The chest radiograph (CXR) is the most commonly used diagnostic imaging modality in children, and is considered to be the gold standard for the diagnosis of pneumonia. As such, physicians in developed countries rely on chest radiography to establish the diagnosis of pneumonia.13 However, there are limited data investigating the reliability of this test for the diagnosis of pneumonia in children.2, 46

Prior investigations have noted poor overall agreement by emergency medicine, infectious diseases, and pulmonary medicine physicians, and even radiologists, in their interpretation of chest radiographs for the diagnosis of pneumonia.2, 5, 710 The World Health Organization (WHO) developed criteria to standardize CXR interpretation for the diagnosis of pneumonia in children for use in epidemiologic studies.11 These standardized definitions of pneumonia have been formally evaluated by the WHO6 and utilized in epidemiologic studies of vaccine efficacy,12 but the overall reliability of these radiographic criteria have not been studied outside of these forums.

We conducted this prospective case‐based study to evaluate the reliability of the radiographic diagnosis of pneumonia among children presenting to a pediatric emergency department with clinical suspicion of pneumonia. We were primarily interested in assessing the overall reliability in CXR interpretation for the diagnosis of pneumonia, and identifying which radiographic features of pneumonia were consistently identified by radiologists.

MATERIALS AND METHODS

RESULTS

Inter‐Rater Reliability

The kappa coefficients of inter‐rater reliability between the radiologists across the 6 clinical measures of interest are displayed in Table 1. As shown, the most reliable measure was that of alveolar infiltrate (Figure 1), which attained a substantial degree of agreement between the radiologists. Two other measures, any infiltrate and pleural effusion, attained moderate reliability, while bronchograms and hilar adenopathy were each classified as having fair reliability. However, interstitial infiltrate (Figure 2) was found to have the lowest kappa estimate, with a slight degree of reliability. When examining inter‐rater reliability among the radiologists separately from each institution, the pattern of results was similar.

Table 1.Inter‐Rater Reliability of Radiologists (n = 6) Evaluating Chest Radiographs in Children Presenting to the ED With Suspected Pneumonia (n = 100)

All Radiologists (n = 6)	Kappa	95% Confidence Interval
Abbreviation: ED, emergency department.
Any infiltrate	0.47	0.39, 0.56
Alveolar infiltrate	0.69	0.60, 0.78
Interstitial infiltrate	0.14	0.05, 0.23
Air bronchograms	0.32	0.24, 0.42
Hilar adenopathy	0.21	0.08, 0.39
Pleural effusion	0.45	0.29, 0.61

Figure 1

Figure 2

At least 4 of the 6 radiologists agreed on the presence or absence of an alveolar infiltrate for 95 of the 100 unique CXRs; all 6 radiologists agreed regarding the presence or absence of an alveolar infiltrate in 72 of the 100 unique CXRs. At least 4 of the 6 radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 96% and 90% of the time, respectively. All 6 of the radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 35% and 27% of the time, respectively.

DISCUSSION

The chest radiograph serves as an integral component of the reference standard for the diagnosis of childhood pneumonia. Few prior studies have assessed the reliability of chest radiograph findings in children.3, 5, 12, 14, 15 We found a high degree of agreement among radiologists for radiologic findings consistent with bacterial pneumonia when standardized interpretation criteria were applied. In this study, we identified radiographic features of pneumonia, such as alveolar infiltrate and pleural effusion, that were consistently identified by different radiologists reviewing the same radiograph and by the same radiologist reviewing the same radiograph. These data support the notion that radiographic features most suggestive of bacterial pneumonia are consistently identified by radiologists.16, 17 There was less consistency in the identification of other radiographic findings, such as interstitial infiltrates, air bronchograms, and hilar lymphadenopathy.

Prior studies have found high levels of disagreement among radiologists in the interpretation of chest radiographs.2, 3, 15, 18 Many of these prior studies emphasized variation in detection of radiographic findings that would not typically alter clinical management. We observed high intra‐rater, and inter‐rater reliability among radiologists for the findings of alveolar infiltrate and pleural effusion. These are the radiographic findings most consistent with a bacterial etiologic agent for pneumonia.19 Other studies have also found that the presence of an alveolar infiltrate is a reliable radiographic finding in children18 and adults.7, 9, 10 These findings support the use of the WHO definition of primary endpoint pneumonia for use in epidemiologic studies.4, 6, 11

This study also confirms a previous report by Cherian et al. that findings of many children with asthma, reactive airways disease, bronchiolitis, and viral infections interstitial infiltrates are less reliable.6 This is not surprising considering the fact that these patients often have radiographic findings due to small airway disease and atelectasis.19, 20 The differentiation between atelectasis and interstitial infiltrate is difficult, particularly in young children. A prior study conducted among neonates observed wide variability in the interpretation of chest radiographs, and that the differentiation of pneumonia from atelectasis was difficult for this patient population.5 The decisions around antimicrobial treatment of children with radiographic findings of interstitial infiltrates should be made in the context of the clinical history and physical examination findings, and clinicians should realize that these radiographic features demonstrate poor reliability for the diagnosis of pneumonia.

Overall reliability for the presence of any infiltrate, and its converse, no infiltrate was considered moderate. This is driven by the low reliability and variability around the radiographic diagnosis of interstitial infiltrates. Our findings are similar to those observed in adults with lower respiratory tract infections.9 The low reliability in identification of interstitial infiltrates may explain why prior studies have demonstrated that the CXR results rarely change management in children who have radiographs performed for suspicion of pneumonia.1, 21 Our study highlights the importance of quantifying CXR findings to include specific comments regarding the presence or absence of alveolar infiltrates, rather than the presence or absence of any infiltrate.

The WHO has procured definitions the radiographic diagnosis of pneumonia, and this definition has been utilized to help standardize the interpretation of chest radiographs for the conduct of epidemiological studies.6, 11 Specifically, the definitions utilized not only define the presence or absence of pneumonia, but also attempt to differentiate a primarily bacterial infection (consolidation or pleural effusion), from a viral or atypical presentation (interstitial pattern). Even under the best of circumstances, the differentiation of viral versus bacterial pneumonia is not always possible, and again, is often made by the treating physician by incorporating the clinical setting within which the radiograph was obtained.

This study had several limitations. Firstly, the included radiographs did not reflect the frequency with which certain radiographic findings would be identified in children evaluated for pneumonia in a pediatric emergency department setting. Radiographs were purposefully selected to encompass a broad spectrum of radiologic findings, including less common findings such as hilar lymphadenopathy and pleural effusions. Thus, the prevalence of pneumonia and other abnormal findings in this study was artificially higher than typically observed among a cohort of children for whom pneumonia is considered, a factor that may limit the generalizability of our results. Secondly, the clinical history was not provided to the radiologists to avoid bias by indication. For this study, we notified the radiologists that all radiographs were performed for clinical suspicion of pneumonia without providing details about the subjects' signs and symptoms. The absence of clinical history, however, does not mirror the real world scenario in which the interpretation of the chest radiograph is frequently made in the context of the clinical history. The relevance of this latter issue is unclear, as Tudor et al. found a nonstatistically significant improvement in the overall accuracy in chest radiograph interpretation when radiologists were provided clinical details.10 The radiologists recruited for this study all practice in an academic children's hospital setting, and thus, the generalizability of our findings may be limited to this type of practice setting. Finally, reproducibility does not imply accuracy, and reliability in identifying specific findings does not necessarily lead to improved or different management. Thus, while the reliability of radiographic findings of alveolar infiltrate and pleural effusion is reassuringly high, the validity of these radiographic features for bacterial pneumonia is not known. Ascertainment of validity can only be assessed through the use of invasive testing such as lung biopsy, as the yield from bacterial testing such as blood cultures is low, and the results of other studies such as viral testing of nasopharyngeal washings do not prove an etiologic cause of pneumonia.

CONCLUSIONS

Radiographic findings of alveolar infiltrates and pleural effusions are highly reliable among radiologists. Radiographic interpretation of interstitial infiltrates appears to be less reliable.

The chest radiograph (CXR) is the most commonly used diagnostic imaging modality in children, and is considered to be the gold standard for the diagnosis of pneumonia. As such, physicians in developed countries rely on chest radiography to establish the diagnosis of pneumonia.13 However, there are limited data investigating the reliability of this test for the diagnosis of pneumonia in children.2, 46

Prior investigations have noted poor overall agreement by emergency medicine, infectious diseases, and pulmonary medicine physicians, and even radiologists, in their interpretation of chest radiographs for the diagnosis of pneumonia.2, 5, 710 The World Health Organization (WHO) developed criteria to standardize CXR interpretation for the diagnosis of pneumonia in children for use in epidemiologic studies.11 These standardized definitions of pneumonia have been formally evaluated by the WHO6 and utilized in epidemiologic studies of vaccine efficacy,12 but the overall reliability of these radiographic criteria have not been studied outside of these forums.

We conducted this prospective case‐based study to evaluate the reliability of the radiographic diagnosis of pneumonia among children presenting to a pediatric emergency department with clinical suspicion of pneumonia. We were primarily interested in assessing the overall reliability in CXR interpretation for the diagnosis of pneumonia, and identifying which radiographic features of pneumonia were consistently identified by radiologists.

MATERIALS AND METHODS

RESULTS

Inter‐Rater Reliability

The kappa coefficients of inter‐rater reliability between the radiologists across the 6 clinical measures of interest are displayed in Table 1. As shown, the most reliable measure was that of alveolar infiltrate (Figure 1), which attained a substantial degree of agreement between the radiologists. Two other measures, any infiltrate and pleural effusion, attained moderate reliability, while bronchograms and hilar adenopathy were each classified as having fair reliability. However, interstitial infiltrate (Figure 2) was found to have the lowest kappa estimate, with a slight degree of reliability. When examining inter‐rater reliability among the radiologists separately from each institution, the pattern of results was similar.

Table 1.Inter‐Rater Reliability of Radiologists (n = 6) Evaluating Chest Radiographs in Children Presenting to the ED With Suspected Pneumonia (n = 100)

All Radiologists (n = 6)	Kappa	95% Confidence Interval
Abbreviation: ED, emergency department.
Any infiltrate	0.47	0.39, 0.56
Alveolar infiltrate	0.69	0.60, 0.78
Interstitial infiltrate	0.14	0.05, 0.23
Air bronchograms	0.32	0.24, 0.42
Hilar adenopathy	0.21	0.08, 0.39
Pleural effusion	0.45	0.29, 0.61

Figure 1

Figure 2

At least 4 of the 6 radiologists agreed on the presence or absence of an alveolar infiltrate for 95 of the 100 unique CXRs; all 6 radiologists agreed regarding the presence or absence of an alveolar infiltrate in 72 of the 100 unique CXRs. At least 4 of the 6 radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 96% and 90% of the time, respectively. All 6 of the radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 35% and 27% of the time, respectively.

DISCUSSION

The chest radiograph serves as an integral component of the reference standard for the diagnosis of childhood pneumonia. Few prior studies have assessed the reliability of chest radiograph findings in children.3, 5, 12, 14, 15 We found a high degree of agreement among radiologists for radiologic findings consistent with bacterial pneumonia when standardized interpretation criteria were applied. In this study, we identified radiographic features of pneumonia, such as alveolar infiltrate and pleural effusion, that were consistently identified by different radiologists reviewing the same radiograph and by the same radiologist reviewing the same radiograph. These data support the notion that radiographic features most suggestive of bacterial pneumonia are consistently identified by radiologists.16, 17 There was less consistency in the identification of other radiographic findings, such as interstitial infiltrates, air bronchograms, and hilar lymphadenopathy.

Prior studies have found high levels of disagreement among radiologists in the interpretation of chest radiographs.2, 3, 15, 18 Many of these prior studies emphasized variation in detection of radiographic findings that would not typically alter clinical management. We observed high intra‐rater, and inter‐rater reliability among radiologists for the findings of alveolar infiltrate and pleural effusion. These are the radiographic findings most consistent with a bacterial etiologic agent for pneumonia.19 Other studies have also found that the presence of an alveolar infiltrate is a reliable radiographic finding in children18 and adults.7, 9, 10 These findings support the use of the WHO definition of primary endpoint pneumonia for use in epidemiologic studies.4, 6, 11

This study also confirms a previous report by Cherian et al. that findings of many children with asthma, reactive airways disease, bronchiolitis, and viral infections interstitial infiltrates are less reliable.6 This is not surprising considering the fact that these patients often have radiographic findings due to small airway disease and atelectasis.19, 20 The differentiation between atelectasis and interstitial infiltrate is difficult, particularly in young children. A prior study conducted among neonates observed wide variability in the interpretation of chest radiographs, and that the differentiation of pneumonia from atelectasis was difficult for this patient population.5 The decisions around antimicrobial treatment of children with radiographic findings of interstitial infiltrates should be made in the context of the clinical history and physical examination findings, and clinicians should realize that these radiographic features demonstrate poor reliability for the diagnosis of pneumonia.

Overall reliability for the presence of any infiltrate, and its converse, no infiltrate was considered moderate. This is driven by the low reliability and variability around the radiographic diagnosis of interstitial infiltrates. Our findings are similar to those observed in adults with lower respiratory tract infections.9 The low reliability in identification of interstitial infiltrates may explain why prior studies have demonstrated that the CXR results rarely change management in children who have radiographs performed for suspicion of pneumonia.1, 21 Our study highlights the importance of quantifying CXR findings to include specific comments regarding the presence or absence of alveolar infiltrates, rather than the presence or absence of any infiltrate.

The WHO has procured definitions the radiographic diagnosis of pneumonia, and this definition has been utilized to help standardize the interpretation of chest radiographs for the conduct of epidemiological studies.6, 11 Specifically, the definitions utilized not only define the presence or absence of pneumonia, but also attempt to differentiate a primarily bacterial infection (consolidation or pleural effusion), from a viral or atypical presentation (interstitial pattern). Even under the best of circumstances, the differentiation of viral versus bacterial pneumonia is not always possible, and again, is often made by the treating physician by incorporating the clinical setting within which the radiograph was obtained.

This study had several limitations. Firstly, the included radiographs did not reflect the frequency with which certain radiographic findings would be identified in children evaluated for pneumonia in a pediatric emergency department setting. Radiographs were purposefully selected to encompass a broad spectrum of radiologic findings, including less common findings such as hilar lymphadenopathy and pleural effusions. Thus, the prevalence of pneumonia and other abnormal findings in this study was artificially higher than typically observed among a cohort of children for whom pneumonia is considered, a factor that may limit the generalizability of our results. Secondly, the clinical history was not provided to the radiologists to avoid bias by indication. For this study, we notified the radiologists that all radiographs were performed for clinical suspicion of pneumonia without providing details about the subjects' signs and symptoms. The absence of clinical history, however, does not mirror the real world scenario in which the interpretation of the chest radiograph is frequently made in the context of the clinical history. The relevance of this latter issue is unclear, as Tudor et al. found a nonstatistically significant improvement in the overall accuracy in chest radiograph interpretation when radiologists were provided clinical details.10 The radiologists recruited for this study all practice in an academic children's hospital setting, and thus, the generalizability of our findings may be limited to this type of practice setting. Finally, reproducibility does not imply accuracy, and reliability in identifying specific findings does not necessarily lead to improved or different management. Thus, while the reliability of radiographic findings of alveolar infiltrate and pleural effusion is reassuringly high, the validity of these radiographic features for bacterial pneumonia is not known. Ascertainment of validity can only be assessed through the use of invasive testing such as lung biopsy, as the yield from bacterial testing such as blood cultures is low, and the results of other studies such as viral testing of nasopharyngeal washings do not prove an etiologic cause of pneumonia.

CONCLUSIONS

Radiographic findings of alveolar infiltrates and pleural effusions are highly reliable among radiologists. Radiographic interpretation of interstitial infiltrates appears to be less reliable.

The chest radiograph (CXR) is the most commonly used diagnostic imaging modality in children, and is considered to be the gold standard for the diagnosis of pneumonia. As such, physicians in developed countries rely on chest radiography to establish the diagnosis of pneumonia.13 However, there are limited data investigating the reliability of this test for the diagnosis of pneumonia in children.2, 46

Prior investigations have noted poor overall agreement by emergency medicine, infectious diseases, and pulmonary medicine physicians, and even radiologists, in their interpretation of chest radiographs for the diagnosis of pneumonia.2, 5, 710 The World Health Organization (WHO) developed criteria to standardize CXR interpretation for the diagnosis of pneumonia in children for use in epidemiologic studies.11 These standardized definitions of pneumonia have been formally evaluated by the WHO6 and utilized in epidemiologic studies of vaccine efficacy,12 but the overall reliability of these radiographic criteria have not been studied outside of these forums.

We conducted this prospective case‐based study to evaluate the reliability of the radiographic diagnosis of pneumonia among children presenting to a pediatric emergency department with clinical suspicion of pneumonia. We were primarily interested in assessing the overall reliability in CXR interpretation for the diagnosis of pneumonia, and identifying which radiographic features of pneumonia were consistently identified by radiologists.

MATERIALS AND METHODS

RESULTS

Inter‐Rater Reliability

The kappa coefficients of inter‐rater reliability between the radiologists across the 6 clinical measures of interest are displayed in Table 1. As shown, the most reliable measure was that of alveolar infiltrate (Figure 1), which attained a substantial degree of agreement between the radiologists. Two other measures, any infiltrate and pleural effusion, attained moderate reliability, while bronchograms and hilar adenopathy were each classified as having fair reliability. However, interstitial infiltrate (Figure 2) was found to have the lowest kappa estimate, with a slight degree of reliability. When examining inter‐rater reliability among the radiologists separately from each institution, the pattern of results was similar.

Table 1.Inter‐Rater Reliability of Radiologists (n = 6) Evaluating Chest Radiographs in Children Presenting to the ED With Suspected Pneumonia (n = 100)

All Radiologists (n = 6)	Kappa	95% Confidence Interval
Abbreviation: ED, emergency department.
Any infiltrate	0.47	0.39, 0.56
Alveolar infiltrate	0.69	0.60, 0.78
Interstitial infiltrate	0.14	0.05, 0.23
Air bronchograms	0.32	0.24, 0.42
Hilar adenopathy	0.21	0.08, 0.39
Pleural effusion	0.45	0.29, 0.61

Figure 1

Figure 2

At least 4 of the 6 radiologists agreed on the presence or absence of an alveolar infiltrate for 95 of the 100 unique CXRs; all 6 radiologists agreed regarding the presence or absence of an alveolar infiltrate in 72 of the 100 unique CXRs. At least 4 of the 6 radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 96% and 90% of the time, respectively. All 6 of the radiologists agreed on the presence or absence of any infiltrate and interstitial infiltrate 35% and 27% of the time, respectively.

DISCUSSION

The chest radiograph serves as an integral component of the reference standard for the diagnosis of childhood pneumonia. Few prior studies have assessed the reliability of chest radiograph findings in children.3, 5, 12, 14, 15 We found a high degree of agreement among radiologists for radiologic findings consistent with bacterial pneumonia when standardized interpretation criteria were applied. In this study, we identified radiographic features of pneumonia, such as alveolar infiltrate and pleural effusion, that were consistently identified by different radiologists reviewing the same radiograph and by the same radiologist reviewing the same radiograph. These data support the notion that radiographic features most suggestive of bacterial pneumonia are consistently identified by radiologists.16, 17 There was less consistency in the identification of other radiographic findings, such as interstitial infiltrates, air bronchograms, and hilar lymphadenopathy.

Prior studies have found high levels of disagreement among radiologists in the interpretation of chest radiographs.2, 3, 15, 18 Many of these prior studies emphasized variation in detection of radiographic findings that would not typically alter clinical management. We observed high intra‐rater, and inter‐rater reliability among radiologists for the findings of alveolar infiltrate and pleural effusion. These are the radiographic findings most consistent with a bacterial etiologic agent for pneumonia.19 Other studies have also found that the presence of an alveolar infiltrate is a reliable radiographic finding in children18 and adults.7, 9, 10 These findings support the use of the WHO definition of primary endpoint pneumonia for use in epidemiologic studies.4, 6, 11

This study also confirms a previous report by Cherian et al. that findings of many children with asthma, reactive airways disease, bronchiolitis, and viral infections interstitial infiltrates are less reliable.6 This is not surprising considering the fact that these patients often have radiographic findings due to small airway disease and atelectasis.19, 20 The differentiation between atelectasis and interstitial infiltrate is difficult, particularly in young children. A prior study conducted among neonates observed wide variability in the interpretation of chest radiographs, and that the differentiation of pneumonia from atelectasis was difficult for this patient population.5 The decisions around antimicrobial treatment of children with radiographic findings of interstitial infiltrates should be made in the context of the clinical history and physical examination findings, and clinicians should realize that these radiographic features demonstrate poor reliability for the diagnosis of pneumonia.

Overall reliability for the presence of any infiltrate, and its converse, no infiltrate was considered moderate. This is driven by the low reliability and variability around the radiographic diagnosis of interstitial infiltrates. Our findings are similar to those observed in adults with lower respiratory tract infections.9 The low reliability in identification of interstitial infiltrates may explain why prior studies have demonstrated that the CXR results rarely change management in children who have radiographs performed for suspicion of pneumonia.1, 21 Our study highlights the importance of quantifying CXR findings to include specific comments regarding the presence or absence of alveolar infiltrates, rather than the presence or absence of any infiltrate.

The WHO has procured definitions the radiographic diagnosis of pneumonia, and this definition has been utilized to help standardize the interpretation of chest radiographs for the conduct of epidemiological studies.6, 11 Specifically, the definitions utilized not only define the presence or absence of pneumonia, but also attempt to differentiate a primarily bacterial infection (consolidation or pleural effusion), from a viral or atypical presentation (interstitial pattern). Even under the best of circumstances, the differentiation of viral versus bacterial pneumonia is not always possible, and again, is often made by the treating physician by incorporating the clinical setting within which the radiograph was obtained.

This study had several limitations. Firstly, the included radiographs did not reflect the frequency with which certain radiographic findings would be identified in children evaluated for pneumonia in a pediatric emergency department setting. Radiographs were purposefully selected to encompass a broad spectrum of radiologic findings, including less common findings such as hilar lymphadenopathy and pleural effusions. Thus, the prevalence of pneumonia and other abnormal findings in this study was artificially higher than typically observed among a cohort of children for whom pneumonia is considered, a factor that may limit the generalizability of our results. Secondly, the clinical history was not provided to the radiologists to avoid bias by indication. For this study, we notified the radiologists that all radiographs were performed for clinical suspicion of pneumonia without providing details about the subjects' signs and symptoms. The absence of clinical history, however, does not mirror the real world scenario in which the interpretation of the chest radiograph is frequently made in the context of the clinical history. The relevance of this latter issue is unclear, as Tudor et al. found a nonstatistically significant improvement in the overall accuracy in chest radiograph interpretation when radiologists were provided clinical details.10 The radiologists recruited for this study all practice in an academic children's hospital setting, and thus, the generalizability of our findings may be limited to this type of practice setting. Finally, reproducibility does not imply accuracy, and reliability in identifying specific findings does not necessarily lead to improved or different management. Thus, while the reliability of radiographic findings of alveolar infiltrate and pleural effusion is reassuringly high, the validity of these radiographic features for bacterial pneumonia is not known. Ascertainment of validity can only be assessed through the use of invasive testing such as lung biopsy, as the yield from bacterial testing such as blood cultures is low, and the results of other studies such as viral testing of nasopharyngeal washings do not prove an etiologic cause of pneumonia.

CONCLUSIONS

Radiographic findings of alveolar infiltrates and pleural effusions are highly reliable among radiologists. Radiographic interpretation of interstitial infiltrates appears to be less reliable.

The management of postoperative pain is essential to perioperative care, and adequate postoperative analgesia has been associated with several key clinical benefits, including fewer postoperative complications, earlier patient ambulation, reduced costs due to shorter hospital stays, and improved rehabilitation.1, 2 While opioids have long been central to postoperative analgesia, they have been associated with various adverse effects, including sedation, dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression.2, 3 Constipation, one of the most common adverse effects resulting from opioid therapy, can be debilitating. Indeed, opioid effects on gut motility can occur even after a single dose.3 The consequences of opioid‐induced constipation (OIC) may be severe enough to warrant a dosage reduction of the opioid; however, this may lead to compromised analgesia, which can hinder recovery.4, 5 Thus, effective treatment of OIC is an important clinical consideration in patients undergoing pain management with opioids. Unfortunately, laxatives and other treatment strategies can have unpredictable or suboptimal results for many patients with OIC; therefore, other options are needed for the treatment of OIC.6, 7

Opioid receptor agonists cause constipation by adversely altering many aspects of intestinal function, including fluid dynamics, gastric emptying, propulsive motor activity, and transit time.3 Opioid receptors are widely distributed in the central nervous system and throughout the intestinal system. The mechanism of OIC may have both peripherally and centrally mediated components.8 Nonselective opioid receptor antagonists block the undesired effects on the gut, but because they cross the blood‐brain barrier, they also interfere with analgesia and may lead to symptoms of withdrawal. Methylnaltrexone is a selective, peripherally acting mu‐opioid receptor antagonist,9 formed by the addition of a methyl group to the amine ring of the mu‐opioid receptor antagonist naltrexone. The resulting quarternary amine has greater polarity, lower lipid solubility, and restricted ability to cross the blood‐brain barrier.10 Thus, methylnaltrexone was designed to decrease the peripheral adverse effects of opioids without interfering with centrally mediated analgesia.

Investigations of methylnaltrexone effects in healthy volunteers showed that methylnaltrexone attenuated morphine‐induced delays in gastric emptying and oral‐cecal transit without affecting analgesia.1113 Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response.1416 Two randomized, double‐blind, placebo‐controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia.17, 18 Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.19

Recently, the use of methylnaltrexone for the treatment of OIC in patients with chronic, nonmalignant pain was assessed in a randomized, double‐blind, placebo‐controlled trial of more than 400 patients. Investigators found that methylnaltrexone induced laxation and was generally well tolerated (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD), supporting the safety and efficacy of methylnaltrexone in the setting of OIC resulting from chronic opioid treatment. The present study aimed to assess the activity of methylnaltrexone in patients receiving mu‐agonist opioid analgesics during rehabilitation, following an orthopedic surgical procedure, who were experiencing acute OIC.

METHODS

Study Design

This randomized, double‐blind, placebo‐controlled, parallel‐group, hypothesis‐generating phase 2 study was conducted from October 2007 to January 2009 at 16 US hospitals and rehabilitation facilities in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki, and was approved by the Institutional Review Board and/or Independent Ethics Committee at each of the participating investigational centers. All patients provided written informed consent prior to study participation.

Eligible patients were randomized by interactive voice response system in a 1:1 ratio to receive once‐daily subcutaneous (SC) injections of either 12 mg methylnaltrexone or placebo (Figure 1). The chosen 12‐mg unit dosing corresponds to approximately 0.15 mg/kg (assuming an 80‐kg patient) and was found to be both efficacious and well tolerated in the treatment of OIC in prior studies, including studies in advanced‐illness patients17, 18 and in patients with chronic, nonmalignant pain (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD.20 The first dose of study medication was administered on the day of randomization or on the next calendar day. Once enrolled, the patient received once‐daily doses of methylnaltrexone for up to 4 or 7 days. Dosing continued until the patient received the maximum number of doses allowed, no longer needed opioid medication, or was discharged from the medical facility. Each patient completed a follow‐up safety visit at 14 3 days following the last dose.

Figure 1

RESULTS

Patient Populations

The flow of patients through the study is summarized in Figure 2. A total of 51 patients were enrolled. Of these, 33 received at least 1 dose of study treatment following double‐blind randomization and comprised both the mITT and safety populations. Seventeen of these patients were enrolled under the original protocol and could receive study drug for up to 7 days, while 16 patients enrolled under a subsequent protocol revision could receive study drug for up to 4 days. This change from a 7‐day to a 4‐day treatment protocol allowed for the capture of more study patients in view of the time pressures of short lengths of stay in postoperative settings. In total, 31 patients received at least 2 doses, and 26 patients received at least 4 doses of study drug. A total of 27 patients completed the study. Baseline demographics and prestudy surgical procedures were similar in both treatment groups (Table 1).

Figure 2

Table 1.Baseline Patient Demographics

Characteristic	Methylnaltrexone (n = 18)	Placebo (n = 15)
NOTE: Modified intent‐to‐treat population. Abbreviations: BMI, body mass index.; SD, standard deviation. * Baseline opioid use was defined as total opioid use within 24 hours prior to randomization.
Mean age, yr (SD)	64.2 (9.0)	65.2 (11.6)
Mean weight, kg (SD)	92.5 (22.5)	91.0 (20.2)
Mean BMI, kg/m2 (SD)	32.3 (7.2)	34.2 (6.41)
Sex, n (%)
Female	11 (61.1)	11 (73.3)
Male	7 (38.9)	4 (26.7)
Race, n (%)
White	14 (77.8)	10 (66.7)
Black	4 (22.2)	5 (33.3)
Type of surgery, n (%)
Total knee replacement	8 (44.4)	7 (46.7)
Total hip replacement	6 (33.3)	6 (40.0)
Spinal fusion	2 (11.1)	0
Fracture reduction	2 (11.1)	2 (13.3)
Median opioid use,* mg (range)	28.00 (6.75‐168.01)	25.00 (9.00‐75.00)
Median time from surgery to study drug administration, days (range)	4 (3‐6)	4 (3‐6)

Efficacy

A significantly greater percentage of patients had a bowel movement within 2 hours (P = 0.021) and 4 hours (P = 0.046) of the first dose of methylnaltrexone compared with patients who received placebo (Figure 3). Within 2 hours, 6 patients (33.3%; 95% confidence interval [CI], 13.34‐59.01) who received methylnaltrexone achieved laxation, while laxation did not occur in any patient who received placebo. By 4 hours posttreatment, 7 patients (38.9%; 95% CI, 17.30‐64.25) in the methylnaltrexone group achieved laxation compared with only 1 patient (6.7%; 95% CI, 0.17‐31.95) on placebo. Three patients in each treatment group received rescue laxatives.

Figure 3

The time to first laxation (Figure 4) was significantly shorter in patients who received methylnaltrexone compared with those in the placebo group. Patients on methylnaltrexone achieved laxation in a median time of 15.8 hours, compared with a median time of 50.9 hours for patients in the placebo group (P = 0.02, log‐rank test). The median time to laxation was less than 1 hour in the 7 methylnaltrexone‐treated patients who experienced laxation within 4 hours following the first dose. Of the remaining 11 methylnaltrexone‐treated patients, one experienced no laxation after 6 doses, and the median time to laxation for the others was 29.9 hours (not shown in figure).

Figure 4

Analysis of the Global Satisfaction With Treatment Scale revealed that more patients expressed overall treatment satisfaction (defined as very satisfied, satisfied, or minimally satisfied) with methylnaltrexone assessed 4 hours ( 30 minutes) after the first dose, compared with patients on placebo (83.3% vs 60.0%, respectively). At the study endpoint, overall treatment satisfaction with methylnaltrexone remained high (83.3%), whereas satisfaction with placebo was 53.3%. Additionally, no patients in the methylnaltrexone group expressed any dissatisfaction with treatment (defined as minimally dissatisfied, dissatisfied, or very dissatisfied) at endpoint, compared with 26.7% of patients in the placebo group who expressed some degree of dissatisfaction.

DISCUSSION

This pilot study suggests that methylnaltrexone actively induces laxation and is generally well tolerated in patients receiving mu‐opioid analgesia, following orthopedic surgery, who develop OIC acutely. It was the first study, to our knowledge, to investigate the efficacy of methylnaltrexone for the treatment of OIC in an acute postoperative setting. The protocol amendment changing the duration of treatment from 7 days to 4 days did not materially affect the results of the study. The response to methylnaltrexone was rapid, with 33.3% experiencing laxation within 2 hours. The median time to laxation was nearly 1.5 days shorter in patients treated with methylnaltrexone compared with those receiving placebo. Correspondingly, overall patient satisfaction was high in the methylnaltrexone group. Efficacy was attained without diminishing opioid analgesia, and without inducing signs or symptoms of opioid withdrawal. The incidence of AEs was similar between groups, and no treatment‐emergent SAEs were reported in this study.

Previous clinical trials investigated the safety and efficacy of methylnaltrexone for the treatment of OIC in patients with advanced illness and with chronic, nonmalignant pain. The present study extends those findings to a population of patients experiencing acute OIC following orthopedic surgery. Previous studies showed that approximately 48% to 62% of advanced‐illness patients experienced laxation within 4 hours of receiving SC methylnaltrexone,17, 18 compared with 38.9% of acute OIC patients in this study. In a clinical trial of patients with chronic, nonmalignant pain, 34.2% of patients experienced laxation within 4 hours of SC methylnaltrexone injection (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA). The differences in laxation response between these trials may be attributable to differences in the patient populations or to methodologic differences between the studies.

Similar to findings demonstrated in a clinical study evaluating methylnaltrexone for OIC in a different patient population, those with advanced illness,22 this study supports the premise that future laxation response with prolonged use is most likely to occur when a laxation response was achieved after the first or second initial administrations of methylnaltrexone. In contradistinction, if laxation does not occur with these early doses, continued methylnaltrexone dosing is less likely to produce a response later.

This study has some limitations that must be considered. First, as this was a hypothesis‐generating study, all efficacy parameters investigated were exploratory in nature. The results reported herein warrant careful consideration, owing to a small sample size that may limit their generalizability, prior to replication in a more rigorously designed study with prespecified efficacy endpoints. Likewise, the assessment of health outcome parameters is limited. Another limitation is the small sample size utilized in this study, potentially resulting in a type II error.

Subcutaneous administration potentially offers a considerable benefit over oral therapies for OIC in this patient population post‐orthopedic surgery. Nausea and vomiting can occur as a consequence of anesthesia and of postoperative opioid analgesia, and may compromise adequate dosing of oral medications prescribed to treat OIC. Subcutaneous delivery of methylnaltrexone may circumvent this potential drawback while providing potentially rapid, effective treatment for OIC. Once‐daily dosing may also help to minimize caregiver burden and patient discomfort by preventing the need for more frequent or unpleasant treatments for OIC, such as enemas.

This study provides an initial positive signal for a broader, albeit off‐label use for methylnaltrexonethat being for the treatment of acute constipation that occurs as a consequence of postoperative opioid‐mediated analgesia in patients following orthopedic procedures. Adequate treatment of OIC, even in the acute postoperative setting, is likely to lead to better overall pain management and improved patient outcomes. Additionally, effective management of acute OIC is likely to be cost‐effective in terms of reducing the duration of hospital stays, reducing the need for nursing resources and the time spent administering rescue treatments for OIC (eg, enemas), and avoiding returns to an acute setting (eg, the emergency department) for treatment. The results presented herein suggest that methylnaltrexone may be effective and have a good safety profile in the treatment of acute OIC following orthopedic surgery. Validation of these results in larger well‐controlled trials would be welcome.

The management of postoperative pain is essential to perioperative care, and adequate postoperative analgesia has been associated with several key clinical benefits, including fewer postoperative complications, earlier patient ambulation, reduced costs due to shorter hospital stays, and improved rehabilitation.1, 2 While opioids have long been central to postoperative analgesia, they have been associated with various adverse effects, including sedation, dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression.2, 3 Constipation, one of the most common adverse effects resulting from opioid therapy, can be debilitating. Indeed, opioid effects on gut motility can occur even after a single dose.3 The consequences of opioid‐induced constipation (OIC) may be severe enough to warrant a dosage reduction of the opioid; however, this may lead to compromised analgesia, which can hinder recovery.4, 5 Thus, effective treatment of OIC is an important clinical consideration in patients undergoing pain management with opioids. Unfortunately, laxatives and other treatment strategies can have unpredictable or suboptimal results for many patients with OIC; therefore, other options are needed for the treatment of OIC.6, 7

Opioid receptor agonists cause constipation by adversely altering many aspects of intestinal function, including fluid dynamics, gastric emptying, propulsive motor activity, and transit time.3 Opioid receptors are widely distributed in the central nervous system and throughout the intestinal system. The mechanism of OIC may have both peripherally and centrally mediated components.8 Nonselective opioid receptor antagonists block the undesired effects on the gut, but because they cross the blood‐brain barrier, they also interfere with analgesia and may lead to symptoms of withdrawal. Methylnaltrexone is a selective, peripherally acting mu‐opioid receptor antagonist,9 formed by the addition of a methyl group to the amine ring of the mu‐opioid receptor antagonist naltrexone. The resulting quarternary amine has greater polarity, lower lipid solubility, and restricted ability to cross the blood‐brain barrier.10 Thus, methylnaltrexone was designed to decrease the peripheral adverse effects of opioids without interfering with centrally mediated analgesia.

Investigations of methylnaltrexone effects in healthy volunteers showed that methylnaltrexone attenuated morphine‐induced delays in gastric emptying and oral‐cecal transit without affecting analgesia.1113 Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response.1416 Two randomized, double‐blind, placebo‐controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia.17, 18 Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.19

Recently, the use of methylnaltrexone for the treatment of OIC in patients with chronic, nonmalignant pain was assessed in a randomized, double‐blind, placebo‐controlled trial of more than 400 patients. Investigators found that methylnaltrexone induced laxation and was generally well tolerated (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD), supporting the safety and efficacy of methylnaltrexone in the setting of OIC resulting from chronic opioid treatment. The present study aimed to assess the activity of methylnaltrexone in patients receiving mu‐agonist opioid analgesics during rehabilitation, following an orthopedic surgical procedure, who were experiencing acute OIC.

METHODS

Study Design

This randomized, double‐blind, placebo‐controlled, parallel‐group, hypothesis‐generating phase 2 study was conducted from October 2007 to January 2009 at 16 US hospitals and rehabilitation facilities in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki, and was approved by the Institutional Review Board and/or Independent Ethics Committee at each of the participating investigational centers. All patients provided written informed consent prior to study participation.

Eligible patients were randomized by interactive voice response system in a 1:1 ratio to receive once‐daily subcutaneous (SC) injections of either 12 mg methylnaltrexone or placebo (Figure 1). The chosen 12‐mg unit dosing corresponds to approximately 0.15 mg/kg (assuming an 80‐kg patient) and was found to be both efficacious and well tolerated in the treatment of OIC in prior studies, including studies in advanced‐illness patients17, 18 and in patients with chronic, nonmalignant pain (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD.20 The first dose of study medication was administered on the day of randomization or on the next calendar day. Once enrolled, the patient received once‐daily doses of methylnaltrexone for up to 4 or 7 days. Dosing continued until the patient received the maximum number of doses allowed, no longer needed opioid medication, or was discharged from the medical facility. Each patient completed a follow‐up safety visit at 14 3 days following the last dose.

Figure 1

RESULTS

Patient Populations

The flow of patients through the study is summarized in Figure 2. A total of 51 patients were enrolled. Of these, 33 received at least 1 dose of study treatment following double‐blind randomization and comprised both the mITT and safety populations. Seventeen of these patients were enrolled under the original protocol and could receive study drug for up to 7 days, while 16 patients enrolled under a subsequent protocol revision could receive study drug for up to 4 days. This change from a 7‐day to a 4‐day treatment protocol allowed for the capture of more study patients in view of the time pressures of short lengths of stay in postoperative settings. In total, 31 patients received at least 2 doses, and 26 patients received at least 4 doses of study drug. A total of 27 patients completed the study. Baseline demographics and prestudy surgical procedures were similar in both treatment groups (Table 1).

Figure 2

Table 1.Baseline Patient Demographics

Characteristic	Methylnaltrexone (n = 18)	Placebo (n = 15)
NOTE: Modified intent‐to‐treat population. Abbreviations: BMI, body mass index.; SD, standard deviation. * Baseline opioid use was defined as total opioid use within 24 hours prior to randomization.
Mean age, yr (SD)	64.2 (9.0)	65.2 (11.6)
Mean weight, kg (SD)	92.5 (22.5)	91.0 (20.2)
Mean BMI, kg/m2 (SD)	32.3 (7.2)	34.2 (6.41)
Sex, n (%)
Female	11 (61.1)	11 (73.3)
Male	7 (38.9)	4 (26.7)
Race, n (%)
White	14 (77.8)	10 (66.7)
Black	4 (22.2)	5 (33.3)
Type of surgery, n (%)
Total knee replacement	8 (44.4)	7 (46.7)
Total hip replacement	6 (33.3)	6 (40.0)
Spinal fusion	2 (11.1)	0
Fracture reduction	2 (11.1)	2 (13.3)
Median opioid use,* mg (range)	28.00 (6.75‐168.01)	25.00 (9.00‐75.00)
Median time from surgery to study drug administration, days (range)	4 (3‐6)	4 (3‐6)

Efficacy

A significantly greater percentage of patients had a bowel movement within 2 hours (P = 0.021) and 4 hours (P = 0.046) of the first dose of methylnaltrexone compared with patients who received placebo (Figure 3). Within 2 hours, 6 patients (33.3%; 95% confidence interval [CI], 13.34‐59.01) who received methylnaltrexone achieved laxation, while laxation did not occur in any patient who received placebo. By 4 hours posttreatment, 7 patients (38.9%; 95% CI, 17.30‐64.25) in the methylnaltrexone group achieved laxation compared with only 1 patient (6.7%; 95% CI, 0.17‐31.95) on placebo. Three patients in each treatment group received rescue laxatives.

Figure 3

The time to first laxation (Figure 4) was significantly shorter in patients who received methylnaltrexone compared with those in the placebo group. Patients on methylnaltrexone achieved laxation in a median time of 15.8 hours, compared with a median time of 50.9 hours for patients in the placebo group (P = 0.02, log‐rank test). The median time to laxation was less than 1 hour in the 7 methylnaltrexone‐treated patients who experienced laxation within 4 hours following the first dose. Of the remaining 11 methylnaltrexone‐treated patients, one experienced no laxation after 6 doses, and the median time to laxation for the others was 29.9 hours (not shown in figure).

Figure 4

Analysis of the Global Satisfaction With Treatment Scale revealed that more patients expressed overall treatment satisfaction (defined as very satisfied, satisfied, or minimally satisfied) with methylnaltrexone assessed 4 hours ( 30 minutes) after the first dose, compared with patients on placebo (83.3% vs 60.0%, respectively). At the study endpoint, overall treatment satisfaction with methylnaltrexone remained high (83.3%), whereas satisfaction with placebo was 53.3%. Additionally, no patients in the methylnaltrexone group expressed any dissatisfaction with treatment (defined as minimally dissatisfied, dissatisfied, or very dissatisfied) at endpoint, compared with 26.7% of patients in the placebo group who expressed some degree of dissatisfaction.

DISCUSSION

This pilot study suggests that methylnaltrexone actively induces laxation and is generally well tolerated in patients receiving mu‐opioid analgesia, following orthopedic surgery, who develop OIC acutely. It was the first study, to our knowledge, to investigate the efficacy of methylnaltrexone for the treatment of OIC in an acute postoperative setting. The protocol amendment changing the duration of treatment from 7 days to 4 days did not materially affect the results of the study. The response to methylnaltrexone was rapid, with 33.3% experiencing laxation within 2 hours. The median time to laxation was nearly 1.5 days shorter in patients treated with methylnaltrexone compared with those receiving placebo. Correspondingly, overall patient satisfaction was high in the methylnaltrexone group. Efficacy was attained without diminishing opioid analgesia, and without inducing signs or symptoms of opioid withdrawal. The incidence of AEs was similar between groups, and no treatment‐emergent SAEs were reported in this study.

Previous clinical trials investigated the safety and efficacy of methylnaltrexone for the treatment of OIC in patients with advanced illness and with chronic, nonmalignant pain. The present study extends those findings to a population of patients experiencing acute OIC following orthopedic surgery. Previous studies showed that approximately 48% to 62% of advanced‐illness patients experienced laxation within 4 hours of receiving SC methylnaltrexone,17, 18 compared with 38.9% of acute OIC patients in this study. In a clinical trial of patients with chronic, nonmalignant pain, 34.2% of patients experienced laxation within 4 hours of SC methylnaltrexone injection (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA). The differences in laxation response between these trials may be attributable to differences in the patient populations or to methodologic differences between the studies.

Similar to findings demonstrated in a clinical study evaluating methylnaltrexone for OIC in a different patient population, those with advanced illness,22 this study supports the premise that future laxation response with prolonged use is most likely to occur when a laxation response was achieved after the first or second initial administrations of methylnaltrexone. In contradistinction, if laxation does not occur with these early doses, continued methylnaltrexone dosing is less likely to produce a response later.

This study has some limitations that must be considered. First, as this was a hypothesis‐generating study, all efficacy parameters investigated were exploratory in nature. The results reported herein warrant careful consideration, owing to a small sample size that may limit their generalizability, prior to replication in a more rigorously designed study with prespecified efficacy endpoints. Likewise, the assessment of health outcome parameters is limited. Another limitation is the small sample size utilized in this study, potentially resulting in a type II error.

Subcutaneous administration potentially offers a considerable benefit over oral therapies for OIC in this patient population post‐orthopedic surgery. Nausea and vomiting can occur as a consequence of anesthesia and of postoperative opioid analgesia, and may compromise adequate dosing of oral medications prescribed to treat OIC. Subcutaneous delivery of methylnaltrexone may circumvent this potential drawback while providing potentially rapid, effective treatment for OIC. Once‐daily dosing may also help to minimize caregiver burden and patient discomfort by preventing the need for more frequent or unpleasant treatments for OIC, such as enemas.

This study provides an initial positive signal for a broader, albeit off‐label use for methylnaltrexonethat being for the treatment of acute constipation that occurs as a consequence of postoperative opioid‐mediated analgesia in patients following orthopedic procedures. Adequate treatment of OIC, even in the acute postoperative setting, is likely to lead to better overall pain management and improved patient outcomes. Additionally, effective management of acute OIC is likely to be cost‐effective in terms of reducing the duration of hospital stays, reducing the need for nursing resources and the time spent administering rescue treatments for OIC (eg, enemas), and avoiding returns to an acute setting (eg, the emergency department) for treatment. The results presented herein suggest that methylnaltrexone may be effective and have a good safety profile in the treatment of acute OIC following orthopedic surgery. Validation of these results in larger well‐controlled trials would be welcome.

The management of postoperative pain is essential to perioperative care, and adequate postoperative analgesia has been associated with several key clinical benefits, including fewer postoperative complications, earlier patient ambulation, reduced costs due to shorter hospital stays, and improved rehabilitation.1, 2 While opioids have long been central to postoperative analgesia, they have been associated with various adverse effects, including sedation, dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression.2, 3 Constipation, one of the most common adverse effects resulting from opioid therapy, can be debilitating. Indeed, opioid effects on gut motility can occur even after a single dose.3 The consequences of opioid‐induced constipation (OIC) may be severe enough to warrant a dosage reduction of the opioid; however, this may lead to compromised analgesia, which can hinder recovery.4, 5 Thus, effective treatment of OIC is an important clinical consideration in patients undergoing pain management with opioids. Unfortunately, laxatives and other treatment strategies can have unpredictable or suboptimal results for many patients with OIC; therefore, other options are needed for the treatment of OIC.6, 7

Opioid receptor agonists cause constipation by adversely altering many aspects of intestinal function, including fluid dynamics, gastric emptying, propulsive motor activity, and transit time.3 Opioid receptors are widely distributed in the central nervous system and throughout the intestinal system. The mechanism of OIC may have both peripherally and centrally mediated components.8 Nonselective opioid receptor antagonists block the undesired effects on the gut, but because they cross the blood‐brain barrier, they also interfere with analgesia and may lead to symptoms of withdrawal. Methylnaltrexone is a selective, peripherally acting mu‐opioid receptor antagonist,9 formed by the addition of a methyl group to the amine ring of the mu‐opioid receptor antagonist naltrexone. The resulting quarternary amine has greater polarity, lower lipid solubility, and restricted ability to cross the blood‐brain barrier.10 Thus, methylnaltrexone was designed to decrease the peripheral adverse effects of opioids without interfering with centrally mediated analgesia.

Investigations of methylnaltrexone effects in healthy volunteers showed that methylnaltrexone attenuated morphine‐induced delays in gastric emptying and oral‐cecal transit without affecting analgesia.1113 Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response.1416 Two randomized, double‐blind, placebo‐controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia.17, 18 Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.19

Recently, the use of methylnaltrexone for the treatment of OIC in patients with chronic, nonmalignant pain was assessed in a randomized, double‐blind, placebo‐controlled trial of more than 400 patients. Investigators found that methylnaltrexone induced laxation and was generally well tolerated (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD), supporting the safety and efficacy of methylnaltrexone in the setting of OIC resulting from chronic opioid treatment. The present study aimed to assess the activity of methylnaltrexone in patients receiving mu‐agonist opioid analgesics during rehabilitation, following an orthopedic surgical procedure, who were experiencing acute OIC.

METHODS

Study Design

This randomized, double‐blind, placebo‐controlled, parallel‐group, hypothesis‐generating phase 2 study was conducted from October 2007 to January 2009 at 16 US hospitals and rehabilitation facilities in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Declaration of Helsinki, and was approved by the Institutional Review Board and/or Independent Ethics Committee at each of the participating investigational centers. All patients provided written informed consent prior to study participation.

Eligible patients were randomized by interactive voice response system in a 1:1 ratio to receive once‐daily subcutaneous (SC) injections of either 12 mg methylnaltrexone or placebo (Figure 1). The chosen 12‐mg unit dosing corresponds to approximately 0.15 mg/kg (assuming an 80‐kg patient) and was found to be both efficacious and well tolerated in the treatment of OIC in prior studies, including studies in advanced‐illness patients17, 18 and in patients with chronic, nonmalignant pain (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA; Duerden et al., 29th Annual Scientific Meeting of the American Pain Society, May 6‐10, 2010, Baltimore, MD.20 The first dose of study medication was administered on the day of randomization or on the next calendar day. Once enrolled, the patient received once‐daily doses of methylnaltrexone for up to 4 or 7 days. Dosing continued until the patient received the maximum number of doses allowed, no longer needed opioid medication, or was discharged from the medical facility. Each patient completed a follow‐up safety visit at 14 3 days following the last dose.

Figure 1

RESULTS

Patient Populations

The flow of patients through the study is summarized in Figure 2. A total of 51 patients were enrolled. Of these, 33 received at least 1 dose of study treatment following double‐blind randomization and comprised both the mITT and safety populations. Seventeen of these patients were enrolled under the original protocol and could receive study drug for up to 7 days, while 16 patients enrolled under a subsequent protocol revision could receive study drug for up to 4 days. This change from a 7‐day to a 4‐day treatment protocol allowed for the capture of more study patients in view of the time pressures of short lengths of stay in postoperative settings. In total, 31 patients received at least 2 doses, and 26 patients received at least 4 doses of study drug. A total of 27 patients completed the study. Baseline demographics and prestudy surgical procedures were similar in both treatment groups (Table 1).

Figure 2

Table 1.Baseline Patient Demographics

Characteristic	Methylnaltrexone (n = 18)	Placebo (n = 15)
NOTE: Modified intent‐to‐treat population. Abbreviations: BMI, body mass index.; SD, standard deviation. * Baseline opioid use was defined as total opioid use within 24 hours prior to randomization.
Mean age, yr (SD)	64.2 (9.0)	65.2 (11.6)
Mean weight, kg (SD)	92.5 (22.5)	91.0 (20.2)
Mean BMI, kg/m2 (SD)	32.3 (7.2)	34.2 (6.41)
Sex, n (%)
Female	11 (61.1)	11 (73.3)
Male	7 (38.9)	4 (26.7)
Race, n (%)
White	14 (77.8)	10 (66.7)
Black	4 (22.2)	5 (33.3)
Type of surgery, n (%)
Total knee replacement	8 (44.4)	7 (46.7)
Total hip replacement	6 (33.3)	6 (40.0)
Spinal fusion	2 (11.1)	0
Fracture reduction	2 (11.1)	2 (13.3)
Median opioid use,* mg (range)	28.00 (6.75‐168.01)	25.00 (9.00‐75.00)
Median time from surgery to study drug administration, days (range)	4 (3‐6)	4 (3‐6)

Efficacy

A significantly greater percentage of patients had a bowel movement within 2 hours (P = 0.021) and 4 hours (P = 0.046) of the first dose of methylnaltrexone compared with patients who received placebo (Figure 3). Within 2 hours, 6 patients (33.3%; 95% confidence interval [CI], 13.34‐59.01) who received methylnaltrexone achieved laxation, while laxation did not occur in any patient who received placebo. By 4 hours posttreatment, 7 patients (38.9%; 95% CI, 17.30‐64.25) in the methylnaltrexone group achieved laxation compared with only 1 patient (6.7%; 95% CI, 0.17‐31.95) on placebo. Three patients in each treatment group received rescue laxatives.

Figure 3

The time to first laxation (Figure 4) was significantly shorter in patients who received methylnaltrexone compared with those in the placebo group. Patients on methylnaltrexone achieved laxation in a median time of 15.8 hours, compared with a median time of 50.9 hours for patients in the placebo group (P = 0.02, log‐rank test). The median time to laxation was less than 1 hour in the 7 methylnaltrexone‐treated patients who experienced laxation within 4 hours following the first dose. Of the remaining 11 methylnaltrexone‐treated patients, one experienced no laxation after 6 doses, and the median time to laxation for the others was 29.9 hours (not shown in figure).

Figure 4

Analysis of the Global Satisfaction With Treatment Scale revealed that more patients expressed overall treatment satisfaction (defined as very satisfied, satisfied, or minimally satisfied) with methylnaltrexone assessed 4 hours ( 30 minutes) after the first dose, compared with patients on placebo (83.3% vs 60.0%, respectively). At the study endpoint, overall treatment satisfaction with methylnaltrexone remained high (83.3%), whereas satisfaction with placebo was 53.3%. Additionally, no patients in the methylnaltrexone group expressed any dissatisfaction with treatment (defined as minimally dissatisfied, dissatisfied, or very dissatisfied) at endpoint, compared with 26.7% of patients in the placebo group who expressed some degree of dissatisfaction.

DISCUSSION

This pilot study suggests that methylnaltrexone actively induces laxation and is generally well tolerated in patients receiving mu‐opioid analgesia, following orthopedic surgery, who develop OIC acutely. It was the first study, to our knowledge, to investigate the efficacy of methylnaltrexone for the treatment of OIC in an acute postoperative setting. The protocol amendment changing the duration of treatment from 7 days to 4 days did not materially affect the results of the study. The response to methylnaltrexone was rapid, with 33.3% experiencing laxation within 2 hours. The median time to laxation was nearly 1.5 days shorter in patients treated with methylnaltrexone compared with those receiving placebo. Correspondingly, overall patient satisfaction was high in the methylnaltrexone group. Efficacy was attained without diminishing opioid analgesia, and without inducing signs or symptoms of opioid withdrawal. The incidence of AEs was similar between groups, and no treatment‐emergent SAEs were reported in this study.

Previous clinical trials investigated the safety and efficacy of methylnaltrexone for the treatment of OIC in patients with advanced illness and with chronic, nonmalignant pain. The present study extends those findings to a population of patients experiencing acute OIC following orthopedic surgery. Previous studies showed that approximately 48% to 62% of advanced‐illness patients experienced laxation within 4 hours of receiving SC methylnaltrexone,17, 18 compared with 38.9% of acute OIC patients in this study. In a clinical trial of patients with chronic, nonmalignant pain, 34.2% of patients experienced laxation within 4 hours of SC methylnaltrexone injection (Blonsky et al., 28th Annual Scientific Meeting of the American Pain Society, May 7‐9, 2009, San Diego, CA). The differences in laxation response between these trials may be attributable to differences in the patient populations or to methodologic differences between the studies.

Similar to findings demonstrated in a clinical study evaluating methylnaltrexone for OIC in a different patient population, those with advanced illness,22 this study supports the premise that future laxation response with prolonged use is most likely to occur when a laxation response was achieved after the first or second initial administrations of methylnaltrexone. In contradistinction, if laxation does not occur with these early doses, continued methylnaltrexone dosing is less likely to produce a response later.

This study has some limitations that must be considered. First, as this was a hypothesis‐generating study, all efficacy parameters investigated were exploratory in nature. The results reported herein warrant careful consideration, owing to a small sample size that may limit their generalizability, prior to replication in a more rigorously designed study with prespecified efficacy endpoints. Likewise, the assessment of health outcome parameters is limited. Another limitation is the small sample size utilized in this study, potentially resulting in a type II error.

Subcutaneous administration potentially offers a considerable benefit over oral therapies for OIC in this patient population post‐orthopedic surgery. Nausea and vomiting can occur as a consequence of anesthesia and of postoperative opioid analgesia, and may compromise adequate dosing of oral medications prescribed to treat OIC. Subcutaneous delivery of methylnaltrexone may circumvent this potential drawback while providing potentially rapid, effective treatment for OIC. Once‐daily dosing may also help to minimize caregiver burden and patient discomfort by preventing the need for more frequent or unpleasant treatments for OIC, such as enemas.

This study provides an initial positive signal for a broader, albeit off‐label use for methylnaltrexonethat being for the treatment of acute constipation that occurs as a consequence of postoperative opioid‐mediated analgesia in patients following orthopedic procedures. Adequate treatment of OIC, even in the acute postoperative setting, is likely to lead to better overall pain management and improved patient outcomes. Additionally, effective management of acute OIC is likely to be cost‐effective in terms of reducing the duration of hospital stays, reducing the need for nursing resources and the time spent administering rescue treatments for OIC (eg, enemas), and avoiding returns to an acute setting (eg, the emergency department) for treatment. The results presented herein suggest that methylnaltrexone may be effective and have a good safety profile in the treatment of acute OIC following orthopedic surgery. Validation of these results in larger well‐controlled trials would be welcome.

Obesity affects all segments of the American population. However, it imposes a larger burden and poses a greater threat to minority populations.1 The increase in overall prevalence of obesity and obesity‐related diseases are especially pronounced in ethnic minorities,2 and the outlook for minorities who develop obesity‐associated diseases such as stroke and chronic renal disease is worse than in their Caucasian counterparts.3

Despite the higher prevalence of obesity in ethnic minorities, the majority of research on the relationship between body mass index (BMI) and mortality has been conducted among Caucasians in the United States. This is due largely to the small number of minority participants in most studies, which makes for low statistical power.4

A curious epidemiologic paradox has been the observation, in many studies, that black adults have lower morbidity and mortality associated with obesity compared to Caucasians.5 In fact, some authors suggest that high BMI among black and other minorities may not be as strong a risk factor for mortality as it is in others.6, 7

Very few studies have specifically examined the contribution of BMI to postoperative outcome in a large cohort of minority patients.8, 9 Similarly, the authors are unaware of any previous studies describing the clinical relevance of being overweight and obese in minority patients undergoing surgery. Therefore, the primary objective of this observational study was to describe the prevalence of overweight and obesity in a large cohort of minority surgical patients, and the impact of BMI class on their postoperative outcome. Our a priori hypothesis was that obese minority surgical patients would have a poorer postoperative outcome and have higher 30‐day all‐cause mortality than normal weight individuals.

METHODS

Study data were derived from the Participant Use Data File of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) for the calendar years 2005 to 2008. This multi‐institutional (186 participating centers) reporting system was designed to provide risk‐adjusted surgical outcome data from throughout the United States.

The methodology for collecting these data, including their accuracy and reproducibility, has been detailed in previous publications.10, 11 It is briefly reviewed here. Dedicated nurse clinical reviewers at each hospital prospectively enrolled patients and collected data in a standardized fashion according to strict ACS‐NSQIP definitions. A systematic sample was obtained by taking the first 40 cases per nurse reviewer on an 8‐day cycle from the operating room log, ensuring that no particular operating room day block time would bias the weighting of cases. Nurse reviewers had completed comprehensive training regarding definitions and data extraction, as well as continuing education and monitoring through the ACS‐NSQIP program. They are assessed for inter‐rater reliability during biennial site visits. Information was obtained from patient medical records, physician office records, and telephone interviews. Patients were followed through their hospital course and after discharge from hospital up to 30 days postoperatively. A high level of accuracy and reproducibility of the data have been previously demonstrated.12

Race was defined as African American, Hispanic, Asian or Pacific Islander, or American Indian/Alaskan native, as identified by the clinical care provider, or within the medical record. Patients were excluded if race was coded as white, or not recorded. We also excluded patients with missing record of height and/or weight. The final study cohort consisted of 119,619 minority patients. We then computed BMI as weight in kilograms divided by the square of the height in meters (BMI = kg/m²). Patients were classified as underweight (BMI 18.5 kg/m²), normal weight (BMI = 18.6‐24.9 kg/m²), overweight (BMI = 25‐29.9 kg/m²), obese (BMI = 30‐39.9 kg/m²), and morbidly obese (BMI 40 kg/m²) in accordance with National Institute of Health (NIH) standards.13

RESULTS

The study cohort included 119,619 surgical patients (Table 1). Their mean (standard deviation [SD]) age was 50.4 (16.9), and the mean (SD) BMI of 30.3 (8.9) kg/m² was in the obese range. The overall prevalence of high BMI (overweight or obese) was 70.8%. A very small proportion, 2.7%, of patients was classified as underweight. Sex‐stratified demographic and behavioral characteristics differed significantly across all the variables in our study cohort. Men were more likely to be overweight, whereas women were more likely to be obese or severely obese. A majority (77.4%) of the patients were non‐elderly adults (<65years) undergoing elective (85.9%) surgical procedures. The minority patients in this study were African American (50%), Hispanic (36%), Asian and Pacific Islander (10%), and American Indian and Alaskan native (4%).

The distribution of baseline preoperative clinical characteristics by BMI class revealed many significant differences (Table 2). Age was significantly different among the BMI classes, with the severely obese group being about 8 years younger than the underweight or normal weight group. Similarly, severely obese patients were more likely to be women, less likely to smoke, more likely to be hypertensive, diabetic, have a history of dyspnea at rest, and more likely to belong to high ASA class. On the other hand, underweight patients were more likely to have disseminated cancer, be current smokers, consume more than 2 alcoholic drinks per day, have active chronic obstructive pulmonary disease (COPD), and have ascites. They were also more likely to be on dialysis and have cardiac disease, as well as a history of stroke. Urgency of surgery also varied significantly across the BMI categories, with the underweight group having the highest incidence of emergency surgery (20.6%) and the severely obese group being the least likely to present for emergency surgery (8.2%).

Perioperative outcomes according to BMI classes documented significant differences (Table 3). Work relative value unit (Work RVU, a measure of surgical complexity), as well as total anesthesia and operation time decreased in a stepwise fashion across the BMI classes to the obese group, followed by increase in these parameters in the severely obese group. Following a decrease to the normal BMI category, there was a positive association between BMI and the incidence of postoperative superficial and deep wound infection, as well as wound disruption.

There was a negative association between BMI class and the likelihood of postoperative sepsis, septic shock, reintubation, delayed ventilator wean, and postoperative pneumonia. Similarly, the proportions of patients who developed postoperative acute renal failure, cardiac arrest, and those who required postoperative blood transfusion or needed reoperation, decreased significantly across the BMI classes, with the highest proportion of cases being in the underweight group and the lowest in the severely obese group. Overall composite morbidity was twice as high in the underweight compared to the severely obese group.

There were 1758 deaths among the study's 119,619 patients, resulting in an overall mortality rate of 1.5%. The overall major complication rate was 13.8%. The distribution of total mortality rate as well as mortality in patients with at least 1 major postoperative complication across BMI classes revealed consistent differences (Figure 1). Over the entire range of BMI classes, there was a progressive, stepwise decrease in the proportion of deaths with increasing BMI. This pattern also occurred among patients who developed at least 1 major postoperative complication, indicating a reduced likelihood of death after a major complication. This is reflective of a reduced likelihood of death after a major complication (failure to rescue) with increasing BMI.

Figure 1

Multivariate logistic regression defined a number of factors associated with 30‐day mortality (Table 4). The Hosmer and Lemeshow goodness‐of‐fit test for this model was not statistically significant (² = 17.8, df = 8, P = 0.23). High ASA physical status was associated with high odds of mortality. Specifically, when controlling for the other covariates in the model, ASA status was associated with a 5‐fold increased relative odds of death (adjusted odds ratio [OR] = 5.30; 95% confidence interval = 4.96‐5.79, P < 0.001). Similarly, occurrence of 1 or more major postoperative complication was associated with 6‐fold increased relative odds of mortality. The paradoxical effect of BMI category observed on univariate analysis was maintained in the multivariate model. Specifically, underweight patients had the highest relative odds of mortality, while severely obese patients had the lowest, compared with patients at a healthy weight (Table 4). Interestingly, smoking had no significant effect on the odds of mortality after controlling for other factors. Similarly, the specific racial group and the timing of the surgical intervention had no significant effect on mortality.

DISCUSSION

In this large, study of minority surgical patients, the impact of BMI on the 30‐day morbidity and mortality was unexpected. The working hypothesis was that overweight and obese patients would have a worse outcome after surgery. However, contrary to this hypothesis, the lowest all‐cause mortality rate was found in the severely obese (BMI 40 kg/m²) group in both men and women. Death rates decreased progressively in a stepwise fashion from the underweight to the severely obese group. Similarly, even in patients who developed at least 1 major postoperative complication, the likelihood of death was still negatively associated with BMI. This negative association of mortality with BMI was observed despite the higher prevalence of chronic diseases, such as hypertension, diabetes, and dyspnea at rest, in the increasing BMI classes.

Controversy remains regarding the association between BMI and mortality, in particular about the shape of the curve for the association between BMI and mortality. Epidemiologic studies have variously described J‐shaped, U‐shaped, monotonic, or linear relationships.16, 17 In the surgical population, a reverse J‐shaped relationship between BMI category and mortality has been described.18, 19 Sometimes this is referred to as obesity paradox or reverse epidemiology: a trend whereby overweight and moderately obese patients have better outcomes and lower risk of death than leaner patients.18 This phenomenon is particularly well described in adult20 and elderly heart failure and hypertensive patients.21 Many of these studies either had very few minority patients,21 or mortality pattern was not analyzed along ethnic lines.

Few studies10 have focused exclusively on minority surgical patients. Some investigators have determined that high BMI in black adults may not be as important a risk factor for mortality6, 7 as in whites. Our data suggest that among minority surgical patients, the relationship appeared to be a downward trend in mortality from low to high BMI, thus revealing the obesity paradox. This pattern was evident even in patients who developed 1 major complication in the postoperative period, suggesting that high BMI also protects against failure to rescueor death after a major complication.

Despite decades of research, the mechanisms underlying the obesity paradox remain speculative.20, 22. Many have posited that adiposity may confer protection against cytokines and various inflammatory mediators in heart failure patients by the production of buffering lipoproteins.23, 24 It is conceivable that similar protection against inflammatory response to surgical tissue trauma is operational in minority patients with high BMI. Another possible reason for the obesity paradox is the clinical presentation and disease progression at the time of surgery. Perhaps, similar to the observation in obese patients with heart failure,25 obese minority patients are symptomatic at an earlier stage of their disease than lean patients, making for earlier diagnosis and treatment. Thus, obesity may simply be a marker of less severe disease at the time of presentation.

Obese patients may also be more aggressively monitored and treated in the perioperative period than lean patients, because of the general perception that they are a high‐risk group.10 This may partly explain the decreased likelihood of failure to rescue with increasing BMI in our patients. Increased vigilance and prompt treatment of complications should reduce the overall morbidity and mortality rate in this group. It is also conceivable that a therapeutic selection bias is operational in the patients we studied. This describes scenarios where relatively healthy obese minority patients were operated upon, while sicker, morbidly obese patients were denied surgery due to perceived prohibitive risks. However, we would have expected a higher proportion of severely obese patients to present for emergency surgery, which is contrary to our finding of the lowest incidence of emergency surgery in the severely obese group. It is also possible that severe obesity may be associated with a higher attrition rate, such that the extremely obese patients did not live long enough to present for surgery. This is somewhat likely, given the significantly younger age of the severely obese patients in our study cohort. It is, however, impossible to determine survival effect from a cross‐sectional hospital‐based study design. Clearly, mechanisms used to explain the obesity paradox in minority surgical patients are likely to remain speculative, owing to the interaction of several factors such as concomitant comorbidities, disease progression at the time of presentation, patients' weight history, and regional fat distribution.

The current study confirms the findings of previous investigators26 about the importance of reducing major postoperative complications in surgical patients. While this may seem axiomatic, it deserves reiteration because the risk of postoperative mortality increases considerably in all the BMI categories following 1 or more major postoperative complication. However, it is not clear why obese and morbidly obese patients had a lower incidence of failure to rescue. This may be related to greater physiologic reserve in the obese and morbidly obese group, especially because patients in the higher BMI groups were significantly younger than the normal weight or lean patients. For the same reason, these younger, severely obese patients may have been more aggressively monitored and treated, thereby increasing the likelihood of being rescued following a major complication. It is also possible that the lower proportion of emergency procedures performed in obese and severely obese groups was somewhat protective, especially because emergency surgery was an independent predictor of overall mortality in this cohort of patients. In fact, when we stratified the patients according to urgency of surgery and explored the bivariate relationship between BMI category and mortality (data not shown) among those undergoing urgent surgery, the geometrical distribution of mortality did show a reverse‐J pattern with the highest proportion of cases in the underweight group, declining in the normal BMI and overweight group, and increasing steadily in obese and severely obese group. To this end, caution should be exercised when interpreting the association of BMI group with postoperative mortality for procedures performed as an emergency.

Smoking and antecedent illness are 2 confounding factors commonly criticized in studies attempting to associated BMI with mortality. This is because smokers tend to weigh less and have higher mortality rates than nonsmokers. The present investigation did not find a significant contribution of smoking to mortality when other factors included in a logistic regression model were considered. The current study's findings are consistent with those of previous data in African American patients,27 and contrasts with the excess mortality described in currently smoking Caucasian men and women.28 It is possible that smoking is not an important effect modifier when considering the relevance of BMI to postoperative mortality in minority patients.

Obesity affects all segments of the American population. However, it imposes a larger burden and poses a greater threat to minority populations.1 The increase in overall prevalence of obesity and obesity‐related diseases are especially pronounced in ethnic minorities,2 and the outlook for minorities who develop obesity‐associated diseases such as stroke and chronic renal disease is worse than in their Caucasian counterparts.3

Despite the higher prevalence of obesity in ethnic minorities, the majority of research on the relationship between body mass index (BMI) and mortality has been conducted among Caucasians in the United States. This is due largely to the small number of minority participants in most studies, which makes for low statistical power.4

A curious epidemiologic paradox has been the observation, in many studies, that black adults have lower morbidity and mortality associated with obesity compared to Caucasians.5 In fact, some authors suggest that high BMI among black and other minorities may not be as strong a risk factor for mortality as it is in others.6, 7

Very few studies have specifically examined the contribution of BMI to postoperative outcome in a large cohort of minority patients.8, 9 Similarly, the authors are unaware of any previous studies describing the clinical relevance of being overweight and obese in minority patients undergoing surgery. Therefore, the primary objective of this observational study was to describe the prevalence of overweight and obesity in a large cohort of minority surgical patients, and the impact of BMI class on their postoperative outcome. Our a priori hypothesis was that obese minority surgical patients would have a poorer postoperative outcome and have higher 30‐day all‐cause mortality than normal weight individuals.

METHODS

Study data were derived from the Participant Use Data File of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) for the calendar years 2005 to 2008. This multi‐institutional (186 participating centers) reporting system was designed to provide risk‐adjusted surgical outcome data from throughout the United States.

The methodology for collecting these data, including their accuracy and reproducibility, has been detailed in previous publications.10, 11 It is briefly reviewed here. Dedicated nurse clinical reviewers at each hospital prospectively enrolled patients and collected data in a standardized fashion according to strict ACS‐NSQIP definitions. A systematic sample was obtained by taking the first 40 cases per nurse reviewer on an 8‐day cycle from the operating room log, ensuring that no particular operating room day block time would bias the weighting of cases. Nurse reviewers had completed comprehensive training regarding definitions and data extraction, as well as continuing education and monitoring through the ACS‐NSQIP program. They are assessed for inter‐rater reliability during biennial site visits. Information was obtained from patient medical records, physician office records, and telephone interviews. Patients were followed through their hospital course and after discharge from hospital up to 30 days postoperatively. A high level of accuracy and reproducibility of the data have been previously demonstrated.12

Race was defined as African American, Hispanic, Asian or Pacific Islander, or American Indian/Alaskan native, as identified by the clinical care provider, or within the medical record. Patients were excluded if race was coded as white, or not recorded. We also excluded patients with missing record of height and/or weight. The final study cohort consisted of 119,619 minority patients. We then computed BMI as weight in kilograms divided by the square of the height in meters (BMI = kg/m²). Patients were classified as underweight (BMI 18.5 kg/m²), normal weight (BMI = 18.6‐24.9 kg/m²), overweight (BMI = 25‐29.9 kg/m²), obese (BMI = 30‐39.9 kg/m²), and morbidly obese (BMI 40 kg/m²) in accordance with National Institute of Health (NIH) standards.13

RESULTS

The study cohort included 119,619 surgical patients (Table 1). Their mean (standard deviation [SD]) age was 50.4 (16.9), and the mean (SD) BMI of 30.3 (8.9) kg/m² was in the obese range. The overall prevalence of high BMI (overweight or obese) was 70.8%. A very small proportion, 2.7%, of patients was classified as underweight. Sex‐stratified demographic and behavioral characteristics differed significantly across all the variables in our study cohort. Men were more likely to be overweight, whereas women were more likely to be obese or severely obese. A majority (77.4%) of the patients were non‐elderly adults (<65years) undergoing elective (85.9%) surgical procedures. The minority patients in this study were African American (50%), Hispanic (36%), Asian and Pacific Islander (10%), and American Indian and Alaskan native (4%).

The distribution of baseline preoperative clinical characteristics by BMI class revealed many significant differences (Table 2). Age was significantly different among the BMI classes, with the severely obese group being about 8 years younger than the underweight or normal weight group. Similarly, severely obese patients were more likely to be women, less likely to smoke, more likely to be hypertensive, diabetic, have a history of dyspnea at rest, and more likely to belong to high ASA class. On the other hand, underweight patients were more likely to have disseminated cancer, be current smokers, consume more than 2 alcoholic drinks per day, have active chronic obstructive pulmonary disease (COPD), and have ascites. They were also more likely to be on dialysis and have cardiac disease, as well as a history of stroke. Urgency of surgery also varied significantly across the BMI categories, with the underweight group having the highest incidence of emergency surgery (20.6%) and the severely obese group being the least likely to present for emergency surgery (8.2%).

Perioperative outcomes according to BMI classes documented significant differences (Table 3). Work relative value unit (Work RVU, a measure of surgical complexity), as well as total anesthesia and operation time decreased in a stepwise fashion across the BMI classes to the obese group, followed by increase in these parameters in the severely obese group. Following a decrease to the normal BMI category, there was a positive association between BMI and the incidence of postoperative superficial and deep wound infection, as well as wound disruption.

There was a negative association between BMI class and the likelihood of postoperative sepsis, septic shock, reintubation, delayed ventilator wean, and postoperative pneumonia. Similarly, the proportions of patients who developed postoperative acute renal failure, cardiac arrest, and those who required postoperative blood transfusion or needed reoperation, decreased significantly across the BMI classes, with the highest proportion of cases being in the underweight group and the lowest in the severely obese group. Overall composite morbidity was twice as high in the underweight compared to the severely obese group.

There were 1758 deaths among the study's 119,619 patients, resulting in an overall mortality rate of 1.5%. The overall major complication rate was 13.8%. The distribution of total mortality rate as well as mortality in patients with at least 1 major postoperative complication across BMI classes revealed consistent differences (Figure 1). Over the entire range of BMI classes, there was a progressive, stepwise decrease in the proportion of deaths with increasing BMI. This pattern also occurred among patients who developed at least 1 major postoperative complication, indicating a reduced likelihood of death after a major complication. This is reflective of a reduced likelihood of death after a major complication (failure to rescue) with increasing BMI.

Figure 1

Multivariate logistic regression defined a number of factors associated with 30‐day mortality (Table 4). The Hosmer and Lemeshow goodness‐of‐fit test for this model was not statistically significant (² = 17.8, df = 8, P = 0.23). High ASA physical status was associated with high odds of mortality. Specifically, when controlling for the other covariates in the model, ASA status was associated with a 5‐fold increased relative odds of death (adjusted odds ratio [OR] = 5.30; 95% confidence interval = 4.96‐5.79, P < 0.001). Similarly, occurrence of 1 or more major postoperative complication was associated with 6‐fold increased relative odds of mortality. The paradoxical effect of BMI category observed on univariate analysis was maintained in the multivariate model. Specifically, underweight patients had the highest relative odds of mortality, while severely obese patients had the lowest, compared with patients at a healthy weight (Table 4). Interestingly, smoking had no significant effect on the odds of mortality after controlling for other factors. Similarly, the specific racial group and the timing of the surgical intervention had no significant effect on mortality.

DISCUSSION

In this large, study of minority surgical patients, the impact of BMI on the 30‐day morbidity and mortality was unexpected. The working hypothesis was that overweight and obese patients would have a worse outcome after surgery. However, contrary to this hypothesis, the lowest all‐cause mortality rate was found in the severely obese (BMI 40 kg/m²) group in both men and women. Death rates decreased progressively in a stepwise fashion from the underweight to the severely obese group. Similarly, even in patients who developed at least 1 major postoperative complication, the likelihood of death was still negatively associated with BMI. This negative association of mortality with BMI was observed despite the higher prevalence of chronic diseases, such as hypertension, diabetes, and dyspnea at rest, in the increasing BMI classes.

Controversy remains regarding the association between BMI and mortality, in particular about the shape of the curve for the association between BMI and mortality. Epidemiologic studies have variously described J‐shaped, U‐shaped, monotonic, or linear relationships.16, 17 In the surgical population, a reverse J‐shaped relationship between BMI category and mortality has been described.18, 19 Sometimes this is referred to as obesity paradox or reverse epidemiology: a trend whereby overweight and moderately obese patients have better outcomes and lower risk of death than leaner patients.18 This phenomenon is particularly well described in adult20 and elderly heart failure and hypertensive patients.21 Many of these studies either had very few minority patients,21 or mortality pattern was not analyzed along ethnic lines.

Few studies10 have focused exclusively on minority surgical patients. Some investigators have determined that high BMI in black adults may not be as important a risk factor for mortality6, 7 as in whites. Our data suggest that among minority surgical patients, the relationship appeared to be a downward trend in mortality from low to high BMI, thus revealing the obesity paradox. This pattern was evident even in patients who developed 1 major complication in the postoperative period, suggesting that high BMI also protects against failure to rescueor death after a major complication.

Despite decades of research, the mechanisms underlying the obesity paradox remain speculative.20, 22. Many have posited that adiposity may confer protection against cytokines and various inflammatory mediators in heart failure patients by the production of buffering lipoproteins.23, 24 It is conceivable that similar protection against inflammatory response to surgical tissue trauma is operational in minority patients with high BMI. Another possible reason for the obesity paradox is the clinical presentation and disease progression at the time of surgery. Perhaps, similar to the observation in obese patients with heart failure,25 obese minority patients are symptomatic at an earlier stage of their disease than lean patients, making for earlier diagnosis and treatment. Thus, obesity may simply be a marker of less severe disease at the time of presentation.

Obese patients may also be more aggressively monitored and treated in the perioperative period than lean patients, because of the general perception that they are a high‐risk group.10 This may partly explain the decreased likelihood of failure to rescue with increasing BMI in our patients. Increased vigilance and prompt treatment of complications should reduce the overall morbidity and mortality rate in this group. It is also conceivable that a therapeutic selection bias is operational in the patients we studied. This describes scenarios where relatively healthy obese minority patients were operated upon, while sicker, morbidly obese patients were denied surgery due to perceived prohibitive risks. However, we would have expected a higher proportion of severely obese patients to present for emergency surgery, which is contrary to our finding of the lowest incidence of emergency surgery in the severely obese group. It is also possible that severe obesity may be associated with a higher attrition rate, such that the extremely obese patients did not live long enough to present for surgery. This is somewhat likely, given the significantly younger age of the severely obese patients in our study cohort. It is, however, impossible to determine survival effect from a cross‐sectional hospital‐based study design. Clearly, mechanisms used to explain the obesity paradox in minority surgical patients are likely to remain speculative, owing to the interaction of several factors such as concomitant comorbidities, disease progression at the time of presentation, patients' weight history, and regional fat distribution.

The current study confirms the findings of previous investigators26 about the importance of reducing major postoperative complications in surgical patients. While this may seem axiomatic, it deserves reiteration because the risk of postoperative mortality increases considerably in all the BMI categories following 1 or more major postoperative complication. However, it is not clear why obese and morbidly obese patients had a lower incidence of failure to rescue. This may be related to greater physiologic reserve in the obese and morbidly obese group, especially because patients in the higher BMI groups were significantly younger than the normal weight or lean patients. For the same reason, these younger, severely obese patients may have been more aggressively monitored and treated, thereby increasing the likelihood of being rescued following a major complication. It is also possible that the lower proportion of emergency procedures performed in obese and severely obese groups was somewhat protective, especially because emergency surgery was an independent predictor of overall mortality in this cohort of patients. In fact, when we stratified the patients according to urgency of surgery and explored the bivariate relationship between BMI category and mortality (data not shown) among those undergoing urgent surgery, the geometrical distribution of mortality did show a reverse‐J pattern with the highest proportion of cases in the underweight group, declining in the normal BMI and overweight group, and increasing steadily in obese and severely obese group. To this end, caution should be exercised when interpreting the association of BMI group with postoperative mortality for procedures performed as an emergency.

Smoking and antecedent illness are 2 confounding factors commonly criticized in studies attempting to associated BMI with mortality. This is because smokers tend to weigh less and have higher mortality rates than nonsmokers. The present investigation did not find a significant contribution of smoking to mortality when other factors included in a logistic regression model were considered. The current study's findings are consistent with those of previous data in African American patients,27 and contrasts with the excess mortality described in currently smoking Caucasian men and women.28 It is possible that smoking is not an important effect modifier when considering the relevance of BMI to postoperative mortality in minority patients.

Obesity affects all segments of the American population. However, it imposes a larger burden and poses a greater threat to minority populations.1 The increase in overall prevalence of obesity and obesity‐related diseases are especially pronounced in ethnic minorities,2 and the outlook for minorities who develop obesity‐associated diseases such as stroke and chronic renal disease is worse than in their Caucasian counterparts.3

Despite the higher prevalence of obesity in ethnic minorities, the majority of research on the relationship between body mass index (BMI) and mortality has been conducted among Caucasians in the United States. This is due largely to the small number of minority participants in most studies, which makes for low statistical power.4

A curious epidemiologic paradox has been the observation, in many studies, that black adults have lower morbidity and mortality associated with obesity compared to Caucasians.5 In fact, some authors suggest that high BMI among black and other minorities may not be as strong a risk factor for mortality as it is in others.6, 7

Very few studies have specifically examined the contribution of BMI to postoperative outcome in a large cohort of minority patients.8, 9 Similarly, the authors are unaware of any previous studies describing the clinical relevance of being overweight and obese in minority patients undergoing surgery. Therefore, the primary objective of this observational study was to describe the prevalence of overweight and obesity in a large cohort of minority surgical patients, and the impact of BMI class on their postoperative outcome. Our a priori hypothesis was that obese minority surgical patients would have a poorer postoperative outcome and have higher 30‐day all‐cause mortality than normal weight individuals.

METHODS

Study data were derived from the Participant Use Data File of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) for the calendar years 2005 to 2008. This multi‐institutional (186 participating centers) reporting system was designed to provide risk‐adjusted surgical outcome data from throughout the United States.

The methodology for collecting these data, including their accuracy and reproducibility, has been detailed in previous publications.10, 11 It is briefly reviewed here. Dedicated nurse clinical reviewers at each hospital prospectively enrolled patients and collected data in a standardized fashion according to strict ACS‐NSQIP definitions. A systematic sample was obtained by taking the first 40 cases per nurse reviewer on an 8‐day cycle from the operating room log, ensuring that no particular operating room day block time would bias the weighting of cases. Nurse reviewers had completed comprehensive training regarding definitions and data extraction, as well as continuing education and monitoring through the ACS‐NSQIP program. They are assessed for inter‐rater reliability during biennial site visits. Information was obtained from patient medical records, physician office records, and telephone interviews. Patients were followed through their hospital course and after discharge from hospital up to 30 days postoperatively. A high level of accuracy and reproducibility of the data have been previously demonstrated.12

Race was defined as African American, Hispanic, Asian or Pacific Islander, or American Indian/Alaskan native, as identified by the clinical care provider, or within the medical record. Patients were excluded if race was coded as white, or not recorded. We also excluded patients with missing record of height and/or weight. The final study cohort consisted of 119,619 minority patients. We then computed BMI as weight in kilograms divided by the square of the height in meters (BMI = kg/m²). Patients were classified as underweight (BMI 18.5 kg/m²), normal weight (BMI = 18.6‐24.9 kg/m²), overweight (BMI = 25‐29.9 kg/m²), obese (BMI = 30‐39.9 kg/m²), and morbidly obese (BMI 40 kg/m²) in accordance with National Institute of Health (NIH) standards.13

RESULTS

The study cohort included 119,619 surgical patients (Table 1). Their mean (standard deviation [SD]) age was 50.4 (16.9), and the mean (SD) BMI of 30.3 (8.9) kg/m² was in the obese range. The overall prevalence of high BMI (overweight or obese) was 70.8%. A very small proportion, 2.7%, of patients was classified as underweight. Sex‐stratified demographic and behavioral characteristics differed significantly across all the variables in our study cohort. Men were more likely to be overweight, whereas women were more likely to be obese or severely obese. A majority (77.4%) of the patients were non‐elderly adults (<65years) undergoing elective (85.9%) surgical procedures. The minority patients in this study were African American (50%), Hispanic (36%), Asian and Pacific Islander (10%), and American Indian and Alaskan native (4%).

The distribution of baseline preoperative clinical characteristics by BMI class revealed many significant differences (Table 2). Age was significantly different among the BMI classes, with the severely obese group being about 8 years younger than the underweight or normal weight group. Similarly, severely obese patients were more likely to be women, less likely to smoke, more likely to be hypertensive, diabetic, have a history of dyspnea at rest, and more likely to belong to high ASA class. On the other hand, underweight patients were more likely to have disseminated cancer, be current smokers, consume more than 2 alcoholic drinks per day, have active chronic obstructive pulmonary disease (COPD), and have ascites. They were also more likely to be on dialysis and have cardiac disease, as well as a history of stroke. Urgency of surgery also varied significantly across the BMI categories, with the underweight group having the highest incidence of emergency surgery (20.6%) and the severely obese group being the least likely to present for emergency surgery (8.2%).

Perioperative outcomes according to BMI classes documented significant differences (Table 3). Work relative value unit (Work RVU, a measure of surgical complexity), as well as total anesthesia and operation time decreased in a stepwise fashion across the BMI classes to the obese group, followed by increase in these parameters in the severely obese group. Following a decrease to the normal BMI category, there was a positive association between BMI and the incidence of postoperative superficial and deep wound infection, as well as wound disruption.

There was a negative association between BMI class and the likelihood of postoperative sepsis, septic shock, reintubation, delayed ventilator wean, and postoperative pneumonia. Similarly, the proportions of patients who developed postoperative acute renal failure, cardiac arrest, and those who required postoperative blood transfusion or needed reoperation, decreased significantly across the BMI classes, with the highest proportion of cases being in the underweight group and the lowest in the severely obese group. Overall composite morbidity was twice as high in the underweight compared to the severely obese group.

There were 1758 deaths among the study's 119,619 patients, resulting in an overall mortality rate of 1.5%. The overall major complication rate was 13.8%. The distribution of total mortality rate as well as mortality in patients with at least 1 major postoperative complication across BMI classes revealed consistent differences (Figure 1). Over the entire range of BMI classes, there was a progressive, stepwise decrease in the proportion of deaths with increasing BMI. This pattern also occurred among patients who developed at least 1 major postoperative complication, indicating a reduced likelihood of death after a major complication. This is reflective of a reduced likelihood of death after a major complication (failure to rescue) with increasing BMI.

Figure 1

Multivariate logistic regression defined a number of factors associated with 30‐day mortality (Table 4). The Hosmer and Lemeshow goodness‐of‐fit test for this model was not statistically significant (² = 17.8, df = 8, P = 0.23). High ASA physical status was associated with high odds of mortality. Specifically, when controlling for the other covariates in the model, ASA status was associated with a 5‐fold increased relative odds of death (adjusted odds ratio [OR] = 5.30; 95% confidence interval = 4.96‐5.79, P < 0.001). Similarly, occurrence of 1 or more major postoperative complication was associated with 6‐fold increased relative odds of mortality. The paradoxical effect of BMI category observed on univariate analysis was maintained in the multivariate model. Specifically, underweight patients had the highest relative odds of mortality, while severely obese patients had the lowest, compared with patients at a healthy weight (Table 4). Interestingly, smoking had no significant effect on the odds of mortality after controlling for other factors. Similarly, the specific racial group and the timing of the surgical intervention had no significant effect on mortality.