Pulmonology

The Food and Drug Administration has approved a new indication for Zerbaxa (ceftolozane and tazobactam), authorizing it for the treatment of both hospital-acquired and ventilator-associated bacterial pneumonia.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The new indication is for patients 18 years and older. It was based on results of a multinational, double-blind study that compared Zerbaxa with a different antibacterial drug in 726 patients hospitalized with hospital-acquired/ventilator-associated bacterial pneumonia. Mortality and cure rates were similar in the Zerbaxa and comparator groups.

The most common adverse events observed in the trial were elevated liver enzyme levels, renal impairment or failure, and diarrhea. Patients with hypersensitivity to beta-lactam drugs should not be receive Zerbaxa.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections. Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. ... That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections,” said Amy Abernethy, MD, PhD, the FDA’s principal deputy commissioner.

Zerbaxa was initially approved in 2014 for treatment of complicated intra-abdominal and urinary tract infections.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved a new indication for Zerbaxa (ceftolozane and tazobactam), authorizing it for the treatment of both hospital-acquired and ventilator-associated bacterial pneumonia.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The new indication is for patients 18 years and older. It was based on results of a multinational, double-blind study that compared Zerbaxa with a different antibacterial drug in 726 patients hospitalized with hospital-acquired/ventilator-associated bacterial pneumonia. Mortality and cure rates were similar in the Zerbaxa and comparator groups.

The most common adverse events observed in the trial were elevated liver enzyme levels, renal impairment or failure, and diarrhea. Patients with hypersensitivity to beta-lactam drugs should not be receive Zerbaxa.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections. Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. ... That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections,” said Amy Abernethy, MD, PhD, the FDA’s principal deputy commissioner.

Zerbaxa was initially approved in 2014 for treatment of complicated intra-abdominal and urinary tract infections.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved a new indication for Zerbaxa (ceftolozane and tazobactam), authorizing it for the treatment of both hospital-acquired and ventilator-associated bacterial pneumonia.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The new indication is for patients 18 years and older. It was based on results of a multinational, double-blind study that compared Zerbaxa with a different antibacterial drug in 726 patients hospitalized with hospital-acquired/ventilator-associated bacterial pneumonia. Mortality and cure rates were similar in the Zerbaxa and comparator groups.

The most common adverse events observed in the trial were elevated liver enzyme levels, renal impairment or failure, and diarrhea. Patients with hypersensitivity to beta-lactam drugs should not be receive Zerbaxa.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections. Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. ... That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections,” said Amy Abernethy, MD, PhD, the FDA’s principal deputy commissioner.

Zerbaxa was initially approved in 2014 for treatment of complicated intra-abdominal and urinary tract infections.

Find the full press release on the FDA website.

[email protected]

BALTIMORE – The biggest barrier to asthma care in public schools is students not having an albuterol inhaler with them, frequently because the parent did not provide an inhaler or did not provide a written order for one, according to new research. Only seven U.S. states have laws allowing schools to stock albuterol for students.

pelvidge/thinkstockphotos.com

“Most students only have access to this lifesaving medication when they bring a personal inhaler,” Alexandra M. Sims, MD, of Children’s National Hospital in Washington and colleagues wrote in their abstract at the annual meeting of Pediatric Academic Societies. “Interventions that address medication availability may be an important step in removing obstacles to asthma care in school.”

One such option is a stock inhaler available for any students to use. National guidelines from the Centers for Disease Control and Prevention recommend that students with asthma have access to inhaled albuterol at school, yet most states do not have legislation related to albuterol stocking in schools, according to the Asthma and Allergy Foundation of America.

Not having access to rescue inhaler medication at school contributes to lost class time and referrals to the emergency department, the authors note in their background information. Yet, “in most U.S. jurisdictions, including the school district we examined, students need both a personal albuterol inhaler and a physician order to receive medication at school.”

To determine what barriers exist regarding students’ asthma care in schools, the authors sent 166 school nurses in an urban school district an anonymous survey during the 2015-2016 school year. The survey asked about 21 factors that could delay or prevent students from returning to class and asked nurses’ agreement or disagreement with 25 additional statements.

The 130 respondents made up a 78% response rate. The institutions represented by the nurses included 44% elementary schools, 9% middle schools, 16% high schools, and 32% other (such as those who may serve multiple schools).

The majority of respondents (72%) agreed that asthma is one of the biggest health problems students face, particularly among middle and high school students (P less than .05). Most (74%) also said an albuterol inhaler at school could reduce the likelihood of students with asthma needing to leave school early.

The largest barrier to students returning to class was parents not providing an albuterol inhaler and/or a written order for an inhaler despite a request from the nurse, according to 69% of the respondents (P less than .05). In high schools in particular, another barrier was students simply not bringing their inhaler to school even though they usually carry one (P less than .01).

Only 15% of nurses saw disease severity as a significant barrier, and 17% cited the staff not adequately recognizing a student’s symptoms.

The researchers did not note use of external funding or author disclosures.

BALTIMORE – The biggest barrier to asthma care in public schools is students not having an albuterol inhaler with them, frequently because the parent did not provide an inhaler or did not provide a written order for one, according to new research. Only seven U.S. states have laws allowing schools to stock albuterol for students.

pelvidge/thinkstockphotos.com

“Most students only have access to this lifesaving medication when they bring a personal inhaler,” Alexandra M. Sims, MD, of Children’s National Hospital in Washington and colleagues wrote in their abstract at the annual meeting of Pediatric Academic Societies. “Interventions that address medication availability may be an important step in removing obstacles to asthma care in school.”

One such option is a stock inhaler available for any students to use. National guidelines from the Centers for Disease Control and Prevention recommend that students with asthma have access to inhaled albuterol at school, yet most states do not have legislation related to albuterol stocking in schools, according to the Asthma and Allergy Foundation of America.

Not having access to rescue inhaler medication at school contributes to lost class time and referrals to the emergency department, the authors note in their background information. Yet, “in most U.S. jurisdictions, including the school district we examined, students need both a personal albuterol inhaler and a physician order to receive medication at school.”

To determine what barriers exist regarding students’ asthma care in schools, the authors sent 166 school nurses in an urban school district an anonymous survey during the 2015-2016 school year. The survey asked about 21 factors that could delay or prevent students from returning to class and asked nurses’ agreement or disagreement with 25 additional statements.

The 130 respondents made up a 78% response rate. The institutions represented by the nurses included 44% elementary schools, 9% middle schools, 16% high schools, and 32% other (such as those who may serve multiple schools).

The majority of respondents (72%) agreed that asthma is one of the biggest health problems students face, particularly among middle and high school students (P less than .05). Most (74%) also said an albuterol inhaler at school could reduce the likelihood of students with asthma needing to leave school early.

The largest barrier to students returning to class was parents not providing an albuterol inhaler and/or a written order for an inhaler despite a request from the nurse, according to 69% of the respondents (P less than .05). In high schools in particular, another barrier was students simply not bringing their inhaler to school even though they usually carry one (P less than .01).

Only 15% of nurses saw disease severity as a significant barrier, and 17% cited the staff not adequately recognizing a student’s symptoms.

The researchers did not note use of external funding or author disclosures.

BALTIMORE – The biggest barrier to asthma care in public schools is students not having an albuterol inhaler with them, frequently because the parent did not provide an inhaler or did not provide a written order for one, according to new research. Only seven U.S. states have laws allowing schools to stock albuterol for students.

pelvidge/thinkstockphotos.com

“Most students only have access to this lifesaving medication when they bring a personal inhaler,” Alexandra M. Sims, MD, of Children’s National Hospital in Washington and colleagues wrote in their abstract at the annual meeting of Pediatric Academic Societies. “Interventions that address medication availability may be an important step in removing obstacles to asthma care in school.”

One such option is a stock inhaler available for any students to use. National guidelines from the Centers for Disease Control and Prevention recommend that students with asthma have access to inhaled albuterol at school, yet most states do not have legislation related to albuterol stocking in schools, according to the Asthma and Allergy Foundation of America.

Not having access to rescue inhaler medication at school contributes to lost class time and referrals to the emergency department, the authors note in their background information. Yet, “in most U.S. jurisdictions, including the school district we examined, students need both a personal albuterol inhaler and a physician order to receive medication at school.”

To determine what barriers exist regarding students’ asthma care in schools, the authors sent 166 school nurses in an urban school district an anonymous survey during the 2015-2016 school year. The survey asked about 21 factors that could delay or prevent students from returning to class and asked nurses’ agreement or disagreement with 25 additional statements.

The 130 respondents made up a 78% response rate. The institutions represented by the nurses included 44% elementary schools, 9% middle schools, 16% high schools, and 32% other (such as those who may serve multiple schools).

The majority of respondents (72%) agreed that asthma is one of the biggest health problems students face, particularly among middle and high school students (P less than .05). Most (74%) also said an albuterol inhaler at school could reduce the likelihood of students with asthma needing to leave school early.

The largest barrier to students returning to class was parents not providing an albuterol inhaler and/or a written order for an inhaler despite a request from the nurse, according to 69% of the respondents (P less than .05). In high schools in particular, another barrier was students simply not bringing their inhaler to school even though they usually carry one (P less than .01).

Only 15% of nurses saw disease severity as a significant barrier, and 17% cited the staff not adequately recognizing a student’s symptoms.

The researchers did not note use of external funding or author disclosures.

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

[email protected]

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

copyright mates/Fotolia.com

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

copyright mates/Fotolia.com

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

copyright mates/Fotolia.com

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

 

 

CLINICAL MANIFESTATIONS OF OSA NOT OBVIOUS AFTER STROKE

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

 

 

POSITIVE AIRWAY PRESSURE THERAPY: BENEFITS, CHALLENGES, ALTERNATIVES

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

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

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

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

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

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

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

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

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

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

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

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

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

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

 

 

MONITORING UNFRACTIONATED HEPARIN IMPROVES OUTCOMES

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

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

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

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

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

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

THE aPTT REFLECTS THROMBIN INHIBITION

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

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

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

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

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

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

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

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

 

 

ANTI-Xa ASSAY VS THE aPTT

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

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

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

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

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

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

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

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

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

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

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

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

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

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

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

 

 

LIMITATIONS OF ANTI-Xa ASSAYS

Anti-Xa assays are hampered by some technical limitations:

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

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

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

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

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

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

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

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

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

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

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

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

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

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

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

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

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

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

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

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

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

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

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

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

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

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

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

 

 

MONITORING UNFRACTIONATED HEPARIN IMPROVES OUTCOMES

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

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

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

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

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

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

THE aPTT REFLECTS THROMBIN INHIBITION

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

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

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

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

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

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

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

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

 

 

ANTI-Xa ASSAY VS THE aPTT

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

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

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

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

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

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

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

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

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

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

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

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

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

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

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

 

 

LIMITATIONS OF ANTI-Xa ASSAYS

Anti-Xa assays are hampered by some technical limitations:

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

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

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

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

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

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

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

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

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

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

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

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

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

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

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

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

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

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

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

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

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

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

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

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

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

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

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

 

 

MONITORING UNFRACTIONATED HEPARIN IMPROVES OUTCOMES

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

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

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

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

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

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

THE aPTT REFLECTS THROMBIN INHIBITION

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

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

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

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

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

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

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

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

 

 

ANTI-Xa ASSAY VS THE aPTT

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

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

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

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

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

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

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

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

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

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

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

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

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

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

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

 

 

LIMITATIONS OF ANTI-Xa ASSAYS

Anti-Xa assays are hampered by some technical limitations:

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

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

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

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

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

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

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

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

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

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

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

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

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

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

A 57-year-old woman was admitted to our hospital for progressive hypoxic respiratory failure that developed after 10 days of empiric treatment at another hospital for an exacerbation of chronic obstructive pulmonary disease (COPD).

Computed tomography (CT) showed a lesion in the upper lobe of the left lung, with new ground-glass opacities with cystic and cavitary changes raising concern for an inflammatory or infectious cause (Figure 1). Respiratory culture of expectorated secretions grew Aspergillus. Assays for beta-d-glucan and serum Aspergillus immunoglobulin G (IgG) antibodies were positive, although given the improvement in her oxygenation requirements and overall clinical status, these were thought to be trivial. Tests for immunoglobulin deficiencies and human immunodeficiency virus were negative, ruling out primary immunodeficiency. However, within the next 48 hours, her respiratory status declined, and voriconazole was started out of concern for invasive pulmonary aspergillosis based on results of serum IgG testing.

Despite 2 days of treatment with voriconazole, the patient developed respiratory failure. Repeat CT showed that the ground-glass opacities were more dense, especially in the lower lobes, and new patchy infiltrates were noted in the left lung. The patient developed a right tension pneumothorax requiring emergency intubation and chest tube insertion.¹ She subsequently developed acute abdominal pain with worsening abdominal distention, diagnosed as pneumoperitoneum. Emergency exploratory laparotomy revealed perforations in the cecum with fecal spillage, requiring ileo­cecectomy and ileostomy.

Pathologic study of bowel specimens confirmed fungal hyphae with “tree-branch” structures consistent with fungal infection in the bowel (Figure 2).

Oral voriconazole was continued. The patient’s respiratory status improved, and she no longer required supplemental oxygen. She was discharged on a regimen of oral voriconazole 200 mg twice daily. However, over the next 12 months, she had additional hospitalizations for severe sepsis from abdominal wound infections, pneumonia, and Clostridium difficile infection. She will require lifelong antifungal treatment.

INVASIVE PULMONARY ASPERGILLOSIS

Invasive pulmonary aspergillosis is the most severe form of aspergillosis and is most often seen in immunocompromised patients. The death rate is as high as 50% in neutropenic patients regardless of the time to diagnosis or effective treatment.² It becomes life-threatening as the infection enters the blood stream, leading to formation of thrombi and precipitating embolism and necrosis in the lungs.³

In immunocompetent patients, COPD, tuberculosis, bronchiectasis, liver disease, severe sepsis, and diabetes mellitus predispose to invasive pulmonary aspergillosis.² Other risk factors include long-term steroid therapy at doses equivalent to prednisone 20 mg/day for at least 13 weeks⁴ and viral infection such as influenza.⁵ Chronic use of inhaled corticosteroids has been hypothesized to increase risk.⁴

Histopathologic confirmation of fungal elements is the gold standard for diagnosis.³ New biomarkers such as beta-d-glucan have shown promise in enabling earlier diagnosis to allow effective treatment of disseminated aspergillosis, as in our patient.⁶

TAKE-HOME MESSAGE

Although not common, invasive aspergillosis can occur in immunocompetent and near-immunocompetent patients, particularly those with COPD or other underlying lung disease.

Acknowledgment: The authors thank Kimberley Woodward, MD, Inova Fairfax Hospital, Falls Church, VA, for her study of the bowel specimen and for providing the histology slide.

A 57-year-old woman was admitted to our hospital for progressive hypoxic respiratory failure that developed after 10 days of empiric treatment at another hospital for an exacerbation of chronic obstructive pulmonary disease (COPD).

Computed tomography (CT) showed a lesion in the upper lobe of the left lung, with new ground-glass opacities with cystic and cavitary changes raising concern for an inflammatory or infectious cause (Figure 1). Respiratory culture of expectorated secretions grew Aspergillus. Assays for beta-d-glucan and serum Aspergillus immunoglobulin G (IgG) antibodies were positive, although given the improvement in her oxygenation requirements and overall clinical status, these were thought to be trivial. Tests for immunoglobulin deficiencies and human immunodeficiency virus were negative, ruling out primary immunodeficiency. However, within the next 48 hours, her respiratory status declined, and voriconazole was started out of concern for invasive pulmonary aspergillosis based on results of serum IgG testing.

Despite 2 days of treatment with voriconazole, the patient developed respiratory failure. Repeat CT showed that the ground-glass opacities were more dense, especially in the lower lobes, and new patchy infiltrates were noted in the left lung. The patient developed a right tension pneumothorax requiring emergency intubation and chest tube insertion.¹ She subsequently developed acute abdominal pain with worsening abdominal distention, diagnosed as pneumoperitoneum. Emergency exploratory laparotomy revealed perforations in the cecum with fecal spillage, requiring ileo­cecectomy and ileostomy.

Pathologic study of bowel specimens confirmed fungal hyphae with “tree-branch” structures consistent with fungal infection in the bowel (Figure 2).

Oral voriconazole was continued. The patient’s respiratory status improved, and she no longer required supplemental oxygen. She was discharged on a regimen of oral voriconazole 200 mg twice daily. However, over the next 12 months, she had additional hospitalizations for severe sepsis from abdominal wound infections, pneumonia, and Clostridium difficile infection. She will require lifelong antifungal treatment.

INVASIVE PULMONARY ASPERGILLOSIS

Invasive pulmonary aspergillosis is the most severe form of aspergillosis and is most often seen in immunocompromised patients. The death rate is as high as 50% in neutropenic patients regardless of the time to diagnosis or effective treatment.² It becomes life-threatening as the infection enters the blood stream, leading to formation of thrombi and precipitating embolism and necrosis in the lungs.³

In immunocompetent patients, COPD, tuberculosis, bronchiectasis, liver disease, severe sepsis, and diabetes mellitus predispose to invasive pulmonary aspergillosis.² Other risk factors include long-term steroid therapy at doses equivalent to prednisone 20 mg/day for at least 13 weeks⁴ and viral infection such as influenza.⁵ Chronic use of inhaled corticosteroids has been hypothesized to increase risk.⁴

Histopathologic confirmation of fungal elements is the gold standard for diagnosis.³ New biomarkers such as beta-d-glucan have shown promise in enabling earlier diagnosis to allow effective treatment of disseminated aspergillosis, as in our patient.⁶

TAKE-HOME MESSAGE

Although not common, invasive aspergillosis can occur in immunocompetent and near-immunocompetent patients, particularly those with COPD or other underlying lung disease.

Acknowledgment: The authors thank Kimberley Woodward, MD, Inova Fairfax Hospital, Falls Church, VA, for her study of the bowel specimen and for providing the histology slide.

A 57-year-old woman was admitted to our hospital for progressive hypoxic respiratory failure that developed after 10 days of empiric treatment at another hospital for an exacerbation of chronic obstructive pulmonary disease (COPD).

Computed tomography (CT) showed a lesion in the upper lobe of the left lung, with new ground-glass opacities with cystic and cavitary changes raising concern for an inflammatory or infectious cause (Figure 1). Respiratory culture of expectorated secretions grew Aspergillus. Assays for beta-d-glucan and serum Aspergillus immunoglobulin G (IgG) antibodies were positive, although given the improvement in her oxygenation requirements and overall clinical status, these were thought to be trivial. Tests for immunoglobulin deficiencies and human immunodeficiency virus were negative, ruling out primary immunodeficiency. However, within the next 48 hours, her respiratory status declined, and voriconazole was started out of concern for invasive pulmonary aspergillosis based on results of serum IgG testing.

Despite 2 days of treatment with voriconazole, the patient developed respiratory failure. Repeat CT showed that the ground-glass opacities were more dense, especially in the lower lobes, and new patchy infiltrates were noted in the left lung. The patient developed a right tension pneumothorax requiring emergency intubation and chest tube insertion.¹ She subsequently developed acute abdominal pain with worsening abdominal distention, diagnosed as pneumoperitoneum. Emergency exploratory laparotomy revealed perforations in the cecum with fecal spillage, requiring ileo­cecectomy and ileostomy.

Pathologic study of bowel specimens confirmed fungal hyphae with “tree-branch” structures consistent with fungal infection in the bowel (Figure 2).

Oral voriconazole was continued. The patient’s respiratory status improved, and she no longer required supplemental oxygen. She was discharged on a regimen of oral voriconazole 200 mg twice daily. However, over the next 12 months, she had additional hospitalizations for severe sepsis from abdominal wound infections, pneumonia, and Clostridium difficile infection. She will require lifelong antifungal treatment.

INVASIVE PULMONARY ASPERGILLOSIS

Invasive pulmonary aspergillosis is the most severe form of aspergillosis and is most often seen in immunocompromised patients. The death rate is as high as 50% in neutropenic patients regardless of the time to diagnosis or effective treatment.² It becomes life-threatening as the infection enters the blood stream, leading to formation of thrombi and precipitating embolism and necrosis in the lungs.³

In immunocompetent patients, COPD, tuberculosis, bronchiectasis, liver disease, severe sepsis, and diabetes mellitus predispose to invasive pulmonary aspergillosis.² Other risk factors include long-term steroid therapy at doses equivalent to prednisone 20 mg/day for at least 13 weeks⁴ and viral infection such as influenza.⁵ Chronic use of inhaled corticosteroids has been hypothesized to increase risk.⁴

Histopathologic confirmation of fungal elements is the gold standard for diagnosis.³ New biomarkers such as beta-d-glucan have shown promise in enabling earlier diagnosis to allow effective treatment of disseminated aspergillosis, as in our patient.⁶

TAKE-HOME MESSAGE

Although not common, invasive aspergillosis can occur in immunocompetent and near-immunocompetent patients, particularly those with COPD or other underlying lung disease.

Acknowledgment: The authors thank Kimberley Woodward, MD, Inova Fairfax Hospital, Falls Church, VA, for her study of the bowel specimen and for providing the histology slide.

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

WHAT ARE THE RISKS OF THORACENTESIS?

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

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

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

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

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

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

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

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

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

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

 

 

WHAT MECHANISMS UNDERLIE POSTPROCEDURAL PNEUMOTHORAX?

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

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

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

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

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

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

KEY POINTS

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

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

WHAT ARE THE RISKS OF THORACENTESIS?

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

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

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

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

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

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

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

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

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

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

 

 

WHAT MECHANISMS UNDERLIE POSTPROCEDURAL PNEUMOTHORAX?

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

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

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

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

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

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

KEY POINTS

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

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

WHAT ARE THE RISKS OF THORACENTESIS?

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

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

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

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

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

HOW OFTEN DOES PNEUMOTHORAX OCCUR AFTER THORACENTESIS?

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

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

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

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

 

 

WHAT MECHANISMS UNDERLIE POSTPROCEDURAL PNEUMOTHORAX?

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

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

WHEN IS RADIOGRAPHY INDICATED AFTER THORACENTESIS?

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

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

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

KEY POINTS

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

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?

To the Editor: The review by May et al¹ of 3 neglected numbers in the complete blood cell count (CBC) was a good reminder to look more closely at the results of the CBCs we often order in primary care. I was surprised to see no mention of the red cell distribution width in relation to another cardiovascular disorder—obstructive sleep apnea.^2,3 I wonder if the authors would comment on this association?