Literature Review

ITL: Physician Reviews of HM-Relevant Research


In This Edition

Literature At A Glance

A guide to this month’s studies

  1. Initial trophic feedings effective for patients with acute lung injury
  2. IM vs. IV benzodiazepines in status epilepticus
  3. CDI risk following antibiotic cessation
  4. Acid suppression associated with increased complications in CDI patients
  5. Perioperative statins and cardiac events in surgical patients
  6. Enoxaparin vs. unfractionated heparin during PCI
  7. Optimal serum potassium levels for AMI patients
  8. PPIs superior to H2-blockers for lowering UGI bleeding following ACS and STEMI

Initial Lower-Volume Enteral Feeding Better Tolerated, but Has No Mortality Benefit

Clinical question: In mechanically ventilated patients with acute lung injury, do initial lower-volume enteral feedings (trophic feedings) improve clinical outcomes when compared with full enteral feedings?

Background: Malnutrition in critically ill patients is associated with poor outcomes, but conflicting data exist regarding the best timing, amount, and formulation of enteral nutrition to initiate. Initiation of lower-volume enteral feeding with periodic assessment of gastric residual volume is common practice, but the effects of this practice are unknown.

Study design: Multicenter randomized controlled open-label study.

Setting: Forty-four hospitals in the National Heart, Lung, and Blood Institute (NHLBI) Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.

Synopsis: One thousand patients with acute lung injury receiving mechanical ventilation for longer than 72 hours were randomized using a Web-based system to receive either trophic or full enteric feedings for the first six days of mechanical ventilation. After the sixth day, a full enteric feeding protocol was used in all patients. All analyses were by intention-to-treat.

There was no significant difference between the trophic and full enteral feeding groups with regard to the primary outcome of ventilator-free days through Day 28 (14.9% vs. 15.0%, P=0.89). There were also no significant differences between groups in secondary outcomes, which included 60-day mortality, ICU-free days, organ-failure-free days, or the incidence of new infections. However, gastrointestinal intolerances occurred less often in the trophic feeding group, and these patients received fewer anti-diarrheal and prokinetic agents. The full feeding group gained 2.1 liters of fluid by Day 7, but this fluid gain did not cause significant differences in measures of circulatory or pulmonary physiology.

Limitations include open-label study design and inclusion of only critically ill adult medical patients with acute lung injury.

Bottom line: Initial lower-volume tube feedings in mechanically ventilated patients with acute lung injury did not improve clinical outcomes compared with full enteral feedings, but they were associated with fewer instances of gastrointestinal intolerance.

Citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795-803.

Intramuscular Benzodiazepines as Good as IV Benzodiazepines in Status Epilepticus

Clinical question: Is intramuscular (IM) midazolam noninferior to intravenous lorazepam in patients in status epilepticus?

Background: Studies have shown that IV benzodiazepines, particularly lorazepam, are effective for patients in status epilepticus. Studies have not evaluated IM benzodiazepines. However, many emergency medical service (EMS) agencies use IM midazolam because IM administration is easier than IV administration, and midazolam has a longer nonrefrigerated shelf life than lorazepam does.

Study design: Randomized, double-blinded clinical trial.

Setting: Thirty-three EMS agencies across the United States.

Synopsis: Based on the 893 adults and children in status epilepticus included in this double-blind study, the researchers found IM midazolam to be noninferior to, and in fact superior to, IV lorazepam for treating seizures prior to arrival at EDs. Specifically, they found 10% more (95% CI 4.0% to 16.1%; P<0.001 for noninferiority and P<0.001 for superiority) seizure-free patients arriving at EDs when IM midazolam was administered. Seizures ceased in patients given IM midazolam in less time on average than it took for paramedics to administer IV lorazepam.

Hospitalists might be less inclined than EMS personnel to use IM midazolam because their patients have established IV access and refrigerated drugs are readily available. However, since IM midazolam was superior to IV lorazepam in this prehospital study, a similar trial in hospitalized patients is warranted. In subsequent trials, it would be useful to administer both midazolam and lorazepam via IM and IV routes, and IM injections by an autoinjector could be compared with the conventional manner.

Bottom line: In the prehospital setting, IM midazolam is at least as good as IV lorazepam in treating status epilepticus in children and adults.

Citation: Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.

Clostridium Difficile Infection Risk Remains High at Least Three Months after Antibiotics Are Stopped

Clinical question: How long are patients at higher risk for Clostridium difficile infection (CDI) after completing antibiotics?

Background: Studies have shown that patients given antibiotics are at higher risk for CDI than those who are not, particularly if they take multiple antibiotics at high doses for a prolonged period of time. However, it is not known how long a patient remains at high risk for CDI after completing antibiotic therapy.

Study design: Case-control study.

Setting: Nine hospitals in Netherlands.

Synopsis: The study compared 337 hospitalized patients who had CDI with 337 nondiarrheal controls and 227 non-CDI diarrheal controls. The study showed a seven- to tenfold increased risk for CDI during antibiotic treatment and in the 30 days following cessation of antibiotics. A 2.7-fold increased risk of CDI was seen in the one- to three-month period after antibiotic treatment was stopped.

Because researchers only obtained information about antibiotic use in the three months preceding the onset of diarrhea, it is unknown if CDI risk remains elevated longer than three months after antibiotics are stopped. Also of note, the enzyme immunoassays used in this study to diagnose C. diff had sensitivities of between 60% and 85%.

As hospitalists, this information can be used to advise patients about their continued risk for CDI after cessation of antibiotics. Further studies are needed to determine the risk after three months.

Bottom line: Patients are at highest risk for CDI up to one month after stopping antibiotics but continue to be at higher risk for at least two additional months.

Citation: Hensgens MPN, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012;67:742-748.

Acid Suppression and Poor Outcomes in C. Diff Patients

Clinical question: What are potential modifiable risk factors associated with increased complications and mortality in patients hospitalized with C. diff infection (CDI)?

Background: CDI is a growing cause of morbidity and mortality in hospitalized patients. Evidence is growing for the association of acid suppression, among other modifiable risk factors, with complications and mortality in patients with CDI.

Study design: Retrospective case review.

Setting: Naval medical center.

Synopsis: A laboratory, medical record, and pharmacy database query found 485 patients with CDI. Complications of CDI were defined as ICU admission, surgery, and megacolon. Factors significantly associated with CDI complications and mortality were admission for CDI, corticosteroid use >5 mg per day, age ≥80 years, and prescription acid suppression (including H2-blockers and proton-pump inhibitors).

The latter two risk factors were associated with mortality alone. In multivariable regression, the odds of mortality among patients on acid suppression was more than four times the odds of those not on acid suppression (OR 4.74, 95% CI, 1.57 to 14.36).

Although this is a retrospective cohort study and cannot prove a causal relationship, the data add to a growing body of evidence supporting the risk of CDI complications and mortality for those on acid suppression.

Bottom line: In hospitalized patients with CDI, acid suppression is associated with increased complications and mortality and should be discontinued in this population when possible.

Citation: Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis. 2011;53:1173-1178.

Perioperative Statins Reduce Cardiac Events for Surgical Patients

Clinical question: Does perioperative statin use improve cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay) in statin-naive patients undergoing cardiac or non-cardiac surgery?

Background: Statins have been hypothesized to reduce perioperative cardiac complications because they reduce vascular and systemic inflammation caused by surgery, and several meta-analyses have demonstrated their efficacy. To date, no meta-analyses have specifically evaluated the benefits of perioperative statins in non-cardiac surgery from randomized controlled trials.

Study design: Systematic review of the literature and meta-analysis.

Setting: Fifteen randomized controlled trials of hospitalized surgical patients.

Synopsis: A systematic review examined the effects of statins on a variety of perioperative cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay); 11 of the 15 patients were undergoing cardiac surgery.

Perioperative statins decreased the risk of atrial fibrillation in patients undergoing cardiac surgery (RR 0.56; 95% CI 0.45-0.69; number needed to treat [NNT], 6). In both cardiac and non-cardiac surgical patients, statins reduced the risk of myocardial infarction (RR 0.53; 95% CI 0.38 to 0.74; NNT 23). Statin treatment also reduced the mean length of hospital stay (in days, mean difference -0.32; 95% CI, -0.53 to -0.11) but did not reduce the length of ICU stay (mean difference -0.08; 95% CI, -0.25 to 0.10). Risk of death was not reduced with statin treatment (RR 0.62; 95% CI, 0.34 to 1.14).

Bottom line: Perioperative statins reduce the risk of postoperative atrial fibrillation in cardiac surgical patients, the risk of postoperative MI in cardiac and non-cardiac surgical patients, and the mean length of hospital stay.

Citation: Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181-188.

Enoxaparin Safe and Effective during Percutaneous Coronary Intervention

Clinical question: Is enoxaparin safe and efficacious compared with unfractionated heparin during percutaneous coronary intervention (PCI)?

Background: Despite problems with the use of unfractionated heparin during PCI, current guidelines give it a Class 1 recommendation for PCI in ST-elevation myocardial infarction (MI). There is growing evidence that enoxaparin can provide predictable, effective anticoagulation during PCI. Although several trials have examined this issue, none have been sufficiently powered to evaluate mortality.

Study design: Systematic review and meta-analysis.

Setting: Twenty-three trials or registries of patients undergoing PCI.

Synopsis: A systematic review found 23 trials representing 30,966 patients that examined the effects of enoxaparin versus unfractionated heparin on risk of mortality, MI, complications of MI, and major bleeding. Of these, 10,243 (33.1%) patients underwent primary PCI for ST elevation MI, 8,750 (28.2%) underwent PCI after fibrinolysis, and 11,973 (38.7%) patients had either scheduled PCI or PCI for non-ST elevation acute coronary syndrome.

Of all the patients, 13,943 (45%) received enoxaparin and 17,023 (55%) received unfractionated heparin. Enoxaparin was associated with significant reductions in all-cause mortality (RR 0.66; 95% CI, 0.57 to 0.76), composite of death or MI (RR 0.68; 95% CI, 0.57 to 0.81), and complications of MI (RR 0.75; 95% CI, 0.6 to 0.85). For patients who received primary PCI for ST elevation MI, enoxaparin reduced the risk of complications of MI by 44% (RR 0.56; 95% CI, 0.42 to 0.76). Enoxaparin also reduced the risk of major bleeding (RR 0.80, 95% CI, 0.68 to 0.95) with even more striking results for the 14 studies that compared intravenous enoxaparin to unfractionated heparin (RR 0.66; 95% CI, 0.52 to 0.83).

Bottom line: Enoxaparin is safe and efficacious when used during PCI. Patients who receive enoxaparin during PCI have reduced risk for death, MI, complications of MI, and major bleeding when compared with patients who receive unfractionated heparin.

Citation: Silvain J, Beygui F, Barthelmy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.

Serum Potassium Levels and Mortality in Acute Myocardial Infarction

Clinical question: What is the relationship between serum potassium levels and mortality in acute myocardial infarction (AMI) patients?

Background: Several smaller studies in the pre-beta-blocker and pre-reperfusion era recommended maintaining serum potassium levels between 4.0 mEq/L and 5.0 mEq/L in AMI patients. However, current studies examining the relationship between potassium levels and mortality in AMI patients are lacking.

Study design: Retrospective cohort study.

Setting: Multicenter study involving 67 hospitals in the U.S.

Synopsis: Using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, this study showed there was a U-shaped relationship between mean post-admission serum potassium level and in-hospital mortality.

Compared with the reference group of 3.5 mEq/L to less than 4.0 mEq/L (mortality rate 4.8%; 95% CI, 4.4% to 5.2%), mortality was comparable for those with mean post-admission potassium of 4.0 mEq/L to less than 4.5 mEq/L (5.0%; 95% CI, 4.7% to 5.3%). Mortality was twice as great for potassium of 4.5 mEq/L to less than 5.0 mEq/L (10.0%; 95% CI, 9.1% to 10.9%), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. Rates of ventricular fibrillation or cardiac arrest were higher among patients with potassium levels of less than 3.0 mEq/L or more than 5.0 mEq/L.

Bottom line: For inpatients with AMI, serum potassium levels of 3.5 mEq/L to 4.5 mEq/L should be maintained for the best outcomes. Repletion of serum potassium to levels greater than 4.5 mEq/L is associated with increased mortality and should be avoided.

Citation: Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307:157-164.

Proton-Pump Inhibitors Better than H2-Blockers in ACS and STEMI

Clinical question: Are proton-pump inhibitors (PPIs) better than H2-blockers at preventing UGI bleeding in patients after acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI)?

Background: It is not definitively known if PPIs are the same or better than H2-blockers in preventing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and anticoagulants) after ACS or STEMI.

Study design: Randomized double-blinded controlled trial.

Setting: Single hospital.

Synopsis: Patients with ACS or STEMI were treated with aspirin, clopidogrel, and enoxaparin or thrombolytics. They were then randomized to either esomeprazole 20 mg or famotidine 40 mg, both administered nightly. They were followed throughout their hospital stay and were then followed between four and 52 weeks after discharge (mean duration: 19 weeks for esomeprazole, 18 weeks for famotidine). The primary end point was time to a composite outcome, consisting of UGI bleeding, obstruction, or perforation. Overall, 313 patients were randomized (164 to esomeprazole and 149 to famotidine).

The treatment groups were equivalent in baseline characteristics, and compliance in both groups was excellent (>98%). The primary endpoint occurred in three patients in the esomeprazole group and in 12 patients in the famotidine group (hazard ratio 0.21; 95% CI, 0.06 to 0.75; P=0.008).

Bottom line: PPIs are superior to H2-blockers in reducing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and enoxaparin or thrombolytics) after ACS and STEMI. This confirms the recommendations of the 2010 ACCF/ACG/AHA Expert Consensus that PPIs should be used in those on dual antiplatelet therapy on anticoagulants.

Citation: Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol. 2012;107:389-396.

Clinical Shorts


A prospective observational study demonstrated that nurse-pharmacist collaboration was a cost-effective intervention to reduce medication discrepancies that could have potentially caused moderate to severe harm on admission and discharge.

Citation: Feldman LS, Costa LL, Feroli ER, et al. Nurse-pharmacist collaboration on medication reconciliation prevents potential harm [published online ahead of print February 27, 2012]. J Hosp Med. doi:10.1002/jhm.1921.


Most adult Medicare beneficiaries who present for emergency care for deliberate self-harm are discharged to the community (62.5%); about half received recommended mental health assessments in the ED (47.5%) or follow-up outpatient mental health treatment within 30 days (52.4%).

Citation: Olfson M, Marcus SC, Bridge JA. Emergency treatment of deliberate self-harm. Arch Gen Psychiatry. 2012;69:80-88.


This study showed that introducing palliative care early led to significant improvements in patients’ quality of life and, compared with patients receiving standard care, these patients had less aggressive care at the end of life.

Citation: Greer JA, Pirl WF, Jackson VA, et al. Effect of early palliative care on chemotherapy use and end-of-life care in patients with metastatic non-small-cell lung cancer. J Clin Oncol. 2012;30:394-400.

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