confusion, disorientation, hallucinations, tangential thoughts, and garbled speech were reported in the 3 probable cases of ADEs. In the highly probable case, tangential thoughts, garbled speech, and miosis were noted on examination, and these findings returned after re-exposure to ertapenem. Of note, these ADEs occurred in patients with normal and abnormal renal function, and in middle-aged and elderly patients.^10,11,13

• Clinicians should include rare adverse effects of common medications in the differential diagnosis.

• The Naranjo score is a validated tool that can be used to systematically assess the probability of an adverse drug effect at the bedside.

• The presentation of ertapenem-associated neurotoxicity may include features of bilateral cerebellar dysfunction.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

Two weeks after undergoing a below-knee amputation (BKA) and 10 days after being discharged to a skilled nursing facility (SNF), an 87-year-old man returned to the emergency department (ED) for evaluation of somnolence and altered mental state. In the ED, he was disoriented and unable to provide a detailed history.

The differential diagnosis for acute confusion and altered consciousness is broad. Initial possibilities include toxic-metabolic abnormalities, medication side effects, and infections. Urinary tract infection, pneumonia, and surgical-site infection should be assessed for first, as they are common causes of postoperative altered mentation. Next to be considered are subclinical seizure, ischemic stroke, and infectious encephalitis or meningitis, along with hemorrhagic stroke and subdural hematoma.

During initial assessment, the clinician should ascertain baseline mental state, the timeline of the change in mental status, recent medication changes, history of substance abuse, and concern about any recent trauma, such as a fall. Performing the physical examination, the clinician should assess vital signs and then focus on identifying localizing neurologic deficits.

First steps in the work-up include a complete metabolic panel, complete blood cell count, urinalysis with culture, and a urine toxicology screen. If the patient has a “toxic” appearance, blood cultures should be obtained. An electrocardiogram should be used to screen for drug toxicity or evidence of cardiac ischemia. If laboratory test results do not reveal an obvious infectious or metabolic cause, a noncontrast computed tomography (CT) of the head should be obtained. In terms of early interventions, a low glucose level should be treated with thiamine and then glucose, and naloxone should be given if there is any suspicion of narcotic overdose.

More history was obtained from the patient’s records. The BKA was performed to address a nonhealing transmetatarsal amputation. Two months earlier, the transmetatarsal amputation had been performed as treatment for a diabetic forefoot ulcer with chronic osteomyelitis. The patient’s post-BKA course was uncomplicated. He was started on intravenous (IV) ertapenem on postoperative day 1, and on postoperative day 4 was discharged to the SNF to complete a 6-week course of antibiotics for osteomyelitis. Past medical history included paroxysmal atrial fibrillation, coronary artery disease, congestive heart failure (ejection fraction 40%), and type 2 diabetes mellitus. Medications given at the SNF were oxycodone, acetaminophen, cholecalciferol, melatonin, digoxin, ondansetron, furosemide, gabapentin, correctional insulin, tamsulosin, senna, docusate, warfarin, and metoprolol. While there, the patient’s family expressed concern about his diminishing “mental ability.” They reported he had been fully alert and oriented on arrival at the SNF, and living independently with his wife before the BKA. Then, a week before the ED presentation, he started becoming more somnolent and forgetful. The gabapentin and oxycodone dosages were reduced to minimize their sedative effects, but he showed no improvement. At the SNF, a somnolence work-up was not performed.

Several of the patient’s medications can contribute to altered mental state. Ertapenem can cause seizures as well as profound mental status changes, though these are more likely in the setting of poor renal function. The mental status changes were noticed about a week into the patient’s course of antibiotics, which suggests a possible temporal correlation with the initiation of ertapenem. An electroencephalogram is required to diagnose nonconvulsive seizure activity. Narcotic overdose should still be considered, despite the recent reduction in oxycodone dosage. Digoxin toxicity, though less likely when the dose is stable and there are no changes in renal function, can cause a confused state. Concurrent use of furosemide could potentiate the toxic effects of digoxin.

Non-medication-related concerns include hypoglycemia, hyperglycemia, and, given his history of atrial fibrillation, cardioembolic stroke. Although generalized confusion is not a common manifestation of stroke, a thalamic stroke can alter mental state but be easily missed if not specifically considered. Additional lab work-up should include a digoxin level and, since he is taking warfarin, a prothrombin time/international normalized ratio (PT/INR). If the initial laboratory studies and head CT do not explain the altered mental state, magnetic resonance imaging (MRI) of the brain should be performed to further assess for stroke.

On physical examination in the ED, the patient was resting comfortably with eyes closed, and arousing to voice. He obeyed commands and participated in the examination. His Glasgow Coma Scale score was 13; temperature, 36.8°C, heart rate, 80 beats per minute; respiratory rate, 16 breaths per minute; blood pressure, 90/57 mm Hg; and 100% peripheral capillary oxygen saturation while breathing ambient air. He appeared well developed. His heart rhythm was irregularly irregular, without murmurs, rubs, or gallops. Respiratory and abdominal examination findings were normal. The left BKA incision was well approximated, with no drainage, dehiscence, fluctuance, or erythema. On neurologic examination, the patient was intermittently oriented only to self. Pupils were equal, round, and reactive to light; extraocular movements were intact; face was symmetric; tongue was midline; sensation on face was equal bilaterally; and shoulder shrug was intact. Strength was 5/5 and symmetric in the elbow and hip and 5/5 in the right knee and ankle (not tested on left because of BKA). Deep tendon reflexes were 3+ and symmetrical at the biceps, brachioradialis, and triceps tendons and 3+ in the right patellar and Achilles tendons. Sensation was intact and symmetrical in the upper and lower extremities. The patient’s speech was slow and slurred, and his answers were unrelated to the questions being asked.

The patient’s mental state is best described as lethargic. As he is only intermittently oriented, he meets the criteria for delirium. He is not obtunded or comatose, and his pupils are at least reactive, not pinpoint, so narcotic overdose is less likely. Thalamic stroke remains in the differential diagnosis; despite the seemingly symmetrical sensation examination, hemisensory deficits cannot be definitively ruled out given the patient’s mental state. A rare entity such as carcinomatosis meningitis or another diffuse, infiltrative neoplastic process could be causing his condition. However, because focal deficits other than abnormal speech and diffuse hyperreflexia are absent, toxic, infectious, or metabolic causes are more likely than structural abnormalities. Still possible is a medication toxicity, such as ertapenem toxicity or, less likely, digoxin toxicity. In terms of infectious possibilities, urinary tract infection could certainly present in this fashion, especially if the patient had a somewhat low neurologic reserve at baseline, and hypotension could be secondary to sepsis. Encephalitis or meningitis remains in the differential diagnosis, though the patient appears nontoxic, and therefore a bacterial etiology is very unlikely.

The patient’s hyperreflexia may be an important clue. Although the strength of his reflexes at baseline is unknown, seizures can cause transiently increased reflexes as well as a confused, lethargic mental state. Reflexes can also be increased by a drug overdose that has caused serotonin syndrome. Of the patient’s medications, only ondansetron can cause this reaction. Hyperthyroidism can cause brisk reflexes and confusion, though more typically it causes agitated confusion. A thyroid-stimulating hormone level should be added to the initial laboratory panel.

A complete blood count revealed white blood cell count 11.86 K/uL with neutrophilic predominance and immature granulocytes, hemoglobin 11.5 g/dL, and platelet count 323 K/uL. Serum sodium was 141 mEq/L, potassium 4.2 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, creatinine 1.14 mg/dL (prior baseline of 0.8-1.0 mg/dL), blood urea nitrogen 26 mg/dL, blood glucose 159 mg/dL, and calcium 9.1 mg/dL. His digoxin level was 1.3 ng/mL (reference range 0.5-1.9 mg/mL) and troponin was undetectable. INR was 2.7 and partial thromboplastin time (PTT) 60 seconds. Vitamin B₁₂ level was 674 pg/mL (reference range >180). A urinalysis had 1+ hyaline casts and was negative for nitrites, leukocyte esterase, blood, and bacteria. An ECG revealed atrial fibrillation with a ventricular rate of 80 beats per minute. A chest radiograph showed clear lung fields. A CT of the head without IV contrast had no evidence of an acute intracranial abnormality. In the ED, 1 liter of IV normal saline was given and blood pressure improved to 127/72 mm Hg.

The head CT does not show intracranial bleeding, and, though it is reassuring that INR is in the therapeutic range, ischemic stroke must remain in the differential diagnosis. Sepsis is less likely given that the criteria for systemic inflammatory response syndrome are not met, and hypotension was rapidly corrected with administration of IV fluids. Urinary tract infection was ruled out with the negative urinalysis. Subclinical seizures remain possible, as does medication-related or other toxicity. A medication overdose, intentional or otherwise, should also be considered.

The patient was admitted to the hospital. On reassessment by the inpatient team, he was oriented only to self, frequently falling asleep, and not recalling earlier conversations when aroused. His speech remained slurred and difficult to understand. Neurologic examination findings were unchanged since the ED examination. On additional cerebellar examination, he had dysmetria with finger-to-nose testing bilaterally and dysdiadochokinesia (impaired rapid alternating movements) of the left hand.

His handedness is not mentioned; the dysdiadochokinesia of the left hand may reflect the patient’s being right-handed, or may signify a focal cerebellar lesion. The cerebellum is also implicated by the bilateral dysmetria. Persistent somnolence in the absence of CT findings suggests a metabolic or infectious process. Metabolic processes that can cause bilateral cerebellar ataxia and somnolence include overdose of a drug or medication. Use of alcohol or a medication such as phenytoin, valproic acid, or a benzodiazepine can cause the symptoms in this case, but was not reported by the family, and there was no documentation of it in the SNF records. Wernicke encephalopathy is rare and is not well supported by the patient’s presentation but should be considered, as it can be easily treated with thiamine. Meningoencephalitis affecting the cerebellum remains possible, but infection is less likely. Both electroencephalogram and brain MRI should be performed, with a specific interest in possible cerebellar lesions. If the MRI is unremarkable, a lumbar puncture should be performed to assess opening pressure and investigate for infectious etiologies.

MRI of the brain showed age-related volume loss and nonspecific white matter disease without acute changes. Lack of a clear explanation for the neurologic findings led to suspicion of a medication side effect. Ertapenem was stopped on admission because it has been reported to rarely cause altered mental status. IV moxifloxacin was started for the osteomyelitis. Over the next 2 days, symptoms began resolving; within 24 hours of ertapenem discontinuation, the patient was awake, alert, and talkative. On examination, he remained dysarthric but was no longer dysmetric. Within 48 hours, the dysarthria was completely resolved, and he was returned to the SNF to complete a course of IV moxifloxacin.

Among elderly patients presenting to the ED, altered mental status is a common complaint, accounting for 10% to 30% of visits.¹ Medications are a common cause of altered mental status among the elderly and are responsible for 40% of delirium cases.¹ The risk of adverse drug events (ADEs) rises with the number of medications prescribed.^1-3 Among patients older than 60 years, the incidence of polypharmacy (defined as taking >5 prescription medications) increased from roughly 20% in 1999 to 40% in 2012.^4,5 The most common ADEs in the ambulatory setting (25%) are central nervous system (CNS) symptoms, including dizziness, sleep disturbances, and mood changes.⁶ A medication effect should be suspected in any elderly patient presenting with altered mental state.

The present patient developed a constellation of neurologic symptoms after starting ertapenem, one of the carbapenem antibiotics, which is a class of medications that can cause CNS ADEs. Carbapenems are renally cleared, and adjustments must be made for acute or chronic changes in kidney function. Carbapenems are associated with increased risk of seizure; the incidence of seizure with ertapenem is 0.2%.^7,8 Food and Drug Administration postmarketing reports have noted ertapenem can cause somnolence and dyskinesia,⁹ and several case reports have described ertapenem-associated CNS side effects, including psychosis and encephalopathy.^10-13 Symptoms and examination findings can include confusion, disorientation, garbled speech, dysphagia, hallucinations, miosis, myoclonus, tremor, and agitation.^10-13 Although reports of dysmetria and dysdiadochokinesia are lacking, suspicion of an ADE in this case was heightened by the timing of the exposure and the absence of alternative infectious, metabolic, and vascular explanations for bilateral cerebellar dysfunction.

The Naranjo Adverse Drug Reaction (ADR) scale may help clinicians differentiate ADEs from other etiologies of symptoms. It uses 10 weighted questions (Table) to estimate the probability that an adverse clinical event is caused by a drug reaction.¹⁴ The present case was assigned 1 point for prior reports of neurologic ADEs associated with ertapenem, 2 for the temporal association, 1 for resolution after medication withdrawal, 2 for lack of alternative causes, and 1 for objective evidence of neurologic dysfunction—for a total of 7 points, indicating ertapenem was probably the cause of the patient’s neurologic symptoms. Of 4 prior cases in which carbapenem toxicity was suspected and the Naranjo scale was used, 3 found a probable relationship, and the fourth a highly probable one.^10,12 Confusion, disorientation, hallucinations, tangential thoughts, and garbled speech were reported in the 3 probable cases of ADEs. In the highly probable case, tangential thoughts, garbled speech, and miosis were noted on examination, and these findings returned after re-exposure to ertapenem. Of note, these ADEs occurred in patients with normal and abnormal renal function, and in middle-aged and elderly patients.^10,11,13

• Clinicians should include rare adverse effects of common medications in the differential diagnosis.

• The Naranjo score is a validated tool that can be used to systematically assess the probability of an adverse drug effect at the bedside.

• The presentation of ertapenem-associated neurotoxicity may include features of bilateral cerebellar dysfunction.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

Two weeks after undergoing a below-knee amputation (BKA) and 10 days after being discharged to a skilled nursing facility (SNF), an 87-year-old man returned to the emergency department (ED) for evaluation of somnolence and altered mental state. In the ED, he was disoriented and unable to provide a detailed history.

The differential diagnosis for acute confusion and altered consciousness is broad. Initial possibilities include toxic-metabolic abnormalities, medication side effects, and infections. Urinary tract infection, pneumonia, and surgical-site infection should be assessed for first, as they are common causes of postoperative altered mentation. Next to be considered are subclinical seizure, ischemic stroke, and infectious encephalitis or meningitis, along with hemorrhagic stroke and subdural hematoma.

During initial assessment, the clinician should ascertain baseline mental state, the timeline of the change in mental status, recent medication changes, history of substance abuse, and concern about any recent trauma, such as a fall. Performing the physical examination, the clinician should assess vital signs and then focus on identifying localizing neurologic deficits.

First steps in the work-up include a complete metabolic panel, complete blood cell count, urinalysis with culture, and a urine toxicology screen. If the patient has a “toxic” appearance, blood cultures should be obtained. An electrocardiogram should be used to screen for drug toxicity or evidence of cardiac ischemia. If laboratory test results do not reveal an obvious infectious or metabolic cause, a noncontrast computed tomography (CT) of the head should be obtained. In terms of early interventions, a low glucose level should be treated with thiamine and then glucose, and naloxone should be given if there is any suspicion of narcotic overdose.

More history was obtained from the patient’s records. The BKA was performed to address a nonhealing transmetatarsal amputation. Two months earlier, the transmetatarsal amputation had been performed as treatment for a diabetic forefoot ulcer with chronic osteomyelitis. The patient’s post-BKA course was uncomplicated. He was started on intravenous (IV) ertapenem on postoperative day 1, and on postoperative day 4 was discharged to the SNF to complete a 6-week course of antibiotics for osteomyelitis. Past medical history included paroxysmal atrial fibrillation, coronary artery disease, congestive heart failure (ejection fraction 40%), and type 2 diabetes mellitus. Medications given at the SNF were oxycodone, acetaminophen, cholecalciferol, melatonin, digoxin, ondansetron, furosemide, gabapentin, correctional insulin, tamsulosin, senna, docusate, warfarin, and metoprolol. While there, the patient’s family expressed concern about his diminishing “mental ability.” They reported he had been fully alert and oriented on arrival at the SNF, and living independently with his wife before the BKA. Then, a week before the ED presentation, he started becoming more somnolent and forgetful. The gabapentin and oxycodone dosages were reduced to minimize their sedative effects, but he showed no improvement. At the SNF, a somnolence work-up was not performed.

Several of the patient’s medications can contribute to altered mental state. Ertapenem can cause seizures as well as profound mental status changes, though these are more likely in the setting of poor renal function. The mental status changes were noticed about a week into the patient’s course of antibiotics, which suggests a possible temporal correlation with the initiation of ertapenem. An electroencephalogram is required to diagnose nonconvulsive seizure activity. Narcotic overdose should still be considered, despite the recent reduction in oxycodone dosage. Digoxin toxicity, though less likely when the dose is stable and there are no changes in renal function, can cause a confused state. Concurrent use of furosemide could potentiate the toxic effects of digoxin.

Non-medication-related concerns include hypoglycemia, hyperglycemia, and, given his history of atrial fibrillation, cardioembolic stroke. Although generalized confusion is not a common manifestation of stroke, a thalamic stroke can alter mental state but be easily missed if not specifically considered. Additional lab work-up should include a digoxin level and, since he is taking warfarin, a prothrombin time/international normalized ratio (PT/INR). If the initial laboratory studies and head CT do not explain the altered mental state, magnetic resonance imaging (MRI) of the brain should be performed to further assess for stroke.

On physical examination in the ED, the patient was resting comfortably with eyes closed, and arousing to voice. He obeyed commands and participated in the examination. His Glasgow Coma Scale score was 13; temperature, 36.8°C, heart rate, 80 beats per minute; respiratory rate, 16 breaths per minute; blood pressure, 90/57 mm Hg; and 100% peripheral capillary oxygen saturation while breathing ambient air. He appeared well developed. His heart rhythm was irregularly irregular, without murmurs, rubs, or gallops. Respiratory and abdominal examination findings were normal. The left BKA incision was well approximated, with no drainage, dehiscence, fluctuance, or erythema. On neurologic examination, the patient was intermittently oriented only to self. Pupils were equal, round, and reactive to light; extraocular movements were intact; face was symmetric; tongue was midline; sensation on face was equal bilaterally; and shoulder shrug was intact. Strength was 5/5 and symmetric in the elbow and hip and 5/5 in the right knee and ankle (not tested on left because of BKA). Deep tendon reflexes were 3+ and symmetrical at the biceps, brachioradialis, and triceps tendons and 3+ in the right patellar and Achilles tendons. Sensation was intact and symmetrical in the upper and lower extremities. The patient’s speech was slow and slurred, and his answers were unrelated to the questions being asked.

The patient’s mental state is best described as lethargic. As he is only intermittently oriented, he meets the criteria for delirium. He is not obtunded or comatose, and his pupils are at least reactive, not pinpoint, so narcotic overdose is less likely. Thalamic stroke remains in the differential diagnosis; despite the seemingly symmetrical sensation examination, hemisensory deficits cannot be definitively ruled out given the patient’s mental state. A rare entity such as carcinomatosis meningitis or another diffuse, infiltrative neoplastic process could be causing his condition. However, because focal deficits other than abnormal speech and diffuse hyperreflexia are absent, toxic, infectious, or metabolic causes are more likely than structural abnormalities. Still possible is a medication toxicity, such as ertapenem toxicity or, less likely, digoxin toxicity. In terms of infectious possibilities, urinary tract infection could certainly present in this fashion, especially if the patient had a somewhat low neurologic reserve at baseline, and hypotension could be secondary to sepsis. Encephalitis or meningitis remains in the differential diagnosis, though the patient appears nontoxic, and therefore a bacterial etiology is very unlikely.

The patient’s hyperreflexia may be an important clue. Although the strength of his reflexes at baseline is unknown, seizures can cause transiently increased reflexes as well as a confused, lethargic mental state. Reflexes can also be increased by a drug overdose that has caused serotonin syndrome. Of the patient’s medications, only ondansetron can cause this reaction. Hyperthyroidism can cause brisk reflexes and confusion, though more typically it causes agitated confusion. A thyroid-stimulating hormone level should be added to the initial laboratory panel.

A complete blood count revealed white blood cell count 11.86 K/uL with neutrophilic predominance and immature granulocytes, hemoglobin 11.5 g/dL, and platelet count 323 K/uL. Serum sodium was 141 mEq/L, potassium 4.2 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, creatinine 1.14 mg/dL (prior baseline of 0.8-1.0 mg/dL), blood urea nitrogen 26 mg/dL, blood glucose 159 mg/dL, and calcium 9.1 mg/dL. His digoxin level was 1.3 ng/mL (reference range 0.5-1.9 mg/mL) and troponin was undetectable. INR was 2.7 and partial thromboplastin time (PTT) 60 seconds. Vitamin B₁₂ level was 674 pg/mL (reference range >180). A urinalysis had 1+ hyaline casts and was negative for nitrites, leukocyte esterase, blood, and bacteria. An ECG revealed atrial fibrillation with a ventricular rate of 80 beats per minute. A chest radiograph showed clear lung fields. A CT of the head without IV contrast had no evidence of an acute intracranial abnormality. In the ED, 1 liter of IV normal saline was given and blood pressure improved to 127/72 mm Hg.

The head CT does not show intracranial bleeding, and, though it is reassuring that INR is in the therapeutic range, ischemic stroke must remain in the differential diagnosis. Sepsis is less likely given that the criteria for systemic inflammatory response syndrome are not met, and hypotension was rapidly corrected with administration of IV fluids. Urinary tract infection was ruled out with the negative urinalysis. Subclinical seizures remain possible, as does medication-related or other toxicity. A medication overdose, intentional or otherwise, should also be considered.

The patient was admitted to the hospital. On reassessment by the inpatient team, he was oriented only to self, frequently falling asleep, and not recalling earlier conversations when aroused. His speech remained slurred and difficult to understand. Neurologic examination findings were unchanged since the ED examination. On additional cerebellar examination, he had dysmetria with finger-to-nose testing bilaterally and dysdiadochokinesia (impaired rapid alternating movements) of the left hand.

His handedness is not mentioned; the dysdiadochokinesia of the left hand may reflect the patient’s being right-handed, or may signify a focal cerebellar lesion. The cerebellum is also implicated by the bilateral dysmetria. Persistent somnolence in the absence of CT findings suggests a metabolic or infectious process. Metabolic processes that can cause bilateral cerebellar ataxia and somnolence include overdose of a drug or medication. Use of alcohol or a medication such as phenytoin, valproic acid, or a benzodiazepine can cause the symptoms in this case, but was not reported by the family, and there was no documentation of it in the SNF records. Wernicke encephalopathy is rare and is not well supported by the patient’s presentation but should be considered, as it can be easily treated with thiamine. Meningoencephalitis affecting the cerebellum remains possible, but infection is less likely. Both electroencephalogram and brain MRI should be performed, with a specific interest in possible cerebellar lesions. If the MRI is unremarkable, a lumbar puncture should be performed to assess opening pressure and investigate for infectious etiologies.

MRI of the brain showed age-related volume loss and nonspecific white matter disease without acute changes. Lack of a clear explanation for the neurologic findings led to suspicion of a medication side effect. Ertapenem was stopped on admission because it has been reported to rarely cause altered mental status. IV moxifloxacin was started for the osteomyelitis. Over the next 2 days, symptoms began resolving; within 24 hours of ertapenem discontinuation, the patient was awake, alert, and talkative. On examination, he remained dysarthric but was no longer dysmetric. Within 48 hours, the dysarthria was completely resolved, and he was returned to the SNF to complete a course of IV moxifloxacin.

Among elderly patients presenting to the ED, altered mental status is a common complaint, accounting for 10% to 30% of visits.¹ Medications are a common cause of altered mental status among the elderly and are responsible for 40% of delirium cases.¹ The risk of adverse drug events (ADEs) rises with the number of medications prescribed.^1-3 Among patients older than 60 years, the incidence of polypharmacy (defined as taking >5 prescription medications) increased from roughly 20% in 1999 to 40% in 2012.^4,5 The most common ADEs in the ambulatory setting (25%) are central nervous system (CNS) symptoms, including dizziness, sleep disturbances, and mood changes.⁶ A medication effect should be suspected in any elderly patient presenting with altered mental state.

The present patient developed a constellation of neurologic symptoms after starting ertapenem, one of the carbapenem antibiotics, which is a class of medications that can cause CNS ADEs. Carbapenems are renally cleared, and adjustments must be made for acute or chronic changes in kidney function. Carbapenems are associated with increased risk of seizure; the incidence of seizure with ertapenem is 0.2%.^7,8 Food and Drug Administration postmarketing reports have noted ertapenem can cause somnolence and dyskinesia,⁹ and several case reports have described ertapenem-associated CNS side effects, including psychosis and encephalopathy.^10-13 Symptoms and examination findings can include confusion, disorientation, garbled speech, dysphagia, hallucinations, miosis, myoclonus, tremor, and agitation.^10-13 Although reports of dysmetria and dysdiadochokinesia are lacking, suspicion of an ADE in this case was heightened by the timing of the exposure and the absence of alternative infectious, metabolic, and vascular explanations for bilateral cerebellar dysfunction.

The Naranjo Adverse Drug Reaction (ADR) scale may help clinicians differentiate ADEs from other etiologies of symptoms. It uses 10 weighted questions (Table) to estimate the probability that an adverse clinical event is caused by a drug reaction.¹⁴ The present case was assigned 1 point for prior reports of neurologic ADEs associated with ertapenem, 2 for the temporal association, 1 for resolution after medication withdrawal, 2 for lack of alternative causes, and 1 for objective evidence of neurologic dysfunction—for a total of 7 points, indicating ertapenem was probably the cause of the patient’s neurologic symptoms. Of 4 prior cases in which carbapenem toxicity was suspected and the Naranjo scale was used, 3 found a probable relationship, and the fourth a highly probable one.^10,12 Confusion, disorientation, hallucinations, tangential thoughts, and garbled speech were reported in the 3 probable cases of ADEs. In the highly probable case, tangential thoughts, garbled speech, and miosis were noted on examination, and these findings returned after re-exposure to ertapenem. Of note, these ADEs occurred in patients with normal and abnormal renal function, and in middle-aged and elderly patients.^10,11,13

• Clinicians should include rare adverse effects of common medications in the differential diagnosis.

• The Naranjo score is a validated tool that can be used to systematically assess the probability of an adverse drug effect at the bedside.

• The presentation of ertapenem-associated neurotoxicity may include features of bilateral cerebellar dysfunction.

Disclosure

Nothing to report.

Pleural effusion can occur in myriad conditions including infection, heart failure, liver disease, and cancer.¹ Consequently, physicians from many disciplines routinely encounter both inpatients and outpatients with this diagnosis. Often, evaluation and treatment require thoracentesis to obtain fluid for analysis or symptom relief.

Although historically performed at the bedside without imaging guidance or intraprocedural monitoring, thoracentesis performed in this fashion carries considerable risk of complications. In fact, it has 1 of the highest rates of iatrogenic pneumothorax among bedside procedures.² However, recent advances in practice and adoption of newer technologies have helped to mitigate risks associated with this procedure. These advances are relevant because approximately 50% of thoracenteses are still performed at the bedside.³ In this review, we aim to identify the most recent key practices that enhance the safety and the effectiveness of thoracentesis for practicing clinicians.

Information Sources and Search Strategy

With the assistance of a research librarian, we performed a systematic search of PubMed-indexed articles from January 1, 2000 to September 30, 2015. Articles were identified using search terms such as thoracentesis, pleural effusion, safety, medical error, adverse event, and ultrasound in combination with Boolean operators. Of note, as thoracentesis is indexed as a subgroup of paracentesis in PubMed, this term was also included to increase the sensitivity of the search. The full search strategy is available in the Appendix. Any references cited in this review outside of the date range of our search are provided only to give relevant background information or establish the origin of commonly performed practices.

Study Eligibility and Selection Criteria

Studies were included if they reported clinical aspects related to thoracentesis. We defined clinical aspects as those strategies that focused on operator training, procedural techniques, technology, management, or prevention of complications. Non-English language articles, animal studies, case reports, conference proceedings, and abstracts were excluded. As our intention was to focus on the contemporary advances related to thoracentesis performance, (eg, ultrasound [US]), our search was limited to studies published after the year 2000. Two authors, Drs. Schildhouse and Lai independently screened studies to determine inclusion, excluding studies with weak methodology, very small sample sizes, and those only tangentially related to our aim. Disagreements regarding study inclusion were resolved by consensus. Drs. Lai, Barsuk, and Mourad identified additional studies by hand review of reference lists and content experts (Figure 1).

Conceptual Framework

All selected articles were categorized by temporal relationship to thoracentesis as pre-, intra-, or postprocedure. Pre-procedural topics were those outcomes that had been identified and addressed before attempting thoracentesis, such as physician training or perceived risks of harm. Intraprocedural considerations included aspects such as use of bedside US, pleural manometry, and large-volume drainage. Finally, postprocedural factors were those related to evaluation after thoracentesis, such as follow-up imaging. This conceptual framework is outlined in Figure 2.

The PubMed search returned a total of 1170 manuscripts, of which 56 articles met inclusion criteria. Four additional articles were identified by experts and included in the study.^4-7 Therefore, 60 articles were identified and included in this review. Study designs included cohort studies, case control studies, systematic reviews, meta-analyses, narrative reviews, consensus guidelines, and randomized controlled trials. A summary of all included articles by topic can be found in the Table.
 

PRE-PROCEDURAL CONSIDERATIONS

Physician Training

Studies indicate that graduate medical education may not adequately prepare clinicians to perform thoracentesis.⁸ In fact, residents have the least exposure and confidence in performing thoracentesis when compared to other bedside procedures.^9,10 In 1 survey, 69% of medical trainees desired more exposure to procedures, and 98% felt that procedural skills were important to master.¹¹ Not surprisingly, then, graduating internal medicine residents perform poorly when assessed on a thoracentesis simulator.¹²

Supplemental training outside of residency is useful to develop and maintain skills for thoracentesis, such as simulation with direct observation in a zero-risk environment. In 1 study, “simulation-based mastery learning” combined an educational video presentation with repeated, deliberate practice on a simulator until procedural competence was acquired, over two 2-hour sessions. In this study, 40 third-year medicine residents demonstrated a 71% improvement in clinical skills performance after course completion, with 93% achieving a passing score. The remaining 7% also achieved passing scores with extra practice time.¹² Others have built upon the concept of simulation-based training. For instance, 2 studies suggest that use of a simulation-based curriculum improved both thoracentesis knowledge and performance skills in a 3-hour session.^13,14 Similarly, 1 prospective study reported that a half-day thoracentesis workshop using simulation and 1:1 direct observation successfully lowered pneumothorax rates from 8.6% to 1.8% in a group of practicing clinicians. Notably, additional interventions including use of bedside US, limiting operators to a focused group, and standardization of equipment were also a part of this quality improvement initiative.⁷ Although repetition is required to gain proficiency when using a simulator, performance and confidence appear to plateau with only 4 simulator trials. In medical students, improvements derived through simulator-based teaching were sustained when retested 6 months following training.¹⁵

An instrument to ensure competency is necessary, given variability in procedural experience among both new graduates and practicing physicians,. Our search did not identify any clinically validated tools that adequately assessed thoracentesis performance. However, some have been proposed¹⁶ and 1 validated in a simulation environment.¹² Regarding the incorporation of US for effusion markup, 1 validated tool used an 11-domain assessment covering knowledge of US machine manipulation, recognition of images with common pleural effusion characteristics, and performance of thoracic US with puncture-site marking on a simulator. When used on 22 participants, scores with the tool could reliably differentiate between novice, intermediate, and advanced groups (P < 0.0001).¹⁷

Patient Selection

Coagulopathies and Anticoagulation. Historically, the accepted cutoff for performing thoracentesis is an international normalized ratio (INR) less than 1.5 and a platelet count greater than 50,000/µL. McVay et al.¹⁸ first showed in 1991 that use of these cutoffs was associated with low rates of periprocedural bleeding, leading to endorsement in the British Thoracic Society (BTS) Pleural Disease Guideline 2010.¹⁹ Other recommendations include the 2012 Society for Interventional Radiology guidelines that endorse correction of an INR greater than 2, or platelets less than 50,000/µL, based almost exclusively on expert opinion.⁵

However, data suggest that thoracentesis may be safely performed outside these parameters. For instance, a prospective study of approximately 9000 thoracenteses over 12 years found that patients with an INR of 1.5-2.9 or platelets of 20,000 - 49,000/µL experienced rates of bleeding complications similar to those with normal values.²⁰ Similarly, a 2014 review²¹ found that the overall risk of hemorrhage during thoracentesis in the setting of moderate coagulopathy (defined as an INR of 1.5 - 3 or platelets of 25,000-50,000/µL), was not increased. In 1 retrospective study of more than 1000 procedures, no differences in hemorrhagic events were noted in patients with bleeding diatheses that received prophylactic fresh frozen plasma or platelets vs. those who did not.²² Of note, included studies used a variety of criteria to define a hemorrhagic complication, which included: an isolated 2 g/dL or more decrement in hemoglobin, presence of bloody fluid on repeat tap with associated hemoglobin decrement, rapid re-accumulation of fluid with a hemoglobin decrement, or transfusion of 2 units or more of whole blood.

Whether it is safe to perform thoracentesis on patients taking antiplatelet therapy is less well understood. Although data are limited, a few small-scale studies^23,24 suggest that hemorrhagic complications following thoracentesis in patients receiving clopidogrel are comparable to the general population. We found no compelling data regarding the safety of thoracentesis in the setting of direct oral anticoagulants, heparin, low-molecular weight heparin, or intravenous direct thrombin inhibitors. Current practice is to generally avoid thoracentesis while these therapeutic anticoagulants are used.

Invasive mechanical ventilation. Pleural effusion is common in patients in the intensive care unit, including those requiring mechanical ventilation.²⁵ Thoracentesis in this population is clinically important: fluid analysis in 1 study was shown to aid the diagnosis in 45% of cases and changes in treatment in 33%.²⁶ However, clinicians may be reluctant to perform thoracentesis on patients who require mechanical ventilation, given the perception of a greater risk of pneumothorax from positive pressure ventilation.

Despite this concern, a 2011 meta-analysis including 19 studies and more than 1100 patients revealed rates of pneumothorax and hemothorax comparable to nonventilated patients.²⁵ Furthermore, a 2015 prospective study that examined thoracentesis in 1377 mechanically ventilated patients revealed no difference in complication rates as well.²⁰ Therefore, evidence suggests that performance of thoracentesis in mechanically ventilated patients is not contraindicated.

Skin Disinfection and Antisepsis Precautions

The 2010 BTS guidelines list empyema and wound infection as possible complications of thoracentesis.¹⁹ However, no data regarding incidence are provided. Additionally, an alcohol-based skin cleanser (such as 2% chlorhexidine gluconate/70% isopropyl alcohol), along with sterile gloves, field, and dressing are suggested as precautionary measures.¹⁹ In 1 single-center registry of 2489 thoracenteses performed using alcohol or iodine-based antiseptic and sterile drapes, no postprocedure infections were identified.²⁷ Of note, we did not find other studies (including case reports) that reported either incidence or rate of infectious complications such as wound infection and empyema. In an era of modern skin antiseptics that have effectively reduced complications such as catheter-related bloodstream infection,²⁸ the incidence of this event is thus likely to be low.

INTRAPROCEDURAL CONSIDERATIONS

Use of Bedside Ultrasound

Portable US has particular advantages for evaluation of pleural effusion vs other imaging modalities. Compared with computerized tomography (CT), bedside US offers similar performance but is less costly, avoids both radiation exposure and need for patient transportation, and provides results instantaneously.^29,30 Compared to chest x-ray (CXR), US is more sensitive at detecting the presence, volume, and characteristics of pleural fluid^30,31 and can be up to 100% sensitive for effusions greater than 100 mL.²⁹ Furthermore, whereas CXR typically requires 200 mL of fluid to be present for detection of an effusion, US can reliably detect as little as 20 mL of fluid.²⁹ When US was used to confirm thoracentesis puncture sites in a study involving 30 physicians of varying experience and 67 consecutive patients, 15% of sites found by clinical exam were inaccurate (less than 10 mm fluid present), 10% were at high risk for organ puncture, and a suitable fluid pocket was found 54% of times when exam could not.⁴

A 2010 meta-analysis of 24 studies and 6605 thoracenteses estimated the overall rate of pneumothorax at 6%; however, procedures performed with US guidance were associated with a 70% reduced risk of this event (odds ratio, 0.30; 95% confidence interval, 0.20 - 0.70).³² In a 2014 randomized control trial of 160 patients that compared thoracentesis with US guidance for site marking vs no US use, 10 pneumothoraces occurred in the control group vs 1 in the US group (12.5% vs 1.25%, P = 0.009).³³ Similarly, another retrospective review of 445 consecutive patients with malignant effusions revealed a pneumothorax rate of 0.97% using US in real time during needle insertion compared to 8.89% for unguided thoracenteses (P < 0.0001).³⁴ Several other studies using US guidance for either site markup or in real time reported similar pneumothorax rates, ranging from 1.1% - 4.8%.^35-37 However, it is unclear if real-time US specifically provides an additive effect vs site marking alone, as no studies directly comparing the 2 methods were found.

Benefits of US also include a higher rate of procedural success, with 1 study demonstrating a 99% success rate when using US vs. 90% without (P = 0.030).³³ A larger volume of fluid removed has been observed with US use as well, and methods have been described using fluid-pocket depth to guide puncture site localization and maximize drainage.³⁸ Finally, US use for thoracentesis has been associated with lower costs and length of stay.^39,40

Intercostal Artery Localization

Although rare (incidence, 0.18%-2%^20,21,39), the occurrence of hemothorax following thoracentesis is potentially catastrophic. This serious complication is often caused by laceration of the intercostal artery (ICA) or 1 of its branches during needle insertion.⁴¹

While risk of injury is theoretically reduced by needle insertion superior to the rib, studies using cadaver dissection and 3D angiography show significant tortuosity of the ICA.^6,41-43 The degree of tortuosity is increased within 6 cm of the midline, in more cephalad rib spaces, and in the elderly (older than 60 years).^41-43 Furthermore, 1 cadaveric study also demonstrated the presence of arterial collaterals branching off the ICA at multiple intercostal spaces, ranging between 8 cm and 11 cm from the midline.⁴¹ This anatomic variability may explain why some have observed low complication and hemothorax rates with an extreme lateral approach.³⁵ Bedside US with color flow Doppler imaging has been used to identify the ICA, with 88% sensitivity compared to CT imaging while adding little to exam time.^44,45 Of note, a 37% drop in the rate of hemothorax was observed in 1 study with routine US guidance alone.³⁹

Pleural Pressure Monitoring and Large-Volume Thoracentesis

While normal intrapleural pressures are approximately -5 to -10 cm H₂O,⁴⁶ the presence of a pleural effusion creates a complex interaction between fluid, compressed lung, and chest wall that can increase these pressures.⁴⁷ During drainage of an effusion, pleural pressures may rapidly drop, provoking re-expansion pulmonary edema (REPE). While rare (0 -1%), clinically-diagnosed REPE is a serious complication that can lead to rapid respiratory failure and death.^20,48 REPE is postulated to be caused by increased capillary permeability resulting from inflammation, driven by rapid re-inflation of the lung when exposed to highly negative intrapleural pressures.^47,49

Measurement of intrapleural pressure using a water manometer during thoracentesis may minimize REPE by terminating fluid drainage when intrapleural pressure begins to drop rapidly.^50,51 A cutoff of -20 cm H₂O has been cited repeatedly as safe since being suggested by Light in 1980, but this is based on animal models.^50,52 In 1 prospective study of 185 thoracenteses in which manometry was performed, 15% of patients had intrapleural pressure drop to less than -20 cm H₂O (at which point the procedure was terminated) but suffered no REPE.⁵⁰

Manometry is valuable in the identification of an unexpandable or trapped lung when pleural pressures drop rapidly with only minimal fluid volume removal.^47,53 Other findings correlated with an unexpandable lung include a negative opening pressure⁴⁷ and large fluctuations in pressure during the respiratory cycle.⁵⁴

While development of symptoms (eg, chest pain, cough, or dyspnea) is often used as a surrogate, the correlation between intrapleural pressure and patient symptoms is inconsistent and not a reliable proxy.⁵⁵ One study found that 22% of patients with chest pain during thoracentesis had intrapleural pressures lower than -20 cm H₂O compared with 8.6% of asymptomatic patients,⁵⁶ but it is unclear if the association is causal.

Thoracentesis is often performed for symptomatic relief and removal of large fluid volume. However, it remains common to halt fluid removal after 1.5 L, a threshold endorsed by BTS.¹⁹ While some investigators have suggested that removal of 2 L or more of pleural fluid does not compromise safety,^57,58 a 4- to 5-fold rise in the risk of pneumothorax was noted in 2 studies.^20,59 when more than 1.5 L of fluid was removed. The majority of these may be related to pneumothorax ex vacuo, a condition in which fluid is drained from the chest, but the lung is unable to expand and fill the space (eg, “trapped lung”), resulting in a persistent pneumothorax. This condition generally does not require treatment.⁶⁰ When manometry is employed at 200-mL intervals with termination at an intrapleural pressure of less than 20 mm H₂O, drainage of 3 L or more has been reported with low rates of pneumothorax and very low rates of REPE.^50,51 However, whether this is cause and effect is unknown because REPE is rare, and more work is needed to determine the role of manometry for its prevention.

POSTPROCEDURAL CONSIDERATIONS

Postprocedure Imaging

Performing an upright CXR following thoracentesis is a practice that remains routinely done by many practitioners to monitor for complications. Such imaging was also endorsed by the American Thoracic Society guidelines.⁶¹ However, more recent data question the utility of this practice. Multiple studies have confirmed that post-thoracentesis CXR is unnecessary unless clinical suspicion for pneumothorax or REPE is present.^36,58,62,63 The BTS guidelines also advocate this approach.¹⁹ Interestingly, a potentially more effective way to screen for postprocedure complications is through bedside US, which has been shown to be more sensitive than CXR in detecting pneumothorax.⁶⁴ In 1 study of 185 patients, bedside US demonstrated a sensitivity of 88% and a specificity of 97% for diagnosing pneumothorax in patients with adequate quality scans, with positive and negative likelihood ratios of 55 and 0.17, respectively.⁶⁵

Thoracentesis remains a core procedural skill for hospitalists, critical care physicians, and emergency physicians. It is the foundational component when investigating and treating pleural effusions. When the most current training, techniques, and technology are used, data suggest this procedure is safe to perform at the bedside. Our review highlights these strategies and evaluates which aspects might be most applicable to clinical practice.

Our findings have several implications for those who perform this procedure. First, appropriate training is central to procedural safety, and both simulation and direct observation by procedural experts have been shown by multiple investigators to improve knowledge and skill. This training should integrate the use of US in performing a focused thoracic exam.

Second, recommendations regarding coagulopathy and a “safe cutoff” of an INR less than 1.5 or platelets greater than 50,000/µL had limited evidentiary support. Rather, multiple studies suggest no difference in bleeding risk following thoracentesis with an INR as high as 3.0 and platelets greater than 25,000/µL. Furthermore, prophylactic transfusion with fresh frozen plasma or platelets before thoracentesis did not alter bleeding risk and exposes patients to transfusion complications. Thus, routine use of this practice can no longer be recommended. Third, further research is needed to understand the bleeding risk for patients on antiplatelet medications, heparin products, and also direct oral anticoagulants, given the growing popularity in their use and the potential consequences of even temporary cessation. Regarding patients on mechanical ventilation, thoracentesis demonstrated no difference in complication rates vs. the general population, and its performance in this population is encouraged when clinically indicated.

Intraprocedural considerations include the use of bedside US. Due to multiple benefits including effusion characterization, puncture site localization, and significantly lower rates of pneumothorax, the standard of care should be to perform thoracentesis with US guidance. Both use of US to mark an effusion immediately prior to puncture or in real time during needle insertion demonstrated benefit; however, it is unclear if 1 method is superior because no direct comparison studies were found. Further work is needed to investigate this potential.

Our review suggests that the location and course of the ICA is variable, especially near the midline, in the elderly, and in higher intercostal spaces, leaving it vulnerable to laceration. We recommend physicians only attempt thoracentesis at least 6 cm lateral to the midline due to ICA tortuosity and, ideally, 12 cm lateral, to avoid the presence of collaterals. Although only 2 small-scale studies were found pertaining to the use of US in identifying the ICA, we encourage physicians to consider learning how to screen for its presence as a part of their routine thoracic US exam in the area underlying the planned puncture site.

Manometry is beneficial because it can diagnose a nonexpandable lung and allows for pleural pressure monitoring.^52,53 A simple U-shaped manometer can be constructed from intravenous tubing included in most thoracentesis kits, which adds little to overall procedure time. While low rates of REPE have been observed when terminating thoracentesis if pressures drop below -20 cm H₂O or chest pain develops, neither measure appears to have reliable predictive value, limiting clinical utility. Further work is required to determine if a “safe pressure cutoff” exists. In general, we recommend the use of manometry when a nonexpandable (trapped) lung is suspected, because large drops in intrapleural pressure, a negative opening pressure, and respiratory variation can help confirm the diagnosis and avoid pneumothorax ex vacuo or unnecessary procedures in the future. As this condition appears to be more common in the setting of larger effusions, use of manometry when large-volume thoracenteses are planned is also reasonable.

Postprocedurally, routine imaging after thoracentesis is not recommended unless there is objective concern for complication. When indicated, bedside US is better positioned for this role compared with CXR, because it is more sensitive in detecting pneumothorax, provides instantaneous results, and avoids radiation exposure.

Our review has limitations. First, we searched only for articles between defined time periods, restricted our search to a single database, and excluded non-English articles. This has the potential to introduce selection bias, as nonprimary articles that fall within our time restrictions may cite older studies that are outside our search range. To minimize this effect, we performed a critical review of all included studies, especially nonprimary articles. Second, despite the focus of our search strategy to identify any articles related to patient safety and adverse events, we cannot guarantee that all relevant articles for any particular complication or risk factor were captured given the lack of more specific search terms. Third, although we performed a systematic search of the literature, we did not perform a formal systematic review or formally grade included studies. As the goal of our review was to categorize and operationalize clinical aspects, this approach was necessary, and we acknowledge that the quality of studies is variable. Lastly, we aimed to generate clinical recommendations for physicians performing thoracentesis at the bedside; others reviewing this literature may find or emphasize different aspects relevant to practice outside this setting.

In conclusion, evaluation and treatment of pleural effusions with bedside thoracentesis is an important skill for physicians of many disciplines. The evidence presented in this review will help inform the process and ensure patient safety. Physicians should consider incorporating these recommendations into their practice.

Acknowledgments

The authors thank Whitney Townsend, MLIS, health sciences informationist, for assistance with serial literature searches.

Disclosure

Nothing to report.

Pleural effusion can occur in myriad conditions including infection, heart failure, liver disease, and cancer.¹ Consequently, physicians from many disciplines routinely encounter both inpatients and outpatients with this diagnosis. Often, evaluation and treatment require thoracentesis to obtain fluid for analysis or symptom relief.

Although historically performed at the bedside without imaging guidance or intraprocedural monitoring, thoracentesis performed in this fashion carries considerable risk of complications. In fact, it has 1 of the highest rates of iatrogenic pneumothorax among bedside procedures.² However, recent advances in practice and adoption of newer technologies have helped to mitigate risks associated with this procedure. These advances are relevant because approximately 50% of thoracenteses are still performed at the bedside.³ In this review, we aim to identify the most recent key practices that enhance the safety and the effectiveness of thoracentesis for practicing clinicians.

Information Sources and Search Strategy

With the assistance of a research librarian, we performed a systematic search of PubMed-indexed articles from January 1, 2000 to September 30, 2015. Articles were identified using search terms such as thoracentesis, pleural effusion, safety, medical error, adverse event, and ultrasound in combination with Boolean operators. Of note, as thoracentesis is indexed as a subgroup of paracentesis in PubMed, this term was also included to increase the sensitivity of the search. The full search strategy is available in the Appendix. Any references cited in this review outside of the date range of our search are provided only to give relevant background information or establish the origin of commonly performed practices.

Study Eligibility and Selection Criteria

Studies were included if they reported clinical aspects related to thoracentesis. We defined clinical aspects as those strategies that focused on operator training, procedural techniques, technology, management, or prevention of complications. Non-English language articles, animal studies, case reports, conference proceedings, and abstracts were excluded. As our intention was to focus on the contemporary advances related to thoracentesis performance, (eg, ultrasound [US]), our search was limited to studies published after the year 2000. Two authors, Drs. Schildhouse and Lai independently screened studies to determine inclusion, excluding studies with weak methodology, very small sample sizes, and those only tangentially related to our aim. Disagreements regarding study inclusion were resolved by consensus. Drs. Lai, Barsuk, and Mourad identified additional studies by hand review of reference lists and content experts (Figure 1).

Conceptual Framework

All selected articles were categorized by temporal relationship to thoracentesis as pre-, intra-, or postprocedure. Pre-procedural topics were those outcomes that had been identified and addressed before attempting thoracentesis, such as physician training or perceived risks of harm. Intraprocedural considerations included aspects such as use of bedside US, pleural manometry, and large-volume drainage. Finally, postprocedural factors were those related to evaluation after thoracentesis, such as follow-up imaging. This conceptual framework is outlined in Figure 2.

The PubMed search returned a total of 1170 manuscripts, of which 56 articles met inclusion criteria. Four additional articles were identified by experts and included in the study.^4-7 Therefore, 60 articles were identified and included in this review. Study designs included cohort studies, case control studies, systematic reviews, meta-analyses, narrative reviews, consensus guidelines, and randomized controlled trials. A summary of all included articles by topic can be found in the Table.
 

PRE-PROCEDURAL CONSIDERATIONS

Physician Training

Studies indicate that graduate medical education may not adequately prepare clinicians to perform thoracentesis.⁸ In fact, residents have the least exposure and confidence in performing thoracentesis when compared to other bedside procedures.^9,10 In 1 survey, 69% of medical trainees desired more exposure to procedures, and 98% felt that procedural skills were important to master.¹¹ Not surprisingly, then, graduating internal medicine residents perform poorly when assessed on a thoracentesis simulator.¹²

Supplemental training outside of residency is useful to develop and maintain skills for thoracentesis, such as simulation with direct observation in a zero-risk environment. In 1 study, “simulation-based mastery learning” combined an educational video presentation with repeated, deliberate practice on a simulator until procedural competence was acquired, over two 2-hour sessions. In this study, 40 third-year medicine residents demonstrated a 71% improvement in clinical skills performance after course completion, with 93% achieving a passing score. The remaining 7% also achieved passing scores with extra practice time.¹² Others have built upon the concept of simulation-based training. For instance, 2 studies suggest that use of a simulation-based curriculum improved both thoracentesis knowledge and performance skills in a 3-hour session.^13,14 Similarly, 1 prospective study reported that a half-day thoracentesis workshop using simulation and 1:1 direct observation successfully lowered pneumothorax rates from 8.6% to 1.8% in a group of practicing clinicians. Notably, additional interventions including use of bedside US, limiting operators to a focused group, and standardization of equipment were also a part of this quality improvement initiative.⁷ Although repetition is required to gain proficiency when using a simulator, performance and confidence appear to plateau with only 4 simulator trials. In medical students, improvements derived through simulator-based teaching were sustained when retested 6 months following training.¹⁵

An instrument to ensure competency is necessary, given variability in procedural experience among both new graduates and practicing physicians,. Our search did not identify any clinically validated tools that adequately assessed thoracentesis performance. However, some have been proposed¹⁶ and 1 validated in a simulation environment.¹² Regarding the incorporation of US for effusion markup, 1 validated tool used an 11-domain assessment covering knowledge of US machine manipulation, recognition of images with common pleural effusion characteristics, and performance of thoracic US with puncture-site marking on a simulator. When used on 22 participants, scores with the tool could reliably differentiate between novice, intermediate, and advanced groups (P < 0.0001).¹⁷

Patient Selection

Coagulopathies and Anticoagulation. Historically, the accepted cutoff for performing thoracentesis is an international normalized ratio (INR) less than 1.5 and a platelet count greater than 50,000/µL. McVay et al.¹⁸ first showed in 1991 that use of these cutoffs was associated with low rates of periprocedural bleeding, leading to endorsement in the British Thoracic Society (BTS) Pleural Disease Guideline 2010.¹⁹ Other recommendations include the 2012 Society for Interventional Radiology guidelines that endorse correction of an INR greater than 2, or platelets less than 50,000/µL, based almost exclusively on expert opinion.⁵

However, data suggest that thoracentesis may be safely performed outside these parameters. For instance, a prospective study of approximately 9000 thoracenteses over 12 years found that patients with an INR of 1.5-2.9 or platelets of 20,000 - 49,000/µL experienced rates of bleeding complications similar to those with normal values.²⁰ Similarly, a 2014 review²¹ found that the overall risk of hemorrhage during thoracentesis in the setting of moderate coagulopathy (defined as an INR of 1.5 - 3 or platelets of 25,000-50,000/µL), was not increased. In 1 retrospective study of more than 1000 procedures, no differences in hemorrhagic events were noted in patients with bleeding diatheses that received prophylactic fresh frozen plasma or platelets vs. those who did not.²² Of note, included studies used a variety of criteria to define a hemorrhagic complication, which included: an isolated 2 g/dL or more decrement in hemoglobin, presence of bloody fluid on repeat tap with associated hemoglobin decrement, rapid re-accumulation of fluid with a hemoglobin decrement, or transfusion of 2 units or more of whole blood.

Whether it is safe to perform thoracentesis on patients taking antiplatelet therapy is less well understood. Although data are limited, a few small-scale studies^23,24 suggest that hemorrhagic complications following thoracentesis in patients receiving clopidogrel are comparable to the general population. We found no compelling data regarding the safety of thoracentesis in the setting of direct oral anticoagulants, heparin, low-molecular weight heparin, or intravenous direct thrombin inhibitors. Current practice is to generally avoid thoracentesis while these therapeutic anticoagulants are used.

Invasive mechanical ventilation. Pleural effusion is common in patients in the intensive care unit, including those requiring mechanical ventilation.²⁵ Thoracentesis in this population is clinically important: fluid analysis in 1 study was shown to aid the diagnosis in 45% of cases and changes in treatment in 33%.²⁶ However, clinicians may be reluctant to perform thoracentesis on patients who require mechanical ventilation, given the perception of a greater risk of pneumothorax from positive pressure ventilation.

Despite this concern, a 2011 meta-analysis including 19 studies and more than 1100 patients revealed rates of pneumothorax and hemothorax comparable to nonventilated patients.²⁵ Furthermore, a 2015 prospective study that examined thoracentesis in 1377 mechanically ventilated patients revealed no difference in complication rates as well.²⁰ Therefore, evidence suggests that performance of thoracentesis in mechanically ventilated patients is not contraindicated.

Skin Disinfection and Antisepsis Precautions

The 2010 BTS guidelines list empyema and wound infection as possible complications of thoracentesis.¹⁹ However, no data regarding incidence are provided. Additionally, an alcohol-based skin cleanser (such as 2% chlorhexidine gluconate/70% isopropyl alcohol), along with sterile gloves, field, and dressing are suggested as precautionary measures.¹⁹ In 1 single-center registry of 2489 thoracenteses performed using alcohol or iodine-based antiseptic and sterile drapes, no postprocedure infections were identified.²⁷ Of note, we did not find other studies (including case reports) that reported either incidence or rate of infectious complications such as wound infection and empyema. In an era of modern skin antiseptics that have effectively reduced complications such as catheter-related bloodstream infection,²⁸ the incidence of this event is thus likely to be low.

INTRAPROCEDURAL CONSIDERATIONS

Use of Bedside Ultrasound

Portable US has particular advantages for evaluation of pleural effusion vs other imaging modalities. Compared with computerized tomography (CT), bedside US offers similar performance but is less costly, avoids both radiation exposure and need for patient transportation, and provides results instantaneously.^29,30 Compared to chest x-ray (CXR), US is more sensitive at detecting the presence, volume, and characteristics of pleural fluid^30,31 and can be up to 100% sensitive for effusions greater than 100 mL.²⁹ Furthermore, whereas CXR typically requires 200 mL of fluid to be present for detection of an effusion, US can reliably detect as little as 20 mL of fluid.²⁹ When US was used to confirm thoracentesis puncture sites in a study involving 30 physicians of varying experience and 67 consecutive patients, 15% of sites found by clinical exam were inaccurate (less than 10 mm fluid present), 10% were at high risk for organ puncture, and a suitable fluid pocket was found 54% of times when exam could not.⁴

A 2010 meta-analysis of 24 studies and 6605 thoracenteses estimated the overall rate of pneumothorax at 6%; however, procedures performed with US guidance were associated with a 70% reduced risk of this event (odds ratio, 0.30; 95% confidence interval, 0.20 - 0.70).³² In a 2014 randomized control trial of 160 patients that compared thoracentesis with US guidance for site marking vs no US use, 10 pneumothoraces occurred in the control group vs 1 in the US group (12.5% vs 1.25%, P = 0.009).³³ Similarly, another retrospective review of 445 consecutive patients with malignant effusions revealed a pneumothorax rate of 0.97% using US in real time during needle insertion compared to 8.89% for unguided thoracenteses (P < 0.0001).³⁴ Several other studies using US guidance for either site markup or in real time reported similar pneumothorax rates, ranging from 1.1% - 4.8%.^35-37 However, it is unclear if real-time US specifically provides an additive effect vs site marking alone, as no studies directly comparing the 2 methods were found.

Benefits of US also include a higher rate of procedural success, with 1 study demonstrating a 99% success rate when using US vs. 90% without (P = 0.030).³³ A larger volume of fluid removed has been observed with US use as well, and methods have been described using fluid-pocket depth to guide puncture site localization and maximize drainage.³⁸ Finally, US use for thoracentesis has been associated with lower costs and length of stay.^39,40

Intercostal Artery Localization

Although rare (incidence, 0.18%-2%^20,21,39), the occurrence of hemothorax following thoracentesis is potentially catastrophic. This serious complication is often caused by laceration of the intercostal artery (ICA) or 1 of its branches during needle insertion.⁴¹

While risk of injury is theoretically reduced by needle insertion superior to the rib, studies using cadaver dissection and 3D angiography show significant tortuosity of the ICA.^6,41-43 The degree of tortuosity is increased within 6 cm of the midline, in more cephalad rib spaces, and in the elderly (older than 60 years).^41-43 Furthermore, 1 cadaveric study also demonstrated the presence of arterial collaterals branching off the ICA at multiple intercostal spaces, ranging between 8 cm and 11 cm from the midline.⁴¹ This anatomic variability may explain why some have observed low complication and hemothorax rates with an extreme lateral approach.³⁵ Bedside US with color flow Doppler imaging has been used to identify the ICA, with 88% sensitivity compared to CT imaging while adding little to exam time.^44,45 Of note, a 37% drop in the rate of hemothorax was observed in 1 study with routine US guidance alone.³⁹

Pleural Pressure Monitoring and Large-Volume Thoracentesis

While normal intrapleural pressures are approximately -5 to -10 cm H₂O,⁴⁶ the presence of a pleural effusion creates a complex interaction between fluid, compressed lung, and chest wall that can increase these pressures.⁴⁷ During drainage of an effusion, pleural pressures may rapidly drop, provoking re-expansion pulmonary edema (REPE). While rare (0 -1%), clinically-diagnosed REPE is a serious complication that can lead to rapid respiratory failure and death.^20,48 REPE is postulated to be caused by increased capillary permeability resulting from inflammation, driven by rapid re-inflation of the lung when exposed to highly negative intrapleural pressures.^47,49

Measurement of intrapleural pressure using a water manometer during thoracentesis may minimize REPE by terminating fluid drainage when intrapleural pressure begins to drop rapidly.^50,51 A cutoff of -20 cm H₂O has been cited repeatedly as safe since being suggested by Light in 1980, but this is based on animal models.^50,52 In 1 prospective study of 185 thoracenteses in which manometry was performed, 15% of patients had intrapleural pressure drop to less than -20 cm H₂O (at which point the procedure was terminated) but suffered no REPE.⁵⁰

Manometry is valuable in the identification of an unexpandable or trapped lung when pleural pressures drop rapidly with only minimal fluid volume removal.^47,53 Other findings correlated with an unexpandable lung include a negative opening pressure⁴⁷ and large fluctuations in pressure during the respiratory cycle.⁵⁴

While development of symptoms (eg, chest pain, cough, or dyspnea) is often used as a surrogate, the correlation between intrapleural pressure and patient symptoms is inconsistent and not a reliable proxy.⁵⁵ One study found that 22% of patients with chest pain during thoracentesis had intrapleural pressures lower than -20 cm H₂O compared with 8.6% of asymptomatic patients,⁵⁶ but it is unclear if the association is causal.

Thoracentesis is often performed for symptomatic relief and removal of large fluid volume. However, it remains common to halt fluid removal after 1.5 L, a threshold endorsed by BTS.¹⁹ While some investigators have suggested that removal of 2 L or more of pleural fluid does not compromise safety,^57,58 a 4- to 5-fold rise in the risk of pneumothorax was noted in 2 studies.^20,59 when more than 1.5 L of fluid was removed. The majority of these may be related to pneumothorax ex vacuo, a condition in which fluid is drained from the chest, but the lung is unable to expand and fill the space (eg, “trapped lung”), resulting in a persistent pneumothorax. This condition generally does not require treatment.⁶⁰ When manometry is employed at 200-mL intervals with termination at an intrapleural pressure of less than 20 mm H₂O, drainage of 3 L or more has been reported with low rates of pneumothorax and very low rates of REPE.^50,51 However, whether this is cause and effect is unknown because REPE is rare, and more work is needed to determine the role of manometry for its prevention.

POSTPROCEDURAL CONSIDERATIONS

Postprocedure Imaging

Performing an upright CXR following thoracentesis is a practice that remains routinely done by many practitioners to monitor for complications. Such imaging was also endorsed by the American Thoracic Society guidelines.⁶¹ However, more recent data question the utility of this practice. Multiple studies have confirmed that post-thoracentesis CXR is unnecessary unless clinical suspicion for pneumothorax or REPE is present.^36,58,62,63 The BTS guidelines also advocate this approach.¹⁹ Interestingly, a potentially more effective way to screen for postprocedure complications is through bedside US, which has been shown to be more sensitive than CXR in detecting pneumothorax.⁶⁴ In 1 study of 185 patients, bedside US demonstrated a sensitivity of 88% and a specificity of 97% for diagnosing pneumothorax in patients with adequate quality scans, with positive and negative likelihood ratios of 55 and 0.17, respectively.⁶⁵

Thoracentesis remains a core procedural skill for hospitalists, critical care physicians, and emergency physicians. It is the foundational component when investigating and treating pleural effusions. When the most current training, techniques, and technology are used, data suggest this procedure is safe to perform at the bedside. Our review highlights these strategies and evaluates which aspects might be most applicable to clinical practice.

Our findings have several implications for those who perform this procedure. First, appropriate training is central to procedural safety, and both simulation and direct observation by procedural experts have been shown by multiple investigators to improve knowledge and skill. This training should integrate the use of US in performing a focused thoracic exam.

Second, recommendations regarding coagulopathy and a “safe cutoff” of an INR less than 1.5 or platelets greater than 50,000/µL had limited evidentiary support. Rather, multiple studies suggest no difference in bleeding risk following thoracentesis with an INR as high as 3.0 and platelets greater than 25,000/µL. Furthermore, prophylactic transfusion with fresh frozen plasma or platelets before thoracentesis did not alter bleeding risk and exposes patients to transfusion complications. Thus, routine use of this practice can no longer be recommended. Third, further research is needed to understand the bleeding risk for patients on antiplatelet medications, heparin products, and also direct oral anticoagulants, given the growing popularity in their use and the potential consequences of even temporary cessation. Regarding patients on mechanical ventilation, thoracentesis demonstrated no difference in complication rates vs. the general population, and its performance in this population is encouraged when clinically indicated.

Intraprocedural considerations include the use of bedside US. Due to multiple benefits including effusion characterization, puncture site localization, and significantly lower rates of pneumothorax, the standard of care should be to perform thoracentesis with US guidance. Both use of US to mark an effusion immediately prior to puncture or in real time during needle insertion demonstrated benefit; however, it is unclear if 1 method is superior because no direct comparison studies were found. Further work is needed to investigate this potential.

Our review suggests that the location and course of the ICA is variable, especially near the midline, in the elderly, and in higher intercostal spaces, leaving it vulnerable to laceration. We recommend physicians only attempt thoracentesis at least 6 cm lateral to the midline due to ICA tortuosity and, ideally, 12 cm lateral, to avoid the presence of collaterals. Although only 2 small-scale studies were found pertaining to the use of US in identifying the ICA, we encourage physicians to consider learning how to screen for its presence as a part of their routine thoracic US exam in the area underlying the planned puncture site.

Manometry is beneficial because it can diagnose a nonexpandable lung and allows for pleural pressure monitoring.^52,53 A simple U-shaped manometer can be constructed from intravenous tubing included in most thoracentesis kits, which adds little to overall procedure time. While low rates of REPE have been observed when terminating thoracentesis if pressures drop below -20 cm H₂O or chest pain develops, neither measure appears to have reliable predictive value, limiting clinical utility. Further work is required to determine if a “safe pressure cutoff” exists. In general, we recommend the use of manometry when a nonexpandable (trapped) lung is suspected, because large drops in intrapleural pressure, a negative opening pressure, and respiratory variation can help confirm the diagnosis and avoid pneumothorax ex vacuo or unnecessary procedures in the future. As this condition appears to be more common in the setting of larger effusions, use of manometry when large-volume thoracenteses are planned is also reasonable.

Postprocedurally, routine imaging after thoracentesis is not recommended unless there is objective concern for complication. When indicated, bedside US is better positioned for this role compared with CXR, because it is more sensitive in detecting pneumothorax, provides instantaneous results, and avoids radiation exposure.

Our review has limitations. First, we searched only for articles between defined time periods, restricted our search to a single database, and excluded non-English articles. This has the potential to introduce selection bias, as nonprimary articles that fall within our time restrictions may cite older studies that are outside our search range. To minimize this effect, we performed a critical review of all included studies, especially nonprimary articles. Second, despite the focus of our search strategy to identify any articles related to patient safety and adverse events, we cannot guarantee that all relevant articles for any particular complication or risk factor were captured given the lack of more specific search terms. Third, although we performed a systematic search of the literature, we did not perform a formal systematic review or formally grade included studies. As the goal of our review was to categorize and operationalize clinical aspects, this approach was necessary, and we acknowledge that the quality of studies is variable. Lastly, we aimed to generate clinical recommendations for physicians performing thoracentesis at the bedside; others reviewing this literature may find or emphasize different aspects relevant to practice outside this setting.

In conclusion, evaluation and treatment of pleural effusions with bedside thoracentesis is an important skill for physicians of many disciplines. The evidence presented in this review will help inform the process and ensure patient safety. Physicians should consider incorporating these recommendations into their practice.

Acknowledgments

The authors thank Whitney Townsend, MLIS, health sciences informationist, for assistance with serial literature searches.

Disclosure

Nothing to report.

Pleural effusion can occur in myriad conditions including infection, heart failure, liver disease, and cancer.¹ Consequently, physicians from many disciplines routinely encounter both inpatients and outpatients with this diagnosis. Often, evaluation and treatment require thoracentesis to obtain fluid for analysis or symptom relief.

Although historically performed at the bedside without imaging guidance or intraprocedural monitoring, thoracentesis performed in this fashion carries considerable risk of complications. In fact, it has 1 of the highest rates of iatrogenic pneumothorax among bedside procedures.² However, recent advances in practice and adoption of newer technologies have helped to mitigate risks associated with this procedure. These advances are relevant because approximately 50% of thoracenteses are still performed at the bedside.³ In this review, we aim to identify the most recent key practices that enhance the safety and the effectiveness of thoracentesis for practicing clinicians.

Information Sources and Search Strategy

With the assistance of a research librarian, we performed a systematic search of PubMed-indexed articles from January 1, 2000 to September 30, 2015. Articles were identified using search terms such as thoracentesis, pleural effusion, safety, medical error, adverse event, and ultrasound in combination with Boolean operators. Of note, as thoracentesis is indexed as a subgroup of paracentesis in PubMed, this term was also included to increase the sensitivity of the search. The full search strategy is available in the Appendix. Any references cited in this review outside of the date range of our search are provided only to give relevant background information or establish the origin of commonly performed practices.

Study Eligibility and Selection Criteria

Studies were included if they reported clinical aspects related to thoracentesis. We defined clinical aspects as those strategies that focused on operator training, procedural techniques, technology, management, or prevention of complications. Non-English language articles, animal studies, case reports, conference proceedings, and abstracts were excluded. As our intention was to focus on the contemporary advances related to thoracentesis performance, (eg, ultrasound [US]), our search was limited to studies published after the year 2000. Two authors, Drs. Schildhouse and Lai independently screened studies to determine inclusion, excluding studies with weak methodology, very small sample sizes, and those only tangentially related to our aim. Disagreements regarding study inclusion were resolved by consensus. Drs. Lai, Barsuk, and Mourad identified additional studies by hand review of reference lists and content experts (Figure 1).

Conceptual Framework

All selected articles were categorized by temporal relationship to thoracentesis as pre-, intra-, or postprocedure. Pre-procedural topics were those outcomes that had been identified and addressed before attempting thoracentesis, such as physician training or perceived risks of harm. Intraprocedural considerations included aspects such as use of bedside US, pleural manometry, and large-volume drainage. Finally, postprocedural factors were those related to evaluation after thoracentesis, such as follow-up imaging. This conceptual framework is outlined in Figure 2.

The PubMed search returned a total of 1170 manuscripts, of which 56 articles met inclusion criteria. Four additional articles were identified by experts and included in the study.^4-7 Therefore, 60 articles were identified and included in this review. Study designs included cohort studies, case control studies, systematic reviews, meta-analyses, narrative reviews, consensus guidelines, and randomized controlled trials. A summary of all included articles by topic can be found in the Table.
 

PRE-PROCEDURAL CONSIDERATIONS

Physician Training

Studies indicate that graduate medical education may not adequately prepare clinicians to perform thoracentesis.⁸ In fact, residents have the least exposure and confidence in performing thoracentesis when compared to other bedside procedures.^9,10 In 1 survey, 69% of medical trainees desired more exposure to procedures, and 98% felt that procedural skills were important to master.¹¹ Not surprisingly, then, graduating internal medicine residents perform poorly when assessed on a thoracentesis simulator.¹²

Supplemental training outside of residency is useful to develop and maintain skills for thoracentesis, such as simulation with direct observation in a zero-risk environment. In 1 study, “simulation-based mastery learning” combined an educational video presentation with repeated, deliberate practice on a simulator until procedural competence was acquired, over two 2-hour sessions. In this study, 40 third-year medicine residents demonstrated a 71% improvement in clinical skills performance after course completion, with 93% achieving a passing score. The remaining 7% also achieved passing scores with extra practice time.¹² Others have built upon the concept of simulation-based training. For instance, 2 studies suggest that use of a simulation-based curriculum improved both thoracentesis knowledge and performance skills in a 3-hour session.^13,14 Similarly, 1 prospective study reported that a half-day thoracentesis workshop using simulation and 1:1 direct observation successfully lowered pneumothorax rates from 8.6% to 1.8% in a group of practicing clinicians. Notably, additional interventions including use of bedside US, limiting operators to a focused group, and standardization of equipment were also a part of this quality improvement initiative.⁷ Although repetition is required to gain proficiency when using a simulator, performance and confidence appear to plateau with only 4 simulator trials. In medical students, improvements derived through simulator-based teaching were sustained when retested 6 months following training.¹⁵

An instrument to ensure competency is necessary, given variability in procedural experience among both new graduates and practicing physicians,. Our search did not identify any clinically validated tools that adequately assessed thoracentesis performance. However, some have been proposed¹⁶ and 1 validated in a simulation environment.¹² Regarding the incorporation of US for effusion markup, 1 validated tool used an 11-domain assessment covering knowledge of US machine manipulation, recognition of images with common pleural effusion characteristics, and performance of thoracic US with puncture-site marking on a simulator. When used on 22 participants, scores with the tool could reliably differentiate between novice, intermediate, and advanced groups (P < 0.0001).¹⁷

Patient Selection

Coagulopathies and Anticoagulation. Historically, the accepted cutoff for performing thoracentesis is an international normalized ratio (INR) less than 1.5 and a platelet count greater than 50,000/µL. McVay et al.¹⁸ first showed in 1991 that use of these cutoffs was associated with low rates of periprocedural bleeding, leading to endorsement in the British Thoracic Society (BTS) Pleural Disease Guideline 2010.¹⁹ Other recommendations include the 2012 Society for Interventional Radiology guidelines that endorse correction of an INR greater than 2, or platelets less than 50,000/µL, based almost exclusively on expert opinion.⁵

However, data suggest that thoracentesis may be safely performed outside these parameters. For instance, a prospective study of approximately 9000 thoracenteses over 12 years found that patients with an INR of 1.5-2.9 or platelets of 20,000 - 49,000/µL experienced rates of bleeding complications similar to those with normal values.²⁰ Similarly, a 2014 review²¹ found that the overall risk of hemorrhage during thoracentesis in the setting of moderate coagulopathy (defined as an INR of 1.5 - 3 or platelets of 25,000-50,000/µL), was not increased. In 1 retrospective study of more than 1000 procedures, no differences in hemorrhagic events were noted in patients with bleeding diatheses that received prophylactic fresh frozen plasma or platelets vs. those who did not.²² Of note, included studies used a variety of criteria to define a hemorrhagic complication, which included: an isolated 2 g/dL or more decrement in hemoglobin, presence of bloody fluid on repeat tap with associated hemoglobin decrement, rapid re-accumulation of fluid with a hemoglobin decrement, or transfusion of 2 units or more of whole blood.

Whether it is safe to perform thoracentesis on patients taking antiplatelet therapy is less well understood. Although data are limited, a few small-scale studies^23,24 suggest that hemorrhagic complications following thoracentesis in patients receiving clopidogrel are comparable to the general population. We found no compelling data regarding the safety of thoracentesis in the setting of direct oral anticoagulants, heparin, low-molecular weight heparin, or intravenous direct thrombin inhibitors. Current practice is to generally avoid thoracentesis while these therapeutic anticoagulants are used.

Invasive mechanical ventilation. Pleural effusion is common in patients in the intensive care unit, including those requiring mechanical ventilation.²⁵ Thoracentesis in this population is clinically important: fluid analysis in 1 study was shown to aid the diagnosis in 45% of cases and changes in treatment in 33%.²⁶ However, clinicians may be reluctant to perform thoracentesis on patients who require mechanical ventilation, given the perception of a greater risk of pneumothorax from positive pressure ventilation.

Despite this concern, a 2011 meta-analysis including 19 studies and more than 1100 patients revealed rates of pneumothorax and hemothorax comparable to nonventilated patients.²⁵ Furthermore, a 2015 prospective study that examined thoracentesis in 1377 mechanically ventilated patients revealed no difference in complication rates as well.²⁰ Therefore, evidence suggests that performance of thoracentesis in mechanically ventilated patients is not contraindicated.

Skin Disinfection and Antisepsis Precautions

The 2010 BTS guidelines list empyema and wound infection as possible complications of thoracentesis.¹⁹ However, no data regarding incidence are provided. Additionally, an alcohol-based skin cleanser (such as 2% chlorhexidine gluconate/70% isopropyl alcohol), along with sterile gloves, field, and dressing are suggested as precautionary measures.¹⁹ In 1 single-center registry of 2489 thoracenteses performed using alcohol or iodine-based antiseptic and sterile drapes, no postprocedure infections were identified.²⁷ Of note, we did not find other studies (including case reports) that reported either incidence or rate of infectious complications such as wound infection and empyema. In an era of modern skin antiseptics that have effectively reduced complications such as catheter-related bloodstream infection,²⁸ the incidence of this event is thus likely to be low.

INTRAPROCEDURAL CONSIDERATIONS

Use of Bedside Ultrasound

Portable US has particular advantages for evaluation of pleural effusion vs other imaging modalities. Compared with computerized tomography (CT), bedside US offers similar performance but is less costly, avoids both radiation exposure and need for patient transportation, and provides results instantaneously.^29,30 Compared to chest x-ray (CXR), US is more sensitive at detecting the presence, volume, and characteristics of pleural fluid^30,31 and can be up to 100% sensitive for effusions greater than 100 mL.²⁹ Furthermore, whereas CXR typically requires 200 mL of fluid to be present for detection of an effusion, US can reliably detect as little as 20 mL of fluid.²⁹ When US was used to confirm thoracentesis puncture sites in a study involving 30 physicians of varying experience and 67 consecutive patients, 15% of sites found by clinical exam were inaccurate (less than 10 mm fluid present), 10% were at high risk for organ puncture, and a suitable fluid pocket was found 54% of times when exam could not.⁴

A 2010 meta-analysis of 24 studies and 6605 thoracenteses estimated the overall rate of pneumothorax at 6%; however, procedures performed with US guidance were associated with a 70% reduced risk of this event (odds ratio, 0.30; 95% confidence interval, 0.20 - 0.70).³² In a 2014 randomized control trial of 160 patients that compared thoracentesis with US guidance for site marking vs no US use, 10 pneumothoraces occurred in the control group vs 1 in the US group (12.5% vs 1.25%, P = 0.009).³³ Similarly, another retrospective review of 445 consecutive patients with malignant effusions revealed a pneumothorax rate of 0.97% using US in real time during needle insertion compared to 8.89% for unguided thoracenteses (P < 0.0001).³⁴ Several other studies using US guidance for either site markup or in real time reported similar pneumothorax rates, ranging from 1.1% - 4.8%.^35-37 However, it is unclear if real-time US specifically provides an additive effect vs site marking alone, as no studies directly comparing the 2 methods were found.

Benefits of US also include a higher rate of procedural success, with 1 study demonstrating a 99% success rate when using US vs. 90% without (P = 0.030).³³ A larger volume of fluid removed has been observed with US use as well, and methods have been described using fluid-pocket depth to guide puncture site localization and maximize drainage.³⁸ Finally, US use for thoracentesis has been associated with lower costs and length of stay.^39,40

Intercostal Artery Localization

Although rare (incidence, 0.18%-2%^20,21,39), the occurrence of hemothorax following thoracentesis is potentially catastrophic. This serious complication is often caused by laceration of the intercostal artery (ICA) or 1 of its branches during needle insertion.⁴¹

While risk of injury is theoretically reduced by needle insertion superior to the rib, studies using cadaver dissection and 3D angiography show significant tortuosity of the ICA.^6,41-43 The degree of tortuosity is increased within 6 cm of the midline, in more cephalad rib spaces, and in the elderly (older than 60 years).^41-43 Furthermore, 1 cadaveric study also demonstrated the presence of arterial collaterals branching off the ICA at multiple intercostal spaces, ranging between 8 cm and 11 cm from the midline.⁴¹ This anatomic variability may explain why some have observed low complication and hemothorax rates with an extreme lateral approach.³⁵ Bedside US with color flow Doppler imaging has been used to identify the ICA, with 88% sensitivity compared to CT imaging while adding little to exam time.^44,45 Of note, a 37% drop in the rate of hemothorax was observed in 1 study with routine US guidance alone.³⁹

Pleural Pressure Monitoring and Large-Volume Thoracentesis

While normal intrapleural pressures are approximately -5 to -10 cm H₂O,⁴⁶ the presence of a pleural effusion creates a complex interaction between fluid, compressed lung, and chest wall that can increase these pressures.⁴⁷ During drainage of an effusion, pleural pressures may rapidly drop, provoking re-expansion pulmonary edema (REPE). While rare (0 -1%), clinically-diagnosed REPE is a serious complication that can lead to rapid respiratory failure and death.^20,48 REPE is postulated to be caused by increased capillary permeability resulting from inflammation, driven by rapid re-inflation of the lung when exposed to highly negative intrapleural pressures.^47,49

Measurement of intrapleural pressure using a water manometer during thoracentesis may minimize REPE by terminating fluid drainage when intrapleural pressure begins to drop rapidly.^50,51 A cutoff of -20 cm H₂O has been cited repeatedly as safe since being suggested by Light in 1980, but this is based on animal models.^50,52 In 1 prospective study of 185 thoracenteses in which manometry was performed, 15% of patients had intrapleural pressure drop to less than -20 cm H₂O (at which point the procedure was terminated) but suffered no REPE.⁵⁰

Manometry is valuable in the identification of an unexpandable or trapped lung when pleural pressures drop rapidly with only minimal fluid volume removal.^47,53 Other findings correlated with an unexpandable lung include a negative opening pressure⁴⁷ and large fluctuations in pressure during the respiratory cycle.⁵⁴

While development of symptoms (eg, chest pain, cough, or dyspnea) is often used as a surrogate, the correlation between intrapleural pressure and patient symptoms is inconsistent and not a reliable proxy.⁵⁵ One study found that 22% of patients with chest pain during thoracentesis had intrapleural pressures lower than -20 cm H₂O compared with 8.6% of asymptomatic patients,⁵⁶ but it is unclear if the association is causal.

Thoracentesis is often performed for symptomatic relief and removal of large fluid volume. However, it remains common to halt fluid removal after 1.5 L, a threshold endorsed by BTS.¹⁹ While some investigators have suggested that removal of 2 L or more of pleural fluid does not compromise safety,^57,58 a 4- to 5-fold rise in the risk of pneumothorax was noted in 2 studies.^20,59 when more than 1.5 L of fluid was removed. The majority of these may be related to pneumothorax ex vacuo, a condition in which fluid is drained from the chest, but the lung is unable to expand and fill the space (eg, “trapped lung”), resulting in a persistent pneumothorax. This condition generally does not require treatment.⁶⁰ When manometry is employed at 200-mL intervals with termination at an intrapleural pressure of less than 20 mm H₂O, drainage of 3 L or more has been reported with low rates of pneumothorax and very low rates of REPE.^50,51 However, whether this is cause and effect is unknown because REPE is rare, and more work is needed to determine the role of manometry for its prevention.

POSTPROCEDURAL CONSIDERATIONS

Postprocedure Imaging

Performing an upright CXR following thoracentesis is a practice that remains routinely done by many practitioners to monitor for complications. Such imaging was also endorsed by the American Thoracic Society guidelines.⁶¹ However, more recent data question the utility of this practice. Multiple studies have confirmed that post-thoracentesis CXR is unnecessary unless clinical suspicion for pneumothorax or REPE is present.^36,58,62,63 The BTS guidelines also advocate this approach.¹⁹ Interestingly, a potentially more effective way to screen for postprocedure complications is through bedside US, which has been shown to be more sensitive than CXR in detecting pneumothorax.⁶⁴ In 1 study of 185 patients, bedside US demonstrated a sensitivity of 88% and a specificity of 97% for diagnosing pneumothorax in patients with adequate quality scans, with positive and negative likelihood ratios of 55 and 0.17, respectively.⁶⁵

Thoracentesis remains a core procedural skill for hospitalists, critical care physicians, and emergency physicians. It is the foundational component when investigating and treating pleural effusions. When the most current training, techniques, and technology are used, data suggest this procedure is safe to perform at the bedside. Our review highlights these strategies and evaluates which aspects might be most applicable to clinical practice.

Our findings have several implications for those who perform this procedure. First, appropriate training is central to procedural safety, and both simulation and direct observation by procedural experts have been shown by multiple investigators to improve knowledge and skill. This training should integrate the use of US in performing a focused thoracic exam.

Second, recommendations regarding coagulopathy and a “safe cutoff” of an INR less than 1.5 or platelets greater than 50,000/µL had limited evidentiary support. Rather, multiple studies suggest no difference in bleeding risk following thoracentesis with an INR as high as 3.0 and platelets greater than 25,000/µL. Furthermore, prophylactic transfusion with fresh frozen plasma or platelets before thoracentesis did not alter bleeding risk and exposes patients to transfusion complications. Thus, routine use of this practice can no longer be recommended. Third, further research is needed to understand the bleeding risk for patients on antiplatelet medications, heparin products, and also direct oral anticoagulants, given the growing popularity in their use and the potential consequences of even temporary cessation. Regarding patients on mechanical ventilation, thoracentesis demonstrated no difference in complication rates vs. the general population, and its performance in this population is encouraged when clinically indicated.

Intraprocedural considerations include the use of bedside US. Due to multiple benefits including effusion characterization, puncture site localization, and significantly lower rates of pneumothorax, the standard of care should be to perform thoracentesis with US guidance. Both use of US to mark an effusion immediately prior to puncture or in real time during needle insertion demonstrated benefit; however, it is unclear if 1 method is superior because no direct comparison studies were found. Further work is needed to investigate this potential.

Our review suggests that the location and course of the ICA is variable, especially near the midline, in the elderly, and in higher intercostal spaces, leaving it vulnerable to laceration. We recommend physicians only attempt thoracentesis at least 6 cm lateral to the midline due to ICA tortuosity and, ideally, 12 cm lateral, to avoid the presence of collaterals. Although only 2 small-scale studies were found pertaining to the use of US in identifying the ICA, we encourage physicians to consider learning how to screen for its presence as a part of their routine thoracic US exam in the area underlying the planned puncture site.

Manometry is beneficial because it can diagnose a nonexpandable lung and allows for pleural pressure monitoring.^52,53 A simple U-shaped manometer can be constructed from intravenous tubing included in most thoracentesis kits, which adds little to overall procedure time. While low rates of REPE have been observed when terminating thoracentesis if pressures drop below -20 cm H₂O or chest pain develops, neither measure appears to have reliable predictive value, limiting clinical utility. Further work is required to determine if a “safe pressure cutoff” exists. In general, we recommend the use of manometry when a nonexpandable (trapped) lung is suspected, because large drops in intrapleural pressure, a negative opening pressure, and respiratory variation can help confirm the diagnosis and avoid pneumothorax ex vacuo or unnecessary procedures in the future. As this condition appears to be more common in the setting of larger effusions, use of manometry when large-volume thoracenteses are planned is also reasonable.

Postprocedurally, routine imaging after thoracentesis is not recommended unless there is objective concern for complication. When indicated, bedside US is better positioned for this role compared with CXR, because it is more sensitive in detecting pneumothorax, provides instantaneous results, and avoids radiation exposure.

Our review has limitations. First, we searched only for articles between defined time periods, restricted our search to a single database, and excluded non-English articles. This has the potential to introduce selection bias, as nonprimary articles that fall within our time restrictions may cite older studies that are outside our search range. To minimize this effect, we performed a critical review of all included studies, especially nonprimary articles. Second, despite the focus of our search strategy to identify any articles related to patient safety and adverse events, we cannot guarantee that all relevant articles for any particular complication or risk factor were captured given the lack of more specific search terms. Third, although we performed a systematic search of the literature, we did not perform a formal systematic review or formally grade included studies. As the goal of our review was to categorize and operationalize clinical aspects, this approach was necessary, and we acknowledge that the quality of studies is variable. Lastly, we aimed to generate clinical recommendations for physicians performing thoracentesis at the bedside; others reviewing this literature may find or emphasize different aspects relevant to practice outside this setting.

In conclusion, evaluation and treatment of pleural effusions with bedside thoracentesis is an important skill for physicians of many disciplines. The evidence presented in this review will help inform the process and ensure patient safety. Physicians should consider incorporating these recommendations into their practice.

Acknowledgments

The authors thank Whitney Townsend, MLIS, health sciences informationist, for assistance with serial literature searches.

Disclosure

Nothing to report.

Of the 36 million US hospitalizations each year, 22% are surgical.¹ Although less frequent than medical hospitalizations, surgical hospitalizations are more than twice as costly.² Additionally, surgical hospitalizations are on average longer than medical hospitalizations.² Given the increased scrutiny on cost and efficiency of care, attention has turned to optimizing perioperative care. Hospitalists are well positioned to provide specific expertise in the complex interdisciplinary medical management of surgical patients.

In recent decades, multiple models of hospitalist involvement in perioperative care have evolved across the United States.^3-19 To consolidate knowledge and experience and to develop a framework for providing the best care for surgical patients, the Society of Hospital Medicine organized the Perioperative Care Work Group in 2015. This framework was designed for interdisciplinary collaboration in building and strengthening perioperative care programs.

The Society of Hospital Medicine recognized hospital medicine programs’ need for guidance in developing collaborative care in perioperative medicine and appointed the Perioperative Care Work Group in May 2015. Work group members are perioperative medicine experts from US medical centers. They have extensive knowledge of the literature as well as administrative and clinical experience in a variety of perioperative care models.

Topic Development. Initial work was focused on reviewing and discussing multiple models of perioperative care and exploring the roles that hospital medicine physicians have within these models. Useful information was summarized to guide hospitals and physicians in designing, implementing, and expanding patient-centric perioperative medicine services with a focus on preoperative and postoperative care. A final document was created; it outlines system-level issues in perioperative care, organized by perioperative phases.

Initial Framework. Group members submitted written descriptions of key issues in each of 4 phases: (1) preoperative, (2) day of surgery, (3) postoperative inpatient, and (4) postdischarge. These descriptions were merged and reviewed by the content experts. Editing and discussion from the entire group were incorporated into the final matrix, which highlighted (1) perioperative phase definitions, (2) requirements for patients to move to next phase, (3) elements of care coordination typically provided by surgery, anesthesiology, and medicine disciplines, (4) concerns and risks particular to each phase, (5) unique considerations for each phase, (6) suggested metrics of success, and (7) key questions for determining the effectiveness of perioperative care in an institution. All members provided final evaluation and editing.

Final Approval. The Perioperative Care Matrix for Inpatient Surgeries (PCMIS) was presented to the board of the Society of Hospital Medicine in fall 2015 and was approved for use in centering and directing discussions regarding perioperative care.

Models of Care. The Perioperative Care Work Group surveyed examples of hospitalist engagement in perioperative care and synthesized these into synopses of existing models of care for the preoperative, day-of-surgery, postoperative-inpatient, and postdischarge phases.

Defining Key Concepts and Issues

Hospitalists have participated in a variety of perioperative roles for more than a decade. Roles include performing in-depth preoperative assessments, providing oversight to presurgical advanced practice provider assessments, providing inpatient comanagement and consultation both before and after surgery, and providing postdischarge follow-up within the surgical period for medical comorbidities.

Although a comprehensive look at the entire perioperative period is important, 4 specific phases were defined to guide this work (Figure). The phases identified were based on time relative to surgery, with unique considerations as to the overall perioperative period. Concerns and potential risks specific to each phase were considered (Table 1).

Models of Care

Multiple examples of hospitalist involvement were collected to inform the program development guidelines. The specifics noted among the reviewed practice models are described here.

Preoperative. In some centers, all patients scheduled for surgery are required to undergo evaluation at the institution’s preoperative clinic. At most others, referral to the preoperative clinic is at the discretion of the surgical specialists, who have been informed of the clinic’s available resources. Factors determining whether a patient has an in-person clinic visit, undergoes a telephone-based medical evaluation, or has a referral deferred to the primary care physician (PCP) include patient complexity and surgery-specific risk. Patients who have major medical comorbidities (eg, chronic lung or heart disease) or are undergoing higher risk procedures (eg, those lasting >1 hour, laparotomy) most often undergo a formal clinic evaluation. Often, even for a patient whose preoperative evaluation is completed by a PCP, the preoperative nursing staff will call before surgery to provide instructions and to confirm that preoperative planning is complete. Confirmation includes ensuring that the surgery consent and preoperative history and physical examination documents are in the medical record, and that all recommended tests have been performed. If deficiencies are found, surgical and preoperative clinic staff are notified.

The United States is focused on sensible, high-value care. Perioperative care is burgeoning with opportunities for improvement, including reducing avoidable complications, developing systems for early recognition and treatment of complications, and streamlining processes to shorten length of stay and improve patient experience. The PCMIS provides the needed platform to catalyze detailed collaborative work between disciplines engaged in perioperative care.

As average age and level of medical comorbidity increase among surgical patients, hospitalists will increasingly be called on to assist in perioperative care. Hospitalists have long been involved in caring for medically complex surgical patients, through comanagement, consultation, and preoperative evaluations. As a provider group, hospitalists have comprehensive skills in quality and systems improvement, and in program development across hospital systems nationwide. Hospitalists have demonstrated their value by focusing on improving patient outcomes and enhancing patient engagement and experiences. Additionally, the perioperative period is fraught with multiple and complicated handoffs, a problem area for which hospital medicine has pioneered solutions and developed unique expertise. Hospital medicine is well prepared to provide skilled and proven leadership in the timely development, improvement, and expansion of perioperative care for this increasingly older and chronically ill population.

Hospitalists are established in multiple perioperative roles for high-risk surgical patients and have the opportunity to expand optimal patient-centric perioperative care systems working in close concert with surgeons and anesthesiologists. The basics of developing these systems include (1) assessing risk for medical complications, (2) planning for perioperative care, (3) developing programs aimed at risk reduction for preventable complications and early identification and intervention for unavoidable complications, and (4) guiding quality improvement efforts, including planning for frequent handoffs and transitions.

As a key partner in developing comprehensive programs in perioperative care, hospital medicine will continue to shape the future of hospital care for all patients. The PCMIS, as developed with support from the Society of Hospital Medicine, will aid efforts to achieve the best perioperative care models for our surgical patients.

Disclosures

Financial activities outside the submitted work: Drs. Pfeifer and Jaffer report payment for development of educational presentations; Dr. Grant reports payment for expert testimony pertaining to hospital medicine; Drs. Grant and Jaffer report royalties from publishing; Drs. Thompson, Pfiefer, Grant, Slawski, and Jaffer report travel expenses for speaking and serving on national committees; and Drs. Slawski and Jaffer serve on the board of the Society of Perioperative Assessment and Quality Improvement. The other authors have nothing to report.

Of the 36 million US hospitalizations each year, 22% are surgical.¹ Although less frequent than medical hospitalizations, surgical hospitalizations are more than twice as costly.² Additionally, surgical hospitalizations are on average longer than medical hospitalizations.² Given the increased scrutiny on cost and efficiency of care, attention has turned to optimizing perioperative care. Hospitalists are well positioned to provide specific expertise in the complex interdisciplinary medical management of surgical patients.

In recent decades, multiple models of hospitalist involvement in perioperative care have evolved across the United States.^3-19 To consolidate knowledge and experience and to develop a framework for providing the best care for surgical patients, the Society of Hospital Medicine organized the Perioperative Care Work Group in 2015. This framework was designed for interdisciplinary collaboration in building and strengthening perioperative care programs.

The Society of Hospital Medicine recognized hospital medicine programs’ need for guidance in developing collaborative care in perioperative medicine and appointed the Perioperative Care Work Group in May 2015. Work group members are perioperative medicine experts from US medical centers. They have extensive knowledge of the literature as well as administrative and clinical experience in a variety of perioperative care models.

Topic Development. Initial work was focused on reviewing and discussing multiple models of perioperative care and exploring the roles that hospital medicine physicians have within these models. Useful information was summarized to guide hospitals and physicians in designing, implementing, and expanding patient-centric perioperative medicine services with a focus on preoperative and postoperative care. A final document was created; it outlines system-level issues in perioperative care, organized by perioperative phases.

Initial Framework. Group members submitted written descriptions of key issues in each of 4 phases: (1) preoperative, (2) day of surgery, (3) postoperative inpatient, and (4) postdischarge. These descriptions were merged and reviewed by the content experts. Editing and discussion from the entire group were incorporated into the final matrix, which highlighted (1) perioperative phase definitions, (2) requirements for patients to move to next phase, (3) elements of care coordination typically provided by surgery, anesthesiology, and medicine disciplines, (4) concerns and risks particular to each phase, (5) unique considerations for each phase, (6) suggested metrics of success, and (7) key questions for determining the effectiveness of perioperative care in an institution. All members provided final evaluation and editing.

Final Approval. The Perioperative Care Matrix for Inpatient Surgeries (PCMIS) was presented to the board of the Society of Hospital Medicine in fall 2015 and was approved for use in centering and directing discussions regarding perioperative care.

Models of Care. The Perioperative Care Work Group surveyed examples of hospitalist engagement in perioperative care and synthesized these into synopses of existing models of care for the preoperative, day-of-surgery, postoperative-inpatient, and postdischarge phases.

Defining Key Concepts and Issues

Hospitalists have participated in a variety of perioperative roles for more than a decade. Roles include performing in-depth preoperative assessments, providing oversight to presurgical advanced practice provider assessments, providing inpatient comanagement and consultation both before and after surgery, and providing postdischarge follow-up within the surgical period for medical comorbidities.

Although a comprehensive look at the entire perioperative period is important, 4 specific phases were defined to guide this work (Figure). The phases identified were based on time relative to surgery, with unique considerations as to the overall perioperative period. Concerns and potential risks specific to each phase were considered (Table 1).

Models of Care

Multiple examples of hospitalist involvement were collected to inform the program development guidelines. The specifics noted among the reviewed practice models are described here.

Preoperative. In some centers, all patients scheduled for surgery are required to undergo evaluation at the institution’s preoperative clinic. At most others, referral to the preoperative clinic is at the discretion of the surgical specialists, who have been informed of the clinic’s available resources. Factors determining whether a patient has an in-person clinic visit, undergoes a telephone-based medical evaluation, or has a referral deferred to the primary care physician (PCP) include patient complexity and surgery-specific risk. Patients who have major medical comorbidities (eg, chronic lung or heart disease) or are undergoing higher risk procedures (eg, those lasting >1 hour, laparotomy) most often undergo a formal clinic evaluation. Often, even for a patient whose preoperative evaluation is completed by a PCP, the preoperative nursing staff will call before surgery to provide instructions and to confirm that preoperative planning is complete. Confirmation includes ensuring that the surgery consent and preoperative history and physical examination documents are in the medical record, and that all recommended tests have been performed. If deficiencies are found, surgical and preoperative clinic staff are notified.

The United States is focused on sensible, high-value care. Perioperative care is burgeoning with opportunities for improvement, including reducing avoidable complications, developing systems for early recognition and treatment of complications, and streamlining processes to shorten length of stay and improve patient experience. The PCMIS provides the needed platform to catalyze detailed collaborative work between disciplines engaged in perioperative care.

As average age and level of medical comorbidity increase among surgical patients, hospitalists will increasingly be called on to assist in perioperative care. Hospitalists have long been involved in caring for medically complex surgical patients, through comanagement, consultation, and preoperative evaluations. As a provider group, hospitalists have comprehensive skills in quality and systems improvement, and in program development across hospital systems nationwide. Hospitalists have demonstrated their value by focusing on improving patient outcomes and enhancing patient engagement and experiences. Additionally, the perioperative period is fraught with multiple and complicated handoffs, a problem area for which hospital medicine has pioneered solutions and developed unique expertise. Hospital medicine is well prepared to provide skilled and proven leadership in the timely development, improvement, and expansion of perioperative care for this increasingly older and chronically ill population.

Hospitalists are established in multiple perioperative roles for high-risk surgical patients and have the opportunity to expand optimal patient-centric perioperative care systems working in close concert with surgeons and anesthesiologists. The basics of developing these systems include (1) assessing risk for medical complications, (2) planning for perioperative care, (3) developing programs aimed at risk reduction for preventable complications and early identification and intervention for unavoidable complications, and (4) guiding quality improvement efforts, including planning for frequent handoffs and transitions.

As a key partner in developing comprehensive programs in perioperative care, hospital medicine will continue to shape the future of hospital care for all patients. The PCMIS, as developed with support from the Society of Hospital Medicine, will aid efforts to achieve the best perioperative care models for our surgical patients.

Disclosures

Financial activities outside the submitted work: Drs. Pfeifer and Jaffer report payment for development of educational presentations; Dr. Grant reports payment for expert testimony pertaining to hospital medicine; Drs. Grant and Jaffer report royalties from publishing; Drs. Thompson, Pfiefer, Grant, Slawski, and Jaffer report travel expenses for speaking and serving on national committees; and Drs. Slawski and Jaffer serve on the board of the Society of Perioperative Assessment and Quality Improvement. The other authors have nothing to report.

Of the 36 million US hospitalizations each year, 22% are surgical.¹ Although less frequent than medical hospitalizations, surgical hospitalizations are more than twice as costly.² Additionally, surgical hospitalizations are on average longer than medical hospitalizations.² Given the increased scrutiny on cost and efficiency of care, attention has turned to optimizing perioperative care. Hospitalists are well positioned to provide specific expertise in the complex interdisciplinary medical management of surgical patients.

In recent decades, multiple models of hospitalist involvement in perioperative care have evolved across the United States.^3-19 To consolidate knowledge and experience and to develop a framework for providing the best care for surgical patients, the Society of Hospital Medicine organized the Perioperative Care Work Group in 2015. This framework was designed for interdisciplinary collaboration in building and strengthening perioperative care programs.

The Society of Hospital Medicine recognized hospital medicine programs’ need for guidance in developing collaborative care in perioperative medicine and appointed the Perioperative Care Work Group in May 2015. Work group members are perioperative medicine experts from US medical centers. They have extensive knowledge of the literature as well as administrative and clinical experience in a variety of perioperative care models.

Topic Development. Initial work was focused on reviewing and discussing multiple models of perioperative care and exploring the roles that hospital medicine physicians have within these models. Useful information was summarized to guide hospitals and physicians in designing, implementing, and expanding patient-centric perioperative medicine services with a focus on preoperative and postoperative care. A final document was created; it outlines system-level issues in perioperative care, organized by perioperative phases.

Initial Framework. Group members submitted written descriptions of key issues in each of 4 phases: (1) preoperative, (2) day of surgery, (3) postoperative inpatient, and (4) postdischarge. These descriptions were merged and reviewed by the content experts. Editing and discussion from the entire group were incorporated into the final matrix, which highlighted (1) perioperative phase definitions, (2) requirements for patients to move to next phase, (3) elements of care coordination typically provided by surgery, anesthesiology, and medicine disciplines, (4) concerns and risks particular to each phase, (5) unique considerations for each phase, (6) suggested metrics of success, and (7) key questions for determining the effectiveness of perioperative care in an institution. All members provided final evaluation and editing.

Final Approval. The Perioperative Care Matrix for Inpatient Surgeries (PCMIS) was presented to the board of the Society of Hospital Medicine in fall 2015 and was approved for use in centering and directing discussions regarding perioperative care.

Models of Care. The Perioperative Care Work Group surveyed examples of hospitalist engagement in perioperative care and synthesized these into synopses of existing models of care for the preoperative, day-of-surgery, postoperative-inpatient, and postdischarge phases.

Defining Key Concepts and Issues

Hospitalists have participated in a variety of perioperative roles for more than a decade. Roles include performing in-depth preoperative assessments, providing oversight to presurgical advanced practice provider assessments, providing inpatient comanagement and consultation both before and after surgery, and providing postdischarge follow-up within the surgical period for medical comorbidities.

Although a comprehensive look at the entire perioperative period is important, 4 specific phases were defined to guide this work (Figure). The phases identified were based on time relative to surgery, with unique considerations as to the overall perioperative period. Concerns and potential risks specific to each phase were considered (Table 1).

Models of Care

Multiple examples of hospitalist involvement were collected to inform the program development guidelines. The specifics noted among the reviewed practice models are described here.

Preoperative. In some centers, all patients scheduled for surgery are required to undergo evaluation at the institution’s preoperative clinic. At most others, referral to the preoperative clinic is at the discretion of the surgical specialists, who have been informed of the clinic’s available resources. Factors determining whether a patient has an in-person clinic visit, undergoes a telephone-based medical evaluation, or has a referral deferred to the primary care physician (PCP) include patient complexity and surgery-specific risk. Patients who have major medical comorbidities (eg, chronic lung or heart disease) or are undergoing higher risk procedures (eg, those lasting >1 hour, laparotomy) most often undergo a formal clinic evaluation. Often, even for a patient whose preoperative evaluation is completed by a PCP, the preoperative nursing staff will call before surgery to provide instructions and to confirm that preoperative planning is complete. Confirmation includes ensuring that the surgery consent and preoperative history and physical examination documents are in the medical record, and that all recommended tests have been performed. If deficiencies are found, surgical and preoperative clinic staff are notified.

The United States is focused on sensible, high-value care. Perioperative care is burgeoning with opportunities for improvement, including reducing avoidable complications, developing systems for early recognition and treatment of complications, and streamlining processes to shorten length of stay and improve patient experience. The PCMIS provides the needed platform to catalyze detailed collaborative work between disciplines engaged in perioperative care.

As average age and level of medical comorbidity increase among surgical patients, hospitalists will increasingly be called on to assist in perioperative care. Hospitalists have long been involved in caring for medically complex surgical patients, through comanagement, consultation, and preoperative evaluations. As a provider group, hospitalists have comprehensive skills in quality and systems improvement, and in program development across hospital systems nationwide. Hospitalists have demonstrated their value by focusing on improving patient outcomes and enhancing patient engagement and experiences. Additionally, the perioperative period is fraught with multiple and complicated handoffs, a problem area for which hospital medicine has pioneered solutions and developed unique expertise. Hospital medicine is well prepared to provide skilled and proven leadership in the timely development, improvement, and expansion of perioperative care for this increasingly older and chronically ill population.

Hospitalists are established in multiple perioperative roles for high-risk surgical patients and have the opportunity to expand optimal patient-centric perioperative care systems working in close concert with surgeons and anesthesiologists. The basics of developing these systems include (1) assessing risk for medical complications, (2) planning for perioperative care, (3) developing programs aimed at risk reduction for preventable complications and early identification and intervention for unavoidable complications, and (4) guiding quality improvement efforts, including planning for frequent handoffs and transitions.

As a key partner in developing comprehensive programs in perioperative care, hospital medicine will continue to shape the future of hospital care for all patients. The PCMIS, as developed with support from the Society of Hospital Medicine, will aid efforts to achieve the best perioperative care models for our surgical patients.

Disclosures

Financial activities outside the submitted work: Drs. Pfeifer and Jaffer report payment for development of educational presentations; Dr. Grant reports payment for expert testimony pertaining to hospital medicine; Drs. Grant and Jaffer report royalties from publishing; Drs. Thompson, Pfiefer, Grant, Slawski, and Jaffer report travel expenses for speaking and serving on national committees; and Drs. Slawski and Jaffer serve on the board of the Society of Perioperative Assessment and Quality Improvement. The other authors have nothing to report.

It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.^1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.

The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.²

Estrogen Receptor-Positive Therapies

Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.

Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.

Advanced Metastatic Treatments

Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.³

Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.

Fulvestrant

The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.⁴ However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.⁵

The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.⁶

These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.⁵

Palbociclib

The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7

A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.⁷ While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.

Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.

Early-Stage Treatment Options

There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.

The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.^8,9

However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.⁸

Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.

The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.

In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.⁹ Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.

Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.^10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.⁸ This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.

The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.

HER2-Positive Breast Cancer

Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.

Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.

New Standard of Care

The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.

New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.¹² In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.¹³

In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.¹² In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).¹⁴ From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.

However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.

Conclusions

The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.

Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.

Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.^1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.

The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.²

Estrogen Receptor-Positive Therapies

Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.

Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.

Advanced Metastatic Treatments

Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.³

Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.

Fulvestrant

The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.⁴ However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.⁵

The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.⁶

These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.⁵

Palbociclib

The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7

A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.⁷ While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.

Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.

Early-Stage Treatment Options

There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.

The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.^8,9

However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.⁸

Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.

The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.

In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.⁹ Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.

Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.^10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.⁸ This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.

The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.

HER2-Positive Breast Cancer

Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.

Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.

New Standard of Care

The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.

New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.¹² In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.¹³

In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.¹² In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).¹⁴ From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.

However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.

Conclusions

The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.

Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.

Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.^1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.

The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.²

Estrogen Receptor-Positive Therapies

Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.

Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.

Advanced Metastatic Treatments

Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.³

Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.

Fulvestrant

The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.⁴ However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.⁵

The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.⁶

These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.⁵

Palbociclib

The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7

A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.⁷ While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.

Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.

Early-Stage Treatment Options

There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.

The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.^8,9

However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.⁸

Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.

The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.

In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.⁹ Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.

Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.^10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.⁸ This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.

The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.

HER2-Positive Breast Cancer

Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.

Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.

New Standard of Care

The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.

New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.¹² In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.¹³

In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.¹² In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).¹⁴ From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.

However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.

Conclusions

The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.

Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.

Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).

Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.

IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.

At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).

Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.

The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.

Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).

Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.

IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.

At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).

Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.

The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.

Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).

Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.

IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.

At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).

Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.

The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.

The American College of Surgeons (ACS) has announced the launch of the new Surgeon Specific Registry (SSR), hosted by QuintilesIMS. The new SSR is set to go live in this spring. The latest version of the registry will have several enhanced features, including improved reporting capabilities, delegate-level access to enter data, and the ability to add custom fields for additional relevant variables.

To help you prepare for this transition, the SSR team will host several educational webinars to demonstrate the new system’s capabilities and features. The ACS encourages both current and potential users to participate. To view the available times and register for one of the upcoming webinars, visit the SSR News and Updates web page at facs.org/quality-programs/ssr/news.

Contact [email protected] if you have any questions.
 

The American College of Surgeons (ACS) has announced the launch of the new Surgeon Specific Registry (SSR), hosted by QuintilesIMS. The new SSR is set to go live in this spring. The latest version of the registry will have several enhanced features, including improved reporting capabilities, delegate-level access to enter data, and the ability to add custom fields for additional relevant variables.

To help you prepare for this transition, the SSR team will host several educational webinars to demonstrate the new system’s capabilities and features. The ACS encourages both current and potential users to participate. To view the available times and register for one of the upcoming webinars, visit the SSR News and Updates web page at facs.org/quality-programs/ssr/news.

Contact [email protected] if you have any questions.
 

The American College of Surgeons (ACS) has announced the launch of the new Surgeon Specific Registry (SSR), hosted by QuintilesIMS. The new SSR is set to go live in this spring. The latest version of the registry will have several enhanced features, including improved reporting capabilities, delegate-level access to enter data, and the ability to add custom fields for additional relevant variables.

To help you prepare for this transition, the SSR team will host several educational webinars to demonstrate the new system’s capabilities and features. The ACS encourages both current and potential users to participate. To view the available times and register for one of the upcoming webinars, visit the SSR News and Updates web page at facs.org/quality-programs/ssr/news.

Contact [email protected] if you have any questions.