Literature at a Glance
- Tight glucose control in critically ill patients is not associated with reduction in short-term mortality, but it is associated with an increased risk of hypoglycemia.
- Intensive glucose-lowering therapy in diabetic patients at high risk for cardiovascular events increased mortality.
- Targeting normal glycated hemoglobin levels with a gliclazide-based regimen does not have an effect on preventing major macrovascular events.
- Non-invasive ventilation has no effect on short-term mortality or rates of tracheal intubation and admission to ICU
- Routine use of a rhythm-control strategy does not reduce the rate of death from cardiovascular causes.
- No clinical benefit exists in employing intensive renal replacement over a conventional approach in critically ill patients.
- Initial UFH bolus and infusion dosing used for NSTE ACS often exceeds recommended weight-adjusted dosing.
- High BNP or NT-pro-BNP levels can differentiate patients who are at a higher risk of complicated hospital course and short-term mortality.
- Use of a silver-coated ET tube reduces the incidence of VAP, as well as delays time to VAP occurrence.
Clinical question: Does tight glucose control for critically ill patients affect mortality?
Background: Intensive glucose control for adult ICU patients has been advocated by numerous professional societies and adopted worldwide as a means to reduce mortality of critically ill patients. Evidence from multiple randomized controlled trials of tight glucose control in the ICU setting, however, shows mixed results.
Study Design: Meta-analysis of randomized controlled trials.
Setting: 29 studies involving 8,432 critically ill patients.
Synopsis: This study evaluated 29 trials involving critically ill adult patients randomized to tight glucose control versus usual care. Comparing these patients, there was no significant difference in short-term mortality (<30 days). Stratification of trials by level of glucose control (very tight <110 mg/dL versus moderately tight <150 mg/dL) and by ICU setting (surgical, medical, or mixed medical-surgical) did not affect mortality.
Tight glucose control was associated with a reduced risk of septicemia, but only in surgical patients. There was no association between tight control and a new need for dialysis, consistent across all ICU settings, as well as with both levels of glucose control. Finally, there was an increased risk of hypoglycemia (<40 mg/dL) with tight control, higher in patients who received very tight control versus those who received moderately tight control.
Limitations of the studies evaluated in this meta-analysis include difficulties with consistently maintaining tight glucose control. Twenty one percent of the trials did not achieve a mean glucose level within 5 mg/dL of the goal. This, along with a lack of standardization in reporting glucose control, makes study comparison problematic.
Bottom Line: Tight glucose control in critically ill patients is not associated with reduction in short-term mortality, but it is associated with an increased risk of hypoglycemia.
Citation: Wiener, RS, Wiener DC, Larson, RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300:933-944.
Clinical Question: Does intensive glucose-lowering therapy reduce cardiac events in high-risk diabetic patients?
Background: Epidemiologic studies have suggested the risk of cardiovascular disease increases with higher levels of glycated hemoglobin in patients with type-2 diabetes. No definitive data from randomized trials exist to test the effect of intensive glucose-lowering therapy on the rate of cardiovascular events in high-risk diabetic patients.
Study Design: Multicenter randomized controlled trial led by the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group.
Setting: 77 clinical centers in the U.S. and Canada.
Synopsis: 10,251 diabetic patients with established cardiovascular disease or additional cardiovascular risk factors, and median glycated hemoglobin level of 8.1%, received either intensive therapy (targeting glycated hemoglobin level <6.0%) or standard therapy (targeting level from 7.0% to 7.9%). The primary outcome was a composite of non-fatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.
Data indicated intensive therapy did decrease the rate of non-fatal myocardial infarctions, however, it did not significantly reduce the primary composite of major cardiovascular events. Moreover, intensive therapy resulted in a significant increase in death from cardiovascular causes, as well as a relative increase of 22% of death from any cause, during follow up of three and a half years. Due to this finding, the intensive therapy regimen was discontinued 17 months before the scheduled end of the study.
Analysis of the data has not identified a cause for the unexpected increased mortality in the intensive therapy group, and has not shown any medication or combination of medications to be responsible.
Bottom Line: Intensive glucose-lowering therapy in diabetic patients at high risk for cardiovascular events increased mortality and did not significantly reduce major cardiovascular events.
Citation: Action to control cardiovascular risk in diabetes study group. Effects of intensive glucose lowering in type-2 diabetes. N Engl J Med. 2008;358:2545-2559.
Clinical Question: Does intensive glucose-lowering therapy decrease major macrovascular and microvascular events in high-risk diabetic patients?
Background: Prospective studies show a direct association between elevated glycated hemoglobin levels in diabetics and increased risk of vascular events. However, definitive evidence from randomized trials about the role of intensive glucose control in preventing vascular disease in diabetics is lacking.
Study Design: Multicenter randomized controlled trial led by the ADVANCE Collaborative Group.
Setting: 215 clinical centers in 20 countries from Asia, Australia, Europe, and North America.
Synopsis: 11,140 diabetic patients received either standard glucose therapy or intensive glucose therapy using gliclazide, as well as other drugs, to reach a targeted glycated hemoglobin of 6.5% or less. The primary outcome was a composite of major macrovascular and microvascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, death from cardiovascular causes, nephropathy, and retinopathy.
Intensive glucose-lowering therapy, as compared to standard therapy, resulted in a 21% relative reduction of new or worsening nephropathy. There was no significant effect on the rate of MI, strokes, death from cardiovascular causes, or retinopathy. Furthermore, intensive glucose control was associated with an increased risk of severe hypoglycemia and increased rate of hospitalization. In contrast to the ACCORD study, intensive therapy did not result in an increase in mortality.
Bottom Line: While targeting normal glycated hemoglobin levels with a gliclazide-based regimen reduced the rate of nephropathy, this strategy did not have an effect on preventing major macrovascular events.
Citation: ADVANCE collaborative group. Intensive blood glucose control and vascular outcomes in patients with type-2 diabetes. N Eng J Med. 2008;358:2560-2572.
Non-invasive Ventilation Does Not Improve Short-Term Mortality in Patients with Acute Cardiogenic Pulmonary Edema
Clinical Question: Does non-invasive ventilation improve survival for patients with acute cardiogenic pulmonary edema?
Background: Acute cardiogenic pulmonary edema is a common medical emergency, but only small trials address outcomes of non-invasive methods of ventilation.
Study Design: A prospective, randomized control study.
Setting: 26 emergency rooms and hospitals in the United Kingdom.
Synopsis: 1,069 patients with a clinical diagnosis of acute cardiogenic pulmonary edema in the emergency room were randomized to one of three treatment strategies: standard oxygen therapy, continuous positive airway pressure (CPAP), or non-invasive intermittent positive pressure ventilation (NIPPV).
There was no significant difference in the seven-day mortality between patients receiving standard oxygen therapy (9.8%) and those treated with non-invasive ventilation (9.5%). Additionally, there was no significant difference in the combined end point of death or intubation within seven days between patients receiving CPAP and NIPPV—the primary end points of the study.
While non-invasive ventilation was associated with greater reductions in dyspnea, heart rate, acidosis, and hypercapnia than was standard oxygen therapy, rates of other secondary outcomes—including tracheal intubation, admission to the critical care unit, myocardial infarction, and 30-day mortality—were similar.
Bottom Line: Although non-invasive ventilation rapidly improves respiratory distress and metabolic disturbances for patients with acute cardiogenic pulmonary edema, it has no effect on short-term mortality or rates of tracheal intubation and admission to ICU.
Citation: Gray A, Goodacre S, Newby D, et al. Non-invasive ventilation in acute cardiogenic pulmonary edema. N Eng J Med. 2008;359:142-151.
Clinical Question: Does the restoration of sinus rhythm in patients with atrial fibrillation and heart failure reduce mortality from cardiovascular causes?
Background: Recent data show rhythm control provides no benefit over rate control among patients with atrial fibrillation, but limited information is available regarding its applicability to patients with heart failure.
Study Design: Multicenter, prospective, double-blind, randomized trial.
Settings: 123 medical centers worldwide.
Synopsis:1,376 patients with a left ventricular ejection fraction of 35% or less, symptoms of heart failure, and a history of atrial fibrillation were randomized (allocation not concealed) either to a rhythm-control (e.g., conversion to sinus rhythm) or rate-control strategy. The primary outcome measured was the time to death from cardiovascular causes. Secondary outcomes included death from any cause, stroke, worsening heart failure, hospitalization, quality of life, cost of therapy, and a composite of death from cardiovascular causes, stroke or worsening heart failure.
Study follow up succeeded with 94% of enrolled patients completing follow up (median=47 months for survivors) or dying. Amiodarone was the drug used most often in the rhythm-control group. Ninety percent of patients received angiotensin converting enzyme inhibitors or angiotensin II receptor blocker, and 90% received anticoagulation.
Among patients with atrial fibrillation and congestive heart failure, the number of deaths from cardiovascular causes was similar in the rate (25%) and rhythm-control group (27%). Furthermore, there were no significant differences in important secondary outcomes, including death from any cause, worsening heart failure, or stroke.
Bottom Line: For patients with heart failure from systolic dysfunction and atrial fibrillation, the routine use of a rhythm-control strategy does not reduce the rate of death from cardiovascular causes as compared with a rate-control strategy.
Citation: Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667-2677.
No Benefit from Intensive Renal Replacement Therapy in Critically Ill Patients with Acute Kidney Injury (AKI)
Clinical Question: Does intensive renal replacement therapy, as compared with a conventional treatment strategy, affect outcomes in critically ill patients?
Background: The optimal timing for the initiation, method, and dosing of renal replacement therapy among patients with AKI remains uncertain. Previous single-center studies limited to single methods of renal replacement therapy have suggested more intensive therapy is associated with improved survival. These results, however, have been inconsistent.
Study Design: Randomized controlled trial.
Setting: Veterans Affairs hospitals and university affiliated medical centers.
Synopsis: This study randomized 1,124 of 4,340 eligible critically ill adults with AKI to receive either intensive renal replacement therapy or a less intensive, more conventional approach. The primary end point of death at day 60 from any cause was 53.6% with intensive therapy and 51.5 % with less intensive therapy (odds ratio, 1.09; 95% CI 0.86 to 1.40; p=0.47). No significant differences were found in secondary end points, including rate of recovery of kidney function, duration of renal-replacement therapy, or evolution of non-renal organ failure.
This study demonstrates providing hemodialysis more frequently than three times per week to hemodynamically stable patients, or providing continuous renal replacement therapy at an effluent flow rate of more than 20 ml/kg/hour to hemodynamically unstable patients, does not improve outcomes. It should be noted, however, the less-intensive treatment strategy in this study provides a dose of renal replacement therapy exceeding the normal dose given in usual care.
Bottom Line: No clinical benefit exists in employing intensive renal replacement over a conventional approach in critically ill patients.
Citation: Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7-20.
Elderly Patients and Females with Acute Coronary Syndrome (ACS) Often Receive Excess Doses of Heparin
Clinical Question: What initial dosing of unfractionated heparin (UFH) for patients with non-ST-segment elevation (NSTE) acute coronary syndrome is most frequently used and how does it affect risk of bleeding?
Background: UFH is commonly used in clinical practice for NSTE ACS, but a wide variability continues to exist in dosing protocols. Clinical studies have shown UFH dosing based on weight provides more effective early anticoagulation. However, the relationship between increasing weight-adjusted doses of UFH and the risk of bleeding has not been well described.
Study Design: Retrospective cohort study.
Setting: 420 U.S. hospitals involved in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation) initiative.
Synopsis: This study used data from patients enrolled in the CRUSADE initiative to investigate UFH dosing amongst 24,021 patients presenting with NSTE ACS. The study showed despite a recommendation to use weight-adjusted UFH dosing for NSTE ACS, there is a continued preference for a fixed dosing regimen of 5,000 U bolus and 1,000 U/hr initial infusion.
This fixed dose means women and the elderly are more likely to receive an excess UFH dose due to their lower body weight. The study found 35% of the group received excess weight-adjusted doses of UFH.
A clear relationship is present between excess weight-adjusted UFH doses and major bleeding, with the risk of major bleeding increasing particularly when UFH dose exceeds the recommended dosing of 70 U/kg bolus and 15 U/kg per hour infusion.
These observations support the need to follow guidelines on weight-adjusted UFH dosing in order to minimize the risk of bleeding in patients with NSTE ACS.
Bottom line: The initial UFH bolus and infusion dosing used for NSTE ACS often exceeds recommended weight-adjusted dosing, leading to higher rates of bleeding, particularly among women and the elderly.
Citation: Melloni C, Alexander KP, Chen AY et al. Unfractionated heparin dosing and risk of major bleeding in non-ST-segment elevation acute coronary syndromes. Am Heart J. 2008;156(2):209-215.
Elevated BNP Level Is a Marker for Higher Risk of Adverse Outcomes in Patients with Pulmonary Embolism
Clinical Question: Can elevated BNP levels predict adverse outcomes in patients with acute pulmonary embolism (PE)?
Background: Plasma brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) often are elevated in patients with PE and right ventricular (RV) dysfunction. The finding of RV dysfunction on echocardiography is an indicator of poor outcome in these patients. The role of BNP levels to differentiate patients with PE who are at higher risk of adverse events and poor clinical outcomes has not been determined.
Study Design: Meta analysis of prospective studies.
Settings: 13 studies involving 1,132 patients.
Synopsis: Elevated levels of BNP or NT-pro-BNP were noted in 51% of patients with acute PE. These patients had a higher rate of complicated inpatient course, as well as a higher risk of 30-day mortality (odds ratio 6.8; 95% CI 4.4-10; odds-ratio 7.6; 95% CI 3.4-17). Additionally, increased BNP levels were significantly associated with RV dysfunction (p<0.0001).
While elevated BNP levels may serve as a marker for increased risk of adverse outcomes, the investigators stress these levels alone should not be used to pursue more aggressive treatment strategies. Elevation of these markers is nonspecific and can be secondary to pre-existing heart, lung, or kidney disease, or older age. Further studies are needed to determine the role of BNP in risk stratifying patients with acute PE to different forms of therapy.
Bottom Line: High BNP or NT-pro-BNP levels can differentiate patients with PE who are at a higher risk of complicated hospital course and short-term mortality.
Citation: Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:425-430.
Clinical Question: Can silver-coated endotracheal tubes reduce the incidence of VAP?
Background: Given the high morbidity linked to VAP, prevention strategies have been sought. Silver has broad-spectrum antimicrobial activity in vitro. Thus, a silver-coated endotracheal tube (ET) was designed to help prevent biofilm formation and bacterial colonization.
Study Design: A prospective, randomized, single-blind, controlled study.
Settings: 54 centers in North America.
Synopsis: Out of 9,417 potentially eligible patients, 2,003 patients expected to require mechanical ventilation for 24 hours or longer were randomized to undergo intubation with endotracheal tubes with and without silver coating. The primary outcome was incidence of VAP based on quantitative culture of bronchoalveolar lavage fluid.
The rate of microbiologically confirmed VAP in patients intubated for 24 hours or longer with the silver-coated ET tube was 4.8%, as compared to 7.5% in the control group. Using silver-coated ET tubes resulted in a 35.9% relative risk reduction of VAP incidence. Furthermore, the silver-coated ET tube was associated with a delayed time to VAP occurrence. Other outcomes, including length of intubation, duration of hospital stay, mortality, and frequency of adverse events, however, did not show statistically significant differences between the two groups.
Bottom Line: Using a silver-coated ET tube reduces the incidence of VAP, as well as delays time to VAP occurrence.
Citation: Kollef MH, Afessa B, Anzueta A, et al. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA. 2008;300:805-813.