In the Literature


In This Edition

Literature at a Glance

A guide to this month’s studies



A prospective study of stroke and TIA patients observed a high prevalence of nontraditional symptoms, with 52% of women reporting one or more nontraditional symptoms, most frequently altered mental status.

Citation: Lisabeth LD, Brown DL, Hughes R, Majersik JJ, Morgenstern LB. Acute stroke symptoms: comparing women and men. Stroke. 2009;40(6):2031-2036.


Small Scottish prospective cohort study of anemic critical-illness survivors observed that half had persistent anemia after six months associated with higher levels of circulating inflammatory markers and decreased reticulocytosis.

Citation: Bateman AP, McArdle F, Walsh TS. Time course of anemia during six months follow up following intensive care discharge and factors associated with impaired recovery of erythropoiesis. Crit Care Med. 2009;37(6):1906-1912.


Literature review of publications that describe various clinical protocols for therapeutic hypothermia outside of clinical trials confirms the results from the large randomized controlled trials.

Citation: Sagalyn E, Band RA, Gaieski DF, Abella BS. Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences. Crit Care Med. 2009;37(7 Suppl):S223-S226.


Observational study of 36,182 patients from the CRUSADE data bank admitted with NSTEMI showed that platelet counts that dropped below 150x109/L had increased rates of bleeding and in-hospital mortality.

Citation: Wang TY, Ou FS, Roe MT, et al. Incidence and prognostic significance of thrombocytopenia developed during acute coronary syndrome in contemporary clinical practice. Circulation. 2009;119(18): 2454-2462.

1) Utility of Cardiac Stress Testing Is Limited for Young Patients with Chest Pain

Clinical question: Does routine, provocative cardiac testing in low-risk adult patients younger than 40 years of age add to the diagnostic evaluation for acute coronary syndrome?

Background: In EDs, aggressive evaluation of chest pain is the standard of care due to high morbidity, mortality, and liability associated with acute coronary syndrome (ACS). Guidelines recommend provocative cardiac testing for all patients for whom ACS is suspected, yet the prevalence is low in patients younger than 40.

Study design: Retrospective observational study.

Setting: ED chest pain observation unit of an urban academic tertiary-care center in New York City.

Synopsis: Two hundred twenty patients between 22 and 39 years old admitted for ACS evaluation between March 2004 and September 2007 were eligible. Patients with known coronary artery disease, diagnostic ECG findings, or evidence of cocaine use were excluded. Provocative cardiac testing for the presence of myocardial ischemia followed serial cardiac biomarker testing to rule out myocardial infarction.

Six patients had positive stress tests. Four underwent subsequent coronary angiography, which demonstrated no evidence of obstructive coronary disease. One refused catheterization, and the other was lost to followup. Age younger than 40 years, nondiagnostic or normal ECG, and two sets of negative cardiac biomarker results at least six hours apart identified a patient group with a low rate of true-positive provocative testing.

This study is limited by its retrospective, single-centered nature; it was unable to include patients admitted to the hospital or those who left the chest-pain unit without provocative testing or against medical advice. The possibility of false-negative provocative testing results was not excluded. The methods of provocative testing were limited to those available prior to 2007.

Bottom line: Cardiac stress testing adds little to the diagnostic evaluation for patients younger than 40 years having nondiagnostic ECG and negative serial biomarker results. However, routine provocative testing is unlikely to decrease until better clinical risk-stratification tools exist for this very-low-prevalence population.

Citation: Hermann LK, Weingart SD, Duvall WL, Henzlova MJ. The limited utility of routine cardiac stress testing in emergency department chest pain patients younger than 40 years. Ann Emerg Med. 2009;54(1):12-16.

2) Family Witness Behavior Impacts Physician Performance during CPR

Clinical question: Does the presence or behavior of a family witness to cardiopulmonary resuscitation (CPR) alter the critical actions performed by physicians?

Background: Because few patients undergoing in-hospital CPR survive to hospital discharge, many hospitals allow at least one family member of the dying patient to be present during the resuscitation attempt. There is little evidence concerning the bereavement outcomes for the family witness or effect on the resuscitation environment and physician performance.

Study design: Randomized controlled study.

Setting: Human patient simulator-based medical resuscitation environment with standardized actors in an academic medical center.

Synopsis: Sixty second- and third-year emergency medicine residents were randomized in pairs and assigned to one of three groups: no family witness, a non-obstructive witness, or a witness displaying overt grief reactions. Trained actors played the roles of social worker and family member. All groups were joined by the social worker and participated in identical cardiac-arrest-code scenarios ending in asystole. The nurse in each group was scripted to make a potentially harmful medication error. Outcomes studied were physician-performance-based, such as length of the resuscitation attempt, time to critical events, and recognition of a potential drug administration error.

Delay in initiation of defibrillator shocks and decrease in the number of shocks delivered occurred in the overt grief reaction group. Failure to recognize the medication error occurred only once, and it was in the control group. No other significant differences were observed between groups.

Limitations to this study are its small size and possibility that physician behavior in simulated environments might not reflect that of real patient-care situations.

Bottom line: Overt grief reactions from family members witnessing CPR attempts might negatively impact important procedural events and decisions made by physicians, specifically the use of defibrillation, which could negatively affect outcomes of CPR.

Citation: Fernandez R, Compton S, Jones KA, Velilla MA. The presence of a family witness impacts physician performance during simulated medical codes. Crit Care Med. 2009;37(6): 1956-1960.

3) Diltiazem Is a Better Choice in Uncomplicated Atrial Fibrillation than Amiodarone or Digoxin

Clinical question: How does IV diltiazem compare to IV amiodarone or digoxin in achieving ventricular rate control in patients hospitalized for acute uncomplicated atrial fibrillation (AF)?

Background: Current guidelines for acute AF management are based on expert opinion and recommend calcium antagonists, beta-blockers, or digoxin for initial ventricular rate control in hemodynamically stable patients. Recommendations lead to wide clinical variations in the first 24 hours of presentation.

Study design: Randomized, open-label trial.

Setting: Single-center study in Hong Kong.

Synopsis: One hundred fifty patients presenting with acute symptomatic AF of <48 hours duration with a rapid ventricular rate were enrolled. The study endpoints were ventricular rate control within the first 24 hours defined as a sustained heart rate of <90 beats per minute for less than four hours. The time to ventricular rate control in patients assigned to the diltiazem group (three hours) was significantly shorter than that of the digoxin group (six hours) or the amiodarone group (seven hours). The percentage of patients who achieved ventricular rate control in the diltiazem group was 90%, compared with 74% in both the digoxin and amiodarone groups. Length of stay was shorter in diltiazem group (3.9 days) when compared with the digoxin group (4.7 days) and amiodarone group (4.7 days).

Major limitations of the study were the lack of beta-blockers as an option for rate control and the exclusion of patients with hemodynamic instability, heart failure, and myocardial infarction. As patients with underlying heart disease were excluded, these results cannot be applied to all patients presenting with acute AF.

Bottom line: Compared with digoxin and amidarone, intravenous diltiazem is safe and effective in achieving ventricular rate control to improve symptoms and to reduce length of hospital stay in acute uncomplicated AF.

Citation: Siu CW, Lau CP, Lee WL, Lam KF, Tse HF. Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation. Crit Care Med. 2009;37(7):2174-2179.

4) D-dimer Might Be a Reliable Assay to Determine Likelihood of Acute Aortic Dissection

Clinical question: Is the D-dimer assay beneficial in the evaluation of acute aortic dissection (AD)?

Background: Aortic dissection is a potentially lethal disorder that is included in the differential diagnosis of chest pain. No studies exist that specifically examine the use of the D-dimer assay to exclude or predict AD. D-dimer has been proven to be a useful tool to help rule out pulmonary embolism (PE) and DVT.

Study design: Prospective.

Setting: Fourteen centers in the U.S., Europe, and Japan.

Synopsis: Of 220 patients enrolled in the study, 87 had radiologically proven AD, and 133 had an initial suspicion of AD but a different final diagnosis. D-dimer assay was obtained on patients with a suspicion of AD within 24 hours of symptom onset. Additionally, appropriate imaging was performed on all patients to identify AD presence.

D-dimer was found to be a useful “rule out” test. At a cutoff level of 500 ng/mL, the negative likelihood ratio was 0.07 (<0.1 being suggestive of a good rule-out tool) and the negative predictive value was >90%. D-dimer was not shown to be as useful to predict the presence of AD in this study.

A major limitation of the study was a relatively small sample size, especially when subgroups were analyzed, therefore decreasing the overall accuracy of the study. Although this study shows promise for the D-dimer assay in the evaluation of suspected AD, it does not establish D-dimer as a reliable enough test to rule out AD without further imaging or evaluation.

Bottom line: Though this study illustrated a high negative predictive value for D-dimer in AD evaluation, physicians are cautioned against allowing a negative D-dimer to affect their management of a patient with a suspected acute aortic dissection.

Citation: Suzuki T, Distante A, Zizza A, et al. Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-bio) experience. Circulation. 2009;119(20):2702-2707.

Clinical Shorts


A prospective randomized clinical study of 121 medical intensive-care unit (MICU) patients revealed that those who received nasoduodenal feeding as opposed to nasogastric feeding achieved nutritional goals earlier and had a lower rate of ventilator-associated pneumonia.

Citation: Hsu CW, Sun SF, Lin SL, et al. Duodenal versus gastric feeding in medical intensive care unit patients: a prospective, randomized, clinical study. Crit Care Med. 2009;37(6):1866-1872.


Retrospective chart review shows Gram’s stain of peritoneal fluid has low sensitivity and positive predictive value, and should not alter treatment when SBP has been identified by absolute neutrophil count.

Citation: Chinnock B, Fox C, Hendey GW. Gram’s stain of peritoneal fluid is rarely helpful in the evaluation of the ascites patient. Ann Emerg Med. 2009;54(1):78-82.


Series of case reports shows patients with Clostridium difficile infection, refractory to oral vancomycin and metronidazole, responded well to intravenous tigecycline.

Citation: Herpers BL, Vlaminckx B, Burkhardt O, et al. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis. 2009;48(12):1732-1735.


This retrospective review found that besides a history of heart failure, myocardial infarction, angina, severe valvular disease, or high cholesterol, an age greater than 65 is an independent predictor for significant preoperative EKG abnormalities.

Citation: Correll D, Hepner D, Chang C, et al. Perioperative electrocardiograms: patient factors predictive of abnormalities. Anesthesiology. 2009;110(6):1217-1222.

5) Acute Kidney Injury Predicts Outcomes of Non-Critically-Ill Patients

Clinical question: Does acute kidney injury affect in-hospital mortality, need for renal replacement therapy, and length of stay in patients who are not critically ill?

Background: Using the Acute Kidney Injury Network’s definition of acute kidney injury (AKI), including an abrupt increase in creatinine of 0.3 mg/dL, the authors previously showed an association with poor outcomes in critically ill patients. There is less evidence as to whether it predicts outcomes in non-critically-ill patients.

Study design: Retrospective cohort and a case-control study.

Setting: Bridgeport (Conn.) Hospital, a 350-bed community teaching hospital affiliated with Yale New Haven Health System.

Synopsis: Seven hundred thirty-five patients admitted to a medical unit who developed AKI, defined as a serum creatinine increase of 0.3 mg/dL or more within a 48-hour period, were compared to 5,089 controls. Patients who were admitted to critical care or who received RRT within the first 48 hours were excluded. AKI patients had higher in-hospital mortality of 14.8%, compared with 1.5% of controls, longer hospital stays of 7.9 versus 3.7 days, higher rates of transfer to the ICU of 28.6% versus 4.3%, and 73 versus zero patients who required renal replacement therapy. All findings were statistically significant (P<0.001). Some patients were omitted because of inadequate data collection.

Two hundred eighty-two patients were randomly selected from each group and matched based on age and demographic characteristics to perform a case-control study. AKI patients were eight times more likely to die in the hospital and five times more likely to have prolonged lengths of stay and transfer to the ICU.

This study does not differentiate between types of AKI and does not show a causal relationship.

Bottom line: AKI, defined as a serum creatinine increase of 0.3 mg/dL or more within a 48-hour period, predicts worse outcomes in non-critically-ill patients.

Citation: Barrantes F, Feng Y, Ivanov O, et al. Acute kidney injury predicts outcomes of non-critically ill patients. Mayo Clin Proc. 2009;84(5):410-416.

6) Statin Therapy after First Stroke Reduces Recurrence and Improves Survival

Clinical question: Does statin therapy after first ischemic stroke reduce recurrence and long-term mortality?

Background: Statin treatment has been shown to reduce primary stroke incidence, but there is less evidence on secondary prevention.

Study design: Retrospective observational study.

Setting: Acute stroke, general medicine, and neurology units at the hospitals affiliated with the University of Ioannina School of Medicine in Athens, Greece.

Synopsis: Seven hundred ninety-four primary ischemic stroke patients were admitted and followed for a 10-year period. Of those, 596 patients were discharged without a statin; 198 patients were discharged on statin therapy. One hundred twelve, or 14.1%, of the 794 patients had a recurrent event. The recurrence rate was 16.3% among those who did not receive a statin versus 7.6% among those who did receive a statin post-discharge (P=0.002).

Bottom line: Post-discharge statin therapy after an initial stroke appears to reduce the risk of recurrence.

Citation: Milionis HJ, Giannopoulos S, Kosmidou M, et al. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology. 2009;72(21):1816-1822.

7) Low-Dose Corticosteroids Provide Modest Benefit to Patients with Vasopressor-Dependent Sepsis and Septic Shock

Clinical question: What are the risks and benefits of corticosteroid treatment in severe sepsis and septic shock?

Background: For more than 50 years, corticosteroids have been used as an adjuvant treatment for sepsis with conflicting benefits on mortality.

Study design: Meta-analysis. Literature Search of Cochrane Library, MEDLINE, EMBASE, and LILACS.

Synopsis: Seventeen randomized controlled trials and three quasi-randomized controlled trials of 3,384 patients were selected for statistical analysis. Overall, corticosteroids did not improve 28-day, all-cause mortality in severe sepsis and septic shock. There was a statistically significant reduction in 28-day mortality only for the subgroup of patients receiving prolonged low-dose steroid treatment (37.5% vs. 44% in the control group).

There was no increased risk of gastrointestinal hemorrhage, superinfection, or neuromuscular weakness seen in treated patients.

The trials differed in the types of corticosteroid used, the time to institution of therapy, bolus versus continuous administration, duration of therapy, and abrupt versus gradual interruption of treatment. All of these factors make the clinical application of the data challenging.

Bottom line: Many questions remain about the optimal dose, timing, and duration of corticosteroids in patients with vasopressor-dependent sepsis and septic shock, but there appears to be a modest mortality benefit with prolonged low-dose corticosteroid therapy.

Citation: Annane D, Bellissant E, Bollaert P, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22): 2362-2375.

8) Testing for FVL Mutation but Not 20210A Predicts Recurrent VTE Risk

Clinical question: Are the rates of recurrent VTE higher in adults with VTE who possess either the factor V Leiden (FVL) or Prothrombin G20210A mutation, and what are the rates of VTE among family members?

Background: Clinicians commonly test for genetic mutations when treating patients who have a thrombotic event. However, the utility of such tests on predicting the risk for recurrent events and on outcomes needs review.

Study design: Meta-analysis.

Setting: Literature search of MEDLINE, EMBASE, the Cochrane Library, CINAHL, and PsycInfo.

Synopsis: Forty-six articles were selected for statistical analysis. The presence of either homozygous or heterozygous FVL mutation increased the risk of recurrent VTE compared with individuals without the FVL mutation (OR 2.65 and 1.56, respectively).

Compared with family members of adults without the FVL mutation, the presence of either homozygous or heterozygous FVL mutation predicts VTE in family members (OR 18 and 3.5, respectively).

The presence of G20210A is not predictive of recurrent VTE compared with individuals without this mutation. There is not sufficient evidence regarding the predictive value of the G20210A mutation on the risk of VTE in family members.

No studies directly address the effect of testing on outcomes other than recurrent VTE. In family members who were tested, there did not seem to be any impact on daily behavior, recognition of VTE risk factors, or perceived stress from testing.

Bottom line: FVL mutation increases the risk of recurrent VTE and predicts VTE in family members. The benefits of testing family members remain unclear.

Citation: Segal J, Brotman, D, Necochea, A, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301 (23):2472-2485. TH


Lower Rates of Serious Bacterial Infection in Young Febrile Infants with Influenza

By Mark Shen, MD

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

Clinical question: What is the risk of serious bacterial infection (SBI) in febrile infants ≤60 days of age with influenza virus infections?

Background: Febrile infants with documented viral infections have a lower rate of SBI than febrile infants who do not have a positive test for a specific virus. The literature strongly supports this finding with respiratory syncytial virus (RSV), although the specific association with influenza is less clear, particularly as there is an increased risk of secondary bacterial infections in patients of all ages with influenza.

Study design: Secondary analysis of a prior prospective study.

Setting: Five pediatric EDs.

Synopsis: This was a secondary analysis of a prior prospective study (1998-2001) that examined the relationship between RSV infection and SBI in febrile infants ≤60 days of age. This analysis was restricted to centers in which bacterial cultures were obtained and the standard evaluation included testing for influenza. Of 844 infants tested for influenza, SBI status could be determined in 809 (95.9%), and 123 tested positive for influenza. Of those with influenza, only three (2.5%) were found to have an SBI, and all three had a urinary tract infection (UTI). By comparison, 13.3% of the influenza-negative patients had SBIs, 10.8% of which were UTIs.

The primary study limitation is the secondary nature of the analysis. The enrollment period was October through March of each year, and influenza virus peaked in December and January of each year studied. In addition, the authors were able to refer to prospectively collected data on SBI status. These data are consistent with other studies demonstrating a lower likelihood of SBI in documented viral infections.

Bottom line: Febrile infants with influenza virus infection are at lower risk of serious bacterial infection.

Citation: Krief WI, Levine DA, Platt SL, et al. Influenza virus infection and the risk of serious bacterial infections in young febrile infants. Pediatrics. 2009;124:30-39.

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