Nita Shrikant Kulkarni, MD

Clinical question

Does the use of fibrinolytic therapy improve mortality and morbidity in normotensive patients with acute pulmonary embolism who are at intermediate risk for adverse outcomes?

Bottom line

For patients with acute pulmonary embolism (PE) at intermediate risk for adverse outcomes, fibrinolytic therapy (tenecteplase plus standard anticoagulation) decreases the incidence of hemodynamic decompensation but does not decrease mortality as compared with anticoagulation alone. Not surprisingly, fibrinolysis also increases bleeding and strokes. You would need to treat 20 people with tenecteplase to cause one episode of bleeding, and 45 people to cause one additional stroke. Given the significant bleeding risk with this therapy, fibrinolysis in patients who are at higher risk of adverse outcomes but are hemodynamically stable cannot be recommended until further research shows a greater clinical benefit. (LOE = 1b)

Reference

Meyer G, Vicaut E, Danays T, et al, for the PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370(15):1402-1411.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

These authors enrolled adult patients with acute PE who were hemodynamically stable and were considered to have an intermediate risk for adverse outcomes as indicated by right ventricular dysfunction or myocardial injury. Right ventricular dysfunction was confirmed by either echocardiography or chest computed tomography, and myocardial injury was confirmed by a positive troponin test result. Using concealed allocation, investigators randomized these patients (N = 1006) to receive either fibrinolysis with tenecteplase at a weight-based dose or matching placebo. Both groups also received full anticoagulation with unfractionated heparin. Baseline characteristics were similar in the 2 groups and analysis was by intention to treat. Fewer patients in the tenecteplase group experienced the primary outcome of death or hemodynamic decompensation at 7 days (2.6% vs 5.6%; odds ratio = 0.44; 95% CI, 0.23 - 0.87). Looking at the individual components of the composite outcome, there was no significant difference in mortality between the 2 groups (1.2% vs 1.8%), but the tenecteplase group had a decreased incidence of hemodynamic decompensation (1.6% vs 5%; P = .002). The significance of this is unclear, as one of the definitions of hemodynamic decompensation was an isolated drop in systolic blood pressure to below 90 mmHg for at least 15 minutes. Major bleeding and hemorrhagic strokes were more common in the tenecteplase group (bleeding: 11.5% vs 2.4%; strokes: 2% vs 0.2%).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does the use of fibrinolytic therapy improve mortality and morbidity in normotensive patients with acute pulmonary embolism who are at intermediate risk for adverse outcomes?

Bottom line

For patients with acute pulmonary embolism (PE) at intermediate risk for adverse outcomes, fibrinolytic therapy (tenecteplase plus standard anticoagulation) decreases the incidence of hemodynamic decompensation but does not decrease mortality as compared with anticoagulation alone. Not surprisingly, fibrinolysis also increases bleeding and strokes. You would need to treat 20 people with tenecteplase to cause one episode of bleeding, and 45 people to cause one additional stroke. Given the significant bleeding risk with this therapy, fibrinolysis in patients who are at higher risk of adverse outcomes but are hemodynamically stable cannot be recommended until further research shows a greater clinical benefit. (LOE = 1b)

Reference

Meyer G, Vicaut E, Danays T, et al, for the PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370(15):1402-1411.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

These authors enrolled adult patients with acute PE who were hemodynamically stable and were considered to have an intermediate risk for adverse outcomes as indicated by right ventricular dysfunction or myocardial injury. Right ventricular dysfunction was confirmed by either echocardiography or chest computed tomography, and myocardial injury was confirmed by a positive troponin test result. Using concealed allocation, investigators randomized these patients (N = 1006) to receive either fibrinolysis with tenecteplase at a weight-based dose or matching placebo. Both groups also received full anticoagulation with unfractionated heparin. Baseline characteristics were similar in the 2 groups and analysis was by intention to treat. Fewer patients in the tenecteplase group experienced the primary outcome of death or hemodynamic decompensation at 7 days (2.6% vs 5.6%; odds ratio = 0.44; 95% CI, 0.23 - 0.87). Looking at the individual components of the composite outcome, there was no significant difference in mortality between the 2 groups (1.2% vs 1.8%), but the tenecteplase group had a decreased incidence of hemodynamic decompensation (1.6% vs 5%; P = .002). The significance of this is unclear, as one of the definitions of hemodynamic decompensation was an isolated drop in systolic blood pressure to below 90 mmHg for at least 15 minutes. Major bleeding and hemorrhagic strokes were more common in the tenecteplase group (bleeding: 11.5% vs 2.4%; strokes: 2% vs 0.2%).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does the use of fibrinolytic therapy improve mortality and morbidity in normotensive patients with acute pulmonary embolism who are at intermediate risk for adverse outcomes?

Bottom line

For patients with acute pulmonary embolism (PE) at intermediate risk for adverse outcomes, fibrinolytic therapy (tenecteplase plus standard anticoagulation) decreases the incidence of hemodynamic decompensation but does not decrease mortality as compared with anticoagulation alone. Not surprisingly, fibrinolysis also increases bleeding and strokes. You would need to treat 20 people with tenecteplase to cause one episode of bleeding, and 45 people to cause one additional stroke. Given the significant bleeding risk with this therapy, fibrinolysis in patients who are at higher risk of adverse outcomes but are hemodynamically stable cannot be recommended until further research shows a greater clinical benefit. (LOE = 1b)

Reference

Meyer G, Vicaut E, Danays T, et al, for the PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370(15):1402-1411.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

These authors enrolled adult patients with acute PE who were hemodynamically stable and were considered to have an intermediate risk for adverse outcomes as indicated by right ventricular dysfunction or myocardial injury. Right ventricular dysfunction was confirmed by either echocardiography or chest computed tomography, and myocardial injury was confirmed by a positive troponin test result. Using concealed allocation, investigators randomized these patients (N = 1006) to receive either fibrinolysis with tenecteplase at a weight-based dose or matching placebo. Both groups also received full anticoagulation with unfractionated heparin. Baseline characteristics were similar in the 2 groups and analysis was by intention to treat. Fewer patients in the tenecteplase group experienced the primary outcome of death or hemodynamic decompensation at 7 days (2.6% vs 5.6%; odds ratio = 0.44; 95% CI, 0.23 - 0.87). Looking at the individual components of the composite outcome, there was no significant difference in mortality between the 2 groups (1.2% vs 1.8%), but the tenecteplase group had a decreased incidence of hemodynamic decompensation (1.6% vs 5%; P = .002). The significance of this is unclear, as one of the definitions of hemodynamic decompensation was an isolated drop in systolic blood pressure to below 90 mmHg for at least 15 minutes. Major bleeding and hemorrhagic strokes were more common in the tenecteplase group (bleeding: 11.5% vs 2.4%; strokes: 2% vs 0.2%).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does ramelteon, a melatonin agonist, prevent delirium in hospitalized patients?

Bottom line

In this small, single-blinded study, ramelteon was shown to be effective in preventing delirium in elderly patients who required hospitalization for acute illness. You would have to treat 3 patients with ramelteon to prevent one episode of delirium. (LOE = 1b)

Reference

Hatta K, Kishi Y, Wada K, et al, for the DELIRIA-J Group. Preventive effects of ramelteon on delirium. JAMA Psychiatry 2014;71(4):397-403.

Study design

Randomized controlled trial (single-blinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators randomized 67 hospitalized patients (24 admitted to intensive care units, 43 admitted to general wards) to receive either ramelteon 8 mg or placebo nightly up to 7 days or until the onset of delirium. Eligible patients were 65 years to 89 years old, were admitted to the hospital via the emergency department, were able to take oral medications, and had an expected length of stay of greater than 48 hours. Patients with psychiatric disorders, severe liver disease, Lewy body disease, or alcohol dependency were excluded. Nurses provided similar delirium prevention care to all patients, including frequent reorientation, adequate lighting, and noise reduction. If patients required treatment for insomnia, hydroxyzine was used with a dose limit of 25 mg per night. Baseline characteristics were similar in the 2 groups, with a mean age of 78 years. For the primary outcome of onset of delirium, experienced psychiatrists, masked to study group, assessed patients in the mornings and afternoons for up to 7 days using a delirium rating scale. Only 1 patient in the ramelteon group was diagnosed with delirium as compared with 11 patients in the placebo group (3% vs 32%; number needed to treat = 3; P = .003). Interestingly, there were no significant differences between the groups in sleep metrics such as difficulty falling asleep and poor sleep quality, although the sample was likely too small to detect such differences. Note that the patients were not masked in this study, which could have potentially affected the overall outcomes. No adverse effects attributed to the study drug were reported.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does ramelteon, a melatonin agonist, prevent delirium in hospitalized patients?

Bottom line

In this small, single-blinded study, ramelteon was shown to be effective in preventing delirium in elderly patients who required hospitalization for acute illness. You would have to treat 3 patients with ramelteon to prevent one episode of delirium. (LOE = 1b)

Reference

Hatta K, Kishi Y, Wada K, et al, for the DELIRIA-J Group. Preventive effects of ramelteon on delirium. JAMA Psychiatry 2014;71(4):397-403.

Study design

Randomized controlled trial (single-blinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators randomized 67 hospitalized patients (24 admitted to intensive care units, 43 admitted to general wards) to receive either ramelteon 8 mg or placebo nightly up to 7 days or until the onset of delirium. Eligible patients were 65 years to 89 years old, were admitted to the hospital via the emergency department, were able to take oral medications, and had an expected length of stay of greater than 48 hours. Patients with psychiatric disorders, severe liver disease, Lewy body disease, or alcohol dependency were excluded. Nurses provided similar delirium prevention care to all patients, including frequent reorientation, adequate lighting, and noise reduction. If patients required treatment for insomnia, hydroxyzine was used with a dose limit of 25 mg per night. Baseline characteristics were similar in the 2 groups, with a mean age of 78 years. For the primary outcome of onset of delirium, experienced psychiatrists, masked to study group, assessed patients in the mornings and afternoons for up to 7 days using a delirium rating scale. Only 1 patient in the ramelteon group was diagnosed with delirium as compared with 11 patients in the placebo group (3% vs 32%; number needed to treat = 3; P = .003). Interestingly, there were no significant differences between the groups in sleep metrics such as difficulty falling asleep and poor sleep quality, although the sample was likely too small to detect such differences. Note that the patients were not masked in this study, which could have potentially affected the overall outcomes. No adverse effects attributed to the study drug were reported.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does ramelteon, a melatonin agonist, prevent delirium in hospitalized patients?

Bottom line

In this small, single-blinded study, ramelteon was shown to be effective in preventing delirium in elderly patients who required hospitalization for acute illness. You would have to treat 3 patients with ramelteon to prevent one episode of delirium. (LOE = 1b)

Reference

Hatta K, Kishi Y, Wada K, et al, for the DELIRIA-J Group. Preventive effects of ramelteon on delirium. JAMA Psychiatry 2014;71(4):397-403.

Study design

Randomized controlled trial (single-blinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Using concealed allocation, these investigators randomized 67 hospitalized patients (24 admitted to intensive care units, 43 admitted to general wards) to receive either ramelteon 8 mg or placebo nightly up to 7 days or until the onset of delirium. Eligible patients were 65 years to 89 years old, were admitted to the hospital via the emergency department, were able to take oral medications, and had an expected length of stay of greater than 48 hours. Patients with psychiatric disorders, severe liver disease, Lewy body disease, or alcohol dependency were excluded. Nurses provided similar delirium prevention care to all patients, including frequent reorientation, adequate lighting, and noise reduction. If patients required treatment for insomnia, hydroxyzine was used with a dose limit of 25 mg per night. Baseline characteristics were similar in the 2 groups, with a mean age of 78 years. For the primary outcome of onset of delirium, experienced psychiatrists, masked to study group, assessed patients in the mornings and afternoons for up to 7 days using a delirium rating scale. Only 1 patient in the ramelteon group was diagnosed with delirium as compared with 11 patients in the placebo group (3% vs 32%; number needed to treat = 3; P = .003). Interestingly, there were no significant differences between the groups in sleep metrics such as difficulty falling asleep and poor sleep quality, although the sample was likely too small to detect such differences. Note that the patients were not masked in this study, which could have potentially affected the overall outcomes. No adverse effects attributed to the study drug were reported.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does an intervention consisting of increased pharmacist involvement and education increase long-term medication adherence in patients after hospitalization for acute coronary syndrome?

Bottom line

Following hospitalization for acute coronary syndrome (ACS), an intervention that emphasizes medication reconciliation, pharmacist-led education, collaboration between pharmacists and physicians, and automated reminders increases patients’ adherence to cardiac medications. However, there was no significant effect seen on clinical outcomes after 1 year. (LOE = 1b)

Reference

Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: A randomized clinical trial. JAMA Intern Med 2014;174(2):186-193.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

In this study performed at 4 Veteran Affairs (VA) medical centers, investigators enrolled 253 patients who were hospitalized with a primary diagnosis of ACS, had an anticipated discharge to home, and used the VA as their primary source of medical and pharmaceutical care. Using concealed allocation, patients were randomized to receive usual care or the intervention. Both groups received standard discharge instructions, discharge medication lists, and education on cardiac medications prior to discharge. The intervention group also received the following: (1) two sessions of medication reconciliation and education by a pharmacist within one month of discharge; (2) automated educational voice messages about medications, as well as access to pharmacists upon request throughout the study; (3) collaboration between the patient’s primary care physician and/or cardiologist; and (4) regular voice messages with reminders to take medications and refill medications for the remainder of the year. All patients were scheduled for a 12-month clinic visit. Baseline characteristics of the 2 groups were similar (mean age = 64 years; all but 5 of the patients were men). Patients in the intervention group received an average of 4 hours of additional pharmacist time. For the primary outcome of adherence to 4 classes of cardioprotective medications (beta-blockers, statins, clopidogrel, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), more patients in the intervention group were adherent compared with the usual care group (89% vs 74%; P = .003). The high adherence in the usual care group reflects a self-selection bias since enrolled patients were those who had volunteered for the study. Despite greater medication adherence in the intervention group, there were no significant differences in the proportion of patients reaching blood pressure and LDL cholesterol goals between the 2 groups. Additionally, tertiary outcomes -- including rehospitalization for myocardial infarction, revascularization, and mortality -- were similar in the 2 groups. The estimated cost for the intervention was approximately $360 per patient, mainly because of additional pharmacist and cardiologist time. No significant differences in costs due to medication prescriptions were noted in the study.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does an intervention consisting of increased pharmacist involvement and education increase long-term medication adherence in patients after hospitalization for acute coronary syndrome?

Bottom line

Following hospitalization for acute coronary syndrome (ACS), an intervention that emphasizes medication reconciliation, pharmacist-led education, collaboration between pharmacists and physicians, and automated reminders increases patients’ adherence to cardiac medications. However, there was no significant effect seen on clinical outcomes after 1 year. (LOE = 1b)

Reference

Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: A randomized clinical trial. JAMA Intern Med 2014;174(2):186-193.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

In this study performed at 4 Veteran Affairs (VA) medical centers, investigators enrolled 253 patients who were hospitalized with a primary diagnosis of ACS, had an anticipated discharge to home, and used the VA as their primary source of medical and pharmaceutical care. Using concealed allocation, patients were randomized to receive usual care or the intervention. Both groups received standard discharge instructions, discharge medication lists, and education on cardiac medications prior to discharge. The intervention group also received the following: (1) two sessions of medication reconciliation and education by a pharmacist within one month of discharge; (2) automated educational voice messages about medications, as well as access to pharmacists upon request throughout the study; (3) collaboration between the patient’s primary care physician and/or cardiologist; and (4) regular voice messages with reminders to take medications and refill medications for the remainder of the year. All patients were scheduled for a 12-month clinic visit. Baseline characteristics of the 2 groups were similar (mean age = 64 years; all but 5 of the patients were men). Patients in the intervention group received an average of 4 hours of additional pharmacist time. For the primary outcome of adherence to 4 classes of cardioprotective medications (beta-blockers, statins, clopidogrel, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), more patients in the intervention group were adherent compared with the usual care group (89% vs 74%; P = .003). The high adherence in the usual care group reflects a self-selection bias since enrolled patients were those who had volunteered for the study. Despite greater medication adherence in the intervention group, there were no significant differences in the proportion of patients reaching blood pressure and LDL cholesterol goals between the 2 groups. Additionally, tertiary outcomes -- including rehospitalization for myocardial infarction, revascularization, and mortality -- were similar in the 2 groups. The estimated cost for the intervention was approximately $360 per patient, mainly because of additional pharmacist and cardiologist time. No significant differences in costs due to medication prescriptions were noted in the study.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does an intervention consisting of increased pharmacist involvement and education increase long-term medication adherence in patients after hospitalization for acute coronary syndrome?

Bottom line

Following hospitalization for acute coronary syndrome (ACS), an intervention that emphasizes medication reconciliation, pharmacist-led education, collaboration between pharmacists and physicians, and automated reminders increases patients’ adherence to cardiac medications. However, there was no significant effect seen on clinical outcomes after 1 year. (LOE = 1b)

Reference

Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: A randomized clinical trial. JAMA Intern Med 2014;174(2):186-193.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location) with outpatient follow-up

Synopsis

In this study performed at 4 Veteran Affairs (VA) medical centers, investigators enrolled 253 patients who were hospitalized with a primary diagnosis of ACS, had an anticipated discharge to home, and used the VA as their primary source of medical and pharmaceutical care. Using concealed allocation, patients were randomized to receive usual care or the intervention. Both groups received standard discharge instructions, discharge medication lists, and education on cardiac medications prior to discharge. The intervention group also received the following: (1) two sessions of medication reconciliation and education by a pharmacist within one month of discharge; (2) automated educational voice messages about medications, as well as access to pharmacists upon request throughout the study; (3) collaboration between the patient’s primary care physician and/or cardiologist; and (4) regular voice messages with reminders to take medications and refill medications for the remainder of the year. All patients were scheduled for a 12-month clinic visit. Baseline characteristics of the 2 groups were similar (mean age = 64 years; all but 5 of the patients were men). Patients in the intervention group received an average of 4 hours of additional pharmacist time. For the primary outcome of adherence to 4 classes of cardioprotective medications (beta-blockers, statins, clopidogrel, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), more patients in the intervention group were adherent compared with the usual care group (89% vs 74%; P = .003). The high adherence in the usual care group reflects a self-selection bias since enrolled patients were those who had volunteered for the study. Despite greater medication adherence in the intervention group, there were no significant differences in the proportion of patients reaching blood pressure and LDL cholesterol goals between the 2 groups. Additionally, tertiary outcomes -- including rehospitalization for myocardial infarction, revascularization, and mortality -- were similar in the 2 groups. The estimated cost for the intervention was approximately $360 per patient, mainly because of additional pharmacist and cardiologist time. No significant differences in costs due to medication prescriptions were noted in the study.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with multivessel disease, which is the better approach for reducing long-term mortality: coronary artery bypass grafting or percutaneous coronary intervention?

Bottom line

When compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) reduces overall mortality and myocardial infarctions (MIs) in patients with multivessel disease. You would need to treat 37 patients with CABG to prevent one death, and 26 patients with CABG to prevent one MI over an average follow-up of 4 years. This is compared with a number needed to treat to harm of 105 to cause one additional stroke with CABG. (LOE = 1a)

Reference

Sipahi I, Akay H, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med 2014;174(2):223-230.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

Existing trials that compare CABG with PCI are underpowered to detect a difference in long-term mortality or MI. To study these outcomes, these investigators searched multiple databases, including MEDLINE and the Cochrane Central Register of Controlled Trials, to find randomized controlled trials that compared the 2 approaches over an average follow-up of at least 1 year in patients with multivessel disease. To ensure that these trials reflected contemporary practice, the authors only included trials in which arterial grafts were used in 90% of the CABG cases and trials in which stents were used in 70% of the PCI cases. Two investigators independently extracted data from the 6 included trials. No formal quality assessment was performed. No publication bias was detected. When taken together, data from the 6 trials (N = 6055) showed that the use of CABG as compared with PCI resulted in a 27% reduction in mortality (relative risk [RR] = 0.73; 95% CI, 0.62-0.86) and a 42% reduction in MI (RR = 0.58; 0.48-0.72). Although there was a nonsignificant trend toward increased strokes in the CABG group (likely related to periprocedural events), this approach also led to fewer repeat revascularizations (number needed to treat [NNT] = 7), as well as fewer overall major adverse cardiac and cerebrovascular events (NNT = 10).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with multivessel disease, which is the better approach for reducing long-term mortality: coronary artery bypass grafting or percutaneous coronary intervention?

Bottom line

When compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) reduces overall mortality and myocardial infarctions (MIs) in patients with multivessel disease. You would need to treat 37 patients with CABG to prevent one death, and 26 patients with CABG to prevent one MI over an average follow-up of 4 years. This is compared with a number needed to treat to harm of 105 to cause one additional stroke with CABG. (LOE = 1a)

Reference

Sipahi I, Akay H, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med 2014;174(2):223-230.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

Existing trials that compare CABG with PCI are underpowered to detect a difference in long-term mortality or MI. To study these outcomes, these investigators searched multiple databases, including MEDLINE and the Cochrane Central Register of Controlled Trials, to find randomized controlled trials that compared the 2 approaches over an average follow-up of at least 1 year in patients with multivessel disease. To ensure that these trials reflected contemporary practice, the authors only included trials in which arterial grafts were used in 90% of the CABG cases and trials in which stents were used in 70% of the PCI cases. Two investigators independently extracted data from the 6 included trials. No formal quality assessment was performed. No publication bias was detected. When taken together, data from the 6 trials (N = 6055) showed that the use of CABG as compared with PCI resulted in a 27% reduction in mortality (relative risk [RR] = 0.73; 95% CI, 0.62-0.86) and a 42% reduction in MI (RR = 0.58; 0.48-0.72). Although there was a nonsignificant trend toward increased strokes in the CABG group (likely related to periprocedural events), this approach also led to fewer repeat revascularizations (number needed to treat [NNT] = 7), as well as fewer overall major adverse cardiac and cerebrovascular events (NNT = 10).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients with multivessel disease, which is the better approach for reducing long-term mortality: coronary artery bypass grafting or percutaneous coronary intervention?

Bottom line

When compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) reduces overall mortality and myocardial infarctions (MIs) in patients with multivessel disease. You would need to treat 37 patients with CABG to prevent one death, and 26 patients with CABG to prevent one MI over an average follow-up of 4 years. This is compared with a number needed to treat to harm of 105 to cause one additional stroke with CABG. (LOE = 1a)

Reference

Sipahi I, Akay H, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med 2014;174(2):223-230.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

Existing trials that compare CABG with PCI are underpowered to detect a difference in long-term mortality or MI. To study these outcomes, these investigators searched multiple databases, including MEDLINE and the Cochrane Central Register of Controlled Trials, to find randomized controlled trials that compared the 2 approaches over an average follow-up of at least 1 year in patients with multivessel disease. To ensure that these trials reflected contemporary practice, the authors only included trials in which arterial grafts were used in 90% of the CABG cases and trials in which stents were used in 70% of the PCI cases. Two investigators independently extracted data from the 6 included trials. No formal quality assessment was performed. No publication bias was detected. When taken together, data from the 6 trials (N = 6055) showed that the use of CABG as compared with PCI resulted in a 27% reduction in mortality (relative risk [RR] = 0.73; 95% CI, 0.62-0.86) and a 42% reduction in MI (RR = 0.58; 0.48-0.72). Although there was a nonsignificant trend toward increased strokes in the CABG group (likely related to periprocedural events), this approach also led to fewer repeat revascularizations (number needed to treat [NNT] = 7), as well as fewer overall major adverse cardiac and cerebrovascular events (NNT = 10).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does a restrictive transfusion strategy with a hemoglobin trigger of less than 7g/dL improve outcomes as compared with a more liberal strategy?

Bottom line

A restrictive strategy using a hemoglobin transfusion trigger of less than 7g/dL leads to decreased morbidity and mortality. Based on this data, you would need to treat 33 patients with a restrictive strategy to prevent 1 death. Additionally, this strategy resulted in a 40% reduction in the number of patients who received a blood transfusion.

Reference

Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes. Am J Med 2014;127(2):124-131. (LOE: 1a-)

Allocation

(Uncertain)

Design

Meta-analysis (randomized controlled trials)

Setting

Various (meta-analysis)

Synopsis

These investigators searched MEDLINE for randomized controlled trials that compared a restrictive blood transfusion strategy using a transfusion trigger of hemoglobin of less than 7g/dL with a more liberal strategy. The authors did not state how study selection was performed, but 2 investigators independently extracted data from included studies. No formal quality assessment was performed. Three studies, with a total of 2364 patients, were chosen for the primary analysis. One study evaluated transfusion strategies in adult critical care, one in pediatric critical care, and one in patients with acute upper gastrointestinal bleeding. When pooled together, the data showed that a restrictive transfusion strategy led to decreased in-hospital mortality (relative risk (RR) = 0.74; 95% CI, 0.60-0.92), as well as decreased overall mortality (RR = 0.80; 0.65-0.98). Other benefits to a restrictive strategy included reduced incidences of acute coronary syndrome, pulmonary edema, and rebleeding. A secondary meta-analysis looked at 16 trials that used a less restrictive transfusion strategy with a hemoglobin trigger range from 7.5 g/dL to 10 g/dL. As compared with a more liberal strategy, this did not significantly affect morbidity or mortality. Although there was no evidence of heterogeneity in the results, it is noted that the 3 trials included in the primary analysis had very different patient populations with different indications for transfusion.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does a restrictive transfusion strategy with a hemoglobin trigger of less than 7g/dL improve outcomes as compared with a more liberal strategy?

Bottom line

A restrictive strategy using a hemoglobin transfusion trigger of less than 7g/dL leads to decreased morbidity and mortality. Based on this data, you would need to treat 33 patients with a restrictive strategy to prevent 1 death. Additionally, this strategy resulted in a 40% reduction in the number of patients who received a blood transfusion.

Reference

Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes. Am J Med 2014;127(2):124-131. (LOE: 1a-)

Allocation

(Uncertain)

Design

Meta-analysis (randomized controlled trials)

Setting

Various (meta-analysis)

Synopsis

These investigators searched MEDLINE for randomized controlled trials that compared a restrictive blood transfusion strategy using a transfusion trigger of hemoglobin of less than 7g/dL with a more liberal strategy. The authors did not state how study selection was performed, but 2 investigators independently extracted data from included studies. No formal quality assessment was performed. Three studies, with a total of 2364 patients, were chosen for the primary analysis. One study evaluated transfusion strategies in adult critical care, one in pediatric critical care, and one in patients with acute upper gastrointestinal bleeding. When pooled together, the data showed that a restrictive transfusion strategy led to decreased in-hospital mortality (relative risk (RR) = 0.74; 95% CI, 0.60-0.92), as well as decreased overall mortality (RR = 0.80; 0.65-0.98). Other benefits to a restrictive strategy included reduced incidences of acute coronary syndrome, pulmonary edema, and rebleeding. A secondary meta-analysis looked at 16 trials that used a less restrictive transfusion strategy with a hemoglobin trigger range from 7.5 g/dL to 10 g/dL. As compared with a more liberal strategy, this did not significantly affect morbidity or mortality. Although there was no evidence of heterogeneity in the results, it is noted that the 3 trials included in the primary analysis had very different patient populations with different indications for transfusion.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does a restrictive transfusion strategy with a hemoglobin trigger of less than 7g/dL improve outcomes as compared with a more liberal strategy?

Bottom line

A restrictive strategy using a hemoglobin transfusion trigger of less than 7g/dL leads to decreased morbidity and mortality. Based on this data, you would need to treat 33 patients with a restrictive strategy to prevent 1 death. Additionally, this strategy resulted in a 40% reduction in the number of patients who received a blood transfusion.

Reference

Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood transfusion strategies on clinical outcomes. Am J Med 2014;127(2):124-131. (LOE: 1a-)

Allocation

(Uncertain)

Design

Meta-analysis (randomized controlled trials)

Setting

Various (meta-analysis)

Synopsis

These investigators searched MEDLINE for randomized controlled trials that compared a restrictive blood transfusion strategy using a transfusion trigger of hemoglobin of less than 7g/dL with a more liberal strategy. The authors did not state how study selection was performed, but 2 investigators independently extracted data from included studies. No formal quality assessment was performed. Three studies, with a total of 2364 patients, were chosen for the primary analysis. One study evaluated transfusion strategies in adult critical care, one in pediatric critical care, and one in patients with acute upper gastrointestinal bleeding. When pooled together, the data showed that a restrictive transfusion strategy led to decreased in-hospital mortality (relative risk (RR) = 0.74; 95% CI, 0.60-0.92), as well as decreased overall mortality (RR = 0.80; 0.65-0.98). Other benefits to a restrictive strategy included reduced incidences of acute coronary syndrome, pulmonary edema, and rebleeding. A secondary meta-analysis looked at 16 trials that used a less restrictive transfusion strategy with a hemoglobin trigger range from 7.5 g/dL to 10 g/dL. As compared with a more liberal strategy, this did not significantly affect morbidity or mortality. Although there was no evidence of heterogeneity in the results, it is noted that the 3 trials included in the primary analysis had very different patient populations with different indications for transfusion.

 Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does tight control of hyperglycemia improve outcomes in the pediatric intensive care unit?

Bottom line

Tight glycemic control does not increase the number of days alive and free from mechanical ventilation for pediatric patients in the intensive care unit (ICU), but does increase the risk of severe hypoglycemia. Children in the ICU for reasons other than cardiac surgery and were treated with tight control had lower overall healthcare costs and reduced lengths of stay. However, these benefits must be weighed against the increased risk of hypoglycemia.

Reference

Macrae D, Grieve R, Allen E, et al, for the CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014;370(2):107-118. (LOE: 1b)

Allocation

(Concealed)

Design

Randomized controlled trial (nonblinded)

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized 1369 patients in the pediatric ICU to receive either tight glycemic control with a target blood glucose of 72 mg/dL to 126 mg/dL (4 - 7 mmol/L) or conventional glycemic control with a target of less than 216 mg/dL (12 mmol/L). Eligible patients were aged between 36 weeks and 16 years. They required mechanical ventilation and vasoactive drugs for an anticipated 12 hours following an injury or major surgery or to treat a critical illness. Children with diabetes were excluded. Analysis was by intention to treat. Baseline characteristics of the 2 groups were similar, and 60% of the patients in the total cohort had undergone cardiac surgery. There was no significant difference detected between the 2 groups for the primary outcome – the number of days alive and free from mechanical ventilation at 30 days. As expected, patients in the tight control group were more likely to have multiple severe hypoglycemic episodes (7.3% vs 1.5%; odds ratio = 5.27; 95% CI, 2.65-10.48). Although major clinical outcomes did not improve, there were some benefits associated with tight control, including reduced costs and reduced lengths of stay in the subgroup of patients who had not undergone cardiac surgery, as well as decreased need for renal replacement therapy in the overall group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does tight control of hyperglycemia improve outcomes in the pediatric intensive care unit?

Bottom line

Tight glycemic control does not increase the number of days alive and free from mechanical ventilation for pediatric patients in the intensive care unit (ICU), but does increase the risk of severe hypoglycemia. Children in the ICU for reasons other than cardiac surgery and were treated with tight control had lower overall healthcare costs and reduced lengths of stay. However, these benefits must be weighed against the increased risk of hypoglycemia.

Reference

Macrae D, Grieve R, Allen E, et al, for the CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014;370(2):107-118. (LOE: 1b)

Allocation

(Concealed)

Design

Randomized controlled trial (nonblinded)

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized 1369 patients in the pediatric ICU to receive either tight glycemic control with a target blood glucose of 72 mg/dL to 126 mg/dL (4 - 7 mmol/L) or conventional glycemic control with a target of less than 216 mg/dL (12 mmol/L). Eligible patients were aged between 36 weeks and 16 years. They required mechanical ventilation and vasoactive drugs for an anticipated 12 hours following an injury or major surgery or to treat a critical illness. Children with diabetes were excluded. Analysis was by intention to treat. Baseline characteristics of the 2 groups were similar, and 60% of the patients in the total cohort had undergone cardiac surgery. There was no significant difference detected between the 2 groups for the primary outcome – the number of days alive and free from mechanical ventilation at 30 days. As expected, patients in the tight control group were more likely to have multiple severe hypoglycemic episodes (7.3% vs 1.5%; odds ratio = 5.27; 95% CI, 2.65-10.48). Although major clinical outcomes did not improve, there were some benefits associated with tight control, including reduced costs and reduced lengths of stay in the subgroup of patients who had not undergone cardiac surgery, as well as decreased need for renal replacement therapy in the overall group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Question

Does tight control of hyperglycemia improve outcomes in the pediatric intensive care unit?

Bottom line

Tight glycemic control does not increase the number of days alive and free from mechanical ventilation for pediatric patients in the intensive care unit (ICU), but does increase the risk of severe hypoglycemia. Children in the ICU for reasons other than cardiac surgery and were treated with tight control had lower overall healthcare costs and reduced lengths of stay. However, these benefits must be weighed against the increased risk of hypoglycemia.

Reference

Macrae D, Grieve R, Allen E, et al, for the CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014;370(2):107-118. (LOE: 1b)

Allocation

(Concealed)

Design

Randomized controlled trial (nonblinded)

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized 1369 patients in the pediatric ICU to receive either tight glycemic control with a target blood glucose of 72 mg/dL to 126 mg/dL (4 - 7 mmol/L) or conventional glycemic control with a target of less than 216 mg/dL (12 mmol/L). Eligible patients were aged between 36 weeks and 16 years. They required mechanical ventilation and vasoactive drugs for an anticipated 12 hours following an injury or major surgery or to treat a critical illness. Children with diabetes were excluded. Analysis was by intention to treat. Baseline characteristics of the 2 groups were similar, and 60% of the patients in the total cohort had undergone cardiac surgery. There was no significant difference detected between the 2 groups for the primary outcome – the number of days alive and free from mechanical ventilation at 30 days. As expected, patients in the tight control group were more likely to have multiple severe hypoglycemic episodes (7.3% vs 1.5%; odds ratio = 5.27; 95% CI, 2.65-10.48). Although major clinical outcomes did not improve, there were some benefits associated with tight control, including reduced costs and reduced lengths of stay in the subgroup of patients who had not undergone cardiac surgery, as well as decreased need for renal replacement therapy in the overall group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.