Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Kenneth Ataga, MD

Photo courtesy of ASH

SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.

The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).

Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.

Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.

Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).

The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.

Patient population

A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.

They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.

Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb⁰-thalassemia, or HbSB⁺-thalassemia.

They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.

Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.

Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.

Study endpoints

The primary endpoint was the annual rate of adjudicated SCPC.

“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.

The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.

The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.

Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.

Efficacy

The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.

Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.

SCD genotype or concomitant hydroxyurea use did not impact these results.

Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.

The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.

The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).

“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”

And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.

“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”

The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).

Safety

One or more adverse events occurred in over 85% of patients in each group.

Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Five patients died while on study, but none of these deaths were related to the study drug.

Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Blood for transfusion

Photo from UAB Hospital

SAN DIEGO—Results of the phase 3 TRIST study support the use of a restrictive red blood cell (RBC) transfusion strategy in patients undergoing hematopoietic stem cell transplant (HSCT) to treat hematologic disorders.

The study suggests a restrictive strategy—in which patients receive 2 RBC units if their hemoglobin level is below 70 g/L—is non-inferior to a liberal strategy—in which patients receive 2 units if their hemoglobin level is below 90 g/L.

Clinical outcomes and health-related quality of life (HRQOL) were similar with both strategies.

Therefore, a restrictive strategy should be considered the standard of care in patients undergoing HSCT, according to study investigator Jason Tay, MD, of the University of Calgary/Tom Baker Cancer Center in Alberta, Canada.

Dr Tay presented results of the TRIST study at the 2016 ASH Annual Meeting (abstract 1032*).

He noted that recent AABB guidelines recommend using a restrictive RBC transfusion strategy in most circumstances. However, these recommendations do not apply to patients treated for hematologic or oncologic diseases who are at risk of bleeding, as there is a lack of randomized trials in such patients.

So Dr Tay and his colleagues decided to conduct a randomized, controlled trial comparing 2 RBC transfusion strategies in patients undergoing HSCT to treat hematologic disorders.

The study enrolled 300 patients who underwent HSCT between March 28, 2011, and February 3, 2016, at 4 Canadian centers.

The patients were randomized to 1 of 2 transfusion strategies from day 0 to day 100 post-HSCT:

• Restrictive strategy (n=149)—patients received 2 RBC units if their hemoglobin levels were below 70 g/L, to target a hemoglobin level of 70-90 g/L
• Liberal strategy (n=150)—patients received 2 RBC units if their hemoglobin levels were below 90 g/L, to target a hemoglobin level of 90-110 g/L.

The median age was 57.47 (range, 48.94-62.66) in the restrictive group and 56.04 (range, 48.27-62.24) in the liberal group. Most patients were male—65.10% and 62.67%, respectively.

Patients had acute leukemia (25.50% and 24.00%, respectively), chronic leukemia (6.71% and 6.00%), myeloproliferative disorders (2.68% and 2.00%), lymphoma (30.87% and 33.33%), myeloma (24.16% and 28.00%), and other disorders (10.07% and 6.67%, respectively).

About half of patients in each transfusion group received an autologous HSCT (49.66% and 50.00%, respectively), and about half received an allogeneic HSCT (50.34% and 50.00%, respectively).

Transfusion use

The total number of RBC units transfused was 407 in the restrictive group and 753 in the liberal group. The median number of RBC units transfused per patient was 2 (range, 0-2) and 4 (range, 2-6), respectively. The mean number was 2.73 and 5.02, respectively (P=0.0004).

The total number of RBC transfusion episodes was 234 in the restrictive group and 407 in the liberal group. The median number per patient was 1 (range, 0-2) and 2 (range, 1-3), respectively, and the mean was 1.57 and 2.70, respectively (P=0.002).

The median storage duration of the RBC units transfused was 17 days (range, 13-23) in the restrictive group and 20 days (range, 15-25) in the liberal group. The mean was 18.46 and 19.95, respectively (P=0.0003).

The between-group difference in the overall mean pre-transfusion hemoglobin per patient over the study period was 13.71 g/L.

The median number of platelet units transfused was 2 (range, 1-3) in the

restrictive group and 3 (range, 1-4) in the liberal group. The mean was 3.84 and 3.61, respectively (P=0.6930).

The median number of platelet transfusion episodes was 2 for both groups (range, 1-3 and

1-4, respectively). The mean was 3.84 in the restrictive group and 3.61 in the liberal group (P=0.77).

Adherence

In both groups, there were cases of non-adherence to the trigger hemoglobin value.

There were 49 non-adherent patients (32.89%) in the restrictive group—35 in whom an RBC transfusion occurred above the assigned trigger and 14 in whom a transfusion did not occur when the assigned trigger was reached.

There were 83 non-adherent patients (55.3%) in the liberal group—11 in whom an RBC transfusion occurred above the assigned trigger and 72 in whom a transfusion did not occur when the assigned trigger was reached.

Sixty-nine patients (46.31%) in the restrictive group and 21 (14%) in the liberal group never received an RBC transfusion.

Outcomes

The study’s primary endpoint was HRQOL, as measured by the FACT-BMT scale.

The total FACT-BMT score at day 100 was 116.3 (range, 98-129.2) in the restrictive group and 109.2 (range, 92.1-125.2) in the liberal group (P<0.0001 for non-inferiority).

Non-inferiority in HRQOL was shown for all other time points assessed as well—day 7 (P<0.001), day 14 (P<0.0001), day 28 (P<0.0001), and day 60 (P<0.0001). Total FACT-BMT scores at all time points were higher for patients in the restrictive group than the liberal one.

The study’s secondary endpoints included clinical outcomes and FACT-Anemia scores at several time points.

There was no significant difference in clinical outcomes between the restrictive and liberal transfusion groups.

There were 2 cases of transplant-related mortality in the restrictive group and 4 in the liberal group (P=0.42). And there were 4 cases of sinusoidal obstruction syndrome in both groups (P=0.98).

The median Bearman toxicity score at day 28 was 2 in both groups (range, 1-3 and 1-4, respectively). The mean was 2.5 in the restrictive group and 2.8 in the liberal group (P=0.33).

There was no significant between-group difference in WHO bleeding score at day 14 (P=0.13), day 28 (P=0.81), or day 100 (P=0.28).

There was no significant difference between the transfusion groups in the length of hospital stay for patients who received autologous HSCT (P=0.95) or allogeneic HSCT (P=0.23) or in the number of hospital readmissions for patients who received autologous HSCT (P=0.29) or allogeneic HSCT (P=0.81).

The total FACT-Anemia score was significantly higher in the restrictive transfusion group at day 7 (P=0.03) and day 60 (P=0.03) post-HSCT.

However, there was no significant between-group difference in FACT-Anemia score at 14 days (P=0.07), 28 days (P=0.51), or 100 days (P=0.14).

Dr Tay said these results suggest a restrictive RBC transfusion strategy is non-inferior to a liberal one in patients undergoing HSCT to treat a hematologic disorder.

“Moreover, a restrictive strategy is safe and results in less blood transfusions,” he said. “We’d like to suggest that a strategy of 70 g/L can be considered the standard of care in patients undergoing a stem cell transplantation.”

*Information presented at the meeting differs from the abstract.

Johns Hopkins clinicians caring

for a child in the pediatric ICU

Photo courtesy of

Johns Hopkins Medicine

New research suggests clinical practice guidelines can reduce the number of potentially unnecessary blood culture draws in critically ill children without endangering doctors’ ability to diagnose and treat sepsis.

The guidelines consist of 2 documents—a screening checklist and a decision algorithm.

In a single-center study, clinicians consulted these documents when considering ordering blood cultures for patients in a pediatric intensive care unit (ICU).

The clinicians said there was an immediate reduction in unnecessary blood draws after they began using these guidelines, and they were able to sustain the reduction over time.

Aaron Milstone, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described these results in JAMA Pediatrics.

The guidelines were created by a team of nurses, vascular access specialists, and physicians across specialties. The team created a fever/sepsis screening checklist and an accompanying decision-making flow chart designed to guide clinicians in the decision to draw blood.

These tools were posted in the pediatric ICU at The Johns Hopkins Hospital with instructions to be completed at the bedside by nurses and physicians. Each week, the team would meet to evaluate the data gathered, review how many cultures were sent from the unit, and discuss in detail individual cases where blood draws were necessary.

The researchers compared patient length of stay, mortality, readmission, and the number of episodes of suspected septic shock at the hospital before and after this intervention was implemented.

In the year before the team introduced the tools, there were 2204 patient visits to the pediatric ICU and 1807 blood cultures drawn.

After the intervention, there were 984 blood cultures drawn for 2356 patient visits, almost halving the number of blood cultures per patient day.

Comparing the pre- and post-intervention periods, there was no statistical difference in the occurrence of septic shock, hospital mortality, or hospital readmission.

Dr Milstone said this means patients experienced no increased risk of a missed sepsis diagnosis because of the intervention.

He and his colleagues said the future directions of this research include further exploring the implications this intervention may have for antibiotic use as well as working to implement the tools in other ICUs. The tools are already being tried at Johns Hopkins All Children’s Hospital in Florida and in the pediatric ICU at the University of Virginia.

Johns Hopkins clinicians caring

for a child in the pediatric ICU

Photo courtesy of

Johns Hopkins Medicine

New research suggests clinical practice guidelines can reduce the number of potentially unnecessary blood culture draws in critically ill children without endangering doctors’ ability to diagnose and treat sepsis.

The guidelines consist of 2 documents—a screening checklist and a decision algorithm.

In a single-center study, clinicians consulted these documents when considering ordering blood cultures for patients in a pediatric intensive care unit (ICU).

The clinicians said there was an immediate reduction in unnecessary blood draws after they began using these guidelines, and they were able to sustain the reduction over time.

Aaron Milstone, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described these results in JAMA Pediatrics.

The guidelines were created by a team of nurses, vascular access specialists, and physicians across specialties. The team created a fever/sepsis screening checklist and an accompanying decision-making flow chart designed to guide clinicians in the decision to draw blood.

These tools were posted in the pediatric ICU at The Johns Hopkins Hospital with instructions to be completed at the bedside by nurses and physicians. Each week, the team would meet to evaluate the data gathered, review how many cultures were sent from the unit, and discuss in detail individual cases where blood draws were necessary.

The researchers compared patient length of stay, mortality, readmission, and the number of episodes of suspected septic shock at the hospital before and after this intervention was implemented.

In the year before the team introduced the tools, there were 2204 patient visits to the pediatric ICU and 1807 blood cultures drawn.

After the intervention, there were 984 blood cultures drawn for 2356 patient visits, almost halving the number of blood cultures per patient day.

Comparing the pre- and post-intervention periods, there was no statistical difference in the occurrence of septic shock, hospital mortality, or hospital readmission.

Dr Milstone said this means patients experienced no increased risk of a missed sepsis diagnosis because of the intervention.

He and his colleagues said the future directions of this research include further exploring the implications this intervention may have for antibiotic use as well as working to implement the tools in other ICUs. The tools are already being tried at Johns Hopkins All Children’s Hospital in Florida and in the pediatric ICU at the University of Virginia.

Johns Hopkins clinicians caring

for a child in the pediatric ICU

Photo courtesy of

Johns Hopkins Medicine

New research suggests clinical practice guidelines can reduce the number of potentially unnecessary blood culture draws in critically ill children without endangering doctors’ ability to diagnose and treat sepsis.

The guidelines consist of 2 documents—a screening checklist and a decision algorithm.

In a single-center study, clinicians consulted these documents when considering ordering blood cultures for patients in a pediatric intensive care unit (ICU).

The clinicians said there was an immediate reduction in unnecessary blood draws after they began using these guidelines, and they were able to sustain the reduction over time.

Aaron Milstone, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described these results in JAMA Pediatrics.

The guidelines were created by a team of nurses, vascular access specialists, and physicians across specialties. The team created a fever/sepsis screening checklist and an accompanying decision-making flow chart designed to guide clinicians in the decision to draw blood.

These tools were posted in the pediatric ICU at The Johns Hopkins Hospital with instructions to be completed at the bedside by nurses and physicians. Each week, the team would meet to evaluate the data gathered, review how many cultures were sent from the unit, and discuss in detail individual cases where blood draws were necessary.

The researchers compared patient length of stay, mortality, readmission, and the number of episodes of suspected septic shock at the hospital before and after this intervention was implemented.

In the year before the team introduced the tools, there were 2204 patient visits to the pediatric ICU and 1807 blood cultures drawn.

After the intervention, there were 984 blood cultures drawn for 2356 patient visits, almost halving the number of blood cultures per patient day.

Comparing the pre- and post-intervention periods, there was no statistical difference in the occurrence of septic shock, hospital mortality, or hospital readmission.

Dr Milstone said this means patients experienced no increased risk of a missed sepsis diagnosis because of the intervention.

He and his colleagues said the future directions of this research include further exploring the implications this intervention may have for antibiotic use as well as working to implement the tools in other ICUs. The tools are already being tried at Johns Hopkins All Children’s Hospital in Florida and in the pediatric ICU at the University of Virginia.

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the past two hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, from 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery.

In the absence of these factors, delivery versus expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended if there are no signs of infection or maternal or fetal compromise. This is because of the significant morbidity and mortality risk associated with births before 34 weeks’ gestation.⁴

Currently, the American College of Obste­tricians and Gynecologists (ACOG) recommends delivery for all women with ­rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and in­consistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

STUDY SUMMARY

Higher birth weights, fewer C-sections, and no increased sepsis

The Preterm Pre-labour Rupture of the Membranes close to Term (PPROMT) trial was a multicenter RCT that included 1,839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Participants were randomized to either expectant management or immediate delivery by induction. Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and two additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (ie, chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the two groups were ­similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥ 24 h, stillbirth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, low birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR], 0.8). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR, 1.2). However, infants born in the immediate delivery group had significantly lower birth weights (2,574.7 g vs 2,673.2 g; absolute difference, –125 g), a higher incidence of respiratory distress (RR, 1.6; number needed to treat [NNT], 32), and spent more time in the NICU/special care nursery (four days vs two days).

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR, 0.6; number needed to harm [NNH], 50) and intrapartum fever (RR, 0.4; NNH, 100). Of the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% of the expectant management group (RR, 1.4; NNT, 14). Six percent of the women assigned to the expectant management group ­developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent, with no significant differ­ences between the two groups.

WHAT’S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (involving 736 women) evaluated expectant management versus induction in the late preterm stage of pregnancy. No increased risk for neonatal sepsis with expectant management was found in either study.^8,9

However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes. The PPROMT study is the largest to indicate that immediate birth increases infant risk for respiratory distress and duration of NICU/special care stay and increases the mother’s risk for cesarean section. It also showed that risk for neonatal sepsis was not higher in the expectant management group.

CAVEATS

Singleton pregnancies only

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. This created variation in fetal and maternal monitoring. The majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage. If one of these occurs, immediate delivery may be necessary.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, as well.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines (updated October 2016) recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(11):820-822.

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the past two hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, from 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery.

In the absence of these factors, delivery versus expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended if there are no signs of infection or maternal or fetal compromise. This is because of the significant morbidity and mortality risk associated with births before 34 weeks’ gestation.⁴

Currently, the American College of Obste­tricians and Gynecologists (ACOG) recommends delivery for all women with ­rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and in­consistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

STUDY SUMMARY

Higher birth weights, fewer C-sections, and no increased sepsis

The Preterm Pre-labour Rupture of the Membranes close to Term (PPROMT) trial was a multicenter RCT that included 1,839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Participants were randomized to either expectant management or immediate delivery by induction. Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and two additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (ie, chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the two groups were ­similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥ 24 h, stillbirth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, low birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR], 0.8). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR, 1.2). However, infants born in the immediate delivery group had significantly lower birth weights (2,574.7 g vs 2,673.2 g; absolute difference, –125 g), a higher incidence of respiratory distress (RR, 1.6; number needed to treat [NNT], 32), and spent more time in the NICU/special care nursery (four days vs two days).

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR, 0.6; number needed to harm [NNH], 50) and intrapartum fever (RR, 0.4; NNH, 100). Of the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% of the expectant management group (RR, 1.4; NNT, 14). Six percent of the women assigned to the expectant management group ­developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent, with no significant differ­ences between the two groups.

WHAT’S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (involving 736 women) evaluated expectant management versus induction in the late preterm stage of pregnancy. No increased risk for neonatal sepsis with expectant management was found in either study.^8,9

However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes. The PPROMT study is the largest to indicate that immediate birth increases infant risk for respiratory distress and duration of NICU/special care stay and increases the mother’s risk for cesarean section. It also showed that risk for neonatal sepsis was not higher in the expectant management group.

CAVEATS

Singleton pregnancies only

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. This created variation in fetal and maternal monitoring. The majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage. If one of these occurs, immediate delivery may be necessary.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, as well.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines (updated October 2016) recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(11):820-822.

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the past two hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, from 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery.

In the absence of these factors, delivery versus expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended if there are no signs of infection or maternal or fetal compromise. This is because of the significant morbidity and mortality risk associated with births before 34 weeks’ gestation.⁴

Currently, the American College of Obste­tricians and Gynecologists (ACOG) recommends delivery for all women with ­rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and in­consistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

STUDY SUMMARY

Higher birth weights, fewer C-sections, and no increased sepsis

The Preterm Pre-labour Rupture of the Membranes close to Term (PPROMT) trial was a multicenter RCT that included 1,839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Participants were randomized to either expectant management or immediate delivery by induction. Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and two additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (ie, chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the two groups were ­similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥ 24 h, stillbirth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, low birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR], 0.8). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR, 1.2). However, infants born in the immediate delivery group had significantly lower birth weights (2,574.7 g vs 2,673.2 g; absolute difference, –125 g), a higher incidence of respiratory distress (RR, 1.6; number needed to treat [NNT], 32), and spent more time in the NICU/special care nursery (four days vs two days).

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR, 0.6; number needed to harm [NNH], 50) and intrapartum fever (RR, 0.4; NNH, 100). Of the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% of the expectant management group (RR, 1.4; NNT, 14). Six percent of the women assigned to the expectant management group ­developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent, with no significant differ­ences between the two groups.

WHAT’S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (involving 736 women) evaluated expectant management versus induction in the late preterm stage of pregnancy. No increased risk for neonatal sepsis with expectant management was found in either study.^8,9

However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes. The PPROMT study is the largest to indicate that immediate birth increases infant risk for respiratory distress and duration of NICU/special care stay and increases the mother’s risk for cesarean section. It also showed that risk for neonatal sepsis was not higher in the expectant management group.

CAVEATS

Singleton pregnancies only

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. This created variation in fetal and maternal monitoring. The majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage. If one of these occurs, immediate delivery may be necessary.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, as well.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines (updated October 2016) recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(11):820-822.

Self-management techniques may help patients with epilepsy and intellectual disabilities suggests a recent review of the medical literature. Michelle Dannenberg and associates found that, while the research on self-management intervention is very limited, 5 high quality pilot and randomized controlled feasibility studies did suggest that such interventions have the potential to improve patients’ knowledge base, reduce the frequency of seizures, and improve their quality of life.

Dannenberg M, Mengoni SE, Gates B et al. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review. Seizure.2016; 41:16-25.

Self-management techniques may help patients with epilepsy and intellectual disabilities suggests a recent review of the medical literature. Michelle Dannenberg and associates found that, while the research on self-management intervention is very limited, 5 high quality pilot and randomized controlled feasibility studies did suggest that such interventions have the potential to improve patients’ knowledge base, reduce the frequency of seizures, and improve their quality of life.

Dannenberg M, Mengoni SE, Gates B et al. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review. Seizure.2016; 41:16-25.

Self-management techniques may help patients with epilepsy and intellectual disabilities suggests a recent review of the medical literature. Michelle Dannenberg and associates found that, while the research on self-management intervention is very limited, 5 high quality pilot and randomized controlled feasibility studies did suggest that such interventions have the potential to improve patients’ knowledge base, reduce the frequency of seizures, and improve their quality of life.

Dannenberg M, Mengoni SE, Gates B et al. Self-management interventions for epilepsy in people with intellectual disabilities: A scoping review. Seizure.2016; 41:16-25.

Pathogenic variants of the SCN8A gene may contribute to a variety of epilepsy types, as well as nonseizure neurodevelopmental disorders, according a recent genetic analysis. Five variants of the gene called sodium channel alpha subunit 8, which codes for the ion pore region of the voltage-gated sodium channel, were detected in the genetic sequencing data from 275 epilepsy panels performed by the Emory Genetics Laboratory. Four of the 5 affected individuals had epilepsy and developmental delay/intellectual disability. The fifth patient had a less severe form of epilepsy that did not impair their cognitive abilities.

Butler KM, da Silva C, Shafir Y et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res. 2016;129:17-25.

Pathogenic variants of the SCN8A gene may contribute to a variety of epilepsy types, as well as nonseizure neurodevelopmental disorders, according a recent genetic analysis. Five variants of the gene called sodium channel alpha subunit 8, which codes for the ion pore region of the voltage-gated sodium channel, were detected in the genetic sequencing data from 275 epilepsy panels performed by the Emory Genetics Laboratory. Four of the 5 affected individuals had epilepsy and developmental delay/intellectual disability. The fifth patient had a less severe form of epilepsy that did not impair their cognitive abilities.

Butler KM, da Silva C, Shafir Y et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res. 2016;129:17-25.

Pathogenic variants of the SCN8A gene may contribute to a variety of epilepsy types, as well as nonseizure neurodevelopmental disorders, according a recent genetic analysis. Five variants of the gene called sodium channel alpha subunit 8, which codes for the ion pore region of the voltage-gated sodium channel, were detected in the genetic sequencing data from 275 epilepsy panels performed by the Emory Genetics Laboratory. Four of the 5 affected individuals had epilepsy and developmental delay/intellectual disability. The fifth patient had a less severe form of epilepsy that did not impair their cognitive abilities.

Butler KM, da Silva C, Shafir Y et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res. 2016;129:17-25.

The precise indications for intracranial electroencephalography (IEEG) remain unresolved and vary among epilepsy surgical centers. The International League Against Epilepsy has issued recommendations on the diagnostic usefulness of IEEG that discuss the application of a variety of modalities and that provide a consensus among experts on its efficacy, safety, ease, and cost benefits. The goal of the guidelines is to reduce over- and underuse of IEEE while at the same time allowing flexibility among the epilepsy centers that perform the procedure.

Jayakar P, Gotman J, Harvey AS et al. Diagnostic utility of invasive EEG for epilepsy surgery: Indications, modalities, and techniques. Epilepsia. 2016;57(11):1735-1747.

The precise indications for intracranial electroencephalography (IEEG) remain unresolved and vary among epilepsy surgical centers. The International League Against Epilepsy has issued recommendations on the diagnostic usefulness of IEEG that discuss the application of a variety of modalities and that provide a consensus among experts on its efficacy, safety, ease, and cost benefits. The goal of the guidelines is to reduce over- and underuse of IEEE while at the same time allowing flexibility among the epilepsy centers that perform the procedure.

Jayakar P, Gotman J, Harvey AS et al. Diagnostic utility of invasive EEG for epilepsy surgery: Indications, modalities, and techniques. Epilepsia. 2016;57(11):1735-1747.

The precise indications for intracranial electroencephalography (IEEG) remain unresolved and vary among epilepsy surgical centers. The International League Against Epilepsy has issued recommendations on the diagnostic usefulness of IEEG that discuss the application of a variety of modalities and that provide a consensus among experts on its efficacy, safety, ease, and cost benefits. The goal of the guidelines is to reduce over- and underuse of IEEE while at the same time allowing flexibility among the epilepsy centers that perform the procedure.

Jayakar P, Gotman J, Harvey AS et al. Diagnostic utility of invasive EEG for epilepsy surgery: Indications, modalities, and techniques. Epilepsia. 2016;57(11):1735-1747.

Nancy Foldvary-Schaefer, DO, MS

Sleep Disorders and Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH

Madeleine Grigg-Damberger, MD

University of New Mexico School of Medicine, Department of Neurology, University of New Mexico, Albuquerque, NM

A 25-year-old, right-handed man with focal epilepsy since age 15 years presented to the epilepsy clinic. His seizures consisted of a visual change that was “like seeing bubbles through a microscope” and lightheadedness that progressed to unresponsiveness with staring, lip smacking, and unintelligible speech lasting 1 to 2 minutes; this was followed by tiredness for several hours. Focal seizures occurred several times per week and secondary generalization once per month despite trials of multiple antiepileptic drugs (AEDs). Birth and development were unremarkable. The patient had had 2 concussions with brief loss of consciousness in early childhood. Neurologic examination was normal.

Video electroencephalogram (EEG) monitoring showed left parieto-occipital spikes (95%) and generalized spike-and-wave complexes (5%). One typical seizure with secondary generalization was recorded as having a generalized, maximal, left-hemisphere EEG pattern. Ictal single-photon emission computed tomography (SPECT; 25-second injection) revealed left temporoparietal hyperfusion. Two subclinical seizures from the left parieto-occipital region were also recorded. Mild bilateral hippocampal atrophy and left hippocampal dysmorphism were seen on magnetic resonance imaging (MRI). Fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated left posterior temporoparietal hypometabolism. The patient underwent intracranial monitoring, which recorded spikes over the left temporo-occipital region, but no seizures were captured. He was discharged with a recommendation to consider vagus nerve stimulation (VNS) therapy.

The patient reported snoring, frequent nocturnal awakenings, and dozing while in sedentary situations. He had a body mass index of 30 kg/m², a circumference of 42 cm, and oropharyngeal crowding. He had had a tonsillectomy in childhood, had gained 14 kg in the last 6 months following job loss, and reported feeling depressed. An overnight polysomnogram (PSG) was performed to detect suspected obstructive sleep apnea (OSA). It showed he had moderate OSA (17 obstructive events per hour of sleep) and oxygen desaturation to 67%. Continuous positive airway pressure (CPAP) therapy eliminated snoring and respiratory events and normalized oxygen saturation. The patient was started on CPAP at home, and the frequency of his seizures decreased without further adjustment of his AEDs. Months later, implantation of the VNS device was performed, and he became seizure free for 8 years despite a lead fracture and a battery failure. After 10 years of VNS and CPAP therapy, the patient had recurrence of daytime sleepiness and rare breakthrough seizures, prompting repeat CPAP titration resulting in airway pressure increase. He remains seizure free.

Diagnosis: Intractable focal epilepsy with comorbid obstructive sleep apnea responsive to CPAP and VNS therapy

Questions and Answers:

1. How common are sleep disorders in people with epilepsy?

Sleep disturbances are 2 to 3 times more common in people with epilepsy than in age-matched controls, with insomnia and OSA being the most common. The prevalence of OSA in adults with epilepsy exceeds 40%, with 16% of cases having moderate to severe OSA. Treatment of OSA in patients with epilepsy, using CPAP therapy in adults or tonsillectomy in children, has been shown to reduce seizures, alleviate daytime sleepiness, and improve sleep quality, depressive symptoms, and quality of life. Treatment of moderate to severe OSA has been shown to reduce the risk of hypertension, type 2 diabetes, obesity, cardiac arrhythmia, heart failure, myocardial infarction, stroke, and sudden death during sleep. This patient’s seizures began to improve after CPAP was initiated even before VNS device implantation and remained controlled despite 2 lapses in VNS therapy over time.

2.            Why is PSG recommended in patients undergoing VNS implantation?
Emergence or worsening of apneas and hypopneas coinciding with VNS activation has been reported in adults and children with epilepsy. The underlying mechanisms are unclear, with both central and peripheral mechanisms proposed. A clinical diagnosis of OSA results in up to one-third of adult cases. Lower stimulating frequencies or prolonging off-time may prevent OSA exacerbations. The VNS device manufacturer recommends screening for OSA and consideration of PSG prior to and following VNS device implantation.

3.            How can epilepsy providers screen patients with epilepsy for OSA?

Clinical instruments such as the STOP-BANG Questionnaire (Snoring, Tiredness/fatigue/sleepiness, Observed apnea, high blood Pressure, BMI >35kg/m², Age >50 years, Neck circumference >40 cm [>16 in], and male Gender) can help identify patients with high probability of OSA. Patients with 3 or more positive responses on the STOP-BANG Questionnaire are considered high risk. High-risk patients should be referred for PSG for diagnostic confirmation.

Nancy Foldvary-Schaefer, DO, MS

Sleep Disorders and Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH

Madeleine Grigg-Damberger, MD

University of New Mexico School of Medicine, Department of Neurology, University of New Mexico, Albuquerque, NM

A 25-year-old, right-handed man with focal epilepsy since age 15 years presented to the epilepsy clinic. His seizures consisted of a visual change that was “like seeing bubbles through a microscope” and lightheadedness that progressed to unresponsiveness with staring, lip smacking, and unintelligible speech lasting 1 to 2 minutes; this was followed by tiredness for several hours. Focal seizures occurred several times per week and secondary generalization once per month despite trials of multiple antiepileptic drugs (AEDs). Birth and development were unremarkable. The patient had had 2 concussions with brief loss of consciousness in early childhood. Neurologic examination was normal.

Video electroencephalogram (EEG) monitoring showed left parieto-occipital spikes (95%) and generalized spike-and-wave complexes (5%). One typical seizure with secondary generalization was recorded as having a generalized, maximal, left-hemisphere EEG pattern. Ictal single-photon emission computed tomography (SPECT; 25-second injection) revealed left temporoparietal hyperfusion. Two subclinical seizures from the left parieto-occipital region were also recorded. Mild bilateral hippocampal atrophy and left hippocampal dysmorphism were seen on magnetic resonance imaging (MRI). Fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated left posterior temporoparietal hypometabolism. The patient underwent intracranial monitoring, which recorded spikes over the left temporo-occipital region, but no seizures were captured. He was discharged with a recommendation to consider vagus nerve stimulation (VNS) therapy.

The patient reported snoring, frequent nocturnal awakenings, and dozing while in sedentary situations. He had a body mass index of 30 kg/m², a circumference of 42 cm, and oropharyngeal crowding. He had had a tonsillectomy in childhood, had gained 14 kg in the last 6 months following job loss, and reported feeling depressed. An overnight polysomnogram (PSG) was performed to detect suspected obstructive sleep apnea (OSA). It showed he had moderate OSA (17 obstructive events per hour of sleep) and oxygen desaturation to 67%. Continuous positive airway pressure (CPAP) therapy eliminated snoring and respiratory events and normalized oxygen saturation. The patient was started on CPAP at home, and the frequency of his seizures decreased without further adjustment of his AEDs. Months later, implantation of the VNS device was performed, and he became seizure free for 8 years despite a lead fracture and a battery failure. After 10 years of VNS and CPAP therapy, the patient had recurrence of daytime sleepiness and rare breakthrough seizures, prompting repeat CPAP titration resulting in airway pressure increase. He remains seizure free.

Diagnosis: Intractable focal epilepsy with comorbid obstructive sleep apnea responsive to CPAP and VNS therapy

Questions and Answers:

1. How common are sleep disorders in people with epilepsy?

Sleep disturbances are 2 to 3 times more common in people with epilepsy than in age-matched controls, with insomnia and OSA being the most common. The prevalence of OSA in adults with epilepsy exceeds 40%, with 16% of cases having moderate to severe OSA. Treatment of OSA in patients with epilepsy, using CPAP therapy in adults or tonsillectomy in children, has been shown to reduce seizures, alleviate daytime sleepiness, and improve sleep quality, depressive symptoms, and quality of life. Treatment of moderate to severe OSA has been shown to reduce the risk of hypertension, type 2 diabetes, obesity, cardiac arrhythmia, heart failure, myocardial infarction, stroke, and sudden death during sleep. This patient’s seizures began to improve after CPAP was initiated even before VNS device implantation and remained controlled despite 2 lapses in VNS therapy over time.

2.            Why is PSG recommended in patients undergoing VNS implantation?
Emergence or worsening of apneas and hypopneas coinciding with VNS activation has been reported in adults and children with epilepsy. The underlying mechanisms are unclear, with both central and peripheral mechanisms proposed. A clinical diagnosis of OSA results in up to one-third of adult cases. Lower stimulating frequencies or prolonging off-time may prevent OSA exacerbations. The VNS device manufacturer recommends screening for OSA and consideration of PSG prior to and following VNS device implantation.

3.            How can epilepsy providers screen patients with epilepsy for OSA?

Clinical instruments such as the STOP-BANG Questionnaire (Snoring, Tiredness/fatigue/sleepiness, Observed apnea, high blood Pressure, BMI >35kg/m², Age >50 years, Neck circumference >40 cm [>16 in], and male Gender) can help identify patients with high probability of OSA. Patients with 3 or more positive responses on the STOP-BANG Questionnaire are considered high risk. High-risk patients should be referred for PSG for diagnostic confirmation.

Nancy Foldvary-Schaefer, DO, MS

Sleep Disorders and Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH

Madeleine Grigg-Damberger, MD

University of New Mexico School of Medicine, Department of Neurology, University of New Mexico, Albuquerque, NM

A 25-year-old, right-handed man with focal epilepsy since age 15 years presented to the epilepsy clinic. His seizures consisted of a visual change that was “like seeing bubbles through a microscope” and lightheadedness that progressed to unresponsiveness with staring, lip smacking, and unintelligible speech lasting 1 to 2 minutes; this was followed by tiredness for several hours. Focal seizures occurred several times per week and secondary generalization once per month despite trials of multiple antiepileptic drugs (AEDs). Birth and development were unremarkable. The patient had had 2 concussions with brief loss of consciousness in early childhood. Neurologic examination was normal.

Video electroencephalogram (EEG) monitoring showed left parieto-occipital spikes (95%) and generalized spike-and-wave complexes (5%). One typical seizure with secondary generalization was recorded as having a generalized, maximal, left-hemisphere EEG pattern. Ictal single-photon emission computed tomography (SPECT; 25-second injection) revealed left temporoparietal hyperfusion. Two subclinical seizures from the left parieto-occipital region were also recorded. Mild bilateral hippocampal atrophy and left hippocampal dysmorphism were seen on magnetic resonance imaging (MRI). Fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated left posterior temporoparietal hypometabolism. The patient underwent intracranial monitoring, which recorded spikes over the left temporo-occipital region, but no seizures were captured. He was discharged with a recommendation to consider vagus nerve stimulation (VNS) therapy.

The patient reported snoring, frequent nocturnal awakenings, and dozing while in sedentary situations. He had a body mass index of 30 kg/m², a circumference of 42 cm, and oropharyngeal crowding. He had had a tonsillectomy in childhood, had gained 14 kg in the last 6 months following job loss, and reported feeling depressed. An overnight polysomnogram (PSG) was performed to detect suspected obstructive sleep apnea (OSA). It showed he had moderate OSA (17 obstructive events per hour of sleep) and oxygen desaturation to 67%. Continuous positive airway pressure (CPAP) therapy eliminated snoring and respiratory events and normalized oxygen saturation. The patient was started on CPAP at home, and the frequency of his seizures decreased without further adjustment of his AEDs. Months later, implantation of the VNS device was performed, and he became seizure free for 8 years despite a lead fracture and a battery failure. After 10 years of VNS and CPAP therapy, the patient had recurrence of daytime sleepiness and rare breakthrough seizures, prompting repeat CPAP titration resulting in airway pressure increase. He remains seizure free.

Diagnosis: Intractable focal epilepsy with comorbid obstructive sleep apnea responsive to CPAP and VNS therapy

Questions and Answers:

1. How common are sleep disorders in people with epilepsy?

Sleep disturbances are 2 to 3 times more common in people with epilepsy than in age-matched controls, with insomnia and OSA being the most common. The prevalence of OSA in adults with epilepsy exceeds 40%, with 16% of cases having moderate to severe OSA. Treatment of OSA in patients with epilepsy, using CPAP therapy in adults or tonsillectomy in children, has been shown to reduce seizures, alleviate daytime sleepiness, and improve sleep quality, depressive symptoms, and quality of life. Treatment of moderate to severe OSA has been shown to reduce the risk of hypertension, type 2 diabetes, obesity, cardiac arrhythmia, heart failure, myocardial infarction, stroke, and sudden death during sleep. This patient’s seizures began to improve after CPAP was initiated even before VNS device implantation and remained controlled despite 2 lapses in VNS therapy over time.

2.            Why is PSG recommended in patients undergoing VNS implantation?
Emergence or worsening of apneas and hypopneas coinciding with VNS activation has been reported in adults and children with epilepsy. The underlying mechanisms are unclear, with both central and peripheral mechanisms proposed. A clinical diagnosis of OSA results in up to one-third of adult cases. Lower stimulating frequencies or prolonging off-time may prevent OSA exacerbations. The VNS device manufacturer recommends screening for OSA and consideration of PSG prior to and following VNS device implantation.

3.            How can epilepsy providers screen patients with epilepsy for OSA?

Clinical instruments such as the STOP-BANG Questionnaire (Snoring, Tiredness/fatigue/sleepiness, Observed apnea, high blood Pressure, BMI >35kg/m², Age >50 years, Neck circumference >40 cm [>16 in], and male Gender) can help identify patients with high probability of OSA. Patients with 3 or more positive responses on the STOP-BANG Questionnaire are considered high risk. High-risk patients should be referred for PSG for diagnostic confirmation.

ORLANDO – Narrow band imaging detects neovascularization associated with endometriosis and can be a useful adjunct to laparoscopic white light evaluation, a prospective cohort trial of 53 women with pelvic pain suggested.

The women in the study had no deep infiltrating endometriosis on preoperative ultrasound. Investigators then conducted a standard laparoscopic survey of the pelvis with white light to identify areas of suspected superficial endometriosis, followed by secondary analysis with narrow band imaging.

©designer491/Thinkstock

ORLANDO – Narrow band imaging detects neovascularization associated with endometriosis and can be a useful adjunct to laparoscopic white light evaluation, a prospective cohort trial of 53 women with pelvic pain suggested.

The women in the study had no deep infiltrating endometriosis on preoperative ultrasound. Investigators then conducted a standard laparoscopic survey of the pelvis with white light to identify areas of suspected superficial endometriosis, followed by secondary analysis with narrow band imaging.

©designer491/Thinkstock

ORLANDO – Narrow band imaging detects neovascularization associated with endometriosis and can be a useful adjunct to laparoscopic white light evaluation, a prospective cohort trial of 53 women with pelvic pain suggested.

The women in the study had no deep infiltrating endometriosis on preoperative ultrasound. Investigators then conducted a standard laparoscopic survey of the pelvis with white light to identify areas of suspected superficial endometriosis, followed by secondary analysis with narrow band imaging.

©designer491/Thinkstock