Literature Review

Clinical Question: Does direct observation underestimate physician compliance with hand hygiene (HH) compared to other professional groups due to the Hawthorne effect?

Background: Although it is well-known that HH is imperative to infection control, physician compliance remains suboptimal and is often reported to be below that of nurses. The Hawthorne effect may be contributing to this perceived difference because nurses, who work on the same unit consistently, may more readily recognize hospital auditors.

Study Design: Observational.

Setting: 800-bed acute-care academic hospital in Canada.

Synopsis: Two students were trained to covertly observe physician and nursing HH compliance on inpatient units. For two months, students rotated units every week to minimize risk of discovery. Their findings were compared with data gathered by hospital auditors over the same time period.

Covertly observed HH compliance was 50% (799/1,597 opportunities) compared with 83.7% (2,769/3,309) reported by hospital auditors (P<0.0002). The difference in physician compliance was 19% (73.2% compliance with overt observation versus 54.2% with covert observation). The difference was much higher for nurses at 40.7% (85.8% compliance with overt observation versus 45.1% with covert observation). Attending physician behaviors heavily influenced team behaviors—79.5% of trainees were compliant if their attending was compliant compared with 18.9% if attending was not (P<0.0002).

Bottom Line: Traditional HH audit findings that physicians are less compliant than nurses may be at least partially due to the Hawthorne effect. Nonetheless, all healthcare providers have substantial room for improvement, and attending physicians are powerful role models to effect this change.

Citation: Kovacs-Litman A, Wong K, Shojania KJ, Callery S, Vearncombe M, Leis J. Do physicians clean their hands? Insights from a covert observational study [published online ahead of print July 5, 2016]. J Hosp Med.

Clinical Question: Does direct observation underestimate physician compliance with hand hygiene (HH) compared to other professional groups due to the Hawthorne effect?

Background: Although it is well-known that HH is imperative to infection control, physician compliance remains suboptimal and is often reported to be below that of nurses. The Hawthorne effect may be contributing to this perceived difference because nurses, who work on the same unit consistently, may more readily recognize hospital auditors.

Study Design: Observational.

Setting: 800-bed acute-care academic hospital in Canada.

Synopsis: Two students were trained to covertly observe physician and nursing HH compliance on inpatient units. For two months, students rotated units every week to minimize risk of discovery. Their findings were compared with data gathered by hospital auditors over the same time period.

Covertly observed HH compliance was 50% (799/1,597 opportunities) compared with 83.7% (2,769/3,309) reported by hospital auditors (P<0.0002). The difference in physician compliance was 19% (73.2% compliance with overt observation versus 54.2% with covert observation). The difference was much higher for nurses at 40.7% (85.8% compliance with overt observation versus 45.1% with covert observation). Attending physician behaviors heavily influenced team behaviors—79.5% of trainees were compliant if their attending was compliant compared with 18.9% if attending was not (P<0.0002).

Bottom Line: Traditional HH audit findings that physicians are less compliant than nurses may be at least partially due to the Hawthorne effect. Nonetheless, all healthcare providers have substantial room for improvement, and attending physicians are powerful role models to effect this change.

Citation: Kovacs-Litman A, Wong K, Shojania KJ, Callery S, Vearncombe M, Leis J. Do physicians clean their hands? Insights from a covert observational study [published online ahead of print July 5, 2016]. J Hosp Med.

Clinical Question: Does direct observation underestimate physician compliance with hand hygiene (HH) compared to other professional groups due to the Hawthorne effect?

Background: Although it is well-known that HH is imperative to infection control, physician compliance remains suboptimal and is often reported to be below that of nurses. The Hawthorne effect may be contributing to this perceived difference because nurses, who work on the same unit consistently, may more readily recognize hospital auditors.

Study Design: Observational.

Setting: 800-bed acute-care academic hospital in Canada.

Synopsis: Two students were trained to covertly observe physician and nursing HH compliance on inpatient units. For two months, students rotated units every week to minimize risk of discovery. Their findings were compared with data gathered by hospital auditors over the same time period.

Covertly observed HH compliance was 50% (799/1,597 opportunities) compared with 83.7% (2,769/3,309) reported by hospital auditors (P<0.0002). The difference in physician compliance was 19% (73.2% compliance with overt observation versus 54.2% with covert observation). The difference was much higher for nurses at 40.7% (85.8% compliance with overt observation versus 45.1% with covert observation). Attending physician behaviors heavily influenced team behaviors—79.5% of trainees were compliant if their attending was compliant compared with 18.9% if attending was not (P<0.0002).

Bottom Line: Traditional HH audit findings that physicians are less compliant than nurses may be at least partially due to the Hawthorne effect. Nonetheless, all healthcare providers have substantial room for improvement, and attending physicians are powerful role models to effect this change.

Citation: Kovacs-Litman A, Wong K, Shojania KJ, Callery S, Vearncombe M, Leis J. Do physicians clean their hands? Insights from a covert observational study [published online ahead of print July 5, 2016]. J Hosp Med.

Switching between generic versions of the same antiepileptic drug made by different manufacturers does not appear to change the risk of seizure-related events in patients with epilepsy, according to a population-based, case–crossover study of generic antiepileptic drug users published online ahead of print September 28 in Neurology. Delays and complications of the medication refilling process might increase a patient’s risk for a seizure, said Aaron Kesselheim, MD, JD, MPH, Associate Professor of Medicine at Harvard Medical School in Boston, and colleagues.

“These results add to the growing literature supporting the routine use of interchangeable generic [antiepileptic drugs] among patients with seizure disorders,” he added.

Although previous observational studies have demonstrated increased seizure activity following a switch from brand name to generic antiepileptic drugs, several recent randomized trials have found no
link between generic drug switching and seizure risk, said Dr. Kesselheim.

Investigators identified 59,344 patients with at least one refill of a prescription from the same manufacturer and 5,200 patients who switched from one generic to another from 2000 to 2010 in the Medicaid Analytic eXtract database and from 2005 to 2013 in a commercial health insurance database. Participants acted as their own controls in the study’s comparison of the effects of a refill or a refill with a switch in manufacturer on seizure-related events (ie, a seizure requiring an emergency department visit or hospitalization) during a hazard period, defined as days 2–36 preceding a seizure-related event, and a control period, defined as days 51–85 preceding the seizure-related event.

Overall, generic antiepileptic refilling of the same medication from the same manufacturer was associated with an 8% increase in the odds of having a seizure-related event. When the refill involved a switch to the same generic drug made by a different manufacturer, the odds of a seizure-related event rose by 9%. When the refill involved a change in the shape or color of the pill, the odds increased by 11% but did not increase when the switch was made to a pill with the same color and shape. The increased odds of seizure-related events became nonsignificant when the researchers adjusted these comparisons for the process of refilling, which “is often not straightforward,” said Dr. Kesselheim. “Patients have expressed frustration with delays and other complicating factors relating to refilling.… Greater work to enhance the refilling process, and to determine whether mail order pharmacies successfully improve outcomes on this point, is necessary.”

The study was not supported by any specific targeted funding. The investigators received support from various foundations and from programs within Harvard University and grants from the Agency for Healthcare Research and Quality and the FDA.The investigators also disclosed acting in a research support role for or receiving financial compensation from several pharmaceutical companies and other organizations.

—Jessica Craig

Suggested Reading

Kesselheim AS, Bykov K, Gagne JJ, et al. Switching generic antiepileptic drug manufacturer not linked to seizures: a case-crossover study. Neurology. 2016 Sep 28 [Epub ahead of print].

Krauss GL, Privitera M. More data on the safety of generic substitution: yes, the blue tablet is OK? Neurology. 2016 Sep 28 [Epub ahead of print].

Switching between generic versions of the same antiepileptic drug made by different manufacturers does not appear to change the risk of seizure-related events in patients with epilepsy, according to a population-based, case–crossover study of generic antiepileptic drug users published online ahead of print September 28 in Neurology. Delays and complications of the medication refilling process might increase a patient’s risk for a seizure, said Aaron Kesselheim, MD, JD, MPH, Associate Professor of Medicine at Harvard Medical School in Boston, and colleagues.

“These results add to the growing literature supporting the routine use of interchangeable generic [antiepileptic drugs] among patients with seizure disorders,” he added.

Although previous observational studies have demonstrated increased seizure activity following a switch from brand name to generic antiepileptic drugs, several recent randomized trials have found no
link between generic drug switching and seizure risk, said Dr. Kesselheim.

Investigators identified 59,344 patients with at least one refill of a prescription from the same manufacturer and 5,200 patients who switched from one generic to another from 2000 to 2010 in the Medicaid Analytic eXtract database and from 2005 to 2013 in a commercial health insurance database. Participants acted as their own controls in the study’s comparison of the effects of a refill or a refill with a switch in manufacturer on seizure-related events (ie, a seizure requiring an emergency department visit or hospitalization) during a hazard period, defined as days 2–36 preceding a seizure-related event, and a control period, defined as days 51–85 preceding the seizure-related event.

Overall, generic antiepileptic refilling of the same medication from the same manufacturer was associated with an 8% increase in the odds of having a seizure-related event. When the refill involved a switch to the same generic drug made by a different manufacturer, the odds of a seizure-related event rose by 9%. When the refill involved a change in the shape or color of the pill, the odds increased by 11% but did not increase when the switch was made to a pill with the same color and shape. The increased odds of seizure-related events became nonsignificant when the researchers adjusted these comparisons for the process of refilling, which “is often not straightforward,” said Dr. Kesselheim. “Patients have expressed frustration with delays and other complicating factors relating to refilling.… Greater work to enhance the refilling process, and to determine whether mail order pharmacies successfully improve outcomes on this point, is necessary.”

The study was not supported by any specific targeted funding. The investigators received support from various foundations and from programs within Harvard University and grants from the Agency for Healthcare Research and Quality and the FDA.The investigators also disclosed acting in a research support role for or receiving financial compensation from several pharmaceutical companies and other organizations.

—Jessica Craig

Suggested Reading

Kesselheim AS, Bykov K, Gagne JJ, et al. Switching generic antiepileptic drug manufacturer not linked to seizures: a case-crossover study. Neurology. 2016 Sep 28 [Epub ahead of print].

Krauss GL, Privitera M. More data on the safety of generic substitution: yes, the blue tablet is OK? Neurology. 2016 Sep 28 [Epub ahead of print].

Switching between generic versions of the same antiepileptic drug made by different manufacturers does not appear to change the risk of seizure-related events in patients with epilepsy, according to a population-based, case–crossover study of generic antiepileptic drug users published online ahead of print September 28 in Neurology. Delays and complications of the medication refilling process might increase a patient’s risk for a seizure, said Aaron Kesselheim, MD, JD, MPH, Associate Professor of Medicine at Harvard Medical School in Boston, and colleagues.

“These results add to the growing literature supporting the routine use of interchangeable generic [antiepileptic drugs] among patients with seizure disorders,” he added.

Although previous observational studies have demonstrated increased seizure activity following a switch from brand name to generic antiepileptic drugs, several recent randomized trials have found no
link between generic drug switching and seizure risk, said Dr. Kesselheim.

Investigators identified 59,344 patients with at least one refill of a prescription from the same manufacturer and 5,200 patients who switched from one generic to another from 2000 to 2010 in the Medicaid Analytic eXtract database and from 2005 to 2013 in a commercial health insurance database. Participants acted as their own controls in the study’s comparison of the effects of a refill or a refill with a switch in manufacturer on seizure-related events (ie, a seizure requiring an emergency department visit or hospitalization) during a hazard period, defined as days 2–36 preceding a seizure-related event, and a control period, defined as days 51–85 preceding the seizure-related event.

Overall, generic antiepileptic refilling of the same medication from the same manufacturer was associated with an 8% increase in the odds of having a seizure-related event. When the refill involved a switch to the same generic drug made by a different manufacturer, the odds of a seizure-related event rose by 9%. When the refill involved a change in the shape or color of the pill, the odds increased by 11% but did not increase when the switch was made to a pill with the same color and shape. The increased odds of seizure-related events became nonsignificant when the researchers adjusted these comparisons for the process of refilling, which “is often not straightforward,” said Dr. Kesselheim. “Patients have expressed frustration with delays and other complicating factors relating to refilling.… Greater work to enhance the refilling process, and to determine whether mail order pharmacies successfully improve outcomes on this point, is necessary.”

The study was not supported by any specific targeted funding. The investigators received support from various foundations and from programs within Harvard University and grants from the Agency for Healthcare Research and Quality and the FDA.The investigators also disclosed acting in a research support role for or receiving financial compensation from several pharmaceutical companies and other organizations.

—Jessica Craig

Suggested Reading

Kesselheim AS, Bykov K, Gagne JJ, et al. Switching generic antiepileptic drug manufacturer not linked to seizures: a case-crossover study. Neurology. 2016 Sep 28 [Epub ahead of print].

Krauss GL, Privitera M. More data on the safety of generic substitution: yes, the blue tablet is OK? Neurology. 2016 Sep 28 [Epub ahead of print].

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: Is there a mortality difference in nondiabetic patients with multivessel coronary artery disease (CAD) treated with coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI)?

Background: Randomized clinical trials have shown a mortality benefit of CABG over PCI with drug-eluting stents (DES) for diabetic patients. The best strategy for nondiabetics, however, has not been well established.

Study Design: Pooled individual patient data from two large randomized clinical trials.

Setting: Multicenter, multinational (Europe, United States, Asia).

Synopsis: Excluding patients with left main disease, a total of 1,275 nondiabetic patients with two- or three-vessel CAD were analyzed. After median follow-up of 61 months, the CABG group had significantly fewer deaths from any cause (hazard ratio [HR], 0.65; 95% CI, 0.43–0.98; P=0.039) as well as fewer deaths from cardiac causes (HR, 0.41; 95% CI, 0.25–0.78; P=0.005) when compared to PCI with DES. The benefit was primarily seen at five-year follow-up in patients with intermediate to severe disease, with a nonsignificant difference detected in patients with less severe disease.

Despite the increasing popularity of DES, this study suggests that for nondiabetic patients with CAD, there is a mortality benefit at five years favoring CABG over PCI with DES. However, in this study stents used for PCI included both older and newer generation DES; a study using only newer DES may reduce the differences in outcomes between the groups.

Bottom Line: Five-year mortality is lower in nondiabetic patients with multivessel CAD treated with CABG compared with PCI with DES.

Citation: Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol. 2016;68(1):29-36.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

Clinical Question: What is the incidence of neutropenia in patients treated with prolonged courses of ceftaroline?

Background: Ceftaroline, a new broad-spectrum cephalosporin antibiotic, is FDA approved for the treatment of skin and soft-tissue infections and community-acquired pneumonia (CAP). Other than a few case reports, previous studies have not assessed the incidence of neutropenia in patients receiving ceftaroline for off-label indications or for prolonged courses.

Study Design: Retrospective chart review.

Setting: Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

Synopsis: The authors identified 67 patients who received ceftaroline for seven or more consecutive days. Overall, ceftaroline exposure for two or more weeks was associated with a 10%–14% incidence of neutropenia (absolute neutrophil count less than 1,800 cells/mm3), and ceftaroline exposure for three or more weeks was associated with a 21% incidence of neutropenia. Both the mean duration of ceftaroline exposure and the total number of ceftaroline doses were associated with incident neutropenia.

This is the first study to systematically assess the incidence of ceftaroline-associated neutropenia. The data support a correlation between cumulative ceftaroline exposure and neutropenia. Hospitalists managing patients with prolonged courses of ceftaroline should carefully monitor hematologic studies during treatment.

Bottom Line: The overall rate of neutropenia in patients receiving prolonged courses of ceftaroline is significant, and it is associated with duration of ceftaroline exposure and total number of doses received.

Citation: Furtek KJ, Kubiak DW, Barra M, Varughese C, Ashbaugh CD, Koo S. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71(7):2010-2013.

Short Take

New Guidelines from IDSA/ATS for Patients with Community-Acquired Pneumonia Can Safely Be Implemented for Hospitalized Patients

A multicenter, non-inferiority randomized clinical trial of 312 patients with community-acquired pneumonia (CAP) found that stopping antibiotics after five days was not associated with worse outcomes and may reduce readmissions.

Citation: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257-1265.

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues.

Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.

An Analysis of CARE-MS II Data

Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.

Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.

Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.

Results Consistently Favored Alemtuzumab

In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.

At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.

In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.

At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.

Structural or Functional Repair?

“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”

The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”

Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.

“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.

—Erik Greb

Suggested Reading

Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].

Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].

In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues.

Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.

An Analysis of CARE-MS II Data

Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.

Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.

Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.

Results Consistently Favored Alemtuzumab

In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.

At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.

In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.

At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.

Structural or Functional Repair?

“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”

The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”

Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.

“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.

—Erik Greb

Suggested Reading

Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].

Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].

In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues.

Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.

An Analysis of CARE-MS II Data

Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.

Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.

Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.

Results Consistently Favored Alemtuzumab

In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.

At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.

In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.

At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.

Structural or Functional Repair?

“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”

The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”

Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.

“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.

—Erik Greb

Suggested Reading

Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].

Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].

Sertraline may help to prevent the onset of depressive disorders after a traumatic brain injury (TBI), according to data published online ahead of print September 14 in JAMA Psychiatry.

“Our findings suggest that sertraline given at a low dosage early after TBI is an efficacious strategy to prevent depression after TBI,” said Ricardo E. Jorge, MD, Professor of Psychiatry and Behavioral Sciences at Baylor College of Medicine in Houston.

Every year, there are approximately 1.7 million cases of TBI in the United States. TBI contributes to 30% of all injury deaths and is a major cause of death and disability in the US, according to the Centers for Disease Control and Prevention.

Depressive disorders are common after TBI. In two studies, 58 of 157 patients developed a depressive disorder during the first year following TBI. Dr. Jorge and his colleagues conducted a double-blind, placebo-controlled study to assess the efficacy of sertraline in preventing depressive disorders following TBI. Their main outcome was time to onset of depressive disorder, as defined by the DSM-IV, associated with TBI.

“We hypothesized that the time from baseline to onset of depressive disorders would be greater in a group of patients randomized to receive sertraline treatment versus a group of patients randomized to receive placebo,” said Dr. Jorge. “We also hypothesized that, when compared with patients receiving placebo, patients receiving sertraline would show better performance in a set of neuropsychologic tests after six months of treatment.”

For the study, 94 patients were randomized to receive 100 mg/day of sertraline or placebo once daily for 24 weeks or until the development of a mood disorder. The age of participants ranged between 18 and 85, and patients had mild, moderate, or severe TBI. In addition, participants were required to have complete recovery of posttraumatic amnesia within four weeks of the traumatic episode. Patients with ongoing depression were excluded from the study. Furthermore, patients with mood disorders were required to have been in full remission for at least a year following discontinuation of treatment.

Researchers used the Mini-International Neuropsychiatric Interview and DSM-IV criteria to diagnose depressive disorders. In addition, participants were evaluated at baseline and at two, four, eight, 12, 16, 20, and 24 weeks. A Mini-International Neuropsychiatric Interview was administered via telephone on weeks six, 10, 14, 18, and 22.

The number of patients needed to treat to prevent development of depression after TBI at 24 weeks was 5.9. There were no incident cases of anxiety disorders, and one patient had suicidal ideation. Nearly all patients reported mild or moderate adverse events in the sertraline and placebo groups. Sexual adverse events were mild and did not significantly impact the quality of life of participants. Frequencies of dry mouth and diarrhea were higher among participants who received sertraline.

“The fact that small doses of sertraline are efficacious to prevent depression after TBI stands in sharp contrast to the lack of efficacy of antidepressants to treat depression in the chronic stage of TBI,” said Dr. Jorge.

Limitations of this study include its scarce representation of ethnic and racial minorities, small sample size, and limited follow-up following incident TBI.

—Erica Tricarico

Suggested Reading

Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline for preventing mood disorders following traumatic brain injury. JAMA Psychiatry. 2016 Sep 14 [Epub ahead of print].

Sertraline may help to prevent the onset of depressive disorders after a traumatic brain injury (TBI), according to data published online ahead of print September 14 in JAMA Psychiatry.

“Our findings suggest that sertraline given at a low dosage early after TBI is an efficacious strategy to prevent depression after TBI,” said Ricardo E. Jorge, MD, Professor of Psychiatry and Behavioral Sciences at Baylor College of Medicine in Houston.

Every year, there are approximately 1.7 million cases of TBI in the United States. TBI contributes to 30% of all injury deaths and is a major cause of death and disability in the US, according to the Centers for Disease Control and Prevention.

Depressive disorders are common after TBI. In two studies, 58 of 157 patients developed a depressive disorder during the first year following TBI. Dr. Jorge and his colleagues conducted a double-blind, placebo-controlled study to assess the efficacy of sertraline in preventing depressive disorders following TBI. Their main outcome was time to onset of depressive disorder, as defined by the DSM-IV, associated with TBI.

“We hypothesized that the time from baseline to onset of depressive disorders would be greater in a group of patients randomized to receive sertraline treatment versus a group of patients randomized to receive placebo,” said Dr. Jorge. “We also hypothesized that, when compared with patients receiving placebo, patients receiving sertraline would show better performance in a set of neuropsychologic tests after six months of treatment.”

For the study, 94 patients were randomized to receive 100 mg/day of sertraline or placebo once daily for 24 weeks or until the development of a mood disorder. The age of participants ranged between 18 and 85, and patients had mild, moderate, or severe TBI. In addition, participants were required to have complete recovery of posttraumatic amnesia within four weeks of the traumatic episode. Patients with ongoing depression were excluded from the study. Furthermore, patients with mood disorders were required to have been in full remission for at least a year following discontinuation of treatment.

Researchers used the Mini-International Neuropsychiatric Interview and DSM-IV criteria to diagnose depressive disorders. In addition, participants were evaluated at baseline and at two, four, eight, 12, 16, 20, and 24 weeks. A Mini-International Neuropsychiatric Interview was administered via telephone on weeks six, 10, 14, 18, and 22.

The number of patients needed to treat to prevent development of depression after TBI at 24 weeks was 5.9. There were no incident cases of anxiety disorders, and one patient had suicidal ideation. Nearly all patients reported mild or moderate adverse events in the sertraline and placebo groups. Sexual adverse events were mild and did not significantly impact the quality of life of participants. Frequencies of dry mouth and diarrhea were higher among participants who received sertraline.

“The fact that small doses of sertraline are efficacious to prevent depression after TBI stands in sharp contrast to the lack of efficacy of antidepressants to treat depression in the chronic stage of TBI,” said Dr. Jorge.

Limitations of this study include its scarce representation of ethnic and racial minorities, small sample size, and limited follow-up following incident TBI.

—Erica Tricarico

Suggested Reading

Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline for preventing mood disorders following traumatic brain injury. JAMA Psychiatry. 2016 Sep 14 [Epub ahead of print].

Sertraline may help to prevent the onset of depressive disorders after a traumatic brain injury (TBI), according to data published online ahead of print September 14 in JAMA Psychiatry.

“Our findings suggest that sertraline given at a low dosage early after TBI is an efficacious strategy to prevent depression after TBI,” said Ricardo E. Jorge, MD, Professor of Psychiatry and Behavioral Sciences at Baylor College of Medicine in Houston.

Every year, there are approximately 1.7 million cases of TBI in the United States. TBI contributes to 30% of all injury deaths and is a major cause of death and disability in the US, according to the Centers for Disease Control and Prevention.

Depressive disorders are common after TBI. In two studies, 58 of 157 patients developed a depressive disorder during the first year following TBI. Dr. Jorge and his colleagues conducted a double-blind, placebo-controlled study to assess the efficacy of sertraline in preventing depressive disorders following TBI. Their main outcome was time to onset of depressive disorder, as defined by the DSM-IV, associated with TBI.

“We hypothesized that the time from baseline to onset of depressive disorders would be greater in a group of patients randomized to receive sertraline treatment versus a group of patients randomized to receive placebo,” said Dr. Jorge. “We also hypothesized that, when compared with patients receiving placebo, patients receiving sertraline would show better performance in a set of neuropsychologic tests after six months of treatment.”

For the study, 94 patients were randomized to receive 100 mg/day of sertraline or placebo once daily for 24 weeks or until the development of a mood disorder. The age of participants ranged between 18 and 85, and patients had mild, moderate, or severe TBI. In addition, participants were required to have complete recovery of posttraumatic amnesia within four weeks of the traumatic episode. Patients with ongoing depression were excluded from the study. Furthermore, patients with mood disorders were required to have been in full remission for at least a year following discontinuation of treatment.

Researchers used the Mini-International Neuropsychiatric Interview and DSM-IV criteria to diagnose depressive disorders. In addition, participants were evaluated at baseline and at two, four, eight, 12, 16, 20, and 24 weeks. A Mini-International Neuropsychiatric Interview was administered via telephone on weeks six, 10, 14, 18, and 22.

The number of patients needed to treat to prevent development of depression after TBI at 24 weeks was 5.9. There were no incident cases of anxiety disorders, and one patient had suicidal ideation. Nearly all patients reported mild or moderate adverse events in the sertraline and placebo groups. Sexual adverse events were mild and did not significantly impact the quality of life of participants. Frequencies of dry mouth and diarrhea were higher among participants who received sertraline.

“The fact that small doses of sertraline are efficacious to prevent depression after TBI stands in sharp contrast to the lack of efficacy of antidepressants to treat depression in the chronic stage of TBI,” said Dr. Jorge.

Limitations of this study include its scarce representation of ethnic and racial minorities, small sample size, and limited follow-up following incident TBI.

—Erica Tricarico

Suggested Reading

Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline for preventing mood disorders following traumatic brain injury. JAMA Psychiatry. 2016 Sep 14 [Epub ahead of print].

Many patients with recent-onset Parkinson’s disease have increased cardiovascular risk, but statin therapy is underused in this population, according to research published online ahead of print September 26 in the Journal of Neurology, Neurosurgery and Psychiatry. Increased cardiovascular risk is associated with greater motor and cognitive severity and greater axial impairment. Increased use of statins may reduce chronic vascular damage, and thereby slow the progression of motor and cognitive decline in this population, said the authors.

Cardiovascular disease influences phenotypic variation in Parkinson’s disease, but data are unclear about whether cardiovascular risk factors influence Parkinson’s disease phenotype, said Diane M. A. Swallow, MB, ChB, a clinical research fellow in movement disorders at Queen Elizabeth University Hospital in Glasgow. She and her colleagues studied prospectively enrolled participants in the UK Tracking Parkinson’s study and the Oxford Discovery study to quantify vascular risk and statin use in patients with recent-onset Parkinson’s disease. The investigators also sought to clarify the relationship between vascular risk and the severity and phenotype of Parkinson’s disease.

Cardiovascular risk was quantified using the QRISK2-2015 prediction algorithm, which computes risk based on traditional risk factors (eg, age, systolic blood pressure, smoking status, and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with BMI, ethnicity, measures of deprivation, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes mellitus, and antihypertensive treatment.

In all, 2,909 patients were analyzed. The population’s mean age was 67.5, mean disease duration was 1.3 years, and 65.3% of the sample was male. As calculated by the QRISK2-2015, 10-year cardiovascular risk was low for 22.3%, medium for 28.7%, and high for 33.8% of the sample, respectively. Statins were prescribed in 15.1% of patients with medium vascular risk and in 37.2% of patients with high vascular risk. In contrast, statins were prescribed in 75.3% of participants with established vascular disease.

Increasing vascular risk was associated with worsening scores on Part 3 of the Unified Parkinson’s Disease Rating Scale when adjusted for age, sex, disease duration, and coffee consumption. Increasing vascular risk was also associated with increasing cognitive impairment, a worsening score on the Montreal Cognitive Assessment (MoCA), and an increasing proportion of patients with mild cognitive impairment and dementia. The motor and cognitive characteristics of participants with high vascular risk were similar to those of participants with established vascular disease.

Among individuals with established vascular disease and a QRISK2 score of 10% or greater, people who were treated with statins were less likely to have the postural instability and gait difficulty subtype of Parkinson’s disease, but had lower total MoCA scores and were more likely to have cognitive impairment. Among patients with established cardiovascular disease, people treated with statins had better cognition, but did not significantly differ in their likelihood of having postural instability and gait difficulty.

“In assessing our findings, we need to consider that the patients are likely to have been recommended for statins based on their clinical findings, so we cannot compare these groups as if they had been randomized to statin therapy. It is clear that increased vascular risk adds to the burden of gait and cognitive impairment that we see in patients with Parkinson’s disease, and that this [risk] is undertreated,” said Dr. Swallow.

—Erik Greb

Suggested Reading

Swallow DM, Lawton MA, Grosset KA, et al. Statins are underused in recent-onset Parkinson’s disease with increased vascular risk: findings from the UK Tracking Parkinson’s and Oxford Parkinson’s Disease Centre (OPDC) discovery cohorts. J Neurol Neurosurg Psychiatry. 2016 Sep 26 [Epub ahead of print].

Many patients with recent-onset Parkinson’s disease have increased cardiovascular risk, but statin therapy is underused in this population, according to research published online ahead of print September 26 in the Journal of Neurology, Neurosurgery and Psychiatry. Increased cardiovascular risk is associated with greater motor and cognitive severity and greater axial impairment. Increased use of statins may reduce chronic vascular damage, and thereby slow the progression of motor and cognitive decline in this population, said the authors.

Cardiovascular disease influences phenotypic variation in Parkinson’s disease, but data are unclear about whether cardiovascular risk factors influence Parkinson’s disease phenotype, said Diane M. A. Swallow, MB, ChB, a clinical research fellow in movement disorders at Queen Elizabeth University Hospital in Glasgow. She and her colleagues studied prospectively enrolled participants in the UK Tracking Parkinson’s study and the Oxford Discovery study to quantify vascular risk and statin use in patients with recent-onset Parkinson’s disease. The investigators also sought to clarify the relationship between vascular risk and the severity and phenotype of Parkinson’s disease.

Cardiovascular risk was quantified using the QRISK2-2015 prediction algorithm, which computes risk based on traditional risk factors (eg, age, systolic blood pressure, smoking status, and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with BMI, ethnicity, measures of deprivation, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes mellitus, and antihypertensive treatment.

In all, 2,909 patients were analyzed. The population’s mean age was 67.5, mean disease duration was 1.3 years, and 65.3% of the sample was male. As calculated by the QRISK2-2015, 10-year cardiovascular risk was low for 22.3%, medium for 28.7%, and high for 33.8% of the sample, respectively. Statins were prescribed in 15.1% of patients with medium vascular risk and in 37.2% of patients with high vascular risk. In contrast, statins were prescribed in 75.3% of participants with established vascular disease.

Increasing vascular risk was associated with worsening scores on Part 3 of the Unified Parkinson’s Disease Rating Scale when adjusted for age, sex, disease duration, and coffee consumption. Increasing vascular risk was also associated with increasing cognitive impairment, a worsening score on the Montreal Cognitive Assessment (MoCA), and an increasing proportion of patients with mild cognitive impairment and dementia. The motor and cognitive characteristics of participants with high vascular risk were similar to those of participants with established vascular disease.

Among individuals with established vascular disease and a QRISK2 score of 10% or greater, people who were treated with statins were less likely to have the postural instability and gait difficulty subtype of Parkinson’s disease, but had lower total MoCA scores and were more likely to have cognitive impairment. Among patients with established cardiovascular disease, people treated with statins had better cognition, but did not significantly differ in their likelihood of having postural instability and gait difficulty.

“In assessing our findings, we need to consider that the patients are likely to have been recommended for statins based on their clinical findings, so we cannot compare these groups as if they had been randomized to statin therapy. It is clear that increased vascular risk adds to the burden of gait and cognitive impairment that we see in patients with Parkinson’s disease, and that this [risk] is undertreated,” said Dr. Swallow.

—Erik Greb

Suggested Reading

Swallow DM, Lawton MA, Grosset KA, et al. Statins are underused in recent-onset Parkinson’s disease with increased vascular risk: findings from the UK Tracking Parkinson’s and Oxford Parkinson’s Disease Centre (OPDC) discovery cohorts. J Neurol Neurosurg Psychiatry. 2016 Sep 26 [Epub ahead of print].

Many patients with recent-onset Parkinson’s disease have increased cardiovascular risk, but statin therapy is underused in this population, according to research published online ahead of print September 26 in the Journal of Neurology, Neurosurgery and Psychiatry. Increased cardiovascular risk is associated with greater motor and cognitive severity and greater axial impairment. Increased use of statins may reduce chronic vascular damage, and thereby slow the progression of motor and cognitive decline in this population, said the authors.

Cardiovascular disease influences phenotypic variation in Parkinson’s disease, but data are unclear about whether cardiovascular risk factors influence Parkinson’s disease phenotype, said Diane M. A. Swallow, MB, ChB, a clinical research fellow in movement disorders at Queen Elizabeth University Hospital in Glasgow. She and her colleagues studied prospectively enrolled participants in the UK Tracking Parkinson’s study and the Oxford Discovery study to quantify vascular risk and statin use in patients with recent-onset Parkinson’s disease. The investigators also sought to clarify the relationship between vascular risk and the severity and phenotype of Parkinson’s disease.

Cardiovascular risk was quantified using the QRISK2-2015 prediction algorithm, which computes risk based on traditional risk factors (eg, age, systolic blood pressure, smoking status, and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with BMI, ethnicity, measures of deprivation, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes mellitus, and antihypertensive treatment.

In all, 2,909 patients were analyzed. The population’s mean age was 67.5, mean disease duration was 1.3 years, and 65.3% of the sample was male. As calculated by the QRISK2-2015, 10-year cardiovascular risk was low for 22.3%, medium for 28.7%, and high for 33.8% of the sample, respectively. Statins were prescribed in 15.1% of patients with medium vascular risk and in 37.2% of patients with high vascular risk. In contrast, statins were prescribed in 75.3% of participants with established vascular disease.

Increasing vascular risk was associated with worsening scores on Part 3 of the Unified Parkinson’s Disease Rating Scale when adjusted for age, sex, disease duration, and coffee consumption. Increasing vascular risk was also associated with increasing cognitive impairment, a worsening score on the Montreal Cognitive Assessment (MoCA), and an increasing proportion of patients with mild cognitive impairment and dementia. The motor and cognitive characteristics of participants with high vascular risk were similar to those of participants with established vascular disease.

Among individuals with established vascular disease and a QRISK2 score of 10% or greater, people who were treated with statins were less likely to have the postural instability and gait difficulty subtype of Parkinson’s disease, but had lower total MoCA scores and were more likely to have cognitive impairment. Among patients with established cardiovascular disease, people treated with statins had better cognition, but did not significantly differ in their likelihood of having postural instability and gait difficulty.

“In assessing our findings, we need to consider that the patients are likely to have been recommended for statins based on their clinical findings, so we cannot compare these groups as if they had been randomized to statin therapy. It is clear that increased vascular risk adds to the burden of gait and cognitive impairment that we see in patients with Parkinson’s disease, and that this [risk] is undertreated,” said Dr. Swallow.

—Erik Greb

Suggested Reading

Swallow DM, Lawton MA, Grosset KA, et al. Statins are underused in recent-onset Parkinson’s disease with increased vascular risk: findings from the UK Tracking Parkinson’s and Oxford Parkinson’s Disease Centre (OPDC) discovery cohorts. J Neurol Neurosurg Psychiatry. 2016 Sep 26 [Epub ahead of print].

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.