Hospital Medicine

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.

"Extreme remedies are very appropriate for extreme diseases"
- Hippocrates Aphorisms

On March 5, 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of the drug ketamine, an old anesthetic that has been put to a new use over the past 10 years as therapy for treatment-resistant severe depression. Ketamine, known on the street as Special K, has long been known to cause dissociation, hallucinations, and other hallucinogenic effects. In many randomized controlled trials, subanesthetic doses administered intravenously have demonstrated rapid and often dramatic relief of depressive symptoms.

Neuroscientists have heralded ketamine as the paradigm of the glutamatergic modifying drug class, which represents the first real breakthrough in the pharmaceutical treatment of depression in decades.¹ There have been 2 major pharmacologic limitations attached to this promising new treatment: the IV form of the drug and the short duration of its antidepressant effect. Pharmaceutical companies and neuroscientists predictably have been engaging in a fast and furious race to successfully overcome these obstacles, hoping to win fame and fortune and bring hope and help to the millions of patients who have failed to fully respond to or been unable to tolerate existing therapies for mood disorders.²

When the FDA approved Spravato (esketamine), a nasal administration of ketamine, many people hoped that researchers had succeeded in overcoming these barriers. The risks of serious adverse events (AEs) as well as the potential for abuse and diversion led the FDA to limit prescriptions under a Risk Evaluation and Mitigation Strategy (REMS).³ Patients self-administer the nasal spray but only in a certified medical facility under the observation of a health care practitioner. Patients also must agree to remain on site for 2 hours after administration of the drug to ensure their safety. The FDA recommends the drug be given twice a week for 4 weeks along with a conventional monoamine-acting antidepressant.When the US Department of Veterans Affairs (VA) cleared the way for use of esketamine, less than 2 weeks after the FDA approval, it also launched a series of controversies over how to use the drug in its massive health care system, which is the subject of this editorial. On March 19, 2019, the VA announced that VA practitioners would be able to prescribe the nasal spray for patients who were determined to have treatment-resistant depression but only after appropriate clinical assessment and in accordance with their patients’ preferences.

A number of controversies have emerged surrounding the VA adoption of esketamine, including its cost/benefit/risk ratio and who should be able to access the medication. Each of these issues has onion layers of political, regulatory, and ethical concerns that can only be superficially noted here and warrant fuller unpeeling. In June The New York Times featured a story alleging that in response to the tragic tide of ever-increasing veteran suicides, the VA sanctioned esketamine prescribing despite its cost and the serious questions experts raised about the data the FDA cited to establish its safety and efficacy. Although the cost to the VA of Spravato is unclear, it is much higher than generic IV ketamine.⁴

The access controversy is almost the ethical inverse of the first. In June 2019, a Veterans Health Administration advisory panel voted against allowing general use of esketamine, limiting it to individual cases of patients who are preapproved and have failed 2 antidepressant trials. Esketamine will not be on the VA formulary for widespread use. Congressional and public advocacy groups have noted that the formulary decision came in the wake of ongoing attention to the role of the pharmaceutical industry in the VA’s rapid adoption of the drug.^5,6 For the thousands of veterans for whom the data show conventional antidepressants even in combination with other psychotropic medications and evidence-based psychotherapies resulted in AEs or only partial remission of depression symptoms, the VA’s restriction will likely seem unfair and even uncaring.⁷

As a practicing VA psychiatrist, I know firsthand how desperately we need new, more effective, and better-tolerated treatments for severe unipolar and bipolar depression. Although I have not prescribed ketamine or esketamine, several of my most respected colleagues do. I have seen patients with chronic, severe, depression respond and even recover in ways that seem just a little short of miraculous when compared with other therapies. Yet as a longtime student of the history of psychiatry, I have also seen that often the treatments that initially seem so auspicious, in time, turn out to have a dark side. Families, communities, the country, VA, and the US Department of Defense and its practitioners in and out of mental health cannot in any moral universe abide by the fact that 20 plus men and women who served take their lives every day.⁸

As the epigraph to this column notes, we must often try radical therapies for grave cases in drastic crises. Yet we must also in making serious public health decisions fraught with unseen consequences take all due and considered diligence that we do not violate the even more fundamental dictum of the Hippocratic School, “at least do not harm.” That means trying to balance safety and availability while VA conducts its own research in a precarious way that leaves almost no stakeholder completely happy.

"Extreme remedies are very appropriate for extreme diseases"
- Hippocrates Aphorisms

On March 5, 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of the drug ketamine, an old anesthetic that has been put to a new use over the past 10 years as therapy for treatment-resistant severe depression. Ketamine, known on the street as Special K, has long been known to cause dissociation, hallucinations, and other hallucinogenic effects. In many randomized controlled trials, subanesthetic doses administered intravenously have demonstrated rapid and often dramatic relief of depressive symptoms.

Neuroscientists have heralded ketamine as the paradigm of the glutamatergic modifying drug class, which represents the first real breakthrough in the pharmaceutical treatment of depression in decades.¹ There have been 2 major pharmacologic limitations attached to this promising new treatment: the IV form of the drug and the short duration of its antidepressant effect. Pharmaceutical companies and neuroscientists predictably have been engaging in a fast and furious race to successfully overcome these obstacles, hoping to win fame and fortune and bring hope and help to the millions of patients who have failed to fully respond to or been unable to tolerate existing therapies for mood disorders.²

When the FDA approved Spravato (esketamine), a nasal administration of ketamine, many people hoped that researchers had succeeded in overcoming these barriers. The risks of serious adverse events (AEs) as well as the potential for abuse and diversion led the FDA to limit prescriptions under a Risk Evaluation and Mitigation Strategy (REMS).³ Patients self-administer the nasal spray but only in a certified medical facility under the observation of a health care practitioner. Patients also must agree to remain on site for 2 hours after administration of the drug to ensure their safety. The FDA recommends the drug be given twice a week for 4 weeks along with a conventional monoamine-acting antidepressant.When the US Department of Veterans Affairs (VA) cleared the way for use of esketamine, less than 2 weeks after the FDA approval, it also launched a series of controversies over how to use the drug in its massive health care system, which is the subject of this editorial. On March 19, 2019, the VA announced that VA practitioners would be able to prescribe the nasal spray for patients who were determined to have treatment-resistant depression but only after appropriate clinical assessment and in accordance with their patients’ preferences.

A number of controversies have emerged surrounding the VA adoption of esketamine, including its cost/benefit/risk ratio and who should be able to access the medication. Each of these issues has onion layers of political, regulatory, and ethical concerns that can only be superficially noted here and warrant fuller unpeeling. In June The New York Times featured a story alleging that in response to the tragic tide of ever-increasing veteran suicides, the VA sanctioned esketamine prescribing despite its cost and the serious questions experts raised about the data the FDA cited to establish its safety and efficacy. Although the cost to the VA of Spravato is unclear, it is much higher than generic IV ketamine.⁴

The access controversy is almost the ethical inverse of the first. In June 2019, a Veterans Health Administration advisory panel voted against allowing general use of esketamine, limiting it to individual cases of patients who are preapproved and have failed 2 antidepressant trials. Esketamine will not be on the VA formulary for widespread use. Congressional and public advocacy groups have noted that the formulary decision came in the wake of ongoing attention to the role of the pharmaceutical industry in the VA’s rapid adoption of the drug.^5,6 For the thousands of veterans for whom the data show conventional antidepressants even in combination with other psychotropic medications and evidence-based psychotherapies resulted in AEs or only partial remission of depression symptoms, the VA’s restriction will likely seem unfair and even uncaring.⁷

As a practicing VA psychiatrist, I know firsthand how desperately we need new, more effective, and better-tolerated treatments for severe unipolar and bipolar depression. Although I have not prescribed ketamine or esketamine, several of my most respected colleagues do. I have seen patients with chronic, severe, depression respond and even recover in ways that seem just a little short of miraculous when compared with other therapies. Yet as a longtime student of the history of psychiatry, I have also seen that often the treatments that initially seem so auspicious, in time, turn out to have a dark side. Families, communities, the country, VA, and the US Department of Defense and its practitioners in and out of mental health cannot in any moral universe abide by the fact that 20 plus men and women who served take their lives every day.⁸

As the epigraph to this column notes, we must often try radical therapies for grave cases in drastic crises. Yet we must also in making serious public health decisions fraught with unseen consequences take all due and considered diligence that we do not violate the even more fundamental dictum of the Hippocratic School, “at least do not harm.” That means trying to balance safety and availability while VA conducts its own research in a precarious way that leaves almost no stakeholder completely happy.

"Extreme remedies are very appropriate for extreme diseases"
- Hippocrates Aphorisms

On March 5, 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of the drug ketamine, an old anesthetic that has been put to a new use over the past 10 years as therapy for treatment-resistant severe depression. Ketamine, known on the street as Special K, has long been known to cause dissociation, hallucinations, and other hallucinogenic effects. In many randomized controlled trials, subanesthetic doses administered intravenously have demonstrated rapid and often dramatic relief of depressive symptoms.

Neuroscientists have heralded ketamine as the paradigm of the glutamatergic modifying drug class, which represents the first real breakthrough in the pharmaceutical treatment of depression in decades.¹ There have been 2 major pharmacologic limitations attached to this promising new treatment: the IV form of the drug and the short duration of its antidepressant effect. Pharmaceutical companies and neuroscientists predictably have been engaging in a fast and furious race to successfully overcome these obstacles, hoping to win fame and fortune and bring hope and help to the millions of patients who have failed to fully respond to or been unable to tolerate existing therapies for mood disorders.²

When the FDA approved Spravato (esketamine), a nasal administration of ketamine, many people hoped that researchers had succeeded in overcoming these barriers. The risks of serious adverse events (AEs) as well as the potential for abuse and diversion led the FDA to limit prescriptions under a Risk Evaluation and Mitigation Strategy (REMS).³ Patients self-administer the nasal spray but only in a certified medical facility under the observation of a health care practitioner. Patients also must agree to remain on site for 2 hours after administration of the drug to ensure their safety. The FDA recommends the drug be given twice a week for 4 weeks along with a conventional monoamine-acting antidepressant.When the US Department of Veterans Affairs (VA) cleared the way for use of esketamine, less than 2 weeks after the FDA approval, it also launched a series of controversies over how to use the drug in its massive health care system, which is the subject of this editorial. On March 19, 2019, the VA announced that VA practitioners would be able to prescribe the nasal spray for patients who were determined to have treatment-resistant depression but only after appropriate clinical assessment and in accordance with their patients’ preferences.

A number of controversies have emerged surrounding the VA adoption of esketamine, including its cost/benefit/risk ratio and who should be able to access the medication. Each of these issues has onion layers of political, regulatory, and ethical concerns that can only be superficially noted here and warrant fuller unpeeling. In June The New York Times featured a story alleging that in response to the tragic tide of ever-increasing veteran suicides, the VA sanctioned esketamine prescribing despite its cost and the serious questions experts raised about the data the FDA cited to establish its safety and efficacy. Although the cost to the VA of Spravato is unclear, it is much higher than generic IV ketamine.⁴

The access controversy is almost the ethical inverse of the first. In June 2019, a Veterans Health Administration advisory panel voted against allowing general use of esketamine, limiting it to individual cases of patients who are preapproved and have failed 2 antidepressant trials. Esketamine will not be on the VA formulary for widespread use. Congressional and public advocacy groups have noted that the formulary decision came in the wake of ongoing attention to the role of the pharmaceutical industry in the VA’s rapid adoption of the drug.^5,6 For the thousands of veterans for whom the data show conventional antidepressants even in combination with other psychotropic medications and evidence-based psychotherapies resulted in AEs or only partial remission of depression symptoms, the VA’s restriction will likely seem unfair and even uncaring.⁷

As a practicing VA psychiatrist, I know firsthand how desperately we need new, more effective, and better-tolerated treatments for severe unipolar and bipolar depression. Although I have not prescribed ketamine or esketamine, several of my most respected colleagues do. I have seen patients with chronic, severe, depression respond and even recover in ways that seem just a little short of miraculous when compared with other therapies. Yet as a longtime student of the history of psychiatry, I have also seen that often the treatments that initially seem so auspicious, in time, turn out to have a dark side. Families, communities, the country, VA, and the US Department of Defense and its practitioners in and out of mental health cannot in any moral universe abide by the fact that 20 plus men and women who served take their lives every day.⁸

As the epigraph to this column notes, we must often try radical therapies for grave cases in drastic crises. Yet we must also in making serious public health decisions fraught with unseen consequences take all due and considered diligence that we do not violate the even more fundamental dictum of the Hippocratic School, “at least do not harm.” That means trying to balance safety and availability while VA conducts its own research in a precarious way that leaves almost no stakeholder completely happy.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated: Onset of action is immediate when administered IV as a bolus.¹ The major anticoagulant effect of heparin is mediated by heparin/antithrombin (AT) interaction. Heparin/AT inactivates factor IIa (thrombin) and factors Xa, IXa, XIa, and XIIa. Heparin is approved for multiple indications, such as venous thromboembolism (VTE) treatment and prophylaxis of medical and surgical patients; stroke prevention in atrial fibrillation (AF); acute coronary syndrome (ACS); vascular and cardiac surgeries; and various interventional procedures (eg, diagnostic angiography and percutaneous coronary intervention [PCI]). It also is used as an anticoagulant in blood transfusions, extracorporeal circulation, and for maintaining patency of central vascular access devices (CVADs).

About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. African swine fever, a contagious virus with no cure, has eliminated about 25% to 35% of China’s pig population, or about 150 million pigs. In July 2019, members of the US House of Representatives Committee on Energy and Commerce sent a letter to the US Food and Drug Administration asking for details on the potential impact of African swine fever on the supply of heparin.²

The US Department of Veterans Affairs (VA) heath care system is currently experiencing a shortage of heparin vials and syringes. It is unclear when resolution of this shortage will occur as it could resolve within several weeks or as late as January 2020.³ Although vials and syringes are the current products that are affected, it is possible the shortage may eventually include IV heparin bags as well.

Since the foremost objective of VA health care providers is to provide timely access to medications for veterans, strategies to conserve unfractionated heparin (UfH) must be used since it is a first-line therapy where few evidence-based alternatives exist. Conservation strategies may include drug rationing, therapeutic substitution, and compounding of needed products using the limited stock available in the pharmacy.⁴ It is important that all staff are educated on facility strategies in order to be familiar with alternatives and limit the potential for near misses, adverse events, and provider frustration.

In shortage situations, the VA-Pharmacy Benefits Management (PBM) defers decisions regarding drug preservation, processes to shift to viable alternatives, and the best practice for safe transitions to local facilities and their subject matter experts.⁵ At the VA Tennessee Valley Healthcare System, a 1A, tertiary, dual campus health care system, a pharmacy task force has formed to track drug shortages impacting the facility’s efficiencies and budgets. This group communicates with the Pharmacy and Therapeutics committee about potential risks to patient care and develops shortage briefs (following an SBAR [situation, background, assessment, recommendation] design) generally authored and championed by at least 1 clinical pharmacy specialist and supervising physicians who are field experts. Prior to dissemination, the SBAR undergoes a rapid peer-review process.

To date, VA PBM has not issued specific guidance on how pharmacists should proceed in case of a shortage. However, we recommend strategies that may be considered for implementation during a potential UfH shortage. For example, pharmacists can use therapeutic alternatives for which best available evidence suggests no disadvantage.⁴ The Table lists alternative agents according to indication and patient-specific considerations that may preclude use. Existing UfH products may also be used for drug compounding (eg, use current stock to provide an indicated aliquot) to meet the need of prioritized patients.⁴ In addition, we suggest prioritizing current UfH/heparinized saline for use for the following groups of patients⁴:

• Emergent/urgent cardiac surgery^1,6;
• Hemodialysis patients^1,7-9 for which the low-molecular-weight heparin (LMWH) dalteparin is deemed inappropriate or the patient is not monitored in the intensive care unit for regional citrate administration;
• VTE prophylaxis for patients with epidurals or chest tubes for which urgent invasive management may occur, recent cardiac or neurosurgery, or for patients with a creatine clearance < 15 mL/min or receiving hemodialysis^10-12;
• Vascular surgery (eg, limb ischemia) and interventions (eg, carotid stenting, endarterectomy)^13,14;
• Mesenteric ischemia (venous thrombosis) with a potential to proceed to laparotomy¹⁵;
• Critically ill patients with arterial lines for which normal saline is deemed inappropriate for line flushing¹⁶;
• Electrophysiology procedures (eg, AF ablation)¹⁷; and
• Contraindication to use of a long-acting alternative listed in the table or a medical necessity exists for using a rapidly reversible agent. Examples for this category include but are not limited to recent gastrointestinal bleeding, central nervous system lesion, and select neurologic diagnoses (eg, cerebral venous sinus thrombosis with hemorrhage, thrombus in vertebral basilar system or anterior circulation, intraparenchymal hemorrhage plus mechanical valve, medium to large cardioembolic stroke with intracardiac thrombus).

Conclusion

The UfH drug shortage represents a significant threat to public health and is a major challenge for US health care systems, including the Veterans Health Administration. Overreliance on a predominant source of crude heparin has affected multiple UfH manufacturers and products. Current alternatives to UfH include low-molecular-weight heparins, IV direct thrombin inhibitors, and SC fondaparinux, with selection supported by guidelines or evolving literature. However, the shortage has the potential to expand to other injectables, such as dalteparin and enoxaparin, and severely limit care for veterans. It is vital that clinicians rapidly address the current shortage by creating a plan to develop efficient and equitable access to UfH, continue to assess supply and update stakeholders, and select evidence-based alternatives while maintaining focus on efficacy and safety.

Acknowledgments

The authors thank Ashley Yost, PharmD, for her coordination of the multidisciplinary task force assigned to efficiently manage the heparin drug shortage. This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville, Tennessee.

Perioperative medicine is an evolving field with a rapidly growing body of literature, particularly in cardiology.

In this update, we review 6 articles to answer questions related to preoperative cardiac risk assessment, perioperative medication management, and postoperative cardiac complications. We surveyed perioperative literature from February 2018 through January 2019 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

These summaries are derived from “Updates in Perioperative Medicine” presented at the 14th Annual Perioperative Medicine Summit (Orlando, FL, February 13–16, 2019) and the 2019 Society of Hospital Medicine Annual Meeting (National Harbor, MD, March 24–27, 2019).

PREOPERATIVE CARDIAC EVALUATION

How well do measures of functional capacity predict perioperative complications and mortality in noncardiac surgical patients?

Functional capacity is commonly assessed in preoperative evaluations to estimate patients’ risks of perioperative complications and death. The American College of Cardiology/American Heart Association¹ and the European Society of Cardiology² guidelines both include estimation of cardiopulmonary fitness as a step in preoperative assessment before major noncardiac surgery.

“Subjective assessment” is one way to estimate functional capacity. Simply put, clinicians try to form a rough idea about the fitness of patients by asking questions about routine activities such as walking or climbing stairs. Although commonly used, subjective assessment of functional capacity lacks strong evidence that it predicts adverse perioperative events.

Cardiopulmonary exercise testing is a third option. It measures peak oxygen consumption and anaerobic threshold during exercise. It is probably the best objective measurement of functional capacity, but not necessarily for predicting postoperative cardiac complications, and it is performed relatively infrequently.

[Wijeysundera DN, Pearse RM, Sulman MA, et al. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet 2018; 391(10140):2631–2640. doi:10.1016/S0140-6736(18)31131-0]

In a multicenter, prospective cohort study, Wijeysundera et al⁴ compared subjective functional capacity assessment, the Duke Activity Status Index, cardiopulmonary exercise testing, and the preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in their ability to predict complications and death in 1,401 noncardiac surgery patients older than 40 with at least 1 cardiovascular risk factor. After surgery, patients had daily electrocardiograms and troponin measurements until postoperative day 3 or discharge.

The primary outcome was the 30-day incidence of death or myocardial infarction (MI). Additional outcomes included the 30-day incidence of death or myocardial injury after noncardiac surgery (MINS), the 1-year mortality rate, and moderate to severe in-hospital perioperative complications.

Findings. Two percent of patients died or had an MI within 30 days of surgery.⁴

Subjective assessment had only a 19.2% sensitivity (95% confidence interval [CI] 14.2–25) but a 94.7% specificity (95% CI 93.2–95.9) for predicting inability to attain 4 metabolic equivalents during exercise.⁴

A lower Duke Activity Status Index predicted the primary outcome of death or MI within 30 days (adjusted odds ratio [OR] 0.96, 95% CI 0.83–0.99, P = .03), and it was the only measure that did so. Additionally, the Duke index and NT-proBNP level predicted the risk of death or MINS within 30 days.⁴

Only elevated NT-proBNP was associated with death at 1 year.⁴

On exercise testing, low peak oxygen consumption was significantly associated with perioperative complications.

Limitations. The number of primary outcome events (death and MI) was low, potentially affecting the statistical power of the study.

Conclusions. Subjective assessment of functional capacity misclassifies too many patients as being at low risk of perioperative complications and should not be used for preoperative risk stratification. Other tools, such as the Duke Activity Status Index and NT-proBNP levels, are better predictors of adverse perioperative cardiovascular outcomes and should be considered for use in preoperative cardiac risk assessment.

Although the Duke Activity Status Index is a better predictor of adverse outcomes than subjective functional capacity assessment, a specific perioperative threshold for risk classification has not been established. Its correlate for metabolic equivalents should be considered for use in clinical practice at this point.

Is perioperative aspirin beneficial in patients undergoing vascular surgery?

The Perioperative Ischemic Evaluation 2 (POISE-2) trial,⁵ a 2-by-2 factorial randomized controlled trial in which patients received perioperative aspirin, clonidine, both, or neither, demonstrated that perioperative aspirin did not reduce cardiovascular events and increased major bleeding. Patients with recently placed coronary stents and those undergoing carotid endarterectomy were excluded because aspirin is known to have a beneficial effect in these patients.

A subsequent substudy⁶ found perioperative aspirin to be beneficial in patients with coronary stents placed more than a year before noncardiac surgery. Whether perioperative aspirin is beneficial in other subgroups was unknown.

[Biccard BM, Sigamani A, Chan MTV, et al. Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2). Br J Surg 2018; 105(12):1591–1597. doi:10.1002/bjs.10925]

Biccard et al⁷ investigated the effect of perioperative aspirin in the subgroup of patients from the POISE-2 trial who underwent vascular surgery. The primary outcome was death or MI within 30 days. Secondary outcomes in this substudy included vascular occlusive complications (amputation and peripheral arterial thrombosis) and major or life-threatening bleeding.

Limitations. There were few adverse events, and this substudy was underpowered for the primary and secondary outcomes.

Conclusion. Starting or continuing aspirin did not improve outcomes, and withdrawing it did not increase cardiovascular or occlusive complications.

Do ACE inhibitors affect risk in noncardiac nonvascular surgery?

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are some of the most commonly used medications for treating hypertension. But whether patients should continue receiving them on the day of surgery or whether they should be held remains unclear.

Although current recommendations are inconsistent, the most recent American College of Cardiology/American Heart Association¹ perioperative practice guidelines say that continuing ACE inhibitors or ARBs is reasonable perioperatively. This recommendation, however, acknowledges that published evidence is limited. There is general agreement that preoperative exposure to ACE inhibitors and ARBs is associated with intraoperative hypotension, but whether this increases the risk of adverse clinical outcomes remains unclear. Needed was a study to determine the effect on perioperative morbidity and mortality of continuing vs withholding ACE inhibitors and ARBs before surgery.

[Shiffermiller JF, Monson BJ, Vokoun CW, et al. Prospective randomized evaluation of preoperative angiotensin-converting enzyme inhibition (PREOP-ACEI). J Hosp Med 2018; 13(10):661–667. doi:10.12788/jhm.3036]

Shiffermiller et al⁸ performed a randomized controlled trial comparing the effect of 2 preoperative ACE inhibitor management protocols in patients undergoing noncardiac nonvascular surgery. Patients were randomized to either receive or not receive their final preoperative ACE inhibitor dose, whether scheduled on the morning of surgery or the night before.

Exclusion criteria included hypotension or hypertension at their preoperative clinic appointment (defined as systolic blood pressure < 90 or ≥ 160 mm Hg, and diastolic blood pressure < 60 or ≥ 95 mm Hg), moderate to severe heart failure, and end-stage renal disease requiring dialysis. Excluded surgery types were cardiac, vascular, organ transplant, oncologic, and all outpatient procedures. Patients taking ARBs were also excluded.

The primary outcome was intraoperative hypotension defined as any systolic blood pressure less than 80 mm Hg from the time of anesthesia induction until transfer to the postanesthesia care unit. Secondary outcomes were measured until hospital discharge and included postoperative acute kidney injury, postoperative hypotension (systolic pressure < 90 mm Hg) and hypertension (systolic pressure > 180 mm Hg), major cardiac events (composite of acute coronary syndrome, acute heart failure, or new-onset arrhythmia), and death.

Findings. A total of 453 patients were screened for eligibility, and of these, 291 were included for randomization. Their average age was 64, 48% were men, and 87% were white. About 50% underwent general anesthesia, 25% spinal, and 25% regional. Over half of the surgeries were orthopedic, and 20% were spine surgeries.

The primary outcome of intraoperative hypotension occurred significantly less often in patients randomized to ACE inhibitor omission than in the continuation group (55% vs 69%, relative risk [RR] 0.81, 95% CI 0.67–0.97, P = .03). This translates to 1 case of intraoperative hypotension for every 7.5 patients continuing an ACE inhibitor perioperatively (number needed to harm 7.5). Intraoperative hypotension associated with vasopressor administration also occurred significantly less frequently in the ACE inhibitor omission group.

Patients in the ACE inhibitor omission group were also less likely to experience postoperative hypotension, but on the other hand, they were more likely to experience severe postoperative hypertension (defined as any systolic blood pressure > 180 mm Hg). The two groups fared the same in terms of rates of acute kidney injury and major adverse cardiac events (MACE) and hospital length of stay, and no patients died in either group.

Limitations. Several factors limit the generalizability of this single-center study, including the many exclusion criteria, the predominance of orthopedic and spine surgeries, and the low-risk patient population (the average Revised Cardiac Risk Index score was 0, range 0–3). Other limitations include not controlling for the specific ACE inhibitor used and not including the precise timing of the final dose in relation to surgery. Lastly, this study lacked power to measure postoperative outcomes.

Conclusions. Continuing ACE inhibitor treatment before noncardiac nonvascular surgery is associated with a greater frequency and duration of intraoperative hypotension, but it did not increase the incidences of acute kidney injury, MACE, or death nor the hospital length of stay.

[Hollmann C, Fernandes NL, Biccard BM. A systematic review of outcomes associated with withholding or continuing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers before noncardiac surgery. Anesth Analg 2018; 127(3):678–687. doi:10.1213/ANE.0000000000002837]

Hollmann et al⁹ performed a meta-analysis to determine whether it is better to continue or withhold ACE inhibitors and ARBs before surgery. The patients were adults undergoing noncardiac surgery and receiving an ACE inhibitor or ARB, which was either withheld or continued on the morning of surgery.

Primary outcomes were all-cause mortality and MACE, while secondary outcomes included the incidence of acute kidney injury, heart failure, stroke, intraoperative and postoperative hypotension, and length of hospital stay. Randomized controlled trials and observational studies were included, while case reports and case-control studies were excluded.

Findings. This meta-analysis included 5 randomized controlled trials and 4 cohort studies, with a total of 6,022 patients; 1,816 had their ACE inhibitor or ARB withheld before surgery, while 4,206 continued therapy. It found no difference between the 2 groups in the incidence of death or MACE, and there were not enough data to determine a difference in heart failure, stroke, acute kidney injury, or hospital length of stay.

Seven studies, with 5,414 patients, examined intraoperative hypotension. The overall incidence was 30%, but was significantly lower if the ACE inhibitor or ARB was withheld (OR 0.63, 95% CI 0.47–0.85, ^P = .002). Findings were similar in an analysis of only the randomized controlled trials. No difference was observed in postoperative hypotension.

Limitations. There was no standard definition of the morbidity outcomes, including hypotension and MACE. The assessment of MACE included data only for MI and not MINS. The specific duration of hypotension was not reported, and this meta-analysis did not take into account different anesthetic techniques. The duration of follow-up varied widely among studies, ranging from the day of hospital discharge to 30 days after surgery. And the randomized controlled trial performed by Shiffermiller et al⁸ was not included.

Conclusions. While continuing ACE inhibitors or ARBs before noncardiac surgery was associated with intraoperative hypotension, it did not seem to affect other outcomes, including death and MACE. The authors propose that a large randomized controlled trial is needed to determine whether continuing or withholding ACE inhibitor or ARB therapy before surgery is safer.

How should we treat MINS?

MINS is associated with an increased risk of cardiovascular events and death in both the short term and long term. MINS is defined as an elevated postoperative troponin level related to an ischemic etiology. However, whether to routinely measure troponin after surgery is unclear, as most patients do not present with ischemic symptoms, and there is no standard of care for treatment of this entity. Limited observational data suggest that starting or intensifying cardiac medications, particularly aspirin and statins, may be beneficial in terms of reducing 30-day mortality rates in patients with MI or cardiac events at 1 year in vascular surgery patients with MINS.

The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial was designed to evaluate the potential of the anticoagulant dabigatran to prevent major vascular complications in patients with MINS.

[Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet 2018; 391(10137):2325–2334. doi:10.1016/S0140-6736(18)30832-8]

Devereaux et al¹⁰ randomized patients who were at least 45 years old and had developed MINS within the previous 35 days to receive dabigatran 110 mg orally twice daily or placebo for up to 2 years. Patients not already taking a proton pump inhibitor were also randomized to take either omeprazole 20 mg once daily or placebo.

The primary efficacy outcome initially was major vascular complications, which included vascular mortality, nonfatal MI, nonhemorrhagic stroke, and peripheral arterial thrombosis. However, amputation and symptomatic venous thromboembolism were subsequently added during the study.

The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Major bleeding required a decrease in hemoglobin of at least 4 g/dL, transfusion of at least 3 units of red blood cells within a 24-hour period, or a procedure to stop the bleeding.

Findings. The original goal was to recruit 3,200 patients, but due to slow enrollment and loss of funding, the sample was reduced to 1,754 patients (877 in each group). Approximately 45% of each group stopped taking the study drug prematurely.

The primary efficacy outcome occurred in significantly fewer patients receiving dabigatran (97, 11%) than placebo (133, 15%, HR 0.72, 95% CI 0.55–0.93, P = .0115). The incidence of the primary safety outcome was similar in both groups: 3% with dabigatran and 4% with placebo (HR 0.92, 95% CI 0.55–1.53, P = .76). The only individual efficacy outcome meeting statistical significance was a lower rate of nonhemorrhagic stroke in the dabigatran group. Subgroup analyses showed a trend benefiting patients randomized within 5 days of MINS or with a diagnosis of MI, although it was not statistically significant.

Limitations. The efficacy outcomes were expanded to include venous thromboembolism and others not directly related to MINS, raising questions about the conclusions. Further, as defined by the protocol, bleeding had to be fairly severe to be deemed major. The high number of patients who discontinued the study drug is another limitation of this study.

Conclusion. Dabigatran lowered the risk of major vascular complications with no significant increase in major bleeding in patients with MINS.

What is the risk of thromboembolism in postoperative atrial fibrillation, and what are the benefits of anticoagulation?

Although nonvalvular atrial fibrillation is associated with increased risks of ischemic stroke and systemic embolic events in nonsurgical patients, the association of new-onset postoperative atrial fibrillation with long-term thromboembolic events in the noncardiac surgical population is not well established.

[Butt JH, Olesen JB, Havers-Borgersen E, et al. Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery. J Am Coll Cardiol 2018; 72(17):2027–2036. doi:10.1016/j.jacc.2018.07.088]

In this retrospective cohort study using a nationwide registry in Denmark, Butt et al¹¹ assessed the long-term risk of thromboembolic events in noncardiac surgical patients with new postoperative atrial fibrillation. Patients were identified who had no previous history of atrial fibrillation and developed it after noncardiac, nonobstetric surgeries, and were matched in a 1:4 ratio with patients who developed nonvalvular atrial fibrillation during nonsurgical hospitalizations. Matching was based on age, sex, heart failure, hypertension, diabetes, known history of thromboembolic events, ischemic heart disease, and the year patients presented with new atrial fibrillation.

Patients were excluded if they received antiarrhythmic drugs or oral anticoagulants before hospitalization or surgery, had cancer in the year prior, or died in the hospital.

The primary outcome of the study was thromboembolic events—a composite of ischemic stroke, transient cerebral ischemia, and peripheral arterial thrombosis or embolism. Secondary outcomes included rehospitalization for atrial fibrillation and all-cause mortality.

Findings. Overall, 0.4% of patients developed new postoperative atrial fibrillation, of whom 3,380 were matched with 15,320 patients with nonvalvular atrial fibrillation. Over a median follow-up of 3.2 years, the risk of thromboembolic events was similar in both groups (31.7 and 29.9 per 1,000 person-years, HR 0.95, 95% CI 0.85–1.07). The groups did not differ in their CHA₂DS₂-VASc risk scores, HAS-BLED risk scores, or year in which patients were diagnosed.

Anticoagulation lowered the risk of thromboembolic events to a similar extent in both groups compared with no anticoagulation:

• In postoperative atrial fibrillation—HR 0.57, 95% CI 0.40–0.67
• In nonvalvular atrial fibrillation—HR 0.56, 95% CI 0.51–0.62.

Despite the similar reduction in thromboembolic events, only 24.4% of the postoperative atrial fibrillation patients were started on anticoagulation therapy within 30 days of discharge, compared with 41.5% of those with nonvalvular atrial fibrillation.

Limitations. Although this was a large study with excellent follow-up data, it was observational. It may have underestimated the number of patients who developed postoperative atrial fibrillation because episodes that were judged not to be clinically significant may not have been charted. Many patients are not monitored with continuous telemetry postoperatively, which also may have led to underestimation of the number of atrial fibrillation events.

The study also did not examine the number of atrial fibrillation episodes per patient, the heart rhythm at discharge or long-term, or indication for and duration of anticoagulation. There were no data regarding international normalized ratio levels.

Conclusions. Postoperative atrial fibrillation is associated with outcomes similar to those of nonsurgical nonvalvular atrial fibrillation. Anticoagulation decreases the risks of stroke and death. However, substantially fewer patients with postoperative atrial fibrillation receive anticoagulation. Anticoagulation should be considered in these patients, while noting bleeding risk.

Perioperative medicine is an evolving field with a rapidly growing body of literature, particularly in cardiology.

In this update, we review 6 articles to answer questions related to preoperative cardiac risk assessment, perioperative medication management, and postoperative cardiac complications. We surveyed perioperative literature from February 2018 through January 2019 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

These summaries are derived from “Updates in Perioperative Medicine” presented at the 14th Annual Perioperative Medicine Summit (Orlando, FL, February 13–16, 2019) and the 2019 Society of Hospital Medicine Annual Meeting (National Harbor, MD, March 24–27, 2019).

PREOPERATIVE CARDIAC EVALUATION

How well do measures of functional capacity predict perioperative complications and mortality in noncardiac surgical patients?

Functional capacity is commonly assessed in preoperative evaluations to estimate patients’ risks of perioperative complications and death. The American College of Cardiology/American Heart Association¹ and the European Society of Cardiology² guidelines both include estimation of cardiopulmonary fitness as a step in preoperative assessment before major noncardiac surgery.

“Subjective assessment” is one way to estimate functional capacity. Simply put, clinicians try to form a rough idea about the fitness of patients by asking questions about routine activities such as walking or climbing stairs. Although commonly used, subjective assessment of functional capacity lacks strong evidence that it predicts adverse perioperative events.

Cardiopulmonary exercise testing is a third option. It measures peak oxygen consumption and anaerobic threshold during exercise. It is probably the best objective measurement of functional capacity, but not necessarily for predicting postoperative cardiac complications, and it is performed relatively infrequently.

[Wijeysundera DN, Pearse RM, Sulman MA, et al. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet 2018; 391(10140):2631–2640. doi:10.1016/S0140-6736(18)31131-0]

In a multicenter, prospective cohort study, Wijeysundera et al⁴ compared subjective functional capacity assessment, the Duke Activity Status Index, cardiopulmonary exercise testing, and the preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in their ability to predict complications and death in 1,401 noncardiac surgery patients older than 40 with at least 1 cardiovascular risk factor. After surgery, patients had daily electrocardiograms and troponin measurements until postoperative day 3 or discharge.

The primary outcome was the 30-day incidence of death or myocardial infarction (MI). Additional outcomes included the 30-day incidence of death or myocardial injury after noncardiac surgery (MINS), the 1-year mortality rate, and moderate to severe in-hospital perioperative complications.

Findings. Two percent of patients died or had an MI within 30 days of surgery.⁴

Subjective assessment had only a 19.2% sensitivity (95% confidence interval [CI] 14.2–25) but a 94.7% specificity (95% CI 93.2–95.9) for predicting inability to attain 4 metabolic equivalents during exercise.⁴

A lower Duke Activity Status Index predicted the primary outcome of death or MI within 30 days (adjusted odds ratio [OR] 0.96, 95% CI 0.83–0.99, P = .03), and it was the only measure that did so. Additionally, the Duke index and NT-proBNP level predicted the risk of death or MINS within 30 days.⁴

Only elevated NT-proBNP was associated with death at 1 year.⁴

On exercise testing, low peak oxygen consumption was significantly associated with perioperative complications.

Limitations. The number of primary outcome events (death and MI) was low, potentially affecting the statistical power of the study.

Conclusions. Subjective assessment of functional capacity misclassifies too many patients as being at low risk of perioperative complications and should not be used for preoperative risk stratification. Other tools, such as the Duke Activity Status Index and NT-proBNP levels, are better predictors of adverse perioperative cardiovascular outcomes and should be considered for use in preoperative cardiac risk assessment.

Although the Duke Activity Status Index is a better predictor of adverse outcomes than subjective functional capacity assessment, a specific perioperative threshold for risk classification has not been established. Its correlate for metabolic equivalents should be considered for use in clinical practice at this point.

Is perioperative aspirin beneficial in patients undergoing vascular surgery?

The Perioperative Ischemic Evaluation 2 (POISE-2) trial,⁵ a 2-by-2 factorial randomized controlled trial in which patients received perioperative aspirin, clonidine, both, or neither, demonstrated that perioperative aspirin did not reduce cardiovascular events and increased major bleeding. Patients with recently placed coronary stents and those undergoing carotid endarterectomy were excluded because aspirin is known to have a beneficial effect in these patients.

A subsequent substudy⁶ found perioperative aspirin to be beneficial in patients with coronary stents placed more than a year before noncardiac surgery. Whether perioperative aspirin is beneficial in other subgroups was unknown.

[Biccard BM, Sigamani A, Chan MTV, et al. Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2). Br J Surg 2018; 105(12):1591–1597. doi:10.1002/bjs.10925]

Biccard et al⁷ investigated the effect of perioperative aspirin in the subgroup of patients from the POISE-2 trial who underwent vascular surgery. The primary outcome was death or MI within 30 days. Secondary outcomes in this substudy included vascular occlusive complications (amputation and peripheral arterial thrombosis) and major or life-threatening bleeding.

Limitations. There were few adverse events, and this substudy was underpowered for the primary and secondary outcomes.

Conclusion. Starting or continuing aspirin did not improve outcomes, and withdrawing it did not increase cardiovascular or occlusive complications.

Do ACE inhibitors affect risk in noncardiac nonvascular surgery?

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are some of the most commonly used medications for treating hypertension. But whether patients should continue receiving them on the day of surgery or whether they should be held remains unclear.

Although current recommendations are inconsistent, the most recent American College of Cardiology/American Heart Association¹ perioperative practice guidelines say that continuing ACE inhibitors or ARBs is reasonable perioperatively. This recommendation, however, acknowledges that published evidence is limited. There is general agreement that preoperative exposure to ACE inhibitors and ARBs is associated with intraoperative hypotension, but whether this increases the risk of adverse clinical outcomes remains unclear. Needed was a study to determine the effect on perioperative morbidity and mortality of continuing vs withholding ACE inhibitors and ARBs before surgery.

[Shiffermiller JF, Monson BJ, Vokoun CW, et al. Prospective randomized evaluation of preoperative angiotensin-converting enzyme inhibition (PREOP-ACEI). J Hosp Med 2018; 13(10):661–667. doi:10.12788/jhm.3036]

Shiffermiller et al⁸ performed a randomized controlled trial comparing the effect of 2 preoperative ACE inhibitor management protocols in patients undergoing noncardiac nonvascular surgery. Patients were randomized to either receive or not receive their final preoperative ACE inhibitor dose, whether scheduled on the morning of surgery or the night before.

Exclusion criteria included hypotension or hypertension at their preoperative clinic appointment (defined as systolic blood pressure < 90 or ≥ 160 mm Hg, and diastolic blood pressure < 60 or ≥ 95 mm Hg), moderate to severe heart failure, and end-stage renal disease requiring dialysis. Excluded surgery types were cardiac, vascular, organ transplant, oncologic, and all outpatient procedures. Patients taking ARBs were also excluded.

The primary outcome was intraoperative hypotension defined as any systolic blood pressure less than 80 mm Hg from the time of anesthesia induction until transfer to the postanesthesia care unit. Secondary outcomes were measured until hospital discharge and included postoperative acute kidney injury, postoperative hypotension (systolic pressure < 90 mm Hg) and hypertension (systolic pressure > 180 mm Hg), major cardiac events (composite of acute coronary syndrome, acute heart failure, or new-onset arrhythmia), and death.

Findings. A total of 453 patients were screened for eligibility, and of these, 291 were included for randomization. Their average age was 64, 48% were men, and 87% were white. About 50% underwent general anesthesia, 25% spinal, and 25% regional. Over half of the surgeries were orthopedic, and 20% were spine surgeries.

The primary outcome of intraoperative hypotension occurred significantly less often in patients randomized to ACE inhibitor omission than in the continuation group (55% vs 69%, relative risk [RR] 0.81, 95% CI 0.67–0.97, P = .03). This translates to 1 case of intraoperative hypotension for every 7.5 patients continuing an ACE inhibitor perioperatively (number needed to harm 7.5). Intraoperative hypotension associated with vasopressor administration also occurred significantly less frequently in the ACE inhibitor omission group.

Patients in the ACE inhibitor omission group were also less likely to experience postoperative hypotension, but on the other hand, they were more likely to experience severe postoperative hypertension (defined as any systolic blood pressure > 180 mm Hg). The two groups fared the same in terms of rates of acute kidney injury and major adverse cardiac events (MACE) and hospital length of stay, and no patients died in either group.

Limitations. Several factors limit the generalizability of this single-center study, including the many exclusion criteria, the predominance of orthopedic and spine surgeries, and the low-risk patient population (the average Revised Cardiac Risk Index score was 0, range 0–3). Other limitations include not controlling for the specific ACE inhibitor used and not including the precise timing of the final dose in relation to surgery. Lastly, this study lacked power to measure postoperative outcomes.

Conclusions. Continuing ACE inhibitor treatment before noncardiac nonvascular surgery is associated with a greater frequency and duration of intraoperative hypotension, but it did not increase the incidences of acute kidney injury, MACE, or death nor the hospital length of stay.

[Hollmann C, Fernandes NL, Biccard BM. A systematic review of outcomes associated with withholding or continuing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers before noncardiac surgery. Anesth Analg 2018; 127(3):678–687. doi:10.1213/ANE.0000000000002837]

Hollmann et al⁹ performed a meta-analysis to determine whether it is better to continue or withhold ACE inhibitors and ARBs before surgery. The patients were adults undergoing noncardiac surgery and receiving an ACE inhibitor or ARB, which was either withheld or continued on the morning of surgery.

Primary outcomes were all-cause mortality and MACE, while secondary outcomes included the incidence of acute kidney injury, heart failure, stroke, intraoperative and postoperative hypotension, and length of hospital stay. Randomized controlled trials and observational studies were included, while case reports and case-control studies were excluded.

Findings. This meta-analysis included 5 randomized controlled trials and 4 cohort studies, with a total of 6,022 patients; 1,816 had their ACE inhibitor or ARB withheld before surgery, while 4,206 continued therapy. It found no difference between the 2 groups in the incidence of death or MACE, and there were not enough data to determine a difference in heart failure, stroke, acute kidney injury, or hospital length of stay.

Seven studies, with 5,414 patients, examined intraoperative hypotension. The overall incidence was 30%, but was significantly lower if the ACE inhibitor or ARB was withheld (OR 0.63, 95% CI 0.47–0.85, ^P = .002). Findings were similar in an analysis of only the randomized controlled trials. No difference was observed in postoperative hypotension.

Limitations. There was no standard definition of the morbidity outcomes, including hypotension and MACE. The assessment of MACE included data only for MI and not MINS. The specific duration of hypotension was not reported, and this meta-analysis did not take into account different anesthetic techniques. The duration of follow-up varied widely among studies, ranging from the day of hospital discharge to 30 days after surgery. And the randomized controlled trial performed by Shiffermiller et al⁸ was not included.

Conclusions. While continuing ACE inhibitors or ARBs before noncardiac surgery was associated with intraoperative hypotension, it did not seem to affect other outcomes, including death and MACE. The authors propose that a large randomized controlled trial is needed to determine whether continuing or withholding ACE inhibitor or ARB therapy before surgery is safer.

How should we treat MINS?

MINS is associated with an increased risk of cardiovascular events and death in both the short term and long term. MINS is defined as an elevated postoperative troponin level related to an ischemic etiology. However, whether to routinely measure troponin after surgery is unclear, as most patients do not present with ischemic symptoms, and there is no standard of care for treatment of this entity. Limited observational data suggest that starting or intensifying cardiac medications, particularly aspirin and statins, may be beneficial in terms of reducing 30-day mortality rates in patients with MI or cardiac events at 1 year in vascular surgery patients with MINS.

The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial was designed to evaluate the potential of the anticoagulant dabigatran to prevent major vascular complications in patients with MINS.

[Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet 2018; 391(10137):2325–2334. doi:10.1016/S0140-6736(18)30832-8]

Devereaux et al¹⁰ randomized patients who were at least 45 years old and had developed MINS within the previous 35 days to receive dabigatran 110 mg orally twice daily or placebo for up to 2 years. Patients not already taking a proton pump inhibitor were also randomized to take either omeprazole 20 mg once daily or placebo.

The primary efficacy outcome initially was major vascular complications, which included vascular mortality, nonfatal MI, nonhemorrhagic stroke, and peripheral arterial thrombosis. However, amputation and symptomatic venous thromboembolism were subsequently added during the study.

The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Major bleeding required a decrease in hemoglobin of at least 4 g/dL, transfusion of at least 3 units of red blood cells within a 24-hour period, or a procedure to stop the bleeding.

Findings. The original goal was to recruit 3,200 patients, but due to slow enrollment and loss of funding, the sample was reduced to 1,754 patients (877 in each group). Approximately 45% of each group stopped taking the study drug prematurely.

The primary efficacy outcome occurred in significantly fewer patients receiving dabigatran (97, 11%) than placebo (133, 15%, HR 0.72, 95% CI 0.55–0.93, P = .0115). The incidence of the primary safety outcome was similar in both groups: 3% with dabigatran and 4% with placebo (HR 0.92, 95% CI 0.55–1.53, P = .76). The only individual efficacy outcome meeting statistical significance was a lower rate of nonhemorrhagic stroke in the dabigatran group. Subgroup analyses showed a trend benefiting patients randomized within 5 days of MINS or with a diagnosis of MI, although it was not statistically significant.

Limitations. The efficacy outcomes were expanded to include venous thromboembolism and others not directly related to MINS, raising questions about the conclusions. Further, as defined by the protocol, bleeding had to be fairly severe to be deemed major. The high number of patients who discontinued the study drug is another limitation of this study.

Conclusion. Dabigatran lowered the risk of major vascular complications with no significant increase in major bleeding in patients with MINS.

What is the risk of thromboembolism in postoperative atrial fibrillation, and what are the benefits of anticoagulation?

Although nonvalvular atrial fibrillation is associated with increased risks of ischemic stroke and systemic embolic events in nonsurgical patients, the association of new-onset postoperative atrial fibrillation with long-term thromboembolic events in the noncardiac surgical population is not well established.

[Butt JH, Olesen JB, Havers-Borgersen E, et al. Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery. J Am Coll Cardiol 2018; 72(17):2027–2036. doi:10.1016/j.jacc.2018.07.088]

In this retrospective cohort study using a nationwide registry in Denmark, Butt et al¹¹ assessed the long-term risk of thromboembolic events in noncardiac surgical patients with new postoperative atrial fibrillation. Patients were identified who had no previous history of atrial fibrillation and developed it after noncardiac, nonobstetric surgeries, and were matched in a 1:4 ratio with patients who developed nonvalvular atrial fibrillation during nonsurgical hospitalizations. Matching was based on age, sex, heart failure, hypertension, diabetes, known history of thromboembolic events, ischemic heart disease, and the year patients presented with new atrial fibrillation.

Patients were excluded if they received antiarrhythmic drugs or oral anticoagulants before hospitalization or surgery, had cancer in the year prior, or died in the hospital.

The primary outcome of the study was thromboembolic events—a composite of ischemic stroke, transient cerebral ischemia, and peripheral arterial thrombosis or embolism. Secondary outcomes included rehospitalization for atrial fibrillation and all-cause mortality.

Findings. Overall, 0.4% of patients developed new postoperative atrial fibrillation, of whom 3,380 were matched with 15,320 patients with nonvalvular atrial fibrillation. Over a median follow-up of 3.2 years, the risk of thromboembolic events was similar in both groups (31.7 and 29.9 per 1,000 person-years, HR 0.95, 95% CI 0.85–1.07). The groups did not differ in their CHA₂DS₂-VASc risk scores, HAS-BLED risk scores, or year in which patients were diagnosed.

Anticoagulation lowered the risk of thromboembolic events to a similar extent in both groups compared with no anticoagulation:

• In postoperative atrial fibrillation—HR 0.57, 95% CI 0.40–0.67
• In nonvalvular atrial fibrillation—HR 0.56, 95% CI 0.51–0.62.

Despite the similar reduction in thromboembolic events, only 24.4% of the postoperative atrial fibrillation patients were started on anticoagulation therapy within 30 days of discharge, compared with 41.5% of those with nonvalvular atrial fibrillation.

Limitations. Although this was a large study with excellent follow-up data, it was observational. It may have underestimated the number of patients who developed postoperative atrial fibrillation because episodes that were judged not to be clinically significant may not have been charted. Many patients are not monitored with continuous telemetry postoperatively, which also may have led to underestimation of the number of atrial fibrillation events.

The study also did not examine the number of atrial fibrillation episodes per patient, the heart rhythm at discharge or long-term, or indication for and duration of anticoagulation. There were no data regarding international normalized ratio levels.

Conclusions. Postoperative atrial fibrillation is associated with outcomes similar to those of nonsurgical nonvalvular atrial fibrillation. Anticoagulation decreases the risks of stroke and death. However, substantially fewer patients with postoperative atrial fibrillation receive anticoagulation. Anticoagulation should be considered in these patients, while noting bleeding risk.

Perioperative medicine is an evolving field with a rapidly growing body of literature, particularly in cardiology.

In this update, we review 6 articles to answer questions related to preoperative cardiac risk assessment, perioperative medication management, and postoperative cardiac complications. We surveyed perioperative literature from February 2018 through January 2019 and chose the final articles by consensus, based on relevance to clinicians who provide preoperative evaluations and postoperative care to surgical patients.

These summaries are derived from “Updates in Perioperative Medicine” presented at the 14th Annual Perioperative Medicine Summit (Orlando, FL, February 13–16, 2019) and the 2019 Society of Hospital Medicine Annual Meeting (National Harbor, MD, March 24–27, 2019).

PREOPERATIVE CARDIAC EVALUATION

How well do measures of functional capacity predict perioperative complications and mortality in noncardiac surgical patients?

Functional capacity is commonly assessed in preoperative evaluations to estimate patients’ risks of perioperative complications and death. The American College of Cardiology/American Heart Association¹ and the European Society of Cardiology² guidelines both include estimation of cardiopulmonary fitness as a step in preoperative assessment before major noncardiac surgery.

“Subjective assessment” is one way to estimate functional capacity. Simply put, clinicians try to form a rough idea about the fitness of patients by asking questions about routine activities such as walking or climbing stairs. Although commonly used, subjective assessment of functional capacity lacks strong evidence that it predicts adverse perioperative events.

Cardiopulmonary exercise testing is a third option. It measures peak oxygen consumption and anaerobic threshold during exercise. It is probably the best objective measurement of functional capacity, but not necessarily for predicting postoperative cardiac complications, and it is performed relatively infrequently.

[Wijeysundera DN, Pearse RM, Sulman MA, et al. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet 2018; 391(10140):2631–2640. doi:10.1016/S0140-6736(18)31131-0]

In a multicenter, prospective cohort study, Wijeysundera et al⁴ compared subjective functional capacity assessment, the Duke Activity Status Index, cardiopulmonary exercise testing, and the preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in their ability to predict complications and death in 1,401 noncardiac surgery patients older than 40 with at least 1 cardiovascular risk factor. After surgery, patients had daily electrocardiograms and troponin measurements until postoperative day 3 or discharge.

The primary outcome was the 30-day incidence of death or myocardial infarction (MI). Additional outcomes included the 30-day incidence of death or myocardial injury after noncardiac surgery (MINS), the 1-year mortality rate, and moderate to severe in-hospital perioperative complications.

Findings. Two percent of patients died or had an MI within 30 days of surgery.⁴

Subjective assessment had only a 19.2% sensitivity (95% confidence interval [CI] 14.2–25) but a 94.7% specificity (95% CI 93.2–95.9) for predicting inability to attain 4 metabolic equivalents during exercise.⁴

A lower Duke Activity Status Index predicted the primary outcome of death or MI within 30 days (adjusted odds ratio [OR] 0.96, 95% CI 0.83–0.99, P = .03), and it was the only measure that did so. Additionally, the Duke index and NT-proBNP level predicted the risk of death or MINS within 30 days.⁴

Only elevated NT-proBNP was associated with death at 1 year.⁴

On exercise testing, low peak oxygen consumption was significantly associated with perioperative complications.

Limitations. The number of primary outcome events (death and MI) was low, potentially affecting the statistical power of the study.

Conclusions. Subjective assessment of functional capacity misclassifies too many patients as being at low risk of perioperative complications and should not be used for preoperative risk stratification. Other tools, such as the Duke Activity Status Index and NT-proBNP levels, are better predictors of adverse perioperative cardiovascular outcomes and should be considered for use in preoperative cardiac risk assessment.

Although the Duke Activity Status Index is a better predictor of adverse outcomes than subjective functional capacity assessment, a specific perioperative threshold for risk classification has not been established. Its correlate for metabolic equivalents should be considered for use in clinical practice at this point.

Is perioperative aspirin beneficial in patients undergoing vascular surgery?

The Perioperative Ischemic Evaluation 2 (POISE-2) trial,⁵ a 2-by-2 factorial randomized controlled trial in which patients received perioperative aspirin, clonidine, both, or neither, demonstrated that perioperative aspirin did not reduce cardiovascular events and increased major bleeding. Patients with recently placed coronary stents and those undergoing carotid endarterectomy were excluded because aspirin is known to have a beneficial effect in these patients.

A subsequent substudy⁶ found perioperative aspirin to be beneficial in patients with coronary stents placed more than a year before noncardiac surgery. Whether perioperative aspirin is beneficial in other subgroups was unknown.

[Biccard BM, Sigamani A, Chan MTV, et al. Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2). Br J Surg 2018; 105(12):1591–1597. doi:10.1002/bjs.10925]

Biccard et al⁷ investigated the effect of perioperative aspirin in the subgroup of patients from the POISE-2 trial who underwent vascular surgery. The primary outcome was death or MI within 30 days. Secondary outcomes in this substudy included vascular occlusive complications (amputation and peripheral arterial thrombosis) and major or life-threatening bleeding.

Limitations. There were few adverse events, and this substudy was underpowered for the primary and secondary outcomes.

Conclusion. Starting or continuing aspirin did not improve outcomes, and withdrawing it did not increase cardiovascular or occlusive complications.

Do ACE inhibitors affect risk in noncardiac nonvascular surgery?

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are some of the most commonly used medications for treating hypertension. But whether patients should continue receiving them on the day of surgery or whether they should be held remains unclear.

Although current recommendations are inconsistent, the most recent American College of Cardiology/American Heart Association¹ perioperative practice guidelines say that continuing ACE inhibitors or ARBs is reasonable perioperatively. This recommendation, however, acknowledges that published evidence is limited. There is general agreement that preoperative exposure to ACE inhibitors and ARBs is associated with intraoperative hypotension, but whether this increases the risk of adverse clinical outcomes remains unclear. Needed was a study to determine the effect on perioperative morbidity and mortality of continuing vs withholding ACE inhibitors and ARBs before surgery.

[Shiffermiller JF, Monson BJ, Vokoun CW, et al. Prospective randomized evaluation of preoperative angiotensin-converting enzyme inhibition (PREOP-ACEI). J Hosp Med 2018; 13(10):661–667. doi:10.12788/jhm.3036]

Shiffermiller et al⁸ performed a randomized controlled trial comparing the effect of 2 preoperative ACE inhibitor management protocols in patients undergoing noncardiac nonvascular surgery. Patients were randomized to either receive or not receive their final preoperative ACE inhibitor dose, whether scheduled on the morning of surgery or the night before.

Exclusion criteria included hypotension or hypertension at their preoperative clinic appointment (defined as systolic blood pressure < 90 or ≥ 160 mm Hg, and diastolic blood pressure < 60 or ≥ 95 mm Hg), moderate to severe heart failure, and end-stage renal disease requiring dialysis. Excluded surgery types were cardiac, vascular, organ transplant, oncologic, and all outpatient procedures. Patients taking ARBs were also excluded.

The primary outcome was intraoperative hypotension defined as any systolic blood pressure less than 80 mm Hg from the time of anesthesia induction until transfer to the postanesthesia care unit. Secondary outcomes were measured until hospital discharge and included postoperative acute kidney injury, postoperative hypotension (systolic pressure < 90 mm Hg) and hypertension (systolic pressure > 180 mm Hg), major cardiac events (composite of acute coronary syndrome, acute heart failure, or new-onset arrhythmia), and death.

Findings. A total of 453 patients were screened for eligibility, and of these, 291 were included for randomization. Their average age was 64, 48% were men, and 87% were white. About 50% underwent general anesthesia, 25% spinal, and 25% regional. Over half of the surgeries were orthopedic, and 20% were spine surgeries.

The primary outcome of intraoperative hypotension occurred significantly less often in patients randomized to ACE inhibitor omission than in the continuation group (55% vs 69%, relative risk [RR] 0.81, 95% CI 0.67–0.97, P = .03). This translates to 1 case of intraoperative hypotension for every 7.5 patients continuing an ACE inhibitor perioperatively (number needed to harm 7.5). Intraoperative hypotension associated with vasopressor administration also occurred significantly less frequently in the ACE inhibitor omission group.

Patients in the ACE inhibitor omission group were also less likely to experience postoperative hypotension, but on the other hand, they were more likely to experience severe postoperative hypertension (defined as any systolic blood pressure > 180 mm Hg). The two groups fared the same in terms of rates of acute kidney injury and major adverse cardiac events (MACE) and hospital length of stay, and no patients died in either group.

Limitations. Several factors limit the generalizability of this single-center study, including the many exclusion criteria, the predominance of orthopedic and spine surgeries, and the low-risk patient population (the average Revised Cardiac Risk Index score was 0, range 0–3). Other limitations include not controlling for the specific ACE inhibitor used and not including the precise timing of the final dose in relation to surgery. Lastly, this study lacked power to measure postoperative outcomes.

Conclusions. Continuing ACE inhibitor treatment before noncardiac nonvascular surgery is associated with a greater frequency and duration of intraoperative hypotension, but it did not increase the incidences of acute kidney injury, MACE, or death nor the hospital length of stay.

[Hollmann C, Fernandes NL, Biccard BM. A systematic review of outcomes associated with withholding or continuing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers before noncardiac surgery. Anesth Analg 2018; 127(3):678–687. doi:10.1213/ANE.0000000000002837]

Hollmann et al⁹ performed a meta-analysis to determine whether it is better to continue or withhold ACE inhibitors and ARBs before surgery. The patients were adults undergoing noncardiac surgery and receiving an ACE inhibitor or ARB, which was either withheld or continued on the morning of surgery.

Primary outcomes were all-cause mortality and MACE, while secondary outcomes included the incidence of acute kidney injury, heart failure, stroke, intraoperative and postoperative hypotension, and length of hospital stay. Randomized controlled trials and observational studies were included, while case reports and case-control studies were excluded.

Findings. This meta-analysis included 5 randomized controlled trials and 4 cohort studies, with a total of 6,022 patients; 1,816 had their ACE inhibitor or ARB withheld before surgery, while 4,206 continued therapy. It found no difference between the 2 groups in the incidence of death or MACE, and there were not enough data to determine a difference in heart failure, stroke, acute kidney injury, or hospital length of stay.

Seven studies, with 5,414 patients, examined intraoperative hypotension. The overall incidence was 30%, but was significantly lower if the ACE inhibitor or ARB was withheld (OR 0.63, 95% CI 0.47–0.85, ^P = .002). Findings were similar in an analysis of only the randomized controlled trials. No difference was observed in postoperative hypotension.

Limitations. There was no standard definition of the morbidity outcomes, including hypotension and MACE. The assessment of MACE included data only for MI and not MINS. The specific duration of hypotension was not reported, and this meta-analysis did not take into account different anesthetic techniques. The duration of follow-up varied widely among studies, ranging from the day of hospital discharge to 30 days after surgery. And the randomized controlled trial performed by Shiffermiller et al⁸ was not included.

Conclusions. While continuing ACE inhibitors or ARBs before noncardiac surgery was associated with intraoperative hypotension, it did not seem to affect other outcomes, including death and MACE. The authors propose that a large randomized controlled trial is needed to determine whether continuing or withholding ACE inhibitor or ARB therapy before surgery is safer.

How should we treat MINS?

MINS is associated with an increased risk of cardiovascular events and death in both the short term and long term. MINS is defined as an elevated postoperative troponin level related to an ischemic etiology. However, whether to routinely measure troponin after surgery is unclear, as most patients do not present with ischemic symptoms, and there is no standard of care for treatment of this entity. Limited observational data suggest that starting or intensifying cardiac medications, particularly aspirin and statins, may be beneficial in terms of reducing 30-day mortality rates in patients with MI or cardiac events at 1 year in vascular surgery patients with MINS.

The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial was designed to evaluate the potential of the anticoagulant dabigatran to prevent major vascular complications in patients with MINS.

[Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet 2018; 391(10137):2325–2334. doi:10.1016/S0140-6736(18)30832-8]

Devereaux et al¹⁰ randomized patients who were at least 45 years old and had developed MINS within the previous 35 days to receive dabigatran 110 mg orally twice daily or placebo for up to 2 years. Patients not already taking a proton pump inhibitor were also randomized to take either omeprazole 20 mg once daily or placebo.

The primary efficacy outcome initially was major vascular complications, which included vascular mortality, nonfatal MI, nonhemorrhagic stroke, and peripheral arterial thrombosis. However, amputation and symptomatic venous thromboembolism were subsequently added during the study.

The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Major bleeding required a decrease in hemoglobin of at least 4 g/dL, transfusion of at least 3 units of red blood cells within a 24-hour period, or a procedure to stop the bleeding.

Findings. The original goal was to recruit 3,200 patients, but due to slow enrollment and loss of funding, the sample was reduced to 1,754 patients (877 in each group). Approximately 45% of each group stopped taking the study drug prematurely.

The primary efficacy outcome occurred in significantly fewer patients receiving dabigatran (97, 11%) than placebo (133, 15%, HR 0.72, 95% CI 0.55–0.93, P = .0115). The incidence of the primary safety outcome was similar in both groups: 3% with dabigatran and 4% with placebo (HR 0.92, 95% CI 0.55–1.53, P = .76). The only individual efficacy outcome meeting statistical significance was a lower rate of nonhemorrhagic stroke in the dabigatran group. Subgroup analyses showed a trend benefiting patients randomized within 5 days of MINS or with a diagnosis of MI, although it was not statistically significant.

Limitations. The efficacy outcomes were expanded to include venous thromboembolism and others not directly related to MINS, raising questions about the conclusions. Further, as defined by the protocol, bleeding had to be fairly severe to be deemed major. The high number of patients who discontinued the study drug is another limitation of this study.

Conclusion. Dabigatran lowered the risk of major vascular complications with no significant increase in major bleeding in patients with MINS.

What is the risk of thromboembolism in postoperative atrial fibrillation, and what are the benefits of anticoagulation?

Although nonvalvular atrial fibrillation is associated with increased risks of ischemic stroke and systemic embolic events in nonsurgical patients, the association of new-onset postoperative atrial fibrillation with long-term thromboembolic events in the noncardiac surgical population is not well established.

[Butt JH, Olesen JB, Havers-Borgersen E, et al. Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery. J Am Coll Cardiol 2018; 72(17):2027–2036. doi:10.1016/j.jacc.2018.07.088]

In this retrospective cohort study using a nationwide registry in Denmark, Butt et al¹¹ assessed the long-term risk of thromboembolic events in noncardiac surgical patients with new postoperative atrial fibrillation. Patients were identified who had no previous history of atrial fibrillation and developed it after noncardiac, nonobstetric surgeries, and were matched in a 1:4 ratio with patients who developed nonvalvular atrial fibrillation during nonsurgical hospitalizations. Matching was based on age, sex, heart failure, hypertension, diabetes, known history of thromboembolic events, ischemic heart disease, and the year patients presented with new atrial fibrillation.

Patients were excluded if they received antiarrhythmic drugs or oral anticoagulants before hospitalization or surgery, had cancer in the year prior, or died in the hospital.

The primary outcome of the study was thromboembolic events—a composite of ischemic stroke, transient cerebral ischemia, and peripheral arterial thrombosis or embolism. Secondary outcomes included rehospitalization for atrial fibrillation and all-cause mortality.

Findings. Overall, 0.4% of patients developed new postoperative atrial fibrillation, of whom 3,380 were matched with 15,320 patients with nonvalvular atrial fibrillation. Over a median follow-up of 3.2 years, the risk of thromboembolic events was similar in both groups (31.7 and 29.9 per 1,000 person-years, HR 0.95, 95% CI 0.85–1.07). The groups did not differ in their CHA₂DS₂-VASc risk scores, HAS-BLED risk scores, or year in which patients were diagnosed.

Anticoagulation lowered the risk of thromboembolic events to a similar extent in both groups compared with no anticoagulation:

• In postoperative atrial fibrillation—HR 0.57, 95% CI 0.40–0.67
• In nonvalvular atrial fibrillation—HR 0.56, 95% CI 0.51–0.62.

Despite the similar reduction in thromboembolic events, only 24.4% of the postoperative atrial fibrillation patients were started on anticoagulation therapy within 30 days of discharge, compared with 41.5% of those with nonvalvular atrial fibrillation.

Limitations. Although this was a large study with excellent follow-up data, it was observational. It may have underestimated the number of patients who developed postoperative atrial fibrillation because episodes that were judged not to be clinically significant may not have been charted. Many patients are not monitored with continuous telemetry postoperatively, which also may have led to underestimation of the number of atrial fibrillation events.

The study also did not examine the number of atrial fibrillation episodes per patient, the heart rhythm at discharge or long-term, or indication for and duration of anticoagulation. There were no data regarding international normalized ratio levels.

Conclusions. Postoperative atrial fibrillation is associated with outcomes similar to those of nonsurgical nonvalvular atrial fibrillation. Anticoagulation decreases the risks of stroke and death. However, substantially fewer patients with postoperative atrial fibrillation receive anticoagulation. Anticoagulation should be considered in these patients, while noting bleeding risk.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

A 78-year-old woman presented to the emergency department with shortness of breath and palpitations and was found to have atrial fibrillation with rapid ventricular response. Medical therapy with drug therapy and cardioversion proved ineffective. She then underwent atrioventricular node ablation and placement of a pacemaker.

At the time of admission, anticoagulation was started with full-dose enoxaparin, injected subcutaneously on the left side of the abdominal wall, as her CHA₂DS₂-VASc score (http://chadvasc.org) was 5, due to age, female sex, and history of heart failure and hypertension.

Four days after admission, she reported lower abdominal pain, and her urine output was minimal. A bladder scan showed more than 500 mL of residual urine. She was hemodynamically stable, but physical examination revealed mild abdominal distention and tenderness in the suprapubic region. Laboratory testing showed a sharp rise in serum creatinine and a drop in hematocrit.

The patient was initially managed conservatively with serial physical examinations, monitoring of the hematocrit, serial imaging studies, and discontinuation of anticoagulation, but the pain and anuria persisted. Repeat computed tomography 15 days after admission showed that the hematoma had expanded, and she now had hydronephrosis on the right side as well, requiring urologic intervention with bilateral nephrostomy tube placement.

The size of the hematoma was evaluated with serial abdominal and pelvic examinations. After several days, her urine output had improved, the nephrostomy tubes were removed, and she was discharged.

RECTUS SHEATH HEMATOMA

Our patient had a giant pelvic hematoma, probably arising from the rectus sheath. This uncommon problem can arise from trauma, anticoagulation, or increased intra-abdominal pressure, but it can also occur spontaneously.¹

In rectus sheath hematoma, a branch of the inferior epigastric artery is injured at its insertion into the rectus abdominis muscle. Symptoms arise if bleeding does not stop spontaneously from a tamponade effect.²

We speculate that in our patient, deep injection of enoxaparin into the abdominal wall injured the inferior epigastric artery, which started the hematoma, and the bleeding was exacerbated by the anticoagulation effect of the enoxaparin.

Another form of pelvic hematoma is retro­peritoneal. It is most commonly caused by trauma but can occur due to rupture of the aorta, compression from tumors, or, infrequently, anticoagulation therapy.³

The role of anticoagulation

Spontaneous pelvic hematoma is usually missed as a cause of abdominal pain in patients on anticoagulation therapy and is mistaken for common acute conditions such as ulcer, diverticulitis, appendicitis, ovarian cyst torsion, and tumor.⁴ It usually develops within 5 days of starting anticoagulation therapy. Symptoms vary depending on the location of the hematoma and are best diagnosed with abdominal computed tomography, with sensitivity as high as 100%.

MANAGEMENT

Conservative management, reserved for patients in stable condition, includes temporarily stopping and reevaluating the risks and benefits of anticoagulation and antiplatelet agents, giving blood transfusions, and controlling pain. If conservative measures fail, options are arterial embolization, stent grafting, and blood vessel ligation.⁵ If these measures fail, patients should undergo surgical evacuation of the hematoma and ligation of bleeding vessels.⁶

TAKE-HOME MESSAGE

Subcutaneous injections, especially of anticoagulants, into the abdominal wall can increase the risk of hematoma. Other risk factors are older age, female sex, and thin body habitus with less abdominal fat.⁷ Healthcare professionals should avoid deep injections into the abdomen and should counsel patients and their caregivers about this, as well. The deltoid region could be a safer alternative.

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

Hospital-acquired infections related to construction and renovation activities account for more than 5,000 deaths per year across the United States.¹

Hospital construction, renovation, and demolition projects ultimately serve the interests of patients, but they also can put inpatients at risk of mold infection, Legionnaires disease, sleep deprivation, exacerbation of lung disease, and in rare cases, physical injury.

Hospitals are in a continuous state of transformation to meet the needs of medical and technologic advances and an increasing patient population,¹ and in the last 10 years, more than $200 billion has been spent on construction projects at US healthcare facilities. Therefore, constant attention is needed to reduce the risks to the health of hospitalized patients during these projects.

HOSPITAL-ACQUIRED INFECTIONS

Mold infections

Construction can cause substantial dust contamination and scatter large amounts of fungal spores. An analysis conducted during a period of excavation at a hospital campus showed a significant association between excavation activities and hospital-acquired mold infections (hazard ratio [HR] 2.8, P = .01) but not yeast infections (HR 0.75, P = .78).²

Aspergillus species have been the organisms most commonly involved in hospital-acquired mold infection. In a review of 53 studies including 458 patients,³A fumigatus was identified in 154 patients, and A flavus was identified in 101 patients. A niger, A terreus, A nidulans, Zygomycetes, and other fungi were also identified, but to a much lesser extent. Hematologic malignancies were the predominant underlying morbidity in 299 patients. Half of the sources of healthcare-associated Aspergillus outbreaks were estimated to result from construction and renovation activities within or surrounding the hospital.³

Heavy demolition and transportation of wreckage have been found to cause the greatest concentrations of Aspergillus species,¹ but even small concentrations may be sufficient to cause infection in high-risk hospitalized patients.³ Invasive pulmonary aspergillosis is the mold infection most commonly associated with these activities, particularly in immunocompromised and critically ill patients. It is characterized by invasion of lung tissue by Aspergillus hyphae. Hematogenous dissemination occurs in about 25% of patients, and the death rate often exceeds 50%.⁴

A review of cases of fungal infection during hospital construction, renovation, and demolition projects from 1976 to 2014 identified 372 infected patients, of whom 180 died.⁵ The majority of infections were due to Aspergillus. Other fungi included Rhizopus, Candida, and Fusarium. Infections occurred mainly in patients with hematologic malignancies and patients who had undergone stem cell transplant (76%), followed by patients with other malignancies or transplant (19%). Rarely affected were patients in the intensive care unit or patients with rheumatologic diseases or on hemodialysis.⁵

Legionnaires disease

Legionnaires disease is a form of atypical pneumonia caused by the bacterium Legionella, often associated with differing degrees of gastrointestinal symptoms. Legionella species are the bacteria most often associated with construction in hospitals, as construction and demolition often result in collections of stagnant water.

The primary mode of transmission is inhalation of contaminated mist or aerosols. Legionella species can also colonize newly constructed hospital buildings within weeks of installation of water fixtures.

In a large university-affiliated hospital, 2 cases of nosocomial legionellosis were identified during a period of major construction.⁶ An epidemiologic investigation traced the source to a widespread contamination of potable water within the hospital. One patient’s isolate was similar to that of a water sample from the faucet in his room, and an association between Legionnaires disease and construction was postulated.

Another institution’s newly constructed hematology-oncology unit identified 10 cases of Legionnaires disease over a 12-week period in patients and visitors with exposure to the unit during and within the incubation period.⁷ A clinical and environmental assessment found 3 clinical isolates of Legionella identical to environmental isolates found from the unit, strongly implicating the potable water system as the likely source.⁷

In Ohio, 11 cases of hospital-acquired Legionnaires disease were identified in patients moved to a newly constructed 12-story addition to a hospital, and 1 of those died.⁸

Legionella infections appear to be less common than mold infections when reviewing the available literature on patients exposed to hospital construction, renovation, or demolition activities. Yet unlike mold infections, which occur mostly in immunocompromised patients, Legionella also affects people with normal immunity.¹

Sleep deprivation

Noise in hospitals has been linked to sleep disturbances in inpatients. A study using noise dosimeters in a university hospital found a mean continuous noise level of 63.5 dBA (A-weighting of decibels indicates risk of hearing loss) over a 24-hour period, a level more than 2 times higher than the recommended 30 dBA.⁹ The same study also found a significant correlation between sleep disturbance in inpatients and increasing noise levels, in a dose-response manner.

Common sources of noise during construction may include power generators, welding and cutting equipment, and transport of materials. While construction activities themselves have yet to be directly linked to sleep deprivation in patients, construction is inevitably accompanied by noise.

Noise is the most common factor interfering with sleep reported by hospitalized patients. Other effects of noise on patients include a rise in heart rate and blood pressure, increased cholesterol and triglyceride levels, increased use of sedatives, and longer length of stay.^9,10 Although construction is rarely done at night, patients generally take naps during the day, so the noise is disruptive.

Physical injuries

Hospitalized patients rarely suffer injuries related to hospital construction. However, these incidents may be underreported. Few cases of physical injury in patients exposed to construction or renovation in healthcare facilities can be found through a Web search.^11,12

Exacerbation of lung disease

Inhalation of indoor air pollutants exposed during renovation can directly trigger an inflammatory response and cause exacerbation in patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease. No study has specifically examined the effect of hospital construction or renovation on exacerbation of chronic lung diseases in hospitalized patients. Nevertheless, dust and indoor air pollutants from building renovation have often been reported as agents associated with work-related asthma.¹³

THE MESSAGE

Although the risks to inpatients during hospital construction projects appear minimal, their effect can at times be detrimental, especially to the immunocompromised. Hospitals should adhere to infection control risk assessment protocols during construction events. The small number of outbreaks of construction-related infections can make the diagnosis of nosocomial origin of these infections challenging; a high index of suspicion is needed.

Currently in the United States, there is no standard regarding acceptable levels of airborne mold concentrations, and data to support routine hospital air sampling or validation of available air samplers are inadequate. This remains an area for future research.^14,15

Certain measures have been shown to significantly decrease the risk of mold infections and other nosocomial infections during construction projects, including¹⁶:

• Effective dust control through containment units and barriers
• Consistent use of high-efficiency particulate air filters in hospital units that care for immunocompromised and critically ill patients
• Routine surveillance.

Noise and vibration can be reduced by temporary walls and careful tool selection and scheduling. Similarly, temporary walls and other barriers help protect healthcare employees and patients from the risk of direct physical injury.

Preconstruction risk assessments that address infection control, safety, noise, and air quality are crucial, and the Joint Commission generally requires such assessments. Further, education of hospital staff and members of the construction team about the potential detrimental effects of hospital construction and renovation is essential to secure a safe environment.        

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

In an effort to improve healthcare for Americans by linking hospital payments to quality of care, Medicare’s Hospital Readmission Reduction Program (HRRP) began penalizing hospitals with “excess” readmission rates in 2012. The decision sparked widespread debate about the definition of a preventable readmission and whether a patient’s socioeconomic status should be considered for risk adjustment. Although coming back to the hospital after an admission is an undesirable outcome for any patient, the suitability of readmission as a quality measure remains a hot and debated topic. Research on the subject skyrocketed; over 12000 articles about hospital readmissions have been indexed in PubMed since 2000, and the number of publications has steadily increased since 2010 (Figure).

Although the HRRP is a Medicare initiative, there has been a substantial focus on readmissions in pediatrics as well. The National Quality Forum has endorsed three quality measures specific to readmission in children: (1) the rate of unplanned readmissions to the pediatric intensive care unit within 24 hours after discharge or transfer, (2) the pediatric lower respiratory infection readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days of hospitalization for lower respiratory infection, and (3) the pediatric all-cause readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days. These endorsements were preceded by studies showing that pediatric readmission rates varied substantially across hospitals and clinical conditions, and that children with chronic illnesses were at the highest risk.

Readmission is an attractive pediatric quality measure for a number of reasons. This measure is easy to apply to data at the hospital, health system, and payor levels at relatively low cost. Relatedly, the all-condition measure can be applied to all pediatric hospitalizations, overcoming the very real challenge in pediatric quality measurement of inadequate sample sizes to discern differences in healthcare quality at the hospital level for many disease-specific measures.¹ In addition, this measure moves beyond process measurement to quantify an outcome relevant to families as well as healthcare systems. Finally, the measure is founded on a compelling conceptual framework (albeit one that remains challenging to prove) that efforts to improve a patient’s hospital-to-home transition and discharge readiness will reduce their likelihood of readmission.

In this issue of the Journal of Hospital Medicine, Katherine Auger and colleagues present their analysis of pediatric readmission rates from 2010 to 2016 across 66 children’s hospitals.² They found that the median seven-day all-cause pediatric readmission rate was 5.1%, with no change in rates over the seven-year study period. Applying proprietary software to identify potentially preventable readmissions (PPR), they reported that approximately 40% of these readmissions may be preventable, a proportion that was also unchanged over time. Interestingly, 88% of the hospitals represented in their data were participating in the Solutions for Patient Safety national learning collaborative during the study period, making efforts to reduce seven-day readmission rates. Despite this, the figures presented in this paper of all-condition and potentially preventable readmission rates over time are very, very flat.

This work by Auger et al. contributes to our understanding about the preventability, or lack thereof, of pediatric all-condition readmissions. If 40% of these readmissions are indeed preventable, then why did Auger et al. not observe a declining proportion of PPR over time as a result of hospital participation in a national collaborative? Past quantitative and qualitative studies provide important context. First, the 40% rate of readmission preventability is twofold higher than that reported in past studies that relied on physician judgement to determine readmission preventability;^3,4 the authors’ use of proprietary software to categorize the preventability of a readmission limits our ability to explain the differences in these rates. However, in these past studies, the rates of initial agreement between physician reviewers about readmission preventability were poor, highlighting the challenges associated with determining readmission preventability. Moreover, qualitative studies suggest that physicians and families lack a shared understanding of the preventability of readmissions.⁵ Finally, a systematic review of pediatric hospital discharge interventions did not identify any one intervention that was consistently effective in reducing hospital readmission rates.⁶ The following important questions remain: Were hospitals’ efforts to reduce PPR targeting the wrong patients? Were the interventions insufficient or ineffective? Or are readmission measures insufficiently sensitive to improved processes of care?

Recognizing that the majority of research on readmission as well as HRRP penalties focuses on adult populations, perhaps we can apply some lessons learned from the HRRP to pediatrics. Recent analyses by Medicare Payment Advisory Commission (MedPAC) suggest that raw and risk-adjusted readmission rates have declined for conditions covered by the HRRP, with readmission rates for HRRP target conditions declining more quickly than that for nontarget conditions.⁷ Just as the HRRP has focused on target conditions with relatively high readmission rates, analogous efforts to focus pediatric readmission reduction on children at greatest risk may enable measurement of change over time. For example, although children with complex chronic medical conditions represent a small proportion of the pediatric population, they account for 60% of all pediatric readmissions in the United States. However, similar to the above-described meta-analysis of readmission reduction efforts in children, at least one meta-analysis has demonstrated that there is no one intervention or even bundle of interventions that has consistently reduced readmissions in adults.⁸ Although the readmission rates for HRRP target conditions have decreased, the results of clinical trials evaluating readmission reduction efforts are difficult to translate into practice given substantial heterogeneity in study designs, interventions, and patient populations.

Does this study by Auger et al. suggest that pediatric readmission reduction efforts are misguided or futile? No. But it does provide compelling data that efforts to reduce all-cause readmissions for all children may not yield measureable changes using the current measures. A narrowed focus on children with chronic illnesses, who account for approximately half of all pediatric admissions, may be warranted. A number of studies have summarized families’ preferences regarding their hospital-to-home transitions; the results indicate that families of children with chronic illness have unique desires and needs.^9,10 Perhaps it is time to take a step back from pediatric readmission reduction efforts, largely inspired by the HRRP, and redirect our resources to implement and evaluate processes and outcomes most valued by children and their families.

Disclosures

Drs. Lagu and Lindenauer have served as consultants for the Yale Center for Outcomes Research and Evaluation (under contract to the Centers for Medicare and Medicaid Services) providing clinical and methodological expertise and input on the development, reevaluation, and implementation of hospital outcome and efficiency measures.

Funding

Dr. Lagu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award R01 HL139985-01A1 and 1R01HL146884-01. Dr. Lindenauer was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K24HL132008.

Disclaimer

The views expressed in this manuscript do not necessarily reflect those of the Yale Center for Outcomes Research and Evaluation or the Centers for Medicare and Medicaid Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

In an effort to improve healthcare for Americans by linking hospital payments to quality of care, Medicare’s Hospital Readmission Reduction Program (HRRP) began penalizing hospitals with “excess” readmission rates in 2012. The decision sparked widespread debate about the definition of a preventable readmission and whether a patient’s socioeconomic status should be considered for risk adjustment. Although coming back to the hospital after an admission is an undesirable outcome for any patient, the suitability of readmission as a quality measure remains a hot and debated topic. Research on the subject skyrocketed; over 12000 articles about hospital readmissions have been indexed in PubMed since 2000, and the number of publications has steadily increased since 2010 (Figure).

Although the HRRP is a Medicare initiative, there has been a substantial focus on readmissions in pediatrics as well. The National Quality Forum has endorsed three quality measures specific to readmission in children: (1) the rate of unplanned readmissions to the pediatric intensive care unit within 24 hours after discharge or transfer, (2) the pediatric lower respiratory infection readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days of hospitalization for lower respiratory infection, and (3) the pediatric all-cause readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days. These endorsements were preceded by studies showing that pediatric readmission rates varied substantially across hospitals and clinical conditions, and that children with chronic illnesses were at the highest risk.

Readmission is an attractive pediatric quality measure for a number of reasons. This measure is easy to apply to data at the hospital, health system, and payor levels at relatively low cost. Relatedly, the all-condition measure can be applied to all pediatric hospitalizations, overcoming the very real challenge in pediatric quality measurement of inadequate sample sizes to discern differences in healthcare quality at the hospital level for many disease-specific measures.¹ In addition, this measure moves beyond process measurement to quantify an outcome relevant to families as well as healthcare systems. Finally, the measure is founded on a compelling conceptual framework (albeit one that remains challenging to prove) that efforts to improve a patient’s hospital-to-home transition and discharge readiness will reduce their likelihood of readmission.

In this issue of the Journal of Hospital Medicine, Katherine Auger and colleagues present their analysis of pediatric readmission rates from 2010 to 2016 across 66 children’s hospitals.² They found that the median seven-day all-cause pediatric readmission rate was 5.1%, with no change in rates over the seven-year study period. Applying proprietary software to identify potentially preventable readmissions (PPR), they reported that approximately 40% of these readmissions may be preventable, a proportion that was also unchanged over time. Interestingly, 88% of the hospitals represented in their data were participating in the Solutions for Patient Safety national learning collaborative during the study period, making efforts to reduce seven-day readmission rates. Despite this, the figures presented in this paper of all-condition and potentially preventable readmission rates over time are very, very flat.

This work by Auger et al. contributes to our understanding about the preventability, or lack thereof, of pediatric all-condition readmissions. If 40% of these readmissions are indeed preventable, then why did Auger et al. not observe a declining proportion of PPR over time as a result of hospital participation in a national collaborative? Past quantitative and qualitative studies provide important context. First, the 40% rate of readmission preventability is twofold higher than that reported in past studies that relied on physician judgement to determine readmission preventability;^3,4 the authors’ use of proprietary software to categorize the preventability of a readmission limits our ability to explain the differences in these rates. However, in these past studies, the rates of initial agreement between physician reviewers about readmission preventability were poor, highlighting the challenges associated with determining readmission preventability. Moreover, qualitative studies suggest that physicians and families lack a shared understanding of the preventability of readmissions.⁵ Finally, a systematic review of pediatric hospital discharge interventions did not identify any one intervention that was consistently effective in reducing hospital readmission rates.⁶ The following important questions remain: Were hospitals’ efforts to reduce PPR targeting the wrong patients? Were the interventions insufficient or ineffective? Or are readmission measures insufficiently sensitive to improved processes of care?

Recognizing that the majority of research on readmission as well as HRRP penalties focuses on adult populations, perhaps we can apply some lessons learned from the HRRP to pediatrics. Recent analyses by Medicare Payment Advisory Commission (MedPAC) suggest that raw and risk-adjusted readmission rates have declined for conditions covered by the HRRP, with readmission rates for HRRP target conditions declining more quickly than that for nontarget conditions.⁷ Just as the HRRP has focused on target conditions with relatively high readmission rates, analogous efforts to focus pediatric readmission reduction on children at greatest risk may enable measurement of change over time. For example, although children with complex chronic medical conditions represent a small proportion of the pediatric population, they account for 60% of all pediatric readmissions in the United States. However, similar to the above-described meta-analysis of readmission reduction efforts in children, at least one meta-analysis has demonstrated that there is no one intervention or even bundle of interventions that has consistently reduced readmissions in adults.⁸ Although the readmission rates for HRRP target conditions have decreased, the results of clinical trials evaluating readmission reduction efforts are difficult to translate into practice given substantial heterogeneity in study designs, interventions, and patient populations.

Does this study by Auger et al. suggest that pediatric readmission reduction efforts are misguided or futile? No. But it does provide compelling data that efforts to reduce all-cause readmissions for all children may not yield measureable changes using the current measures. A narrowed focus on children with chronic illnesses, who account for approximately half of all pediatric admissions, may be warranted. A number of studies have summarized families’ preferences regarding their hospital-to-home transitions; the results indicate that families of children with chronic illness have unique desires and needs.^9,10 Perhaps it is time to take a step back from pediatric readmission reduction efforts, largely inspired by the HRRP, and redirect our resources to implement and evaluate processes and outcomes most valued by children and their families.

Disclosures

Drs. Lagu and Lindenauer have served as consultants for the Yale Center for Outcomes Research and Evaluation (under contract to the Centers for Medicare and Medicaid Services) providing clinical and methodological expertise and input on the development, reevaluation, and implementation of hospital outcome and efficiency measures.

Funding

Dr. Lagu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award R01 HL139985-01A1 and 1R01HL146884-01. Dr. Lindenauer was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K24HL132008.

Disclaimer

The views expressed in this manuscript do not necessarily reflect those of the Yale Center for Outcomes Research and Evaluation or the Centers for Medicare and Medicaid Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

In an effort to improve healthcare for Americans by linking hospital payments to quality of care, Medicare’s Hospital Readmission Reduction Program (HRRP) began penalizing hospitals with “excess” readmission rates in 2012. The decision sparked widespread debate about the definition of a preventable readmission and whether a patient’s socioeconomic status should be considered for risk adjustment. Although coming back to the hospital after an admission is an undesirable outcome for any patient, the suitability of readmission as a quality measure remains a hot and debated topic. Research on the subject skyrocketed; over 12000 articles about hospital readmissions have been indexed in PubMed since 2000, and the number of publications has steadily increased since 2010 (Figure).

Although the HRRP is a Medicare initiative, there has been a substantial focus on readmissions in pediatrics as well. The National Quality Forum has endorsed three quality measures specific to readmission in children: (1) the rate of unplanned readmissions to the pediatric intensive care unit within 24 hours after discharge or transfer, (2) the pediatric lower respiratory infection readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days of hospitalization for lower respiratory infection, and (3) the pediatric all-cause readmission measure, defined as the percentage of admissions followed by one or more readmissions within 30 days. These endorsements were preceded by studies showing that pediatric readmission rates varied substantially across hospitals and clinical conditions, and that children with chronic illnesses were at the highest risk.

Readmission is an attractive pediatric quality measure for a number of reasons. This measure is easy to apply to data at the hospital, health system, and payor levels at relatively low cost. Relatedly, the all-condition measure can be applied to all pediatric hospitalizations, overcoming the very real challenge in pediatric quality measurement of inadequate sample sizes to discern differences in healthcare quality at the hospital level for many disease-specific measures.¹ In addition, this measure moves beyond process measurement to quantify an outcome relevant to families as well as healthcare systems. Finally, the measure is founded on a compelling conceptual framework (albeit one that remains challenging to prove) that efforts to improve a patient’s hospital-to-home transition and discharge readiness will reduce their likelihood of readmission.

In this issue of the Journal of Hospital Medicine, Katherine Auger and colleagues present their analysis of pediatric readmission rates from 2010 to 2016 across 66 children’s hospitals.² They found that the median seven-day all-cause pediatric readmission rate was 5.1%, with no change in rates over the seven-year study period. Applying proprietary software to identify potentially preventable readmissions (PPR), they reported that approximately 40% of these readmissions may be preventable, a proportion that was also unchanged over time. Interestingly, 88% of the hospitals represented in their data were participating in the Solutions for Patient Safety national learning collaborative during the study period, making efforts to reduce seven-day readmission rates. Despite this, the figures presented in this paper of all-condition and potentially preventable readmission rates over time are very, very flat.

This work by Auger et al. contributes to our understanding about the preventability, or lack thereof, of pediatric all-condition readmissions. If 40% of these readmissions are indeed preventable, then why did Auger et al. not observe a declining proportion of PPR over time as a result of hospital participation in a national collaborative? Past quantitative and qualitative studies provide important context. First, the 40% rate of readmission preventability is twofold higher than that reported in past studies that relied on physician judgement to determine readmission preventability;^3,4 the authors’ use of proprietary software to categorize the preventability of a readmission limits our ability to explain the differences in these rates. However, in these past studies, the rates of initial agreement between physician reviewers about readmission preventability were poor, highlighting the challenges associated with determining readmission preventability. Moreover, qualitative studies suggest that physicians and families lack a shared understanding of the preventability of readmissions.⁵ Finally, a systematic review of pediatric hospital discharge interventions did not identify any one intervention that was consistently effective in reducing hospital readmission rates.⁶ The following important questions remain: Were hospitals’ efforts to reduce PPR targeting the wrong patients? Were the interventions insufficient or ineffective? Or are readmission measures insufficiently sensitive to improved processes of care?

Recognizing that the majority of research on readmission as well as HRRP penalties focuses on adult populations, perhaps we can apply some lessons learned from the HRRP to pediatrics. Recent analyses by Medicare Payment Advisory Commission (MedPAC) suggest that raw and risk-adjusted readmission rates have declined for conditions covered by the HRRP, with readmission rates for HRRP target conditions declining more quickly than that for nontarget conditions.⁷ Just as the HRRP has focused on target conditions with relatively high readmission rates, analogous efforts to focus pediatric readmission reduction on children at greatest risk may enable measurement of change over time. For example, although children with complex chronic medical conditions represent a small proportion of the pediatric population, they account for 60% of all pediatric readmissions in the United States. However, similar to the above-described meta-analysis of readmission reduction efforts in children, at least one meta-analysis has demonstrated that there is no one intervention or even bundle of interventions that has consistently reduced readmissions in adults.⁸ Although the readmission rates for HRRP target conditions have decreased, the results of clinical trials evaluating readmission reduction efforts are difficult to translate into practice given substantial heterogeneity in study designs, interventions, and patient populations.

Does this study by Auger et al. suggest that pediatric readmission reduction efforts are misguided or futile? No. But it does provide compelling data that efforts to reduce all-cause readmissions for all children may not yield measureable changes using the current measures. A narrowed focus on children with chronic illnesses, who account for approximately half of all pediatric admissions, may be warranted. A number of studies have summarized families’ preferences regarding their hospital-to-home transitions; the results indicate that families of children with chronic illness have unique desires and needs.^9,10 Perhaps it is time to take a step back from pediatric readmission reduction efforts, largely inspired by the HRRP, and redirect our resources to implement and evaluate processes and outcomes most valued by children and their families.

Disclosures

Drs. Lagu and Lindenauer have served as consultants for the Yale Center for Outcomes Research and Evaluation (under contract to the Centers for Medicare and Medicaid Services) providing clinical and methodological expertise and input on the development, reevaluation, and implementation of hospital outcome and efficiency measures.

Funding

Dr. Lagu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award R01 HL139985-01A1 and 1R01HL146884-01. Dr. Lindenauer was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K24HL132008.

Disclaimer

The views expressed in this manuscript do not necessarily reflect those of the Yale Center for Outcomes Research and Evaluation or the Centers for Medicare and Medicaid Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Of all the errors that occur in modern healthcare, medication errors are among the most ubiquitous and consequential. Adverse drug events (ADEs) account for approximately 700,000 emergency department visits, 100,000 hospitalizations, and 1.3 million people are injured by medication errors annually.¹ Among the most frequent causes of preventable ADEs are errors on the medication lists when patients are admitted to hospitals.² Therefore, preventing discrepancies between medications the patient is prescribed (and actually taking) inside and outside the hospital—the so-called “medication reconciliation”—is an intense, ongoing area of focus for health systems, pharmacies, and numerous quality and safety organizations seeking to reduce ADEs.

Past studies of medication reconciliation interventions have suggested benefit from restricting medication reconciliation to admission or discharge, pharmacist or pharmacy technician-led medication reconciliation, and pharmacy-led interventions (ie, telephone follow-up/home visit, patient counseling) for ensuring an accurate medication list.^3-5 Recent evidence suggests that pharmacist discharge medication reconciliation is associated with decreased readmission rates, decreased medication discrepancies, and adverse events associated with drug therapy issues.⁴ The successful interventions were promising, but disseminating such interventions can often be very complex.⁶

In this issue of the Journal of Hospital Medicine, Mixon et al. report the results of a subanalysis of the MARQUIS trial,⁷ wherein they individually examined the on-protocol effects of the interventions that MARQUIS recommended, comparing hospitals to their own running baseline data at the implementation of each intervention to data following the implementation. The authors found that only three of the nine interventions were associated with reducing potentially harmful discrepancies in the medication list—training existing staff to perform discharge medication reconciliation, hiring additional staff for this purpose, and defining roles and responsibilities and roles clearly—and that two were actually associated with harm—training existing staff to take best possible medication histories (BPMHs) and implementing a new Electronic Medical Record (EMR). MARQUIS is unique in not just attempting but in reporting “best case” real-world implementation using available literature to design mentored, practical approaches to those same interventions at sites not involved in their initial setup and validation.

EMR implementation should in theory improve accuracy (or at least legibility), but it can also contribute to new types of inaccuracy or, as the authors propose, deprioritize quality and safety as organizational goals during the rigors of digitization. Similarly, training staff to take a BPMH might create false confidence in the results or interact with medication reconciliation in other complex ways. Opting to add more work instead of hiring additional staff may have increased the burden of medication review and thus contributed to its inaccuracy.

On the contrary, certain interventions, such as having clear accountability for the medication list, hiring additional staff to construct that list, and clearly defining the roles of those involved in the reconciliation process, were associated with improved medication reconciliation. All these strategies require resource allocation, but at least the current study provides evidence that such resource allocation can be effective in new settings as they were in their original ones.

The study has important acknowledged limitations. The on-protocol analysis limited the authors to reporting associations rather than causality. Moreover, the original trial ran from 2011 to 2014, which was a time of rapid EMR implementation and new recognition of the problems posed by the same; several organizations are in a far more mature EMR context today. Conversely, newer technologies such as patient-facing medication reconciliation applications, cross-organization medication lists available from some EMR vendors, and health platforms that collect data from multiple EMRs were not evaluated because they did not exist at the time of the original trial. Another important trend in healthcare, the rise of Accountable Care Organizations and their focus on integration and defragmentation, may have an important part to play in medication list accuracy. All the above-mentioned aspects will be important avenues for ongoing research in real-world medication reconciliation.

Mixon’s findings come at a time when medication reconciliation is again a national health informatics priority, a key component of the Medicare Access and CHIP reauthorization Act of 2015 and Merit-based Incentive Payments System⁸ since 2019, with hospitals reporting medication reconciliation rates for financial in addition to quality and safety reasons. Hopefully, this study and others, in combination with the abovementioned incentives, will stimulate further research into impactful strategies for medication reconciliation and ideal ways to implement them. With luck, the end result will be more generalizable interventions, with a track record of success, that would help ensure that patients are prescribed, are reporting, are taking, and are noted to be taking the medications that they and their providers intended, both on presentation to the hospital and on discharge home.

Disclosures

Vicki Jue has no conflicts of interest to report. Raman Khanna reports developing CareWeb, a communication platform that has been licensed to Voalte, Inc. This work is unrelated to the current editorial. No other conflicts of interest to report.

Of all the errors that occur in modern healthcare, medication errors are among the most ubiquitous and consequential. Adverse drug events (ADEs) account for approximately 700,000 emergency department visits, 100,000 hospitalizations, and 1.3 million people are injured by medication errors annually.¹ Among the most frequent causes of preventable ADEs are errors on the medication lists when patients are admitted to hospitals.² Therefore, preventing discrepancies between medications the patient is prescribed (and actually taking) inside and outside the hospital—the so-called “medication reconciliation”—is an intense, ongoing area of focus for health systems, pharmacies, and numerous quality and safety organizations seeking to reduce ADEs.

Past studies of medication reconciliation interventions have suggested benefit from restricting medication reconciliation to admission or discharge, pharmacist or pharmacy technician-led medication reconciliation, and pharmacy-led interventions (ie, telephone follow-up/home visit, patient counseling) for ensuring an accurate medication list.^3-5 Recent evidence suggests that pharmacist discharge medication reconciliation is associated with decreased readmission rates, decreased medication discrepancies, and adverse events associated with drug therapy issues.⁴ The successful interventions were promising, but disseminating such interventions can often be very complex.⁶

In this issue of the Journal of Hospital Medicine, Mixon et al. report the results of a subanalysis of the MARQUIS trial,⁷ wherein they individually examined the on-protocol effects of the interventions that MARQUIS recommended, comparing hospitals to their own running baseline data at the implementation of each intervention to data following the implementation. The authors found that only three of the nine interventions were associated with reducing potentially harmful discrepancies in the medication list—training existing staff to perform discharge medication reconciliation, hiring additional staff for this purpose, and defining roles and responsibilities and roles clearly—and that two were actually associated with harm—training existing staff to take best possible medication histories (BPMHs) and implementing a new Electronic Medical Record (EMR). MARQUIS is unique in not just attempting but in reporting “best case” real-world implementation using available literature to design mentored, practical approaches to those same interventions at sites not involved in their initial setup and validation.

EMR implementation should in theory improve accuracy (or at least legibility), but it can also contribute to new types of inaccuracy or, as the authors propose, deprioritize quality and safety as organizational goals during the rigors of digitization. Similarly, training staff to take a BPMH might create false confidence in the results or interact with medication reconciliation in other complex ways. Opting to add more work instead of hiring additional staff may have increased the burden of medication review and thus contributed to its inaccuracy.

On the contrary, certain interventions, such as having clear accountability for the medication list, hiring additional staff to construct that list, and clearly defining the roles of those involved in the reconciliation process, were associated with improved medication reconciliation. All these strategies require resource allocation, but at least the current study provides evidence that such resource allocation can be effective in new settings as they were in their original ones.

The study has important acknowledged limitations. The on-protocol analysis limited the authors to reporting associations rather than causality. Moreover, the original trial ran from 2011 to 2014, which was a time of rapid EMR implementation and new recognition of the problems posed by the same; several organizations are in a far more mature EMR context today. Conversely, newer technologies such as patient-facing medication reconciliation applications, cross-organization medication lists available from some EMR vendors, and health platforms that collect data from multiple EMRs were not evaluated because they did not exist at the time of the original trial. Another important trend in healthcare, the rise of Accountable Care Organizations and their focus on integration and defragmentation, may have an important part to play in medication list accuracy. All the above-mentioned aspects will be important avenues for ongoing research in real-world medication reconciliation.

Mixon’s findings come at a time when medication reconciliation is again a national health informatics priority, a key component of the Medicare Access and CHIP reauthorization Act of 2015 and Merit-based Incentive Payments System⁸ since 2019, with hospitals reporting medication reconciliation rates for financial in addition to quality and safety reasons. Hopefully, this study and others, in combination with the abovementioned incentives, will stimulate further research into impactful strategies for medication reconciliation and ideal ways to implement them. With luck, the end result will be more generalizable interventions, with a track record of success, that would help ensure that patients are prescribed, are reporting, are taking, and are noted to be taking the medications that they and their providers intended, both on presentation to the hospital and on discharge home.

Disclosures

Vicki Jue has no conflicts of interest to report. Raman Khanna reports developing CareWeb, a communication platform that has been licensed to Voalte, Inc. This work is unrelated to the current editorial. No other conflicts of interest to report.

Of all the errors that occur in modern healthcare, medication errors are among the most ubiquitous and consequential. Adverse drug events (ADEs) account for approximately 700,000 emergency department visits, 100,000 hospitalizations, and 1.3 million people are injured by medication errors annually.¹ Among the most frequent causes of preventable ADEs are errors on the medication lists when patients are admitted to hospitals.² Therefore, preventing discrepancies between medications the patient is prescribed (and actually taking) inside and outside the hospital—the so-called “medication reconciliation”—is an intense, ongoing area of focus for health systems, pharmacies, and numerous quality and safety organizations seeking to reduce ADEs.

Past studies of medication reconciliation interventions have suggested benefit from restricting medication reconciliation to admission or discharge, pharmacist or pharmacy technician-led medication reconciliation, and pharmacy-led interventions (ie, telephone follow-up/home visit, patient counseling) for ensuring an accurate medication list.^3-5 Recent evidence suggests that pharmacist discharge medication reconciliation is associated with decreased readmission rates, decreased medication discrepancies, and adverse events associated with drug therapy issues.⁴ The successful interventions were promising, but disseminating such interventions can often be very complex.⁶

In this issue of the Journal of Hospital Medicine, Mixon et al. report the results of a subanalysis of the MARQUIS trial,⁷ wherein they individually examined the on-protocol effects of the interventions that MARQUIS recommended, comparing hospitals to their own running baseline data at the implementation of each intervention to data following the implementation. The authors found that only three of the nine interventions were associated with reducing potentially harmful discrepancies in the medication list—training existing staff to perform discharge medication reconciliation, hiring additional staff for this purpose, and defining roles and responsibilities and roles clearly—and that two were actually associated with harm—training existing staff to take best possible medication histories (BPMHs) and implementing a new Electronic Medical Record (EMR). MARQUIS is unique in not just attempting but in reporting “best case” real-world implementation using available literature to design mentored, practical approaches to those same interventions at sites not involved in their initial setup and validation.

EMR implementation should in theory improve accuracy (or at least legibility), but it can also contribute to new types of inaccuracy or, as the authors propose, deprioritize quality and safety as organizational goals during the rigors of digitization. Similarly, training staff to take a BPMH might create false confidence in the results or interact with medication reconciliation in other complex ways. Opting to add more work instead of hiring additional staff may have increased the burden of medication review and thus contributed to its inaccuracy.

On the contrary, certain interventions, such as having clear accountability for the medication list, hiring additional staff to construct that list, and clearly defining the roles of those involved in the reconciliation process, were associated with improved medication reconciliation. All these strategies require resource allocation, but at least the current study provides evidence that such resource allocation can be effective in new settings as they were in their original ones.

The study has important acknowledged limitations. The on-protocol analysis limited the authors to reporting associations rather than causality. Moreover, the original trial ran from 2011 to 2014, which was a time of rapid EMR implementation and new recognition of the problems posed by the same; several organizations are in a far more mature EMR context today. Conversely, newer technologies such as patient-facing medication reconciliation applications, cross-organization medication lists available from some EMR vendors, and health platforms that collect data from multiple EMRs were not evaluated because they did not exist at the time of the original trial. Another important trend in healthcare, the rise of Accountable Care Organizations and their focus on integration and defragmentation, may have an important part to play in medication list accuracy. All the above-mentioned aspects will be important avenues for ongoing research in real-world medication reconciliation.

Mixon’s findings come at a time when medication reconciliation is again a national health informatics priority, a key component of the Medicare Access and CHIP reauthorization Act of 2015 and Merit-based Incentive Payments System⁸ since 2019, with hospitals reporting medication reconciliation rates for financial in addition to quality and safety reasons. Hopefully, this study and others, in combination with the abovementioned incentives, will stimulate further research into impactful strategies for medication reconciliation and ideal ways to implement them. With luck, the end result will be more generalizable interventions, with a track record of success, that would help ensure that patients are prescribed, are reporting, are taking, and are noted to be taking the medications that they and their providers intended, both on presentation to the hospital and on discharge home.

Disclosures

Vicki Jue has no conflicts of interest to report. Raman Khanna reports developing CareWeb, a communication platform that has been licensed to Voalte, Inc. This work is unrelated to the current editorial. No other conflicts of interest to report.