Patient Care

In the Literature: HM-Related Research You Need to Know


Literature at a Glance

A guide to this month’s studies

  1. Risks of preoperative tobacco use
  2. Timing of perioperative beta-blocker use and outcomes
  3. Continuous vs. bolus dose diuretics in CHF
  4. Outcomes of carotid endearterectomy and carotid artery stenting
  5. Protocol for low-risk chest pain
  6. Effect of esomeprazole on recurrent ulcer rates in clopidogrel users
  7. Effect of ICU QI project on hospital mortality
  8. Acute kidney injury risks after coronary angiography

Smokers Have Worse Perioperative Outcomes

Clinical question: Do current smokers have worse 30-day postoperative outcomes than nonsmokers after noncardiac surgery?

Background: Approximately 20% of adults in the U.S. smoke cigarettes, and a significant fraction of surgical patients are current smokers. Despite concerns that smoking is associated with worse postoperative outcomes, these increased risks have not been quantified across multiple outcomes.

Study design: Retrospective cohort study.

Setting: Surgical patients in 200 centers throughout the United States.

Synopsis: Data from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2008 were acquired, and 391,006 patient records were reviewed. Postoperative morbidity and mortality were significantly greater in smokers. Current smokers had a 40% increased odds of death at 30 days compared to people who had never smoked (OR 1.38, 95% CI, 1.11-1.72). Current smokers also had significantly greater odds of pulmonary complications, including pneumonia (OR 2.09, 95% CI, 1.80-2.43), unplanned intubation (OR 1.87, 95% CI, 1.58-2.21), and mechanical ventilation (OR 1.53, 95% CI, 1.31-1.79).

Furthermore, current smokers had significantly greater odds of postoperative cardiac arrest (OR 1.57, 95% CI, 1.10-2.25), myocardial infarction (OR 1.80, 95% CI, 1.11-2.25), and stroke (OR 1.73, 95% CI, 1.18-2.53). Odds of infectious complications were increased in current smokers, including deep incisional infections (OR 1.42, 95% CI, 1.21-1.68), sepsis (OR 1.30, 95% CI, 1.20-1.60), and septic shock (OR 1.55, 95% CI, 1.29-1.87).

Limitations of this study include self-reporting of smoking habits and absence of detailed smoking history just before and after surgery.

Bottom line: Current smokers have significantly increased postoperative morbidity and mortality after noncardiac surgery.

Citation: Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology. 2011;114(4):837-846.

Clinical Short


Retrospective review of patients with acute pulmonary embolism in emergency departments reveals low mortality rate (1%), but patients with fatal pulmonary emboli had low rates of empiric anticoagulation and fibrinolytic administration.

Citation: Pollack CV, Schreiber D, Goldhaber S, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57(6):700-706.

Chronic Beta-Blockade Reduces Postoperative Myocardial Ischemia

Clinical question: Does the timing of beta-blocker exposure affect cardiovascular outcomes in patients undergoing elective, noncardiac surgery?

Background: Several studies have demonstrated that beta-blockers are associated with decreased perioperative cardiovascular morbidity and mortality. Study designs have varied greatly, and differences in dosing and timing of beta-blocker administration have caused conflicting results. The question of when to initiate beta-blockers prior to surgery remains controversial.

Study design: Prospective cohort study.

Setting: Three academic medical centers in Canada.

Synopsis: Data from 1,398 patients who had elective, noncardiac surgery with either acute (n=436) or chronic (n=962) beta-blocker exposure were analyzed. Acute exposure was defined as receiving a beta-blocker for the first time within 48 hours after surgery, whereas chronic beta-blocker exposure was defined as receiving a beta-blocker seven to 10 days prior to surgery.

Patients with chronic beta-blocker exposure were more likely to have a history of coronary disease, heart failure, or hypertension and were more likely to be receiving statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors. The primary outcome was a composite of major cardiac events, including myocardial infarction, nonfatal cardiac arrest, and 30-day mortality.

Major cardiac events occurred more often in patients with acute versus chronic beta-blocker exposure in both the entire cohort (8.3% vs. 4.7%) and in the propensity-matched cohort (8.0% vs. 3.0%). Myocardial infarction accounted for the majority of cardiac events.

There are several limitations of this study: The sample size was small, the beta-blocker and dosage used varied, and the indication and exact duration of chronic beta-blocker therapy was unknown.

Bottom line: Chronic beta-blocker therapy reduces major cardiac events compared with acute beta-blocker therapy in patients undergoing elective, noncardiac surgery.

Citation: Ellenberger C, Tait G, Beattie WS. Chronic beta-blockade is associated with a better outcome after elective noncardiac surgery than acute beta-blockade: a single-center propensity-matched cohort study. Anesthesiology. 2011;114(4):817-823.

Continuous and Bolus Dosing of Furosemide Provides Similar Outcomes in Heart Failure

Clinical question: Does continuous infusion compared to bolus dosing of furosemide improve clinical outcomes in patients with acute decompensated heart failure?

Background: Diuresis with furosemide is commonly used to manage acute decompensated heart failure, but it is uncertain which dosing strategy is optimal. Continuous infusion of furosemide has been proposed as a more effective method of diuresis compared with bolus dosing, especially when higher doses are required, but data comparing the two strategies are limited.

Study design: Randomized, double-blind, controlled trial.

Setting: Twenty-six clinical sites in the U.S. and Canada.

Synopsis: Researchers randomized 308 patients with acute decompensated heart failure to either continuous or bolus intravenous dosing, which was calculated as either the equivalent of their daily oral dose (low-dose strategy) or 2.5 times their daily dose (high-dose strategy). Mean ejection fraction was 35%. Primary endpoints were patients’ assessment of symptoms based on a visual-analogue scale quantified as area under the curve, as well as change in serum creatinine level at 72 hours.

No significant differences between the continuous and bolus dosing groups were evidenced in primary endpoints at 72 hours. Patients in the bolus group had more dose increases at 48 hours (21% vs. 11%, P=0.01). Patients in the high-dose group were more likely to change from intravenous to oral doses at 48 hours (31% vs. 17%, P<0.001) and had greater net fluid loss (4.9L vs. 3.6L, P=0.01). More patients in the high-dose versus low-dose group had an increase in creatinine ≥0.3 mg/dL (23% vs. 14%, P=0.04). Hospital length of stay, readmission, and mortality rates were similar between the groups.

Bottom line: Diuretic therapy administered by continuous infusion or bolus dosing in patients with acute decompensated heart failure have equivocal effects on patients’ symptoms and kidney function.

Citation: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805.

Clinical Short


Case-control study shows that bisphosphonate therapy for ≥5 years in older women increases the risk of subtrochanteric or femoral shaft fractures, although the absolute risk of these fractures is low.

Citation: Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783-789.

Carotid Endarterectomy Is Better than Carotid Artery Stenting

Clinical question: How do the clinical outcomes of carotid artery stenting compare with those of carotid endarterectomy?

Background: Whether carotid artery stenting or carotid endarterectomy is the preferred therapy for patients with carotid artery stenosis has been highly controversial. This study was a meta-analysis of all available data from randomized trials comparing carotid endarterectomy to carotid artery stenting.

Study design: Meta-analysis.

Setting: Teaching and nonteaching hospitals.

Synopsis: Thirteen randomized trials were identified with 3,723 patients who had undergone endarterectomy and 3,754 patients who had undergone carotid artery stenting. Outcomes included stroke, myocardial infarction, cranial nerve injury, and death or stroke, and these outcomes were divided as either short-term (<30 days) or long-term (>1 year) outcomes.

Patients who had undergone carotid artery stenting had less risk of short-term myocardial infarction (OR 0.48, 95% CI, 0.29–9.78, P=0.003) and less risk of cranial nerve injury (OR 0.09, 95% CI, 0.05–0.16, P<0.001). However, carotid artery stenting had a significantly higher risk of short-term stroke and combined death or stroke, and also significantly higher long-term risk of stroke and combined death or stroke. The association between carotid artery stenting and stroke was stronger in the subgroup of patients >68 years but not in patients <68 years. There was no significant heterogeneity, and no significant modifying associations were revealed by meta-regression analysis.

Limitations include potentially unpublished small studies favoring carotid endarterectomy and a significant publication bias regarding short-term death.

Bottom line: Although carotid artery stenting has less short-term risk of myocardial infarction and cranial nerve injury, carotid endarterectomy has less short-term and long-term risks of stroke and death.

Citation: Economopoulus KP, Sergentanis TN, Tsivgoulis G, Mariolis AD, Stefanadis C. Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes. Stroke. 2011;42:687-692.

Chest Pain Protocol Can Identify Low-Risk Chest Pain in Emergency Departments

Clinical question: Can a two-hour accelerated diagnostic protocol (ADP) based on electrocardiogram, point-of-care biomarkers, and Thrombolysis in Myocardial Infarction (TIMI) score safely identify patients with chest pain at very low short-term risk of major cardiac events?

Background: Evaluation of patients presenting to EDs with chest pain utilize significant amounts of hospital resources. A safe, reproducible, and expeditious process to identify patients at low risk for short-term cardiac events is desired.

Study design: Prospective cohort study.

Setting: Fourteen urban EDs in nine countries across the Asia-Pacific region.

Synopsis: The study included 3,582 patients presenting to an ED with at least five minutes of chest pain suggestive of an acute coronary syndrome and for whom further evaluation with serial cardiac biomarkers was planned. A negative ADP was defined as TIMI score of 0, no new ischemic changes on initial electrocardiogram, and normal cardiac biomarkers at zero and two hours after arrival.

All components of the ADP were negative for 352 patients (9.8%). Only three low-risk patients (0.9%) by ADP had a major cardiac event during the 30-day follow-up period, yielding a negative predictive value of 99.1% (95% CI, 97.3-99.8%). Mean hospital stay for the low-risk group with a negative ADP was 43 hours with a median of 26 hours. The authors suggest that a 10% reduction in prolonged workups of patients with chest pain could be seen with implementation of this protocol.

Potential limitations include applicability only to a select cohort of patients with chest pain and the low specificity of the protocol.

Bottom line: A two-hour diagnostic protocol can help expedite discharge of patients with very-low-risk chest pain.

Citation: Than T, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;337:1077-1084.

Clinical Shorts


Randomized, placebo-controlled trial of 150 patients hospitalized with sickle cell crisis found no significant difference in duration of vaso-occlusive pain crisis with inhaled nitric oxide versus placebo.

Citation: Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis. JAMA. 2011;305(9):893-902.


Meta-analysis demonstrates that self-monitoring of international normalized ratio and self-titration of warfarin by motivated patients is associated with fewer deaths and thromboembolic events without increasing the risk of major bleeding.

Citation: Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: Effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med. 2011;154(7):472-482.


Randomized trial comparing tracheotomy by fifth vs. 15th day of mechanical ventilation shows no difference in length of hospital stay, frequency of ventilator-associated pneumonia, mortality, or quality of life.

Citation: Trouillet J, Luyt C, Guiguet M, et al. Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac surgery. Ann Intern Med. 2011;154(6):373-383.

Esomeprazole Reduces Peptic Ulcer Recurrence in Patients on Clopidogrel

Clinical question: Does esomeprazole prevent recurrent peptic ulcers in patients with atherosclerosis on clopidogrel?

Background: Although clopidogrel is sometimes used as an alternative antiplatelet agent to aspirin, a significant rate of recurrent ulcer bleeding on clopidogrel has been described. No previous prospective trial has studied whether a proton-pump inhibitor (PPI) can reduce the risk of peptic ulcer recurrence or bleeding in atherosclerotic patients on clopidogrel.

Study design: Randomized controlled trial.

Setting: A single veterans hospital in Taiwan.

Synopsis: One hundred sixty-five patients were enrolled with a past history of peptic ulcer disease, no signs of ulcer recurrence by endoscopy, and current use of clopidogrel 37.5 mg to 75 mg per day. All patients had atherosclerosis and had been on clopidogrel for at least two weeks, without aspirin, corticosteroids, anticoagulants, or recent treatment with a PPI. Patients were randomized to clopidogrel 75 mg at night (n=82) or clopidogrel 75 mg at night plus esomeprazole 20 mg before breakfast. Follow-up endoscopy was performed at six months or as needed for symptoms.

Recurrence of ulcer was found in 1.2% of patients on clopidogrel plus esomeprazole versus 11.0% in patients on clopidogrel alone (95% CI, 2.6-17.0%; P=0.009). The pharmacodynamic study revealed no significant differences in platelet aggregation within or between treatment groups on day 1 or day 28. No significant differences were seen on the incidence of ischemic events in this setting, but the trial was underpowered to draw conclusions on this outcome.

An important limitation is that the findings of this study are applicable only to patients on clopidogrel monotherapy and not dual antiplatelet therapy.

Bottom line: A significant reduction in recurrent peptic ulcers is seen with the combination of esomeprazole plus clopidogrel, versus clopidogrel alone, in patients with atherosclerosis and a history of peptic ulcer disease.

Citation: Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology. 2011;140:791-798.

ICU Quality-Improvement Project Reduces Hospital Mortality

Clinical question: Does a quality-improvement (QI) project in the ICU reduce in-hospital mortality and length of stay among elderly adults?

Background: Previous studies have shown that ICU-acquired infections are associated with increased morbidity and mortality, and QI initiatives reduce hospital-acquired infections. However, it has not been demonstrated that QI projects in the ICU reduce in-hospital mortality or length of stay.

Study design: Retrospective cohort study.

Setting: Four hundred fifty-nine Midwestern hospitals.

Synopsis: This study included 238,937 adults age >65 who were hospitalized in an ICU from 2001 to 2006 at one of 95 hospitals invited to implement the Keystone ICU Project. The control group included 1,091,547 elderly adults at one of 364 hospitals not invited to participate in the project. The Keystone ICU Project implements evidence-based practices to reduce rates of catheter-related bloodstream infections and ventilator-associated pneumonia.

Hospital mortality was not significantly reduced during initiation or implementation of the project; however, a significant reduction in hospital mortality occurred in the study group during one to 12 months post-implementation (OR=0.83 vs. 0.88, P=0.041) and 13 to 22 months post-implementation (OR=0.76 vs. 0.84, P=0.007). In contrast, length of stay did not differ significantly between the two groups, but the study was underpowered for this outcome.

The study is limited by the complexity of the Keystone ICU Project, as well as the exclusion of smaller hospitals and nonelderly adults. The study is promising because implementing a QI project in the ICU is associated with no known harms and might confer a mortality benefit at a relatively low cost.

Bottom line: Elderly adults had lower in-hospital mortality after implementation of the Keystone QI project in ICUs.

Citation: Lipitz-Snyderman A, Steinwachs D, Needham DM, Colantuoni E, Morlock LL, Pronovost PJ. Impact of a statewide intensive care unit quality improvement initiative on hospital mortality and length of stay: retrospective comparative analysis. BMJ. 2011;342:d219.

Serious Long-Term Risks with Acute Kidney Injury after Coronary Angiography

Clinical question: Does postcoronary angiography acute kidney injury (AKI) increase the risk of poor long-term clinical outcomes?

Background: Previous studies have shown that AKI following coronary angiography increases the risk of poor short-term clinical outcomes, such as in-hospital myocardial infarction, prolonged hospital stay, and early mortality. Little is known about the long-term cardiovascular and renal outcomes following post-coronary angiography AKI.

Study design: Retrospective cohort study.

Setting: All coronary angiography centers in Alberta, Canada.

Synopsis: The study included 14,782 adults who were ≥18 years of age, underwent coronary angiography, had a baseline creatinine measurement, did not have end-stage renal disease (ESRD), and had a creatinine measurement within seven days after coronary angiography.

During a median follow-up period of 19.7 months, 1,099 (7.4%) patients developed stage 1 AKI and 321 (2.2%) developed stage 2 or 3 AKI. Mortality increased twofold with stage 1 AKI and >3-fold with stage 2 or 3 AKI. Risk of ESRD increased substantially by >11-fold in patients with stage 2 or 3 AKI. Risk of hospitalization for subsequent AKI, myocardial infarction, and heart failure also increased significantly following post-coronary angiography AKI.

Patients who experienced AKI were older, had more severe CAD, were more likely to have such comorbidities as DM, HTN, and heart failure, and had lower baseline GFRs. However, the underlying comorbidities do not completely explain the increased risk of poor long-term outcomes in the adjusted analysis.

Limitations include missing or underestimating mild cases of AKI, residual confounding from unmeasured variables, and inability of retrospective comparative studies to establish causality.

Bottom line: Adults with post-coronary angiography AKI are at increased risk of poor long-term cardiovascular and renal outcomes.

Citation: James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation. 2011;123(4):409-416. TH

Pediatric HM Literature

Proton-Pump Inhibitors Ineffective for Gastroesophageal Reflux Disease in Children

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: What is the efficacy of proton-pump inhibitors (PPIs) in children with gastroesophageal reflux disease (GERD)?

Background: Gastroesophageal reflux is both a common and normal phenomenon in infants. GERD refers to the presence of abnormal symptoms ascribed to the reflux and frequently is treated in children in a manner similar to adults with reflux esophagitis. PPIs often are prescribed as front-line treatment, and their use has increased dramatically in recent years, though their effectiveness in children remains unclear.

Study design: Systematic review of the literature.

Setting: Hawaii’s largest health insurer.

Synopsis: Medline, Embase, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs) and crossover studies performed to evaluate the efficacy of PPIs in children 0-17 years with GERD and no complicating diseases. Ten RCTs and two crossover studies were analyzed and rated independently by two reviewers.

Due to significant heterogeneity between the studies, a meta-analysis was not possible; studies were discussed separately. PPIs offered no advantage when compared with controls (alginates, ranitidine, different dosages of PPIs), and similar rates of adverse events were reported between treatment groups.

This study is hampered by notable heterogeneity of patient type, symptoms, and study design in many of the trials. However, the results are in line with discussions at a recent FDA Gastrointestinal Drugs Advisory Committee meeting, which reviewed the lack of efficacy of PPIs in infants in four recent Phase 3 clinical trials.

Bottom line: Little evidence supports the widespread use of PPIs in children.

Citation: Van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM, Benninga MA. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935.

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