Clinical Inquiries

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

A Cochrane review of Pap smear sampling devices for nonpregnant women concludes that the cervical brush with spatula is more effective at collecting endocervical cells and producing adequate Pap smears.¹ Based on more limited evidence, the higher rate of adequate smears is associated with the detection of more cytologic abnormalities. However, the manufacturer of Cytobrush (Medscand) recommends that the device not be used after the first 10 weeks of pregnancy, raising issues of both effectiveness and safety in this population.

Upon review of the literature, these concerns appear to be unfounded. In multiple studies involving more than 25,000 pregnant and nonpregnant patients, the brush was consistently shown to be the method obtaining the highest rate of adequate smears—ie, those containing endocervical cells.^2-10 Furthermore, in studies including about 1900 pregnant patients, the brush with spatula caused no significantly increased risk of serious adverse outcomes, nor any trend in that direction.^5-7,9-11 The device did cause a slight increase in self-limited vaginal spotting.

In theory, a more accurate Pap smear could lead to patient-oriented outcomes, such as less need for procedures to diagnose and treat cervical cytologic abnormalities, reduced incidence of invasive cervical cancer, and fewer patient deaths from cervical cancer. No data on these outcomes is available. Some studies did look for differences in the detection of cytologic abnormalities between the brush with spatula and the swab with spatula methods. Most small studies and a meta-analysis showed no difference.^2,3,8,9 One study showed a trend towards improved yield; in another study, the brush with spatula significantly improved the ability to detect cytologic abnormalities in pregnant patients.^7,10

Three studies addressed cost-effectiveness of the brush in pregnancy.^3,9,12 Especially when including the cost of repeat Pap smears for inadequate specimens, the brush with spatula was rated most cost-effective in all 3 studies.

Comparison of the use of conventional Pap smear collection techniques with newer liquid-based cytology or human papilloma virus (HPV) typing has not yet been addressed in the literature.

Recommendations from others

“The Working Group’s Recommendations for Women in Low Risk Pregnancy” through the Veterans Health Administration lists use of a nylon cervical brush—no type is specified—as the appropriate sampling device in the late first trimester of pregnancy.¹³ No recommendations specific to the Cytobrush were found.

The following organizations have made no recommendations for or against the use of the Cytobrush in pregnancy: US Preventive Services Task Force, American College of Obstetricians and Gynecologists, American Academy of Family Physicians, or the American Academy of Nurse-Midwives.

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Multiple studies and reviews have compared tissue adhesives with sutures or adhesive strips for wound closure. A Cochrane review found 10 studies, which included 970 patients in the emergency-room setting. Review of these articles found no significant difference in cosmetic appearance between tissue adhesive closure and standard suture closure with a 3-month follow-up period in acute, linear wounds under low tension. Wound erythema (number needed to treat [NNT]=10) and dehiscence rates (NNT=25) were lower for tissue adhesives.¹ In the 6 studies that reported time data, treatment with tissue adhesive took 4.7 fewer minutes. In all 6 studies that reported patients’ perception of pain, pain was significantly less with tissue adhesive (weighted mean difference=13.7 mm [on 100-mm scale]; 95% confidence interval [CI], –20.0 to –6.9).

A multicenter, randomized trial studied 924 wounds (383 traumatic, 541 surgical) and reported no difference in cosmetic appearance upon grading by both a clinician and the patients themselves.² This study was not included in the Cochrane review because of the inclusion of surgical wounds. In a clinical trial reported after the Cochrane review, Holger and colleagues³ studied tissue adhesives against standard wound closure using either nylon or absorbable gut sutures. The study included 145 patients, 84 of whom had at least a 9-month follow-up. No significant difference was noted in a visual analog grading scale, with a 10- to 15-mm difference (out of 100 mm) considered significant.³ Tissue adhesive closure was, on average, 5.7 minutes faster than standard wound closure with sutures for superficial lacerations. Pain outcomes in the studies showed that closure with tissue adhesive was less painful due to the lack of a need for anesthesia.⁴

Recommendations from others

No major guidelines were found regarding the use of skin adhesives for wound closure.

Evidence summary

Multiple studies and reviews have compared tissue adhesives with sutures or adhesive strips for wound closure. A Cochrane review found 10 studies, which included 970 patients in the emergency-room setting. Review of these articles found no significant difference in cosmetic appearance between tissue adhesive closure and standard suture closure with a 3-month follow-up period in acute, linear wounds under low tension. Wound erythema (number needed to treat [NNT]=10) and dehiscence rates (NNT=25) were lower for tissue adhesives.¹ In the 6 studies that reported time data, treatment with tissue adhesive took 4.7 fewer minutes. In all 6 studies that reported patients’ perception of pain, pain was significantly less with tissue adhesive (weighted mean difference=13.7 mm [on 100-mm scale]; 95% confidence interval [CI], –20.0 to –6.9).

A multicenter, randomized trial studied 924 wounds (383 traumatic, 541 surgical) and reported no difference in cosmetic appearance upon grading by both a clinician and the patients themselves.² This study was not included in the Cochrane review because of the inclusion of surgical wounds. In a clinical trial reported after the Cochrane review, Holger and colleagues³ studied tissue adhesives against standard wound closure using either nylon or absorbable gut sutures. The study included 145 patients, 84 of whom had at least a 9-month follow-up. No significant difference was noted in a visual analog grading scale, with a 10- to 15-mm difference (out of 100 mm) considered significant.³ Tissue adhesive closure was, on average, 5.7 minutes faster than standard wound closure with sutures for superficial lacerations. Pain outcomes in the studies showed that closure with tissue adhesive was less painful due to the lack of a need for anesthesia.⁴

Recommendations from others

No major guidelines were found regarding the use of skin adhesives for wound closure.

Evidence summary

Multiple studies and reviews have compared tissue adhesives with sutures or adhesive strips for wound closure. A Cochrane review found 10 studies, which included 970 patients in the emergency-room setting. Review of these articles found no significant difference in cosmetic appearance between tissue adhesive closure and standard suture closure with a 3-month follow-up period in acute, linear wounds under low tension. Wound erythema (number needed to treat [NNT]=10) and dehiscence rates (NNT=25) were lower for tissue adhesives.¹ In the 6 studies that reported time data, treatment with tissue adhesive took 4.7 fewer minutes. In all 6 studies that reported patients’ perception of pain, pain was significantly less with tissue adhesive (weighted mean difference=13.7 mm [on 100-mm scale]; 95% confidence interval [CI], –20.0 to –6.9).

A multicenter, randomized trial studied 924 wounds (383 traumatic, 541 surgical) and reported no difference in cosmetic appearance upon grading by both a clinician and the patients themselves.² This study was not included in the Cochrane review because of the inclusion of surgical wounds. In a clinical trial reported after the Cochrane review, Holger and colleagues³ studied tissue adhesives against standard wound closure using either nylon or absorbable gut sutures. The study included 145 patients, 84 of whom had at least a 9-month follow-up. No significant difference was noted in a visual analog grading scale, with a 10- to 15-mm difference (out of 100 mm) considered significant.³ Tissue adhesive closure was, on average, 5.7 minutes faster than standard wound closure with sutures for superficial lacerations. Pain outcomes in the studies showed that closure with tissue adhesive was less painful due to the lack of a need for anesthesia.⁴

Recommendations from others

No major guidelines were found regarding the use of skin adhesives for wound closure.

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

Evidence summary

Thrombotic complications are common in lowerlimb fractures. In 1968, a prospective observational study evaluated the natural history of DVT and pulmonary embolism (PE) in tibial fractures treated with open reduction and internal fixation with early mobilization. Seventy-six consecutive patients with 79 tibial fractures were evaluated with venograms, most within 1 month of injury. The overall incidence of thrombosis was 45%. Half were minor, involving 1 to 3 of the paired deep venous trunks of the lower leg without clinical signs of embolism. Twelve patients (16%) had extensive thrombosis, involving 4 to 6 of the deep venous trunks. Three of these had nonfatal PE diagnosed clinically, and 1 had a fatal PE confirmed at autopsy. The mean age of those with extensive thrombosis or PE was 54 years, and these events were uncommon below age 25 years.¹

Incidence of DVT and PE was also evaluated in a cohort of 102 unselected patients who underwent operative fixation for lower-limb fractures, excluding patella, ankle, and foot fractures. All underwent venography approximately 9 days after fixation and were followed clinically for 6 weeks. The overall incidence of DVT was 28% (40% with femoral shaft, 43% with tibial plateau, 22% with tibial shaft, and 12% with tibial plafond [distal articular tibia]). Four developed clinical evidence of PE during hospitalization but only 1 had objective confirmation. None of the patients showed clinical evidence of PE as outpatients.²

LMWH prophylaxis significantly reduced thrombosis in patients with lower-limb fractures in 3 out of 4 RCTs. The first RCT evaluated 253 patients with lower-limb fractures immobilized in plaster casts after surgical fixation. Half the patients received subcutaneous LMWH (nadroparin [Fraxiparin], a European LMWH similar to enoxaparin), and half received no thrombosis prophylaxis. Based on compression ultrasound at the time of cast removal (17 days postinjury, on average), the overall DVT incidence was 11%. Six patients (5%) receiving LMWH had DVTs vs 21 (17%) in the control group (number needed to treat [NNT]=8 to prevent 1 DVT detectible by compression ultrasound). Two thirds of patients with DVT were asymptomatic. One third had clinical signs of DVT, including 1 patient diagnosed with PE on clinical grounds. There was no difference in bleeding complications between the treatment groups.³

A second RCT evaluated LMWH (Mono-Embolex, a European LMWH) prophylaxis in 328 outpatients with lower limb injuries, which included fractures, severe contusions, and ligamentous injuries. All were treated nonsurgically with cast immobilization (mean=18.8 days, range=2–72 days) and 176 patients used daily LMWH injections. All underwent Doppler evaluation for leg thromboses after cast removal, and positive results were confirmed with venograms. Overall, there were no DVTs among the LMWH prophylaxis group and 7 DVTs (4.3%) in the group without LMWH prophylaxis (P<.006). Among those with fractures, the untreated DVT rate was 5.9% (vs 0% with LMWH prophylaxis). Those over age 40 who did not use LMWH had a DVT rate of 11.4% (vs 1.7% in younger patients). Without LMWH prophylaxis, casting for more than 10 days approximately doubled the risk of DVT compared with less than 10 days (6.1% vs 3.1%). This study did not report on the anatomic location of DVTs or if they were clinically evident.⁴

The third RCT evaluated reviparin (another European LMWH) vs placebo in 440 outpatients with lower limb injuries, of whom 293 had fractures. About half had surgical management and all were treated with a plaster cast or brace for an average of 44 days. Most were ambulatory with crutches. All underwent venography within a week of cast removal. The DVT rate for fracture patients using reviparin was 10.4%, vs 18.2% among those without LMWH prophylaxis (absolute risk reduction=7.8%; NNT=12.8). Three fourths of the DVTs were in distal veins, and 21% of the DVTs in the LMWH patients occurred in deep veins compared with 34% in patients without. Two pulmonary emboli occurred, both in patients without LMWH prophylaxis.⁵

The final RCT evaluated tinzaparin (yet another European LMWH) in 300 adult outpatients immobilized in plaster for at least 3 weeks. Most patients (205 out of 300) underwent venography, and the overall DVT rate was 10% (tinzaparin) vs 17% (controls). Among the 150 fracture patients who underwent venography, the DVT rate was 11% (tinzaparin) vs 13% (controls). This difference was not significant, probably due to insufficient numbers. None of the DVTs was clinically detectable.⁶

In hip fracture and hip arthroplasty, warfarin and LMWH are both effective in preventing thrombosis. No studies have specifically evaluated warfarin prophylaxis in lower extremity fractures or compared it with LMWH.

Recommendations from others

The American College of Chest Physicians (ACCP) says that LMWH prophylaxis reduces the risk of asymptomatic DVTs and is standard of care in Europe. The ACCP does not recommend thromboprophylaxis for isolated lower extremity fractures in the US because of cost and insufficient evidence of clinically important reduction in venous thromboembolism (VTE). However, ACCP lists unspecified “lower extremity or pelvic fracture” as a risk factor for VTE, and does recommend that trauma patients with at least 1 risk factor for VTE receive thromboprophylaxis. They make no recommendation about the use of warfarin.⁷

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

Evidence summary

Faris et al⁴ conducted a meta-analysis of randomized controlled trials that used diuretics (pertanide, furosemide, furosemide-hydrochlorothiazide) in congestive heart failure (TABLE).⁴ Of the 18 trials, 8 were placebo-controlled and 10 used active controls (diuretics vs angiotensin-converting enzyme [ACE] inhibitors, digoxin, or ibopamine, a dopamine agonist). Three placebo-controlled trials (N=221) showed an absolute risk reduction in death of 8% in diuretic-treated patients (number needed to treat [NNT]=12.5). Four placebo-controlled trials (N=448) showed a significantly lower rate of admissions for worsening failure among diuretic-treated patients (NNT=8.5), and 4 of the active-controlled trials (N=150) showed a nonsignificant trend toward decreased admissions. Six active-controlled studies (N=174) showed significantly increased exercise capacity for patients on diuretics. One of these latter trials also assessed quality of life, edema, and New York Heart Association (NYHA) class, and demonstrated no change in these outcomes in the treatment and placebo groups.⁵

The studies used in this meta-analysis had numerous shortcomings: the individual trials had small numbers of patients (N=14–139), short follow-up periods (typically 4–8 weeks), and inadequate statistical power to clearly demonstrate morbidity/mortality reductions. There was significant heterogeneity between studies. Crossover studies were included, some studies did not clearly report masking and assessment of outcome measures, and assessment of study validity was not clear. Studies employed a variety of diuretic types and doses, used different controls, and did not clarify whether patients’ congestive heart failure was caused primarily by diastolic or systolic dysfunction.

It is worth noting that diuretic use also carries some risk. One large retrospective study evaluated 6796 patients using potassium-sparing diuretics vs non–potassium-sparing diuretics in the Studies of Left Ventricular Dysfunction (SOLVD) trial.⁶ Rates of hospitalization or death from worsening congestive heart failure were significantly higher in the non–potassium-sparing diuretic population than in the nondiuretic population (relative risk [RR]=1.31, 95% confidence interval [CI], 1.09–1.57; number needed to harm=5.78). This increased risk was not found for patients taking potassium-sparing diuretics (RR=0.99; 95% CI, 0.76–1.30).

Another retrospective study of SOLVD patients found a significant and independent association with increased risk of arrhythmic death among patients taking non–potassium-sparing diuretics (RR=1.33; 95% CI, 1.05–1.69).⁷

A retrospective study of 1153 patients with NYHA Class III to IV heart failure, who were enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), found high diuretic doses to be independently associated with mortality (adjusted hazard ratio [HR]=1.37; P=.004), sudden death (HR=1.39; P=.042), and pump failure death (HR=1.51; P=.034).⁸

The authors caution that there is no proof of causation between furosemide and death; diuretic resistance may explain the poor outcomes, or the use of loop diuretics at high doses may be proxy of more severe illness, and thus poorer outcome.

TABLE
Clinical effects of diuretics in congestive heart failure

Recommendations from others

The American College of Cardiology recommends using diuretics in the setting of left ventricular systolic dysfunction and fluid retention (level of evidence [LOE]: A), and recommends using diuretics in diastolic dysfunction to control pulmonary congestion and peripheral edema (LOE: C).⁹

The European Society of Cardiology notes that no randomized controlled trials have assessed survival effects of diuretics in congestive heart failure, but recommends using diuretics for symptomatic treatment of volume overload (LOE: A). This society also cites evidence that diuretic use improves exercise tolerance (LOE: B). They recommend that diuretics be used always in addition to an ACE inhibitor, that loop diuretics be used if symptoms are more than mild and if glomerular filtration rate (GFR) <30 cc/min, and that thiazide diuretics can be used with loop diuretics for synergistic effects in severe congestive heart failure. ¹⁰

Evidence summary

Faris et al⁴ conducted a meta-analysis of randomized controlled trials that used diuretics (pertanide, furosemide, furosemide-hydrochlorothiazide) in congestive heart failure (TABLE).⁴ Of the 18 trials, 8 were placebo-controlled and 10 used active controls (diuretics vs angiotensin-converting enzyme [ACE] inhibitors, digoxin, or ibopamine, a dopamine agonist). Three placebo-controlled trials (N=221) showed an absolute risk reduction in death of 8% in diuretic-treated patients (number needed to treat [NNT]=12.5). Four placebo-controlled trials (N=448) showed a significantly lower rate of admissions for worsening failure among diuretic-treated patients (NNT=8.5), and 4 of the active-controlled trials (N=150) showed a nonsignificant trend toward decreased admissions. Six active-controlled studies (N=174) showed significantly increased exercise capacity for patients on diuretics. One of these latter trials also assessed quality of life, edema, and New York Heart Association (NYHA) class, and demonstrated no change in these outcomes in the treatment and placebo groups.⁵

The studies used in this meta-analysis had numerous shortcomings: the individual trials had small numbers of patients (N=14–139), short follow-up periods (typically 4–8 weeks), and inadequate statistical power to clearly demonstrate morbidity/mortality reductions. There was significant heterogeneity between studies. Crossover studies were included, some studies did not clearly report masking and assessment of outcome measures, and assessment of study validity was not clear. Studies employed a variety of diuretic types and doses, used different controls, and did not clarify whether patients’ congestive heart failure was caused primarily by diastolic or systolic dysfunction.

It is worth noting that diuretic use also carries some risk. One large retrospective study evaluated 6796 patients using potassium-sparing diuretics vs non–potassium-sparing diuretics in the Studies of Left Ventricular Dysfunction (SOLVD) trial.⁶ Rates of hospitalization or death from worsening congestive heart failure were significantly higher in the non–potassium-sparing diuretic population than in the nondiuretic population (relative risk [RR]=1.31, 95% confidence interval [CI], 1.09–1.57; number needed to harm=5.78). This increased risk was not found for patients taking potassium-sparing diuretics (RR=0.99; 95% CI, 0.76–1.30).

Another retrospective study of SOLVD patients found a significant and independent association with increased risk of arrhythmic death among patients taking non–potassium-sparing diuretics (RR=1.33; 95% CI, 1.05–1.69).⁷

A retrospective study of 1153 patients with NYHA Class III to IV heart failure, who were enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), found high diuretic doses to be independently associated with mortality (adjusted hazard ratio [HR]=1.37; P=.004), sudden death (HR=1.39; P=.042), and pump failure death (HR=1.51; P=.034).⁸

The authors caution that there is no proof of causation between furosemide and death; diuretic resistance may explain the poor outcomes, or the use of loop diuretics at high doses may be proxy of more severe illness, and thus poorer outcome.

TABLE
Clinical effects of diuretics in congestive heart failure

Recommendations from others

The American College of Cardiology recommends using diuretics in the setting of left ventricular systolic dysfunction and fluid retention (level of evidence [LOE]: A), and recommends using diuretics in diastolic dysfunction to control pulmonary congestion and peripheral edema (LOE: C).⁹

The European Society of Cardiology notes that no randomized controlled trials have assessed survival effects of diuretics in congestive heart failure, but recommends using diuretics for symptomatic treatment of volume overload (LOE: A). This society also cites evidence that diuretic use improves exercise tolerance (LOE: B). They recommend that diuretics be used always in addition to an ACE inhibitor, that loop diuretics be used if symptoms are more than mild and if glomerular filtration rate (GFR) <30 cc/min, and that thiazide diuretics can be used with loop diuretics for synergistic effects in severe congestive heart failure. ¹⁰

Evidence summary

Faris et al⁴ conducted a meta-analysis of randomized controlled trials that used diuretics (pertanide, furosemide, furosemide-hydrochlorothiazide) in congestive heart failure (TABLE).⁴ Of the 18 trials, 8 were placebo-controlled and 10 used active controls (diuretics vs angiotensin-converting enzyme [ACE] inhibitors, digoxin, or ibopamine, a dopamine agonist). Three placebo-controlled trials (N=221) showed an absolute risk reduction in death of 8% in diuretic-treated patients (number needed to treat [NNT]=12.5). Four placebo-controlled trials (N=448) showed a significantly lower rate of admissions for worsening failure among diuretic-treated patients (NNT=8.5), and 4 of the active-controlled trials (N=150) showed a nonsignificant trend toward decreased admissions. Six active-controlled studies (N=174) showed significantly increased exercise capacity for patients on diuretics. One of these latter trials also assessed quality of life, edema, and New York Heart Association (NYHA) class, and demonstrated no change in these outcomes in the treatment and placebo groups.⁵

The studies used in this meta-analysis had numerous shortcomings: the individual trials had small numbers of patients (N=14–139), short follow-up periods (typically 4–8 weeks), and inadequate statistical power to clearly demonstrate morbidity/mortality reductions. There was significant heterogeneity between studies. Crossover studies were included, some studies did not clearly report masking and assessment of outcome measures, and assessment of study validity was not clear. Studies employed a variety of diuretic types and doses, used different controls, and did not clarify whether patients’ congestive heart failure was caused primarily by diastolic or systolic dysfunction.

It is worth noting that diuretic use also carries some risk. One large retrospective study evaluated 6796 patients using potassium-sparing diuretics vs non–potassium-sparing diuretics in the Studies of Left Ventricular Dysfunction (SOLVD) trial.⁶ Rates of hospitalization or death from worsening congestive heart failure were significantly higher in the non–potassium-sparing diuretic population than in the nondiuretic population (relative risk [RR]=1.31, 95% confidence interval [CI], 1.09–1.57; number needed to harm=5.78). This increased risk was not found for patients taking potassium-sparing diuretics (RR=0.99; 95% CI, 0.76–1.30).

Another retrospective study of SOLVD patients found a significant and independent association with increased risk of arrhythmic death among patients taking non–potassium-sparing diuretics (RR=1.33; 95% CI, 1.05–1.69).⁷

A retrospective study of 1153 patients with NYHA Class III to IV heart failure, who were enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), found high diuretic doses to be independently associated with mortality (adjusted hazard ratio [HR]=1.37; P=.004), sudden death (HR=1.39; P=.042), and pump failure death (HR=1.51; P=.034).⁸

The authors caution that there is no proof of causation between furosemide and death; diuretic resistance may explain the poor outcomes, or the use of loop diuretics at high doses may be proxy of more severe illness, and thus poorer outcome.

TABLE
Clinical effects of diuretics in congestive heart failure

Recommendations from others

The American College of Cardiology recommends using diuretics in the setting of left ventricular systolic dysfunction and fluid retention (level of evidence [LOE]: A), and recommends using diuretics in diastolic dysfunction to control pulmonary congestion and peripheral edema (LOE: C).⁹

The European Society of Cardiology notes that no randomized controlled trials have assessed survival effects of diuretics in congestive heart failure, but recommends using diuretics for symptomatic treatment of volume overload (LOE: A). This society also cites evidence that diuretic use improves exercise tolerance (LOE: B). They recommend that diuretics be used always in addition to an ACE inhibitor, that loop diuretics be used if symptoms are more than mild and if glomerular filtration rate (GFR) <30 cc/min, and that thiazide diuretics can be used with loop diuretics for synergistic effects in severe congestive heart failure. ¹⁰

Evidence summary

Use of smokeless tobacco can lead to nicotine dependence and cause periodontal disease, leukoplakia, cancer, and possibly cardiovascular disease.^1-3 Patients who abruptly stop using smokeless tobacco may experience withdrawal symptoms similar to that observed in smokers.³

Nicotine gum

A small double-blind study randomized 79 male smokeless tobacco users to chew nicotine gum (0 mg, 2 mg, or 4 mg) for 5 days.⁴ Sixty patients completed the study. No significant differences in withdrawal symptoms, including cravings, concentration, or restlessness, were noted among the 3 groups (P>.05). However, further analysis demonstrated that patients with high blood levels of cotinine who received nicotine gum 2 mg experienced decreased cravings compared with placebo (P<.001), and a trend towards decreased cravings with 4 mg gum was noted (P<.06). Limitations of this study: quit rates were not reported, participants did not have to be motivated to quit smokeless tobacco in order to enroll, and it is not known if patients were counseled about the appropriate “chew and park” technique for nicotine gum.

Another study randomized 234 male smokeless tobacco users to receive group behavioral treatment plus nicotine gum 2 mg (B/NRT); group behavioral treatment plus placebo (B/Pl); minimal contact plus nicotine gum 2 mg (MC/NRT); or minimal contact plus placebo (MC/Pl).⁵

Group behavioral treatment consisted of 8 group counseling sessions 45 to 60 minutes in length; minimal contact involved 4 brief one-on-one sessions with a nurse. Patients chewed a minimum of 6 pieces of nicotine or placebo gum per day.

At 4 weeks, point prevalence abstinence rates were as follows: B/NRT, 63.6%; B/Pl, 66%; MC/NRT, 35.3%; and MC/Pl, 48.1% (P<.01). Abstinence rates remained significantly different at 1 and 6 month follow-ups, but not at 12 months. Post-hoc logistic regression favored group behavioral therapy plus NRT at 6 months. Moreover, survival analysis of continuous prevalence rates demonstrated that the least effective treatment was minimal contact plus NRT.

The authors theorized that nicotine gum may actually worsen risk of relapse in smokeless tobacco users due to behavioral similarities associated with use, but that behavioral treatment may help regain abstinence after a lapse. Gum users experienced lessened withdrawal symptoms including cravings, irritability, anxiety, and difficulty concentrating (P<.01). Results indicate that behavioral interventions may be more effective than NRT; however, low doses of nicotine gum were used.

Nicotine transdermal patches

A randomized double-blind study examined nicotine transdermal patches in smokeless tobacco users.⁶ Researchers recruited 422 participants from a Minnesota college campus and surrounding metropolitan area through advertisements; they were randomly assigned to nicotine patch plus mint snuff (a nicotine-free product), nicotine patch and no mint snuff, placebo patch plus mint snuff, or placebo patch and no mint snuff. The patch was dosed as 21-mg patch for 6 weeks, 14-mg patch for 2 weeks, and 7-mg patch for 2 weeks. All patients participated in 8 weekly individual 10-minute sessions with a therapist.

Continuous 10-week abstinence rates were 69% for nicotine patch and mint snuff, 58% for nicotine patch and no mint snuff, 46% for placebo patch and mint snuff, and 51% for placebo patch and no mint snuff (P=.002). After 15 weeks the abstinence rates were no longer different between the treatment groups. Patch users experienced lower total withdrawal scores (P=.002) as well as decreased craving (P<.001), irritability (P<.001), and restlessness (P=.019). Total withdrawal scores were not improved for mint snuff users; however, subsets of total withdrawal scores were lower for cravings (P=.005), irritability (P=.046), and anxiety (P=.012).

Meta-analysis

The Cochrane Database of Systematic Reviews published a meta-analysis of 6 studies that examined NRT or bupropion in smokeless tobacco users.³ The primary outcome for the meta-analysis was tobacco abstinence 6 months or more after the intervention. Neither nicotine patches (odds ratio [OR]=1.16; 95% confidence interval [CI], 0.88–1.54) nor nicotine gum (OR=0.98; 95% CI, 0.59–1.63) were shown to improve abstinence over placebo at 6 months. The authors highlight the need for larger studies that compare different NRT products, doses, and duration.

One small randomized trial of bupropion was included, but it found no effect on tobacco abstention (OR=1.00; 95% CI, 0.23–4.37). Another small RCT found an effect; however, it was excluded from the meta-analysis because subjects were followed for only 3 months. The meta-analysis also concluded that behavioral interventions appear to be effective for increasing tobacco abstinence rates. Results were heterogeneous, and study quality was mixed. One post-hoc finding appeared to show that most effective behavioral interventions were coupled with an oral exam with direct feedback.

Recommendations from others

The United States Department of Health and Human Services recommends that smokeless tobacco users should be treated with the same counseling and interventions utilized for smokers, but commented that evidence is currently insufficient to suggest that NRT increases long-term abstinence.⁷ British guidelines concluded that no evidence clearly shows that nicotine gum or patches are effective cessation aids for smokeless tobacco users.²

Evidence summary

Use of smokeless tobacco can lead to nicotine dependence and cause periodontal disease, leukoplakia, cancer, and possibly cardiovascular disease.^1-3 Patients who abruptly stop using smokeless tobacco may experience withdrawal symptoms similar to that observed in smokers.³

Nicotine gum

A small double-blind study randomized 79 male smokeless tobacco users to chew nicotine gum (0 mg, 2 mg, or 4 mg) for 5 days.⁴ Sixty patients completed the study. No significant differences in withdrawal symptoms, including cravings, concentration, or restlessness, were noted among the 3 groups (P>.05). However, further analysis demonstrated that patients with high blood levels of cotinine who received nicotine gum 2 mg experienced decreased cravings compared with placebo (P<.001), and a trend towards decreased cravings with 4 mg gum was noted (P<.06). Limitations of this study: quit rates were not reported, participants did not have to be motivated to quit smokeless tobacco in order to enroll, and it is not known if patients were counseled about the appropriate “chew and park” technique for nicotine gum.

Another study randomized 234 male smokeless tobacco users to receive group behavioral treatment plus nicotine gum 2 mg (B/NRT); group behavioral treatment plus placebo (B/Pl); minimal contact plus nicotine gum 2 mg (MC/NRT); or minimal contact plus placebo (MC/Pl).⁵

Group behavioral treatment consisted of 8 group counseling sessions 45 to 60 minutes in length; minimal contact involved 4 brief one-on-one sessions with a nurse. Patients chewed a minimum of 6 pieces of nicotine or placebo gum per day.

At 4 weeks, point prevalence abstinence rates were as follows: B/NRT, 63.6%; B/Pl, 66%; MC/NRT, 35.3%; and MC/Pl, 48.1% (P<.01). Abstinence rates remained significantly different at 1 and 6 month follow-ups, but not at 12 months. Post-hoc logistic regression favored group behavioral therapy plus NRT at 6 months. Moreover, survival analysis of continuous prevalence rates demonstrated that the least effective treatment was minimal contact plus NRT.

The authors theorized that nicotine gum may actually worsen risk of relapse in smokeless tobacco users due to behavioral similarities associated with use, but that behavioral treatment may help regain abstinence after a lapse. Gum users experienced lessened withdrawal symptoms including cravings, irritability, anxiety, and difficulty concentrating (P<.01). Results indicate that behavioral interventions may be more effective than NRT; however, low doses of nicotine gum were used.

Nicotine transdermal patches

A randomized double-blind study examined nicotine transdermal patches in smokeless tobacco users.⁶ Researchers recruited 422 participants from a Minnesota college campus and surrounding metropolitan area through advertisements; they were randomly assigned to nicotine patch plus mint snuff (a nicotine-free product), nicotine patch and no mint snuff, placebo patch plus mint snuff, or placebo patch and no mint snuff. The patch was dosed as 21-mg patch for 6 weeks, 14-mg patch for 2 weeks, and 7-mg patch for 2 weeks. All patients participated in 8 weekly individual 10-minute sessions with a therapist.

Continuous 10-week abstinence rates were 69% for nicotine patch and mint snuff, 58% for nicotine patch and no mint snuff, 46% for placebo patch and mint snuff, and 51% for placebo patch and no mint snuff (P=.002). After 15 weeks the abstinence rates were no longer different between the treatment groups. Patch users experienced lower total withdrawal scores (P=.002) as well as decreased craving (P<.001), irritability (P<.001), and restlessness (P=.019). Total withdrawal scores were not improved for mint snuff users; however, subsets of total withdrawal scores were lower for cravings (P=.005), irritability (P=.046), and anxiety (P=.012).

Meta-analysis

The Cochrane Database of Systematic Reviews published a meta-analysis of 6 studies that examined NRT or bupropion in smokeless tobacco users.³ The primary outcome for the meta-analysis was tobacco abstinence 6 months or more after the intervention. Neither nicotine patches (odds ratio [OR]=1.16; 95% confidence interval [CI], 0.88–1.54) nor nicotine gum (OR=0.98; 95% CI, 0.59–1.63) were shown to improve abstinence over placebo at 6 months. The authors highlight the need for larger studies that compare different NRT products, doses, and duration.

One small randomized trial of bupropion was included, but it found no effect on tobacco abstention (OR=1.00; 95% CI, 0.23–4.37). Another small RCT found an effect; however, it was excluded from the meta-analysis because subjects were followed for only 3 months. The meta-analysis also concluded that behavioral interventions appear to be effective for increasing tobacco abstinence rates. Results were heterogeneous, and study quality was mixed. One post-hoc finding appeared to show that most effective behavioral interventions were coupled with an oral exam with direct feedback.

Recommendations from others

The United States Department of Health and Human Services recommends that smokeless tobacco users should be treated with the same counseling and interventions utilized for smokers, but commented that evidence is currently insufficient to suggest that NRT increases long-term abstinence.⁷ British guidelines concluded that no evidence clearly shows that nicotine gum or patches are effective cessation aids for smokeless tobacco users.²

Evidence summary

Use of smokeless tobacco can lead to nicotine dependence and cause periodontal disease, leukoplakia, cancer, and possibly cardiovascular disease.^1-3 Patients who abruptly stop using smokeless tobacco may experience withdrawal symptoms similar to that observed in smokers.³

Nicotine gum

A small double-blind study randomized 79 male smokeless tobacco users to chew nicotine gum (0 mg, 2 mg, or 4 mg) for 5 days.⁴ Sixty patients completed the study. No significant differences in withdrawal symptoms, including cravings, concentration, or restlessness, were noted among the 3 groups (P>.05). However, further analysis demonstrated that patients with high blood levels of cotinine who received nicotine gum 2 mg experienced decreased cravings compared with placebo (P<.001), and a trend towards decreased cravings with 4 mg gum was noted (P<.06). Limitations of this study: quit rates were not reported, participants did not have to be motivated to quit smokeless tobacco in order to enroll, and it is not known if patients were counseled about the appropriate “chew and park” technique for nicotine gum.

Another study randomized 234 male smokeless tobacco users to receive group behavioral treatment plus nicotine gum 2 mg (B/NRT); group behavioral treatment plus placebo (B/Pl); minimal contact plus nicotine gum 2 mg (MC/NRT); or minimal contact plus placebo (MC/Pl).⁵

Group behavioral treatment consisted of 8 group counseling sessions 45 to 60 minutes in length; minimal contact involved 4 brief one-on-one sessions with a nurse. Patients chewed a minimum of 6 pieces of nicotine or placebo gum per day.

At 4 weeks, point prevalence abstinence rates were as follows: B/NRT, 63.6%; B/Pl, 66%; MC/NRT, 35.3%; and MC/Pl, 48.1% (P<.01). Abstinence rates remained significantly different at 1 and 6 month follow-ups, but not at 12 months. Post-hoc logistic regression favored group behavioral therapy plus NRT at 6 months. Moreover, survival analysis of continuous prevalence rates demonstrated that the least effective treatment was minimal contact plus NRT.

The authors theorized that nicotine gum may actually worsen risk of relapse in smokeless tobacco users due to behavioral similarities associated with use, but that behavioral treatment may help regain abstinence after a lapse. Gum users experienced lessened withdrawal symptoms including cravings, irritability, anxiety, and difficulty concentrating (P<.01). Results indicate that behavioral interventions may be more effective than NRT; however, low doses of nicotine gum were used.

Nicotine transdermal patches

A randomized double-blind study examined nicotine transdermal patches in smokeless tobacco users.⁶ Researchers recruited 422 participants from a Minnesota college campus and surrounding metropolitan area through advertisements; they were randomly assigned to nicotine patch plus mint snuff (a nicotine-free product), nicotine patch and no mint snuff, placebo patch plus mint snuff, or placebo patch and no mint snuff. The patch was dosed as 21-mg patch for 6 weeks, 14-mg patch for 2 weeks, and 7-mg patch for 2 weeks. All patients participated in 8 weekly individual 10-minute sessions with a therapist.

Continuous 10-week abstinence rates were 69% for nicotine patch and mint snuff, 58% for nicotine patch and no mint snuff, 46% for placebo patch and mint snuff, and 51% for placebo patch and no mint snuff (P=.002). After 15 weeks the abstinence rates were no longer different between the treatment groups. Patch users experienced lower total withdrawal scores (P=.002) as well as decreased craving (P<.001), irritability (P<.001), and restlessness (P=.019). Total withdrawal scores were not improved for mint snuff users; however, subsets of total withdrawal scores were lower for cravings (P=.005), irritability (P=.046), and anxiety (P=.012).

Meta-analysis

The Cochrane Database of Systematic Reviews published a meta-analysis of 6 studies that examined NRT or bupropion in smokeless tobacco users.³ The primary outcome for the meta-analysis was tobacco abstinence 6 months or more after the intervention. Neither nicotine patches (odds ratio [OR]=1.16; 95% confidence interval [CI], 0.88–1.54) nor nicotine gum (OR=0.98; 95% CI, 0.59–1.63) were shown to improve abstinence over placebo at 6 months. The authors highlight the need for larger studies that compare different NRT products, doses, and duration.

One small randomized trial of bupropion was included, but it found no effect on tobacco abstention (OR=1.00; 95% CI, 0.23–4.37). Another small RCT found an effect; however, it was excluded from the meta-analysis because subjects were followed for only 3 months. The meta-analysis also concluded that behavioral interventions appear to be effective for increasing tobacco abstinence rates. Results were heterogeneous, and study quality was mixed. One post-hoc finding appeared to show that most effective behavioral interventions were coupled with an oral exam with direct feedback.

Recommendations from others

The United States Department of Health and Human Services recommends that smokeless tobacco users should be treated with the same counseling and interventions utilized for smokers, but commented that evidence is currently insufficient to suggest that NRT increases long-term abstinence.⁷ British guidelines concluded that no evidence clearly shows that nicotine gum or patches are effective cessation aids for smokeless tobacco users.²

Evidence summary

Intravascular administration of radiocontrast is frequently associated with acute reductions in renal function, particularly for patients with risk factors (TABLE 1). Most studies have used operational definitions of contrast nephropathy based on predefined elevations in serum creatinine from baseline, the great majority of which are transient and clinically insignificant. It is unclear if interventions that reduce the rate of mild creatinine elevations (TABLE 2) also reduce the risk of clinically relevant adverse outcomes.

A single RCT showed decreased risk of contrast nephropathy for patients pretreated with intravenous fluids containing sodium bicarbonate compared with those pretreated with a sodium chloride solution (number needed to treat [NNT]=8.4).² Another RCT showed that periprocedural hydration with isotonic saline is superior to half-normal saline in preventing contrast nephropathy (NNT=77).³ Several studies have demonstrated decreased risk of contrast nephropathy for high-risk patients when low-osmolality contrast media are used rather than high-osmolality contrast media (NNT=27).⁴ A single study suggested that iso-osmolar contrast media generate less contrast induced nephropathy than low-osmolar contrast media.⁵ Because the primary outcome in these studies was a change in serum creatinine, the NNTs listed above may not predict clinical outcomes.

Periprocedural administration of acetylcysteine reduces the risk of contrast nephropathy in high-risk patients (odds ratio=0.56; 95% confidence interval, 0.37–0.84). Oral acetylcysteine is effective if intervention is begun 24 hours before contrast administration.⁶ Preliminary evidence shows that intravenous administration of acetylcysteine immediately before contrast administration lowers the risk of contrast nephropathy.⁷ Oral acetylcysteine is low in cost and has no known side effects.

A single RCT suggests that hemofiltration initiated 4 to 6 hours before contrast administration reduces the incidence of contrast nephropathy among high-risk patients.⁸ The study was unusual in that patients in the intervention group experienced statistically significant reductions in several clinically relevant outcomes, including in-hospital mortality and cumulative 1-year mortality (in-hospital mortality, NNT=8.3; cumulative 1-year mortality, NNT=5). Hemofiltration is expensive and is not available in many institutions.

TABLE 1
Risk factors for the development of contrast nephropathy

TABLE 2
Interventions to reduce risk of contrast nephropathy

Recommendations from others

The American College of Radiology recommends using low-osmolality contrast media for patients with renal insufficiency, particularly those with diabetes.⁹ Clinical Evidence found support for the use of low-osmolality contrast media, periprocedural hydration, and acetylcysteine as interventions to reduce the risk of contrast nephropathy.¹⁰

Evidence summary

Intravascular administration of radiocontrast is frequently associated with acute reductions in renal function, particularly for patients with risk factors (TABLE 1). Most studies have used operational definitions of contrast nephropathy based on predefined elevations in serum creatinine from baseline, the great majority of which are transient and clinically insignificant. It is unclear if interventions that reduce the rate of mild creatinine elevations (TABLE 2) also reduce the risk of clinically relevant adverse outcomes.

A single RCT showed decreased risk of contrast nephropathy for patients pretreated with intravenous fluids containing sodium bicarbonate compared with those pretreated with a sodium chloride solution (number needed to treat [NNT]=8.4).² Another RCT showed that periprocedural hydration with isotonic saline is superior to half-normal saline in preventing contrast nephropathy (NNT=77).³ Several studies have demonstrated decreased risk of contrast nephropathy for high-risk patients when low-osmolality contrast media are used rather than high-osmolality contrast media (NNT=27).⁴ A single study suggested that iso-osmolar contrast media generate less contrast induced nephropathy than low-osmolar contrast media.⁵ Because the primary outcome in these studies was a change in serum creatinine, the NNTs listed above may not predict clinical outcomes.

Periprocedural administration of acetylcysteine reduces the risk of contrast nephropathy in high-risk patients (odds ratio=0.56; 95% confidence interval, 0.37–0.84). Oral acetylcysteine is effective if intervention is begun 24 hours before contrast administration.⁶ Preliminary evidence shows that intravenous administration of acetylcysteine immediately before contrast administration lowers the risk of contrast nephropathy.⁷ Oral acetylcysteine is low in cost and has no known side effects.

A single RCT suggests that hemofiltration initiated 4 to 6 hours before contrast administration reduces the incidence of contrast nephropathy among high-risk patients.⁸ The study was unusual in that patients in the intervention group experienced statistically significant reductions in several clinically relevant outcomes, including in-hospital mortality and cumulative 1-year mortality (in-hospital mortality, NNT=8.3; cumulative 1-year mortality, NNT=5). Hemofiltration is expensive and is not available in many institutions.

TABLE 1
Risk factors for the development of contrast nephropathy

TABLE 2
Interventions to reduce risk of contrast nephropathy

Recommendations from others

The American College of Radiology recommends using low-osmolality contrast media for patients with renal insufficiency, particularly those with diabetes.⁹ Clinical Evidence found support for the use of low-osmolality contrast media, periprocedural hydration, and acetylcysteine as interventions to reduce the risk of contrast nephropathy.¹⁰

Evidence summary

Intravascular administration of radiocontrast is frequently associated with acute reductions in renal function, particularly for patients with risk factors (TABLE 1). Most studies have used operational definitions of contrast nephropathy based on predefined elevations in serum creatinine from baseline, the great majority of which are transient and clinically insignificant. It is unclear if interventions that reduce the rate of mild creatinine elevations (TABLE 2) also reduce the risk of clinically relevant adverse outcomes.

A single RCT showed decreased risk of contrast nephropathy for patients pretreated with intravenous fluids containing sodium bicarbonate compared with those pretreated with a sodium chloride solution (number needed to treat [NNT]=8.4).² Another RCT showed that periprocedural hydration with isotonic saline is superior to half-normal saline in preventing contrast nephropathy (NNT=77).³ Several studies have demonstrated decreased risk of contrast nephropathy for high-risk patients when low-osmolality contrast media are used rather than high-osmolality contrast media (NNT=27).⁴ A single study suggested that iso-osmolar contrast media generate less contrast induced nephropathy than low-osmolar contrast media.⁵ Because the primary outcome in these studies was a change in serum creatinine, the NNTs listed above may not predict clinical outcomes.

Periprocedural administration of acetylcysteine reduces the risk of contrast nephropathy in high-risk patients (odds ratio=0.56; 95% confidence interval, 0.37–0.84). Oral acetylcysteine is effective if intervention is begun 24 hours before contrast administration.⁶ Preliminary evidence shows that intravenous administration of acetylcysteine immediately before contrast administration lowers the risk of contrast nephropathy.⁷ Oral acetylcysteine is low in cost and has no known side effects.

A single RCT suggests that hemofiltration initiated 4 to 6 hours before contrast administration reduces the incidence of contrast nephropathy among high-risk patients.⁸ The study was unusual in that patients in the intervention group experienced statistically significant reductions in several clinically relevant outcomes, including in-hospital mortality and cumulative 1-year mortality (in-hospital mortality, NNT=8.3; cumulative 1-year mortality, NNT=5). Hemofiltration is expensive and is not available in many institutions.

TABLE 1
Risk factors for the development of contrast nephropathy

TABLE 2
Interventions to reduce risk of contrast nephropathy

Recommendations from others

The American College of Radiology recommends using low-osmolality contrast media for patients with renal insufficiency, particularly those with diabetes.⁹ Clinical Evidence found support for the use of low-osmolality contrast media, periprocedural hydration, and acetylcysteine as interventions to reduce the risk of contrast nephropathy.¹⁰

Evidence summary

Three landmark placebo-controlled studies have established that thiazide diuretic–based treatment reduces morbidity and mortality among patients with hypertension.^1-3 Based on these data, thiazide diuretic therapy is considered the gold-standard treatment for uncomplicated hypertension.

Several other clinical trials have subsequently compared the effect of thiazide diuretics with that of other antihypertensive agents (beta-blockers, calcium channel blockers, and alpha-blockers) on patient-oriented outcomes. These were analyzed in a recent meta-analysis of 42 clinical trials that included 192,478 patients randomized to 7 treatment strategies including placebo.⁴ Results from the largest antihypertensive clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), were included in this meta-analysis.⁵ Comparative results are depicted in the Table. Although these data showed no differences between drug therapies in total and cardiovascular disease mortality, low-dose diuretics reduced certain cardiovascular endpoints (ie, heart failure, stroke, cardiovascular disease events) more than other drug therapies.

Angiotensin receptor blockers (ARBs) have not been compared with thiazide diuretics in a trial. Two long-term trials have compared an ARB to other types of drug therapy: losartan vs atenolol in the Losartan Intervention for Endpoint Reduction (LIFE) trial,⁶ and valsartan vs amlodipine in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.⁷ In the LIFE trial, the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke was less with losartan than atenolol (23.8 vs 27.9 events per 1000 patient-years, losartan and atenolol, respectively; number needed to treat=243 people-years, P=.021).⁶ However, in the VALUE trial, the primary endpoint of time to cardiac event was not different between valsartan and amlodipine (25.5 vs 24.7 events per 1000 patient-years, valsartan and amlodipine, respectively; P=.49).⁷

TABLE
First-line treatments for hypertension

Recommendations from others

The Seventh Report of the Joint National Committee (JNC7) recommended thiazide diuretics as preferred initial agents in uncomplicated hypertension.⁸ The European Society of Hypertension/European Society Cardiology recommended either a diuretic, beta-blocker, calcium channel blocker, ACE inhibitor, or ARB for initial therapy stating that blood pressure control to recommended values via any agent is more important than the type of agent used.⁹ Both guidelines identified other antihypertensives that may be used in addition to or in place of thiazide diuretics for compelling indications, such as heart failure, diabetes, high-risk cardiovascular disease, chronic kidney disease, post-myocardial infarction, and secondary stroke prevention.

Evidence summary

Three landmark placebo-controlled studies have established that thiazide diuretic–based treatment reduces morbidity and mortality among patients with hypertension.^1-3 Based on these data, thiazide diuretic therapy is considered the gold-standard treatment for uncomplicated hypertension.

Several other clinical trials have subsequently compared the effect of thiazide diuretics with that of other antihypertensive agents (beta-blockers, calcium channel blockers, and alpha-blockers) on patient-oriented outcomes. These were analyzed in a recent meta-analysis of 42 clinical trials that included 192,478 patients randomized to 7 treatment strategies including placebo.⁴ Results from the largest antihypertensive clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), were included in this meta-analysis.⁵ Comparative results are depicted in the Table. Although these data showed no differences between drug therapies in total and cardiovascular disease mortality, low-dose diuretics reduced certain cardiovascular endpoints (ie, heart failure, stroke, cardiovascular disease events) more than other drug therapies.

Angiotensin receptor blockers (ARBs) have not been compared with thiazide diuretics in a trial. Two long-term trials have compared an ARB to other types of drug therapy: losartan vs atenolol in the Losartan Intervention for Endpoint Reduction (LIFE) trial,⁶ and valsartan vs amlodipine in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.⁷ In the LIFE trial, the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke was less with losartan than atenolol (23.8 vs 27.9 events per 1000 patient-years, losartan and atenolol, respectively; number needed to treat=243 people-years, P=.021).⁶ However, in the VALUE trial, the primary endpoint of time to cardiac event was not different between valsartan and amlodipine (25.5 vs 24.7 events per 1000 patient-years, valsartan and amlodipine, respectively; P=.49).⁷

TABLE
First-line treatments for hypertension

Recommendations from others

The Seventh Report of the Joint National Committee (JNC7) recommended thiazide diuretics as preferred initial agents in uncomplicated hypertension.⁸ The European Society of Hypertension/European Society Cardiology recommended either a diuretic, beta-blocker, calcium channel blocker, ACE inhibitor, or ARB for initial therapy stating that blood pressure control to recommended values via any agent is more important than the type of agent used.⁹ Both guidelines identified other antihypertensives that may be used in addition to or in place of thiazide diuretics for compelling indications, such as heart failure, diabetes, high-risk cardiovascular disease, chronic kidney disease, post-myocardial infarction, and secondary stroke prevention.

Evidence summary

Three landmark placebo-controlled studies have established that thiazide diuretic–based treatment reduces morbidity and mortality among patients with hypertension.^1-3 Based on these data, thiazide diuretic therapy is considered the gold-standard treatment for uncomplicated hypertension.

Several other clinical trials have subsequently compared the effect of thiazide diuretics with that of other antihypertensive agents (beta-blockers, calcium channel blockers, and alpha-blockers) on patient-oriented outcomes. These were analyzed in a recent meta-analysis of 42 clinical trials that included 192,478 patients randomized to 7 treatment strategies including placebo.⁴ Results from the largest antihypertensive clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), were included in this meta-analysis.⁵ Comparative results are depicted in the Table. Although these data showed no differences between drug therapies in total and cardiovascular disease mortality, low-dose diuretics reduced certain cardiovascular endpoints (ie, heart failure, stroke, cardiovascular disease events) more than other drug therapies.

Angiotensin receptor blockers (ARBs) have not been compared with thiazide diuretics in a trial. Two long-term trials have compared an ARB to other types of drug therapy: losartan vs atenolol in the Losartan Intervention for Endpoint Reduction (LIFE) trial,⁶ and valsartan vs amlodipine in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.⁷ In the LIFE trial, the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke was less with losartan than atenolol (23.8 vs 27.9 events per 1000 patient-years, losartan and atenolol, respectively; number needed to treat=243 people-years, P=.021).⁶ However, in the VALUE trial, the primary endpoint of time to cardiac event was not different between valsartan and amlodipine (25.5 vs 24.7 events per 1000 patient-years, valsartan and amlodipine, respectively; P=.49).⁷

TABLE
First-line treatments for hypertension

Recommendations from others

The Seventh Report of the Joint National Committee (JNC7) recommended thiazide diuretics as preferred initial agents in uncomplicated hypertension.⁸ The European Society of Hypertension/European Society Cardiology recommended either a diuretic, beta-blocker, calcium channel blocker, ACE inhibitor, or ARB for initial therapy stating that blood pressure control to recommended values via any agent is more important than the type of agent used.⁹ Both guidelines identified other antihypertensives that may be used in addition to or in place of thiazide diuretics for compelling indications, such as heart failure, diabetes, high-risk cardiovascular disease, chronic kidney disease, post-myocardial infarction, and secondary stroke prevention.

Evidence summary

Studies investigating the role of sputum Gram stain and culture are both difficult to interpret and compare. The difficulty in obtaining an adequate sputum sample, variation in preparation, levels of skill in interpretation, and the lack of a gold standard for the microbiologic diagnosis of pneumonia all contribute to these difficulties.¹

The sole meta-analysis identified 12 studies that met 17 specified study criteria regarding the use of sputum Gram stain for patients with com-munity-acquired pneumococcal pneumonia.¹ Sample sizes ranged from 16 to 404; reference standards were most frequently sputum culture but also included culture of transtracheal and bronchial aspirates. Results revealed that patients with community-acquired pneumococcal pneumonia were able to produce a valid sputum sample (≥20 neutrophils, <10 squamous epithe-lial cells per low-power field) 70% of the time; the sensitivity of sputum Gram stain ranged from 15% to 69% (when reviewed by a lab technician); and specificity ranged from 11% to 100%.

Because of the heterogeneity of test characteristics, interpreter skill levels, study populations, and reference standards among the studies in this meta-analysis, no single estimate of Gram stain sensitivity or specificity could be reached. Similarly, information regarding the sensitivity and specificity of sputum culture is lacking. Small studies (n=13–85) using blood culture, transthoracic aspi-rate, or transtracheal aspirate as reference standards in untreated cases of definite pneumococcal pneumonia demonstrate sensitivities ranging from 36% to 100%.² There are no reliable data regarding the specificity of sputum culture.

Recent nonrandomized studies and case series have called into question the role of sputum analysis in CAP. In a case-control study of 605 patients hospitalized with CAP diagnosed by chest x-ray and either cough, chest pain, auscultatory findings, or leukocytosis, establishing an etiologic diagnosis did not influence the choice of antibiotic therapy, length of hospital stay, or mortality.³ Of the 482 patients who had microbiological diagnostics performed (Mycoplasma pneumoniae serology, respiratory virus serology, blood culture, or sputum culture), only 132 (27%) had a presumptive etiologic diagnosis made. Therapy was narrowed or focused in 49 of the 132 (37%) patients who had a presumptive eti-ologic diagnosis, while 84 of the 350 (24%) without a presumptive diagnosis had their therapy narrowed (P>.05). There was no difference in in-hospi-tal changes of therapy, the proportion of new regi-mens having a narrower antimicrobial spectrum than the initial one, length of hospital stay, death in hospital, or death within 3 months after admission.

A prospective study of 74 patients suggested sputum studies had little use in a highly selected population aged <65 years with nonsevere, uncomplicated CAP and no comorbidities. In the 74 patients who produced a valid sputum sample, Gram stain failed to identify the causative agent in any patient (sensitivity 0%), and sputum cultures identified a pathogen in only 4 patients (sensitivity 5%). All patients responded similarly and, even with the identification of a pathogen in 4 patients, there were no changes in initial empiric antibi-otics.⁴ In a retrospective case series, 19 of 54 (35%) patients with SCAP did not respond to initial empiric antibiotics and had a change in their antibiotic regimen. There was no difference in mortality between the group that had empiric antibiotic change (11 patients) and the group that had a change based on sputum culture results (3 patients) (relative risk reduction= –0.14; 95% confidence interval, –0.47 to 0.12).⁵ While these studies suggest the need for re-evaluation of routine sputum analysis, the strength of their conclusions are weakened by lack of randomization, small sample size, inadequate blinding, and lack of control group comparison.

Demographic evidence and nonrandomized trials suggest that patients with CAP who have increased risk of infection from multiple-resistant bacteria, such as patients from long-term care facilities, are a unique population that might need to be evaluated differently. However, the only evidence available regarding the utility of either spu-tum Gram stain or culture for patients with NHAP derives from expert opinion. These authors suggest that determining a causative diagnosis of pneumonia in this population is desirable and postulate that sputum examination would permit recognition of multiply resistant organisms that are being isolated with increasing frequency in long-term care facilities.^6,7 However, the same authors acknowledge that the elderly are often too weak or too confused to provide adequate sputum specimens, resulting in a low diagnostic yield, and no data demonstrate that spu-tum evaluation favorably influences the outcome of pneumonia in these patient populations.

Recommendations from others

The Infectious Disease Society of America (IDSA) and the Canadian Infectious Disease Society/Canadian Thoracic Society (CIDS/CTS) recommend routine sputum analysis for all inpa-tients with CAP or NHAP,^8,9 while the American Thoracic Society (ATS)¹⁰ recommends performing sputum analysis only if a drug-resistant pathogen or an organism not covered by usual empiric therapy is suspected. For those with CAP or NHAP treated as outpatients, the ATS, the IDSA, and the CIDS/CTS recommend microbiological testing only if drug-resistant bacteria or an organism not covered by usual empiric therapy is suspected.

Evidence summary

Studies investigating the role of sputum Gram stain and culture are both difficult to interpret and compare. The difficulty in obtaining an adequate sputum sample, variation in preparation, levels of skill in interpretation, and the lack of a gold standard for the microbiologic diagnosis of pneumonia all contribute to these difficulties.¹

The sole meta-analysis identified 12 studies that met 17 specified study criteria regarding the use of sputum Gram stain for patients with com-munity-acquired pneumococcal pneumonia.¹ Sample sizes ranged from 16 to 404; reference standards were most frequently sputum culture but also included culture of transtracheal and bronchial aspirates. Results revealed that patients with community-acquired pneumococcal pneumonia were able to produce a valid sputum sample (≥20 neutrophils, <10 squamous epithe-lial cells per low-power field) 70% of the time; the sensitivity of sputum Gram stain ranged from 15% to 69% (when reviewed by a lab technician); and specificity ranged from 11% to 100%.

Because of the heterogeneity of test characteristics, interpreter skill levels, study populations, and reference standards among the studies in this meta-analysis, no single estimate of Gram stain sensitivity or specificity could be reached. Similarly, information regarding the sensitivity and specificity of sputum culture is lacking. Small studies (n=13–85) using blood culture, transthoracic aspi-rate, or transtracheal aspirate as reference standards in untreated cases of definite pneumococcal pneumonia demonstrate sensitivities ranging from 36% to 100%.² There are no reliable data regarding the specificity of sputum culture.

Recent nonrandomized studies and case series have called into question the role of sputum analysis in CAP. In a case-control study of 605 patients hospitalized with CAP diagnosed by chest x-ray and either cough, chest pain, auscultatory findings, or leukocytosis, establishing an etiologic diagnosis did not influence the choice of antibiotic therapy, length of hospital stay, or mortality.³ Of the 482 patients who had microbiological diagnostics performed (Mycoplasma pneumoniae serology, respiratory virus serology, blood culture, or sputum culture), only 132 (27%) had a presumptive etiologic diagnosis made. Therapy was narrowed or focused in 49 of the 132 (37%) patients who had a presumptive eti-ologic diagnosis, while 84 of the 350 (24%) without a presumptive diagnosis had their therapy narrowed (P>.05). There was no difference in in-hospi-tal changes of therapy, the proportion of new regi-mens having a narrower antimicrobial spectrum than the initial one, length of hospital stay, death in hospital, or death within 3 months after admission.

A prospective study of 74 patients suggested sputum studies had little use in a highly selected population aged <65 years with nonsevere, uncomplicated CAP and no comorbidities. In the 74 patients who produced a valid sputum sample, Gram stain failed to identify the causative agent in any patient (sensitivity 0%), and sputum cultures identified a pathogen in only 4 patients (sensitivity 5%). All patients responded similarly and, even with the identification of a pathogen in 4 patients, there were no changes in initial empiric antibi-otics.⁴ In a retrospective case series, 19 of 54 (35%) patients with SCAP did not respond to initial empiric antibiotics and had a change in their antibiotic regimen. There was no difference in mortality between the group that had empiric antibiotic change (11 patients) and the group that had a change based on sputum culture results (3 patients) (relative risk reduction= –0.14; 95% confidence interval, –0.47 to 0.12).⁵ While these studies suggest the need for re-evaluation of routine sputum analysis, the strength of their conclusions are weakened by lack of randomization, small sample size, inadequate blinding, and lack of control group comparison.

Demographic evidence and nonrandomized trials suggest that patients with CAP who have increased risk of infection from multiple-resistant bacteria, such as patients from long-term care facilities, are a unique population that might need to be evaluated differently. However, the only evidence available regarding the utility of either spu-tum Gram stain or culture for patients with NHAP derives from expert opinion. These authors suggest that determining a causative diagnosis of pneumonia in this population is desirable and postulate that sputum examination would permit recognition of multiply resistant organisms that are being isolated with increasing frequency in long-term care facilities.^6,7 However, the same authors acknowledge that the elderly are often too weak or too confused to provide adequate sputum specimens, resulting in a low diagnostic yield, and no data demonstrate that spu-tum evaluation favorably influences the outcome of pneumonia in these patient populations.

Recommendations from others

The Infectious Disease Society of America (IDSA) and the Canadian Infectious Disease Society/Canadian Thoracic Society (CIDS/CTS) recommend routine sputum analysis for all inpa-tients with CAP or NHAP,^8,9 while the American Thoracic Society (ATS)¹⁰ recommends performing sputum analysis only if a drug-resistant pathogen or an organism not covered by usual empiric therapy is suspected. For those with CAP or NHAP treated as outpatients, the ATS, the IDSA, and the CIDS/CTS recommend microbiological testing only if drug-resistant bacteria or an organism not covered by usual empiric therapy is suspected.

Evidence summary

Studies investigating the role of sputum Gram stain and culture are both difficult to interpret and compare. The difficulty in obtaining an adequate sputum sample, variation in preparation, levels of skill in interpretation, and the lack of a gold standard for the microbiologic diagnosis of pneumonia all contribute to these difficulties.¹

The sole meta-analysis identified 12 studies that met 17 specified study criteria regarding the use of sputum Gram stain for patients with com-munity-acquired pneumococcal pneumonia.¹ Sample sizes ranged from 16 to 404; reference standards were most frequently sputum culture but also included culture of transtracheal and bronchial aspirates. Results revealed that patients with community-acquired pneumococcal pneumonia were able to produce a valid sputum sample (≥20 neutrophils, <10 squamous epithe-lial cells per low-power field) 70% of the time; the sensitivity of sputum Gram stain ranged from 15% to 69% (when reviewed by a lab technician); and specificity ranged from 11% to 100%.

Because of the heterogeneity of test characteristics, interpreter skill levels, study populations, and reference standards among the studies in this meta-analysis, no single estimate of Gram stain sensitivity or specificity could be reached. Similarly, information regarding the sensitivity and specificity of sputum culture is lacking. Small studies (n=13–85) using blood culture, transthoracic aspi-rate, or transtracheal aspirate as reference standards in untreated cases of definite pneumococcal pneumonia demonstrate sensitivities ranging from 36% to 100%.² There are no reliable data regarding the specificity of sputum culture.

Recent nonrandomized studies and case series have called into question the role of sputum analysis in CAP. In a case-control study of 605 patients hospitalized with CAP diagnosed by chest x-ray and either cough, chest pain, auscultatory findings, or leukocytosis, establishing an etiologic diagnosis did not influence the choice of antibiotic therapy, length of hospital stay, or mortality.³ Of the 482 patients who had microbiological diagnostics performed (Mycoplasma pneumoniae serology, respiratory virus serology, blood culture, or sputum culture), only 132 (27%) had a presumptive etiologic diagnosis made. Therapy was narrowed or focused in 49 of the 132 (37%) patients who had a presumptive eti-ologic diagnosis, while 84 of the 350 (24%) without a presumptive diagnosis had their therapy narrowed (P>.05). There was no difference in in-hospi-tal changes of therapy, the proportion of new regi-mens having a narrower antimicrobial spectrum than the initial one, length of hospital stay, death in hospital, or death within 3 months after admission.

A prospective study of 74 patients suggested sputum studies had little use in a highly selected population aged <65 years with nonsevere, uncomplicated CAP and no comorbidities. In the 74 patients who produced a valid sputum sample, Gram stain failed to identify the causative agent in any patient (sensitivity 0%), and sputum cultures identified a pathogen in only 4 patients (sensitivity 5%). All patients responded similarly and, even with the identification of a pathogen in 4 patients, there were no changes in initial empiric antibi-otics.⁴ In a retrospective case series, 19 of 54 (35%) patients with SCAP did not respond to initial empiric antibiotics and had a change in their antibiotic regimen. There was no difference in mortality between the group that had empiric antibiotic change (11 patients) and the group that had a change based on sputum culture results (3 patients) (relative risk reduction= –0.14; 95% confidence interval, –0.47 to 0.12).⁵ While these studies suggest the need for re-evaluation of routine sputum analysis, the strength of their conclusions are weakened by lack of randomization, small sample size, inadequate blinding, and lack of control group comparison.

Demographic evidence and nonrandomized trials suggest that patients with CAP who have increased risk of infection from multiple-resistant bacteria, such as patients from long-term care facilities, are a unique population that might need to be evaluated differently. However, the only evidence available regarding the utility of either spu-tum Gram stain or culture for patients with NHAP derives from expert opinion. These authors suggest that determining a causative diagnosis of pneumonia in this population is desirable and postulate that sputum examination would permit recognition of multiply resistant organisms that are being isolated with increasing frequency in long-term care facilities.^6,7 However, the same authors acknowledge that the elderly are often too weak or too confused to provide adequate sputum specimens, resulting in a low diagnostic yield, and no data demonstrate that spu-tum evaluation favorably influences the outcome of pneumonia in these patient populations.

Recommendations from others

The Infectious Disease Society of America (IDSA) and the Canadian Infectious Disease Society/Canadian Thoracic Society (CIDS/CTS) recommend routine sputum analysis for all inpa-tients with CAP or NHAP,^8,9 while the American Thoracic Society (ATS)¹⁰ recommends performing sputum analysis only if a drug-resistant pathogen or an organism not covered by usual empiric therapy is suspected. For those with CAP or NHAP treated as outpatients, the ATS, the IDSA, and the CIDS/CTS recommend microbiological testing only if drug-resistant bacteria or an organism not covered by usual empiric therapy is suspected.