Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

From the National Initiative for Children’s Healthcare Quality, Boston, MA.

This month JCOM launches a series calling attention to 5 teams working to improve care for individuals with sickle cell disease and sickle cell trait in the Hemoglobinopathy Learning Collaborative (—Ed.)

Sickle cell disease affects close to 100,000 people in United States [1]. This condition is characterized by chronic anemia and unpredictable pain episodes beginning in early childhood and leading to changes in functioning, diminished health-related quality of life, end-organ damage, increased health care use, and in some cases early mortality [2–5]. Sickle cell disease is identified through universal newborn screening [6] and is found in one in 2474 newborn Americans [7], with Americans of African ancestry most frequently affected. It is estimated that over 2 million Americans are genetic carriers of the sickle cell gene.

Although there have been major advancements in sickle cell care within the past several decades, there still exist significant variations in care and mortality [8–14]. Ongoing strategies to improve patient access to efficacious treatments are essential to improve outcomes for individuals with sickle cell disease.

Recognizing the compelling need for a focused national effort to improve care for this population and the relative lack of private resources committed to it [15], Congress established 2 federal programs to enhance newborn screening and improve follow-up and care and outcomes for this population: the Sickle Cell Disease Newborn Screening Program in 2002 [16] and the Sickle Cell Disease Treatment Demonstration Program in 2004 [17]. The programs are funded by the Health Resources and Services Administration and administered by the National Initiative for Children’s Healthcare Quality (NICHQ)’s Working to Improve Sickle Cell Healthcare (WISCH) program [2]. NICHQ became the coordinating center for the programs in 2011 and 2010, respectively. Diverse grantees are now working together in a Hemoglobinopathy Learning Collaborative, coordinated and facilitated by NICHQ and its partners Boston Medical Center and the Sickle Cell Disease Association of America. The current rounds of funding continue through 2014 for the Sickle Cell Disease Treatment Demonstration Program and 2015 for the Sickle Cell Disease Newborn Screening Program.

The Hemoglobinopathy Learning Collaborative grantees are developing strategies that will result in more coordinated and appropriate care in order that individuals with sickle cell disease experience fewer complications, acute care visits, and hospitalizations; enhanced quality of life; and more compassionate and respectful treatment from the health care system. Processes are also being developed to ensure that individuals screened for sickle cell disease and sickle cell trait receive genetic counseling, education and appropriate follow-up care for their condition. The aims of the collaborative are aligned with the national quality strategy of the Triple Aim—better care, better health, and lower overall health care costs [18]. The strategies and approaches developed and tested by the teams will be disseminated to the broader sickle cell community for use in the treatment and management of individuals with sickle cell disease.

The Hemoglobinopathy Learning Collaborative’s approach is based on the structure of the Breakthrough Series Learning Collaborative [19–21], a model championed by the Institute for Healthcare Improvement that brings together health care organizations that share a commitment to making major, rapid changes in order to produce breakthrough improvements in quality. Using a process known as the Model for Improvement [22], the teams develop ideas for changes, test small-scale changes using Plan-Do-Study-Act (PDSA) cycles, and measure to determine if the changes are leading to improvement. This method can quickly identify promising ideas and adapt and develop them to into robust, reliable standard processes [2].

There are 15 improvement teams working on quality improvement projects focused on improving acute care management, provision of recommended care, transition, self-management, provider education, and screening, counseling, and education for individuals with SCD and SCT. The 5 articles in this special series span these major content areas, from improving outcomes in the emergency department using standardized order sets to assessing the readiness of adolescents to transition to adult care, to using health information technology to improve care coordination, to developing a home pain management plan, and to using patient navigators to help coordinate care and resources. The series begins with the article by Treadwell et al in this issue and will continue for the next several months. The WISCH teams will serve as leaders for sustainable and positive change for treatment of individuals with sickle cell disease and sickle cell trait in the United States. Their work is an important step towards transforming care for people with sickle cell disease, so that each person with sickle cell disease will receive the highest quality of care throughout their lifespan.

Corresponding author: Suzette Oyeku, MD, MPH, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, 3444 Kossuth Ave, 1st Fl, Bronx, NY 10467, [email protected].

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

A Clinical Psychiatry News reader wrote in recently to object to the use of the term "shrink" in our column name. The writer noted, "We spend a lot of time trying to destigmatize the field, then use terms like this among ourselves. It’s odd and offensive." The feedback made me pause and wonder to myself if the term "shrink" is, in fact, stigmatizing.

Let me first give a little history of the decision to name our column "Shrink Rap News." In 2006, I was sitting at the kitchen table and decided I wanted a blog. I didn’t know what a blog actually was, but I wanted one. I went to blogger.com to set up a free website and was asked what I’d like to call my blog. On an impulse, I titled it "Shrink Rap." There was no debate or consideration, and no consultation. I liked the play on words with "shrink wrap," which is used for food storage, and I liked the connotation of psychiatrists talking, or "rapping." In a matter of hours, my impulsive thought was turned into the Shrink Rap blog.

Over the next few days, I invited Dr. Steve Daviss and Dr. Annette Hanson to join me in this venture, and Shrink Rap has continued to publish regular blog posts for 8.5 years now. Steve initially balked at the use of "shrink," but when he went to start our podcast, he titled it "My Three Shrinks" and modified the logo from an old television show, "My Three Sons." When we went to title our book, I wanted to call it "Off the Couch," but I was told that there was no room for couches anywhere. After many months of lively debate, we ended up in a restaurant with our editor and a whiteboard, and by the end of the evening we were back at Shrink Rap for a title for the book.

When Clinical Psychiatry News and Psychology Today approached us to write for their sites, we decided to remain with an image that was working for us, and used Shrink Rap News and Shrink Rap Today for column titles. Because the term may imply something less than a serious look at psychiatric issues, the umbrella name for all our endeavors is The Accessible Psychiatry Project.

So, is the term "shrink" actually stigmatizing? When I think of words as being part of stigma, I think of racial and religious slurs, and those induce a visceral response of disgust in me. For whatever reason, I personally don’t have a clear negative association to the term "shrink" or even "headshrinker." To me, it evokes something lighthearted and includes having a sense of humor about the field. I imagine if psychiatrists ever had actually shrunken heads, I might feel differently. Others may well have another response to the term, but the emotional link to something negative is just not there for me.

From a site called World Wide Words – Investigating the English Language Across the Globe, which is devoted to linguistics and run by a British etymologist, I found the following history of the term "headshrinker":

The original meaning of the term head-shrinker was in reference to a member of a group in Amazonia, the Jivaro, who preserved the heads of their enemies by stripping the skin from the skull, which resulted in a shrunken mummified remnant the size of a fist. The term isn’t that old – it’s first recorded from 1926.

All the early evidence suggests that the person who invented the psychiatrist sense worked in the movies (no jokes please). We have to assume that the term came about because people regarded the process of psychiatry as being like head-shrinking because it reduced the size of the swollen egos so common in show business. Or perhaps they were suspicious about what psychiatrists actually did to their heads and how they did it and so made a joke to relieve the tension.

The earliest example we have is from an article in Time in November 1950 to which an editor has helpfully added a footnote to say that head-shrinker was Hollywood jargon for a psychiatrist. The term afterward became moderately popular, in part because it was used in the film Rebel Without a Cause in 1955. Robert Heinlein felt his readers needed it to be explained when he introduced it in "Time for the Stars" in 1956: " ‘Dr. Devereaux is the boss head-shrinker.’ I looked puzzled and Uncle Steve went on, ‘You don’t savvy? Psychiatrist.’ " By the time it turns up in West Side Story on Broadway in 1957, it was becoming established.

Shrink, the abbreviation, became popular in the United States in the 1970s, though it had first appeared in one of Thomas Pynchon’s books, "The Crying of Lot 49," in 1965, and there is anecdotal evidence that it was around earlier, which is only to be expected of a slang term that would have been mainly transmitted through the spoken word in its earliest days.

The issue of stigma in mental health has gotten a lot of attention as being one reason that people who have difficulties may not seek help. Certainly, words can be powerful, but I wonder if the term "shrink" might actually be easier for patients to use? "I’m going to see my shrink," might imply a visit with any number of mental health professionals and might disassociate it from the implication that the patient is going to see a psychiatrist for treatment of a mental illness, a condition that the media is all too happy to tell us causes people to commit mass murders.

"Shrink" may have a disparaging tone to it, or it may have a ring of affection, depending on the context. Certainly, there are many negative associations and jokes related to being an attorney, and one friend told me that his son was "going to the dark side" when the son applied to law school. Still, there is no stigma associated with having an appointment with one’s lawyer, leading me to believe that a profession can be stigmatized without stigmatizing the clientele.

Some words have taken on a pervasively negative meaning; others are harder to capture. After 8 years, Shrink Rap is now a platform for our writing, invested with its own meanings to us and our readers. The psychiatrist who wrote in to say it is offensive, odd, and stigmatizing certainly has a different set of associations to the word then we do, or we would never have let this be a title for our work.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011).

A Clinical Psychiatry News reader wrote in recently to object to the use of the term "shrink" in our column name. The writer noted, "We spend a lot of time trying to destigmatize the field, then use terms like this among ourselves. It’s odd and offensive." The feedback made me pause and wonder to myself if the term "shrink" is, in fact, stigmatizing.

Let me first give a little history of the decision to name our column "Shrink Rap News." In 2006, I was sitting at the kitchen table and decided I wanted a blog. I didn’t know what a blog actually was, but I wanted one. I went to blogger.com to set up a free website and was asked what I’d like to call my blog. On an impulse, I titled it "Shrink Rap." There was no debate or consideration, and no consultation. I liked the play on words with "shrink wrap," which is used for food storage, and I liked the connotation of psychiatrists talking, or "rapping." In a matter of hours, my impulsive thought was turned into the Shrink Rap blog.

Over the next few days, I invited Dr. Steve Daviss and Dr. Annette Hanson to join me in this venture, and Shrink Rap has continued to publish regular blog posts for 8.5 years now. Steve initially balked at the use of "shrink," but when he went to start our podcast, he titled it "My Three Shrinks" and modified the logo from an old television show, "My Three Sons." When we went to title our book, I wanted to call it "Off the Couch," but I was told that there was no room for couches anywhere. After many months of lively debate, we ended up in a restaurant with our editor and a whiteboard, and by the end of the evening we were back at Shrink Rap for a title for the book.

When Clinical Psychiatry News and Psychology Today approached us to write for their sites, we decided to remain with an image that was working for us, and used Shrink Rap News and Shrink Rap Today for column titles. Because the term may imply something less than a serious look at psychiatric issues, the umbrella name for all our endeavors is The Accessible Psychiatry Project.

So, is the term "shrink" actually stigmatizing? When I think of words as being part of stigma, I think of racial and religious slurs, and those induce a visceral response of disgust in me. For whatever reason, I personally don’t have a clear negative association to the term "shrink" or even "headshrinker." To me, it evokes something lighthearted and includes having a sense of humor about the field. I imagine if psychiatrists ever had actually shrunken heads, I might feel differently. Others may well have another response to the term, but the emotional link to something negative is just not there for me.

From a site called World Wide Words – Investigating the English Language Across the Globe, which is devoted to linguistics and run by a British etymologist, I found the following history of the term "headshrinker":

The original meaning of the term head-shrinker was in reference to a member of a group in Amazonia, the Jivaro, who preserved the heads of their enemies by stripping the skin from the skull, which resulted in a shrunken mummified remnant the size of a fist. The term isn’t that old – it’s first recorded from 1926.

All the early evidence suggests that the person who invented the psychiatrist sense worked in the movies (no jokes please). We have to assume that the term came about because people regarded the process of psychiatry as being like head-shrinking because it reduced the size of the swollen egos so common in show business. Or perhaps they were suspicious about what psychiatrists actually did to their heads and how they did it and so made a joke to relieve the tension.

The earliest example we have is from an article in Time in November 1950 to which an editor has helpfully added a footnote to say that head-shrinker was Hollywood jargon for a psychiatrist. The term afterward became moderately popular, in part because it was used in the film Rebel Without a Cause in 1955. Robert Heinlein felt his readers needed it to be explained when he introduced it in "Time for the Stars" in 1956: " ‘Dr. Devereaux is the boss head-shrinker.’ I looked puzzled and Uncle Steve went on, ‘You don’t savvy? Psychiatrist.’ " By the time it turns up in West Side Story on Broadway in 1957, it was becoming established.

Shrink, the abbreviation, became popular in the United States in the 1970s, though it had first appeared in one of Thomas Pynchon’s books, "The Crying of Lot 49," in 1965, and there is anecdotal evidence that it was around earlier, which is only to be expected of a slang term that would have been mainly transmitted through the spoken word in its earliest days.

The issue of stigma in mental health has gotten a lot of attention as being one reason that people who have difficulties may not seek help. Certainly, words can be powerful, but I wonder if the term "shrink" might actually be easier for patients to use? "I’m going to see my shrink," might imply a visit with any number of mental health professionals and might disassociate it from the implication that the patient is going to see a psychiatrist for treatment of a mental illness, a condition that the media is all too happy to tell us causes people to commit mass murders.

"Shrink" may have a disparaging tone to it, or it may have a ring of affection, depending on the context. Certainly, there are many negative associations and jokes related to being an attorney, and one friend told me that his son was "going to the dark side" when the son applied to law school. Still, there is no stigma associated with having an appointment with one’s lawyer, leading me to believe that a profession can be stigmatized without stigmatizing the clientele.

Some words have taken on a pervasively negative meaning; others are harder to capture. After 8 years, Shrink Rap is now a platform for our writing, invested with its own meanings to us and our readers. The psychiatrist who wrote in to say it is offensive, odd, and stigmatizing certainly has a different set of associations to the word then we do, or we would never have let this be a title for our work.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011).

A Clinical Psychiatry News reader wrote in recently to object to the use of the term "shrink" in our column name. The writer noted, "We spend a lot of time trying to destigmatize the field, then use terms like this among ourselves. It’s odd and offensive." The feedback made me pause and wonder to myself if the term "shrink" is, in fact, stigmatizing.

Let me first give a little history of the decision to name our column "Shrink Rap News." In 2006, I was sitting at the kitchen table and decided I wanted a blog. I didn’t know what a blog actually was, but I wanted one. I went to blogger.com to set up a free website and was asked what I’d like to call my blog. On an impulse, I titled it "Shrink Rap." There was no debate or consideration, and no consultation. I liked the play on words with "shrink wrap," which is used for food storage, and I liked the connotation of psychiatrists talking, or "rapping." In a matter of hours, my impulsive thought was turned into the Shrink Rap blog.

Over the next few days, I invited Dr. Steve Daviss and Dr. Annette Hanson to join me in this venture, and Shrink Rap has continued to publish regular blog posts for 8.5 years now. Steve initially balked at the use of "shrink," but when he went to start our podcast, he titled it "My Three Shrinks" and modified the logo from an old television show, "My Three Sons." When we went to title our book, I wanted to call it "Off the Couch," but I was told that there was no room for couches anywhere. After many months of lively debate, we ended up in a restaurant with our editor and a whiteboard, and by the end of the evening we were back at Shrink Rap for a title for the book.

When Clinical Psychiatry News and Psychology Today approached us to write for their sites, we decided to remain with an image that was working for us, and used Shrink Rap News and Shrink Rap Today for column titles. Because the term may imply something less than a serious look at psychiatric issues, the umbrella name for all our endeavors is The Accessible Psychiatry Project.

So, is the term "shrink" actually stigmatizing? When I think of words as being part of stigma, I think of racial and religious slurs, and those induce a visceral response of disgust in me. For whatever reason, I personally don’t have a clear negative association to the term "shrink" or even "headshrinker." To me, it evokes something lighthearted and includes having a sense of humor about the field. I imagine if psychiatrists ever had actually shrunken heads, I might feel differently. Others may well have another response to the term, but the emotional link to something negative is just not there for me.

From a site called World Wide Words – Investigating the English Language Across the Globe, which is devoted to linguistics and run by a British etymologist, I found the following history of the term "headshrinker":

The original meaning of the term head-shrinker was in reference to a member of a group in Amazonia, the Jivaro, who preserved the heads of their enemies by stripping the skin from the skull, which resulted in a shrunken mummified remnant the size of a fist. The term isn’t that old – it’s first recorded from 1926.

All the early evidence suggests that the person who invented the psychiatrist sense worked in the movies (no jokes please). We have to assume that the term came about because people regarded the process of psychiatry as being like head-shrinking because it reduced the size of the swollen egos so common in show business. Or perhaps they were suspicious about what psychiatrists actually did to their heads and how they did it and so made a joke to relieve the tension.

The earliest example we have is from an article in Time in November 1950 to which an editor has helpfully added a footnote to say that head-shrinker was Hollywood jargon for a psychiatrist. The term afterward became moderately popular, in part because it was used in the film Rebel Without a Cause in 1955. Robert Heinlein felt his readers needed it to be explained when he introduced it in "Time for the Stars" in 1956: " ‘Dr. Devereaux is the boss head-shrinker.’ I looked puzzled and Uncle Steve went on, ‘You don’t savvy? Psychiatrist.’ " By the time it turns up in West Side Story on Broadway in 1957, it was becoming established.

Shrink, the abbreviation, became popular in the United States in the 1970s, though it had first appeared in one of Thomas Pynchon’s books, "The Crying of Lot 49," in 1965, and there is anecdotal evidence that it was around earlier, which is only to be expected of a slang term that would have been mainly transmitted through the spoken word in its earliest days.

The issue of stigma in mental health has gotten a lot of attention as being one reason that people who have difficulties may not seek help. Certainly, words can be powerful, but I wonder if the term "shrink" might actually be easier for patients to use? "I’m going to see my shrink," might imply a visit with any number of mental health professionals and might disassociate it from the implication that the patient is going to see a psychiatrist for treatment of a mental illness, a condition that the media is all too happy to tell us causes people to commit mass murders.

"Shrink" may have a disparaging tone to it, or it may have a ring of affection, depending on the context. Certainly, there are many negative associations and jokes related to being an attorney, and one friend told me that his son was "going to the dark side" when the son applied to law school. Still, there is no stigma associated with having an appointment with one’s lawyer, leading me to believe that a profession can be stigmatized without stigmatizing the clientele.

Some words have taken on a pervasively negative meaning; others are harder to capture. After 8 years, Shrink Rap is now a platform for our writing, invested with its own meanings to us and our readers. The psychiatrist who wrote in to say it is offensive, odd, and stigmatizing certainly has a different set of associations to the word then we do, or we would never have let this be a title for our work.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011).

The U.S. prevalence of amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is about 4 cases per 100,000 Americans, according to the Centers for Disease Control and Prevention.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is usually fatal within 2-5 years of diagnosis. A hereditary form of the disease accounts for between 10% and 15% of cases. In the rest, the cause or causes are unknown, although chemical and infectious exposures are among the suspected triggers.

The new prevalence figures, which the CDC published in its Morbidity and Mortality Weekly Report issued July 25 (MMWR 2014;63[SS07]:1-14), represent the first national prevalence findings for ALS in the United States, and derive from surveillance begun in 2009 by the federal Agency for Toxic Substances and Disease Registry in Atlanta, where Dr. Paul Mehta led the investigation.

Dr. Mehta and his colleagues identified cases from Medicare, Medicaid, Veterans Heath Administration, and Veterans Benefits Administration databases, as well a secure public website through which ALS patients could self-report to the CDC by answering a series of screening questions.

Between October 2010 and the end of 2011, the registry identified 12,187 people 18 years and older with ALS, for a prevalence of 3.9 cases of ALS per 100,000 – findings that are consistent, the researchers said, with those from long-running European ALS registries.

As in other studies, men had a higher prevalence of ALS than did women (4.8 per 100,000 vs. 3.0 per 100,000). "Factors such as occupational history and environmental exposures might be associated with this finding," the researchers wrote in their analysis.

The prevalence of ALS among whites was more than double that of blacks (4.2 per vs. 2.0). "The reason for this difference in prevalence by race is unknown and needs to be investigated further," Dr. Mehta and his associates wrote. However, they noted, the race findings were also consistent with other studies.

The age group 70-79 was associated with the highest prevalence rate, at 17.0 per 100,000, followed by 60-69 at about 12.

Dr. Mehta and his colleagues acknowledged that their study had several limitations, including the fact that the ALS registry was relatively new; that ALS is not a notifiable disease in most states, making it difficult to capture all cases; that data errors or file duplication could have occurred; and that it was not possible to calculate ALS incidence, only prevalence, because most cases in the registry did not have a diagnosis date.

No conflicts of interest were mentioned in the report.

The U.S. prevalence of amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is about 4 cases per 100,000 Americans, according to the Centers for Disease Control and Prevention.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is usually fatal within 2-5 years of diagnosis. A hereditary form of the disease accounts for between 10% and 15% of cases. In the rest, the cause or causes are unknown, although chemical and infectious exposures are among the suspected triggers.

The new prevalence figures, which the CDC published in its Morbidity and Mortality Weekly Report issued July 25 (MMWR 2014;63[SS07]:1-14), represent the first national prevalence findings for ALS in the United States, and derive from surveillance begun in 2009 by the federal Agency for Toxic Substances and Disease Registry in Atlanta, where Dr. Paul Mehta led the investigation.

Dr. Mehta and his colleagues identified cases from Medicare, Medicaid, Veterans Heath Administration, and Veterans Benefits Administration databases, as well a secure public website through which ALS patients could self-report to the CDC by answering a series of screening questions.

Between October 2010 and the end of 2011, the registry identified 12,187 people 18 years and older with ALS, for a prevalence of 3.9 cases of ALS per 100,000 – findings that are consistent, the researchers said, with those from long-running European ALS registries.

As in other studies, men had a higher prevalence of ALS than did women (4.8 per 100,000 vs. 3.0 per 100,000). "Factors such as occupational history and environmental exposures might be associated with this finding," the researchers wrote in their analysis.

The prevalence of ALS among whites was more than double that of blacks (4.2 per vs. 2.0). "The reason for this difference in prevalence by race is unknown and needs to be investigated further," Dr. Mehta and his associates wrote. However, they noted, the race findings were also consistent with other studies.

The age group 70-79 was associated with the highest prevalence rate, at 17.0 per 100,000, followed by 60-69 at about 12.

Dr. Mehta and his colleagues acknowledged that their study had several limitations, including the fact that the ALS registry was relatively new; that ALS is not a notifiable disease in most states, making it difficult to capture all cases; that data errors or file duplication could have occurred; and that it was not possible to calculate ALS incidence, only prevalence, because most cases in the registry did not have a diagnosis date.

No conflicts of interest were mentioned in the report.

The U.S. prevalence of amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is about 4 cases per 100,000 Americans, according to the Centers for Disease Control and Prevention.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is usually fatal within 2-5 years of diagnosis. A hereditary form of the disease accounts for between 10% and 15% of cases. In the rest, the cause or causes are unknown, although chemical and infectious exposures are among the suspected triggers.

The new prevalence figures, which the CDC published in its Morbidity and Mortality Weekly Report issued July 25 (MMWR 2014;63[SS07]:1-14), represent the first national prevalence findings for ALS in the United States, and derive from surveillance begun in 2009 by the federal Agency for Toxic Substances and Disease Registry in Atlanta, where Dr. Paul Mehta led the investigation.

Dr. Mehta and his colleagues identified cases from Medicare, Medicaid, Veterans Heath Administration, and Veterans Benefits Administration databases, as well a secure public website through which ALS patients could self-report to the CDC by answering a series of screening questions.

Between October 2010 and the end of 2011, the registry identified 12,187 people 18 years and older with ALS, for a prevalence of 3.9 cases of ALS per 100,000 – findings that are consistent, the researchers said, with those from long-running European ALS registries.

As in other studies, men had a higher prevalence of ALS than did women (4.8 per 100,000 vs. 3.0 per 100,000). "Factors such as occupational history and environmental exposures might be associated with this finding," the researchers wrote in their analysis.

The prevalence of ALS among whites was more than double that of blacks (4.2 per vs. 2.0). "The reason for this difference in prevalence by race is unknown and needs to be investigated further," Dr. Mehta and his associates wrote. However, they noted, the race findings were also consistent with other studies.

The age group 70-79 was associated with the highest prevalence rate, at 17.0 per 100,000, followed by 60-69 at about 12.

Dr. Mehta and his colleagues acknowledged that their study had several limitations, including the fact that the ALS registry was relatively new; that ALS is not a notifiable disease in most states, making it difficult to capture all cases; that data errors or file duplication could have occurred; and that it was not possible to calculate ALS incidence, only prevalence, because most cases in the registry did not have a diagnosis date.

No conflicts of interest were mentioned in the report.

Pregnant silhouette

Credit: Ninan Matthews

Low-molecular-weight heparin (LMWH) does not reduce complications in pregnant women with thrombophilia, according to a study published in The Lancet.

Thrombophilia increases the risk of pregnancy-associated venous thromboembolism (VTE), pregnancy loss, and placenta-mediated pregnancy complications.

For years, physicians have believed that daily antepartum injections of LMWH can reduce these complications, but results of a randomized trial suggest this is not the case.

The LMWH dalteparin provided no positive benefits for mothers or their children. In fact, the study indicated that LMWH could actually cause pregnant women minor harm by increasing the risk of bleeding, increasing the rate of induced labor, and reducing access to anesthesia during childbirth.

“These results mean that many women around the world can save themselves a lot of unnecessary pain during pregnancy,” said study author Marc Rodger, MD, of the Ottawa Hospital Research Institute in Canada.

“While I wish we could have shown that LMWH prevents complications, we actually proved it doesn’t help. However, I’m very glad that we can now spare these women all those unnecessary needles.”

To assess the safety and efficacy of LMWH, Dr Rodger and his colleagues analyzed 289 pregnant women with thrombophilia who were at an increased risk of VTE or had previous placenta-mediated pregnancy complications.

The subjects were randomized to no treatment (n=143) or antepartum prophylactic doses of dalteparin (n=146)—5000 IU once daily up to 20 weeks’ gestation and twice daily thereafter until at least 37 weeks’ gestation.

Some patients crossed over during treatment. So for the on-treatment and safety analyses, there were 143 patients in the dalteparin arm and 141 in the control arm.

Patients met the primary efficacy endpoint if they experienced 1 or more of the following: severe or early onset pre-eclampsia, a small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or VTE.

Results showed that dalteparin did not reduce the incidence of this composite outcome in either the intent-to-treat analysis or the on-treatment analysis.

In the intent-to-treat analysis, 17.1% (25/146) of patients in the dalteparin arm met the endpoint, as did 18.9% (27/143) of those in the control arm. In the on-treatment analysis, 19.6% (28/143) of patients in the dalteparin arm met the endpoint, as did 17% (24/141) of those in the control arm.

The safety analysis revealed no significant difference in the incidence of major bleeding between the dalteparin and control arms—2.1% (3/143) and 1.4% (2/141), respectively.

Minor bleeding was more common in the dalteparin arm than the control arm, occurring in 19.6% (28/143) and 9.2% (13/141) of patients, respectively (P=0.01).

Dr Rodger said he hopes these results will prompt physicians to stop prescribing LMWH to pregnant women with thrombophilia and/or previous pregnancy complications when it isn’t warranted.

“These findings allow us to move on, to pursue other potentially effective methods for treating pregnant women with thrombophilia and/or complications from placenta blood clots,” he said.

He and his colleagues noted, however, that patients with one type of thrombophilia—anti-phospholipid antibodies—may benefit from anticoagulant therapy, as it can prevent recurrent pregnancy loss.

Furthermore, some women should take low-dose aspirin while pregnant to help prevent pregnancy complications. And all women with thrombophilia should receive anticoagulant therapy to prevent thrombosis after delivery.

So it seems that some pregnant women might still benefit from taking anticoagulants, but this requires further study.

Pregnant silhouette

Credit: Ninan Matthews

Low-molecular-weight heparin (LMWH) does not reduce complications in pregnant women with thrombophilia, according to a study published in The Lancet.

Thrombophilia increases the risk of pregnancy-associated venous thromboembolism (VTE), pregnancy loss, and placenta-mediated pregnancy complications.

For years, physicians have believed that daily antepartum injections of LMWH can reduce these complications, but results of a randomized trial suggest this is not the case.

The LMWH dalteparin provided no positive benefits for mothers or their children. In fact, the study indicated that LMWH could actually cause pregnant women minor harm by increasing the risk of bleeding, increasing the rate of induced labor, and reducing access to anesthesia during childbirth.

“These results mean that many women around the world can save themselves a lot of unnecessary pain during pregnancy,” said study author Marc Rodger, MD, of the Ottawa Hospital Research Institute in Canada.

“While I wish we could have shown that LMWH prevents complications, we actually proved it doesn’t help. However, I’m very glad that we can now spare these women all those unnecessary needles.”

To assess the safety and efficacy of LMWH, Dr Rodger and his colleagues analyzed 289 pregnant women with thrombophilia who were at an increased risk of VTE or had previous placenta-mediated pregnancy complications.

The subjects were randomized to no treatment (n=143) or antepartum prophylactic doses of dalteparin (n=146)—5000 IU once daily up to 20 weeks’ gestation and twice daily thereafter until at least 37 weeks’ gestation.

Some patients crossed over during treatment. So for the on-treatment and safety analyses, there were 143 patients in the dalteparin arm and 141 in the control arm.

Patients met the primary efficacy endpoint if they experienced 1 or more of the following: severe or early onset pre-eclampsia, a small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or VTE.

Results showed that dalteparin did not reduce the incidence of this composite outcome in either the intent-to-treat analysis or the on-treatment analysis.

In the intent-to-treat analysis, 17.1% (25/146) of patients in the dalteparin arm met the endpoint, as did 18.9% (27/143) of those in the control arm. In the on-treatment analysis, 19.6% (28/143) of patients in the dalteparin arm met the endpoint, as did 17% (24/141) of those in the control arm.

The safety analysis revealed no significant difference in the incidence of major bleeding between the dalteparin and control arms—2.1% (3/143) and 1.4% (2/141), respectively.

Minor bleeding was more common in the dalteparin arm than the control arm, occurring in 19.6% (28/143) and 9.2% (13/141) of patients, respectively (P=0.01).

Dr Rodger said he hopes these results will prompt physicians to stop prescribing LMWH to pregnant women with thrombophilia and/or previous pregnancy complications when it isn’t warranted.

“These findings allow us to move on, to pursue other potentially effective methods for treating pregnant women with thrombophilia and/or complications from placenta blood clots,” he said.

He and his colleagues noted, however, that patients with one type of thrombophilia—anti-phospholipid antibodies—may benefit from anticoagulant therapy, as it can prevent recurrent pregnancy loss.

Furthermore, some women should take low-dose aspirin while pregnant to help prevent pregnancy complications. And all women with thrombophilia should receive anticoagulant therapy to prevent thrombosis after delivery.

So it seems that some pregnant women might still benefit from taking anticoagulants, but this requires further study.

Pregnant silhouette

Credit: Ninan Matthews

Low-molecular-weight heparin (LMWH) does not reduce complications in pregnant women with thrombophilia, according to a study published in The Lancet.

Thrombophilia increases the risk of pregnancy-associated venous thromboembolism (VTE), pregnancy loss, and placenta-mediated pregnancy complications.

For years, physicians have believed that daily antepartum injections of LMWH can reduce these complications, but results of a randomized trial suggest this is not the case.

The LMWH dalteparin provided no positive benefits for mothers or their children. In fact, the study indicated that LMWH could actually cause pregnant women minor harm by increasing the risk of bleeding, increasing the rate of induced labor, and reducing access to anesthesia during childbirth.

“These results mean that many women around the world can save themselves a lot of unnecessary pain during pregnancy,” said study author Marc Rodger, MD, of the Ottawa Hospital Research Institute in Canada.

“While I wish we could have shown that LMWH prevents complications, we actually proved it doesn’t help. However, I’m very glad that we can now spare these women all those unnecessary needles.”

To assess the safety and efficacy of LMWH, Dr Rodger and his colleagues analyzed 289 pregnant women with thrombophilia who were at an increased risk of VTE or had previous placenta-mediated pregnancy complications.

The subjects were randomized to no treatment (n=143) or antepartum prophylactic doses of dalteparin (n=146)—5000 IU once daily up to 20 weeks’ gestation and twice daily thereafter until at least 37 weeks’ gestation.

Some patients crossed over during treatment. So for the on-treatment and safety analyses, there were 143 patients in the dalteparin arm and 141 in the control arm.

Patients met the primary efficacy endpoint if they experienced 1 or more of the following: severe or early onset pre-eclampsia, a small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or VTE.

Results showed that dalteparin did not reduce the incidence of this composite outcome in either the intent-to-treat analysis or the on-treatment analysis.

In the intent-to-treat analysis, 17.1% (25/146) of patients in the dalteparin arm met the endpoint, as did 18.9% (27/143) of those in the control arm. In the on-treatment analysis, 19.6% (28/143) of patients in the dalteparin arm met the endpoint, as did 17% (24/141) of those in the control arm.

The safety analysis revealed no significant difference in the incidence of major bleeding between the dalteparin and control arms—2.1% (3/143) and 1.4% (2/141), respectively.

Minor bleeding was more common in the dalteparin arm than the control arm, occurring in 19.6% (28/143) and 9.2% (13/141) of patients, respectively (P=0.01).

Dr Rodger said he hopes these results will prompt physicians to stop prescribing LMWH to pregnant women with thrombophilia and/or previous pregnancy complications when it isn’t warranted.

“These findings allow us to move on, to pursue other potentially effective methods for treating pregnant women with thrombophilia and/or complications from placenta blood clots,” he said.

He and his colleagues noted, however, that patients with one type of thrombophilia—anti-phospholipid antibodies—may benefit from anticoagulant therapy, as it can prevent recurrent pregnancy loss.

Furthermore, some women should take low-dose aspirin while pregnant to help prevent pregnancy complications. And all women with thrombophilia should receive anticoagulant therapy to prevent thrombosis after delivery.

So it seems that some pregnant women might still benefit from taking anticoagulants, but this requires further study.

Stem cells for transplant

Credit: Chad McNeeley

New research suggests a majority of US patients who need unrelated hematopoietic stem cell transplants can find a suitable donor on the Be The Match Registry.

However, the likelihood of finding an 8/8 HLA-matched adult donor is often low, particularly for patients of diverse ethnic or racial backgrounds.

And finding a 6/6 HLA-matched cord blood donor is a long shot regardless of race or ethnicity, although patients younger than 20 years of age have better odds.

These findings appear in NEJM.

“This research confirms that physicians should identify the best available donor with minimal delay,” said study author Dennis Confer, MD, chief medical officer at National Marrow Donor Program/Be the Match in Minneapolis.

“Transplant should not be postponed in anticipation of finding a perfect match. Using a suitable match reflects current clinical practice.”

Dr Confer and his colleagues built population-based genetic models for 21 racial and ethnic groups to predict the likelihood of identifying a suitable adult or cord blood donor for each group.

The researchers used data on HLA genotypes and cord blood unit cell doses from the National Marrow Donor Program’s Be the Match registry, which included 10,759,087 adult donors and 186,166 cord blood units at the end of 2012.

The team found the likelihood of identifying an 8/8 HLA-matched donor is highest for white patients of European descent, at 75%, but it’s only 46% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the probability of finding an 8/8 matched donor ranges from 16% (the lowest figure) to 19%.

And figures range from 27% to 57% for Hispanics, Asians, Pacific Islanders, and Native Americans (which includes individuals from the Caribbean and North, Central, and South America).

The likelihood of identifying a 7/8 matched donor is, again, highest for white patients of European descent, at 97%. And it’s 90% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the likelihood of finding a 7/8 matched donor ranges from 66% (the lowest figure) to 76%. And it ranges from 72% to 91% for Hispanics, Asians, Pacific Islanders, and Native Americans.

The probability of identifying a 6/6 cord blood match is low for all racial/ethnic groups, but age plays a role. For patients age 20 and older, figures range from 1%—for both African and black Caribbean patients—to 17% for white Europeans. For patients younger than 20, figures range from 6% to 38% for the same groups.

For patients 20 and older, the likelihood of finding a 5/6 cord blood match ranges from 23% for African patients to 66% for white Europeans. And for the younger age group, the figures range from 56% to 87% for the same groups.

“We cannot yet find a suitably matched and available donor for every patient,” Dr Confer noted. “So we cannot slow down our efforts to expand the registry and fund more research to overcome these challenges.”

“To find a match for all patients, it is critical that those who join the registry remain committed to donate when called, and that we continue to add people to the Be The Match Registry for racial and ethnic groups of highest need.”

Stem cells for transplant

Credit: Chad McNeeley

New research suggests a majority of US patients who need unrelated hematopoietic stem cell transplants can find a suitable donor on the Be The Match Registry.

However, the likelihood of finding an 8/8 HLA-matched adult donor is often low, particularly for patients of diverse ethnic or racial backgrounds.

And finding a 6/6 HLA-matched cord blood donor is a long shot regardless of race or ethnicity, although patients younger than 20 years of age have better odds.

These findings appear in NEJM.

“This research confirms that physicians should identify the best available donor with minimal delay,” said study author Dennis Confer, MD, chief medical officer at National Marrow Donor Program/Be the Match in Minneapolis.

“Transplant should not be postponed in anticipation of finding a perfect match. Using a suitable match reflects current clinical practice.”

Dr Confer and his colleagues built population-based genetic models for 21 racial and ethnic groups to predict the likelihood of identifying a suitable adult or cord blood donor for each group.

The researchers used data on HLA genotypes and cord blood unit cell doses from the National Marrow Donor Program’s Be the Match registry, which included 10,759,087 adult donors and 186,166 cord blood units at the end of 2012.

The team found the likelihood of identifying an 8/8 HLA-matched donor is highest for white patients of European descent, at 75%, but it’s only 46% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the probability of finding an 8/8 matched donor ranges from 16% (the lowest figure) to 19%.

And figures range from 27% to 57% for Hispanics, Asians, Pacific Islanders, and Native Americans (which includes individuals from the Caribbean and North, Central, and South America).

The likelihood of identifying a 7/8 matched donor is, again, highest for white patients of European descent, at 97%. And it’s 90% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the likelihood of finding a 7/8 matched donor ranges from 66% (the lowest figure) to 76%. And it ranges from 72% to 91% for Hispanics, Asians, Pacific Islanders, and Native Americans.

The probability of identifying a 6/6 cord blood match is low for all racial/ethnic groups, but age plays a role. For patients age 20 and older, figures range from 1%—for both African and black Caribbean patients—to 17% for white Europeans. For patients younger than 20, figures range from 6% to 38% for the same groups.

For patients 20 and older, the likelihood of finding a 5/6 cord blood match ranges from 23% for African patients to 66% for white Europeans. And for the younger age group, the figures range from 56% to 87% for the same groups.

“We cannot yet find a suitably matched and available donor for every patient,” Dr Confer noted. “So we cannot slow down our efforts to expand the registry and fund more research to overcome these challenges.”

“To find a match for all patients, it is critical that those who join the registry remain committed to donate when called, and that we continue to add people to the Be The Match Registry for racial and ethnic groups of highest need.”

Stem cells for transplant

Credit: Chad McNeeley

New research suggests a majority of US patients who need unrelated hematopoietic stem cell transplants can find a suitable donor on the Be The Match Registry.

However, the likelihood of finding an 8/8 HLA-matched adult donor is often low, particularly for patients of diverse ethnic or racial backgrounds.

And finding a 6/6 HLA-matched cord blood donor is a long shot regardless of race or ethnicity, although patients younger than 20 years of age have better odds.

These findings appear in NEJM.

“This research confirms that physicians should identify the best available donor with minimal delay,” said study author Dennis Confer, MD, chief medical officer at National Marrow Donor Program/Be the Match in Minneapolis.

“Transplant should not be postponed in anticipation of finding a perfect match. Using a suitable match reflects current clinical practice.”

Dr Confer and his colleagues built population-based genetic models for 21 racial and ethnic groups to predict the likelihood of identifying a suitable adult or cord blood donor for each group.

The researchers used data on HLA genotypes and cord blood unit cell doses from the National Marrow Donor Program’s Be the Match registry, which included 10,759,087 adult donors and 186,166 cord blood units at the end of 2012.

The team found the likelihood of identifying an 8/8 HLA-matched donor is highest for white patients of European descent, at 75%, but it’s only 46% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the probability of finding an 8/8 matched donor ranges from 16% (the lowest figure) to 19%.

And figures range from 27% to 57% for Hispanics, Asians, Pacific Islanders, and Native Americans (which includes individuals from the Caribbean and North, Central, and South America).

The likelihood of identifying a 7/8 matched donor is, again, highest for white patients of European descent, at 97%. And it’s 90% for white patients of Middle Eastern or North African descent.

For black Americans of all ethnic backgrounds, the likelihood of finding a 7/8 matched donor ranges from 66% (the lowest figure) to 76%. And it ranges from 72% to 91% for Hispanics, Asians, Pacific Islanders, and Native Americans.

The probability of identifying a 6/6 cord blood match is low for all racial/ethnic groups, but age plays a role. For patients age 20 and older, figures range from 1%—for both African and black Caribbean patients—to 17% for white Europeans. For patients younger than 20, figures range from 6% to 38% for the same groups.

For patients 20 and older, the likelihood of finding a 5/6 cord blood match ranges from 23% for African patients to 66% for white Europeans. And for the younger age group, the figures range from 56% to 87% for the same groups.

“We cannot yet find a suitably matched and available donor for every patient,” Dr Confer noted. “So we cannot slow down our efforts to expand the registry and fund more research to overcome these challenges.”

“To find a match for all patients, it is critical that those who join the registry remain committed to donate when called, and that we continue to add people to the Be The Match Registry for racial and ethnic groups of highest need.”

Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Audrey Odom, MD, PhD

Credit: Robert Boston

Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.

The team reported this finding in Nature Communications.

The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.

Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.

But over time, the drug often becomes less effective.

“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”

Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.

This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”

Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.

Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.

“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”

Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.

Patient receiving chemotherapy

Credit: Rhoda Baer

A biosimilar of the erythropoiesis-stimulating agent epoetin alfa can elicit responses in patients with chemotherapy-induced anemia, according to a study published in BMC Cancer.

The agent, epoetin zeta (Retacrit), produced a hemoglobin (Hb) response in more than 80% of patients at 3- and 6-month time points.

Response rates were similar in patients with hematologic malignancies and those with solid tumors.

And the rate of clinically significant adverse events was low. This included thromboembolic events, bleeding, infection, local intolerability, and increased blood pressure.

Mauricette Michallet, MD, PhD, of Centre Hospitalier Lyon in France, and her colleagues conducted this study, known as ORHEO. It was sponsored by Hospira, the makers of epoetin zeta.

The researchers evaluated 2310 adult patients with chemotherapy-induced anemia (Hb<11 g/dL). Patients had solid tumors (n=1838), lymphomas (n=301), or multiple myeloma (n=171).

Patients were taking a number of treatments aside from epoetin zeta and chemotherapy. This included intravenous iron (10%), oral iron (16%), antithrombotic agents (12%), folates (7%), vitamin B (4%), and other vitamins (2%). An additional 17% of patients were reported as being on “other treatments.”

In all, 99.9% of patients received epoetin zeta. The primary endpoint was the rate of response.

Response was defined as an increase in Hb levels to at least 10 g/dL since enrollment, an increase in Hb levels of at least 1 g/dL since enrollment, or reaching target Hb levels set at the start of study, without any blood transfusions in the 3 weeks prior to measurement. In patients with baseline Hb levels of at least 10 g/dL, only those who reached their Hb target or had an increase greater than 1 g/dL were considered responders.

Eighty-two percent of patients achieved a response at 3 months, and 87% had a response at 6 months. The overall mean change in Hb level was 1.52 ± 1.61 at 3 months and 1.72 ± 1.61 g/dL at 6 months. The rate of transfusion was 9% at 3 months and 6% at 6 months.

Between enrollment and month 6, 1202 patients discontinued epoetin zeta. Forty percent stopped because Hb levels were met, 27% stopped because they were stopping or changing chemotherapy, 15% stopped for both of the aforementioned reasons, 11% stopped because epoetin zeta was ineffective, and 2% stopped due to adverse events.

Seventeen percent of patients experienced an adverse event, including thromboembolic events (4%), infection (5%), bleeding (2%), local intolerability (0.2%), increased blood pressure (2%), and “other” events (9%).

Epoetin zeta was approved in Europe in 2007. For epoetin biosimilars to gain approval in the European Union, companies must agree to conduct post-marketing studies.